Liver Function Test

Common Liver Function Test

LFT
ALT
AST

Clinical implication
Hepatocellular injury
Hepatocellular injury

Bilirubin Cholestasis, biliary obstruction (high direct bilirubin) AlkPO4

Cholestasis, biliary obstruction, SOL, infiltrative lesion

Albumin Synthetic function

GGT
5-NT

Cholestasis or biliary obstruction

Cholestasis or biliary obstruction

Hepatocellular Injury
Examples: Viral hepatitis Ischemic/hypoxic Drugs Autoimmune hepatitis etc.

Common Liver Function Test

LFT
ALT
AST

Clinical implication
Hepatocellular injury
Hepatocellular injury

Bilirubin Cholestasis, biliary obstruction (=high direct bilirubin) AlkPO4

Cholestasis, biliary obstruction, SOL, infiltrative lesion

Albumin Synthetic function

GGT 5-NT

Cholestasis or biliary obstruction Cholestasis or biliary obstruction

Normal Bilirubin Pathway

Cholestasis

Definition
Obstruction of bile flow

Clinical presentation

Jaundice, pruritus Increasing AlkPO4, TB, GGT

LFT profile

Intrahepatic Cholestasis

Biliary Tract Obstruction

GGT is often elevated in people who have

three or more alcoholic drinks per day; thus, it is a useful marker for moderate alcohol intake.

Levels of Liver Injury

I. Markers of Liver Function A. Albumin B. Bilirubin C. Prothrombin time II. Markers of hepatocellular disease A. Alanine Aminotransferase (ALT) B. Aspartate Aminotransferase (AST) III. Markers of cholestasis A. Alkaline Phosphatase B. Gamma-glutamyl transferase (GGT) IV. Disease specific markers A. Definite value 1. Viral Hepatitis Serology 2. Iron study 3. Ceruloplasmin B. Limited value: 1. AMA, ASMA 2. Alpha-1 antitrypsin

Case Study

Case 1
32 7 7 d PTA 4 d PTA .. AST 4617 U/L, ALT 5538 U/L, ALP 144 U/L TB 11.8 mg/dl, DB 6.2 mg/dl

Pattern of abnormal LFT? Hepatocellular injury

Biochemical Patterns of Liver Damage

Hepatocellular necrosis
AST / ALT
AlkPO4

Cholestasis

8-200x
1-3x

1-8x
3-10x

Pattern of abnormal LFT? Hepatocellular injury Differential diagnosis?

Differential diagnosis

Acute viral hepatitis

Systemic infection

Autoimmune disease
Hematologic malignancy

Differential diagnosis

Acute viral hepatitis

Systemic infection (x)

Autoimmune disease (x)

Hematologic malignancy (x)

Investigation ?

Investigation

HBsAg
Anti-HBc IgM

Anti-HAV IgM
Anti-HCV

Anti-HDV

Investigation

HBsAg
Anti-HBc IgM

Anti-HAV IgM
Anti-HCV (x)

Anti-HDV (x)

HBsAg (-), anti HBc IgM (-), anti HAV IgM (+) 1 d PTA Alc (-), smoking (-), herbal use (-), blood Tx (-) (-) Temp 38.3 C, moderate jaundice Abdomen: Liver 3 cm below RCM, Spleen (-) No ascites

Impression Acute hepatitis A

Investigation
AST 870, ALT 1093 U/L, GGT 455 U/L, ALP 182 U/L TB 61.2 mg/dl, DB 38.9 U/L Prothrombin time 12.9 sec, INR 1.08, thrombin time 10.5 sec Hct 24%, Hb 8 g/dl, WBC 29,500 (PMN 76%), plt 427,000 /mm3

Impression 1. Acute hepatitis A (with atypical manifestation)

Acute Hepatitis A
Symptom

Total anti-HAV

ALT
Fecal HAV

IgM anti-HAV

12

24

Months after exposure

Atypical Manifestation of Acute Hepatitis A

Cholestasis Relapse Extrahepatic Autoimmune trigger

Autoimmune hepatitis (type 1)

Investigation
AST 870, ALT 1093 U/L, GGT 455 U/L, ALP 182 U/L TB 61.2 mg/dl, DB 38.9 U/L Prothrombin time 12.9 sec, INR 1.08, thrombin time 10.5 sec Hct 24%, Hb 8 g/dl, WBC 29,500 (PMN 76%), plt 427,000 /mm3

Impression 1. Acute hepatitis A 2. Intravascular hemolysis (G-6PD deficiency)

Cause of Severe ALT/AST Elevation

(>15 times normal)

Acute viral hepatitis Medications / toxins

(HAV & HBV)

Ischemic hepatitis
Autoimmune hepatitis Wilsons disease Acute Budd-chiari syndrome

Cause of Severe ALT/AST Elevation

(>15 times normal)

Acute viral hepatitis Medications / toxins

(HAV & HBV)

Ischemic hepatitis
Autoimmune hepatitis Wilsons disease Acute Budd-chiari syndrome

Serum Transminases
: Typical Ranges
Toxic or Ischemic injury Acute viral hepatitis

Alcoholic hepatitis
Chronic hepatitis Cirrhosis Normal
10 30 100 300 500 1,000 3,000 10,000 U/L

Johnston DE, Am Fam Physician 1995;59(8):2223-30.

