Your Complete Guide to Liver Health

A Johns Hopkins Press Health Book

 Your Complete Guide to
LIVER HEALTH
Coping with Fatty Liver, Hepatitis,
Cancer, and More

PAUL J. THULUVATH, MD, FRCP

JOHNS HOPKINS UNIVERSITY PRESS

Baltimore
Note to the Reader: This book is not meant to substitute for medical care, and
treatment should not be based solely on its contents. Instead, treatment must be
developed in a dialogue between the individual and their physician. Our book has
been written to help with that dialogue.
Drug dosage: The author and publisher have made reasonable efforts to
determine that the selection of drugs discussed in this text conforms to the
practices of the general medical community. The medications described do not
necessarily have specific approval by the US Food and Drug Administration for
use in the diseases for which they are recommended. In view of ongoing research,
changes in governmental regulation, and the constant flow of information relating
to drug therapy and drug reactions, the reader is urged to check the package
insert of each drug for any change in indications and dosage and for warnings and
precautions. This is particularly important when the recommended agent is a new
and/or infrequently used drug.

© 2022 Johns Hopkins University Press

All rights reserved. Published 2022
Printed in the United States of America on acid-free paper
246897531

Johns Hopkins University Press

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Baltimore, Maryland 21218-4363
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Library of Congress Cataloging-in-Publication Data

Names: Thuluvath, Paul J., author.

Title: Your complete guide to liver health : coping with fatty liver, hepatitis, cancer,
and more / Paul J. Thuluvath, MD, FRCP.
Description: Baltimore : Johns Hopkins University Press, [2022] | Series: A Johns
Hopkins Press health book | Includes bibliographical references and index.
Identifiers: LCCN 2021036195 | ISBN 9781421443812 (hardcover) | ISBN
9781421443829 (paperback) | ISBN 9781421443836 (ebook)
Subjects: LCSH: Liver—Diseases. | Liver—Diseases—Prevention. | Self-care,
Health.
Classification: LCC RC845 .T48 2022 | DDC 616.3/62—dc23
LC record available at https://lccn.loc.gov/2021036195

A catalog record for this book is available from the British Library.

Figures 1.1, 1.2, 2.1, 9.1, and 9.5 © Link Studios, LLC. Figures 2.2, 9.2, and 9.4 by
Jane Whitney. Figures 6.1 and 6.3 by Jade Myers. Figures 4.1, 5.1, 6.2, and 7.1
are from AdobeStock.

Special discounts are available for bulk purchases of this book. For more
information, please contact Special Sales at specialsales@jh.edu.
To my mother, Selena, my best teacher; my father, Joseph,
my silent supporter; my wife and best friend, Reeja, the
inspiration behind my scholarly activities; and my children,
Nimisha and Avesh, who followed my path in medicine
 Contents

CHAPTER 1. Understanding Liver Disease

CHAPTER 2. Diagnosing Liver Disease
CHAPTER 3. What Is Viral Hepatitis?
CHAPTER 4. Understanding Hepatitis B
CHAPTER 5. Understanding Hepatitis C
CHAPTER 6. Alcohol and the Liver
CHAPTER 7. Non-Alcoholic Fatty Liver Disease
CHAPTER 8. Other Causes of Liver Diseases
CHAPTER 9. Complications of Liver Disease
CHAPTER 10. Liver Cancer
CHAPTER 11. Liver Transplantation
CHAPTER 12. Liver Health

Patient Resources
Index
Your Complete Guide to Liver Health
 CHAPTER 1

Understanding Liver Disease

The liver is one of the body’s hardest-working organs, helping to

digest food and get rid of toxins. To understand more about how liver
disease affects the liver, it’s important to learn more about the liver
and what it does.

UNDERSTANDING HOW THE LIVER WORKS

The liver, one of the body’s largest organs, is in the upper right side
of the belly and has two large sections: the right and left lobes (figure
1.1). The liver works together with other organs—like the gallbladder,
pancreas, and the intestines—to help the body process food (figure
1.2).
Many important jobs are performed by the liver (table 1.1),
including:

1. Making proteins
2. Making, storing, and processing fats
3. Processing and storing carbohydrates
4. Creating and secreting bile to help the intestines absorb fats
and fat-soluble vitamins
5. Getting rid of potentially harmful chemicals the body produces
6. Getting rid of toxins, such as drugs, alcohol, and harmful
substances from the environment
 FIGURE 1.1. The liver, gallbladder, and pancreas

TABLE 1.1. Important jobs of the liver

Plays a major role in processing carbohydrates, proteins, and fats

Makes proteins, including:

• albumin (helps maintain the volume of blood)
• fibrinogen (needed for blood clotting)
• transferrin (helps the blood carry iron)
• prothrombin (helps the blood clot)

Processes many drugs, so the body can use them

Gets rid of many toxins, including drugs, alcohol, ammonia formed from breaking
down proteins, and bilirubin formed from breaking down old red blood cells
Gets rid of tumor cells, bacteria, yeasts, viruses, and parasites

Stores many vitamins and minerals

 FIGURE 1.2. The digestive system

LIVER DISEASE, DAMAGE, OR INJURY

Liver disease is any condition that damages the liver and prevents it
from doing its jobs properly. There are many different types of liver
disease and several causes of that disease. The most common
causes include viruses, inherited conditions, non-alcoholic fatty liver
disease, or alcohol (table 1.2). Additionally, cytomegalovirus, or CMV
(which can cause serious birth defects), Epstein-Barr virus, or EBV
(which causes “mono,” or infectious mononucleosis), and herpes
simplex virus, or HSV, can also trigger an acute (new) liver injury.
CMV and EBV infections are common and often asymptomatic
(without symptoms), but these viruses may cause more severe injury
in individuals who are immunocompromised (have a weakened
immune system). Although liver enzyme abnormalities are common
in COVID-19, it is not known whether these abnormalities are the
direct result of a viral infection.
Any of the above conditions can damage the liver cells, but no
matter what the cause, the damage prevents this organ from working
normally.

STAGES OF LIVER DAMAGE

The liver is usually able to repair itself when it gets damaged. It can
withstand a lot of harm before a person may start to feel any
symptoms. In other words, most people who have liver damage do
not have any symptoms in the early stages of the disease or its
harmful changes.
 Fibrosis
In situations where the damage is caught early, the liver can repair
itself (regenerate new liver cells) and start working normally again.
The healing process may result in the formation of scar tissue
(fibrosis).
TABLE 1.2. Causes of liver disease
Condition Types

Inherited disorders hemochromatosis

alpha-1 antitrypsin deficiency
Wilson disease

Infections caused by viruses* hepatitis A

hepatitis B
hepatitis C
hepatitis D
hepatitis E

Autoimmune disorders autoimmune hepatitis

primary biliary cholangitis
primary sclerosing cholangitis

Other causes alcohol

non-alcoholic fatty liver disease
medications and supplements
*Viruses such as the herpes simplex virus (HSV), cytomegalovirus (CMV), and
Epstein-Barr virus (EBV) may also cause acute liver injury.

Cirrhosis
After a long period of continued damage, the liver cannot always
repair itself. The amount of scar tissue may just be too high.
Because scar tissue does not work like healthy tissue, the liver
gradually will not be able to do its jobs well. When the liver has a
significant amount of scar tissue that has replaced the healthy tissue,
the liver slowly becomes shrunken, lumpy, and hard—a condition
known as cirrhosis of the liver. With long-term damage, symptoms do
not start to show up until the liver has sustained a lot of harm. Many
people do not develop symptoms until the late stages of cirrhosis,
after many years of liver damage.
So, whether or not you have symptoms, it is important to diagnose
and manage liver disease. If you wait until symptoms start to appear,
it may be too late to fix the problem.

Is Fibrosis (Scarring) Reversible?

Until recently, physicians and research scientists believed that
scarring of the liver was irreversible. Some recent observations,
however, suggest that scarring can be reversed to some extent if the
cause of the scarring is removed. Studies of chronic hepatitis B have
clearly demonstrated the possibility that even early cirrhosis can be
reversed after the hepatitis B virus is cleared (eliminated) from the
body. Many studies of people who have hepatitis C with significant
scarring also show that clearance of the hepatitis C virus reduces the
severity of fibrosis. Trials are in progress for individuals with fatty
liver disease to determine whether scarring could be reversed.
Despite the possibility that early cirrhosis is potentially reversible, no
convincing evidence has suggested that long-standing cirrhosis can
be reversed.

SIGNS AND SYMPTOMS OF LIVER DISEASE

No matter what the cause of liver damage, the symptoms—what a

person experiences—and physical signs—what a doctor finds during
a physical examination—of all types of liver disease are similar. The
common general symptoms of liver damage and the possible causes
of that damage are shown in table 1.3.
If people experience pain as a main symptom, more than likely
they have a problem that is not related to liver disease. For example,
if a person has yellowing skin and feels severe pain after eating
meals, they may have a bile duct blockage because of gallstones.
 • People who have early stages of liver disease usually don’t have any
symptoms.
• When a person has symptoms, they usually have had liver disease for many
years (late-stage liver disease).
• As soon as an individual has any symptoms, they should see a doctor right
away for help.

TABLE 1.3. General symptoms and possible causes of liver disease

Symptoms Possible cause
• Poor appetite acute hepatitis
• Loss of taste
• Nausea
• Discomfort or pain in the upper right
belly
• Yellowing skin (jaundice)
• Dark-colored urine
• Itching

• Severe pain in the upper right belly, bile duct blockage due to gallstones
especially after meals
• Yellowing skin

• Painless yellowing skin cancer of the pancreas, gallbladder, or

• Pale-colored stools bile ducts
• Weight loss
• Age older than 50 years

• Yellowing skin liver scarring (cirrhosis)

• Fluid in the legs
• Swelling of the abdomen (ascites)
• Memory loss

CHRONIC LIVER DISEASE

During the early stages of long-term (chronic) liver disease, people

rarely have any symptoms. In general, individuals develop symptoms
only during the later stages of liver disease, so it is important for
everyone to see their doctor regularly for checkups. Sometimes
people will refuse treatment, because they do not have any
symptoms, but it’s best to manage the disease as early as possible
for better health.
People who have chronic liver disease may have general
symptoms, such as feeling tired and mild discomfort in the upper
right belly. The symptoms of later stages of liver disease, which may
have progressed to advanced scarring of the liver (cirrhosis), are
listed in table 1.4.
TABLE 1.4. Symptoms and signs of advanced liver disease

Symptoms
• severe fatigue
• short-term memory problems
• jaundice
• impotence in men
• enlarged breasts in men (gynecomastia)
• swelling of the abdomen or legs
• vomiting blood or passing black stools

Signs
• spider-like collections of blood vessels (spider nevi) on the face, arms, or
chest
• loss of armpit or pubic hair
• redness (erythema) of the palms
• decrease in size of the testicles
• prominent veins on the abdominal wall
• fluid in the belly (ascites)
• flapping tremors (asterixis)
• wasting away of muscles

All of the symptoms of later stages of liver disease can appear

with other conditions, meaning none of them occur only in people
who have liver disease. For example, some pregnant women have
redness in their palms and some red spots with “spidery legs” that
turn white when pressed. These spots may be related to the
hormone estrogen, which is usually processed by the liver (which is
why pregnant women may develop this sign). People who have any
of these listed symptoms should talk to a doctor first before coming
to any conclusions.
As liver disease progresses, people may notice swelling in their
legs (pitting edema) and swelling in their belly (ascites). Some of the
serious signs of liver disease (ascites, bleeding, and confusion) are
explained in more detail in later chapters.

COMPLICATIONS OF LIVER DISEASE

From Cirrhosis
As we mentioned before, when the liver suffers damage from liver
disease or injury for a long time, it forms scar tissue to replace the
healthy tissue. This condition, called cirrhosis, can happen after
many years in people who experience liver disease or injury. If the
cirrhosis is diagnosed early and its cause is treated, the damage
may be reversed. In general, cirrhosis is the presence of a lot of scar
tissue throughout the liver, with normal liver tissue appearing as
nodules (rounded or irregularly shaped small masses). To the naked
eye, a healthy liver normally has a smooth surface, but a liver that
has cirrhosis has lumps and bumps.
As cirrhosis progresses and more scar tissue forms, the liver
cannot work properly, resulting in serious complications, including
swelling in the belly and legs, confusion, and bleeding from the
stomach or esophagus. When these complications occur in people
who had a previously stable liver disease, it is described as
decompensation of liver disease.

Other Serious Complications

Liver cancer is the commonest and most serious complication of
cirrhosis. People who have hepatitis B and do not have any fibrosis
may also develop liver cancer, because the hepatitis B virus is a
cancer-causing virus.
Advanced liver disease may also cause damage to other organs.
Kidney failure, which is one of the most serious complications of
advanced cirrhosis, is caused by increased blood pressure in the
portal vein—the blood vessel that takes blood from the digestive
system to the liver—and decreased blood flow to the kidney.
Rarely (in less than 5 percent of cases of cirrhosis), people with
liver disease may develop lung issues, including shortness of breath,
not enough oxygen in their blood (because blood is bypassing the
lungs, a condition known as hepatopulmonary syndrome), or
increased pressure in the blood vessel going to the lungs
(portopulmonary hypertension).
Advanced liver disease may also cause the heart to stop working
(cirrhotic cardiomyopathy). This condition is extremely rare.
Advanced cirrhosis sometimes results in a wasting away of muscles,
malnutrition, vitamin deficiencies, and bone disease (osteopenia, or
bone thinning, and osteoporosis).

In chapter 2, we describe how liver disease is diagnosed.

FURTHER READING
The progression of liver disease. American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/the-progression-of-liver-
disease/.
Viral hepatitis and liver disease. US Department of Veterans Affairs.
https://www.hepatitis.va.gov/basics/liver-single-page.asp.
Schuppan D and Afdal NH. Liver cirrhosis. Lancet. 2008 Mar 8;371(9615): 838–
851. https://doi.org/10.1016/S0140-6736(08)60383-9/.
 CHAPTER 2

Diagnosing Liver Disease

A doctor can check for liver disease by first taking a history of your
symptoms and performing a physical examination. The doctor will
ask about your family history or habits that may raise your risk of
developing liver disease. The doctor will also do blood tests, imaging
tests, or a liver biopsy. This chapter will explain how a doctor checks
for liver disease.

BLOOD TESTS

When the liver becomes damaged or infected, the liver cells release
more liver enzymes into the blood. Having higher than normal levels
of these liver enzymes in the blood can mean the liver is damaged.
Sometimes, people who may believe they are healthy learn that they
have higher liver enzymes levels when they have a yearly physical
examination or other routine blood work. Often the levels are only
slightly higher than normal, but such levels do not necessarily
correlate with the seriousness of any liver disease. Even having
slightly higher than normal levels of liver enzymes could indicate
something serious, so it is important to see a doctor about having
more tests.
Liver function tests are the most commonly used blood tests to
check for liver injury and disease (table 2.1). The liver function tests
measure the levels of liver enzymes, proteins, and bilirubin in the
blood. The last test listed in the table is prothrombin time, which
measures how long it takes for blood to clot.

Liver Enzymes
Liver function tests show the amounts of different liver enzymes in
the blood. A doctor uses these tests to learn about the type of liver
injury or infection, measure the severity of the damage, and check to
see how a person responds to treatment. The most commonly
elevated enzymes are aspartate aminotransferase (AST), alanine
aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-
glutamyl transpeptidase (GGT). The doctor can make a better
diagnosis from these tests, based on which enzymes are higher than
normal and the amount to which they are higher. For example, if a
person has higher than normal levels of AST and ALT, this usually
indicates that their liver cells have been damaged. The meaning of
each test is shown in table 2.2.
TABLE 2.1. Common liver function blood tests to check for liver diseases

albumin

immunoglobulins (Ig)

bilirubin (total, direct, and indirect)

aspartate aminotransferase (AST)

alanine aminotransferase (ALT)

alkaline phosphatase (ALP)

gamma-glutamyl transpeptidase (GGT)

lactic dehydrogenase (LDH)

prothrombin time (PT)

TABLE 2.2. What do the test results mean?

Test Meaning of results
Aspartate aminotransferase higher than normal levels mean liver cell
(AST) damage (it can also come from muscles)

Alanine aminotransferase (ALT) higher than normal levels mean liver cell
damage

Alkaline phosphatase (ALP) higher than normal levels mean damage to the
tube (bile duct) that carries bile from the liver (it
can also come from bones or, rarely, the
 intestine)

Gamma glutamyl higher than normal levels mean damage to the

transpeptidase (GGT) tube (bile duct) that carries bile from the liver (it
can come from drinking alcohol or taking other
medicines)

Albumin lower than normal levels mean major liver

damage

Bilirubin higher than normal levels mean damage to or

blockage of the tube (bile duct) that carries bile
from the liver, or significant liver damage

Prothrombin time (PT) or higher than normal levels mean major liver
international normalized ratio damage (or the person is taking blood-thinning
(INR) medicines)

People who take a high dose of Tylenol (acetaminophen) may

have levels of AST and ALT that are 20 to 200 times higher than
normal. People who have chronic hepatitis B or C may have levels of
AST and ALT that are 2 to 20 times greater than normal. Both the
normal enzyme levels and higher than normal levels that happen
with different stages of liver disease are listed in table 2.3.
TABLE 2.3. Levels of liver enzymes associated with specific liver diseases
Test Normal values Abnormal values with diseases
Test Normal values Abnormal values with diseases
Aspartate men: 0–30 U/L 1 to 20 times higher than normal (20–
aminotransferase (units per liter) 600 U/L)
(AST), alanine women: 0–18 U/L • chronic hepatitis B
aminotransferase • hepatitis C
(ALT) • hepatitis caused by the immune
system attacking the liver
(autoimmune hepatitis)
• medication-related
20 to 50 times higher than normal (600–
1500 U/L)
• acute hepatitis C
• hepatitis caused by the immune
system attacking the liver
(autoimmune hepatitis)
20 to 200 times higher than normal
(600–6000 U/L)
• acute hepatitis A
• acute hepatitis B
• too much acetaminophen (Tylenol)
• hepatitis caused by not enough blood
getting to the liver

Alkaline 30–130 U/L 1 to 2 times higher than normal (30–260

phosphatase (ALP) U/L)
• any liver disease
• medication-related
2 to 4 times higher than normal (60–520
U/L)
• primary biliary cholangitis
• primary sclerosing cholangitis
• medication-related
more than 3 times higher than normal
(90–390 U/L)
• bile duct obstruction
• intrahepatic cholestasis
• medication-related
 Based on the patterns and levels of different liver enzymes, a
doctor can better figure out the nature of the liver injury and know
how to possibly treat that person. But because the range of
abnormalities in liver enzymes can vary widely, there are no set
values that can be used to diagnose any particular disease.

Albumin, Prothrombin Time, and Bilirubin

The liver makes albumin, which is a protein in the blood that can do
many things, such as carrying vitamins and minerals in the blood.
Measuring the amount of albumin in the blood can help a doctor
know if there is a serious problem with the liver. Levels of albumin
become low after there has been long-term damage to the liver.
Prothrombin is one of the proteins that the liver makes to help the
blood clot. The prothrombin time test measures how long it takes for
a person’s blood to clot. A longer clotting time means the liver has
more damage.
Bilirubin is a yellow substance in the blood that is made when red
blood cells break down normally. The liver processes bilirubin and
stores it in the gallbladder. Bilirubin is part of bile, which helps you
digest your food. Levels of bilirubin could be higher for many
reasons, including more red blood cell breakdown, liver injury or
cirrhosis, blockage of bile ducts, infection, or the use of some
medications.
Measurements of albumin and bilirubin levels and prothrombin
time can provide information about how advanced the liver damage
may be. For example, people who have cirrhosis may have a lower
albumin level and a higher prothrombin time, which means their
condition is getting worse.

HEPATITIS TESTING

In addition to doing the blood tests and liver function tests described
above, a doctor will request several other blood tests to check for
infections, including hepatitis A, B, and C. The common tests for
hepatitis A, B, and C are shown in table 2.4.
TABLE 2.4. Tests for hepatitis A, B, and C infections
Test If present, the results mean
Hepatitis A
Hepatitis A IgM antibody the person has an acute hepatitis A
infection

Hepatitis A IgG antibody the person has been exposed to

hepatitis A (through an infection or
vaccination)

Hepatitis A total (IgM + IgG) antibody the person either has a new infection or
has had the infection before, but if that
person doesn’t have any symptoms, the
results mean they previously had an
infection
Hepatitis B
Hepatitis B DNA the person has an active virus infection

Hepatitis B core IgM antibody the person has a new hepatitis B

infection

Hepatitis B core IgG antibody the person has had an infection before
or has an ongoing long-term infection

Hepatitis B surface antigen the person has an active infection

Hepatitis B surface antibody the person is completely immune, either

by having had the infection before or by
being vaccinated

Hepatitis B virus e antigen the person has an active infection, but if

that person does not have this antigen,
it does not mean they don’t have an
active infection (a mutated virus may not
release this protein into the blood, a
condition also known as hepatitis Be
antigen negative disease)
Test If present, the results mean
Hepatitis B virus e antibody the person may have some immunity,
but the presence of this antibody does
not always mean immunity; people who
do not have the hepatitis B virus e
antigen but have an active virus may
have this antibody if the virus has
mutated (a condition also known as
hepatitis Be antigen negative disease)
Hepatitis C
Hepatitis C antibody the person has an active infection or
has had a hepatitis C infection before

Hepatitis C RNA by PCR the person has an active infection

Hepatitis C genotype and subtype an indication of what type of hepatitis C

infection the person has (types 1 to 6)
Hepatitis D
Hepatitis D antibody the person has been exposed to
hepatitis D

Hepatitis D RNA the person has an active infection

Hepatitis E
Hepatitis E IgG antibody the person has been exposed to
hepatitis E (through an infection)

Hepatitis E IgM antibody the person has an acute infection

When a person is exposed to any infection, their body’s immune

system makes antibodies against that infection. Antibodies are a
type of protein that the body makes to help fight the infection by
clinging to surface proteins (antigens) on a virus. Special blood tests
look for particular antibodies for certain types of hepatitis.

Hepatitis A Testing
A doctor can request a simple blood test to check for hepatitis A. If a
person has recently been infected with the hepatitis A virus, they will
have immunoglobulin M (IgM) antibodies in their blood. A person
who has had hepatitis A for a long time or who has had the hepatitis
A vaccine will have immunoglobulin G (IgG) antibodies in their blood.

Hepatitis B Testing
To check for a hepatitis B infection, a doctor will look for several
different things in a person’s blood to be entirely certain they are
infected (see table 2.4). People who currently have hepatitis B or
who have ever had the infection will always have some hepatitis B
DNA in their liver cells. All of the results of the following tests give
your doctor a full picture about your infection:

1. Hepatitis B surface antigen (HBsAg): This test determines

whether the virus is present in your blood by checking for the
specific hepatitis B virus protein (antigen).
2. Hepatitis B surface antibody (HBsAb): This test shows that the
person has antibodies against hepatitis B, either from having
and recovering from a past hepatitis B infection or from being
vaccinated for hepatitis B.
3. Hepatitis B core IgM antibody (anti-HBcAb IgM): This test
checks for a new, current hepatitis B infection.
4. Hepatitis B core IgG antibody (anti-HBcAb IgG): This test will
show if a person has had a past or chronic hepatitis B infection.
5. Hepatitis B DNA: This test measures how much hepatitis B
virus DNA is in your blood.
6. Hepatitis B virus e antigen (HBeAg): The hepatitis B virus
makes this protein in the infected liver cells and releases the
protein into your blood. In general, the presence of this protein
in the blood indicates very high levels of virus in the blood and a
very active infection. But a negative test does not mean the
virus is not making copies of itself; a negative result could mean
that there is a mutation of the hepatitis B virus.
7. Hepatitis B virus e antibody (HBeAb): This is an antibody made
in response to the hepatitis Be antigen. The presence of this
antibody may suggest the person is recovering. It is also
present in mutations of the hepatitis B virus (known as hepatitis
Be antigen negative disease). It is not a protective antibody, and
 its presence does not mean that the person is less infectious.

Your doctor may request other blood tests to determine the

specific type of hepatitis B infection and the amounts of virus in your
blood. Your physician may also check for hepatitis D (HDV), as it
may coexist with hepatitis B.

Hepatitis C Testing
When a person is infected with hepatitis C, their immune system
produces antibodies against the hepatitis C virus. A doctor will
request the following tests to check if a person has hepatitis C
infection:

1. Hepatitis C antibody test: This test checks for hepatitis C

antibodies in the blood. The test can’t tell the difference
between an active hepatitis C infection and a past hepatitis C
infection. Anyone who has ever had a hepatitis C infection will
have hepatitis C antibodies in their blood. Sometimes (although
it rarely happens), people who have hepatitis C will not have
antibodies, either because they have a new (acute) infection or
because they may be immunocompromised from an HIV
infection.
2. Polymerase chain reaction (PCR) test, to check for hepatitis C
virus ribonucleic acid (RNA): If a person has antibodies in their
blood, this test will prove that the person has hepatitis C by
checking for the amount of hepatitis C genetic material (RNA) in
the blood. The amount of virus RNA does not indicate whether
the infection is mild or severe.

The doctor may request more hepatitis C tests to find out the
specific type of hepatitis C (known as a genotype) you have.

Hepatitis D Testing
Hepatitis D testing is done only for those with hepatitis B, as these
two viruses may coexist. A positive antibody test indicates that the
person has been exposed to hepatitis D, and a positive RNA test
would suggest an ongoing active infection.
 Hepatitis E Testing
Hepatitis E is not common in developed countries, but sporadic
infections have been reported. In an acute infection, a test for the
hepatitis E IgM antibody will be positive. The presence of the IgG
antibody suggests previous exposure to hepatitis E. A hepatitis E
RNA test is available only for research purposes.

OTHER BLOOD TESTS

To check for other types of liver damage or injury, a doctor can use
other blood tests, which include checking for anti-nuclear antibodies,
anti–smooth muscle antibodies, anti-mitochondrial antibodies, and
other proteins. Some of these tests are listed in table 2.5.
TABLE 2.5. Other blood tests used to diagnose liver diseases
Test Why it’s important

Immunoglobulins higher than normal levels may mean the person has
hepatitis caused by the immune system attacking the
liver (autoimmune hepatitis)

Anti-nuclear antibody higher than normal levels may mean the person has
hepatitis caused by the immune system attacking the
liver (autoimmune hepatitis); also seen in lupus

Anti–smooth muscle higher than normal levels may mean the person has
antibody hepatitis caused by the immune system attacking the
liver (autoimmune hepatitis)

Anti-mitochondrial if present, may mean the person has immune-mediated

antibody damage to small bile ducts (primary biliary cholangitis, or
PBC)

Ferritin higher than normal levels may mean the person has a
condition where too much iron builds up in the body
(hemochromatosis), and levels can be higher in those
with an acute (new onset) liver inflammation from any
cause

Iron saturation higher than normal levels may mean the person has a
condition where too much iron builds up in the body
 (hemochromatosis)

Alpha-fetoprotein higher than normal levels may mean the person has liver
cancer (if higher than 400 IU/ml, they almost definitely
indicate cancer)

Hemochromatosis gene analysis is a useful test for people who

may have hemochromatosis (too much iron in their blood), and it
could be used to screen family members of individuals with
hemochromatosis who have an identified gene mutation.

RADIOLOGICAL TESTS

A doctor can request radiological tests to check for liver disease,

including ultrasound, a computed tomography (CT) scan, and
magnetic resonance imaging (MRI). These tests can look for fat,
tumors, or cirrhosis in the liver.
Other special tests can look at the tubes (bile ducts) that take bile
from the liver to see if they are damaged or blocked: magnetic
resonance cholangio-pancreatography (MRCP), endoscopic
retrograde cholangio-pancreatography (ERCP), or percutaneous
transhepatic cholangiography (PTC).
The doctor can also take special X-rays of the blood vessels
(angiograms) to see if the vessels are narrowed or occluded
(blocked).
If a doctor finds anything in these tests that is not normal, they
may do a liver biopsy to make a firm diagnosis.

LIVER BIOPSY

Doctors may take a sample of liver tissue (liver biopsy) to check for
liver disease. In a liver biopsy, a needle is inserted into the liver and
a small sample of tissue is taken. This tissue will be tested to check
for the type of disease and the amount of damage to the liver.
During a liver biopsy, the doctor first numbs the patient’s skin with
an anesthetic and then passes a needle between their ribs (figure
2.1). The doctor usually does the biopsy with the assistance of an
ultrasound device, to help guide the procedure.
Problems after having a liver biopsy rarely happen (less than 1 in
2,000). Possible problems include bleeding, damage to an organ
close to the liver (colon, gallbladder, lungs), pain, or infection.
Because these complications are very rare, most doctors consider
the benefits of having a liver biopsy to be greater than the possible
risks.
Before doing a liver biopsy, the doctor will do some more blood
testing to check if it is safe to perform this procedure using the above
method. Otherwise, the doctor can get the tissue sample by passing
a tube through the neck vein (transjugular) and getting a tissue
sample using a special needle. People should not take aspirin or
similar medications (ibuprofen or other nonsteroidal anti-
inflammatory medicines, also known as NSAIDs) for one week
before the biopsy and for 48–72 hours afterward. These medicines
increase the risk of bleeding because of their effects on platelets in
the blood.

FIGURE 2.1. A liver biopsy

 OTHER TESTS TO ASSESS THE SEVERITY OF
SCARRING

Because of the possible problems that can happen after having a

liver biopsy, doctors can use other tests, like FibroSURE and
FibroScan, to check for the severity of liver damage and scarring.
Compared with having a liver biopsy, these tests are not as accurate
(about 75–85 percent accuracy) in checking for scarring and the
amount of liver damage, but these tests don’t use any needles and
could be administered to a patient more often, if necessary.
There are many blood tests that are commercially available, and
they use a combination of serum markers to predict the severity of
scarring. There are many pitfalls with blood tests in assessing the
severity of scarring, as shown below:

• The presence, not of biological markers (biomarkers), but

surrogates, which reflect either liver functions or the turnover of
scar tissue (matrix), but not the deposit of scar tissue.
• Biomarkers that are related not just to the liver, but instead
reflect any inflammatory conditions.
• Biomarkers that are affected by the liver’s clearance of the
marker and influenced by the severity of the inflammation.
• Biomarkers that cannot differentiate mild to severe (F1 to F3)
scarring in a reliable manner but are relatively good at signaling
either a normal liver or cirrhosis.

The relative accuracy of these tests is shown in table 2.6.

More often, radiological (either ultrasound or MRI-based) tests are
used these days to assess the severity of scarring by measuring the
stiffness of the affected tissue. This is an evolving area, and currently
there are many options, as shown below. The physics behind these
techniques is that scarred tissue responds differently when it is
excited (stimulated). The devices produce shear waves (electronic
sound waves), which travel faster in scarred tissue. Scarred tissue
also shows less strain when it is compressed by pressure from the
waves. Many other factors, however, also affect liver stiffness,
including liver inflammation, heart failure, amount of liver fat, type of
liver disease, and jaundice (yellowing skin or eyes). These factors
reduce the accuracy of these tests.
TABLE 2.6. Accuracy of non-invasive blood tests used to assess fibrosis
Test Accuracy

AST:ALT ratio 60% to 70%

AST / platelet count 70% to 80%

FibroSURE 75% to 85%

FibroMeter 80% to 85%

Ultrasound-Based Tests
These are:

• Shear wave elastography (SWE)

Transient elastography (TE)
Acoustic radiation force impulse (ARFI) elastography
• Strain elastography
Supersonic shear imaging (SSI)
Hitachi real-time elastography (HI-RTE)

The main difference between shear wave elastography and strain

elastography is the method of excitation. The most commonly used
ultrasound technique is transient elastography. With TE, an external
device, called a transducer, produces shear waves with low-
frequency (50 Hz) vibrations and amplitudes (displacements created
by the vibrations). As a shear wave is transmitted through the liver,
TE measures its average speed by pulse-echo ultrasound
acquisition (the pulses that travel through the tissue and the echoes
from those pulses). That speed is then expressed in kilopascals, or
kPa (a unit of pressure), and measurement cut-offs have been
developed to assess the severity of scarring.
This test is approximately 80 percent accurate, but its results are
even better for people with cirrhosis. A diagram of how transient
elastography is done is shown in figure 2.2. The procedure, which
only takes five minutes, is begun after a person has fasted for three
hours. There are no potential complications associated with this test.

FIGURE 2.2. How transient elastography is done

MRI-Based Test
MR elastography is another technique using MRI, but it scans the
entire liver. This procedure is more expensive than ultrasound-based
techniques, and its accuracy is only marginally better.

Physicians may use a combination of tests to understand the nature

and severity of liver damage.

FURTHER READING
Liver disease. MedlinePlus. https://medlineplus.gov/liverdiseases.html.
Lala V et al. Liver function tests. 2020 Jul 4. In: StatPearls [internet]. Treasure
Island (FL): StatPearls Publishing; 2021 Jan.
https://www.ncbi.nlm.nih.gov/books/NBK482489/.
Kulakarni A et al. Analysis and interpretation of classic liver enzymes. Pract
Gastroenterol. 2018 Nov;42(11).
 https://practicalgastro.com/2018/11/30/analysis-and-interpretation-of-classic-
liver-enzymes/.
Diagnosis of cirrhosis. National Institute of Diabetes and Digestive and Kidney
Diseases. www.niddk.nih.gov/health-information/liver-
disease/cirrhosis/diagnosis/.
 CHAPTER 3

What Is Viral Hepatitis?

Hepatitis means “inflammation of the liver.” Bacteria, viruses, toxins,

or medications can cause this inflammation. It could be even caused
by your immune system damaging itself (in a process called
autoimmunity). The most common causes of hepatitis are viruses—
namely, the hepatitis A, hepatitis B, hepatitis C, and hepatitis E
viruses. These viruses all have one thing in common: They invade
normal liver cells and take over those cells to make copies of
themselves.

Viral infections, including hepatitis A, B, C, and E, are the most common

causes of hepatitis. Hepatitis E is very uncommon in the United States.
Hepatitis D, also known as delta virus, needs the hepatitis B virus to make
copies of itself, so hepatitis D is only seen in people who are infected with
hepatitis B.

VIRAL HEPATITIS

In the United States, the most common viruses that cause hepatitis
are hepatitis A, hepatitis B, and hepatitis C. According to the Centers
for Disease Control and Prevention (CDC), in 2018, hepatitis C
infected more than 50,300 new people, and hepatitis B infected more
than 22,600 new people; hepatitis A infects about 24,000 people
each year.
The tests used for the diagnosis of viral hepatitis are shown in
table 2.4 (chapter 2).

SYMPTOMS
It can take weeks or months after a person has been exposed to the
hepatitis virus to have the infection. Most people with any type of
hepatitis infection (whether it’s acute or chronic) have no symptoms,
don’t feel sick, and don’t know they are infected. People who have
new (acute) infections will often have no symptoms. The symptoms
for hepatitis A, hepatitis B, and hepatitis C are similar. Symptoms
people infected with hepatitis may experience are:

• Fatigue
• Loss of appetite
• Yellowing skin or eyes
• Nausea / upset stomach
• Vomiting
• Abdominal pain
• Joint pain
• Dark-colored urine
• Light-colored stools

TYPES OF VIRAL HEPATITIS

Hepatitis A
Hepatitis A, caused by the hepatitis A virus, is very contagious. A
person infected with hepatitis A has the virus in their blood and their
stools. It is usually spread when a person eats food or drinks water
contaminated with feces from a person who has hepatitis A. It can
also be spread through close or sexual contact with an infected
person. Hepatitis A infections are always short lasting (acute), but
they can be present from a few weeks to a few months. Sometimes
the illness can be serious. No treatment exists for hepatitis A
infections, but medications can help relieve some of the symptoms,
such as an upset stomach and vomiting. Hepatitis A infections can
be prevented with a vaccine (2 doses, 6 months apart). Practicing
good hygiene by washing your hands before cooking and eating will
help prevent infection.
TABLE 3.1. Types of hepatitis infections
 Is there a
Infection Duration How is it spread? Is there a cure? vaccine?

