Case presentation

Dr syeda shaheera zaidi

Bio data
Name: Sumera w/o Farooq Age: 20years Occupation: house wife Residance: Larkana Marital status: married Date of admission: 17/07/11 Mode of admission: emergency

Presenting complaints
Jaundice------ since childhood Generalized weakness--------10 days Vomitting-------10 days Fever-----------2 days

HX of presenting illness
The patient has hx of jaundice since 3 months of her life when at that time she gradually developed yellow discoluration of her eyes along with discolouration of urine and some rash but no hx of fever , vomitting, abdominal pain at that time and since than intensity of jaundice varies but never completely resolved. For this complaints pt underwent liver biopsy at the age of 5 years but no record avialable

 The patient also diagnosed as epileptic for 2 years but fit free for 6 months and currently 27 weeks pregnant and was in her usual state of health 15 days back when she developed vomittings. Vomitting usually occur after taking food, yellow in colour, non projectile , not blood stained. No hx of abdominal pain, melena, itching associated but pt initially experienced few episodes of diarrhea

 The pt also has generalized weakness for 15 days and feels difficult to perform daily activities The pt also has hx of fever for last 2 days. Fever is low grade, intermittent not associated with chills or rigors.

Past history
Medical: hx of generalized tonic clonic fits for 2 years associated with uprolling of eyes and urinary and fecal incontinance.Fits occur1-2/month but now fit free for last 6 months although took antiepileptic for just 1.5 months surgical: not significant Blood transfusion:nil

Personal hx
Sleep: decreased Apetite: decreased Bowel habits: constipation Micturition: normal Addiction: nil

Gynea/ obs hx
Married for 2 years Primary gravida No previous abortions/IUD/ still births Menstrual hx: normal

Family history
parents alive and healthy 1 of her younger sister(7 years old) also suffering from jaundice since childhood 1 sister had some abdominal mass for which she underwent laparotomy

Drug history
She has been taking syp hepamrez for many years

socioeconomic
Belong to low socioeconomic status

General physical examination

Young female of average ht and built, somewhat slow in response but otherwise oriented to time, place and person, looking pale and icteric Vitals BP:120/70 Pulse:120/min Temp:98.6F R/R:30/min

Aneamia: ++ Jaundice: +++ Edema: +(dorsum of feet, pitting) dehydration: -ve Cynosis: -ve Clubbing: -ve JVP: not raised Lymph node: not enlarged Palmer erythema: -ve

 Asterexis: -ve Scratch mark: -ve Thyroid: not palpable

Abdominal examination
Distended, no visible veins, striae, pulsations, moving equally with respiration HOF :26 weeks Liver: edge just palpable Spleen: palpable 2-3 cm below costal margin No signs of free fluid Gut sounds: audible

CNS examination
GCS: 15/15 Moving all 4 limbs Plantars: bilaterally down going SOMI: -ve Horizontal nystagmus in both eyes Cranial nerves: intact

chest
Equal air entery on both sides NVB with no added sounds

CVS
S1 and s2 audible in all 4 areas

Differential daignosis
Acute hepatitis? Hepatitis E Heamoglobinopathy Congenital hyperbillirubinemia e.g Gilberts/ crigler najjar Chronic liver disease Epilepsy

investigations
CBC Hb: 6.7 gm/dl MCV: 67.8fl PCV: 26.5% MCH: 17.0pg MCHC: 25.2gm/dl TLC: 8.6 X10e9/l Neutrophil: 84% Platelets:370x10E9/L

 Peripheral film:hypochromic, microcytic, anisocytosis

UCE
BUN: 11 mg/dl Cr: 0.4mg/dl Na: 136meq/l K: 3.7meq/l Cl: 100meq/l

LFTs
Billi T: 27.64mg/dl Billi Direct: 3.26 mg/dl Billi indirect: 24.38mg/dl SGPT: 146U/L ALP: 200 U/L

RBS: 103 mg/dl LDH: 359 U/L Uric acid: 4.07 mg/dl Retic count: 4.9% ( corrected retic = 2.88%)

