Dr.

Eman Hassan
M.B.B.S., M.Sc., Ph.D

www.gmu.ac.ae COLLEGE OF MEDICINE

 Introduction

• The three distinctive, but overlapping, forms of liver disease are

collectively referred to as alcoholic liver disease:

1. Hepatic steatosis
2. Alcoholic hepatitis
3. Cirrhosis
 Hepatic Steatosis (Fatty Liver): Morphology

Macroscopically, the fatty liver of chronic

alcoholism is a large soft organ that is yellow and
greasy.
Microscopically
• Following even moderate intake of alcohol, small
lipid droplets accumulate in hepatocytes that
coalesce into large droplets which displace the
nucleus to the periphery of the hepatocyte (signet
ring appearance).
• This transformation begins in the centrilobular
zone to involve the entire lobule in severe cases. Alcoholic steatosis and steatofibrosis. A mix 
of small and large fat droplets, most 
• The fatty change is completely reversible prominent around the central vein and 
extends outward to the portal tracts. Some 
fibrosis (stained blue) is present in a 
characteristic perisinusoidal chicken wire fence 
pattern.(Masson trichrome stain).
 Alcoholic Steato-Hepatitis: Morphology
Alcoholic hepatitis is characterized by
1. Hepatocyte swelling and necrosis:
• Single or scattered foci of cells undergo
swelling (ballooning) and necrosis.
• The swelling results from the accumulation
of fat and water, as well as proteins
2. Neutrophilic reaction:
• Neutrophils permeate the lobule and
accumulate around degenerating
hepatocytes, particularly those having
Mallory-Denk bodies
 Alcoholic Steato-Hepatitis: Morphology Cont..,
3. Mallory-Denk bodies:
• These are present as clumped, amorphous,
eosinophilic inclusion found in the cytoplasm
of in the ballooned hepatocytes

• Mallory bodies are damaged intermediate

filaments within the hepatocytes.

• These inclusions are a characteristic but not

specific feature of alcoholic liver disease, as they
also are seen in nonalcoholic fatty liver
disease, Wilson disease and in chronic biliary
tract disease.
 Alcoholic Cirrhosis
Alcoholic steatofibrosis. 
 Alcoholic hepatitis is often accompanied by prominent activation 
of sinusoidal stellate cells and portal fibroblasts, giving rise to 
fibrosis. 
 Fibrosis begins with sclerosis of central veins. Perisinusoidal 
scar then accumulates in the space of Disse of the
centrilobular region, spreading outward, encircling individual or 
small clusters of hepatocytes in a chicken wire fence pattern. 
 These webs of scar eventually link to portal tracts and then 
begin to condense into central-portal fibrous septa. With developing 
nodularity, cirrhosis becomes established. When alcohol use 
continues without interruption over the long term, the continual 
subdivision of established nodules by new webs of, perisinusoidal 
scarring leads to a classic micronodular or Laennec
cirrhosis.
Early stages of scarring can regress with cessation of alcohol use, 
but the farther along toward cirrhosis complete regression is rare
 Alcoholic Cirrhosis

• A, The characteristic diffuse nodularity of the surface is induced by the underlying scarring.
• The average size of the nodules is 3 cm. typical of micronodular cirrhosis of alcoholic liver disease. The greenish tint is due to
cholestasis.
• B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The fatty accumulation is no longer
seen in this stage. (Masson trichrome)
 Alcoholic liver disease: Pathogenesis

Short-term ingestion of up to 80 gm of alcohol over one to several days

generally produces mild, reversible hepatic changes, such as fatty liver.
Daily intake of 80 gm or more of ethanol generates significant risk for severe
hepatic injury,
and Daily ingestion of 160 gm or more for 10 to 20 years is associated more
consistently with severe injury.
Only 10% to 15% of alcoholics, however, develop cirrhosis.
 Pharmacokinetics and Metabolism of Alcohol

Exposure to alcohol increases steatosis, dysfunction of

mitochondrial and cellular membranes, hypoxia and oxidative
stress.
• Hepatocellular steatosis results from,
1) shunting from catabolism and toward lipid biosynthesis, owing to
generation of excess reduced nicotinamide-adenine dinucleotide (NADH +
H+)
2) impaired secretion of lipoproteins
3) increased peripheral catabolism of fat, thus releasing free fatty acids into the
circulation
↑ Lipogenesis Alcohol is metabolized by alcohol dehydrogenase
↓ FA oxidation (ADH) into acetaldehyde, then further metabolized
by aldehyde dehydrogenase (ALDH) into acetic acid,
which is finally oxidized into carbon dioxide (CO2)
and water ( H2O). This process generates NADH, and
increases the NADH/NAD+ ratio. A higher NADH
concentration induces fatty acid synthesis while a
decreased NAD level results in decreased fatty acid
oxidation. Subsequently, the higher levels of fatty
acids signal the liver cells to compound it to glycerol
to form triglycerides. These triglycerides
accumulate, resulting in fatty liver.
 Hepatic steatosis: Clinical features
• Hepatic steatosis may become evident as hepatomegaly with mild
elevation of serum bilirubin and alkaline phosphatase levels.

• Alternatively, there might be no clinical or biochemical evidence of liver

disease.

• Severe hepatic dysfunction is unusual.