Hepatitis short- • food or water no yes

A (HAV) term contaminated with
feces from an
infected person

Hepatitis short- • infected mother to no, but the virus can yes
B (HBV) term or baby (common) be slowed or
long- • sex with an infected stopped very
term person efficiently
• sharing needles or
other drug equipment
with an infected
person

Hepatitis short- • sharing needles or yes (more than 95% no

C (HCV) term or other drug equipment can be cured)
long- with an infected
term person
• sex with an infected
person
• infected mother to
baby (rare)

Hepatitis short- • sharing needles or no no

D (HDV) term or other drug equipment
long- with an infected
term person
• sex with an infected
person

Hepatitis short- • food or water no none

E (HEV) term contaminated with available in
feces from an the United
infected person States
• blood transfusion
from an infected
person (very rare)
• infected mother to
baby (extremely rare)
Note: Viruses such as the herpes simplex virus (HSV), cytomegalovirus (CMV),
and Epstein-Barr virus (EBV) may also cause acute liver injury. Liver enzyme
abnormalities are common in SARS-CoV-2 (COVID-19) infections, but it is not
known whether such abnormalities are the direct result of the infection.

Hepatitis B
Hepatitis B, caused by the hepatitis B virus, can be spread through
having sex with an infected person or by sharing needles, syringes,
or other drug-injection equipment. Hepatitis B can also be passed
from an infected mother to her baby at birth. Hepatitis B infections
can be either short lasting (acute) or long lasting (chronic). Acute
infections will happen within a few weeks after a person is infected
with the hepatitis B virus. These infections can be mild or severe.
Most adults (around 95 percent) become immune to the virus and
recover from the infection. Most children and babies (roughly 90
percent) who are infected have the infection for the rest of their lives.
No cure exists for hepatitis B, but medications can stop or slow the
virus from causing damage to the liver. Hepatitis B can be prevented
with a vaccine (2 doses, 1 month apart).

Hepatitis C
Hepatitis C, caused by the hepatitis C virus, spreads when blood
from a person infected with the virus enters the body of an
uninfected person. The most common way of spreading hepatitis C
is by people sharing syringes or needles to inject drugs. A less
common way is through sexual contact. Hepatitis C infections can be
either short lasting (acute) or long lasting (chronic). About half of the
people who become infected develop a lifelong infection. Several
treatments exist for hepatitis C. Unlike hepatitis B, hepatitis C can be
easily cured.

Hepatitis D
Hepatitis D, which is sometimes called the “delta virus,” is only found
in people who have hepatitis B. The hepatitis D virus spreads when
blood from a person infected with the virus enters the body of an
uninfected person. Both viruses can infect a person at the same time
(coinfection), or people with hepatitis B may contract hepatitis D later
(superinfection). Hepatitis D infections can be either short lasting
(acute) or long lasting (chronic). Hepatitis D could be treated with
interferon, but success rates are not very high. No vaccine exists to
prevent hepatitis D, but preventing hepatitis B infections will also
help prevent hepatitis D infections.

Hepatitis E
Hepatitis E is usually spread when a person eats food or drinks
water contaminated with feces from a person infected with hepatitis
E. Rarely, it can be spread by a transfusion of blood products
contaminated with hepatitis E. Hepatitis E can also be passed from
an infected mother to her baby. In the United States, hepatitis E is
rare; it is mostly seen in South Asia. Hepatitis E is usually short
lasting, although occasional chronic infections have been reported in
immunocompromised people. No reliable vaccine exists to prevent
hepatitis E infections.

Other Viruses
Other viruses—such as herpes simplex virus (HSV), Epstein-Barr
virus (EBV), and cytomegalovirus (CMV)—may also cause acute
liver injury. These infections are usually asymptomatic or self-
limiting. CMV infections are the most common opportunistic
infections in organ transplant recipients. In immunocompromised
people, these infections could be very severe.

Chapters 4 and 5 contain more information about hepatitis B and C.

FURTHER READING
Viral hepatitis and liver disease. US Department of Veterans Affairs.
https://www.hepatitis.va.gov/basics/liver-single-page.asp.
What is viral hepatitis? Centers for Disease Control and Prevention.
https://www.cdc.gov/hepatitis/abc/index.htm.
What is viral hepatitis? National Institute of Diabetes and Digestive and Kidney
Diseases. https://www.niddk.nih.gov/health-information/liver-disease/viral-
hepatitis/what-is-viral-hepatitis/.
Hepatitis D. World Health Organization. https://www.who.int/news-room/fact-
sheets/detail/hepatitis-d/.
Shah PA et al. An update on the management of hepatitis D. Gastroenterol Rep.
2019;7:396–402. https://doi.org/10.1093/gastro/goz052/.
 CHAPTER 4

Understanding Hepatitis B

Worldwide, hepatitis B is a much bigger problem than hepatitis C.

There are approximately 250 million people with hepatitis B, and it
causes more than 500,000 deaths per year. Hepatitis B is more
common in parts of Africa and Asia, where many people, while in the
womb, contract the infection from their mother (vertical
transmission). Up to 10 percent of the people in Asia, and as many
as 50 percent in sub-Saharan Africa, are exposed to hepatitis B.
Hepatitis B is also more common in those with hepatitis C or HIV
because of a similar spread of these infections. According to the
CDC, approximately 900,000 people in the United States have
chronic hepatitis B.
Hepatitis B and hepatitis C are similar in many ways, but there are
also many differences. Hepatitis C is a RNA virus, while hepatitis B
is a DNA virus. Both are spread in a similar manner, but hepatitis B
is more infectious than either HIV or hepatitis C. Another major
difference is that hepatitis C is curable, whereas hepatitis B is not.
Nonetheless, hepatitis B can be suppressed very effectively with
medications.
Hepatitis B is a very complex DNA virus (figure 4.1). A hepatitis B
infection, caused by the hepatitis B virus, can be a short-lasting
(acute) illness or a long-term (chronic) illness.

Acute hepatitis B infection: When someone first becomes infected

with hepatitis B, they have an acute infection. These infections
usually last six months or less.
Chronic hepatitis B infection: These types of infections are when the
hepatitis B virus stays active for more than six months.

Whether a person develops a long-term (chronic) illness depends

partly on their age. Most adults (90–95 percent) who have a hepatitis
B infection recover without treatment and without suffering from a
long-term illness. But most babies (90 percent) and children younger
than 5 years old who become infected with hepatitis B will have the
disease for the rest of their lives (also known as immune tolerant
hepatitis B). Infected babies and young children usually do not
develop liver disease, but they have a higher risk of liver cancer
occurring when they get older.
Worldwide, hepatitis B is the most common cause of liver cancer.
 FIGURE 4.1. The structure of the hepatitis B virus

SYMPTOMS

People may or may not have any symptoms when they first become
infected with the hepatitis B virus (acute infection). Whether they
start to feel symptoms partly depends on their age. Most children
with acute infections are asymptomatic, but most adults with acute
hepatitis B will have some signs of the disease.
A person who has a hepatitis B infection may have some of the
following symptoms:

• Fever
• Fatigue
• Poor appetite
• Nausea
• Vomiting
• Discomfort or pain in the upper right belly
• Joint pain
• Yellowing skin or eyes
• Dark-colored urine
• Light-colored stools

Most people with long-term hepatitis B have no symptoms until the

disease has progressed to cirrhosis.

HOW HEPATITIS B IS SPREAD

The hepatitis B virus spreads when blood, semen, or other body

fluids from a person infected with the hepatitis B virus enters the
body of someone who is not infected with the virus. This can happen
when a person:

1. Shares intravenous needles, syringes, or drug equipment with

an infected person
2. Has sex with an infected person
 3. Shares toothbrushes, shaving razors, or medical supplies with
an infected person
4. Is accidentally exposed to the hepatitis B virus by a needlestick
or spill

In addition, a mother who has hepatitis B can pass the infection to

her baby during birth.
Some people who have a higher risk of getting infected include:

• Those who share needles during intravenous drug use

• Those who live with an infected person
• Health care workers who may be exposed to infected blood and
other body fluids
• Those who travel to a part of the world where hepatitis B is
common (the transmission routes are the same as above).

Anyone who has a higher risk of becoming infected can prevent the infection
with the hepatitis B vaccine. Ideally, everyone should receive the hepatitis B
vaccine.

DIAGNOSING HEPATITIS B

To check if you have a hepatitis B infection, a doctor will test for

several different things in your blood to be entirely certain you are
infected (tables 2.4 and 4.1). People who currently have hepatitis B
or who have ever had the infection will always have some hepatitis B
DNA in their liver cells, so it’s important to have the full set of tests to
know whether you have a current or past infection. The results of
these tests will give your doctor a complete picture about your
infection, including if you have a short-term or a long-term infection.
TABLE 4.1. Tests for a hepatitis B infection
Test If present, the results mean
Hepatitis B DNA (HBV DNA) the person has an active virus infection

Hepatitis B core IgM antibody (HBcIgM) the person has a new hepatitis B
 infection

Hepatitis B core IgG antibody (HBcIgG) the person has had an infection before
or has an ongoing long-term infection

Hepatitis B core total antibody the person has an acute or chronic

(measures both IgG and IgM) infection (if an acute infection is
suspected, your doctor will request an
IgM antibody test)

Hepatitis B surface antigen (HBsAg) the person has an active infection

Hepatitis B surface antibody (HBsAb) the person is completely immune by

either having had the infection before or
by being vaccinated

Hepatitis B virus e antigen (HBeAg) the person has an active infection, but if
that individual does not have this
antigen, it does not mean they don’t
have an infection (a mutated virus may
not release this antigen into the blood)

Hepatitis B virus e antibody (HBeAb) the person may have some immunity,
but the presence of this antibody does
not always mean immunity; people who
do not have the hepatitis B virus e
antigen but have an active virus could
have this antibody if the virus has
mutated and does not release the
hepatitis B virus e antigen

For most people, their doctor can tell the difference between an
acute and a chronic infection, based on the results of the hepatitis B
core IgM antibody test. IgM antibodies are usually present in the
blood when a person has an acute hepatitis B infection.
People who have hepatitis B should also be tested for:

1. Hepatitis C
2. HIV
3. Hepatitis D

People who have hepatitis B have a higher risk of having liver

cancer. So anyone who has a hepatitis B infection should talk to their
doctor about whether they should have regular cancer screenings
(about every six months), depending on their age, health, and family
history of liver cancer or liver disease.

TREATMENT

There is no cure for hepatitis B, but treatment can help people

recover from the infection.

For Acute Hepatitis B

Most people who have acute hepatitis B usually get better without
any treatment. In about 90–95 percent of adults who have this
infection, they will recover without any problems. To help with
recovery, their doctor may recommend getting sufficient rest, eating
well, avoiding alcohol, and staying hydrated.
In some people who have severe acute infections, their doctor
may recommend starting treatment with medicines (table 4.2). It is
extremely rare (less than 1 percent) for someone to need a liver
transplant.

• All those without immunity to hepatitis B (the presence of

hepatitis B surface antibodies) who are in contact with a person
with acute hepatitis B, either in their household or sexually,
should have treatment with hepatitis B immune globulin and a
vaccination to prevent this infection.

For Chronic Hepatitis B

About 5 percent of adults who have acute hepatitis B infections
develop a long-term (chronic) infection, meaning the infection lasts
longer than six months. Those who have a chronic infection may
develop severe liver damage (chronic hepatitis) and cirrhosis. The
complications of cirrhosis from this type of infection are the same as
those for cirrhosis from any other causes.
Many people who have long-term infections will need medications
to help them feel better, prevent the progression of liver disease, and
reduce the risk of liver cancer. Treatment, however, will not help
everyone who has a long-term hepatitis B infection. For example,
taking medication may not help people who don’t have any signs of
damage to their liver, based on blood tests or a liver biopsy. Talk to
your doctor to decide if treatment is right for you.

Visit Your Doctor

Tell your doctor that you have had a hepatitis B infection if you need:
• Chemotherapy
• An organ transplant
• Treatment for hepatitis C.
A hepatitis B infection can flare up and get worse.

If You Take Medicine for Hepatitis B

Once a person starts treatment for a hepatitis B infection, they may
need to take medication for the rest of their lives. They should visit
their doctor every three to six months to check if the treatment is
working well, find out if their liver disease may be getting better or
worse, and be tested for liver cancer (every six months).

If You Don’t Take Medicine for Hepatitis B

Even if you don’t need to take medication, you still should see your
doctor regularly to make sure the infection is not getting worse
because of the following possibilities:

1. The infection can flare up for no reason.

2. You still have a risk of developing liver cancer.

IS TREATMENT RIGHT FOR YOU?

Talk to a doctor to figure out if treatment is the best option. There are
many different things to consider when deciding whether to start
treatment.
In general, most people who have a long-term hepatitis B infection
should take medication if:
 • They have higher than normal levels of liver enzymes and very
high levels of hepatitis B virus DNA in their blood.
• They have signs of liver damage.
• They have cirrhosis.
• They have liver cancer.
• They are going through chemotherapy or planning to have an
organ transplant, even if they do not have an active hepatitis B
infection and the levels of the hepatitis B virus in their blood are
very low.
• They are pregnant and have very high levels of the hepatitis B
virus in their blood (if so, they should get treatment in the third
trimester to lower the risk of passing the infection to the baby).
• They have hepatitis C and have hepatitis B virus DNA in their
blood.

In addition, the doctor will consider many other factors, such as

whether the person has the hepatitis Be antigen in their blood, the
levels of hepatitis B virus DNA in their blood, and whether they have
a family history of liver cancer.
The doctor may also take a sample of liver tissue (liver biopsy) to
check for liver disease, depending on the results of other tests and
the levels of liver enzymes.

TYPES OF TREATMENTS

There is no cure for hepatitis B, but there are very effective

treatments to suppress the replication of the virus.
The two most common medicines used to treat hepatitis B are
entecavir and tenofovir. Other treatments—such as telbivudine,
adefovir, and lamivudine—are not used today, because entecavir
and tenofovir are more effective and safer. Both entecavir and
tenofovir are very potent in treating hepatitis B infections by
preventing the hepatitis B virus from multiplying in the body, which
can then help prevent the progression of liver damage and lower the
risk of developing liver cancer.
Both entecavir and tenofovir are pills, taken once daily. They are
very safe and have hardly any side effects. Entecavir and tenofovir
could be used without dose adjustments, even in the presence of
liver failure, but the dose may need to be changed in the case of
kidney dysfunction.
There are two preparations of tenofovir available in the market,
and both are equally effective. There may be a marginal benefit with
tenofovir alafenamide (25 mg, daily) in older people and those with
renal insufficiency when compared with tenofovir disoproxil fumarate
(tenofovir DF, 300 mg daily). Tenofovir alafenamide may generate
less osteoporosis and is less likely to cause renal insufficiency.

• There is no safety data on tenofovir alafenamide or entecavir in

pregnant women. Therefore, tenofovir DF is the drug of choice in
pregnancy.

Side Effects of Entecavir or Tenofovir

Side effects are minimal or none with both medications. Very rarely,
tenofovir DF may cause kidney dysfunction or bone thinning
(osteopenia). Using tenofovir alafenamide could minimize these side
effects.
Unusual side effects of these medications include muscle
weakness or peripheral neuropathy. In those with advanced
cirrhosis, especially with kidney failure, lactic acid can build up in the
body (lactic acidosis).

Treatment Monitoring
It is important to take these medicines exactly as instructed by your
doctor and to talk to your doctor regularly. Rarely, the hepatitis B
virus can change (mutate), so the medicines don’t work any more in
treating the infection.

• People who test positive for the hepatitis Be antigen may be able
to stop taking medicines for a hepatitis B infection, based on
their progress. Always talk to your doctor about any changes to
your treatment.
• For people who have active liver disease and do not have the
hepatitis B virus e antigen in their blood, there are no tests to
 determine when to stop treatment. Most physicians will consider
continuing treatment for the rest of the person’s life, or until the
hepatitis B surface antigen disappears.

In general, the majority of people with an active hepatitis B

infection will need lifelong treatment and follow-ups. Those with
hepatitis B also need to be screened for liver cancer on a regular
basis for the rest of their life, irrespective of whether they have liver
disease, since hepatitis B is a cancer virus.
TABLE 4.2. Medicines to treat hepatitis B
Antiviral
medication How it is taken Preferred groups Side effects

Entecavir pill taken once a people with renal RARE but can
day on an empty insufficiency include the
stomach following:
• in those with
advanced
cirrhosis,
especially with
kidney failure,
lactic acid can
build up in the
body (lactic
acidosis)

Tenofovir pill taken once a older people RARE but can

alafenamide, 25 mg day with food people with renal include the
daily insufficiency following:
• in those with
advanced
cirrhosis,
especially with
kidney failure,
lactic acid can
build up in the
body (lactic
acidosis)

Tenofovir disoproxil pill taken once a pregnant women RARE but can
fumarate, 300 mg day, with or without (pregnancy include the
daily food category B) following:
• kidney
dysfunction
• thinning of bones
(osteopenia)
• peripheral
neuropathy
• in those with
advanced
cirrhosis,
especially with
kidney failure,
lactic acid can
build up in the
body (lactic
acidosis)

Interferons injection weekly those who prefer COMMON

short-term (1 year)
• flu-like illness,
treatment
mood disorders,
loss of appetite,
weight loss, low
blood counts

Note: Side effects (such as nausea, vomiting, diarrhea, headache, skin rash,
fatigue, dizziness, and sleep problems) have been reported with both entecavir
and tenofovir, but these are very infrequent.

OTHER MONITORING

Hepatitis B is a chronic (lifelong) disease. Even if a person does not

require treatment, there is a possibility that the disease could flare up
without any precipitating cause. It is therefore important to follow up
with their physician as recommended (usually every 3–12 months,
depending on multiple factors). Surveillance for liver cancer is also
necessary, even if the person does not require hepatitis B treatment.
If a person has had exposure to hepatitis B, it is important to
inform their cancer specialist of this if they ever need chemotherapy.
Inactive hepatitis B could flare up during chemotherapy or if the
immune system is suppressed with medications (such as after an
organ transplant). This also applies to people who have both HCV
and hepatitis B. Before any treatment of hepatitis C, it is important to
discuss the management of hepatitis B with your physician, as
inactive hepatitis B could flare up during treatment for hepatitis C.

PREVENTION

The most effective way to prevent an infection with hepatitis B in

people who have not had this disease before is to get the hepatitis B
vaccine. This vaccine is safe, and the side effects are very rare.
Once individuals have had hepatitis B, they do not benefit from
vaccination. In the United States, hepatitis B vaccination has
become routine only recently, so most adults do not have immunity
against hepatitis B. The new hepatitis B vaccine is given as 2 doses,
1 month apart.
Because it is common for mothers to pass the hepatitis B infection
to their babies at birth, every pregnant woman should be tested for
hepatitis B. If a pregnant woman has a hepatitis B infection and has
high levels of the hepatitis B virus in her blood, she should see a
doctor who specializes in treating liver disease. The doctor will
decide whether the woman should start taking medicine when it is
safe during the pregnancy (usually in the last three months). Every
at-risk child should be vaccinated right after they are born.

FUTURE TREATMENT

At this time, hepatitis B is incurable, but there is ongoing intense

research to find a cure for this disease. Currently available
medications do not inhibit or eradicate covalently closed circular
DNA (cccDNA), which is seen in the nucleus of infected liver cells in
people with hepatitis B. There are many potential preventive
molecules—including cccDNA inhibitors, immune modulators, capsid
inhibitors, small interfering RNA, and hepatitis B surface antigen
inhibitors—in developmental stages. As with hepatitis C, we hope to
find a cure for hepatitis B in the near future, using a combination of
molecules.
FURTHER READING
Hepatitis B. Centers for Disease Control and Prevention.
https://www.cdc.gov/hepatitis/hbv/index.htm.
Hepatitis B. World Health Organization. https://www.who.int/news-room/fact-
sheets/detail/hepatitis-b/.
What is hepatitis B? Hepatitis B Foundation. https://www.hepb.org/what-is-
hepatitis-b/what-is-hepb/.
The liver story. https://www.youtube.com/watch?v=9hW_lF9evCc/.
NIH strategic plan details pathway to achieving hepatitis B cure. National Institutes
of Health. https://www.nih.gov/news-events/news-releases/nih-strategic-plan-
details-pathway-achieving-hepatitis-b-cure/.
Boortalary T et al. Achieving a cure: The next frontier in hepatitis B treatment. In:
Liver Cancer [internet]. Brisbane (AU): Exon Publications; 2021 Apr 6.
https://www.ncbi.nlm.nih.gov/books/NBK569795/.
 CHAPTER 5

Understanding Hepatitis C

Approximately 2.4 million adults in the United States live with chronic
hepatitis C. According to CDC estimates, 50,300 adults in the United
States were infected with hepatitis C in 2018. Worldwide, it is
estimated that 120 to 200 million people live with hepatitis C.
Approximately 400,000 people worldwide die from hepatitis C–
related liver disease or cancer every year. Unlike hepatitis B,
hepatitis C is an RNA virus. The structure of the hepatitis C virus is
shown in figure 5.1.

FIGURE 5.1. The structure of the hepatitis C virus

 Hepatitis C, caused by the hepatitis C virus, can be either a short-
lasting (acute) or long-lasting (chronic) illness. On average, it takes
45 days from the beginning of the infection for symptoms to start to
appear, but this time period can range from 15 days to 6 months.

Acute hepatitis C infection: When someone first becomes infected

with hepatitis C, they have an acute infection. These infections
usually last six months or less.
Chronic hepatitis C infection: In these types of infections, the
hepatitis C virus stays active for more than six months.

About 30–50 percent of the people who have an acute hepatitis C

infection will be cured without any treatment or long-term problems.
Almost 50–70 percent of the people who have hepatitis C, however,
will develop a long-lasting (chronic) infection. Chronic hepatitis C can
cause long-term health problems, such as liver cirrhosis, liver
cancer, and death.
There are several different types of hepatitis C viruses, which can
be grouped into various categories (genotypes). Hepatitis C has
genotypes 1 to 6 and many more subtypes within those. In the
United States, about 70 percent of the people with hepatitis C have
genotype 1.

SYMPTOMS

Most people (about 80–90 percent) who have acute hepatitis C

infections do not have any symptoms. About 10–20 percent of the
people who have acute hepatitis C will experience some of the
following symptoms:

• Fatigue
• Loss of taste
• Loss of appetite
• Nausea or vomiting
• Yellow-colored skin or eyes
• Dark-colored urine
• Light-colored stools
People who have chronic hepatitis C rarely have symptoms, but if
they do, they may feel tired or have discomfort in their upper right
belly.

HOW HEPATITIS C IS SPREAD

The hepatitis C virus spreads when blood or blood products from a

person infected with the hepatitis C virus enter the body of someone
who is not infected with the virus. This can happen when a person:

1. Shares intravenous needles or other drug equipment with an

infected person
2. Gets a blood transfusion from an infected person
3. Gets an organ from an infected donor
4. Has sex with an infected person
5. Is accidentally exposed to the hepatitis C virus by a needlestick
or spill
6. Gets a tattoo with equipment that is not clean
7. Shares toothbrushes or shaving razors with an infected person

In addition, a mother who has hepatitis C can pass the infection to

her baby during birth.
The most common way of spreading hepatitis C is by people
sharing syringes or needles to inject drugs. Less common ways are
through sexual contact, accidentally getting stuck by a needle, a
blood transfusion with infected blood, or an infected mother passing
the virus to her baby at birth.
 Before the discovery of hepatitis C in 1989, little was known about the
infection, which was most commonly spread by transfusions with infected
blood products and could cause chronic liver disease.
The discovery marked a major breakthrough in understanding transfusion-
related hepatitis, resulting in the routine screening of blood products for
hepatitis C. Thanks to these more-thorough screening procedures and safer
practices among users, the number of new hepatitis infections has gone down
in the United States, from about 230,000 per year in 1989 to 50,300
(estimated) in 2018.

Some people who are at a higher risk of becoming infected with

hepatitis C include:

• People who use intravenous drugs

• People who were born between 1945 and 1965
• People who received a blood transfusion before 1989
• People who have HIV
• Men who have sex with men
• People who receive hemodialysis
• People who have hemophilia
• People who have multiple sexual partners
• People who are in prison
• People who inhale drugs
• Sexual partners of those infected with both hepatitis C and HIV

Most daily activities are safe and carry no risk of a hepatitis C infection.
• Sharing food or drinks
• Living in the same household
• Kissing, hugging, shaking hands
• Close, nonsexual body contact

DIAGNOSING HEPATITIS C

To determine if you have a hepatitis C infection, a doctor will do

some of the blood tests listed in chapter 2, including checking your
levels of liver enzymes. But, because many people who have a
hepatitis C infection have normal levels of liver enzymes and have
no symptoms, the doctor will test for several different things in your
blood to be entirely certain whether you are infected (table 5.1).
People who currently have hepatitis C will always have some
hepatitis C RNA in their blood, so it’s important to have the full set of
tests to know whether you have a current or past infection. All of the
results of these tests give your doctor a complete picture of your
infection, including if the infection is acute or chronic.

Hepatitis C Antibodies
A person who has or ever has had a hepatitis C infection will have
hepatitis C antibodies in their blood. Rarely, a person who has never
had hepatitis C will have hepatitis C antibodies in their blood (false
positive antibodies). These occur more commonly in immune-
mediated diseases (diseases related to the immune system), such
as rheumatoid arthritis, lupus, and autoimmune liver diseases. In
general, the hepatitis C antibody test is accurate, and 80 percent of
those not previously treated whose blood contains detectable
amounts of these antibodies have an ongoing hepatitis C infection.
TABLE 5.1. Tests for a hepatitis C infection
Test If present, the results mean

Hepatitis C antibody test the person has an active infection or

has had a hepatitis C infection before

Hepatitis C RNA by PCR the person has an active infection

Hepatitis C genotype and subtype an indication of what type of hepatitis C

infection the person has (types 1 to 6)

Hepatitis C RNA PCR test

To find out whether a person has an active hepatitis C infection, a
blood test called an HCV RNA test is used. This test could detect
small amounts of the virus circulating in the blood. This procedure
could be done as a qualitative measurement (with a “yes” or “no”
result) or as a quantitative test (to determine the amount of virus
present). Qualitative tests are rarely used these days.
The quantitative PCR test measures the amount of hepatitis C
genetic material (RNA) in the blood. The quantitative PCR result is
described in international units (IU) per milliliter (ml) of blood. This
test is used to determine whether a person has a current hepatitis C
infection, as well as to show whether a hepatitis C treatment is
working sufficiently. The test is not used to check whether you have
a severe infection. In other words, a higher quantitative number does
not necessarily mean that the infection is very serious or is getting
worse.
The doctor will use other blood tests, an ultrasound of the liver,
and additional tests to determine the amount of damage to the liver
and figure out the best treatment plan.
People who have hepatitis C should also be tested for:

1. Hepatitis A
2. Hepatitis B
3. HIV
4. Other liver diseases

Since hepatitis C is common, and the way the disease shows up

may vary in children and in people with an HIV infection, it is
described in more detail in the next section.

ACUTE HEPATITIS C

Acute hepatitis C is a short-term illness that occurs within the first six
months after exposure to the hepatitis C virus. The hepatitis C virus
is the cause of 15 percent of all acute hepatitis cases reported in the
United States. The number of new hepatitis C infections had
decreased significantly over the past three decades in the United
States, but, more recently, an increase has occurred, which has
been attributed to the opioid epidemic.
Acute hepatitis C infection may occur from 2 to 12 weeks after the
time of exposure (on average, 7 weeks), and illness from the
infection may last for 2–12 weeks. Acute hepatitis C can be mild—
only about 10–20 percent of the people who have the infection will
develop symptoms. Very rarely, the acute infection can be severe
and prolonged (lasting for weeks to months), accompanied by
jaundice or liver failure.
About 30 percent (or higher, if jaundice develops) of the people
who have acute hepatitis C are cured spontaneously. These people
will have hepatitis C antibodies in their blood for the rest of their life,
but they will have no hepatitis C virus in their body. Nonetheless, the
presence of antibodies does not protect these people from a future
reinfection by the hepatitis C virus.
There are no blood tests that can distinguish between a person
who has an acute hepatitis C infection and someone who has had
the infection for a long time (chronic infection). A physician may
suspect a person has an acute hepatitis C infection under the
following circumstances:

• The person has had an identifiable exposure to the virus,

followed by an increase in liver enzymes or the presence of
symptoms.
• The person has previously had consistently normal liver
enzymes, later followed by a marked increase in liver enzymes
and the presence of symptoms.
• The person had an earlier negative hepatitis C RNA test result,
but a second test result is positive.

The only way for a physician to conclusively diagnose an acute

hepatitis C infection is to record the development of antibodies
(called seroconversion) in an individual who previously lacked those
antibodies. This process happens most frequently when a
needlestick occurs that exposes a person to the hepatitis C virus and
the individual is monitored for a certain length of time, or in studies
that look at high-risk individuals who test negative for a hepatitis C
infection. Testing for hepatitis C antibodies, however, is not a reliable
way to confirm an acute hepatitis C infection, because in as many as
30 percent of the people, the production of antibodies may be
delayed when symptoms appear.
 CHRONIC HEPATITIS C

Once chronic hepatitis C develops, the likelihood that the person will
spontaneously clear the virus is less than 10 percent. People with
chronic hepatitis C rarely have any symptoms when the disease is
mild. People in the advanced stages of liver disease are the ones
who develop symptoms—such as jaundice, fluid in the abdomen,
swelling in the legs, or confusion—which is an important reason for
individuals who have chronic hepatitis C to seek help before these
conditions occur.
Because people who have hepatitis C often do not have
symptoms, many of them learn they have liver disease as a result of
routine blood tests. After diagnosing hepatitis C in an individual, the
physician will assess the severity of the liver disease (described in
chapter 2) by a combination of blood tests, FibroScan, or (rarely) a
liver biopsy. Today, a liver biopsy is performed only when other non-
invasive tests are inconclusive or when another accompanying liver
disease is suspected.

Stages of Liver Scarring (Fibrosis)

Your doctor may describe the severity of scarring in terms of stages.
Stage 0 is when there is no liver scarring. A commonly used scoring
system (Metavir) describes liver scarring (fibrosis) as minimal or mild
(early, or stage 1), moderate (intermediate, or stage 2), severe
(advanced, or stage 3), or established (stage 4) cirrhosis. Scoring
systems are applicable to almost all liver diseases and are not
unique for hepatitis C.

Progression to Cirrhosis in Chronic Hepatitis C

Approximately 20–30 percent of the people who have hepatitis C will
develop cirrhosis within 10 to 20 years after they become infected,
and around 30 percent may develop cirrhosis after 40–50 years. It is
important to remember, however, that 30–40 percent of the people
who have hepatitis C may never develop any serious liver damage.
Alcohol is perhaps the most important risk factor in predicting a
progression to cirrhosis, and individuals who have hepatitis C should
abstain from drinking alcohol. Other risk factors for developing
cirrhosis are acquiring a hepatitis C infection through a blood
transfusion and contracting hepatitis C after the age of 50. HIV
coinfection also makes hepatitis C–induced liver disease worse. No
convincing evidence suggests that the amount of hepatitis C virus in
the blood (the viral load) and the virus’s genetic subtype (genotype)
predict the progression of this disease.

Some Strategies for Preventing the Progression of Hepatitis C

or Other Liver Diseases
1. Avoid drinking alcohol completely.
2. Receive vaccinations for hepatitis A and hepatitis B.
3. Maintain good general health, weight, and lifestyle.
4. Control your cholesterol and triglyceride levels, high blood
pressure (hypertension), and diabetes.
5. Stop smoking.
6. Seek treatment for a hepatitis C infection. A cure will reduce the
risks of progression to cirrhosis and the development of liver
cancer.

COINFECTION WITH HIV AND HEPATITIS C

Because hepatitis C and HIV are blood-borne infections, it is

common for individuals to be infected with both the hepatitis C virus
and HIV. Worldwide, approximately 40 million people have HIV and,
of those, between 4 and 5 million also have hepatitis C. In the United
States, between 25 and 33 percent of those who have HIV—
approximately 150,000 to 300,000 people—also have hepatitis C.
With the availability of effective HIV treatments, such as highly
active anti-retroviral therapy (HAART), hepatitis C–related liver
disease has emerged as a major cause of death among people who
have HIV. The 10-year survival rate for people receiving HAART is
nearly 90 percent, reinforcing the importance of treating hepatitis C
in those who have HIV.
Among people who have HIV and use intravenous drugs,
between 60 and 90 percent also have hepatitis C. In contrast,
intravenous drug use was reported by between 15 and 30 percent of
the people who only had HIV. Among people who contracted HIV
through contaminated blood products, approximately 50–70 percent
have hepatitis C. The risk of transmission from each needlestick
exposure is 10 times higher for hepatitis C than for HIV.
The rate of a hepatitis C infection is low (7–14 percent) in people
who become infected with HIV through sexual behaviors. This low
prevalence of hepatitis C among sexual partners of people who have
HIV indicates a lesser transmission rate of hepatitis C through sexual
exposure. Nonetheless, to further prevent the spread of HIV and
hepatitis C, people infected with both diseases should use condoms
during sexual intercourse.

• All HIV-infected individuals should be tested for hepatitis C with

a hepatitis C antibody test.
• Individuals at high risk of a hepatitis C infection should routinely
undergo a PCR test to detect hepatitis C RNA, even if hepatitis
C antibodies are not present.

Effect of an HIV Infection on Hepatitis C

For many people, an HIV infection worsens hepatitis C–induced liver
disease, especially in those who have low CD4 (T cells, or white
blood cells that fight infection) counts. For people who have acute
hepatitis C, an HIV infection decreases the likelihood of spontaneous
clearance of the hepatitis C virus from 15 to 30 percent down to 5 to
10 percent. And for those who have a chronic hepatitis C infection,
HIV infection causes higher hepatitis C viral counts and a faster
progression to liver disease. Many studies have shown that the risk
of developing cirrhosis is twice as high for individuals who have both
diseases. Also, there is a much shorter length of time for developing
cirrhosis in people who have both diseases than in those who only
have hepatitis C (7 years versus 23 years). Similarly, the risk of
death from liver disease is higher in coinfected individuals.
People who have HIV are surviving longer because of HAART,
and thus a significant number of people who have HIV are now dying
of complications from advanced liver disease, including liver cancer.
Once cirrhosis occurs, coinfected people have a six times higher risk
of developing complications from cirrhosis—abdominal swelling
(ascites), mental confusion (hepatic encephalopathy), and bleeding
from blood vessels (variceal bleeding)—compared with people who
only have hepatitis C. Therefore, it is extremely important for
coinfected people to receive treatment for their hepatitis C infection.
Although an HIV infection adversely affects the natural progression
of hepatitis C disease, the presence of a hepatitis C infection does
not seem to affect the progress of HIV disease.
The following are important considerations for those who have
both HIV and a hepatitis C infection:

1. People who have acute hepatitis C and HIV are less likely to
get better on their own than those who don’t have HIV.
2. People who have chronic hepatitis C and HIV are more likely to
have high amounts of the hepatitis C virus in their blood and
more serious damage to their liver.
3. Some studies have shown that people with both infections are
much more likely to have cirrhosis of the liver, as well as to
develop cirrhosis much faster.
4. People who have both HIV and hepatitis C infections are more
likely to develop liver cancer than people who only have a
hepatitis C infection.
5. People who have both HIV and hepatitis C infections and then
develop cirrhosis (late-stage liver disease) have a much higher
risk of other, very serious problems with their liver such as
swelling and bleeding.