Coagulation profile
PT: 26.5/26 APTT: 10.3/10.5

Protein total: 5.0g/dl Albumin: 2.3 g/dl Globulin: 2.7 gm/dl A/G ratio: 0.9

Urine DR
pH: 6.0 RBCs: 1-2/hpf Pus cells: numerous/hpf Protein: ++ Glucose: -ve

Viral profile
HBsAg: -ve Anti HCV: -ve Anti HAV IgM: -ve Anti HEV IgM: -ve

 MPx3: all ve ICT malaria: -ve (for both vivax and falciparum)

U/S abdomen
Liver:enlarged, 17.1 cm with decreased echogenecity. PV: normal, intrahepatic ducts not dilated Gall bladder: sludge and multiple calculi largest measuring 1.0 cm CBD: normal Spleen:enlrged measuring15.3 cm

U/S for fetal well being

Single alive intrauterine fetus corresponding to 30 weeks+/- 1 week

Hospital course
2nd DOA(18/07/11) Pt had episode of GTCs at 12 am for about 20 sec during blood transfusion and she was given inj diazepam and 25% dextrose water No spike of fever recorded

 3rd day of admission(19/07/11) Pt had another episode of GTCs at 11 am and was given inj phenytoin as loading dose and serum Ca sent that came out 7.2 mg/dl so inj ca gluconate was also given Pt now developed ALOC and GCS droped to 10/15 At 5 pm she suddenly delievered alive fetus and remained semiconsious Her chest had bilateral crepts and she was

Course in MICU
Consious level remain same GCS 9/15 Further episodes of GTCs despite maintainance dosing of phenytoin LP was done and inj ceftriaxone 2gm bid started in place of fortum and flagyl Blood transfusions given LFTs starts improving

CSF DR
Colourless, Clear, Web not seen Protein: 70 mg% Glucose: 93 mg% Leucocytes: <05/cumm Erythrocytes: 1-2/ hpf Gram stain: no organism seen

lfts Billi T Billi D

19/07/11 21/07/11 23/07/11 25/07/11 20.68 3.63 18.04 2.24 11.28 1.61 9.76 1.22

Billi indirect SGPT

ALP

17.05
77 158

15.08
63 169

9.67
36 172

8.54
32 165

ABGs
Fio2: 21% pH: 7.50 PCO2: 26 mm Hg PO2: 113 mmHg SO2: 99% HCO3 :20 meq/l ABE: -2

Hb electrophoresis -----awaited ANA and serum ceruloplasmin-----awaited Neuro opinion seeked: plan for MRI brain Phenytoin levels sent

Final diagnosis

Liver Function Test

Liver Function Test

interpretation must be performed within the context of the patients risk factors, symptoms, concomitant conditions, medications, and physical findings rarely provide specific Dx, but rather suggest a general category of liver disease differing laboratories differing normal values

Liver Function Test

Mild (times)
AST ALT ALP GGT <2-3 <2-3 <1.5-2 <2-3

Moderate (times)
2-3 to 20 2-3 to 20 1.5-2 to 5 2-3 to 10

Marked (times)
>20 >20 >5 >10

Liver Function Test

Advantages sensitive, noninvasive method of screening liver dysfunction pattern of laboratory test abnormalities to recognize type of liver disorder assess severity of liver dysfunction follow cause of liver disease Disadvantages lack sensitivity
normal results in serious liver disease

not specific for liver dysfunction seldom lead to specific diagnosis

Initial Approach
history and physical examination algorithm approach useful mainly when no clinical clues
history patients symptoms risk factors for liver disease concomitant conditions medications occupational exposure to hepatotoxins physical examination body habitus splenomegaly ascites cutaneous stigmata of chronic liver disease

Liver Function Test

classified in 3 groups synthetic function : albumin, PT hepatocyte injury : AST, ALT cholestasis : bilirubin, ALP, GGT PT, albumin, bilirubin-most common tests used as prognostic factors

Liver Function Test

Liver chemistry test ALT Clinical implication of abnormality Hepatocellular damage

AST
Bilirubin ALP PT

Hepatocellular damage
Cholestasis, impair conjugation, or biliary obstruction Cholestasis, infiltrative disease, or biliary obstruction Synthetic function