• Alcohol withdrawal and the provision of an adequate diet are

sufficient treatment.
 Alcoholic hepatitis: Clinical features
• Alcoholic hepatitis
• usually following a bout of heavy drinking.
• Symptoms and laboratory manifestations may be minimal or those of hepatic failure. The
nonspecific symptoms of malaise, anorexia, weight loss, upper abdominal discomfort,
tender hepatomegaly,
• The laboratory findings are hyperbilirubinemia, elevated alkaline phosphatase, and often, a
neutrophilic leukocytosis.
• Most causes of liver cell injury are associated with a greater increase in ALT (alanine
transaminase) than AST (aspartate transaminase ); however, an AST to ALT ratio of
2:1 or greater is suggestive of alcoholic liver disease, particularly in the setting
of an elevated gamma-glutamyl transferase (GGT)
• With proper nutrition and total cessation of alcohol consumption, the alcoholic hepatitis
may clear slowly. However, in some patients, the hepatitis persists despite abstinence
and progresses to cirrhosis.
 Alcoholic cirrhosis: Clinical features
• The manifestations of alcoholic cirrhosis are similar to those of other
forms of cirrhosis
• Commonly, the first signs of cirrhosis relate to complications of
portal hypertension, including life-threatening variceal hemorrhage.
• Alternatively, malaise, weakness, weight loss, and loss of appetite
precede the appearance of jaundice, ascites, and peripheral edema, the
latter due to impaired synthesis of albumin.
• Laboratory findings reflect the developing hepatic compromise, with
elevated serum aminotransferase, hyperbilirubinemia, variable elevation
of serum alkaline phosphatase, hypoproteinemia and anemia.
• Finally, cirrhosis may be clinically silent, discovered only at autopsy or
when stress such as infection or trauma tips the balance toward hepatic
insufficiency
 Alcoholic liver disease: Prognosis
In the end-stage alcoholic, the proximate causes of death are
(1) hepatic coma,
(2) a massive gastrointestinal hemorrhage,
(3) an intercurrent infection
(4) hepatorenal syndrome
(5) hepatocellular carcinoma in 1% to 6% of cases.
 Cirrhosis

Cirrhosis is defined as a diffuse process characterized by fibrosis and the

conversion of normal liver architecture into structurally abnormal nodules.

Not focal but rather involve most (if not all) of the diseased liver
Fibrous septa in the form of delicate bands or broad scars around multiple
adjacent lobules.
Parenchymal nodules,
 Micronodules very small, less than 3 mm in diameter
 Macronodules, larger over 3cm, encircled by these fibrous bands.
Clinical Features
All forms of cirrhosis may be clinically silent.
When symptoms appear, they typically are nonspecific and
include anorexia, weight loss, weakness, and, in advanced
disease, frank debilitation.
Late portal hypertension, hepatic failure may develop.
Most cases of ultimately fatal cirrhosis involve one of the
following mechanisms:
• Progressive liver failure
• A complication related to portal hypertension
• The development of hepatocellular carcinoma
Micro description
Disruption in architecture of
entire liver (loss of normal
central-portal relationships)
with bridging fibrous septa
(delicate bands, broad scars)
and
rounded parenchymal nodules
of regenerating hepatocytes
without central veins;
also abnormal vasculature due
to parenchymal damage and
scarring
 Portal Hypertension

Increased resistance to portal blood flow

Portal hypertension is an increase in the blood

pressure within a system of veins called the
portal venous system.

 Veins coming from the intestine, spleen, and

pancreas merge into the portal vein, which then
branches into smaller vessels and travels through
the liver.
 Portal Hypertension: Causes

Causes are pre-, intra- and post-hepatic

● Prehepatic: obstructive thrombosis and narrowing of portal vein before it
ramifies in the liver
● Intrahepatic: usually cirrhosis, due to increased resistance to portal flow
at level of sinusoids and compression of central veins by perivenular
fibrosis and expansive parenchymal nodules
● Posthepatic: congestive heart failure, constrictive pericarditis, hepatic
vein outflow obstruction
● Rare causes: schistosomiasis, massive fatty change, miliary tuberculosis
 Portal Hypertension: Complications
Complications:
Ascites,
Portosystemic venous shunts (hemorrhoidal veins (piles)
gasteroesophageal junction and esophageal varices, and
abdominal wall collaterals cause caput medusae on abdominal
/ thorax]),
Congestive splenomegaly
Hepatic encephalopathy
 Ascites

Ascites refers to the collection of excess fluid in the peritoneal cavity.

It usually becomes clinically detectable when at least 500 mL have accumulated,
but many liters may collect, causing massive abdominal distention.
 Ascites generally is a serous fluid containing as much as 3 g/dL of protein (largely
albumin).
More importantly, the serum to ascites albumin gradient is ≥1.1 g/dL.
The fluid may contain a scant number of mesothelial cells and mononuclear
leukocytes.
Influx of neutrophils suggests secondary infection, whereas presence of red cells
points to possible disseminated intra abdominal cancer.
Ascites: Pathogenesis

The pathogenesis of ascites is complex, involving one or

more of the following mechanisms:
• Increased movement of intravascular fluid into the
extravascular space of Disse, caused by sinusoidal
hypertension and hypoalbuminemia.
• Leakage of fluid from the hepatic interstitium into the
peritoneal cavity.
• Renal retention of sodium and water due to secondary
hyperaldosteronism
Learning Objectives

1. List the 3 forms of alcoholic liver disease

2. Describe the morphology of hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis
3. List the risk factors of developing alcoholic cirrhosis
4. Describe the clinical features of hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis
5. Describe the causes of death in alcoholic liver disease
6. Define cirrhosis, Portal hypertension, ascites
7. Enumerate the clinical features and complications of cirrhosis
8. Classify portal hypertension based on the causes.
9. Enumerate the clinical features and complications of portal hypertension.
10.Explain the mechanisms involved in the development of ascites.
 Reading Rssources

Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease.
9th ed. Elsevier Saunders ; 2015. ISBN-13: 978-145-5726-134. Chapter 18,
PP 821-879 (avilable on the clinical key:
http://www.gmu-elibrary.com/resources)