Treatment of Hepatitis C in People Who Have HIV

The cure rates for hepatitis C in people who have HIV are similar to
those in individuals without HIV. Therefore, all people who have HIV
should consider hepatitis C treatment, which is similar for those with
and without HIV.
In general, anti-retroviral medications should not be interrupted to
start treatment for hepatitis C. Those newly diagnosed with HIV and
not yet on HIV medications preferably should start HIV medications
four to six weeks before beginning treatment for the hepatitis C virus.
 • People who have hepatitis C and HIV should not drink alcohol. The disease
can progress more rapidly in individuals who consume alcohol.
• People with both hepatitis C and HIV should be treated for hepatitis C.
• If a person is newly found to be infected with both HIV and hepatitis C, they
should talk to their doctor about the best time to start treatment for each
infection, the best medicines to treat each infection, and the possible side
effects of each medication.

The only consideration when selecting a medication for hepatitis

C is drug-drug interactions (negative interactions between drugs).
HIV medications may need to be switched occasionally to reduce
these interactions. Your physician will make this determination. If a
change is necessary, it is wise to wait for four to six weeks before
starting treatment for hepatitis C.

• All people who have HIV and hepatitis C should consider HIV
treatment, irrespective of their CD4 counts.
• A physician should look at possible drug interactions with HIV
medications when treatment for hepatitis C is initiated.
• People who are newly diagnosed with HIV and hepatitis C
preferably should begin HIV treatment four to six weeks before
starting treatment for hepatitis C. Similarly, if HIV medications
need to be changed because of potential drug-drug interactions,
it is preferable to wait for four to six weeks after the switch before
starting hepatitis C treatment.

Advanced Liver Disease in People Who Have HIV

People who have advanced (decompensated) cirrhosis and HIV
should seek the expertise of a liver specialist. Treatment of hepatitis
C may carry major risks for these individuals, and they may not
tolerate hepatitis C treatment. Some people may require a liver
transplant before their hepatitis C is treated. Survival rates after a
transplant are similar to those for individuals who only have hepatitis
C.
People who have both HIV and hepatitis C are more likely to
develop liver cancer than those with only hepatitis C. Screening for
liver cancer is important for people with HIV who are coinfected with
either hepatitis B or hepatitis C.

HEPATITIS C IN CHILDREN

Many aspects of hepatitis C are different for children than for adults,
including the method of transmission, the natural history of the
disease, and subsequent complications. Only a small proportion of
people with chronic hepatitis C are children. Approximately 240,000
children in the United States have hepatitis C antibodies, but only
from 68,000 to fewer than 100,000 are infected with the virus (as
confirmed by a hepatitis C RNA test).
The advent of blood screening for hepatitis C in 1990 had a
significant impact on the rate of infection in children, as well as for
the general population. Children who had hemophilia and received
multiple transfusions of blood or blood products before 1990 had
infection rates ranging between 50 and 95 percent. Among children
who received multiple blood transfusions before 1990, either for
cancers or during surgery for congenital heart disease, 10–20
percent were infected with hepatitis C. Children who received
hemodialysis treatment before 1990 also had a hepatitis C infection
rate of 10–20 percent.
Hepatitis C does not spread from child to child. The American
Academy of Pediatrics recommends that children who have hepatitis
C do not need to have any restrictions on attending school or
daycare and participating in sports, including sports with body
contact.
In low-income countries, a significant number of children become
infected through unsafe blood products and contaminated needles
(when reused), syringes (when reused), and medical instruments.
Unfortunately, this source of transmission will remain a major
pathway for infection in low-income countries.

Transmission from Mothers to Babies

Hepatitis C transmission from a mother to her baby during
pregnancy or delivery, although rare, currently remains the main
method by which children become infected with hepatitis C. About 1
percent (ranging from 0.1 to 2.4 percent) of pregnant women are
infected with hepatitis C, and only 4–7 percent of pregnant women
who have an active hepatitis C infection give it to their babies. The
transmission rates are higher when mothers are also infected with
HIV. If a mother has both HIV and hepatitis C infections, the rate of
transmission of the hepatitis C virus to the infant is two to four times
higher.
The effect of other factors—including severe liver disease in the
mother, amniocentesis, the type of delivery, and complications during
birth—on mother-to-infant transmissions remains largely unknown.
Suggestions to physicians include avoiding the use of internal fetal
scalp monitors and breaking the mother’s water too early (more than
six hours) before delivery. There are no specific recommendations
on the method (cesarean versus vaginal) or timing of delivery to
prevent the transmission of a hepatitis C infection. Nonetheless,
women should not have a cesarean section merely to prevent
passing either or both of the HIV and hepatitis C viruses to their
babies.
Also, breastfeeding does not increase the risk of transmission,
unless the mother’s nipples are bleeding.
Testing all pregnant women for hepatitis C is recommended,
instead of merely risk-based screening. These women should also
be tested for hepatitis B and HIV. Treating hepatitis C during
pregnancy is not recommended.

Natural Progression of the Disease in Children

As in adults, an acute infection in children may be asymptomatic.
Most children who have chronic hepatitis C do not exhibit any
physical or cognitive (mental) symptoms until they develop advanced
liver disease.
The natural history of hepatitis C acquired from mothers remains
poorly defined. Infection occurs when the baby’s immune system is
not completely developed. For a short amount of time, some infants
may have the virus in their blood without developing a hepatitis C
infection. Other infants may have an acute, self-limiting infection that
is noticeable. Children who acquire hepatitis C from their mother
have a rate of spontaneous clearance of the virus as high as 50
percent.
The natural progression of a hepatitis C infection in children
depends on how the child got the infection. In children who became
infected through a blood transfusion, the underlying disease—such
as hemophilia or cancer—may predict how hepatitis C progresses.
For example, in children who have thalassemia (an inherited
disorder where the body does not make enough hemoglobin and
therefore has fewer healthy red blood cells than normal), an iron
overload in their blood may cause liver disease (including cirrhosis).
When they become infected with hepatitis C, their disease may
progress faster.
The risk of serious liver injury appears to be lower for children
who have hepatitis C than for adults with that disease. Although
cirrhosis can occur in children, it happens less frequently than in
adults, and cirrhosis that requires a liver transplant is extremely rare.

HOW CAN WE PREVENT HEPATITIS C INFECTIONS?

Management after Accidental Exposure to Hepatitis C

Accidental exposure typically happens to healthcare workers, mainly
by needlestick injuries, and carries a less than 2 percent risk of
hepatitis C transmission. Dealing with this type of exposure is difficult
because of no clear guidelines and a lack of data.
There is no evidence to suggest that antiviral treatment
immediately after exposure (without any evidence of transmission) is
beneficial. Most physicians agree that it is best to continue
monitoring the exposed person by testing for hepatitis C RNA for
three to six months after exposure.
Approximately one-half of individuals exposed in this manner may
clear the virus spontaneously, especially if they develop symptoms.
Once the infection is confirmed with a PCR test, however, it is wise
to consider immediate antiviral therapy.

Prevention of Hepatitis C in Children

• Mother-to-infant transmission is the most common way for
children to become infected with hepatitis C in developed
 countries. More research is needed to identify factors that affect
transmission of the hepatitis C virus during pregnancy and
delivery and help develop effective ways to prevent
transmission.
• It is very important to identify infected children by screening
babies born to mothers who have hepatitis C.

Preventing hepatitis C infections in adolescents requires educating

them about high-risk behaviors, such as consuming alcohol and
injecting drugs.

TREATMENT OF HEPATITIS C

Hepatitis C can be cured—in other words, the person will not have
any more virus in their blood if the treatment is successful. There are
several medicines, called antivirals, available to treat hepatitis C that
fight the virus and help clear it permanently. All of the medicines that
are now in use are very effective (95–100 percent cure rates) in
curing hepatitis C infections, which can then help prevent liver
disease from getting worse.

Tests Done Before Starting Treatment

Before beginning treatment for hepatitis C, a doctor will do a number
of tests, including blood tests, an ultrasound of the liver, and
(perhaps) tests to understand the severity of scarring (fibrosis).

In the past, there were many different medicines to treat hepatitis C. They had
serious side effects, had to be injected, and had to be taken for a long time.
Because of more research, since 2014 new and improved medications have
been made. These new medicines are even more effective (more than 95
percent cure rates) at treating the virus and have much less serious side
effects.

One common test is to find out what genotype of the hepatitis C

virus a person has. Knowing this information can help in deciding
what the best medication is for the treatment, how much medicine
should be taken, and how long it should be used. This has become
less important, however, with the more effective treatments that are
currently available.
In addition, everyone with hepatitis C needs to be tested for
hepatitis B. If the person had a previous exposure to hepatitis B,
there is a very small chance of reactivating the hepatitis B virus
during hepatitis C treatment.

Most Commonly Used Medications

Several medicines are used to treat hepatitis C (table 5.2). The two
most common ones are:

1. Sofosbuvir/velpatasvir (Epclusa)
2. Glecaprevir/pibrentasvir (Mavyret)

Those who were not cured using these medications (less than 5
percent) could be treated with a three-drug combination of
sofosbuvir/velpatasvir/voxilaprevir (Vosevi) for 12 weeks, with an
expected cure rate of 97 percent.
All of these medicines are very effective at treating hepatitis C and
cure between 98 and 100 percent of the people infected by this
virus. The length of treatment varies from 8 to 12 weeks.
TABLE 5.2. Medicines to treat hepatitis C
Dose and how
Medicine long to take it Best for

Sofosbuvir/velpatasvir (Epclusa) 1 pill daily, • people with any genotype

taken for 12 • people older than 3 years
weeks old
• people who have an organ
transplant

Glecaprevir/pibrentasvir (Mavyret) 3 pills daily, • people with any genotype

taken for 8 • people older than 12 years
weeks old
• people who have an organ
transplant
• people who have kidney
 failure

Sofosbuvir/ledipasvir (Harvoni) 1 pill daily, • genotypes 1, 4, 5, 6

taken for 8–12 • people older than 3 years
weeks, old
depending on • people who have an organ
the amount of transplant
virus in the
blood and other
medicines the
person has
tried

Sofosbuvir/velpatasvir/voxilaprevir 1 pill daily, • adults who haven’t had

(Vosevi) taken for 12 success with other
weeks treatments

Note: Those with advanced (decompensated) cirrhosis should consult a liver

specialist before beginning any treatments for hepatitis C.

Interaction with Other Medications

Drug-drug interactions can occur, and there are some medicines that
should be avoided for optimal treatment results. Therefore, you must
definitely give your doctor a complete list of your medications,
including over-the-counter supplements. Common interactions with
hepatitis C medications are shown in tables 5.3 and 5.4.
TABLE 5.3. Medications to avoid during treatment with Harvoni, Epclusa, or Vosevi

Acid medications (acid is important for drug absorption):

• separate using antacids and taking acid medications by 4 hours
• H2-receptor blockers—use with caution at lower doses
• omeprazole—use with caution, and take no more than 20 mg

Anti-convulsants (medications to control seizures)—co-administration is not

recommended:
• carbamazepine
• phenytoin
• phenobarbital
• oxcarbazepine

Anti-mycobacterials (medications to treat tuberculosis)—co-administration is not

recommended:
• rifabutin
• rifampin
• rifapentine

Anti-cancer medication—not recommended:

• topotecan

Blood thinners:
• dabigatran etexilate—monitor when used with Vosevi

Heart medications:
• amiodarone should be avoided—could result in death
• digoxin—levels need to be monitored
• statins (lipid-lowering medications)—check with your doctor

Herbal supplements:
• St. John’s wort (Hypericum perforatum)—avoid

HIV medications (protease inhibitor)—check with your doctor about drug-drug

interactions:
• efavirenz, tipranavir/ritonavir—not recommended
• tenofovir—use with caution

Note: This is not a complete list. Check with your doctor or pharmacist before
starting these medicines.

TABLE 5.4. Medications to avoid during treatment with Mavyret

Acid medications:
• no restrictions

Anti-mycobacterials (medications to treat tuberculosis):

• rifampin—avoid

Anticonvulsants (medications to control seizures):

• carbamazepine—avoid

Blood thinners (check with your doctor or pharmacist):

• dabigatran etexilate may need a dose modification

Heart medications:
 • digoxin—levels need to be monitored
• statins (lipid-lowering medications)—check with your doctor

Herbal suppplements:
• St. John’s wort (Hypericum perforatum)—avoid

HIV medications (protease inhibitors)—check with your doctor about drug-drug

interactions:
• atazanavir—avoid
• darunavir, lopinavir, ritonavir, efavirenz—not recommended

Immunosuppressants:
• avoid in cyclosporine-based immunosuppression

Oral contraceptives:
• medication containing ethinyl estradiol—avoid

Note: This is not a complete list. Check with your doctor or pharmacist before
starting these medicines.

Common Side Effects

The hepatitis C medications in table 5.2 are very well tolerated, and
side effects are minimal (table 5.5). Most of these side effects are
very mild, and the majority of people do not experience any of them.
Less than 1 percent of those taking hepatitis C medicines
discontinue their treatment because of these side effects.
TABLE 5.5. Common side effects
Sofosbuvir/velpatasvir (Epclusa) Glecaprevir/pibrentasvir (Mavyret)

• Headache • Headache
• Tiredness • Tiredness
• Nausea • Nausea
• Lack of energy • Diarrhea
• Insomnia

Note: Side effects of sofosbuvir/ledipasvir (Harvoni) and

sofosbvir/velpatasvir/voxilaprevir (Vosevi) are similar to those of sofosburvir/
velpatasvir (Epclusa). Diarrhea may occur with Vosevi and Harvoni.
 Monitoring During and After Treatment
Your doctor will periodically see you and monitor your treatment
progress. Those with cirrhosis may require closer monitoring.
If, 12 weeks after the treatment is discontinued, a person has
undetectable levels of the hepatitis C virus in their blood, that person
is cured. The antibodies will stay in a person’s blood for the rest of
their life, but this does not mean the person has an active infection.

• A cured person can be reinfected with hepatitis C, so it’s

important to avoid behaviors that may be risky.

People who are cured of hepatitis C will see improvements in the

damage that had been done to their liver, such as scarring (fibrosis)
and cirrhosis. A cure will also lower their risk of developing liver
cancer. For people who have a lot of scarring and advanced
cirrhosis, it’s important to keep seeing their doctor regularly, both to
check on the progress of their liver disease and to look for signs of
possible cancer.

Treatment of Acute Hepatitis C

As previously mentioned, approximately 30 percent of the individuals
who have an acute hepatitis C infection will spontaneously clear the
virus and require no treatment. Spontaneous viral clearance rates of
44–67 percent have been reported in those who develop jaundice. In
contrast to treatments for chronic hepatitis C, there have been no
large clinical trials with newer medications to guide the treatment of
people who have an acute hepatitis C infection. Nevertheless, the
limited data available lead to the conclusion that, by receiving 8–12
weeks of treatment with the newer oral medications, 98–100 percent
of patients with acute hepatitis C could be cured.

• Between 10 and 20 percent of the people who have acute

hepatitis C develop symptoms, so acute hepatitis C can often be
overlooked.
• People who have symptoms are more likely to spontaneously
clear the virus, so they can wait to make a decision about
starting antiviral therapy for three months from the time when
 symptoms appear.
• An 8–12 week treatment with oral medications could cure almost
all patients with acute hepatitis C.

Treatment of Hepatitis C in Children

Not all medications approved for adults (see table 5.2) can be used
in children.

• The combination of sofosbuvir and velpatasvir (Epclusa) is

approved for children older than 3 years, for all genotypes.
• The combination of glecaprevir and pibrentasvir (Mavyret) is
approved for children older than 12 years, for all genotypes.
• The combination of sofosbuvir and ledipasvir (Harvoni) is
approved for children older than 3 years with genotypes 1, 4, 5,
and 6.

For children who are younger than 3 years old, the current strategy
is to defer treatment until they reach that age.

FURTHER READING
Hepatitis C. World Health Organization. https://www.who.int/news-room/fact-
sheets/detail/hepatitis-c/.
Hepatitis C. Centers for Disease Control and Prevention.
https://www.cdc.gov/hepatitis/hcv/index.htm.
Hepatitis C information center. American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-
liver/hepatitis-c/.
Hepatitis C. National Institute of Diabetes and Digestive and Kidney Diseases.
https://www.niddk.nih.gov/health-information/liver-disease/viral-
hepatitis/hepatitis-c/.
 CHAPTER 6

Alcohol and the Liver

Alcoholism is a worldwide problem. Estimates of the global burden of

alcoholism are shown below:

• 3.3 million deaths from alcoholism per year

• 5.9 percent of all deaths (7.6 percent male, 4.0 percent female)
• the third leading preventable cause of death in high-income
countries
• 5.1 percent of the global burden of disease is attributable to
alcohol-related diseases

FIGURE 6.1. Total alcohol per capita consumption (15+ years), in liters of pure
alcohol, in 2010. Source: World Health Organization

TOP FIVE RISK FACTORS FOR DISEASE, DISABILITY,

AND DEATH
Daily drinking and binge drinking are increasing worldwide. This is
seen in high-income and middle-income countries across the globe.
In addition to its direct impact on health, excessive alcohol
consumption has a negative impact at multiple levels, including
family life, disabilities, and traffic accidents.
Although the focus of this chapter is on liver disease, increased
alcohol consumption can cause damage to many other parts of the
body:

• Inflammation of the pancreas (pancreatitis)

• Depression
• Seizures
• Cancers of the mouth, throat, esophagus, colon, pancreas, liver,
and breast
• Intentional and unintentional injuries, including traffic accidents
• Heart disease
• Pregnancy complications (fetal alcohol syndrome, pre-term birth
complications)
• Pneumonia and tuberculosis

One of the liver’s main jobs is to break down toxins and remove
them from the body. Alcohol is one of those toxins. In general, if a
healthy person consumes a reasonable amount of alcohol, their liver
can get rid of the alcohol without it causing harm to their liver. A
reasonable (moderate) amount of alcohol for the average adult is:

• One drink per day for women

• Two drinks per day for men

The risk of alcoholic liver disease increases with increased

alcohol intake:

• An increased risk occurs when a person’s pure alcohol intake is

more than 1.1 fluid ounces (30 grams) per day
• In the United States, approximately 45 percent of all deaths from
liver disease are related to alcohol
 In terms of damage to the liver, the type of alcohol (beer, wine,
liquor) or its quality (cheap versus high-end) doesn’t make as much
of a difference as the amount of alcohol in the drink and how often a
person consumes alcohol. Many consider beer and wine to be less
toxic than whiskey, brandy, or rum, but this supposition is false. The
more a person drinks, and the more often they drink, the greater the
damage they do to their liver. The amount of alcohol in the beverage
is very important. One drink is roughly equal to 0.5 fluid ounces (14
grams) of pure alcohol (figure 6.2).
The safe amount of alcohol an individual could consume daily is
shown in table 6.1.

FIGURE 6.2. One drink = approximately 0.5 fluid ounces (14 grams) of pure alcohol

TABLE 6.1. How much alcohol is safe?

Type of person Amount
Healthy adult men maximum: 2 drinks a day

Healthy adult women maximum: 1 drink a day

People who have liver diseases none

People who had a liver transplant none

Note: One drink is defined as equal to the following:

beer: 12 fluid ounces (355 milliliters), or 1 can/bottle
wine: 5 fluid ounces (148 milliliters), or 1 glass
80-proof liquor: 1.5 fluid ounces (44 milliliters), or 1 cocktail or drink

THE EFFECTS OF ALCOHOL

On the Liver
When a person consumes alcohol, enzymes (alcohol
dehydrogenase) in the liver cells convert the alcohol to
acetaldehyde. Chronic drinking can create (induce) other enzymes
that add to this conversion. Acetaldehyde is then changed
(metabolized) to acetate in specialized subunits (the mitochondria)
within liver cells. This process can result in the formation of
molecules that are known as reactive oxygen species (ROS), which
can damage liver cells. Acetaldehyde, directly or through other
enzymes, can cause the liver to produce fatty acids, which then
accumulate in the liver over a period of time and create alcoholic
fatty liver. In the early stages of alcoholic liver disease, the only
abnormality seen in the liver is an increased amount of fat (fatty
liver).
Increases in acetaldehyde, acetate, ROS, and other chemicals
that are produced by excessive drinking may trigger a reaction in the
immune system, causing an inflammation of the liver. This stage is
called alcoholic hepatitis. This is a serious condition that may cause
a yellow discoloration of the eyes (jaundice), fatigue, and liver failure.
Alcoholic hepatitis may result in the onset of jaundice and liver
failure after years of alcoholism. Although women are prone to
alcohol-induced liver disease, alcoholic hepatitis is seen mostly in
middle-aged men. The usual symptoms of alcoholic hepatitis are
loss of appetite, jaundice, fever, pain in the upper right belly,
abdominal swelling, muscle weakness, or confusion. In many
people, this is a life-threatening condition. A doctor can easily
recognize this condition, based on blood tests and a physical
examination. A liver biopsy is rarely necessary. Using simple blood
tests (serum bilirubin and prothrombin time), the doctor can also
estimate the severity of this risk and decide on potential treatment
options (discussed later in this chapter).
Inflammation of the liver also activates the type of cells (stellate
cells) that cause collagen (scar tissue) to be formed in the liver. Too
much scar tissue leads to cirrhosis. If a liver biopsy is done for
people who show signs of alcoholic hepatitis, 50 percent of them will
have cirrhosis.

FIGURE 6.3. Alcoholic liver disease

Many factors determine whether a person is going to develop liver

disease. The most important element is the amount of alcohol
consumed. Other factors that increase a person’s risk of developing
liver disease are:

• Having a family history of alcoholic liver disease or other genetic

traits
• Being a woman
• Being overweight
• Being Asian, African American, or Hispanic
• Eating poorly
• Having other liver diseases

About 10–20 percent of the people who drink heavily will develop
liver disease. It is important to recognize that some people are
genetically susceptible to developing alcohol-induced liver disease,
but there are no easy ways or tests to identify such individuals.
Alcoholic liver disease covers a spectrum, starting with fatty liver
on one end and cirrhosis and cancer at the other end. The
progression is:

1. Alcoholic fatty liver

2. Alcoholic hepatitis
3. Alcoholic cirrhosis

The effects of these three stages of fatty liver disease are shown in
table 6.2.
Some people may start with alcoholic fatty liver disease, then
progress to alcoholic hepatitis, and end up with cirrhosis. But other
people may develop alcoholic hepatitis without having any
symptoms, or develop cirrhosis without going through the alcoholic
hepatitis stage.
TABLE 6.2. Stages of alcoholic liver diseases
Stage What happens

Alcoholic fatty liver drinking too much alcohol results in fat buildup in the
liver cells and damages the liver
the damage can be reversed when the person stops
drinking alcohol

Alcoholic hepatitis alcohol and chemical byproducts may trigger an

immune-system response, causing inflammation of the
liver; symptoms may appear acutely, but some people
may not have any symptoms
common symptoms are:
• fevers
• tiredness
• nausea and vomiting
• poor appetite
• discomfort in the upper right belly
• swelling of the abdomen
• memory problems and confusion
Stage What happens
Alcoholic cirrhosis scar tissue replaces healthy liver tissue, and the liver
becomes small and shrunken, which may cause:
• jaundice
• swelling of the abdomen
• memory problems and confusion
• bleeding from the stomach
• wasting away of muscles
• liver cancer

In People Who Have Liver Disease

For people who have any liver disease, particularly those who have
hepatitis C, drinking alcohol, even in moderate amounts, can have
damaging effects:

• Making the liver damage worse and causing more-serious

damage, including cirrhosis, to happen faster
• Making the hepatitis infection worse by increasing the amount of
the virus in the blood
• Increasing the risk of liver cancer

Alcoholism may prevent spontaneous clearance of the virus after

a hepatitis C infection, leading to chronic infection and liver disease.
Experimental studies show that alcohol increases the replication of
the hepatitis C virus. Most studies show increased hepatitis C RNA
levels in alcoholics, compared with non-alcoholics. Even a moderate
amount of alcohol (one or two drinks a day, or a total of seven drinks
a week) has a significant impact on hepatitis C RNA levels and the
liver’s progress toward cirrhosis. Overwhelming evidence suggests
that in the presence of hepatitis C, even small amounts of alcohol
may increase the progression of liver fibrosis and the development of
cirrhosis. These studies clearly suggest that for the liver, hepatitis C
and alcohol are a harmful combination. To prevent the rapid
development of liver disease and improve the cure rate, two of the
most important actions are to abstain from alcohol and get treatment
for hepatitis C.
 People who heavily drink alcohol and have a hepatitis C infection have a much
higher risk of developing cirrhosis and liver cancer.

On Other Liver Diseases

The effect of alcohol on other liver diseases is not well studied. In
many people with non-alcoholic fatty liver, drinking alcohol may
make their disease worse. This is also likely to be true for all other
liver diseases. Significant alcohol consumption also carries a serious
risk for the development of liver cancer.

People with any liver disease should avoid drinking alcohol regularly. Ideally,
they should abstain from alcohol.

PREVENTING ALCOHOLIC LIVER DISEASE

The best way to prevent alcoholic liver disease is not to drink alcohol
on a regular basis and not to exceed the recommended limits. Other
factors that may help reduce risks or complications are:

• Maintain a healthy weight—and lifestyle—with exercise

• Stop smoking, which will also reduce the probability of heart
disease and cancers
• Go to a doctor for routine checkups and get blood tests regularly
• Get the vaccines for hepatitis A and B

The most important factor in preventing alcoholic liver disease is

to minimize alcohol consumption, including binge drinking.

TREATMENT OF ALCOHOLIC LIVER DISEASE

Those with evidence of liver disease should avoid alcohol

completely. The only way to do this is to abruptly stop drinking
alcohol. A slow weaning process simply does not work. Some people
may need medications to reduce their alcohol withdrawal symptoms,
and almost all of them would benefit from alcohol rehabilitation.
Counseling could be done in an outpatient or in-patient setting.
Outpatient counseling could be either individual sessions or group
therapy. Unfortunately, the success rate of complete abstinence from
alcohol is less than 40 percent, even among those who have severe
liver disease. Nonetheless, the following factors will help improve
this success rate:

• Acknowledgment of the problem (most people are reluctant to

accept the fact that they are alcoholics)
• Willingness to seek help (most people believe they do not need
help)
• Management of underlying depression (this problem is often
undiagnosed)
• Good social and family support (many alcoholics have burnt their
bridges)
• Follow-ups with the doctors treating the condition (compliance is
usually poor)

Complete abstinence from alcohol is the only proven treatment for alcoholic
liver disease.

Alcoholic Hepatitis
Alcoholic hepatitis is a serious disease, with very high death rates,
especially in those who develop jaundice. Abstinence from alcohol is
a must. Other treatments for this condition are mostly supportive
ones:

• Good nutrition (multiple meals and snacks), especially foods

high in protein (at least 1.5 grams/kilogram, or 0.75
grams/pound) and high in calories (35–40 kilocalories/kilogram,
or 18–20 kilocalories/pound)
• Nutritional supplements
Vitamin supplements—B1 (thiamine), B6 (pyridoxine), and
B9 (folate)
 Mineral supplements—phosphate and magnesium
• Routine checks for infection
• Tests using cultures of body fluids and sputum (mucus, or
phlegm, from the lungs) if an infection suspected

For those with severe alcoholic hepatitis, a trial treatment with

steroids (40 mg of prednisolone daily, for 1 week) is recommended.
This treatment should be discontinued after one week if the
response is unsatisfactory. (Your doctor can assess the result by
blood tests, using a scoring system called Lille scores.) If there is an
improvement, treatment should be continued for four weeks.
Based on the current evidence, the optimal treatment of alcoholic
hepatitis includes:

1. Supportive care and abstinence from alcohol for people with

mild to moderate hepatitis
2. Supportive care, abstinence from alcohol, and a trial treatment
with prednisolone for people with severe alcoholic hepatitis
3. A liver transplant as an option (although very controversial) if
the above treatments fail

Alcoholic Cirrhosis
Many people will already have cirrhosis when they are diagnosed
with alcoholic liver disease. Approximately one in four individuals (25
percent) will develop a complication of cirrhosis within a year after
the diagnosis, and one in two (50 percent) within five years. The risk
is higher in those who do not abstain from alcohol. If a person
continues to drink after developing a complication, 7 in 10 (70
percent) will die within five years. Those with cirrhosis will need
periodic screening for complications from this condition, including
liver cancer.

Combating Alcoholism at the Societal Level

A multipronged approach is needed to combat alcoholism at the
societal level, both from the community and at all legislative levels.
Awareness and early diagnosis are important. Once diagnosed,
there should be multiple kinds of interventions, including education
and the treatment of underlying disorders, such as depression.
Legislation and the enforcement of various rules and laws
regarding alcohol have also been shown to reduce alcoholism in
many countries around the world. These include:

• Greater taxation (to substantially increase the cost of alcoholic

drinks)
• Effective enforcement of “no driving under the influence” (DUI)
laws
• Control of opening times for liquor stores and bars
• A ban on alcohol-related advertisements
• Education for children on responsible drinking
FURTHER READING
Alcohol-related liver disease. American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-
liver/alcohol-related-liver-disease/.
Crabb DW et al. Diagnosis and treatment of alcohol-associated liver diseases:
2019 practice guidance from the American Association for the Study of Liver
Diseases. Hepatology 2020;71:306–333. https://doi.org/10.1002/hep.30866/.
European Association for the Study of the Liver. EASL clinical practice guidelines:
Management of alcohol-related liver disease. J Hepatol. 2018 Jul;69(1):154–
181. https://doi.org/10.1016/j.jhep.2018.03.018/. Epub 2018 Apr 5.
Treatment of alcohol problems: Finding and getting help. National Institute on
Alcohol Abuse and Alcoholism.
https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/treatment-
alcohol-problems-finding-and-getting-help/.
 CHAPTER 7

Non-Alcoholic Fatty Liver

Disease

Fat can accumulate in the liver for many reasons, but two common
causes of fatty liver are alcoholism and metabolic syndrome (a set of
conditions that occur together, including increased blood pressure,
high blood sugar, excess body fat around the waist, and abnormal
cholesterol or triglyceride levels). Other causes are shown below.

Common causes of fatty liver:

• Alcohol
• Non-alcoholic fatty liver disease (NAFLD)
Other causes of fatty liver:
• Hepatitis C
• Wilson disease
• Lipodystrophy (loss of adipose, or fat, tissue)
• Abetalipoproteinemia (a very rare genetic disorder that causes
interference in the normal intestinal absorption of fats—including fat-
soluble vitamins—and in fat mobilization by the liver)
• Starvation
• Total parenteral nutrition (intravenous feeding)
• Medications
• Amiodarone
• Methotrexate
• Tamoxifen
• Steroids

Fatty liver is usually diagnosed by liver imaging (using ultrasound,

a CT scan, or an MRI). FibroScan (a specialized ultrasound) and MR
elastography (an MRI-based technique) can diagnose as well as
quantify the amount of fat in the liver.
By definition, a fatty liver contains more than 5 percent fat. Based
on the amount of fat in the liver, the severity of the condition could be
graded as follows.

Grade Amount of Fat

0 < 5%
5% to 33%
1
34% to 66%
2 ≥ 67%
3

NON-ALCOHOLIC FATTY LIVER DISEASE

The focus of this chapter is on non-alcoholic fatty liver disease

(NAFLD)—its causes, associated conditions, natural progression,
and long-term outcomes.

How Common Is NAFLD?

This disease is very common worldwide and is seen in one out of
four adults. Approximately 70 million Americans are thought to have
NAFLD. There are geographical differences in how widespread
NAFLD is:

• Highest in the Middle East (32 percent) and South America (30
percent)
• Midrange in North America and Europe (24 percent) and in Asia
(27 percent)
• Lowest in Africa (13.5 percent)

NAFLD is more commonly seen in men and older people. It is less

common in blacks, compared with whites and Hispanics. The
amount of people with NAFLD has been greater in high-income
countries, but this number is rapidly shifting, and many middle-
income countries are now catching up.
 NAFLD is very common in diabetics and in people with high
cholesterol and triglyceride levels. NAFLD is seen in 50 to 70
percent of those with diabetes, and 50 percent of those who go to
clinics for disorders from lipids.
NAFLD is seen in children, too, and it is becoming an increasing
problem with the obesity epidemic happening all over the world.

Who Develops Fatty Liver?

Lean people rarely have fatty liver, but they may develop this
condition if they have pre-diabetes or diabetes. People with fatty liver
have one or more of the following conditions:

1. Obesity
2. High cholesterol or triglyceride levels
3. Diabetes or pre-diabetes
4. Hypertension
5. Metabolic syndrome

Metabolic syndrome is diagnosed if three or more of the following five criteria

are met:
1. Waist circumference over 40 inches (102 cm) in men or 35 inches (88
cm) in women
2. Blood pressure over 130/85 mmHg or taking medications for
hypertension
3. Fasting triglyceride level over 150 mg/dl
4. Fasting HDL cholesterol level less than 40 mg/dl in men or less than 50
mg/dl in women
5. Fasting blood sugar over 100 mg/dl or taking medications for diabetes

Other Conditions Associated with NAFLD

There are a few other clinical conditions that are associated with
NAFLD:

• Polycystic ovary syndrome, or PCOS (a hormone disorder)

• Other endocrine disorders:
Hypothyroidism (an underactive thyroid)
 Hypogonadism (low levels of testosterone in men)
Hypopituitarism (an underactive pituitary gland)
• Sleep apnea
• Whipple surgery (removal of a part of the pancreas, usually
because of pancreatic cancer)

Why Does Fat Accumulate in the Liver?

Liver is the processing center for fat (fatty acids, to be more precise).
The accumulation of fat in the liver can result from an increased
delivery of fatty acid or a decrease in its disposal. Fatty acids arrive
in the liver from three sources: (1) stored fat (usually from the central
part of abdomen, particularly in obese individuals), (2) daily fat
intake, as well as fatty acids produced by bacterial flora in the
digestive tract, (3) fatty acid produced in the liver of diabetics or pre-
diabetics, due to insulin resistance. Of these three sources, the first
and second contribute up to 75 percent of the fatty acids entering the
liver, with more than two-thirds coming from stored fat under the skin
and inside the abdomen (visceral fat).
Liver processes fat by burning it (oxidizing it via mitochondria
inside the liver cells) or by exporting it as very low-density
lipoproteins (complex particles that transport cholesterol and
triglycerides). If the influx of fatty acids is greater than the liver’s
ability to burn or export them, the liver stores the extra fatty acids as
lipid droplets (triglycerides) in the liver. Over a period of time, stored
lipid droplets increase the size of the liver. This expansion
sometimes causes discomfort in the upper right belly or a mild
elevation in liver enzymes. But the majority of people with fatty liver
will have no symptoms or no liver enzyme abnormalities. Fatty liver
is usually identified incidentally, through an ultrasound done for other
purposes.

Progression of NAFLD
Not all of the people with NAFLD will have progressive liver disease.
About 5–10 percent develop an inflammation of liver, called non-
alcoholic steatohepatitis (NASH). NASH is usually a progressive
condition, resulting in scarring of the liver (fibrosis) and cirrhosis.
Some individuals may develop complications of cirrhosis, including
liver cancer.
For people with NASH, it may take 20–30 years for this disease to
progress to cirrhosis. This time period may be even longer in those
who have fatty liver without much inflammation. It is reassuring that
only a minority of people will develop progressive liver disease.
Only a small number of individuals with fatty liver will develop
progressive liver disease, although—because of its greater
prevalence worldwide—the death rate for people with this condition
is expected to go up significantly (three to four times higher) across
the globe in the next decade.

FIGURE 7.1. The NAFLD spectrum

Why Does the Disease Progress in Some and Not in Others?