Albumin
GGT

Synthetic function
Cholestasis or biliary obstruction

Bile acids
5`-nucleotidase LDH

Cholestasis or biliary obstruction

Cholestasis or biliary obstruction Hepatocellular damage, not specific

Albumin
depend on nutrition, volume status, vascular integrity, catabolism, hormone, loss in stool and urine not specific for liver disease T1/2 19-21 D
not reliable indicator of acute liver disease

Hypoalbuminemia
globulin 1.decrease synthesis -protein malnutrition -chronic liver disease -chronic inflammation 2.increase loss chol/TG Hb

-NS
3.increase Vd (ascites, overhydration) 4.increase turnover (catabolic state, steroid)

Globulin
produced by stimulated B lymphocyte elevation in chronic liver disease chronic inflammation and malignant disease

Prothrombin time
liver synthesize coagulation factor except FVIII most present in excess, clotting abnormality occur only when substantial impairment in ability of liver to synthesis PT : FI, II, V, VII, IX and X T1/2 FVII 6 hrs. (shortest)

Prothrombin time
prolonged : vitamin K deficiency (malnutrition, malabsorption, antibiotics) massive transfusion congenital disease liver disease (acute as well as chronic) warfarin DIC

AST and ALT

most frequent used markers of hepatocellular necrosis, but not correlate with eventual outcome

decrease : recovery or poor prognosis

poor prognosis : rapid fall with rising of bilirubin and PT

AST, ALT
level of transminase elevation predominant AST / ALT elevation
rate of transaminase declination

ALT and AST

>15 times : acute hepatic injury 5-15 times : less useful <5 times : chronic hepatic injury improved acute hepatic injury

AST/ALT ratio
< 1 : majority of liver disease >2
extrahepatic source alcoholic hepatitis ischemic and toxin acute Wilsons disease : hemolysis cirrhosis

>4 : fulminant Wilsons disease

AST/ALT ratio
90 80 70

60

50

40

AST/ALT >1 AST/ALT >2

30

20

10

alcoholic

post necrotic cirrhosis

chronic hepatitis

obstructive jaundice

viral hepatitis

Rate of Transaminase Declination

rapid ischemic short half life drug acute biliary tract obstruction fulminant hepatitis

slow acute viral hepatitis long half life drug AIH metabolic disease

ALT and AST < 5 times

ALT predominant Chronic hepatitis B, C Acute hepatitis (A-E, EBV, CMV) Steatohepatitis Hemochromatosis Medications/toxins Autoimmune hepatitis Alpha1-antitrypsin deficiency Wilsons disease Celiac disease
*almost any types of liver disease

AST predominant Alcohol-related liver injury Steatohepatitis Cirrhosis Drug Nonhepatic

Hemolysis Myopathy Thyroid disease Strenuous exercise

ALT and AST < 5 times and AST predominant

history alcohol intake (history from patient and family members) hemolysis studies aldolase CPK macro-AST

Alcoholic hepatitis
appropriate history of alcoholic consumption, serologic exclusion of other liver disease 40-80 g/D, 20-40 g/D 10-12 yrs. characteristic pattern
AST rarely exceeds 300 IU/dl AST/ALT >1 in 92%, >2 in 70%
pyridoxine deficiency alcohol induces release of mitochondrial AST

GGT/ALP >2.5

ALT and AST > 15 times

Acute viral hepatitis (A-E, herpes) Medications/toxins Ischemic hepatitis Acute bile duct obstruction Autoimmune hepatitis Wilsons disease Acute Budd-Chiari syndrome Hepatic artery ligation Heat stroke

AST predominate : medication/toxin, ischemic >75 times : ischemic, toxic, viral (less common)

(shock liver, acute hepatic circulatory insufficiency)

Ischemic hepatitis

low-flow hemodynamic state

hypotension, sepsis, cardiac arrhythmia, MI, HF, hemorrhage, extensive burns, severe trauma, heat stroke

hypotension often not documented usually subclinical

Ischemic hepatitis
sudden and massive (>2000) elevation of liver enzyme, tend to decrease rapidly and return normal within 1 wk. mild and transient elevation of bilirubin (80% < 2 mg/dl) and ALP extreme elevation LDH (>5000), ALT/LDH < 1.5 rare acute liver failure Rx and prognosis underlying disease