Acute & Chronic Viral Hepatitis

Acute viral hepatitis

Hepatitis A Hepatitis B Hepatitis B

Chronic viral hepatitis

Hepatitis C
Hepatitis D

Case 2
32 3 3 .. Alc (-), smoking (-), herbal use (-), blood Tx (-) (-)

 Temp 37 C, look weak, moderate jaundice, no stigmata of Chronic liver disease Lymph nodes (-) Abdomen: No ascites, liver just palpable, no splenomegaly

Investigation
AST 440 U/L, ALT 578 U/L, GGT 455 U/L, ALP 182 U/L TB 10 mg/dl, DB 8.5 U/L, TP 9 mg/dl, ALB 3.5 mg/dl

Impression
Chronic hepatitis

Differential diagnosis

Viral hepatitis
Drug and herbal medicine

Autoimmune hepatitis
Wilson disease

Hemochromatosis

 Temp 37 C, look weak, moderate jaundice, no stigmata of Chronic liver disease Lymph nodes (-) Abdomen: No ascites, liver just palpable, no splenomegaly

Investigation
AST 440 U/L, ALT 578 U/L, GGT 455 U/L, ALP 182 U/L TB 10 mg/dl, DB 8.5 U/L, TP 9 mg/dl, ALB 3.5 mg/dl HBs Ag (-), anti HBc IgG (-), anti HCV (-)

Differential diagnosis

Viral hepatitis
Drug and herbal medicine

Autoimmune hepatitis
Wilson disease

Hemochromatosis

Differential diagnosis

Viral hepatitis (x)

Drug and herbal medicine

Autoimmune hepatitis
Wilson disease

Hemochromatosis (x)

..FU

Impression

Chronic hepatitis Cause? Investigation?

Further Investigation
Serum Cu 113 ug/L (80-155) Ceruloplasmin 37 (18-45) 24 hr urine Cu 45 ug/L (0-80) ANA (+) 1:320, anti DNA (+) 127.8 IU/ml, ASMA (-), Ig G level 41 mg/dl (7-16) Ultrasound abdomen parenchymatous liver, no duct dilatation

Autoimmune Hepatitis : Liver Biopsy

Autoimmune Hepatitis : Diagnostic Criteria

Chronic Hepatitis with Negative Viral Markers

Differential diagnosis:
Drugs / toxin / herbal medicine Autoimmune hepatitis Wilson disease Hemochromatosis
(ANA, ASMA, IgG)

(Cu, ceruloplasmin) (ferritin, iron, TIBC)

Non-alcoholic steatohepatitis Alpha 1-antitrypsin deficiency

Acute Hepatitis with Negative Viral Markers

Differential diagnosis:
Drugs / toxin / herbal medicine Autoimmune hepatitis Wilson disease Hemochromatosis
(ANA, ASMA, IgG)

(Cu, ceruloplasmin) (ferritin, iron, TIBC)

Non-alcoholic steatohepatitis Alpha 1-antitrypsin deficiency

Cause of Mild-Moderate ALT/AST Elevation

Hepatic: ALT-predominant

Chronic hepatitis B, C Steatosis / steatohepatitis Medications / herbal medicine Hemochromatosis Autoimmune hepatitis Wilsons disease Alcohol-related liver injury Steatosis / steatohepatitis Cirrhosis Hemolysis Myopathy Thyroid disease Strenuous exercise

Hepatic: AST-predominant

Non-hepatic

Cause of Mild-Moderate ALT/AST Elevation

Hepatic: ALT-predominant

Chronic hepatitis B, C Steatosis / steatohepatitis Medications / herbal medicine Hemochromatosis Autoimmune hepatitis Wilsons disease Alcohol-related liver injury Steatosis / steatohepatitis Cirrhosis Hemolysis Myopathy Thyroid disease Strenuous exercise

Hepatic: AST-predominant

Non-hepatic

Cause of Mild-Moderate ALT/AST Elevation

Hepatic: ALT-predominant

Chronic hepatitis B, C Steatosis / steatohepatitis Medications / herbal medicine Hemochromatosis Autoimmune hepatitis Wilson disease Alcohol-related liver injury Steatosis / steatohepatitis Cirrhosis Hemolysis Myopathy Thyroid disease Strenuous exercise

Hepatic: AST-predominant

Non-hepatic

Factors Affecting AST and ALT Besides Liver Injury

Time of day Day to day Gender / race Body mass index Exercise Hemolysis Muscle injury

A FU Study of Elevated ALT in Blood Donors

Time (year)
(Torezen-Filho MA, et al. Liver International 2004;24:575-81)

A FU Study of Elevated ALT in Blood Donors

: BMI and Alcohol

Time (year)

Time (year)
(Torezen-Filho MA, et al. Liver International 2004;24:575-81)

Non-alcoholic Steatohepatitis (NASH)

Non-alcoholic Steatohepatitis (NASH)

Associated or Risk Factors:

NIDDM Obesity Central obesity Hypertriglyceridemia; low HDL-C >45 years of age Co-associated with gall stone
(Farrell GC. J Gastro Hepatol 2003;18:124)

Case 3
32 3 4 yrs PTA 1-2 5-6 3 mo PTA 5 .