There are no good explanations for why some people develop NASH
and others do not. Similarly, we do not understand why some people
end up with cirrhosis, while NASH has an indolent course in others.
Many speculations exist, including genetic factors; environmental
factors; co-morbid risk factors (occurring at the same time), such as
alcoholism or diabetes; and, perhaps, even characteristics of
intestinal bacterial flora (the microbiome). Although our
understanding of NASH is improving, we are not at a stage where
we can predict the progression of this disease. Nevertheless, those
with NASH plus type 2 diabetes seem to have a greater chance for
the disease to get worse.

Does Fatty Liver Affect Life Expectancy?

People with fatty liver appear to be at greater risk of dying from heart
disease, cancers, or liver disease. Having fatty liver makes a person
5 times more likely to die from heart disease, and 15 times more
likely to die prematurely from all causes, when compared with those
without fatty liver disease. Fatty liver could reduce a person’s life
expectancy by as much as five to eight years. Therefore, it is
important to effectively manage the various conditions involved in
metabolic syndrome, which otherwise could lead to the development
of fatty liver.
Fatty liver alone does not increase the risk of death from liver
disease, but people with NASH have a greater risk of dying from
cirrhosis (12 times higher) or liver cancer (5 times higher), compared
with those without fatty liver.

HOW IS NASH DIAGNOSED?

Fatty liver disease can be diagnosed with imaging tests, and NASH
is suspected when the liver enzymes are significantly elevated in the
presence of fatty liver. A liver biopsy is needed to confirm the
diagnosis, rule out other causes of liver disease, and help determine
the severity of liver scarring (fibrosis).
Since the amount of fibrosis could be assessed non-invasively (by
FibroScan, MR elastography, or a combination of blood tests and
imaging) with 80–90 percent accuracy, a liver biopsy should only be
performed under the following conditions:

1. When a diagnosis is uncertain: there are no known risk factors,

but fatty liver and/or abnormal levels of liver enzymes are
present.
2. When there is more than one potential cause for liver disease:
 for instance, if tests show elevated iron saturation or the
presence of auto-antibodies.
3. To determine the severity of fibrosis in those who are likely to
have advanced liver disease: useful for predictive purposes,
clinical trials, or a choice of other therapeutic options

MANAGEMENT OF NAFLD

There are no approved medications for fatty liver or NASH. The most
important aspect of treatment for these conditions is optimal
management of the affected person’s weight and any co-morbid
conditions, such as diabetes, hyperlipidemia (high cholesterol), and
hypertension. Those who have risk factors for coronary artery
disease may also benefit from additional preventive actions,
including undergoing tests to screen for occult (not immediately
apparent) diseases and no longer smoking (if applicable). Alcohol
consumption should be reduced to a minimum (not more than one
drink per day, and, ideally, only infrequently).
Lifestyle modification (discussed in the next section) is the
mainstay of a treatment strategy for NAFLD. Currently there are no
approved medications for this condition, but many clinical trials are in
progress for dealing with fatty liver, NASH, and cirrhosis. Another
option that could be considered is bariatric (weight-loss) surgery, as
long as that individual has multiple other conditions that may benefit
from this type of surgery. A liver transplant is a possibility for people
with advanced cirrhosis and other complications.

Lifestyle Modification
This includes diet control and regular exercise. According to the
World Health Organization, exercise should include 45 minutes of
vigorous exercise (enough to raise your heart rate), four to five days
per week. The important aspect of diet control is to reduce your
intake of calories (discussed in the next section). Unfortunately, less
than 10 percent of adults follow this lifestyle modification.
An improvement in various disease conditions—fatty liver, liver
inflammation, and liver scarring—is dependent on the degree of your
weight loss.
 Lifestyle modification is also an essential part of a management
strategy to reduce other metabolic complications.

Liver biopsy improvements, based on weight loss:

• More than 3–5 percent reduces fatty liver (steatosis)
• Over 7–9 percent reduces inflammation
• At 10 percent or more, reduces scarring (fibrosis)

Dietary Advice for Those with Fatty Liver

The two most common risk factors for NAFLD are excess caloric
intake and reduced physical activity. Consequently, lifestyle
modification is critical in managing fatty liver disease, as well as
preventing its progression to NASH and cirrhosis.
The basic strategy is to lose weight. Both dieting and exercise are
equally important to promote weight loss and improve (reduce)
insulin resistance. The goal is to lose 10 percent of your baseline
weight. For example, if your initial weight is 200 pounds, you should
try to lose 20 pounds. The normal recommendation is to lose no
more than one to two pounds per week for the first six months. In
people with fatty liver who are modestly obese, vigorous exercise
provides benefits, even when there is no weight loss, possibly
because stored excess fat may be replaced with lean muscle mass.
There are many other ways to achieve weight loss. A general
approach is to decrease the amount of calories in your meals by
making different food choices. A reasonable diet should be high in
fiber; low in saturated fats; and, preferably, contain a combination of
plant and animal proteins. Most importantly, this diet should be
followed on a long-term basis. In other words, you should:

1. Choose more foods with a higher fiber and water content, such
as fruits and vegetables
2. Consume fewer fatty and sugary foods
3. Reduce the portion size, which is critical

Excess calories could come from many sources, but added

sugars, especially in sweetened beverages, are a problem for both
adults and children throughout the world. People who consume
sugary beverages, ice cream, and other sweets tend to gain weight
easily, as all of these items contain easily absorbable sugars. While
fructose (a type of sugar) is harmful in sweetened beverages,
fructose in fresh fruit may have a beneficial effect. Another source of
excess calories is a diet rich in saturated fat and cholesterol. These
elements may play a major role in hardening of the blood vessels,
and heart attacks are a leading cause of death in people with
NAFLD. Saturated fats are present in animal-based foods, including
meat, dairy products, and eggs, as well as in palm and coconut oils.
While saturated fats are harmful, omega-3 fatty acids may have
protective benefits.
A common and controversial topic is whether the kinds of food
you eat—and the proportion of carbohydrates, protein, and fat in that
food—make a real difference. There are different theories and
speculations, but no consensus. It is generally agreed that
processed carbohydrates from refined flours are more harmful than
carbohydrates derived from unrefined plant-based foods like
oatmeal, sweet potatoes, and lentils. Similarly, unsaturated fats from
nuts, seeds, and fish rich in omega-3 fatty acids are better than
saturated fats from meat, butter, cheese, and eggs.
There is evidence to suggest that people who eat more whole
grains have a lower risk of cardiovascular disease, obesity
(especially central-body obesity), and diabetes. A diet rich in whole
grains may also reduce NAFLD. Potential explanations for this
include a lowered caloric intake and, possibly, a modification in gut
bacteria (the latter has been implicated in causing NAFLD). The
ability to help control a person’s blood-sugar level with different
foods, especially with an oat-based diet, has been shown to be
beneficial in reducing obesity and abdominal fat, and in improving
lipid profiles (measurements of the healthy and unhealthy fats in the
blood).
A Mediterranean-type diet is less likely to cause insulin resistance
and NAFLD. This type of diet is typically low in saturated fats and
animal protein, and high in monounsaturated fatty acids (for
example, olive oil), with an adequate balance between omega-3 and
omega-6 fatty acids. It is mostly a plant-based diet, with lots of
vegetables, fruits, legumes (such as peas and beans), whole grains,
nuts, and seeds. A Mediterranean diet helps prevent coronary artery
disease and thus provides an additional benefit for people with
NAFLD.

Dietary Supplements
In a clinical trial for people with NASH, vitamin E, at a dose of 800 IU
per day, was shown to decrease fat in the liver. Higher doses of
vitamin E, however, may increase the risk of prostate cancer and
perhaps heighten the likelihood of dying for people with heart
diseases. Vitamin E may also interact with other medications.
Therefore, lower doses of vitamin E (200–400 IU) are preferable,
although the overall benefit of lower doses is unproven. Vitamin E
does not improve scar tissue in the liver and is only recommended
for adults with NASH who do not have diabetes or cirrhosis.

Summary of Dietary Recommendations

Plant-based foods—such as vegetables, fruits, legumes, whole
grains, nuts, and seeds—are healthier than foods with refined grains
and added sugars.

• Have the bulk of your diet come from plant-based foods

• Plant-based diets may also reduce cholesterol levels and,
theoretically, polyphenols (organic compounds) from plant-based
foods may reduce oxidative stress (a chemical imbalance in the
body), inflammation, and insulin resistance
• Plant-based diets are beneficial because they are high in fiber
and contain fewer refined sugars
• Limit (as much as possible) the consumption of added sugars
from processed foods and sweetened beverages
• Decrease the amount of saturated fats and transfats in the foods
you eat, and increase your amount of omega-3 fatty acids
• Reduce the quantity of fast foods, bakery goods, and sweets in
your diet.
• Exercise for 45 minutes a day, four to five days a week
• Reduce your weight by at least 10 percent from how much you
 weighed at the time NAFLD was diagnosed
• Consider bariatric surgery in the presence of morbid obesity (a
body mass index greater than 40) and other conditions, such as
high blood pressure, diabetes, sleep apnea, and the like

MEDICATIONS

Only a small number of individuals with NAFLD will develop

progressive liver disease. Approximately 25 percent of the people
with NAFLD who have liver inflammation (NASH) at the time of their
diagnosis may also have advanced scarring of their liver. Advanced
scarring is associated with an increased risk of death. Based on
prediction models, the number of people with NASH is expected to
increase by more than 50 percent in the United States and
elsewhere by 2030. The prevalence of decompensated cirrhosis
(complications from a previously stable liver condition) and cancer
related to NAFLD is also expected to increase globally.
Currently, the US Food and Drug Administration (FDA) has not
approved any treatment options to improve scarring (fibrosis) caused
by NAFLD. A number of compounds targeting multiple pathways
involved in the progression of NAFLD are currently in different
phases of clinical trials. Many of these medications that showed
promise in the early stages of such trials were found to be ineffective
in phase-3 trials.
Use of a combination of drugs is currently being explored in
multiple ongoing studies. Developing a combination therapeutic
strategy to tackle NASH ideally should involve a drug that targets the
metabolic components that cause fatty liver, as well as other agents
that reduce inflammation and scarring. One major challenge in the
treatment trials is identifying reliable biomarkers—without needing
multiple liver biopsies—to measure improvement in the amount of
scarring, within a defined time period, in a disease with a long
natural history.
TABLE 7.1. Current status of pharmacotherapy on liver scarring
No proven benefit Possible benefit Probable benefit
vitamin E pentoxifylline obeticholic acid
metformin pioglitazone
ursodeoxycholic acid cenicriviroc
simtuzumab elafibranor
selonsertib liraglutide
emricasan

Until we identify an effective medication or a combination of

medications, the mainstay in the treatment of fatty liver is weight loss
through moderate-intensity exercise, along with a low-calorie diet.
Bariatric surgery is an option for obese patients who do not respond
well to traditional lifestyle modifications. A critical need is to develop
effective medications to improve or slow down scarring of the liver,
given the magnitude of its clinical implications.

• Fatty liver (NAFLD) is seen in one in four adults in the United States.
• NASH is less common, but it is a progressive disease.
• Deaths in people with NAFLD are mostly from cardiovascular events, cancer,
and liver disease, in that order.
• There are no FDA-approved medications for NAFLD, but clinical trials are in
progress.
• Bariatric surgery is an option for people whose lifestyle modifications fail.
• For individuals with liver cancer and cirrhosis with complications, a liver
transplant is an option.

FURTHER READING
Nonalcoholic fatty liver disease (NAFLD). American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/non-
alcoholic-fatty-liver-disease/.
Jennison E et al. Diagnosis and management of non-alcoholic fatty liver disease.
Postgrad Med J. 2019 Jun;95(1124):314–322.
https://doi.org/10.1136/postgradmedj-2018-136316/. Epub 2019 May 13.
Hazlehurst JM et al. Non-alcoholic fatty liver disease and diabetes. Metabolism
2016;65:1096–1108. https://doi.org/10.1016/j.metabol.2016.01.001/. Epub 2016
Jan 11.
Worm N. Beyond body weight-loss: Dietary strategies targeting intrahepatic fat in
NAFLD. Nutrients. 2020 May 6;12(5):1316.
 https://doi.org/10.3390/nu12051316/.
Koeckerling D et al. Fighting liver fat. Endocr Connect. 2020 Jul;9(7): R173–R186.
https://doi.org/10.1530/EC-20-0174/.
Neuberger J. Follow-up of liver transplant recipients. Best Pract Res Clin
Gastroenterol. 2020 Jun–Aug;46–47:101682.
https://doi.org/10.1016/j.bpg.2020.101682/. Epub 2020 Sep 11.
 CHAPTER 8

Other Causes of Liver Diseases

Although viral hepatitis (hepatitis C and hepatitis B), excess alcohol

consumption, and metabolic syndrome from non-alcoholic fatty liver
disease are the most common causes of chronic liver diseases that
result in cirrhosis, there are many other causes. These will be
discussed very briefly in this chapter.

There are a number of other causes of liver diseases, including:

• Autoimmune liver diseases
Autoimmune hepatitis (AIH)
Primary biliary cholangitis (PBC)
Primary sclerosing cholangitis (PSC)
Overlap syndrome (a combination of more than one type of
autoimmune disease)
• Genetic disorders
Hemochromatosis
Wilson disease
Alpha-1 antitrypsin deficiency
• Drug-induced liver injuries (DILIs)
Acute (any drug could cause it)
Chronic (only common drugs are listed here)
Amiodarone
Methotrexate
Minocycline
Nitrofurantoin

AUTOIMMUNE HEPATITIS (AIH)

People with autoimmune hepatitis have elevated levels of liver

enzymes (mostly AST and ALT). This condition is predominantly
seen in middle-aged women, but it could develop at any age and in
both sexes. The common symptoms are fatigue, joint pain, loss of
appetite, and (in severe cases) yellow discoloration of the eyes
(jaundice). Those with autoimmune hepatitis may also have other
autoimmune conditions, such as thyroid disorders, or have a family
history of other autoimmune diseases. AIH can develop suddenly or
occur over a lengthy period of time. Also, a person’s liver enzyme
elevations could be intermittent. Rarely, AIH can lead to liver failure
over a short period of time.
AIH is often suspected when there are no other obvious causes of
liver diseases. Blood tests usually show the presence of auto-
antibodies—such as anti-smooth muscle antibodies (ASMA), anti-
nuclear antibodies (ANA), or, in young people, anti–liver-kidney
microsomal antibodies (anti-LKM). Autoimmune hepatitis could be
subtyped (types 1 to 3), based on the presence of these antibodies.
In addition, immunoglobulins (a type of protein) may also be elevated
in the blood. It is important to note, however, that false positive
antibodies are common in the presence of viral hepatitis or non-
alcoholic fatty liver disease, and sometimes they are even seen in
the absence of any disease. Some medications, such as minocycline
or nitrofurantoin, can induce autoimmune-like hepatitis.
If autoimmune hepatitis is suspected, you should consult a liver
specialist, since this is a lifelong disease. Therefore, it is important to
have a firm diagnosis before initiating treatment. Most liver
specialists could make a diagnosis of autoimmune hepatitis based
on blood tests and a liver biopsy. With borderline findings from these
procedures, however, a specialist may use previously published
criteria (table 8.1).
TABLE 8.1. Simplified criteria to make a diagnosis of autoimmune hepatitis (AIH)
Criteria Points

IgG > 16 g /L 1

IgG > 18 g /L 2

ANA, ASMA, or anti-LKM > 1:40 1

ANA, ASMA, or anti-LKM > 1:80 or SLA/LP* positive 2

Histology compatible with AIH 1

Histology typical of AIH 2

Absence of viral hepatitis 2

Note: If the score is more than 5, the condition is probably autoimmune hepatitis. If
the score is more than 6, the condition is definitely autoimmune hepatitis.
*SLA/LP = soluble liver antigen / liver pancreas

Treatment
The treatment for autoimmune hepatitis is very effective, and more
than 90 percent of the people with this condition will go into
remission by taking steroids (prednisone or prednisolone). Liver
enzymes will return to normal when the disease is in remission. To
reduce the side effects of steroids, these drugs are often combined
with another medication, called azathioprine. The purpose of the
treatment for AIH is to suppress the immune system and thereby
reduce liver damage caused by an overactive immune system. In
most people, the disease could be controlled with doses of
prednisone (less than 10 mg daily) and azathioprine (100 mg daily).
Those who do not tolerate or respond to azathioprine have other
options. People who have significant side effects from prednisone
could use a different type of steroid called budesonide (6–9 mg daily)
to reduce the side effects of prednisone.
The failure rate of an azathioprine and prednisone combination is
less than 10 percent. For those who do not tolerate or respond to
azathioprine, AIH could be managed with other medications, such as
mycophenolate mofetil (MMF), tacrolimus, or cyclosporine. MMF is
the best studied second-line treatment for autoimmune hepatitis, but
it carries the potential risk of birth defects and should be used
cautiously in women of childbearing age. Tacrolimus (commonly
prescribed after an organ transplant) is another second-line option.
The treatment for AIH is usually lifelong for 70–80 percent of the
people with this disease. The prednisone dose is minimized or
eliminated for many people with AIH within three years. The usual
practice is to also attempt to wean a person off azathioprine after
three years. This could be done if their levels of liver enzymes and
immunoglobulins are normal for three years, or, preferably, if a liver
biopsy does not show any ongoing inflammation of the liver. In 20–
30 percent of people with AIH, their liver enzymes will remain
normal, but 70–80 percent of these individuals will relapse, so their
treatment will need to be restarted. Many liver specialists may once
more attempt to wean patients off the medications after another
three years of treatment. If this fails, the treatment is continued for
life.

Prognosis
The prognosis for individuals with autoimmune hepatitis is excellent.
The majority will have a normal life expectancy and an excellent
quality of life, but they will need lifelong follow-ups, since the disease
may relapse, even during treatment. Those who are on a long-term
treatment plan with azathioprine may need periodic skin
examinations (for skin cancer) and should follow common, age-
appropriate forms of surveillance for breast, colon, and prostate
cancer. Individuals who are on steroids should have periodic bone
density measurements (to check for bone thinning).
Very rarely, people who are diagnosed with advanced cirrhosis, or
those with severe autoimmune hepatitis and liver failure, may need a
liver transplant. The outcomes of liver transplants are excellent.

PRIMARY BILIARY CHOLANGITIS (PBC)

Primary biliary cholangitis is a rare disease. Approximately 95

percent of the cases of PBC are seen in middle-aged women. Those
with this condition are mostly diagnosed during an investigation of
elevated liver enzyme levels found on routine blood tests. People
with PBC predominantly have elevated ALP levels, with relatively
normal or mildly elevated AST and ALT levels.
When symptoms are present, the most common one is itching.
Other symptoms may include fatigue and joint pain. Like people with
AIH, other autoimmune disorders are common in individuals who
have PBC or have family members with this condition.
The characteristic blood test abnormality in diagnosing PBC is the
presence of anti-mitochondrial antibodies (AMA), which are seen in
up to 95 percent of people who have PBC. Immunoglobulins,
especially IgM, may be elevated. A diagnosis of PBC can be made if
two out of three of the following criteria are met:

1. An elevated alkaline phosphatase (ALP) level

2. A positive anti-mitochondrial antibody (AMA) test
3. Characteristic liver biopsy findings, showing inflammation of
tiny bile ducts

A liver biopsy is not essential for a firm diagnosis of PBC. The

procedure is often done, however, to determine the severity of
scarring (fibrosis) or to confirm suspected PBC when the diagnosis is
in doubt. About 5 percent of the people with this condition may not
have AMA in their blood. For those individuals, a diagnosis is made
on the basis of a liver biopsy.

Treatment
Progress has been made recently in the management of PBC.
Previously, PBC was considered to be a progressive liver disease,
but our understanding of the disease’s progression has now
improved. Although there is no cure for this condition, it could be
controlled in 60–70 percent of the people with PBC, either with
ursodeoxycholic acid (UDCA, or ursodiol) alone, or in combination
with obeticholic acid (OCA) or fenofibrate. The goal of this treatment
is to normalize the ALP level, or at least bring it down to less than
1.6 times the upper limit of the normal range. When this target blood
level is reached, the disease does not appear to progress further, or
to only do so very slowly.
The treatment for PBC is lifelong. Ursodeoxycholic acid has
minimal side effects. Some individuals may experience abdominal
discomfort, and this could be managed in most people by adjusting
the dose. Obeticholic acid is expensive, and up to 20 percent of
those taking this drug may experience itching as a side effect.

Prognosis
People with advanced cirrhosis that is secondary to PBC need to be
monitored for complications of hypertension in the portal veins
(varices) and liver cancer. A bone density test is important,
especially since the disease is predominantly seen in post-
menopausal women. If jaundice is present, affected individuals
should take fat-soluble vitamin supplements. A liver transplant can
cure those with PBC and other complications. Post–liver transplant
recurrences of PBC are very uncommon, and survival after a
transplant is excellent.

PRIMARY SCLEROSING CHOLANGITIS (PSC)

Primary sclerosing cholangitis (PSC) is a rare condition, seen mostly

in young to middle-aged men. This disease is caused by
inflammation of the large and medium-sized bile ducts. In a few
cases it only involves the small bile ducts. Just as in PBC, the
predominant blood test abnormality in PSC is elevated levels of ALP.
About 80 percent of the people with PSC will have a history of either
ulcerative colitis (an inflammatory colon disease) or Crohn’s disease
(an inflammatory disease of the small and large intestines). A
diagnosis of PSC is made on the basis of cholangiography, used to
examine the bile ducts: either by magnetic resonance
cholangiography, or MRC (a special type of MRI), or by endoscopic
retrograde cholangiography, or ERC (using X-rays and a long,
flexible, lighted tube called an endoscope). Although auto-antibodies
are seen in blood tests of people with PSC, these auto-antibodies
are not useful in diagnosing the disease. PSC typically has a
“beaded appearance”—irregular narrowing and widening (dilatation)
at multiple areas in the bile ducts.
Usually, PSC is suspected if routine blood tests show an elevated
ALP level in a person with a history of ulcerative colitis or Crohn’s
disease. About 10–15 percent of those with PSC may have
intermittent pain in their upper right belly, with or without a fever.
Itching is another symptom associated with PSC.

Treatment
There is no effective treatment for PSC. Ursodeoxycholic acid,
although frequently prescribed, does not appear to change the
progression of the disease. Sometimes the bile ducts may be
clogged by inflammatory strictures (narrowings), caused by scar
tissue. These strictures could be dilated with a balloon, guided by an
endoscope, during ERC. This could relieve jaundice or itching and
may delay the disease’s progression.

Prognosis
In the majority of people with primary sclerosing cholangitis, the
disease will progress slowly, and many individuals may require a
liver transplant within 20 years after being diagnosed with PSC. One
of the serious complications of PSC is cancer of the bile duct or
gallbladder. People with PSC should be monitored for these cancers,
which may occur in 10–15 percent of the individuals who are
affected by PSC during their lifetime. Those with ulcerative colitis or
Crohn’s disease also need to be monitored for colon cancer.

OVERLAP SYNDROME

Sometimes people with predominant features of autoimmune

hepatitis (AIH), primary biliary cholangitis (PBC), or primary
sclerosing cholangitis (PSC) may have “overlapping” biochemical,
immunological, histological (microscopic), or cholangiographic
components of more than one disease. This condition is called
overlap syndrome, and it is seen in up to 10 percent of the people
with AIH. The main characteristics of autoimmune hepatitis, primary
biliary cholangitis, or primary sclerosing cholangitis are shown in
table 8.2.
Liver specialists suspect overlap syndrome when the clinical or
biochemical abnormalities are not typical of one disease alone, or
when the treatment response is suboptimal. Although AIH, PBC, and
PSC may overlap with each other, the overlap of PBC with AIH is
more meaningful, since AIH is easily controllable with medications.
An overlap between PSC and AIH is often seen in children.
A PBC-AIH overlap can be difficult to diagnose at times. Various
criteria for determining this overlap have been proposed. One such
set of standards is known as the Paris criteria (table 8.3).
PBC-AIH overlap syndrome is suspected when at least two of the
three accepted criteria for PBC, along with an interface with hepatitis
plus one of the two other features of AIH, are present. If an overlap
syndrome between PBC and AIH is suspected, the initial treatment is
based on which disease predominates. Depending on the response,
the treatment for the other condition may be added. Many people
may end up taking a combination of azathioprine and UDCA.
An overlap syndrome between PSC and AIH is suspected (mostly
in children and young adults) when the following components are
present:

• Clinical, biochemical, and histologic features of AIH, with

atypically elevated ALP levels
• A negative anti-mitochondrial antibody (AMA) test
• Cholangiographic features of PSC seen during an ERC or
MRCP procedure
• Failure to normalize liver enzymes with immunosuppression (the
use of drugs to suppress the immune system)

Main characteristics of autoimmune hepatitis, primary biliary cholangitis,

TABLE 8.2.
and primary sclerosing cholangitis

Autoimmune Hepatitis (AIH)

ASMA (~80%) • interface with hepatitis; • all ages—bimodal peak

ANA (~80%) lymphoplasmacytic • women 4:1
(lymphocyte and plasma) • acute or chronic
anti-LKM 1 (~5%)
infiltrates • responds well to
anti-SLA/LP* (~20%)
immunosuppression
IgG elevated

Primary Biliary Cholangitis (PBC)

AMA (90%) • florid ductal (bile duct) • middle-aged people

ANA (20% to 50%) injury; lymphocytic • women 9:1
infiltrates • florid ductal injury
IgM elevated
• responds well to UDCA
or OCA

Primary Sclerosing Cholangitis (PSC)

ANA, ASMA, and pANCA† • periductal fibrosis (bile • usually young to middle-
may be seen and Ig may duct–scarring) aged people
be elevated • diagnosis by • men 2:1
cholangiogram • variable response to
UDCA

*SLA/LP = soluble liver antigen / liver pancreas

†pANCA = anti-neutrophil cytoplasmic antibody that targets a specific protein
called myeloperoxidase

TABLE 8.3. Paris criteria for PBC-AIH overlap

PBC criteria* AIH criteria*

ALP ≥ 2 times upper limit of normal ALT ≥ 5 ULN

(ULN) or GGT ≥ 5 ULN

Positive AMA 1:40 IgG ≥ 2 ULN or positive ASMA

Liver histology: florid bile duct lesion Liver histology: moderate or severe
periportal (around the portal vein) or
periseptal (around the septum)
lymphocytic piecemeal necrosis (cell
death)

Sources: Chazouillères O et al. Hepatology. 1998 Aug;28(2):296–301; Kuiper EM

et al. Clin Gastroenterol Hepatol. 2010 Jun;8(6):530–534.
Note: A sensitivity of 92 percent and a specificity of 97 percent are seen for a
diagnosis of overlap syndrome made using the Paris criteria, with clinical judgment
serving as the gold standard.
*At least two of the three accepted criteria of PBC, along with an interface with
hepatitis plus one or two AIH criteria, must be present.

The treatment for PSC-AIH overlap syndrome is with

immunosuppression plus UDCA, or an immunosuppressive
treatment alone.
Sometimes AIH occurs with elevated levels of ALP or bilirubin,
without PBC or PSC overlap syndromes. This could be due to a
negative AMA test for PBC or small duct PSC, as long as
medication-induced cholestasis (a reduced or blocked flow of bile) is
ruled out.
 HEMOCHROMATOSIS

This is a common genetic disorder, affecting roughly 1 in 500

individuals, that is mainly seen in white people. Hemochromatosis is
the result of excess iron accumulation in multiple organs, including
the liver, heart, pancreas, skin, thyroid, and joints. The excess iron
causes damage to the cells; then scarring in the affected organ; and,
finally, organ failure.
Our bodies tightly regulate iron absorption from the intestine to
maintain optimal iron storage. The body does not have a way to
excrete excess iron. Therefore, if the mechanism that controls iron
absorption fails, iron will continue to be absorbed from the intestine,
irrespective of the amount of iron that is already stored elsewhere in
the body. This occurs even with a normal intake of iron.
There are different genetic mutations (types 1–4) that cause
hemochromatosis, but the most common mutation (type 1) results
from a change in the homeostatic iron regulator (HFE) gene.
Hemochromatosis is usually seen in middle-aged men, as women
are protected from this condition through menstrual blood loss. For
that reason, hemochromatosis in women develops in old age, unless
they had a hysterectomy when they were young. It takes many years
for iron storage to reach a sufficient level to cause damage to the
organs. Today, hemochromatosis is often diagnosed during routine
blood tests, when an individual’s liver enzymes are found to be
elevated. Unfortunately, this diagnosis is often missed, and many
people with this test result are instead diagnosed with cirrhosis or
liver cancer, since there are usually no symptoms during the early
stages of hemochromatosis. Liver cancer is a common—and serious
—complication of this disease.
The main characteristics of hemochromatosis are as follows:

1. It is a common genetic disorder in the white population (a

majority of individuals inherited it as an autosomal recessive
condition, meaning both parents need to contribute one copy of
the gene).
2. It results in an excess of stored iron, which causes damage to
multiple organs, including the liver, heart, pancreas, thyroid, and
 joints.
3. In its beginning stages, affected individuals will have no
symptoms. The early symptoms are fatigue and joint pain.
4. It is usually diagnosed when cirrhosis is also present.
5. A person’s skin may become tanned (darkened) in later stages,
and that individual may develop diabetes. This condition is
therefore often referred to as “bronze diabetes.”
6. Blood tests may show an elevated level of liver enzymes,
greater iron saturation (more than 45 percent saturation by iron
carrying a protein called transferrin), and a higher amount of
stored iron (serum ferritin) in the liver.
7. Gene testing (a blood test for the HFE mutation) will confirm the
diagnosis in 90 percent of the affected people. Less-common
genetic mutation tests are not easily available.
8. An MRI of the liver (to measure iron storage), and a liver biopsy
(to measure iron levels), are also helpful in making a firm
diagnosis.

Treatment
Although this condition is often missed in people, treatment is
relatively easy in the early stages of hemochromatosis. The
treatment consists of repeatedly drawing blood (phlebotomies). This
is usually done once a week at first, removing roughly a pint of
blood. The frequency of this procedure is decreased as the body’s
iron stores are reduced to within normal limits, which may take up to
50–100 phlebotomies.
When red blood cells are removed, the body will produce more
red blood cells, which then utilize the stored iron, and thus slowly
deplete the excess iron stores. Once iron stores reach a normal level
(assessed by measuring iron saturation and the amount of serum
ferritin in the blood), the frequency of phlebotomies could be reduced
to three or four times per year.
In addition to phlebotomies, individuals with hemochromatosis
should not take iron supplements or vitamin C. Moreover, they
should not drink alcohol. Those with hemochromatosis should also
undergo periodic screening for liver cancer.
 • An affected person’s immediate family members should be screened for
hemochromatosis.
• Those with hemochromatosis should undergo liver cancer surveillance, as
liver cancer is a common complication of this condition.

Prognosis
Only those people who also have complications from cirrhosis or
liver cancer will need a liver transplant.

WILSON DISEASE

Unlike hemochromatosis, which is fairly common, Wilson disease is

a rare autosomal recessive disease that causes an excess
accumulation of copper, primarily in the liver or certain areas of the
brain, resulting in tissue damage. Wilson disease, which usually
occurs in young people, causes both liver disease and neurological
disorders.
Wilson disease is caused by mutations of the gene (ATP7B gene)
responsible for the liver’s normal excretion of copper into bile. This
mutation causes copper to accumulate in the liver, brain, cornea of
the eye, and other organs. Organ damage is predominantly seen in
the liver and brain, although joints and the kidneys may also be
involved. Some individuals may develop anemia from red blood cells
breaking down (hemolysis). Neurological complications include
tremors, speech problems, or personality disorders (people with this
latter symptom could be admitted to psychiatry wards). Wilson
disease could easily be missed during its early stages, unless a
doctor strongly suspects its presence through clinical observation.
As with most liver diseases, there are no symptoms in the early
stages of Wilson disease. Symptoms related to liver disease appear
only in the presence of liver failure or cirrhosis. If Wilson disease is
suspected, your doctor will perform the following tests:

• A serum ceruloplasmin test to measure the amount of the

protein (ceruloplasmin) that stores copper in the liver and carries
 it from the liver into the blood (the level of ceruloplasmin may be
reduced)
• A 24-hour measurement to detect copper in the urine
• An eye examination for abnormalities (Kayser-Fleischer rings)
due to copper accumulating in the cornea

A diagnosis of Wilson disease is confirmed by a liver biopsy and

measurement of the amount of copper in the liver.

Treatment
The purpose of the treatment for Wilson disease is to remove copper
from the body. Three medications are commonly used: trientine,
penicillamine, and oral zinc supplements. Trientine is the preferred
drug to remove copper, because it has fewer side effects. Orally
ingested zinc competes with copper and slows down its absorption in
the body. Hence oral zinc supplements are used in combination with
either trientine or penicillamine.
The treatment for Wilson disease is lifelong. Close monitoring is
needed to be sure the treatment is being followed (a major problem
in young people), as well as to look for side effects. Individuals with
Wilson disease should undergo periodic surveillance for liver cancer.
People who have Wilson disease should minimize their
consumption of foods with a higher copper content, including
shellfish, liver, nuts, dried fruits, chocolate, and mushrooms.

Prognosis
A liver transplant can cure people with acute liver failure or those
with complications from cirrhosis.

ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin deficiency is very rare disorder that may cause

liver or lung damage (often both), due to an inadequate amount of
the alpha-1 antitrypsin (AAT) enzyme. This deficiency is caused by
the mutation of a gene called SERPINA 1. To get the disease, a
person has to inherit two copies of the mutated gene, one from each
parent. The normal genotype is referred to as MM, and the abnormal
one as ZZ.
AAT protects lung cells (alveoli) from damage caused by an
enzyme (elastase) released by white blood cells in response to an
infection. A low level of this enzyme causes emphysema. In liver
cells, the accumulation of a variant of AAT causes liver damage,
resulting in cirrhosis and liver cancer. Rarely, a person’s skin may
also be involved.
Alpha-1 antitrypsin deficiency is suspected if an individual has a
family history of emphysema without any known risk factors, or in the
presence of both emphysema and liver disease. AAT is often
diagnosed during an investigation of abnormal liver enzymes or
emphysema. In the affected person, chest X-rays may indicate
emphysema, and blood tests may show low alpha-1 antitrypsin
levels. ATT is confirmed by genotyping or a liver biopsy (if there is
evidence of liver disease).

Treatment
There is no treatment for liver disease that is secondary to AAT
deficiency. Those with emphysema and a severe AAT deficiency
may benefit from an infusion of human alpha-1 antitrypsin, pooled
from multiple donors. Since the mechanism of liver damage is
different, this treatment does not benefit those with liver disease. As
in most liver diseases, people with an AAT deficiency should not
drink alcohol, and they should have periodic, non-invasive tests to
assess liver scarring.

Prognosis
In people with complications of cirrhosis or liver cancer, a liver
transplant is an option to cure those conditions.
FURTHER READING

Autoimmune Hepatitis
Autoimmune hepatitis. American Liver Foundation. https://liverfoundation.org/for-
patients/about-the-liver/diseases-of-the-liver/autoimmune-hepatitis/.
Autoimmune hepatitis. National Institute of Diabetes and Digestive and Kidney
Diseases. https://www.niddk.nih.gov/health-information/liver-
disease/autoimmune-hepatitis/.
European Association for the Study of the Liver. EASL clinical practice guidelines:
Autoimmune hepatitis. J Hepatol. 2015;63:971–1004.
https://doi.org/10.1016/j.jhep.2015.06.030/.
Heneghan MA et al. Autoimmune hepatitis. Lancet 2013 Oct;382:1433–1444.
https://doi.org/10.1016/S0140-6736(12)62163-1/.