Ischemic hepatitis

Acute biliary obstruction

aminotransferase peak early and decline rapidly over 24-72 hr. despite unresolved obstruction after aminotransferase decrease, bilirubin and ALP increase 25% of patients with AST > 10X

Acute biliary obstruction

LDH
non specific rhabdomyolysis, MI, hemolysis, stroke, renal infarction, acute or chronic liver disease use in
ischemic hepatitis : transient, massive elevation malignant infiltration of liver : sustained elevation with ALP

Bilirubin
UDP-glucoronyltransferase

RE cell HEME UCB

plasma UCB + albumin

hepatocyte UCB+ligandin

bile

urobilinogen

stercobilinogen

Bilirubin
Direct bilirubin : reacted directly with reagent Indirect bilirubin : require addition of alcohol for color development Unconjugated bilirubin = indirect form Conjugated bilirubin = bilirubin mono and di-glucoronides

Diagnostic approach in elevated serum bilirubin

elevated bilirubin
History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin

hemolysis studies, review medications

Isolated unconjugated hyperbilirubinemia

IDB fraction > 85% of total bilirubin 1. increase production :
hemolysis
chronic hemolysis-not sustained increase of bilirubin >5 mg/dl in normal hepatic function

ineffective erythropoiesis : folate, drug : rifampicin, ribavirin, probenecid resolution of hematoma Gilberts syndrome Crigler-Najjar syndrome

2. defects in hepatic uptake/conjugation

Gilberts syndrome
benign, unconjugated hyperbilirubinemia with otherwise normal liver chemistries up to 5% of normal population polymorphism in gene encoding bilirubin UDP-GT impair ability to conjugate bilirubin prominent in fasting state, systemic illnesses, hemolysis, some medications

Gilberts syndrome
Dx :
asymptomatic, healthy mild unconjugated hyperbilirubinemia (<4 mg/dl) with otherwise normal liver chemistries test exclusion medications and hemolysis

Indirect Hyperbilirubinemia
Bilirubin hemolysis Gilberts syndrome 5 mg/dl 5 mg/dl AST, ALT increase AST normal Alb N N Glob N N PT N N

Diagnostic approach in elevated serum bilirubin

elevated bilirubin
History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin

Conjugated hyperbilirubinemia
DB > 50% of total bilirubin cant differentiate obstruction and parenchymal disease Delta fraction
CB tightly bound to albumin tendency of hyperbilirubinemia to resolve more slowly than other biochemical tests

Conjugated hyperbilirubinemia
Bile duct obstruction Hepatitis Cirrhosis Medications/Toxins Primary biliary cirrhosis Primary sclerosing cholangitis Sepsis Total parenteral nutrition Intrahepatic cholestasis of pregnancy Benign recurrent cholestasis Vanishing bile duct syndromes Dubin-Johnson syndrome Rotor syndrome

Diagnostic approach in elevated serum bilirubin

elevated bilirubin
History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST
Rotors syndrome Dubin-Johnson syndrome

Diagnostic approach in elevated serum bilirubin

elevated bilirubin
History and PE

unconjugated bilirubin normal ALP, ALT, AST

conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST
AST, ALT ALP Dubin-Johnson syndrome predominate predominate / /
as elevated ALT evaluation U/S Rotors syndrome

hemolysis studies, review medications

present

absent

ERCP

as elevated ALT evaluation review medications AMA, ERCP, liver biopsy

Alkaline phosphatase
family of isoenzyme catalyze hydrolysis of No. of P esters at alkaline pH require Zn for activity present in nearly all tissues (liver, bone, intestinal, placenta, kidney) liver ALP
isoenzyme, 5-nucleotidase, GGT

Alkaline phosphatase
Physiologic >60 yr. child and adolescent pregnancy blood group O post meal (fatty meal) Pathologic intrahepatic extrahepatic

Alkaline phosphatase
Intrahepatic
viral alcohol drug pregnancy PBC PSC TPN sepsis vanishing bile duct syndrome benign recurrent cholestasis benign post-op. cholestasis paraneoplastic syndrome venoocclusive disease GVHD