Primary Biliary Cholangitis

Primary biliary cholangitis (PBC). American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-
liver/primary-biliary-cholangitis/.
National Institute of Diabetes and Digestive and Kidney Diseases. Primary biliary
cholangitis (primary biliary cirrhosis. National Institute of Diabetes and Digestive
and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-
disease/primary-biliary-cholangitis/.
Chascsa DM, Lindor KD. Emerging therapies for PBC. J Gastroenterol. 2020
Mar;55(3):261–272. https://doi.org/10.1007/s00535-020-01664-0/.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC). American Liver Foundation.
https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-
liver/primary-sclerosing-cholangitis/.
Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med 2016 Sep
22;375:1161–1170. https://doi.org/10.1056/NEJMra1506330/.

Hemochromatosis
Hemochromatosis. National Institute of Diabetes and Digestive and Kidney
Diseases. https://www.niddk.nih.gov/health-information/liver-
disease/hemochromatosis/.
Hemochromatosis. National Heart, Lung, and Blood Institute.
https://www.nhlbi.nih.gov/health-topics/hemochromatosis/.
Hereditary hemochromatosis. Centers for Disease Control and Prevention.
https://www.cdc.gov/genomics/disease/hemochromatosis.htm.

Wilson Disease
Wilson Disease Association. https://www.wilsonsdisease.org.
Wilson disease. National Institute of Diabetes and Digestive and Kidney Diseases.
https://www.niddk.nih.gov/health-information/liver-disease/wilson-disease/.
Wilson disease. American Liver Foundation. https://liverfoundation.org/for-
patients/about-the-liver/diseases-of-the-liver/wilson-disease/.
Wilson disease. National Organization for Rare Disorders.
https://rarediseases.org/rare-diseases/wilson-disease/.
Alpha-1 Antitrypsin Deficiency
Patel D et al. Alpha-1 antitrypsin deficiency liver disease. Transl Gastroenterol
Hepatol. 2021;6: 23. Published online 2021 Apr 5.
https://doi.org/10.21037/tgh.2020.02.23/.
Liver disease: The liver in alpha-1 antitrypsin deficiency. Alpha-1 Foundation,
https://www.alpha1.org/newly-diagnosed/learning-about-alpha-1/liver-disease/.
Alpha-1 antitrypsin deficiency. National Organization for Rare Disorders.
https://rarediseases.org/rare-diseases/alpha-1-antitrypsin-deficiency/.
 CHAPTER 9

Complications of Liver Disease

This chapter will discuss complications of liver disease, under three

subsections:

1. Acute liver failure

2. Chronic liver failure (decompensated cirrhosis)
3. The impact of liver disease on organs other than the liver

ACUTE LIVER FAILURE

Liver failure occurs when the liver cannot perform some of its
functions. Most often, liver failure develops gradually, over many
years. In acute liver failure, however, the liver loses its functions
quickly, usually within six months, but sometimes over a period of
several days.
Acute liver failure is a rare condition, but it can be associated with
a fatal outcome. Approximately 2,000 cases of acute liver failure are
reported in the United States every year. This condition is more
common in countries that have high rates of hepatitis A, B, and E
infections.
People who experience acute liver failure can have any of the
following symptoms:

• Mental changes (hepatic encephalopathy), including irritability

and confusion, caused by the liver’s inability to eliminate
ammonia and other toxins in the blood
• Easily bruised parts of the body or bleeding from the gums,
caused by the decreased production of blood-clotting factors
• Yellow discoloration of the eyes or skin (jaundice)
 Causes
The causes and outcomes of acute liver failure may vary, depending
on the subtype. Some of the possible factors are listed in table 9.1.
Acute liver failure is commonly caused by medications, such as
acetaminophen. In the United States, acetaminophen (generally
referred to by its brand name, Tylenol) is becoming the most
common cause of liver failure. This condition usually occurs when a
large amount of acetaminophen is consumed, either intentionally or
inadvertently. People who use medications that contain both
acetaminophen and narcotic drugs (such as codeine) to control pain
may underestimate the amount of acetaminophen they use. The
FDA is attempting to reduce this risk by banning pain medications
that are co-formulated with acetaminophen. Keep in mind that
acetaminophen is more likely to cause liver failure in people who
drink alcohol excessively. Moreover, some people may
underestimate the amount of acetaminophen they consume when
they are under the influence of alcohol. Acute liver failure can also
occur in people who have other liver diseases and take more than
the recommended dose of acetaminophen. Therefore, everyone—
whether they are healthy or have liver disease—should avoid taking
more than 2,000 milligrams (four 500 mg tablets or capsules) of
acetaminophen in one day.
TABLE 9.1. Possible causes of acute liver failure

Tylenol (acetaminophen)

other medications or herbal preparations

hepatitis B

autoimmune hepatitis

hepatitis A

ischemic hepatitis

Budd-Chiari syndrome (obstruction of hepatic vein blood flow)

Wilson disease
mushroom poisoning

In addition to acetaminophen, many other medications—including

nonsteroidal anti-inflammatory drugs (ibuprofen and similar drugs),
antibiotics, anti-seizure drugs, and anti-tuberculosis medicines—can
cause acute liver failure.
Viral hepatitis (hepatitis A, B, or E) or autoimmune hepatitis can
also bring on acute liver failure, but hepatitis C usually does not.
Nonetheless, because hepatitis A or B is more likely to cause acute
liver failure in someone who already has a hepatitis C infection,
individuals with hepatitis C should be vaccinated for hepatitis A and
B.
Acute liver failure could also be brought about by an inadequate
blood supply to the liver (ischemic hepatitis). This condition is more
common in elderly individuals and people who have heart conditions.
After any major surgery, liver failure may suddenly develop in the
immediate post-operative period, a condition most commonly caused
by the rapid worsening of a previously unidentified chronic liver
disease. Acute liver failure after surgery, however, can also be
caused by insufficient blood flow to the liver, or by a toxic reaction to
anesthetic agents or antibiotics.
For approximately 20 percent of individuals with acute liver failure,
its cause is unknown. A physician may perform a liver biopsy if the
reason for the acute failure cannot be identified. Most people who
have acute liver failure, however, will not require a liver biopsy.
Acute liver failure is an urgent condition that leads to the failure of
other organs (multi-organ failure). Early recognition of the reason
why this failure occurred may help in its successful treatment.
Therefore, for the best outcome, it is important to seek help from a
medical center that has plenty of experience in treating liver disease.

Treatment
Treatment for acute liver failure is based on the cause of the
disease. There are no specific treatments if the reason for the
condition is not listed in table 9.2.
Early treatment using N-acetylcysteine (NAC) has been shown to
improve a person’s chances of recovery without a liver transplant. If
poisoning from eating death-cap mushrooms (Amanita phalloides) is
suspected, the recommended treatment is a combination of
intravenous penicillin and silibinin, given together. A liver transplant
is the only treatment option for most people who have acute liver
failure caused by Wilson disease. Although treatment with
penicillamine, trientine, or zinc is not effective in many instances,
these medications could occasionally be beneficial. Early diagnosis
of acute liver failure may avoid a liver transplant for many people
who have autoimmune hepatitis. Most physicians will start a trial
treatment of intravenous steroids before proceeding with a liver
transplant. Antiviral treatments are not helpful for the management of
acute liver failure caused by viral hepatitis.
TABLE 9.2. Potential treatment for acute liver failure
Cause Treatment

Acetaminophen N-acetylcysteine (NAC) administered intravenously or by

mouth

Mushroom poisoning combination of penicillin and silibinin administered

intravenously

Wilson disease trientine or pencillamine in combination with zinc could

be tried while awaiting a liver transplant

Autoimmune hepatitis steroids administered intravenously

Budd-Chiari syndrome blood thinners and sometimes TIPS (a type of shunt) to

open up blocked hepatic veins

In cases of acute Budd-Chiari syndrome (caused by blood clots

blocking the hepatic veins, which carry blood from the liver to the
heart), medications that can dissolve the blood clots (thrombolytic
therapy) or the placement of stents (small metal tubes) to open the
clogged veins may relieve liver congestion and reverse acute liver
failure. Pregnancy-associated acute liver failure usually goes away
after the baby is born.

Prognosis
The survival rate for individuals who have acute liver failure can be
influenced by its cause. People whose acute liver failure is caused
by acetaminophen use or hepatitis A have a better chance of
survival than those for whom the cause is unknown (presumably a
viral condition) or results from other medications. Individuals who
have both Wilson disease and acute liver failure are less likely to
survive without a liver transplant. When a person experiences acute
liver failure, the decision about whether a liver transplant is
necessary has to be made quickly.
The complications of acute liver failure include the following:

1. Hepatic encephalopathy
2. Swelling in the brain
3. Metabolic complications, including hypoglycemia (low blood
sugar), acidosis (too much acid in the body), and alkalosis (too
much bicarbonate [alkali] or not enough acid in the blood)
4. Gastrointestinal bleeding
5. Bacterial infections
6. Clotting abnormalities
7. Respiratory failure
8. Circulatory complications
9. Kidney failure

People with acute liver failure are best treated in medical centers
that are equipped for liver transplants. It is much better to transfer a
patient to a liver transplant facility before that individual goes into a
coma. Helicopter transport is preferable to traveling in a pressurized
aircraft or by automobile. The United Network for Organ Sharing’s
current rules permit people who have acute liver failure to be listed
as “status 1,” ensuring that they have the highest priority on the
waiting list for a transplant.

Liver Transplants
Before the advent of liver transplants, the survival rate for people
with acute liver failure was between 10 and 20 percent.
Transplantation has improved the survival rate considerably and is
now the gold standard for treatment.
 CHRONIC LIVER FAILURE

Most people who have liver disease do not have any symptoms until
their liver has been damaged for a long time. When a person with
liver disease starts to feel very tired, or their skin turns yellow, that
means their liver damage has gotten worse, and they have cirrhosis.
Individuals with either of these signs should see their doctor right
away.
Some of the symptoms that a person with late-stage liver disease
may have are listed in table 9.3. But these signs could also happen
because of other conditions—not just liver disease—so it’s important
to see a doctor to rule out any other medical problems.
TABLE 9.3. Symptoms of late-stage liver disease

Symptoms
• severe fatigue
• short-term memory problems
• yellowing skin (jaundice)
• impotence in men
• enlarged breasts in men (gynecomastia)
• swelling of the abdomen or legs
• vomiting blood or passing black stools

Signs
• spider-like collections of blood vessels (spider nevi) on the face, arms, or
chest
• loss of armpit or pubic hair
• redness (erythema) in the palms
• decrease in size of the testicles
• prominent veins on the abdominal wall
• fluid in the belly (ascites)
• flapping tremors (asterixis)
• wasting away of muscles

Cirrhosis is a serious result of liver disease, no matter what the

cause. When a person develops cirrhosis after long-term liver
damage, their liver cannot do its work normally. If the cirrhosis is
found early on, and the cause is treated, then the damage will stop
and, in some people, their liver can reverse the damage.
Some of the serious problems that can happen when a person
develops cirrhosis are:

• Fluid buildup, which causes

Swelling in the abdomen (ascites)
Swelling in the legs (edema)
Swelling in different parts of the body (anasarca)
• Bacterial infections
In the fluid that builds up in the abdomen (spontaneous
bacterial peritonitis)
In the urinary system (kidneys, bladder, urethra)
In the respiratory tract (sinuses, nose, airway, lungs)
• Internal bleeding in the digestive system
From larger veins in the esophagus (esophageal varices)
From large veins in the stomach (gastric varices)
From large veins in the large or small intestine (ectopic
varices)
• A change in a person’s mental state (hepatic encephalopathy):
Altered sleep patterns
Short-term memory problems
Confusion
Coma (rare)
• Liver cancer
• Wasting away of muscles

Most of these conditions are caused by higher blood pressure in

the blood vessel that carries blood from the intestines, pancreas, and
spleen to the liver (the portal vein). To understand the causes of
these major problems and the ways in which a doctor will manage
them to help a person feel better, it’s important to know more about
the liver and how it works.

Changes in the Liver’s Blood Flow

The liver gets blood from two different blood vessels:
 1. The hepatic artery, which brings oxygen-rich blood from the
heart to the liver
2. The portal vein, which brings blood from the intestine,
pancreas, and spleen to the liver

The portal vein supplies most of the blood to the liver

(approximately 70 percent). The liver processes the important
nutrients in blood coming from the intestine, gets rid of some of the
toxins carried from the intestine, and processes the medicines that
the intestine absorbed. The remaining 30 percent of the liver’s blood
supply comes from the hepatic artery. The liver is unique because of
this dual blood supply, which provides an advantage if the portal
blood flow is blocked (by a blood clot, tumor, or scarring due to
cirrhosis), because the hepatic artery can compensate, to some
extent, by increasing the blood flow to the liver. If the hepatic artery
is blocked, however, the portal vein cannot bring additional blood to
the liver.
 FIGURE 9.1. Liver anatomy, showing blood vessels and bile ducts

Under healthy conditions, the liver can accommodate significant

increases in blood flow—for example, after eating—without raising
the pressure in the portal vein. The portal vein branches into smaller
veins, which then become small channels, called sinusoids. The
sinusoids bathe the liver cells (hepatocytes), and then drain into
small veins (branches of the hepatic veins). These small veins join to
become three relatively large hepatic veins (the right, middle, and left
hepatic veins). Blood in the hepatic veins drains into the inferior vena
cava, the large vein that empties the blood from the lower part of the
body into the right-hand side of the heart.
Normal pressure in the portal vein is less than 5–12 mm Hg
(millimeters of mercury), and the pressure difference between the
portal vein and the inferior vena cava (the porto-venous gradient) is
less than 5 mm Hg. In a healthy individual, this pressure difference
remains more or less constant. In a healthy liver, large increases in
blood flow can be easily accommodated without an increase in portal
vein pressure.
For people who have cirrhosis, this blood flow can become
clogged because of scar tissue, nodules, and blood clots in the small
branches of the portal vein. In addition, people with cirrhosis undergo
changes in their nervous system and their hormones, which also
hinder blood flow in the liver. When these problems are combined,
they lead to an increase in pressure in the portal vein (portal
hypertension).
Although other factors can cause portal hypertension, cirrhosis is
the most common factor. Portal hypertension is diagnosed when the
porto-venous gradient is more than 5 mm Hg, but the complications
of portal hypertension usually appear when the pressure exceeds 10
mm Hg. There are no reliable, non-invasive ways to measure portal
vein pressure. A direct means is to insert a needle into the liver and
push the needle into the portal vein, but this method is rarely used.
The portal vein pressure usually is measured indirectly, by placing a
catheter (a thin, hollow tube), with a balloon at its tip, into the hepatic
vein. The catheter is inserted into a neck vein and then guided into
the hepatic vein. Pressure readings are taken with the balloon both
inflated (hepatic vein wedge pressure, which is a reflection of portal
vein pressure) and deflated (hepatic vein free pressure). The
difference between the wedge pressure and the free pressure (the
hepatic vein wedge pressure gradient) is an approximation of the
porto-venous gradient.
FIGURE 9.2. The relationship between blood vessels, liver cells, and bile ducts
 FIGURE 9.3. Cirrhosis of the liver can lead to high blood pressure in the portal vein

Fluid Buildup
One major problem that happens in people who have cirrhosis is a
buildup of fluid in the belly (ascites) and legs (edema). Individuals
who have ascites initially may not have any discomfort, other than
from the cosmetic appearance caused by a large belly. As ascites
gets worse, people may feel significant discomfort and pain, and
they may have difficulty breathing.
To help control the buildup of fluid in the belly, the first step a
doctor will probably suggest is that an individual should reduce the
amount of salt in their diet. People who have this type of fluid buildup
should not consume more than 2,000 mg of sodium per day, so
paying attention to how much salt is in your food is very important. A
good way to control your sodium intake is to eat fewer processed
foods and more fresh foods. Getting the advice of a registered
dietician or a nutritionist can be helpful in making the healthiest diet
choices.
If cutting down the amount of salt in a person’s diet doesn’t help
reduce fluid buildup, a doctor may prescribe medicines (called
diuretics) to help that individual produce more urine. The doctor may
suggest taking both furosemide and spironolactone, so they can
work together. Furosemide is fast acting and may cause a loss of
potassium. Spironolactone is slow acting and uses a different
mechanism, thereby conserving potassium. Taking a combination of
the two medications helps keep the potassium levels steady and
avoids the need for potassium supplements. Depending on how a
person reacts to the medicines, their doctor may adjust the amount
they need to take. It is very important to take these medicines
according to the doctor’s instructions, because serious problems—
like kidney failure—can occur.
Another way a doctor may try to get rid of excess fluid in the belly
is to remove the fluid by placing a needle in the belly (a process
called paracentesis). First, the doctor will use an ultrasound to figure
out the correct place to insert the needle. Before taking out a lot of
fluid, the doctor will give that individual some intravenous albumin (a
protein made by the liver). This infusion of albumin is important for
maintaining blood flow to the kidneys and allowing the kidneys to
work properly.

People undergoing paracentesis should ask their doctor if they should get
albumin before any fluid is taken out, because some physicians may not do
this. An albumin infusion is given to prevent kidney damage.

When a person’s liver disease continues to get worse, controlling

the amount of sodium and taking diuretics will often not help in
reducing the amount of fluid built up in their belly. For these
individuals, getting a new liver through a transplant from an organ
donor may be the best way to treat their condition. If a person cannot
have a liver transplant, a doctor may try to place a small tube in their
liver to connect the portal vein to the hepatic vein. This should help
drain some of the extra blood from the portal vein and allow that
blood to go back to the heart. This procedure is called a transjugular
intrahepatic portosystemic shunt (TIPS). It may be of benefit to
people who have fluid buildup in their belly, but it has some very
serious risks, including an ammonia buildup that can cause mental
confusion (hepatic encephalopathy).
 FIGURE 9.4. A transjugular intrahepatic portosystemic shunt (TIPS or TIPSS)

Infections
A person who has fluid buildup in their belly may also get infections
caused by bacteria in that fluid. This serious problem is called
spontaneous bacterial peritonitis. These infections can be deadly in
almost 30 percent of the people who have fluid buildup. Anyone who
has fluid buildup in their body and has a fever, pain in their belly, or
mental confusion should see their doctor right away.
The doctor will check the fluid for possible infections by inserting a
needle into the belly, removing some of the fluid, and counting the
number of white blood cells (the blood cells the body uses to fight
infections). The doctor may prescribe antibiotics to help treat the
infection. People who have gotten these types of infections once are
very likely to get them again. Thus, to prevent any future infections,
they may need to take antibiotics for the rest of their lives.

Bleeding
When the blood pressure in the portal vein increases, the body tries
to lower that pressure by opening up new blood vessels to help take
blood away from the liver. Over time and with greater pressure,
these smaller blood vessels get larger to handle more blood flowing
to them. As the pressure increases, they can burst and bleed (figure
9.5). These larger blood vessels (varices) can burst in the
esophagus (the tube from the throat to the stomach), stomach, or
other organs in the body (such as the large or small intestines or the
rectum). Swollen blood vessels in the esophagus (esophageal
varices) are a common source of this bleeding.

FIGURE 9.5. Bleeding in the blood vessels in the esophagus, as viewed from inside
the esophagus
Preventing First-Time Bleeding
A doctor can check whether an individual risks having a burst blood
vessel by inserting a tube in the person’s throat and looking into their
stomach and esophagus with a video camera. This procedure is
called an endoscopy. Based on the size of the veins, their color, and
other characteristics, the doctor can tell whether that individual has a
risk of bleeding. If so, the doctor will help lower that risk by using
various treatment options (table 9.4).
If the person has a high probability of bleeding, the doctor may
prescribe medicines (propranolol, nadolol, or carvedilol) to help lower
that risk. These drugs do not reduce the risk of bleeding completely,
but they can reduce it by about 60 percent. The doctor will probably
begin with a small dose and then increase it slowly. People who
have a risk of bleeding from the stomach or esophagus must take
these medicines for the rest of their lives, or until they have a liver
transplant.
TABLE 9.4. Treatment options for variceal bleeding
Treatment Reason to apply treatment

Using medicines (either prevent bleeding by lowering blood pressure in the veins
propranolol, nadolol, or
carvedilol)

Using a rubber band prevent a blood vessel from bursting or stop a bleeding
(banding) blood vessel

Using a metal tube stop bleeding and prevent future bleeding by lowering
(TIPS) the pressure in the portal vein by taking blood from the
portal vein to the hepatic vein

Using a balloon stop bleeding in a blood vessel

(balloon tamponade)

Injecting glue stop bleeding from gastric varices

Another way the doctor may try to lower a person’s risk of

bleeding is to use a rubber band to stop the blood flowing to the
affected blood vessel (variceal banding). During an endoscopy, the
doctor can suck the enlarged blood vessel into the endoscope, use a
small device (like a cap) attached to the endoscope, and put a
rubber band over the blood vessel. This procedure is relatively
simple, with only very few (and rare) risks, including bleeding and
narrowing of the esophagus. The doctor may need to repeat this
procedure up to two to four times over a period of three months
before the vein disappears.
To help lower the risk of bleeding, the doctor may suggest that a
person should take both medicines plus have the banding
procedure. If the individual cannot safely take these medicines, the
doctor may only do the banding procedure. In general, banding is
superior to medications in reducing the risk of bleeding. Banding is
an invasive procedure, however, so a doctor may present both
options to the patient and base the treatment on that individual’s
preference.

Sudden Bleeding
Each time a blood vessel bursts, that person has a 20–40 percent
risk of dying. About one-third of all deaths in individuals who have
cirrhosis are caused by burst varices. Those who have blood vessels
burst in their stomach have the highest risk of dying (greater than 50
percent).
After the first blood vessel bursts, a person’s chances of survival
depend on the stage of liver disease. Often, an individual who has
cirrhosis will only find out they have this liver disease after they have
bleeding in their stomach or esophagus. The signs of bleeding are:

1. Throwing up blood
2. Having red or black stools
3. Experiencing significant dizziness

If a person has any of these symptoms, they should go to a hospital

right away. Getting help early can improve that individual’s chances
of recovering.
In the emergency room, the doctor may check to see how much
blood the person has lost, give them replacement blood, administer
antibiotics to prevent any bacterial infection, check for blood clots in
the portal vein, and prescribe medicines to help lower the pressure in
their blood vessels and stop the bleeding.
After stabilizing the person, the doctor will locate where the
bleeding is by performing an endoscopy and then try to stop the
bleeding by putting bands on the affected blood vessels. If the
bleeding doesn’t cease, the doctor may use a special balloon to
compress the blood vessels (a process called balloon tamponade).
Most bleeding will be stopped using these steps. If none of these
methods work, the doctor (usually an interventional radiologist) may
try to insert a small metal tube (stent) into the portal vein, to drain
blood from this vein into the hepatic vein and lower the blood
pressure in the portal vein (a TIPS procedure).

How to Prevent Repeat Bleeding

Once a person has a burst blood vessel, they are much more likely
to have this happen in the future. If that individual survives after the
first time such bleeding occurs, they have a very high risk of having
additional bleeding in the following two years, especially during the
first six weeks after the initial bleeding.
Their doctor will again suggest using medicines and the banding
procedure—methods used to stop the first bleeding episode. The
doctor is more likely to use both of these treatments together,
because the combination works better than either one by itself.
When medicines and banding do not help prevent repeated
bleeding, the doctor may suggest using a TIPS procedure, which
works well to prevent the bleeding from happening again. This
procedure, however, risks having the tube become narrowed or
blocked. For the best results, the physician has to periodically check
the stent to ensure that there is no blockage, but this monitoring is
expensive.
For people who have late-stage liver disease, these treatment
options will not help their liver get better or help them survive. The
best treatment for these individuals is to have a liver transplant.

Changes in a Person’s Mental State

As cirrhosis and liver disease progress, people may develop memory
problems and, later, mental confusion. These symptoms, known as
hepatic encephalopathy, occur when toxins are not eliminated from
the body by the liver.
A healthy liver processes ammonia and other toxins that get into
the blood from the intestine. When a person has cirrhosis, this may
not take place, because their liver is not working properly. Instead,
blood is being diverted through other veins and bypasses the liver.
When this happens, these toxins may reach the brain, causing a
variety of symptoms, including sleep disturbances, memory
problems, confusion, and, in extreme cases, coma.
These symptoms are often brought on by constipation or a high-
protein diet. Although eating a normal amount of protein is
encouraged, people who have advanced cirrhosis should avoid high-
protein diets and should make every effort to increase their fiber
intake, which may help them avoid constipation. Individuals who
have advanced cirrhosis are encouraged to eat plenty of vegetables.
Also, a physician may prescribe a medicine called lactulose, a syrup
that causes an increase in bowel movements and changes the
bowel’s pH and its microorganisms (bacterial flora), thereby reducing
the amount of ammonia that is formed and then absorbed.
If lactulose does not work in relieving hepatic encephalopathy, the
physician may prescribe antibiotics, such as rifaximin (Xifaxan) or,
rarely, metronidazole. Rifaxamin, a non-absorbable antibiotic, is
preferred because of its efficacy (effectiveness) and its relatively
fewer side effects. The only disadvantage is its higher cost,
compared with other antibiotics. When none of these approaches are
successful, the physician may recommend a protein-restricted diet.
Bleeding, infections, abnormalities in electrolytes (minerals in
blood and other bodily fluids), or kidney failure often cause hepatic
encephalopathy.

Liver Cancer and Other Complications

Cirrhosis can cause other problems, such as liver cancer,
osteoporosis, and, in advanced cases, vitamin and mineral
deficiencies. People who have late-stage cirrhosis are often
malnourished.
Liver cancer is one of the most dreaded complications of cirrhosis
and is often found in advanced stages of this disease, when the
options to treat the cancer are few. Liver cancer is one of the most
common forms of cancer, causing about 10 percent of all adult
deaths. (Liver cancer is discussed in more detail in chapter 10.)
People who have cirrhosis should be screened for liver cancer
every six months. Early stages of liver cancer can be treated very
effectively.

IMPACT OF LIVER DISEASE ON ORGANS OTHER

THAN THE LIVER

Liver disease may also affect other organs. A few of these non-liver
conditions are specific to individuals with viral hepatitis (hepatitis C
and hepatitis B). Additionally, advanced cirrhosis could affect the
lungs, heart, kidneys, brain and nervous system, bones, and
muscles.
Approximately 5 percent of the people who have hepatitis C may
develop diseases in organs other than the liver (table 9.5). People
with hepatitis B may also be affected by 1–10 percent of the
conditions listed in table 9.5. The problems that affect other organs
are believed to be caused by excessive stimulation of the immune
system from a chronic hepatitis C or hepatitis B infection, rather than
by the hepatitis C or B virus. Keep in mind that most of these
conditions can arise without having a hepatitis C or B infection. They
can also randomly occur in people with hepatitis C or hepatitis B.
TABLE 9.5. Conditions possibly associated with hepatitis C or a hepatitis C infection

Strong association (mostly with hepatitis C):

• a combination of cryoglobulinemia and leukocytoclastic vasculitis (a thickening
of blood proteins and inflammation of blood vessels)
• membranoproliferative glomerulonephritis (an inflammation of the filters, called
glomeruli, in the kidney)
• sialadenitis (an immune disorder that destroys tear glands and salivary
glands)

Probable association (mostly with hepatitis C):

• porphyria cutanea tarda (a skin condition in which blisters appear in exposed
parts of the skin)

Suspected association (hepatitis C and, to a lesser extent, hepatitis B):

 • autoimmune thyroid disease (thyroiditis)
• idiopathic thrombocytopenia (a blood disorder from low platelet counts)
• Behçet’s disease (an inflammation affecting many parts of the body)
• cancer of the lymphatic system (non-Hodgkin’s lymphoma)
• mucosa-associated lymphoid tissue (MALT) lymphoma (cancer of the mucus
lining of the stomach and other mucous membranes, including those of organs
such as the salivary glands, thyroid, and lungs)
• lichen planus (a skin condition in which bumps appear on the skin; it can
involve the oral mucosa, genitals, and nails)
• Hyde’s prurigo nodularis (presence of multiple skin nodules and intense
itching)
• Mooren’s corneal ulcer (a painful ulceration of the cornea; a rare condition)
• idiopathic pulmonary fibrosis (lung-tissue scarring without a known cause)
• diabetes
• CREST syndrome (a multi-symptom form of scleroderma, which is a
hardening and thickening of connective tissues)

Some of the conditions described in table 9.5 probably are caused

by an abnormal over-production of B-cells (a type of white blood
cell), such as membranoproliferative glomerulonephritis, lymphoma,
cryoglobulinemia, leukocytoclastic vasculitis, and MALT lymphoma.
Others are autoimmune diseases, such as Behçet’s disease, Hyde’s
prurigo nodularis, Mooren’s corneal ulcer, and lichen planus.
Sialadenitis, thyroiditis, idiopathic thrombocytopenia, and other
conditions (such as porphyria cutanea tarda) remain poorly
explained. Many of these disorders improve after treatment for
hepatitis C or hepatitis B, although some remain unchanged. The
internet has a wealth of information about and pictures of these
conditions, but a few common ones are briefly discussed here.

Essential Mixed Cryoglobulinemia

The most common (and proven) condition that occurs in association
with a hepatitis C infection is mixed cryoglobulinemia. A person
affected with this disease has proteins (called cryoglobulins) in the
blood that thicken only at cold temperatures. Approximately 5–8
percent of the people with this disorder will develop B-cell lymphoma
(malignant tumors of the lymph system). Rarely, cryoglobulinemia
will involve more than one organ, and this condition may be life
threatening, especially with severe inflammation of blood vessel
walls (vasculitis). In other rare instances, cryoglobulinemia may
involve fluid leakage into the covering of the heart (pericardial
effusion) or the covering of the lungs (pleural effusion). The
treatment will be effective to some extent when the precipitating
cause (hepatitis C) is cured, but this response is not universal.

Membranoproliferative Glomerulonephritis
People with both membranous and membranoproliferative
glomerulonephritis, a type of kidney disease in which the filters in the
kidney (called glomeruli) are inflamed, are more likely to have a
hepatitis C or hepatitis B infection than individuals who have other
types of kidney disease. Membranoproliferative glomerulonephritis,
which can occur with or without cryoglobulinemia also being present,
may not be associated with either a hepatitis B or hepatitis C
infection. If membranoproliferative glomerulonephritis is suspected, a
physician will perform a kidney biopsy. Individuals who have
glomerulonephritis may not have other symptoms of chronic liver
disease. In those who also have hepatitis B, children are the ones
more likely to be affected.
People with membranoproliferative glomerulonephritis usually
have a large amount of protein in their urine, blood in their urine,
swelling in their legs, and mild to moderate kidney damage.
Approximately 60 to 70 percent of the individuals with this condition
may have detectable cryoglobulins in their blood. Studies show that
treatment of a hepatitis C or hepatitis B infection may improve
membranoproliferative glomerulonephritis. In children with a kidney
disease associated with hepatitis B, 30 to 60 percent of them will
improve without any treatment (spontaneous remission). In adults
with hepatitis B and kidney disease, 30 percent may develop kidney
failure, and up to 10 percent may require dialysis or a kidney
transplant.

Polyarteritis Nodosa
Polyarteritis nodosa, a type of immune-mediated inflammation of the
small and large blood vessels, could be caused by hepatitis B and is
usually seen after a person’s recent exposure to hepatitis B. Up to
50 percent of the people with acute polyarteritis nodosa may have a
hepatitis B infection. Those with acute polyarteritis nodosa may have
symptoms such as high fever, anemia, joint pain, blood in the urine,
chest pain, high blood pressure, nervous system problems, or
bleeding from the gastrointestinal tract, depending on the extent to
which the blood vessels are involved. Unless treated, 30 percent of
those with this disease could die within five years.

Sialadenitis
Sialadenitis, or inflammation of the salivary glands, could be caused
by many conditions. It can occur with a hepatitis C infection.
Sialadenitis is also frequently seen with cryoglobulinemia. Although
Sjögren’s syndrome involves a similar inflammation of the salivary
glands, these are two separate diseases. Sialadenitis that occurs
with a hepatitis C infection is considered to be part of the hepatitis
C–related over-production of lymphocytes (white blood cells). The
presence of this condition may increase a person’s risk of B-cell non-
Hodgkin’s lymphoma.

Porphyria Cutanea Tarda

Porphyria cutanea tarda is a general term used for a skin condition
caused by deposits of a chemical (porphyrin) in the skin, making the
skin sensitive to sunlight. It can be a genetic (inherited) disorder or
an acquired condition. Porphyrins are created during the production
of heme (a component of hemoglobin that carries oxygen in red
blood cells). Porphyria cutanea tarda results from a deficiency in an
enzyme called uroporphyrinogen decarboxylase, leading to an over-
production of porphyrins.
A person with this disease typically has increased skin fragility
and develops fluid-filled sacs or lesions (called vesicles and bullae)
on areas of the skin that are frequently exposed to the sun (usually
the back of the hands or the forearms), which leads to skin
discoloration or scarring from the formation of small white bumps
(called milia). Different forms of this skin condition include thick hair
growth on the face and body, dark spots, and thickened skin that
develops over a period of time. Typically, the disease affects middle-
aged men who drink alcohol excessively and have symptoms of liver
disease and iron overload. This condition is also associated with
hepatitis C and, to a lesser extent, with a hepatitis B infection.
Although porphyria cutanea tarda can occur in people who do not
have viral hepatitis, individuals with this skin condition frequently also
have hepatitis C or hepatitis B. Despite this strong association, the
exact mechanism by which viral hepatitis causes porphyria cutanea
tarda remains unclear. The conventional treatment for porphyria
cutanea tarda is to repeatedly remove blood, thus reducing the
amount of iron in the body to the point of a mild iron deficiency. In
addition, everyone who has porphyria cutanea tarda should avoid
drinking alcohol and not take estrogen supplements (either hormone
replacement pills or contraceptive pills).

Lichen Planus
Lichen planus is a benign disease, characterized by itchy bumps on
the skin. These bumps may be violet in color and can appear on the
wrists, ankles, and genitals, as well as in the mouth. This condition is
believed to be caused by the over-production of T-cell lymphocytes.
The prevalence of hepatitis C in people who have lichen planus
varies considerably from one geographic area to another, and the
evidence linking hepatitis B with lichen planus is even weaker.

Autoimmune Thyroid Disease

There may be an association between autoimmune thyroid disease
and a hepatitis C infection. Autoimmune thyroid disease is also seen
in people with autoimmune hepatitis and primary biliary cholangitis.
Studies have documented a high prevalence of thyroid antibodies in
individuals who have a chronic hepatitis C infection. Both
underactive thyroid (hypothyroidism) and overactive thyroid
(hyperthyroidism) conditions have been observed in people with
hepatitis C who are treated with alpha-interferon.

Non-Hodgkin’s Lymphoma
Several reports, particularly from studies in southern Europe, have
suggested a relationship between a hepatitis C infection and non-
Hodgkin’s lymphoma. The association of non-Hodgkin’s lymphoma
with hepatitis B is inconsistent. The development of non-Hodgkin’s
lymphoma among people who had a hepatitis C infection was seen
most frequently in connection with cryoglobulinemia.

Other Non-Liver Complications

Several other conditions—including idiopathic pulmonary fibrosis,
cutaneous necrotizing vasculitis (an inflammation of the small blood
vessels), Mooren’s corneal ulcer, idiopathic thrombocytopenia,
diabetes, Behçet’s disease, and CREST syndrome—have been
described in association with viral hepatitis, but no studies have
proven that viral hepatitis is the cause. An increasing number of
studies have found a relationship between type 2 diabetes and a
hepatitis C infection. Nonetheless, because both conditions are
common, it is difficult to prove a cause-and-effect relationship.

IMPACT OF CIRRHOSIS ON OTHER MAJOR ORGANS

In people with cirrhosis, especially in the presence of increased

portal vein pressure, other organs may also be affected. Some
organs are involved with compensated cirrhosis (severe liver
damage), and others with decompensated cirrhosis (liver failure).
(Some of these complications have been discussed previously.)

Kidney Disease
The kidneys are frequently involved when a person has advanced
cirrhosis.

Hepatopulmonary Syndrome and Portopulmonary Hypertension

Hepatopulmonary syndrome and portopulmonary hypertension are
two conditions, specific to cirrhosis, that cause lung problems. These
diseases are seen in less than 5 percent of the people with cirrhosis.
Hepatopulmonary syndrome is the result of blood bypassing the
lungs or being shunted through the base of the lungs, causing low
oxygen saturation in the blood. People with this condition have
shortness of breath, which gets worse when they sit up. With a
normal amount of air in a room, their blood oxygen level will be low.
A liver transplant is a good treatment option for this condition.
In some individuals, pressure in their pulmonary artery (the blood
vessel that drains blood into the lungs) may become high, causing
pulmonary hypertension. This condition usually occurs in people with
lung disease. Rarely, cirrhosis can cause a similar problem, which is
known as portopulmonary hypertension. This is a serious
complication of cirrhosis and requires treatment from specialists with
expertise in this condition. A liver transplant could cure a mild case
of portopulmonary hypertension.

Heart Disease
A type of heart disease called cirrhotic cardiomyopathy may be seen
in people with advanced cirrhosis who have high portal vein
pressure. This condition causes the heart to pump blood less
efficiently and leads to low blood pressure or heart failure. Cirrhotic
cardiomyopathy is seen more often when a person with this disease
is under stress. EKG abnormalities (particularly a prolonged QTc
interval, when the heart rate is slower than normal) are common. No
effective medical treatment exists for this condition, but a liver
transplant can cure it.
FURTHER READING
Goldberg E, Chopra S. Cirrhosis in adults: Overview of complications, general
management, and prognosis. https://www.uptodate.com/contents/cirrhosis-in-
adults-overview-of-complications-general-management-and-prognosis/.
Runyon BA. Introduction to the revised American Association for the Study of Liver
Diseases practice guideline management of adult patients with ascites due to
cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651–1653.
https://doi.org/10.1002/hep.26359/.
Garcia-Tsao G et al. Portal hypertensive bleeding in cirrhosis: Risk stratification,
diagnosis, and management: 2016 practice guidance by the American
Association for the Study of Liver Diseases. Hepatology. 2017 Jan;65(1):310–
335. https://doi.org/10.1002/hep.28906/. Epub 2016 Dec 1.
European Association for the Study of the Liver. EASL clinical practice guidelines
for the management of patients with decompensated cirrhosis. J Hepatol. 2018
Aug;69(2):406–460. https://doi.org/10.1016/j.jhep.2018.03.024/. Epub 2018 Apr
10.
Aithal GP et al. Guidelines on the management of ascites in cirrhosis. Gut
2021;70:9–29. https://doi.org/10.1136/gutjnl-2020-321790/. Epub 2020 Oct 16.
European Association for the Study of the Liver. EASL clinical practice guidelines
on the management of ascites, spontaneous bacterial peritonitis, and
 hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3): 397–417.
https://doi.org/10.1016/j.jhep.2010.05.004/. Epub 2010 Jun 1.
Lange PA, Stoller JK. Hepatopulmonary syndrome in adults: Prevalence, causes,
clinical manifestations, and diagnosis.
https://www.uptodate.com/contents/hepatopulmonary-syndrome-in-adults-
prevalence-causes-clinical-manifestations-and-diagnosis/.
 CHAPTER 10

Liver Cancer

Cancer of the liver cells, also known as hepatocellular carcinoma

(HCC), is one of the most common cancers in the world. Worldwide,
more than 800,000 people are diagnosed with liver cancer every
year, and it causes more than 700,000 deaths a year. In the United
States, 42,000 patients are diagnosed with liver cancer yearly, and
around 30,000 people die from it every year. In the United States
and parts of Europe, the number of liver cancer cases is increasing,
because the number of people who have NASH cirrhosis is
increasing.
Liver cancer is more common in men (two to four times higher)
than in women. The risk of liver cancer increases with age.
In addition to HCC, there are other types of cancer that could start
from the liver. These are rare (approximately 10–20 percent of all
liver cancers) and include intrahepatic cholangiocarcinoma (cancer
originating from bile ducts), and angiosarcoma or hemangiosarcoma
(cancers originating from blood vessels). Cancers can also begin
elsewhere and spread to the liver (metastatic liver cancer).
This chapter will focus mostly on HCC. Intrahepatic
cholangiocarcinoma could also be managed similarly.

POSSIBLE CAUSES OF HCC

Compared with people who don’t have any liver disease, individuals
who have other types of liver disease are more likely to develop liver
cancer, especially those who have had hepatitis B or hepatitis C
(table 10.1)
TABLE 10.1. Causes of liver cancer

Common causes
 • cirrhosis from any cause
• hepatitis B
• hepatitis C
• hemochromatosis

Other risk factors

• smoking
• alcoholism
• obesity
• diabetes
• aflatoxins
• anabolic steroids

For people who have hepatitis C or hepatitis B infections, drinking

alcohol makes them more likely to develop cancer. Individuals who
have cirrhosis, no matter what the cause, are also more likely to
develop liver cancer. In addition, obesity has been shown to increase
a person’s chances of developing liver cancer. Other risk factors are
diabetes and smoking.
Cirrhosis, irrespective of the cause, is a predisposing risk factor
for the development of liver cancer. In a given population, this risk is
three to four times higher for people who have cirrhosis than for
those who have chronic hepatitis without cirrhosis. Among
individuals who have a hepatitis C infection, 5 percent develop liver
cancer during their lifetime. The risk appears to increase, however,
with severe cirrhosis. Approximately 15 percent of the people who
have cirrhosis and hepatitis C will develop liver cancer during their
lifetime.
Another risk factor (not currently seen in high-income countries)
that can cause liver cancer is cancer-causing toxins (aflatoxins). In
certain regions of Southeast Asia and sub-Saharan Africa, exposure
to aflatoxins is common. Two types of fungi found in poorly stored
grains, nuts, and seeds produce these toxins. Chemicals such as
vinyl chloride (used in the plastics industry) may cause
angiosarcoma (cancer in the inner lining of the blood vessels) and
increase the risk of HCC, but their use is strictly controlled.
Genetic disorders—such as alpha-1 antitrypsin deficiency, Wilson
disease, hemochromatosis, glycogen storage disorders (glycogen is
a complex form of sugar), and tryrosinemia (elevated blood levels of
the amino acid tyrosine) are also risk factors for HCC.

SYMPTOMS

Many people who have liver cancer have no symptoms, as

symptoms are only seen in advanced stages of the disease. Most
people with cirrhosis and HCC have symptoms that are related to
cirrhosis.
Some of the symptoms that people can have with advanced
cancer are:

• Weight loss
• Loss of appetite
• Nausea and vomiting
• Fatigue
• Yellowing skin
• Pain in the belly

SCREENING AND TESTING

The earlier a person knows they have liver cancer, the better their
chances for treatment and a cure. Screening is a way of checking for
cancer before a person may have any symptoms. Individuals who
have any of the other conditions that make them more likely to
develop cancer, especially people who have hepatitis B or cirrhosis
from any cause, should see their doctor every six months to have a
cancer screening. People who have ever had liver cancer before
should also see their doctor for regular surveillance, because they
are more likely to develop liver cancer again.
There is no reliable blood test for liver cancer. Instead, a doctor
will check for liver cancer by doing the following actions:

• Checking the blood for higher than normal levels of alpha-

fetoprotein (AFP)
 • Doing an ultrasound scan
• Using computed tomography (CT) or magnetic resonance
imaging (MRI)
• Taking some liver tissue to check for cancer (a biopsy) if a
diagnosis cannot be established through blood tests or imaging

Alpha-fetoprotein is a protein made in the liver. The levels of AFP

in a healthy adult are usually very low. About two-thirds of the people
who have liver cancer have higher than normal levels of AFP in their
blood. If an individual has levels that are greater than 400 ng/ml
(nanograms per milliliter), they are likely to have liver cancer. When
a person’s levels of AFP keep rising, it usually means that they
probably have liver cancer. But it’s important to know that this is not
a foolproof test. Elevated levels may or may not mean that a person
has liver cancer. Nonetheless, any individual who has higher than
normal levels of AFP should also have an ultrasound. If the doctor is
not sure whether a person has liver cancer based on the AFP blood
test and an ultrasound, a CT scan or an MRI scan may also be done.
Of the various imaging tests, CT and MRI scans are more accurate
than an ultrasound examination, but the first two tests are more
costly than an ultrasound.
In addition, a doctor may take a biopsy of the liver to test for liver
cancer and do a CT scan of other parts of the body to make sure the
cancer has not spread. The risk of transmitting liver cancer by
means of the biopsy needle (cancer spreading along the skin track)
is low.
Any person who has liver cancer should be tested for hepatitis B,
hepatitis C, and checked for other possible causes, such as
hemochromatosis.
Blood tests and an ultrasound (some medical centers also use CT
or MRI scans) are two common ways of checking for liver cancer, but
these techniques may not be able to find all liver cancers, especially
if an individual has tumors that are small. But, if people make sure
their doctor screens them every six months, they have a better
chance of any cancer being discovered at an early stage. If a person
has liver cancer, the size of the tumor, whether it has spread to any
lymph nodes, and whether it has spread to other parts of the body
will all help a doctor figure out what stage of cancer that person has.

TREATMENT

The treatment options for liver cancer are:

• Surgery
Removing the tumor and the surrounding part of the affected
liver
Getting a new liver through a transplant
• Local treatment (with needles)
Heating the cancer cells to destroy them (radiofrequency
ablation or microwave ablation)
Injecting the tumor with alcohol (percutaneous ethanol
injection)
Freezing the cancer cells to destroy them (cryotherapy)
• Local treatments using a catheter in the blood vessel that feeds
the tumor
Blocking the tumor’s blood supply and treating the tumor with
anti-cancer drugs (embolization or transarterial
chemoembolization, known as TACE)
Injecting the the tumor’s blood supply with radioactive beads
(transarterial embolization with beads of radiation, known as
TARE)
• Radiation therapy
Destroying the tumor with external beam radiation therapy
Proton beam radiation therapy
• Chemotherapy
Using medications, including immunotherapy (activating the
immune system to destroy tumors)

In the future, gene therapy may become applicable in the

management of liver cancer.
The treatments for liver cancer and their results are shown in
table 10.2.
When a person has liver cancer, a doctor will look at several
things to decide on the best treatment plan for that individual:

• The number of tumors, the size of the tumor(s), and where they
are located, including whether they are close to any blood
vessels
• Whether the liver cancer has spread to other parts of the body
• The stage of the liver disease, and whether the person has
cirrhosis
• How bad the cirrhosis is, or whether the person has developed
high pressure in the portal vein (by checking for varices via
endoscopy)
• Whether the person has any other serious diseases
• Whether the person is healthy

There are more choices for the best way to treat liver cancer if the
cancer is caught early, the tumors are small, and the cancer has not
spread to other parts of the body. Many people, however, do not
learn they have liver cancer until they experience symptoms, which
usually means they have late-stage liver cancer. Individuals with
late-stage liver cancer who also have symptoms usually only live for
few months after they learn they have liver cancer.
TABLE 10.2. Treatments for liver cancer
Treatment What is done Results

Liver transplant replaces the whole liver five-year survival rate of

with a liver from an organ 60% to 75%
donor

Liver surgery removes the tumor and five-year survival rate of

parts of the liver that are 35% to 42%, but the
affected by cancer chances of having liver
cancer again are high
(50% to 85%)

Radiofrequency and destroys the tumor by five-year survival rate of

microwave ablation inserting a needle into the 35% to 50%, but the
tumor and applying heat chances of having liver
cancer again are high
(50% to 85%)
Percutaneous ethanol destroys the tumor by five-year survival rate of
injection injecting concentrated 30% to 40%, but the
alcohol directly into the chances of having liver
tumor (not frequently cancer again are high
used) (50% to 85%)

Cryosurgery destroys the tumor by limited data are available,

freezing the tumor (not but it may be similar to
commonly used) radiofrequency ablation

Transarterial radiotherapy injects yttrium-90 into the used when no other

tumor treatments are possible

Chemotherapy gives anti-cancer pills to used when no other

keep the cancer from treatments are possible
growing

External beam radiation destroys the tumor by limited data are available,
radiation but possibly it is effective
in some

Proton beam radiation uses very focused only very limited data are
radiation, limiting possible available
damage to the
surrounding organs

If the cancer is caught in the early stages and has not spread to
other parts of the body, today there are many options to cure it (table
10.2). Recommendations about the best choice of treatment are
listed in table 10.3. A doctor may use several different methods to
treat the same person.
TABLE 10.3. Tumor size and treatment options for liver cancer
Tumor size Treatment options

Small tumor(s) (usually • liver transplant

less than 3 cm, or ~ • liver resection
1.25 inches) • radiofrequency ablation
• microwave ablation
• alcohol injection
• cryosurgery
 • transarterial chemoembolization

Tumor(s) (3 to 5 cm, or • liver transplant

~ 1.25 to 2 inches) • liver resection
• transarterial chemoembolization
• transarterial radioembolization
• external beam radiation

Large tumor(s) (5 cm or • surgery (in the absence of cirrhosis)

more, or ~ 2 inches or • transarterial chemoembolization
more) • transarterial radiation (yttrium-90)
• proton beam radiation

Tumor spreads outside • chemotherapy with or without immunotherapy

the liver (metastases)
or into a major hepatic
blood vessel

Removing the Tumor with Surgery

Liver cancer is caught early in only 20 percent of the people affected
by it. For them, the tumor can be removed with surgery. This is the
best treatment for people who do not have cirrhosis.
The chances of a person’s survival after surgery are greatest in
the following circumstances:

• The tumors are smaller than 2 inches (5 centimeters)

• A tumor is fibrolamellar (usually the type of cancer children
have)
• A tumor is not on a blood vessel

But most individuals who have liver cancer also have cirrhosis
(except people who have hepatitis B, or children with the
fibrolamellar type of liver cancer). If a person has cirrhosis and their
liver disease is mild, a doctor may try to remove the tumor with
surgery. For individuals who do not have cirrhosis, the risk of dying
from liver surgery (when it is performed by an experienced surgeon)
is less than 3 percent, but that risk rises to about 8 percent in people
who have cirrhosis.
 On average, the chance of surviving for five years after surgery is
about 35 percent, but that figure is higher if the person has small
tumors. If an individual has this type of surgery and the liver cancer
returns, that person may be considered for a liver transplant if they
meet the transplant conditions.

Getting a New Liver through a Transplant

For people who have late-stage cirrhosis and liver cancer, the best
treatment is a liver transplant. The cure rate is high, and these
individuals are less likely to get liver cancer again. Before a person
can have a liver transplant, their doctor will figure out if they have a
good chance for the transplant to be a success by looking at several
conditions that have to be met (known as the Milan criteria):

• If the person has only one tumor, the tumor is smaller than 5
centimeters
• If the person has more than one tumor but fewer than three, all
tumors are smaller than 3 centimeters
• The tumor has not spread to other parts of the body
• The tumor has not spread to a large blood vessel of the liver

People who meet these requirements have a 70–85 percent

chance of living for five years after they are diagnosed with liver
cancer (five-year survival rate). People who have larger tumors or
more than three tumors may be able to get a liver transplant, but the
results are usually not as good. There are criteria to shrink large
tumors and then have a liver transplant if the tumors could be
reduced enough in size to fulfill the Milan criteria.
The reasons why a person may not be suitable for surgery or a
liver transplant are listed in table 10.4, along with other treatment
choices. A doctor will look at the size of the tumor, its location, and
how severe the liver disease is when deciding on what alternative
treatments to use. Sometimes these treatments are intended as
temporary solutions until a liver transplant can be done.
TABLE 10.4. Treatments for individuals who cannot have surgery

People who have one or more of the following conditions are not considered to be
good candidates for tumor removal by surgery:
• advanced cirrhosis
• swelling in the belly
• bleeding from blood vessels (varices) or the presence of large varices
• mental confusion (hepatic encephalopathy)
• tumors that have spread to other parts of the body
• tumors that have spread to the liver’s blood vessels
• other serious heart or lung conditions

People who have one or more of the following conditions are not considered to be
good candidates for a liver transplant:
• tumors outside the Milan criteria (cannot be shrunk to fulfill the criteria)
• tumors that have spread to other parts of the body
• tumors that have spread to the liver’s blood vessels or the lymph nodes
• other serious heart or lung conditions
• other cancers
• age older than 70 years

Destroying the Tumor with Heat

There are two ways to destroy liver cancer cells with heat: using
either radio waves or microwave energy.

Radiofrequency Ablation
If an individual has a small tumor, the cure rates after this type of
treatment are similar to those for people who have liver surgery. The
use of radiofrequency ablation has become popular and is now the
preferred way to treat small tumors. A doctor can use this type of
ablation to treat the liver cancer, or to keep the tumor from growing
too quickly while the individual waits for a liver transplant. If the
person’s liver cancer returns after having this form of treatment, they
could be considered for a liver transplant if they meet the transplant
conditions.

Microwave Ablation
Microwave ablation uses heat from microwaves to destroy the liver
cancer cells. This treatment is fast, can be used on several tumors at
the same time, and can work for tumors that are larger than the ones
that can respond to radiofrequency ablation. Many cancer centers
now use microwave ablation instead of radiofrequency ablation to
treat liver cancer.

Injecting the Tumor with Alcohol

In this form of treatment, a doctor injects alcohol into the tumor to
destroy the liver cancer cells (percutaneous ethanol injection). This
method works well for tumors that are smaller (less than 2 cm, or
approximately 0.75 inches) and is not that expensive. For the best
results, a doctor needs to repeat these injections over several
intervals of time. The chances of surviving for five years after this
treatment are about 40 percent.

Cryotherapy
Unlike radiofrequency ablation or microwave ablation, where heat is
used to destroy tumor cells, cryosurgery (also known as
cryoablation) uses extreme cold to destroy tumor cells. Special
catheters that can deliver liquid nitrogen or argon gas to the tumor
produce this extreme cold. This technique, however, is not frequently
employed.

Blocking the Tumor’s Blood Supply with or without

Chemotherapy
When using this treatment, a doctor will cut off the main blood supply
to the liver cancer (embolization). Without its blood supply, the tumor
will die. But because a tumor can get blood from many different
blood vessels, the tumor may not be completely destroyed, so this
treatment will not be successful.
Usually a doctor cuts off the blood supply and also injects the
tumor with anti-cancer drugs (transarterial chemoembolization, or
TACE). Unfortunately, some tumors receive blood from more than
one arterial branch, or some cancer cells survive, leading to an
inadequate treatment response or a recurrence of the tumor. This
treatment does not cure a person’s liver cancer, but is a way to slow
down the the growth of the tumor. The chances of surviving five
years after this treatment are only 6 percent, perhaps because TACE
is used for people who have late-stage liver cancer.
 Injecting the Tumor with Radioactive Beads
With this treatment, a doctor cuts off the main blood supply to the
tumor and injects special radioactive beads to destroy the tumor
cells (transarterial radiation therapy, or TARE). A doctor uses this
treatment for people who have larger tumors. TARE is not
considered to be a cure, but it helps prevent the tumor from growing
too quickly. Some cancer centers prefer this option to TACE.

Destroying the Tumor with Proton Beam Radiation Therapy

This treatment uses high doses of proton beam radiation from
outside of the body to destroy the liver cancer cells. This type of
radiation can target and destroy the tumor without causing damage
to the surrounding organs. A doctor will use this treatment for people
who have larger tumors. Proton beam radiation is more expensive
and is available only in a limited number of cancer centers. It’s not
clear from research studies how well this treatment works.
Some centers also use external beam radiation therapy or
stereotactic body radiation therapy as alternative to more
conventional therapies.

Using Medications
There are many medicines that can be used to treat liver cancer
(chemotherapy), especially in people with late-stage liver cancer for
whom other treatments will not work. These medicines will keep the
tumor from growing too quickly, but they do not cure liver cancer.
The medications can fall under following groups:

• Receptor tyrosine kinase inhibitors (TKIs block proteins that

cause tumor growth)
Sorafenib
Lenvatinib
Regorafenib
Cabozantinib
Ramucirumab
• Checkpoint inhibitors (immunotherapy)
Nivolumab
 Pembrolizumab
• Combination treatment (a TKI plus a checkpoint inhibitor, or one
of these two inhibitors with other treatments, such as TACE or
TARE)

The tumor responds in about a third of the people with combination

treatments, and individuals who benefit from it will live longer. These
treatments are not considered to be curative.
People who take a TKI may have side effects, such as a rash
(mostly on the hands and feet), fatigue, diarrhea, and high blood
pressure. Immunotherapy may induce immune-mediated diseases,
such as an elevation in liver enzymes, thyroid disease, or
inflammation of the bowel (colitis).
Chemotherapy is rapidly evolving as a treatment for liver cancer,
and more of these medications should be approved in the near
future.

EARLY DETECTION AND PREVENTION

The best way to prevent liver cancer is to try to avoid the things that
put people in greater danger of getting this disease. Universal
vaccination for hepatitis B will reduce the risk of cancer worldwide.
People who have a significant likelihood of contracting a hepatitis B
infection because of certain behaviors should definitely get the
vaccine for hepatitis B. There is some evidence that coffee
consumption may reduce the cancer risk in people with cirrhosis
(discussed in chapter 12). Treatment for hepatitis B and C will
reduce the possibility of getting liver cancer. People with liver
disease should minimize their alcohol intake and stop smoking. Body
weight should be controlled if an individual is obese.
In order to have a major impact on reducing the death rate from
liver cancer worldwide, an inexpensive yet sensitive diagnostic tool—
and an equally effective treatment—would have to be made
available. To date, no such test exists. Early detection of liver cancer,
however, is possible with an ultrasound and an AFP measurement
every six months for people who have a higher risk of developing
cancer. Everyone with cirrhosis or hepatitis B (even those who do
not have liver disease) should have regular screenings for liver
cancer. Most people who have liver cancer go to their physician at
an advanced stage of the disease, too late for any effective
treatment. Screening for liver cancer could improve the cure rates by
detecting small tumors earlier.

People who need to be screened for liver cancer every six months:
• Anyone with cirrhosis from any cause
• Anyone with hepatitis B

A TEAM APPROACH

People who have liver cancer may have the best results at a cancer
center that uses a team approach. These centers have many
different doctors who have special training in treating liver disease.
These physicians will talk to a person about their condition and give
that individual the best advice on how to treat it.
FURTHER READING
Liver cancer: Know the risks; Understand the symptoms. American Liver
Foundation. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-
the-liver/liver-cancer/.
Thuluvath PJ et al. Role of locoregional therapies in patients with hepatocellular
cancer awaiting liver transplantation. Am J Gastroenterol. 2021 Jan
1;116(1):57–67. https://doi.org/10.14309/ajg.0000000000000999.
Doycheva I, Thuluvath PJ. Systemic therapy for advanced hepatocellular
carcinoma: An update of a rapidly evolving field. J Clin Exp Hepatol. 2019 Sep–
Oct;9(5):588–596. https://doi.org/10.1016/j.jceh.2019.07.012/. Epub 2019 Aug
2.
Sangro B et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev
Gastroenterol Hepatol. 2021 Apr 13;1–19. https://doi.org/10.1038/s41575-021-
00438-0/.
Mehta N et al. Liver transplantation for hepatocellular carcinoma: Working Group
Report from the ILTS Transplant Oncology Consensus Conference.
Transplantation. 2020 Jun;104(6):1136–1142.
https://doi.org/10.1097/TP.0000000000003174/.
 CHAPTER 11

Liver Transplantation

A doctor may suggest a liver transplant when a person’s liver

disease has caused so much damage that their liver no longer is
able to help keep them alive (liver failure) and other treatments will
not work. During this surgery, the patient will get a new healthy liver
from an individual who has recently died or part of a liver from
someone who is still living. A liver transplant is successful for most
people and will help them have longer, healthier lives.

COMMON REASONS TO NEED A LIVER TRANSPLANT

The reasons why a person may need a liver transplant are listed in
table 11.1.
Every year, more people need liver transplants, but there are not
enough healthy donor livers to meet this demand. Thus many
individuals have to wait a long time before they can get a healthy
liver, and about 10–20 percent of them will die before they are able
to get a transplant.
Livers for transplants can come from people who have recently
died, but often there are not enough designated organ donors to
provide livers in this way. For this reason, doctors may suggest a
transplant from a person who is living. In this type of surgery, a
portion of that individual’s healthy liver is given to the patient to
replace their damaged liver. Because the liver can grow back in a
few weeks, both the person who donates part of their liver and
recipient of the transplant will have a healthy liver.
TABLE 11.1. Reasons for a liver transplant

1. Fluid in the abdomen (ascites) that does not respond to sodium restriction and
diuretics
2. Infection of fluid in the abdomen (spontaneous bacterial peritonitis)

3. Confusion (hepatic encephalopathy)

4. Yellow discoloration of the eyes (persistent jaundice)

5. Presence of a small liver cancer

6. Kidney failure caused by liver disease (hepatorenal syndrome)

7. Bleeding from the stomach or esophagus despite a transjugular intrahepatic

portosystemic shunt (TIPS)

8. Child-Pugh score Child C cirrhosis (unlikely to improve with treatment, with

abstinence from alcohol, or with medications)

9. High MELD score (20 or more)

DECIDING WHO GETS A LIVER TRANSPLANT

Having one of the conditions listed in table 11.1 is just part of figuring
out whether a person needs a liver transplant. A doctor will look at
several things in deciding whether a transplant may be the best
treatment choice for that individual and base their choice on the
following questions:

1. Will the person get healthier from the liver transplant (both
immediately and in the future)?
2. What kind of liver disease does the person have?
3. What stage of liver disease does the person have?
4. What kinds of symptoms does the person have? Does having
those symptoms prevent the person from being healthy
physically, mentally, and emotionally?
5. What is the person’s chance of surviving the surgery (both
immediately and in the future)?
6. What are the benefits to the person in having a transplant
versus not having a transplant?
7. What are the disadvantages to the person in having a
transplant versus not having a transplant?
 Depending on the answers to all of these questions, if a doctor
decides that a liver transplant may be the right choice for that
individual, the doctor will then help the person find a transplant team
to talk to them about the next steps.
For example, an individual who has early-stage alcoholic cirrhosis
and does not have any major problems or symptoms has the same
odds of living for another five years, whether they have a transplant
or not. So the cost of the liver transplant, the medicines a person
needs to take after transplant surgery, and all the risks of having
major surgery may not be right for them at that time. But, if their
condition keeps getting worse over time, they can talk to their doctor
again to help them decide about the possibility of having a transplant
in the future.

THE TRANSPLANT EVALUATION PROCESS

A candidate for a transplant will first meet with a transplant team—a

group of people who have special training in liver transplant surgery.
The team members will talk to that individual to help decide whether
to recommend a transplant. The transplant team is made up of a
hepatologist (liver doctor), surgeon, social worker, psychologist,
financial coordinator, and transplant coordinator. The evaluation
process can last several hours, depending on the transplant center.
During that time, the team will look in detail at a person’s physical
condition and conduct blood and other tests to check that individual’s
health and mental condition—as well as assess the patient’s
finances, insurance, and social support system—and discuss the
best choices for that person, based on the team’s experience and
understanding of the latest research.
In evaluating a person for a possible liver transplant, the
transplant team will consider the following:

1. Does the person have a disease or condition that will be helped

with a liver transplant? If so, how soon does that individual need
a liver transplant? Does the person have a late-stage disease
that meets at least some of the conditions to have a liver
transplant?
 2. Does the person have any other diseases or conditions that
would prevent them from having a good result after a liver
transplant?
3. Does the individual have people who can help take care of
them and support them before and after the transplant surgery?
Does that person have a past history of alcohol or recreational
drug use? If so, is there a chance that the individual may start
to drink alcohol and use drugs again?
4. Would it help if the person could have a transplant from a living
donor, so they could get a transplant faster?

Reasons for a Transplant

The transplant team then thinks about the answers to each of those
four questions and asks the following ones:

1. Does the person have a disease or condition that will be helped

with a liver transplant?
2. If so, how soon does that individual need a liver transplant?
3. Does the person have a late-stage disease that meets at least
some of the conditions to have a liver transplant?

If a person has any of the conditions listed in table 11.1, they may
need a transplant. In addition, the decision of whether an individual
would need a transplant should be based in their physical health and
how long they may have left to live if they didn’t get a transplant.
Doctors use two different measurement systems to figure out the
level (stage) of liver disease and a person’s chances of dying from
that disease: the Child-Pugh score, and the Model for End-Stage
Liver Disease (MELD) sodium (MELD-Na) score. MELD-Na scores
are used to prioritize organ allocation in the United States.

Child-Pugh Score
The Child-Pugh score (table 11.2) measures how serious a person’s
liver disease is and what their chances of surviving it are by looking
at the results of blood tests, the levels of certain proteins in the
blood, and that individual’s symptoms. Each of these has a point
value. To figure out a person’s Child-Pugh score, all of the points are
added together. The total falls into one of three categories:

• Child A: A score of 5–6 points means the person has the least
serious form of liver disease, with a very high chance of
surviving after five years.
• Child B: A score of 7–9 points means the person has moderate
liver disease, with a 75 percent chance of surviving after five
years.
• Child C: A score of 10–15 points means the person has severe
liver disease, with about a 50 percent chance of surviving after
five years.

Model for End-Stage Liver Disease–Sodium Score

Doctors use the model for end-stage liver disease–sodium (MELD-
Na) score to predict a person’s risk of death if they have severe liver
disease. The MELD-Na score is a number, based on the results of
four different blood test results in people more than 12 years old
(table 11.3).
A MELD-Na score can range from 6 (less sick) to 40 (extremely
sick). A higher score means that the person’s condition may be more
serious and need a liver transplant. For example, if an individual has
a score greater than 25, they will be put higher on the list to get a
transplant, because they are more likely to die without a transplant
than a person who has a score of less than 10. A pediatric end-stage
liver disease (PELD) score is calculated for children younger than
12.
TABLE 11.2. Child-Pugh score calculation
Characteristic 1 Point 2 Points 3 Points

Encephalopathy none grades 1 to 2 grades 3 to 4

Fluid in the none slight (or controlled at least moderate

abdomen (ascites) by a diuretic) (despite a diuretic)

Bilirubin (mg/dl) <2 2 to 3 >3

Albumin (g/dl) > 3.5 2.8 to 3.5 < 2.8

International < 1.7 1.7 to 2.3 > 2.3
normalized ratio
(INR)

TABLE 11.3. Model for end-stage liver disease–sodium (MELD-Na) score

Blood tests as basis for the score

Serum bilirubin
International normalized ratio (INR)
Serum creatinine
Serum sodium (sodium values less than 125 mmol/L will be set to 125, and
values greater than 137 mmol/L will be set to 137)

Note: MELD-Na is a mathematical score. It can be easily calculated for free on the
Organ Procurement and Transplantation Network website,
https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/.

The United Network for Organ Sharing (UNOS), the organization

that manages the organ donation system in the United States, uses
MELD-Na scores to help determine which people need a transplant
the most and how soon they need it. An individual’s score can go up
or down, depending on their condition, so the transplant team will
keep assessing that person’s MELD-Na score periodically.
The only exception to this scoring system is people who are
“status 1”—those whose livers have suddenly stopped working and
are likely to die in a matter of days without a liver transplant.
A person’s MELD-Na score is just one part of the decision about
whether that individual will get a transplant—and how soon. The
transplant team will look at many different factors, such as the
potential recipient’s age, how many donors and how many people
needing a transplant live in a particular region, how geographically
close the recipient is to the source of the donated liver, the blood
type, and the donor’s age. UNOS has developed new rules for
making sure that donated livers are given fairly and equitably to the
people who need them most.
Once the transplant team decides to put a person on the waiting
list for a liver transplant, they will continue to check that individual’s
MELD score (or PELD score, for children) to see whether their
condition is getting better, staying the same, or getting worse. If that
person’s MELD score changes to a much lower number, they could
be taken off the list.

Other Diseases
• Does a person have any other diseases or conditions that would
prevent them from having a good result after a liver transplant?

The most important part of the process that the transplant team
uses to evaluate a person who may need a liver transplant is to
check whether that individual can handle the operation and have a
healthy life afterward. Because transplantation involves major
surgery, if the chances of a person dying from having this operation
are higher than the worsening condition of their liver, then a liver
transplant may not be the best decision. The transplant team will
look at any other health problems that individual has, such as
diabetes, heart disease, kidney disease, and cancer. Various
reasons why a person may not have a good result after a liver
transplant are listed in table 11.4, but these are just some of the
things the transplant team will look at.
People who have kidney failure may need both a liver and a
kidney transplant. A transplant doctor may decide to put some of
these individuals on the lists for both liver and kidney transplants but,
for others, decide to do a liver transplant first and, if necessary,
perform a kidney transplant later. A person’s age has less to do with
the result of the operation than with their chance of living a healthy
life in the long term. People who have diabetes or heart disease are
about 40 percent more likely to die within five years after having a
transplant than individuals who do not have these two conditions.
TABLE 11.4. Risk factors that predict a poor outcome after a liver transplant

1. Age older than 70 years

2. Uncontrolled diabetes with diabetes-related complications, such as generalized

vascular disease

3. Severe obesity (body mass index more than 40)

4. Coronary heart disease

5. Kidney failure

6. Transplant while in the intensive care unit

7. MELD-Na scores more than 35

8. Poor performance status (measurements of how well the person is able to

carry out ordinary daily activities)

Support System and History of Drug or Alcohol Use

• Does the individual have people who can help take care of them
and support them before and after the transplant surgery? Does
that person have a past habit of alcohol or recreational drug
use? If so, is there a chance that individual may start to drink
alcohol and use drugs again?

Often the hardest part of determining whether a transplant is the

best choice for a person is checking on their social support system.
Having someone else to help that person go to doctor appointments,
take their medicines the right way, and assist them after the
operation is very important in having a good result after the
transplant. The transplant team’s social worker and psychologist will
talk to the patient about having this support and help the team make
the best decision. After their evaluation, the whole transplant team
discusses that individual’s situation before making a decision.
A person who is placed on the list for a liver transplant must avoid
all recreational drug use and alcohol consumption. If an individual
has a problem with drug or alcohol addiction, most transplant centers
will require that person to finish an approved rehabilitation program
and have proof that they haven’t drunk any alcohol or used
recreational drugs for at least six months before they can be
considered for a transplant. People who do not follow this restriction
while on the waiting list for a liver transplant will be taken off the list.
The transplant programs have strict rules in place to make the
process of getting a liver transplant as fair as possible for everyone
on the waiting list.
 Living Donor Liver Transplants
• Would it help if the person could have a transplant from a living
donor, so they could get a transplant faster?

Getting part of a liver from a donor who is alive has some

advantages:

1. More potential living donors, to help more people needing a

transplant
2. Less time spent waiting for a donor, especially for individuals
who need a liver transplant right away
3. More time for the transplant team to help the person getting the
transplant prepare for the procedure
4. Less time for the donated liver tissue to be without blood flow
before it is put into the person receiving the transplant

The ability to get a liver transplant faster is helpful for people who
don’t have a high MELD-Na score but still need a liver transplant
soon, such as those who have major complications from cirrhosis.
Many individuals may able to have part of a liver donated from a
family member or friend who is willing to do so. Thus the first step is
talking to the transplant team about all of these possibilities.
The biggest problem with a liver donation from a living person is
that the donor has a chance of getting sick and dying (roughly less
than 1 in 400 people). For a healthy individual donating part of their
liver, transplant surgery is a major operation that can be risky and
does not directly help them in any way, other than getting a chance
to help someone else. Any individual needing a transplant who is
considering a discussion about this living donor option with the
transplant team should first meet all the conditions for having a liver
donated from a person who has recently died, as well as understand
that the live person who is donating part of their liver has some major
hazards to their health. The risks should be less than the benefits of
having the operation. Moreover, the person who is donating a part of
their liver should think very carefully about all of the risks to their
health before they decide to proceed with this major operation.
Making sure the donor stays healthy after the operation is extremely
important.