Extrahepatic
intraluminal obstruction : gall stones, ascariasis, hemobilia disease of BD : PSC, choledochal cyst, cholangioCA, AIDS cholangiopathy external compression : LN, GB CA, Mirizzis syndrome, CA pancreas, ampullar adenoma

Alkaline phosphatase
in biliary obstruction
induction of ALP synthesis 2 to enhanced translation of mRNA ALP levels, may not rise until 1-2 days T1/2 1 wk, take several days for levels to normalise after resolution

in malignancy ..
no identifiable liver/bone involvement biochemical distinct from liver ALP associated variety of different CA ex lung CA

Alkaline phosphatase
initial evaluation : determine hepatic or nonhepatic origin, concomitant elevation of other serum LFT level not a reliable indicator of severity of underlying liver disease degree not help to distinguish intrahepatic and extrahepatic

Isolated hepatic ALP elevation

Partial bile duct obstruction Medications Infiltrative liver disease Hepatic metastasis PBC PSC Hepatitis Cirrhosis Vanishing bile duct syndromes Benign recurrent cholestasis

Infiltrative diseases
modest (up to 3x) rise in aminotransferase, and up to 20x rise in ALP, bilirubin N-5x

TB Fungal infection HCC Lymphoma Metastatic malignancy Amyloidosis Sarcoidosis Other granulomatous diseases

Alkaline phosphatase
ALP > 1000 : malignant biliary obstruction, sepsis, AIDS with systemic infection decrease : hypothyroidism, pernicious anemia, Zn deficiency, congenital, Wilsons disease, severe hepatic insufficiency

Medications elevation of bilirubin and ALP

Anabolic steroid Allopurinol Amoxicillin-clavuronic acid Captopril Carbamazepine Chlorpropamide Cyproheptadine Diltiazem Erythromycin Estrogens Floxuridine Flucloxacillin Fluphenazine

Gold salts Imipramine Indinavir Iprindole Nevirapine Methytestosterone Methylenedioxymethamphetam ine Oxaprozin Pizotyline Quinidine Tolbutamide TPN Trimethoprimsulfamethoxazole

Diagnostic approach in elevated serum alkaline phosphatase

elevated ALP
History and PE normal bilirubin, ALT, AST abnormal liver chemistries

GGT or 5nucleotidase
negative positive

yes

U/S

no

not hepatobiliary

no duct dilatation

U/S review medication AMA liver biopsy

ERCP

AMA

negative

observation
> 6 months

as elevated ALT evaluation, liver biopsy, ERCP

-glutamyltransferase (GGT)
catalyzed transfer of -glutamyl groups of peptides to other amino acid abundant in liver, kidney, pancreas, intestine, and prostate, spleen, heart, brain but not in bone T1/2
7-10 days 28 days in alcohol-associated liver injury

-glutamyltransferase (GGT)
increase
alcohol drug anticonvulsant (CBZ, phenytoin, and barbiturate), warfarin, OC almost all type of liver diseases COPD, renal failure, DM, hyperthyroidism, RA, AMI, pancreatic disease

Summary
Hepatocellular necrosis toxin/ ischemia AST/ALT ALP Bilirubin PT albumin 50-100X 1-3X 1-5X viral 5-50X 1-3X 1-30X alcohol 2-5X 1-10X 1-30X Biliary obstruction complete 1-5X 2-20X 1-30X partial 1-5X 2-10X 1-5X 1-3X 1-20X 1-5X normal normal Infiltration

increase in severe, unresponsive to vit K increase in subacute/chronic

increase, responsive to vit K usually normal, decrease in advance

Take home message

initial evaluation : assess in clinical context classified in 3 groups synthetic function : albumin, clotting time cholestasis : bilirubin, ALP, GGT hepatocyte injury : AST, ALT

Liver Function Test

misnomer
not effectively assess actual function not always specific for the liver limited information regarding presence or severity of complication

Liver Chemistry Test

Liver Function Test

normal may have abnormal test normal value not ensure that patient is free of liver disease level of abnormality does not reflect severity but may help in DDx decrease in the value does not mean improvement limitation in sensitivity and specificity

Thank You

Piyanant Chonmaitree, MD.Department of Medicine Srinakharinwirot University