TRANSPLANT SURGERY

Before the Transplant

The transplant team will base their decision about whether to place a
person on the list for a liver transplant on the answers to all the
questions the team has looked at. Once someone is in line for a
transplant, the transplant team will do a lot of tests to better
understand that person’s health and make sure the individual is
ready for this major operation. Some of the testing includes:

• Looking at how the lungs are working (lung function tests)

• Taking a chest X-ray
• Checking to see how the patient’s heart is working
(electrocardiogram)
• Taking a picture of the heart with ultrasound (echocardiogram)
and a stress test (how the heart functions under stress)
• Doing blood tests
• Testing for HIV, hepatitis B, and other infections
• Taking an ultrasound picture of the blood vessels around the
heart and neck (carotid arteries) if the doctor thinks the person
has heart disease
• Taking a CT scan or an MRI to look at the blood vessels in and
around the liver

During this evaluation, the patient will meet with all the members
of the transplant team, including any specialist doctors. The team’s
psychologist and social worker will help that individual prepare for all
of the things that are involved with having major surgery, as well as
understand the liver transplant process. After the evaluation is
finished, the entire transplant team will get together to talk about the
evaluation results and decide for certain if a liver transplant is right
for that patient.

After the Transplant

After a liver transplant operation, the patient may have many short-
term and long-term problems. Liver surgeons are very experienced
these days, and immediate surgical complications have been
reduced. It is a complex surgery, however, and may take three to six
hours, even when done by an experienced team. The potential and
immediate surgical complications are listed in table 11.5.
TABLE 11.5. Immediate complications of a liver transplant
Complications Outcome

Complications from • blood loss is common and may require many units of blood
surgery or blood products
• blockage of an artery in the lungs is extremely rare
• blockage of a liver artery may require another surgery or
radiological intervention (less than 2% to 3%)
• a liver graft that is not working (less than 5%) usually
requires a retransplant
• a bile leak (up to 10%) is easily managed with a stent

Potential infections • bacterial infections (of the chest, urinary tract, abdominal
cavity, and wound) in the first few days
• viral infection (opportunistic infections, such as
cytomegalovirus) after the first 2 to 3 weeks
• fungal (yeast) infections in the immediate post-operative
period

Organ rejection • minor rejection (~20% to 40%) is easily treated with

medications, including steroids and, rarely, a monoclonal
antibody

Death • occurs in less than 5% of transplant recipients

Many of the short-term and long-term problems can be prevented

if the patient learns a lot about the process, follows all the
transplants team’s instructions after the surgery (table 11.6), and
gets tested regularly (table 11.7).
A person may choose to go back to their regular doctor after the
transplant. Learning as much as possible about the process will help
an individual know what they need to do after the surgery. Even if
they see their regular doctor, it may be a good idea to keep in touch
with the transplant team by phone. If the patient does not hear back,
they should keep calling until they reach a transplant team doctor.
TABLE 11.6. How organ recipients can improve liver transplant outcomes

1. Be well informed about a liver transplant, including its risks and complications.
2. Follow the transplant team’s instructions. Because the team manages many
liver transplant patients, team members are likely to be a better source of
information than many websites or other people’s experiences. Major concerns
regarding these instructions should be discussed with a transplant physician.
3. Have blood tests done periodically, as recommended by the transplant team
(see table 11.7). Follow up on blood test results and make sure the team has
seen the results. If possible, obtain a copy for your medical records. Learn what
the blood tests mean. Call the transplant physician if there is a major change in
your blood test results or you have any new symptoms. Sometimes the
physician may not have received or seen the test results.
4. Take medications as recommended. Do not miss any doses, and do not self-
treat.
5. Maintain your health and manage any other health conditions. Optimal health
maintenance is essential for a better outcome. The long-term outcome depends
on better management of other conditions or drug-related complications, such
as diabetes, hypertension, obesity, high cholesterol, kidney failure, and
cancers. Few people die from liver disease after the immediate post-operative
period.

TABLE 11.7. How often should a liver transplant recipient get blood tests?
Time period after the transplant How often to get tested?
0 to 3 months 1 to 2 times per week

3 to 6 months every 1 to 2 weeks

6 to 12 months every 2 to 4 weeks

1 to 5 years every 4 to 6 weeks

after 5 years every 3 months

Take Anti-Rejection Medications

When an individual has had a liver transplant, their body will treat the
new liver as a foreign object. Their immune system will “attack” the
new liver, making it less able to help the person recover from their
liver disease. These anti-rejection (immunosuppressive) medicines
will prevent the patient’s immune system from doing that and will
help their body not reject the new liver. A person has to take these
medicines for the rest of their life. The most common medicines
given to people who have had liver transplants are listed in table
11.8.
These medicines will help save a person’s life. They are, however,
associated with a few side effects. By making sure a person has
healthy (therapeutic) levels of the medicines in their body, some of
these side effects can be avoided. This is why it’s important to get
regular blood tests and talk to a doctor about the results. For some
of these medicines, the patient should have a blood test before
taking the medication, to measure the appropriate amount (trough
level) of that medicine correctly.
When taking these immunosuppressive medicines, it is very
important to talk to your doctor or to a pharmacist about any other
medications you are using, to make sure all the medicines will still
work and will not cause serious drug-drug interactions. Some
commonly used antibiotics can keep the anti-rejection drugs from
working. Therefore, it is important to check with your pharmacist or
your doctor before taking any new medicines.
TABLE 11.8. Common immunosuppressive agents taken after a liver transplant
Agent Properties

Tacrolimus A commonly used calcineurin (an enzyme that activates T

(Prograf), twice cells) inhibitor. Blood levels should be maintained between 6
daily and 12 ng/ml (trough levels before taking the medicine in the
morning), depending on the interval after the transplant and
other immunosuppressive medications being used.

Cyclosporine A commonly used calcineurin inhibitor. Blood levels should

(generic and be maintained between 100 and 200 ng/ml (trough levels
Neoral), twice daily before taking the medicine in the morning), depending on the
interval after the transplant and other immunosuppressive
medications being used.
Sirolimus, once A relatively new drug approved for a kidney transplant, with
daily no kidney toxicity. Blood levels should be maintained
between 6 and 10 ng/ml.

Mycophenolate A drug used with tacrolimus, cyclosporine, or steroids. As a

mofetil (Cellcept or single agent, it is inadequate for immunosuppression, so it is
Myfortic) used in combination with other drugs. Blood levels are not
monitored.

Prednisone A drug used only in the first few weeks after surgery, as most
people are weaned off this drug by six months. It is used with
other drugs in the immediate post-operative period.

Avoid Some Activities

Most people can lead a normal life after having a liver transplant.
Nonetheless, to stay as healthy as possible, they need to do certain
things and avoid other actions:

• Right after having transplant surgery, stay away from crowded

places, don’t be near people who are sick, don’t eat raw
shellfish, and don’t do any gardening.
• Do not have close contact with anyone who has recently had a
live vaccine (such as an oral polio vaccine).
• Do not get any live vaccines. Talk to a doctor first about whether
a vaccine is needed.
• Do not lift anything heavy for the first few months after surgery,
and then gradually begin to exercise.
• Do not drink any alcohol.
• Do not take any new medicines, even if only for a short time.
Check with a doctor first before taking any additional
medications.
• Talk to a transplant doctor before changing anything about the
anti-rejection medicines.

PROBLEMS AFTER SURGERY

Immediate Problems
The surgical team will closely check all people who have had a liver
transplant to make sure any problems that happen right after surgery
are taken care of immediately. Some of these issues can occur right
after the operation, such as complications from the surgery itself and
bacterial infections (see table 11.5).
Around two to four weeks after the transplant, people may get
other infections, because their immune system is weak from the anti-
rejection medicines. To prevent some of these infections, a doctor
may give special antiviral medicines (valgancicloviror for 3 months),
anti-fungal medications (fluconazole for 3 months), or antibiotics (a
sulfamethoxazole/trimethoprim combination, commonly known under
the brand name Bactrim, for up to 6 months).

Later Problems
Problems that can happen later are listed in table 11.9. The
immunosuppressive drugs, as well as other conditions the patient
had before the surgery, can cause many of these problems. Being
overweight, having high blood pressure, and having diabetes are the
most common conditions an individual will have before the surgery
that can cause more problems after the transplant. When a person
with these conditions is taking immunosuppressive drugs, that
individual is more likely to have serious heart problems. Transplant
recipients should make sure they are following steps to stay healthy
and control these conditions, to keep such problems from
happening.
TABLE 11.9. Late complications of a liver transplant
Complication Outcome

Hypertension is common (20% to 30%) and may be related to tacrolimus

or cyclosporine

Diabetes may be related to tacrolimus or cyclosporine (10% to 15%)

Kidney failure develops after five years in up to 20% of transplant

recipients, probably because of tacrolimus, cyclosporine,
diabetes, or hypertension

High cholesterol may be related to medications (sirolimus is known to cause

high cholesterol), obesity, or diabetes
Complication Outcome
Anemia is common (30% to 40%); may be multifactorial and is
usually mild

Osteoporosis is common, especially with steroid use

Cancer is common as skin cancer; other cancers include breast,

colon, and prostate cancer

Lymphoproliferative may be related to Epstein-Barr virus (the same virus that

disease causes infectious mononucleosis); seen in less than 3% of
transplant recipients

Obesity is the most common problem

Bile duct problems occur in up to 10% of transplant recipients

Recurrent disease depends on the primary disease

A person who has had a transplant is more likely to get skin

cancer (basal and squamous cell cancer), and they should see a
skin doctor (dermatologist) once a year to check for these possible
forms of cancer. They also have a higher risk of having other types
of cancers, such as breast, prostate, or colon cancer. People who
have inflammatory bowel disease should have a colonoscopy every
year to check for colon cancer.
The field of liver transplantation keeps changing as more research
is done to improve the process. For example, liver transplant doctors
are conducting ongoing research to find out if some people could
stop taking immunosuppression medicines a few years after their
liver transplant.
FURTHER READING
Liver Transplant. American Liver Foundation. https://liverfoundation.org/for-
patients/about-the-liver/liver-transplant/.
Living donor liver transplant: An introduction for donors and recipients. American
Liver Foundation. https://liverfoundation.org/living-donor-liver-transplant-an-
introduction/.
Transplant living. United Network for Organ Sharing. https://transplantliving.org/.
Liver policy: Making liver distribution more fair and equitable. United Network for
 Organ Sharing. https://unos.org/policy/liver-distribution/.
European Association for the Study of the Liver. EASL clinical practice guidelines:
Liver transplantation. J Hepatol. 2016 Feb;64(2):433–485.
https://doi.org/10.1016/j.jhep.2015.10.006/. Epub 2015 Nov 17.
Martin P et al. Evaluation for liver transplantation in adults: 2013 practice guideline
by the American Association for the Study of Liver Diseases and the American
Society of Transplantation. Hepatology. 2014 Mar;59(3): 1144–65.
https://doi.org/10.1002/hep.26972/.
 CHAPTER 12

Liver Health

A liver that functions well is extremely important for our well-being.

As discussed in earlier chapters, the liver has many important
functions, including making essential proteins; processing fats and
carbohydrates; creating and secreting bile to help the intestines
absorb fats and fat-soluble vitamins; getting rid of potentially harmful
chemicals the body produces; and getting rid of toxins, such as from
drugs, alcohol, and environmental poisons.
The original concept of “liver health” perhaps came from
traditional Chinese and Indian medicine, but the idea that a healthy
liver is essential for the proper functioning of the human body was
recognized all over the ancient world. Today’s modern medicine
accepts this widely held belief, but there are many fundamental
differences in the interpretation of liver health. While many assume
that liver health could be sustained by taking herbal or mineral
supplements, the scientific evidence suggests that liver health can
be maintained only by avoiding toxins (including unnecessary
medications and excessive alcohol), preventing viral infections (by
being vaccinated and not engaging in high-risk behaviors), and
keeping an ideal body weight through good nutrition and exercise.
Despite the overwhelming absence of scientific evidence, the use
of nutritional supplements and “liver-cleansing” methods are widely
practiced all over the world. This chapter will examine these
practices in more detail. Estimates indicate that 20 percent of the US
population takes herbal preparations and spends approximately $50
billion on these unproven remedies. According to the Global
Wellness Institute, approximately $360 billion is spent worldwide on
traditional and complementary medicine.

COMPLEMENTARY AND ALTERNATIVE MEDICINE

 (CAM) IN THE TREATMENT OF LIVER DISEASE

The National Center for Complementary and Alternative Medicine

defines complementary and alternative medicine (CAM) as “a group
of diverse medical and healthcare systems, practices, and products
that are not presently considered to be part of conventional
medicine.” Under the Dietary Supplement Health and Education Act
(DSHEA) of 1994, herbs are classified as dietary supplements.
Under the wording of this law, supplements are broadly defined as
“anything that supplements the diet” and include vitamins, minerals,
herbs, amino acids, enzymes, and herbal extracts. The FDA has little
regulatory control over dietary supplements. Therefore, these
products remain unregulated. Unlike drugs approved by the FDA,
supplements can be sold without manufacturers or regulators
demonstrating the clinical benefits of these items. Although
marketers cannot make explicit health claims for a supplement (like
“cures cancer”), they can promote its known effect on what the 1994
act calls the “structure and function” of the body (claims such as
“protects against cell damage”), and they can give the product any
name they like (“Liver Master,” “Liver Health,” “LiverWell,”
“LiverCleanse,” “LiverDetox,” “Anti-Alcohol Complex,” and so on).
The use of herbal medicines can be traced as far back as 2100
BC in ancient China (the Xia dynasty) and India (the Vedic period).
The utilization of herbal plants and alternative techniques (such as
acupuncture) was originally confined to Asia and Africa but now has
become universal. The current increase in the use of alternative
medicine by people who have liver disease could be attributed partly
to the failure of conventional treatments to cure some of the more
common forms of liver disease, such as hepatitis B and non-
alcoholic fatty liver disease. Another reason for the popularity of
herbal preparations is the perception that they are “natural” and
therefore are a safer form of therapy. The holistic and spiritual
appeal of these substances also attracts people with chronic liver
diseases to these forms of treatment.
Many herbal preparations for liver disease fall within “mainstream”
homeopathic, traditional Chinese, and Ayurvedic medicine. A
discussion of all such preparations is beyond the scope of this book,
but this chapter focuses on some commonly used herbal medicines
and supplements available in the United States. The loose
classification of CAM supplements and techniques used in treating
liver disease listed in table 12.1 is not complete by any standards,
and it is increasing.
TABLE 12.1. Complementary and alternative medicines used in the treatment of liver
disease
Supplements or medications
Poorly defined
Defined formulations formulations Techniques

silymarin TJ-9 acupuncture

Phyllanthus amarus compound 861 prayer
St. John’s wort Liv 52 spirituality
glycyrrhizin CH-100 massage therapy
homeopathy hypnotherapy
Ayurvedic medicine energy therapy
traditional Chinese
medicine

Herbal Products
In US surveys, more than one in three people (30 to 60 percent) who
had liver disease said they were using naturopathic remedies. The
most common item is milk thistle, followed by green tea, St. John’s
wort, and dandelion root. Many individuals ingest multiple
preparations, and most people do not tell their physician they are
taking herbal products. The use of herbal preparations and
supplements is increasing in the United States and rest of the world.
A scientific review of herbal preparations is challenging, because
many of them are not standardized and often contain concoctions of
various extracts. These products are unregulated, so preparations
marketed under the same or similar names might have completely
different compositions. Most of the herbal products available on the
market have not been tested in clinical trials. Even when they are
tested, the measures that are used (the end points) are often
subjective (“feeling good,” “having more energy,” and so on) rather
than reproducible data (such as clearance of a virus, improvement in
liver biopsy findings, a decrease in the size of a tumor). In addition,
the toxicity of herbal remedies—their harmful effects—is poorly
reported or documented. Some herbal preparations may also contain
subtherapeutic doses of conventional (allopathic) medications, which
are deliberately mixed in, making matters worse as far as clinical
tests are concerned. Some commonly used preparations are
discussed in the following sections.

Milk Thistle (Silymarin)

Milk thistle is an extract from Silybum marianum, a plant grown
commercially throughout the United States. The active component in
milk thistle extract is silymarin, a mixture of plant compounds called
flavonolignans (silydianin, silychristin, and silybin). Silybin (also
known as silibinin) makes up 60 to 70 percent of silymarin and is its
most biologically active ingredient, with the remaining 30 to 40
percent being chemically undefined.
Silybin is the major active ingredient of silymarin, and its
pharmacological properties are well understood. In laboratory
experiments, silybin shows antioxidant properties (that is, it prevents
the formation of chemicals called free radicals, which damage cells)
and appears to protect liver cells and reduce inflammation and
scarring, with little or no toxicity. Nonetheless, the clinical trials of
silybin were done with only small numbers of people, were poorly
designed, and used variable and subjective measures of its effects.
Many clinical trials have been conducted to assess the efficacy of
silymarin for treating acute viral hepatitis. These trials were not
conducted according to the usual scientific standards. Moreover, in
many of the trials, the cause of the person’s acute hepatitis was
poorly defined and the follow-up period was short. The results
showed inconsistent benefits, with some demonstrating favorable
effects in the treatment groups and others not indicating any
difference between the treated and untreated (control) groups. On
the basis of current evidence, the use of silymarin for the treatment
of acute viral hepatitis (A or B) cannot be justified. No good trials
have been conducted on the use of silymarin for people who have a
chronic hepatitis B infection. Silymarin has no role in treating
hepatitis C.
Silymarin has also been tested in people with alcohol-related liver
disease, primary biliary cholangitis and non-alcoholic fatty liver
disease. Some of these studies showed an improvement in liver
enzymes in the treatment group compared with the control group,
but the results are inconsistent. No side effects related to silymarin
were observed in clinical trials, suggesting that silymarin is safe even
at higher than customary doses. Milk thistle does not cause any
drug-drug interactions. There is no firm evidence, however, to
suggest that it has any long-term benefits for people who have acute
or chronic liver disease.

St. John’s Wort

St. John’s wort is a widely used herbal preparation with potentially
serious herb-drug interactions with many medicines, including
medications used for the treatment of hepatitis C and as
immunosuppressants (drugs used to suppress the immune system)
after an organ transplant. St. John’s wort, an extract of the herb
Hypericum perforatum, contains many pharmacologically active
ingredients. The main ingredient is hyperforin, a substance that may
have some beneficial properties for people who experience
moderate or severe depression. There is no evidence, however, that
St. John’s wort is comparable or superior to commonly used
antidepressants. Many people take this preparation, perhaps for its
mood-elevating effect. Nonetheless, St. John’s wort has many
possible adverse effects because of the potential herb-drug
interaction with commonly used medications.

St. John’s wort induces the production of enzymes that clear some commonly
used medications from the body. This results in reduced blood levels of these
medications and makes them ineffective or less effective. If you are taking St.
John’s wort, please ask your physician whether it is safe to do so.

Glycyrrhizin
Glycyrrhizin, containing chemicals called sulfated saponins and
lectins, is derived from licorice root. It has been used for more than
20 years in Japan to treat chronic hepatitis. The standardized
glycyrrhizin-containing aqueous (liquid) extract, called Stronger Neo-
Minophagen C (SNMC), has been tested in many people who have
liver disease. Clinical trials have shown improvement in liver enzyme
levels in people with chronic hepatitis who took SNMC. In a long-
term study, SNMC reduced the development of liver cancer in people
who had a hepatitis C infection, but low potassium levels and
hypertension were observed in 10 and 3 percent, respectively, of
those treated with SNMC. These effects are thought to be related to
its hormonal properties (resembling the effect of hormones called
mineralocorticoids), and caution needs to be exercised when using
this compound for people who have preexisting portal hypertension,
as it may worsen peripheral edema (swelling in the legs) and cause
electrolyte abnormalities. It is safer to avoid this herbal product for
those reasons.

Phyllanthus amarus
The herb Phyllanthus amarus, known as “bahupatra” in India,
contains compounds called hypophyllanthins and polyphenols and is
said to have antiviral properties. Despite claims in some clinical
studies of the clearance of hepatitis B surface antigens, there is no
firm evidence that this substance is beneficial.

TJ-9 (“Xiao Chai Hu Tang” or “Sho-saiko-to”)

The Chinese herbal medicine known as TJ-9 is widely used in Japan
for the treatment of liver disorders. It is a dried mixture of seven
herbs (from the roots of Scutellaria, Glycyrrhiza, Bupleurum, and
ginseng (Panax); Pinella tubers; jujube fruit; and ginger root). The
major alkaloids from Scutellaria, called baicalin and baicalein, are
strong antioxidants and are known to inhibit cell multiplication and
induce the death of liver cancer cells. Despite its wide use, there are
few clinical trials with TJ-9. The potential benefit of this compound in
preventing liver cancer was also tested in a five-year study of 260
people who had cirrhosis. The rates of liver cancer development
were similar in the treatment and control groups, but there was a
trend favoring the treatment group for people who did not have
hepatitis B. There was no difference in survival rates between the
treatment and control groups, suggesting that the benefits of this
compound, if any, are marginal.

Compound 861
Compound 861, which comes from China, is an aqueous extract of
many herbs. In laboratory experiments, it has been shown to reduce
scarring of the liver. There are no well-conducted studies, however,
to confirm that this is an effective compound.

Liv 52
The Ayurvedic drug known as Liv 52, widely used in India, is an
extract of several plants. As with many other herbs, there are animal
experiments showing potential benefits from its use. Some studies
on people who had acute hepatitis reported an improvement in their
liver enzymes, but these studies had no control group. Thus it is
difficult to draw any conclusions, especially since spontaneous
improvement in liver enzyme levels is common in acute hepatitis. A
two-year clinical trial, consisting of 188 people who had alcohol-
related liver disease, failed to show any survival benefit for people
with cirrhosis, and the death rate was higher in the treatment group
for people who had more-advanced liver disease (81 percent versus
40 percent in the control group). Because of its potential toxicity,
people with liver disease should not use this drug.

Other Drugs and Herbal Products

CH-100 is a Chinese herb that has been used for the treatment of
hepatitis C, but no consistent beneficial effects have been identified
so far. Many other compounds are used by people who have liver
disease, including picroliv, thymosin, bing gan ling, kurorinone,
Iscador Qu, and Acanthopanax senticosus. The active ingredients in
these substances are mostly unknown, and there are no good
clinical trials showing any benefits from using these products. In
general, these compounds should be avoided.

OTHER TREATMENT OPTIONS

 Homeopathy
Homeopathy is based on the belief that very tiny quantities of natural
ingredients—such as sulfur, snake venom, duck liver, squid ink,
mercury, arsenic, and a host of other naturally occurring compounds
—may cure illnesses. Modern homeopathic mixtures are sometimes
diluted a million times or more, often so many times that no active
ingredients may be left in them. Homeopathy was first introduced in
the United States in 1825, and its use has recently increased, with
homeopathic medicine sales rising substantially in this country. Many
people use homeopathic medications, but no good clinical trials of
these medications have been conducted.

Acupuncture
A survey conducted among people who had hepatitis C indicated
that 1 in 10 had received acupuncture as an alternative attempt at
therapy. Acupuncture has been studied in people who have hepatitis
B and as an adjunctive (secondary) treatment for pain following liver
cancer surgery. There is no evidence of a liver disease–related
benefit from acupuncture, and there is a potential risk of contracting
blood-borne infections if sterile techniques are not employed.

Coffee, Green Tea, Iron Supplements, and Vitamins

Coffee
There is some evidence to suggest that drinking two or more cups of
coffee a day may prevent the development and progression of liver
cancer. There may be other beneficial effects (improvement in liver
enzymes, slower progression of fibrosis) for other liver diseases,
including fatty liver disease.
Caffeine (in coffee and tea) is a naturally occurring
methylxanthine, and in laboratory experiments it has been shown to
prevent the multiplication of cancer cells. Several studies have
confirmed the benefit of coffee in cancer reduction. This benefit was
seen in both men and women, regardless of the cause of liver
disease—even in those who drank alcohol regularly. A low
consumption of coffee was associated with a 30 percent reduction in
liver cancer risk, and high consumption was associated with a 60
percent reduction. Based on these studies, it is reasonable to
conclude that coffee drinking is beneficial for people with liver
disease.

There is evidence to suggest that coffee consumption is beneficial for people

with liver disease, and the regular consumption of two or more cups of coffee
may reduce the risk of liver cancer.

Green Tea
Although green tea consumption is common, liver injury due to green
tea or its extracts is uncommon. One problem with green tea,
however, is that there are hundreds of different types of green tea
available around the world. It is therefore not known whether any
specific type of green tea (or its impurities) is the culprit in rare cases
where it causes liver damage. Green tea consumption is increasing
in western countries for its medicinal properties, including its alleged
weight-loss characteristics. Clinical trials have not shown any liver
benefits from drinking green tea for weight-loss purposes, but these
studies also have not indicated any adverse effects, suggesting that
liver injury is very uncommon. Green tea extracts, widely available in
the United States, are derived from the leaves of Camellia sinesis
plants.
There are multiple types of green tea, and many of them may vary
from batch to batch, with some impurities. The exact cause of liver
damage from green tea is unclear, for the same reasons. Many
green tea products have been shown to contain a number of
unknown herbs or other commonly used medicines, such as anti-
inflammatory agents, steroids, sildenafil (Viagra), and so on. These
ingredients are never documented on the package.

Iron Supplements or an Iron-Rich Diet

Adequate iron intake is important to maintain normal levels of
hemoglobin (the chemical that carries oxygen in red blood cells), and
iron deficiency will lead to anemia. Iron absorption is controlled in the
small intestine, but the long-term ingestion of excess iron (in food or
as supplements) may lead to “iron overload,” which may then cause
damage to liver cells.
People who have liver disease should avoid iron supplements if
they do not have an iron deficiency. Please ask your doctor about
the safety of using iron supplements if you have been told you need
to take them.

Vitamins
Higher doses (above clinically recommended doses) of vitamin A,
niacin (vitamin B3), vitamin C, and vitamin D can result in liver
damage. Niacin and vitamin A can cause serious liver damage and
should not be taken without consulting a doctor. Abnormalities from a
vitamin C overdose are usually transient.
It is safe to take vitamin D if blood tests show low levels of it, as
vitamin D has many beneficial effects, including maintaining bone
density. Low bone density (osteopenia and osteoporosis) is common
in people who have cirrhosis. Low vitamin D levels are also common
in the general population, as well as in individuals with liver disease.
Excess vitamin D levels may be harmful, however, and people
should avoid an excess intake of vitamin D.

Potential Liver Toxicity from Herbal and Dietary Supplements

In the United States, findings suggest that 20 percent of drug-
induced liver injury is due to dietary supplements. In literature from
elsewhere in the world, this ranges from 2 to 70 percent, with the
wide variation mostly due to reporting bias. The list of liver-damaging
supplements in table 12.2 is not complete, but it can be used as a
guide.
The major causes of liver injury in the United States are anabolic
steroids (used as body-building supplements), green tea extracts,
and nutritional supplements that contain multiple ingredients.
In addition to being damaging to the liver, many herbal
preparations may interfere with the elimination of other commonly
used medications (table 12.3). This interference can cause either low
or high blood levels of other medications.
Please let your doctor know that you are using any of these
preparations if you are also taking other medications. Avoid them
during hepatitis C treatment.
TABLE 12.2. Supplements with a potential for causing liver damage
Indication for use Supplements
Joint problems flavocoxid (Limbrel), Schiff Move Free products,
glucosamine (only weak evidence)

Pain control black cohosh, comfrey

Weight loss conjugated linoleic acid, ephedra (ma huang),

germander, green tea, Herbalife products, Hydroxycut
products, usnic acid

Gastrointestinal OxyElitePro® (for weight loss), aloe vera, chaparral,

problems greater celandine

Psychological problems kava-kava, skullcap, valerian

Other indications noni, pennyroyal, Liv 52

Herbal preparations and other substances that may increase or

TABLE 12.3.
decrease other medication levels

danshen germander papaya

devil’s claw gingko biloba pyrrolizidines
dong quai ginseng Sho-saiko-to
echinacea glycyrrhizin St. John’s wort
feverfew grapefruit juice tamarind
garlic kava-kava

Summary on Supplements
Herbal preparations are widely used by people who have liver
diseases, despite the absence of scientific evidence regarding their
benefits. Some herbal preparations have been shown to improve
liver enzyme levels but not have any positive impact on viral counts,
liver biopsy results, or the incidence of liver cancer. In addition, some
herbal preparations are associated with toxic effects or with herb-
drug interactions (such as St. John’s wort), while others, like milk
thistle (silymarin) and TJ-9, are relatively safe.
There is increasing evidence that two or more cups of coffee a
day may be beneficial for people who have chronic liver disease.
Iron supplements should be used only if an individual has an iron
deficiency. Similarly, vitamin A or niacin supplementation (outside a
multivitamin pill) should be under the supervision of a doctor. People
should consult with their physician before they decide to use any
herbal preparations.
Anyone who is planning to use an herbal preparation may also
benefit from visiting the LiverTox website (see “Further Reading”),
developed by a division of the National Institutes of Health, that
examines the short-term and long-term safety of herbal preparations
and dietary supplements.

SAFETY OF ACETAMINOPHEN (TYLENOL)

Therapeutic doses of acetaminophen (less than 2,000 mg per day)

are safe for the general population, as well as for those who have
chronic liver diseases, including cirrhosis. The only exception is for
individuals who drink excessive amounts of alcohol. There is a
general belief that people who have liver disease should completely
avoid acetaminophen. The body eliminates therapeutic doses of
acetaminophen, however, without any toxicity, even in the presence
of advanced cirrhosis. Other pain medications, such as nonsteroidal
anti-inflammatory drugs (ibuprofen, naproxen, indomethacin, etc.)
may cause gastrointestinal bleeding and kidney toxicity. Thus people
who have esophageal or gastric varices and those with kidney
dysfunction should avoid such drugs.
For individuals with cirrhosis, it is preferable to use
acetaminophen carefully (never to exceed 2,000 mg per day) for
pain management and avoid nonsteroidal anti-inflammatory drugs.
Although narcotics could be used, they are likely to create addiction
and may cause hepatic encephalopathy (confusion) in people who
have cirrhosis.

MAINTAINING LIVER HEALTH

In pursuit of liver health, often people do more harm than good by

taking supplements. Liver health can be maintained by avoiding
harmful activities, minimizing alcohol intake, not using unproven
herbal remedies, not over-supplementing with vitamins and minerals,
and maintaining an ideal body weight through exercise and diet.
Vaccination for hepatitis A and B and controlling diabetes or high
cholesterol and triglyceride levels are also important. If liver disease
is suspected, you should seek expert care to avoid progressive liver
damage. Those with chronic liver diseases should follow up with a
liver doctor.
TABLE 12.4. Maintaining liver health
Things to do Things to watch out for

• vaccinate for hepatitis A and B • limit your alcohol intake (maximum of

• check for hepatitis B and C and treat if 2 drinks for men and 1 for women per
present day if there is no liver disease)
• maintain ideal body weight with diet • avoid high-risk behaviors
and exercise • avoid herbal supplements
• control diabetes well (if present) • do not over-supplement with minerals
• control cholesterol and triglycerides (if and vitamins
high) • do not ignore liver enzyme
• seek expert help if a liver disease or abnormalities
fatty liver is suspected • discuss any problems with your doctor
• learn about your liver disease, if it is before taking over-the-counter
diagnosed medications

MALNUTRITION IN LIVER DISEASE

Although the role of overnutrition in the context of fatty liver was

discussed in detail in chapter 7, malnutrition is equally common in
people with advanced liver disease. Many factors contribute to
malnutrition, including malabsorption; increased or altered
metabolism; loss of taste; inadequate intake of sodium due to salt
restriction; hormonal changes; changes in the intestinal bacterial
flora; or an ongoing inflammation. In addition, reduced physical
activities or a lack of exercise may lead to further deterioration in
muscle mass and strength. Malnutrition may make a person
susceptible to infections and hepatic encephalopathy. Among
transplant recipients, malnutrition may increase their recovery time
and decrease their quality of life.
It may be useful to seek the help of a dietician with an interest in
liver disease if you are suffering from cirrhosis. A detailed dietary
recommendation is beyond the scope of this book, but general
guidelines, based on published recommendations, are summarized
in table 12.5.
Nutritional supplementation alone may not reduce a wasting away
of muscles. For people with liver disease, a tolerable amount of
exercise should be continued, after discussing an appropriate level
of activity with their physician. There are websites that provide useful
information with regard to graded exercise regimens, such as
Wellness Toolbox (see “Further Reading”). Exercise should be
started slowly (three to four days per week) and increased to daily
exercise (walking up to 40 minutes daily). Those who are very
debilitated may have to start with one to two minutes of walking,
followed by resting for one to two minutes, and gradually build up the
duration of their exercise. Walking could be indoors or outdoors.
TABLE 12.5. General dietary guidance for people with cirrhosis
Calories
(kcal/kg
body Protein (g/kg
Condition weight) body weight) Salt Supplements Special diet

Cirrhosis > 35 1.2–1.5 no one MVT none

without added
complications salt

Advanced > 35 1.2–1.5 (at 2g one MVT and late evening

cirrhosis least 1.5 if (2000 replace deficient snack
malnourished) mg) minerals and
frequent small
vitamins*
meals in
those with HE
BCAA in
special
circumstances

Note: MVT = over-the-counter multivitamin tablets; HE = hepatic encephalopathy;

BCAA = branched chain amino acids.
*Vitamin D, iron, vitamin E, vitamin K, vitamin A, or zinc if deficient.

FURTHER READING
Taking care of your liver. American Liver Foundation. https://liverfoundation.org/for-
patients/about-the-liver/health-wellness/#1507301343822-50491142-06d3/.
Diet and liver disease. British Liver Trust. https://britishlivertrust.org.uk/information-
and-support/living-with-a-liver-condition/diet-and-liver-disease/.
Buchard B et al. Assessment of malnutrition, sarcopenia, and frailty in patients with
cirrhosis: Which tools should we use in clinical practice? Nutrients 2020 Jan
9;12(1):186. https://doi.org/10.3390/nu12010186/.
Bunchorntavakul C, Reddy, KR. Review article: Malnutrition/sarcopenia and frailty
in patients with cirrhosis. Aliment Pharmacol Ther. 2020 Jan;51(1):64–77.
https://doi.org/10.1111/apt.15571/. Epub 2019 Nov 8.
Cirrhosis—Overview. Wellness Toolbox. https://wellnesstoolbox.ca/cirrhosis/.
European Association for the Study of the Liver. EASL clinical practice guidelines
on nutrition in chronic liver disease. J. Hepatol. 2019 Jan;70: 172–193.
https://doi.org/10.1016/j.jhep.2018.06.024/. Epub 2018 Aug 23.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National
Institute of Diabetes and Digestive and Kidney Diseases.
www.ncbi.nlm.nih.gov/books/NBK547852/.
Tandon P et al. Exercise in cirrhosis: Translating evidence and experience to
practice. J Hepatol. 2018 Nov;69:1164–1177.
https://doi.org/10.1016/j.jhep.2018.06.017/. Epub 2018 Jun 30.
Traub J et al. Malnutrition in patients with liver cirrhosis. Nutrients 2021; 13:540.
https://doi.org/10.3390/nu13020540/.
 Patient Resources

ORGANIZATIONS
• American Association for the Study of Liver Diseases
1001 North Fairfax Street, Suite 400
Alexandria, VA 22314
Tel: 703-299-9766
Fax: 703-299-9622
Email: aasld@aasld.org
www.aasld.org

• American Liver Foundation

39 Broadway, Suite 2700
New York, NY 10006
Tel: 212-668-1000
Fax: 212-483-8179
Hepatitis C helpline: 1-800-465-4837
https://liverfoundation.org

• Centers for Disease Control and Prevention

Division of Viral Hepatitis
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB
Prevention
1600 Clifton Road, Mailstop G-37
Atlanta, GA 30333
Tel: 1-800-CDC-INFO (1-800-232-4636)
TTY: 1-888-232-6348
www.cdc.gov/hepatitis/hcv/index.htm

• National Institute of Diabetes and Digestive and Kidney Diseases

website
 LiverTox: Clinical and Research Information on Drug-Induced
Liver Injury, www.ncbi.nlm.nih.gov/books/NBK547852/

Other Useful Organizations

• Hepatitis C Advocacy, https://hepcadvocacy.org
• Hepatitis B Foundation, www.hepb.org
• Hepatitis C Association, www.hepcassoc.org
• Hepatitis Foundation International, https://hepatitisfoundation.org
CLINICAL TRIALS
• ClinicalTrials.gov (a service of the National Institutes of Health),
https://clinicaltrials.gov
MEDICATION ASSISTANCE PROGRAMS
• AbbVie, www.rxabbvie.com
• Genentech Patient Assistance for Pegasys and Copegus, 1-888-
941-3331
• Gilead Patient Assistance for Sovaldi, 1-855-769-7284,
www.mysupportpath.com
• Johnson & Johnson Patient Assistance Foundation, 1-800-652-
6227, www.jjpaf.org
• Medicare, www.medicare.gov
• Patient Access Network (PAN) Foundation (for underinsured
patients), 1-866-316-PANF (1-866-316-7263),
www.panfoundation.org
• RxAssist, Patient Assistance Program Center, www.rxassist.org

FINDING A SPECIALIST
• American Association for Study of Liver Diseases, www.aasld.org
• American Gastroenterological Association, www.gastro.org
• American Liver Foundation, www.liverfoundation.org
• Infectious Disease Society of America, www.idsociety.org

LIVER TRANSPLANTATION
 • United Network for Organ Sharing (UNOS)
1100 Boulders Parkway, Suite 500
P.O. Box 13770
Richmond, VA 23225-8770
Tel: 804-330-8602
www.unos.org

MELD AND PELD CALCULATIONS

• Organ Procurement and Transplantation Network, Allocation
Calculators, https://optn.transplant.hrsa.gov/resources/about-
meld-and-peld/

DRUG INTERACTIONS
• University of Liverpool Interaction Checker, www.hep-
druginteractions.org
 Index

Page numbers in italics indicate figures

abetalipoproteinemia, 82
accidental exposure to hepatitis, 36, 48, 53, 61–62
acetaldehyde, 73
acetaminophen, 13, 14, 114–15, 116, 117, 187–88
acetate, 73
acidosis, 117
acoustic radiation force impulse (ARFI) elastography, 25
acupuncture, 177, 183
aflatoxins, 142
AFP (alpha-fetoprotein), 21, 144, 154
AIDS. See HIV/AIDS
alanine aminotransferase (ALT), 12–14, 24, 97, 100
albumin, 2, 12, 13, 15, 125, 161
alcoholic cirrhosis, 74, 75, 76, 80
alcoholic fatty liver, 73, 74, 75, 76, 82
alcoholic hepatitis, 73–74, 75, 76, 79–80
alcoholic liver disease, 5, 70, 72, 73–81, 179, 182
alcohol use: and acetaminophen use, 115, 187
avoiding, 54, 57, 73, 76–77, 107, 110, 137, 171
consumption guidelines, 71–73, 88, 188
and deaths, 70, 72
health consequences of, 71
and liver cancer risk, 76, 77, 142, 154
rehab for, 78–79, 164
and transplants, 73, 159, 164, 171
alkaline phosphatase (ALP), 12–14, 100, 101, 102, 104–5
alkalosis, 117
alpha-1 antitrypsin deficiency, 5, 110–11, 143
alpha-fetoprotein (AFP), 21, 144, 154
ALT (alanine aminotransferase), 12–14, 24, 97, 100
alternative medicine, 175–87, 189
ammonia, 2, 113, 125, 131
anabolic steroids, 142, 185
anasarca, 119
anemia, 108, 135, 172, 184
angiogram, 22
angiosarcoma, 141, 143
antacids, 65
antibiotics, 126, 131, 171, 172
antibodies: defined, 18. See also specific antibodies
anti-convulsants, 65, 66, 115
anti-fungals, 172
antigens: defined, 18. See also specific antigens
anti-liver-kidney microsomal antibodies (anti-LKM), 97, 98, 99, 104
anti-mitochondrial antibodies (AMA), 20, 21, 100, 104, 105
anti-nuclear antibodies (ANA), 20, 21, 97, 98, 99, 104
antioxidants, 178, 181
anti-SLA/LP, 104
anti-smooth muscle antibodies (ASMA), 20, 21, 97, 98, 99, 104
antiviral treatment, 43, 61–62, 63–68, 117, 171–72
ARFI (acoustic radiation force impulse) elastography, 25
armpit hair, loss of, 8, 119
ascites: and coinfection with HIV, 56
defined, 9
and liver transplant, 157, 161
and surgery, 150
as symptom/complication, 7, 8, 9, 74, 76, 119, 124
ASMA (anti-smooth muscle antibodies), 20, 21, 97, 98, 99, 104
aspartate aminotransferase (AST), 12–14, 24, 97, 100
asterixis (flapping tremors), 8, 119
ATP7B gene, 108
autoimmune disorders, 96–105
overlap syndrome, 103–5
primary biliary cholangitis, 5, 21, 100–101, 103–5, 137
primary sclerosing cholangitis, 5, 14, 101–5
autoimmune hepatitis. See hepatitis, autoimmune
autoimmune thyroid disease, 133, 134, 137
Ayurvedic medicine, 175, 176–77, 181–82
azathioprine, 98–99, 103

bacterial flora, 85, 87, 91, 131

bacterial infections, 118, 119–20, 126, 167, 172
balloon tamponade, 128, 130
banding, variceal, 128, 129, 130
bariatric surgery, 89, 92, 94
B-cell lymphoma, 134, 136
Behçet’s disease, 133, 134, 138
belly, fluid in. See ascites
bile, role of liver in, 1–2
bile ducts, 121, 123
blockages, 6, 7
cancer of, 7, 102–3
imaging tests, 22
and liver function tests, 13, 14
and liver transplant complications, 167, 173. See also primary
biliary cholangitis; primary sclerosing cholangitis
bilirubin, 2, 11–13, 15, 74, 105, 161
bleeding: gastrointestinal, 76, 118
gums, 114
and polyarteritis nodosa, 135
variceal bleeding, 56, 120, 127–31, 150, 157
blood: clotting abnormalities, 118
transfusions, 29, 31, 48, 49, 54, 59. See also prothrombin /
prothrombin time (PT)
blood pressure: and cirrhosis, 120–24
and hepatitis C, 54
and liver transplant complications, 172
in metabolic syndrome, 82, 84
and NAFLD, 84
and primary biliary cholangitis, 101
and variceal bleeding, 127–31. See also portal hypertension;
portopulmonary hypertension
bone health, 10, 42, 43, 99, 101, 173
brain: swelling of, 117
and Wilson disease, 108. See also hepatic encephalopathy
branched chain amino acids, 190
breast cancer, 99, 173
bronze diabetes. See hemochromatosis
Budd-Chiari syndrome, 114, 116, 117

caffeine, 183
cancer: and alcohol, 71
and autoimmune hepatitis, 99
and drug-drug interactions, 65
from liver transplant, 173
and NAFLD, 94
and primary sclerosing cholangitis, 102–3. See also specific types,
e.g., liver cancer
carbohydrates: in diet, 90–91
and role of liver, 1–2
ceruloplasmin, 109
CH-100, 177, 182
chemotherapy, 39, 40, 44, 146, 147, 148, 153–54
Child-Pugh scores, 157, 160, 161
children: cirrhosis in, 61
hepatitis B in, 30, 34, 35
hepatitis C in, 59–61, 62, 68
membranoproliferative glomerulonephritis in, 135
NAFLD in, 84
overlap syndrome in, 103
transplants in, 61, 161. See also hepatitis, maternal transmission
of
Chinese medicine, 175, 176–77, 181–82
cholangiography, 22, 102, 104
cholesterol, 54, 82, 84, 91, 92, 172, 188
cirrhosis: alcoholic, 74, 75, 76, 80
assessing level of, 25
bacterial infections from, 119–20, 126
bleeding from, 120, 127–31
in children, 61
 complications from, 9–10, 119–20, 124–39
deaths from, 87
defined, 5
diet for, 189–90
effect on other organs, 10, 132–39
fluid buildup from, 119, 124–26
and hepatitis B treatment, 40
and hepatitis C, 56, 57, 58, 67, 77
lifestyle changes for, 88–92
and liver cancer, 10, 120, 132, 142, 143–44, 146, 154, 155
and liver transplant evaluation, 157
and malnutrition, 189
medications research, 93–94
mental effects of, 120, 131–32
and NAFLD/NASH, 86, 87, 88–92, 93
progression of, 56, 57, 77
reversibility of, 6
and surgical risk, 149, 150
symptoms of, 7
and wasting, 76, 120
cirrhotic cardiomyopathy, 10, 139
coffee, 183, 187
colon cancer, 99, 103, 173
coma, 118, 120, 131
complementary medicine, 175–87, 189
compound 861, 177, 181
computed tomography. See CT (computed tomography)
constipation, 131, 132
copper, 108
COVID-19, 4
creatinine, 161
CREST syndrome, 133, 138
Crohn’s disease, 102, 103
cryoglobulinemia, 133, 134, 136, 137
cryotherapy, 145, 147, 148, 152
CT (computed tomography), 22, 83, 144, 145, 166
cutaneous necrotizing vasculitis, 138
cyclosporine, 99, 170, 172
cytomegalovirus, 4, 5, 31

deaths: from acute liver failure, 113

from alcoholic hepatitis, 79
from alcoholic liver disease, 72, 79
and alcoholism, 70, 72
from cirrhosis, 87
from hepatitis B, 33
from hepatitis C, 46, 56
from liver cancer, 87, 132, 141
and liver transplants, 156, 165, 167
and MELD-Na score, 160–62
from NAFLD/NASH, 86, 87, 90, 94
and polyarteritis nodosa, 135
from variceal bleeding, 129
decompensation of liver disease: defined, 9. See also cirrhosis
delta virus. See hepatitis D
diabetes: as complication of liver disease, 133, 138
as complication of liver transplant, 172
and fatty liver, 85
and hepatitis C, 54, 138
and liver cancer, 142
and liver health tips, 188
and liver transplant evaluation, 163
and NAFLD, 84
diagnosis, 11–26
of alcoholic hepatitis, 74
assessing level of fibrosis, 23–26
of autoimmune hepatitis, 21, 97–98, 104
of fatty liver, 83
of hemochromatosis, 106–7
of hepatitis B, 36–38
of hepatitis C, 50–54
for liver cancer, 21, 144–45
and liver function tests, 11–15, 52
of NAFLD, 83
 of NASH, 87–88
of overlap syndrome, 103–4
of portal hypertension, 122–23
of primary biliary cholangitis, 100
of Wilson disease, 108–9. See also liver biopsy; testing
diet: and alcoholic hepatitis, 75, 79
and alcoholic liver disease, 75, 79
and cirrhosis, 189–90
and constipation, 131, 132
copper in, 109
and hepatic encephalopathy, 131, 132
iron-rich, 184
and liver health tips, 188
and malnutrition, 189
Mediterranean, 91
and NAFLD, 89–92, 94
protein in, 131, 132
sodium in, 124
and Wilson disease, 109
digestive system, 3
bacterial flora, 85, 87, 91, 131. See also stomach; variceal
bleeding
diuretics, 124
drug-induced liver injuries, 96, 114
drug interactions, 58, 64–66, 170, 179–80, 185, 186
drug use, 29, 30, 35–36, 48, 49, 55, 159, 164

edema, 7, 8, 9, 119, 124, 180

elastography, 25–26, 83, 88
electrolyte abnormalities, 132, 180
embolization, 145, 148, 152
emphysema, 110
endoscopic retrograde cholangiography (ERC), 102, 104
endoscopic retrograde cholangio-pancreatography (ERCP), 22
endoscopy, 128, 129, 130, 146
entecavir, 41–42, 43
Epclusa, 63, 64, 65, 67, 68
Epstein-Barr virus, 4, 5, 31
ERC (endoscopic retrograde cholangiography), 102, 104
ERCP (endoscopic retrograde cholangio-pancreatography), 22
erythema, 8, 9, 119
esophagus, 3, 120, 127, 127–31, 157
estrogen, 66, 137
ethnicity. See race/ethnicity
exercise, 89, 90, 92, 94, 188, 189
external beam radiation therapy, 146, 147, 148, 153
eyes: Mooren’s corneal ulcer, 133, 134, 138
and Wilson disease, 109. See also jaundice

fat, dietary: and NAFLD, 90, 91, 92

role of liver in, 1–2, 85
fatty liver: alcoholic, 73, 74, 75, 76, 82
causes of, 82, 85–86
grades of, 83. See also NAFLD
ferritin, 21, 107
fiber, 90, 131
fibrinogen, 2
fibrolamellar tumors, 149
FibroMeter, 24
FibroScan, 23, 53, 83, 88
fibrosis: assessing level of, 23–26, 100, 110
defined, 4
and hepatitis C, 6, 53–54, 67, 77
Metavir scoring, 53–54
and NAFLD/NASH, 86, 88, 93
reversal of, 6, 89
stages of, 53–54
FibroSURE, 23, 24
fluid buildup, 119, 124–26. See also ascites; edema
food and hepatitis transmission, 28, 29, 31, 49. See also diet
fungal infections, 167, 172

gallbladder, 2, 3
cancer of, 6, 102–3
 gallstones, 6, 7
gamma-glutamyl transpeptidase (GGT), 12–13, 105
gene therapy, 146
genetic disorders: as cause of liver disease, 4, 5, 96, 105–11
and fatty liver, 82
list of, 96
and liver cancer, 143
and NAFLD, 86, 87
screening for, 21, 107
GGT (gamma-glutamyl transpeptidase), 12–13, 105
glecaprevir. See Mavyret
glomeruli, 134–35
glue, 128
glycogen storage disorders, 143
glycyrrhizin, 177, 180, 186
green tea extract, 177, 184, 185, 186

hair, loss of armpit/pubic, 8, 119

hands, red (erythema), 8, 9, 119
Harvoni, 64, 65, 67, 68
HAV. See hepatitis A
HBV. See hepatitis B
HCC. See liver cancer
HCV. See hepatitis C
HDV. See hepatitis D
heart: and cirrhosis complications, 10, 134, 139
heart disease, 71, 134, 163
and liver transplant, 163, 166, 172
and NAFLD, 90, 94
hemangiosarcoma, 141
hemochromatosis, 5, 21, 105–8, 142, 143, 145
hemodialysis, 49, 59
hemophilia, 49, 59
hepatic artery, 120–24, 121, 123
hepatic encephalopathy: diet for, 190
and liver transplant, 157, 161
and surgery, 150
 as symptom/complication, 56, 74, 76, 113, 117, 120, 131–32
and TIPS, 125
treatment for, 131–32
hepatic veins, 121, 122, 123, 123
hepatitis, alcoholic, 73–74, 75, 76, 79–80
hepatitis, autoimmune: and autoimmune thyroid disease, 137
as cause of liver disease, 5, 97–100
diagnosis and testing for, 14, 21, 97–98, 104
enzyme levels in, 14, 97
liver failure from, 115, 116
and overlap syndrome, 103–5
treatment for, 98–100, 116, 117
hepatitis, ischemic, 114, 115
hepatitis, maternal transmission of: hepatitis B, 29, 30, 33, 36, 40,
44–45
hepatitis C, 29, 48, 59–61, 62
hepatitis E, 29, 31
hepatitis, viral: as cause of liver disease/failure, 5, 114, 115
defined, 27
diagnosis of, 36–38, 50–54
medications for, 39–43, 63–68
numbers of cases, 27, 52
overview of, 27–32
symptoms of, 7, 28
testing for, 14, 15–20, 36–38, 51, 52–53, 62–63, 145, 166. See
also vaccines; specific forms
hepatitis A: acute infection, 14, 16, 28
as cause of liver disease/failure, 5, 115, 117
numbers of cases, 27
spread of, 28, 29
symptoms of, 28
testing for, 14, 15, 16, 18, 51
treatment of, 29, 30, 179
vaccine, 29, 30, 54, 78, 115, 188
hepatitis A antibodies, 16, 18
hepatitis B, 33–45, 34
acute infection, 14, 16, 30, 33–34, 36–39
 as cause of liver disease/failure, 5, 114, 115
in children, 30, 34, 35
chronic infection, 6, 13, 14, 18, 30, 33–34, 36–38, 39–43
deaths from, 33
diagnosis of, 36–38
effect on other organs, 132, 133, 135, 136, 137
immune tolerant, 34
and liver cancer, 10, 34, 38, 39, 40, 42, 44, 58, 141–45, 154, 155
numbers of cases, 27, 33
overview of, 29, 30
research on, 45
reversing of cirrhosis in, 6
spread of, 29, 30, 33, 35–36
symptoms of, 28, 35
testing for, 13, 14, 15, 16–17, 18–19, 36–38, 51, 63, 166
treatment of, 29, 30, 33, 38–43, 154, 179, 181, 183
vaccine, 29, 30, 36, 39, 44–45, 54, 78, 115, 154, 188
hepatitis B antibodies, 16, 18, 37, 38
hepatitis B antigens, 16, 18, 19, 37
hepatitis B DNA, 16, 19, 37, 40
hepatitis Be antigen negative disease, 16, 17, 19
hepatitis C, 46, 46–69
acute infection, 14, 30, 47, 51–53, 60–61, 67–68
and alcohol, 54, 57, 76–77
and blood screening, 49, 61
as cause of fatty liver, 82
as cause of liver disease, 5
in children, 59–61, 62, 68
chronic infection, 13, 30, 47, 53–54
coinfection with HIV, 54, 55–58, 60
deaths from, 46, 56
and diabetes, 54, 138
diagnosis of, 50–54
effect on other organs, 132, 133, 134, 135, 136, 137, 138
and fibrosis, 6, 53–54, 67, 77
genotypes, 17, 20, 47, 50, 63, 64, 68
and hepatitis B treatment, 40
 and hepatitis D coinfection, 19, 27, 31
and liver cancer, 54, 56, 57, 58, 67, 77, 141–42, 145, 154
numbers of cases, 27, 46, 49, 52
overview of, 29, 30
progression of cirrhosis in, 54, 56, 57, 77
reinfection, 67
reversing of fibrosis in, 6
spread of, 29, 30, 33, 48–49, 59–61
symptoms of, 28, 47–48, 52, 53
testing for, 13, 14, 15, 17, 19–20, 52, 145
testing for other conditions, 51
treatment of, 29, 30, 33, 39, 44, 57–58, 61, 62–68, 154, 179–80,
182, 183, 185
vaccine, 29
hepatitis C antibodies, 17, 19–20, 50, 52–53
hepatitis C RNA, 17, 19, 50, 51, 52, 77
hepatitis D: as cause of liver disease, 5
hepatitis C coinfection, 19, 27, 31
spread of, 29, 31
testing for, 17, 19, 20, 38
treatment of, 29, 31
hepatitis D antibodies, 17
hepatitis D RNA, 17
hepatitis E: acute infection, 17, 20, 31
as cause of liver disease/liver failure, 5, 115
chronic infection, 31
spread of, 29, 31
testing for, 17, 20
treatment of, 29
vaccine, 29
hepatitis E antibodies, 17, 20
hepatocellular carcinoma. See liver cancer
hepatopulmonary syndrome, 10, 138–39
hepatorenal syndrome, 157
herbal supplements, 65, 66, 114, 175–82, 184–87, 189
herpes simplex virus, 4, 5, 31
HEV. See hepatitis E
HFE gene, 106
Hitachi real-time elastography (HI-RTE), 25
HIV/AIDS: and hepatitis C, 49, 54, 55–58, 60, 65
number of cases, 55
testing for, 38, 51, 166
homeopathy, 177, 182
homeostatic iron regulator (HFE) gene, 106
Hyde’s prurigo nodularis, 133, 134
hypertension. See blood pressure
hyperthyroidism, 137
hypoglycemia, 117
hypothyroidism, 85, 137

immune tolerant hepatitis B, 34

immunoglobulins (Ig): and autoimmune hepatitis, 97, 98, 99, 104
and overlap syndrome, 104, 105
and primary biliary cholangitis, 100, 104
testing, 12, 13, 16–18, 20, 21
immunosuppressive medications, 66, 169–70
immunotherapy, 146, 147, 148, 153, 154
Indian medicine, 175, 176–77, 181–82
inferior vena cava, 121, 122
inflammation, 89, 92, 94
inflammatory bowel disease (IBS), 173
insulin resistance, 85, 89, 91, 92
interferon, 31, 43, 137
international normalized ratio (INR), 13, 161
intra-arterial/transarterial radiation therapy (TARE), 145, 147, 148,
152
intrahepatic cholangiocarcinoma, 141
intrahepatic cholestasis, 14
iron: in diet, 184
and hemochromatosis, 5, 21, 105–8, 142, 143, 145
iron saturation, 21, 107
and porphyria cutanea tarda, 136, 137
ischemic hepatitis, 114, 115
jaundice: and alcoholic cirrhosis, 76
and alcoholic hepatitis, 73–74
and autoimmune hepatitis, 97
defined, 25
as general symptom, 7, 8, 114, 119
and hepatitis, 7, 28, 35, 48, 52
and liver cancer, 143
and liver transplant evaluation, 157
and primary biliary cholangitis, 101

Kayser-Fleischer rings, 109

kidneys: effects of liver disease on, 10, 118, 133, 134–35
and hepatic encephalopathy, 132
and hepatitis B, 41, 42, 43, 135
and hepatitis C medications, 64
and liver transplants, 157, 163, 172
and treatment for fluid buildup, 125
kidney transplant, 135, 163, 170

lactic acidosis, 42, 43

lactic dehydrogenase (LDH), 12, 13
lactulose, 131
ledipasvir. See Harvoni
legs, fluid in. See edema
leukocytoclastic vasculitis, 133, 134
lichen planus, 133, 134, 137
lifestyle modifications, 88–92, 94
Lille scores, 79
lipodystrophy, 82
Liv 52, 177, 181–82, 186
liver, 2, 3, 121, 123
blood supply, 120–24
damage stages, 4–6
failure, acute, 113–18
failure, chronic, 118–32
failure, defined, 156
health tips, 188
 role of, 1–2, 71, 73, 120. See also cirrhosis; diagnosis; fibrosis;
hepatitis; medications; testing; treatment
liver biopsy, 23
described, 22–23
transjugular, 23
and treatment decisions, 41
liver cancer, 141–55
and alcohol consumption, 76, 77, 142, 154
and alcoholic cirrhosis, 76, 80
causes of, 141–43
in children, 34
as complication of cirrhosis, 10, 120, 132, 142
deaths from, 87, 132, 141
diagnosis of, 21, 144–45
and hemochromatosis, 106, 107, 108, 142, 143, 145
and hepatitis B, 10, 34, 38, 39, 40, 42, 44, 58, 141–45, 154
and hepatitis C, 54, 56, 57, 58, 67, 77, 141–42, 145, 154
liver transplant for, 145, 149–50, 157
metastatic, 141
and NASH, 86–87
numbers of cases, 141
prevention of, 154–55
and primary biliary cholangitis, 101
re-occurrence of, 147, 151
screening for, 38, 42, 58, 80, 107, 108, 132, 143–45, 154–55
and SNMC, 180
staging, 146
survival rates, 146, 147, 149, 150, 151, 152
symptoms of, 143
testing for, 21, 143–45
treatment of, 145–54, 181
and Wilson disease, 109
liver disease: causes overview, 4, 5, 96
complications overview, 9–10
decompensation of, defined, 9
defined, 4
effects on other organs, 10, 132–39
 overview of, 1–10
stages of, 4–6, 146, 157, 159, 160
symptoms overview, 4, 5–9. See also alcoholic liver disease;
cirrhosis; diagnosis; fibrosis; genetic disorders; hepatitis; NAFLD;
testing; treatment
liver function tests, 11–15, 87–88
liver resection, 145, 147, 148–49
liver transplant, 156–73
alcohol consumption after, 73, 171
Child-Pugh scores, 157, 160, 161
in children, 61, 161
complications from, 167–73
deaths during wait for, 156
deaths from, 167
evaluation for, 157–66
and fluid buildup, 125, 157
follow up, 168, 169
and list priority, 160–62
for liver cancer, 145, 149–50, 157
from living donors, 156, 159, 164–65
and malnutrition, 189
MELD-Na scores, 157, 160–62, 163, 165
Milan criteria, 149, 150
and organ rejection, 167
PELD score, 161
post-surgery, 167–71
preparation for, 166
reasons for, 159–60
risks of, 162, 165
survival rates, 150, 158, 160
lung function tests, 166
lungs: and alpha-1 antitrypsin deficiency, 110
and liver disease complications, 10, 133, 134, 138, 139
and liver transplant, 166, 167
lymphoma, 133, 134, 136, 137
lymphoproliferative disease, 173
magnetic resonance cholangiography (MRC), 102
magnetic resonance cholangio-pancreatography (MRCP), 22, 104
magnetic resonance imaging. See MRI (magnetic resonance
imaging)
malnutrition, 189
MALT (mucosa-associated lymphoid tissue) lymphoma, 133, 134
maternal transmission of hepatitis. See hepatitis, maternal
transmission of
Mavyret, 63, 64, 66, 67, 68
medications: autoimmune-like hepatitis from, 97
as cause of fatty liver, 82
as cause of liver disease/failure, 5, 114–15
for hepatitis B, 39–43
for hepatitis C, 63–68
for liver transplant, 168, 169–70
for NAFLD, 93–94
for primary biliary cholangitis, 101
for primary sclerosing cholangitis, 102
research on cirrhosis, 93–94
for variceal bleeding, 128–29. See also drug interactions
Mediterranean diet, 91
MELD/MELD-Na scores, 157, 160–62, 163, 165
membranoproliferative glomerulonephritis, 133, 134–35
mental confusion. See hepatic encephalopathy
metabolic syndrome, 82, 84
Metavir system, 53–54
microwave ablation, 145, 147, 148, 151
Milan criteria, 149, 150
milk thistle (silymarin), 177, 178–79
Model for End-Stage Liver Disease (MELD) sodium scores. See
MELD/MELD-Na scores
Mooren’s corneal ulcer, 133, 134, 138
MRCP (magnetic resonance cholangio-pancreatography), 22, 104
MR elastography, 26, 83, 88
MRI (magnetic resonance imaging), 22, 24, 26, 83, 107, 144, 145,
166
mucosa-associated lymphoid tissue (MALT) lymphoma, 133, 134
muscles, wasting of. See wasting
mushroom poisoning, 114, 116
mycophenolate mofetil (Myfortic), 99, 170

N-acetylcysteine (NAC), 116

NAFLD (non-alcoholic fatty liver disease), 4, 5, 6, 77, 82–94, 179
NASH (non-alcoholic steatohepatitis), 86–87, 88–94, 141
needlesticks, 36, 48, 53, 55, 61–62
niacin (vitamin B3), 185
non-alcoholic fatty liver disease. See NAFLD
non-alcoholic steatohepatitis. See NASH
non-Hodgkin’s lymphoma, 133, 134, 136, 137
nonsteroidal anti-inflammatory medicines (NSAIDs), 23, 115, 187

obesity: and alcoholic liver disease, 75, 78

diet recommendations for, 91, 92
and liver cancer risk, 142, 154
and liver transplant, 163, 168, 173
and NAFLD, 84
obeticholic acid (OCA), 93, 101, 104
omega-3 fatty acids, 90, 91, 92
organ transplants: and hepatitis B, 39, 40
and hepatitis C, 48, 64
kidney transplant, 135, 163, 170
rejection in, 167, 169–70. See also liver transplant
osteopenia. See bone health
overlap syndrome, 103–5

pANCA, 104
pancreas, 2, 3
pancreatic cancer, 6
pancreatitis, 71
paracentesis, 125
Paris criteria, 103, 105
pediatric end-stage liver disease (PELD) score, 161
penicillamine, 109, 116
penicillin, 116
percutaneous ethanol injection, 145, 147, 148, 151
percutaneous transhepatic cholangiography (PTC), 22
pericardial effusion, 134
peripheral neuropathy, 42, 43
phlebotomy, 107
Phyllanthus amarus, 177, 181
pibrentasvir. See Mavyret
poisoning, mushroom, 114, 116
polyarteritis nodosa, 135
porphyria cutanea tarda, 133, 134, 136–37
porphyrin, 136
portal hypertension, 10, 122–24, 127–31, 139, 146, 180
portal vein, 121
portopulmonary hypertension, 10, 138–39
prednisolone, 79, 80, 98–99
prednisone, 98–99, 170
pregnancy: and alcohol, 71
delivery and hepatitis C transmission, 59–60, 62
erythema in, 9
and hepatitis B treatment, 40, 41, 44–45
liver failure related to, 117
spider nevi in, 9. See also hepatitis, maternal transmission of
primary biliary cholangitis, 5, 21, 100–101, 103–5, 137, 179
primary sclerosing cholangitis, 5, 14, 101–5
prostate cancer, 99, 173
protein: in blood, 11, 12
in diet, 131, 132
and role of liver, 1–2
prothrombin / prothrombin time (PT), 2, 12, 13, 15, 74
proton beam radiation therapy, 146, 147, 148, 153
PTC (percutaneous transhepatic cholangiography), 22
pubic hair, loss of, 8, 119
pulmonary fibrosis, idiopathic, 133, 138

race/ethnicity: and alcoholic liver disease, 75

and hemochromatosis, 105, 106
and NAFLD, 84
radiation therapy, 146, 147, 148, 153
radiofrequency ablation, 145, 147, 148, 151
radiological tests, 22, 24–26
razors, sharing of, 36, 48
reactive oxygen species (ROS), 73
respiratory system, 118, 120. See also lungs

salivary glands, 133, 134, 136

scarring. See fibrosis
SERPINA 1 gene, 110
sexual activity and hepatitis transmission, 28, 29, 30, 35, 48, 49, 55
shear wave elastography (SWE), 25–26
sialadenitis, 133, 134, 136
silibinin, 116, 178
silymarin (milk thistle), 177, 178–79
sinusoids, 121, 122, 123
sirolimus, 170, 172
Sjögren’s syndrome, 136
skin: and hemochromatosis, 107
itching, 133, 134, 136–37. See also jaundice
skin cancer, 99, 173
sleep disturbances, 120, 131
smoking, 54, 78, 142, 154
SNMC (Stronger Neo-Minophagen C), 180
social support: and alcoholism, 79
and transplant evaluation, 158, 159, 164
sodium: and fluid buildup from cirrhosis, 124
and MELD-Na score, 160–62, 163, 165
sofosbuvir, 63, 64, 65, 67, 68
spider nevi, 8, 9, 119
spontaneous bacterial peritonitis, 119, 126, 157
SSI (supersonic shear imaging), 25
stellate cells, 74
stereotactic body radiation therapy, 153
steroids: and bone health, 99
as cause of fatty liver, 82
treatment with, 79, 80, 98–99, 116, 117, 167, 170
steroids, anabolic, 142, 185
St. John’s wort, 65, 66, 177, 179–80, 186
stomach, 3
bleeding as symptom, 76
and liver transplant, 157. See also variceal bleeding
strain elastography, 25
Stronger Neo-Minophagen C (SNMC), 180
supersonic shear imaging (SSI), 25
supplements: as cause of liver disease, 5, 114, 185–86
cautions, 175–82, 184–87, 189
defined, 176
and drug interactions, 65, 66, 179–80, 186
for NASH, 91–92
surgery: for liver cancer treatment, 145, 147, 148–50
liver failure from, 115
surgical complications, 167. See also liver transplant
SWE (shear wave elastography), 25–26

TACE (transarterial chemoembolization), 145, 148, 152

tacrolimus, 99, 170, 172
TARE (transarterial radiation therapy), 145, 147, 148, 152
tattoos, 48
TE (transient elastography), 25, 26
tenofovir, 41–42, 43, 65
testicles, 8, 119
testing: for alcoholic hepatitis, 74, 79
assessing level of fibrosis, 23–26
for autoimmune hepatitis, 14, 21, 97, 104
genetic testing, 107
for hemochromatosis, 21, 107, 145
for liver cancer, 21, 143–45
liver function tests, 11–15, 87–88
and liver transplant, 158, 160, 161, 166, 168, 169
for NASH, 87–88
overview of, 11–26
radiological tests, 22, 24–26
for viral hepatitis, 13, 14, 15–20, 36–38, 51, 52–53, 62–63, 145,
 166
for Wilson disease, 109
thrombocytopenia, idiopathic, 133, 134, 138
thrombolytic therapy, 117
thyroid, 85, 133, 134, 137
TIPS (transjugular intrahepatic portosystemic shunt), 116, 125, 126,
128, 130
TJ-9, 177, 181, 182
TKIs (tyrosine kinase inhibitors), 153, 154
toothbrushes, sharing of, 36, 48
transarterial chemoembolization (TACE), 145, 148, 152
transarterial radiation therapy (TARE), 145, 147, 148, 152
transferrin, 2, 107
transient elastography (TE), 25, 26
transjugular intrahepatic portosystemic shunt. See TIPS
transplant team, 158–66, 168
treatment: for acute liver failure, 116–18
for alcoholic hepatitis, 79–80
for alcoholic liver disease, 78–80, 179, 182
alternative, 175–87
for autoimmune hepatitis, 98–100, 116, 117
for fluid buildup, 124–25
for hemochromatosis, 107
for hepatic encephalopathy, 131–32
for hepatitis A, 29, 30, 179
for hepatitis B, 29, 30, 33, 38–43, 154, 179, 181, 183
for hepatitis C, 29, 30, 33, 57–58, 61, 62–68, 179–80, 182, 183,
185
for hepatitis D, 29, 31
for hepatitis E, 29
for liver cancer, 145–54, 181
liver cancer risk from, 154
for NAFLD/NASH, 88–89, 91–94, 179
for overlap syndrome, 103, 105
for porphyria cutanea tarda, 137
for primary biliary cholangitis, 101, 179
for primary sclerosing cholangitis, 102
 for spontaneous bacterial peritonitis, 126
for variceal bleeding, 128–31
for Wilson disease, 109. See also liver transplant; medications
tremors, flapping (asterixis), 8, 119
trientine, 109, 116
triglycerides, 54, 82, 84, 85, 188
tryrosinemia, 143
tyrosine kinase inhibitors (TKIs), 153, 154

UDCA. See ursodeoxycholic acid (UDCA)

ulcerative colitis, 102, 103
ultrasound, 22, 24–26, 144, 145, 154
United Network for Organ Sharing (UNOS), 161–62
ursodeoxycholic acid (UDCA), 93, 101, 102, 103, 104, 105

vaccines: after liver transplant, 171

hepatitis A, 29, 30, 54, 78, 115, 188
hepatitis B, 29, 30, 36, 39, 44–45, 54, 78, 115, 154, 188
hepatitis C, 29
hepatitis E, 29
variceal banding, 128, 129, 130
variceal bleeding, 56, 120, 127–31, 150, 157
vasculitis, 134, 138
velpatasvir. See Epclusa; Vosevi
viral hepatitis. See hepatitis, viral
viral infections and liver transplant, 167, 171–72
vitamin A, 185, 188
vitamin B3 (niacin), 185
vitamin C, 107, 185
vitamin D, 185
vitamin E, 91–92, 93
vitamin supplements, 185, 187, 188, 190
Vosevi, 63, 64, 65, 67
voxilaprevir. See Vosevi

wasting, 8, 10, 76, 119, 189

water, contaminated, 28, 29, 31
weight loss, 7, 89–90, 92, 94, 143, 184, 186
Wilson disease, 5, 82, 108–9, 114, 116, 117, 143

zinc supplements, 109, 116