 Alcohol (-), blood Tx (-), herbal use (-) (-) Temp 36.5 C No jaundice, not pale, no stigmata chronic liver dz Abdomen: No ascites, no mass, Liver (-), spleen (-) PR: No rectal shelf

Investigation
Hct 32%, WBC 7200 /mm3 (PMN 70%), plt 365,000 /mm3 AST 45 U/L, ALT 40 U/L, ALP 470 U/L (50-136) GGT 390 U/L (15-85), TB 1.2 mg/dl HBsAg (-), Anti HCV (-), AFP 10 U/L, CA19-9 30 U/L

Differential diagnosis?

Factors Affect Alkaline Phosphatase

Day to day Food ingestion Gender / race Body mass index Smoking Pregnancy Bone disease

Causes of Elevated Alkaline Phosphatase

Non-hepatic Bone disease Pregnancy Childhood growth Hepatobiliary Space occupying lesions Infiltrating diseases of the liver Bile duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Medications

Causes of Elevated Alkaline Phosphatase

Non-hepatic Bone disease Pregnancy Childhood growth Hepatobiliary Space occupying lesions Infiltrating diseases of the liver Bile duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Medications

Further investigation?

Ultrasound Upper Abdomen

8 cm mass at left lobe of the liver

CT Scan Finding

Gross Pathology

Hepatocellular Carcinoma : Fibrolamellar Type

Characteristic features: Good prognosis

Occur in young patient Common in Caucasians No association with cirrhosis or viral hepatitis Normal AFP

Case 4
56 5 1 mo PTA 4-5 5 d PTA AST 418 U/L, ALT 592 U/L, ALP 334 U/L, TB/DB 8.6/6.6 U/L

 Alc (+) 30 yrs, herbal use (-), blood Tx (-) Known case DM & HT 7 yrs (-) No fever, no jaundice Abdomen: Normal

Investigation
AST 15 U/L, ALT 45 U/L, ALP 137 U/L, TB/DB 1.5/0.4 mg/dl HBsAg (-), anti HBc IgM (-), anti HAV IgM (-)

Impression Jaundice caused?

Further investigation?

Differential diagnosis

Acute viral hepatitis

Systemic infection

Ischemic hepatitis
Infiltrative disease Space occupying lesion Bile duct obstruction

Differential diagnosis

Acute viral hepatitis

Systemic infection

(x)
(x)

Ischemic hepatitis
Infiltrative disease

(x)
(x)

Space occupying lesion (x) Bile duct obstruction = CBD stone

Ultrasound Abdomen
: Finding
Dilatation of CBD (12 cm) Some distal CBD stones Multiple gall stones Normal gall bladder wall

ERCP
: Finding

* Endoscopic Retrograde Cholangio-Pancreatography

Elevated AlkPO4 and/or Direct Bilirubin

Ultrasound
Dilated bile ducts
ERCP MRCP

Non-dilated bile ducts

Depends on clinical data

? Duct disease

? Intra-hepatic cholestasis AMA, Liver biopsy

ERCP

MRCP

Common Causes of Biliary Obstruction

Intrahepatic PSC SOL Portal hepatis Cholangio CA PSC Suprapancreatic Pancreatic CA Metastatic dz. Intrapancreatic Pancreatic CA Pancreatitis

Gall bladder CA
Metastatic dz.

Pancreatitis
Iatrogenic Cholangio CA

CBD stone
Ampullary stenosis Ampullary CA Cholangio CA

CBD Stones
: Some Hints

Mildly elevated AlkPO4 (< 5 times UL) Increased bilirubin 50%-72% (2-14 mg/dl) Elevated AST (up to 3-5 times UL)

Conditions with CBD Obstruction

Without Bile Duct Dilatation
1/3 - CBD obstruction without dilatation Possible causes:
1. Early obstruction 2. Intermittent obstruction from stones

3. Sclerosing cholangitis

Case 5
47 3 Known case dyslipidemia 3 gemfibrozil (Lopid) 2 6 mo PTA Gemfibrozil 4 mo PTA Atorvastatin (Lipitor)

3 mo PTA ( 1 ) atorvastatin

Alc (-), herbal use (-), blood Tx (-) (-)

Moderate jaundice, no stigmata of chronic liver diseases Xanthroma at eyelids Abdomen: Liver (-), spleen (-)

Investigation
AST 60 U/L, ALT 132 U/L, ALP 333 U/L (50-136) GGT 559 U/L (15-85) TB 23.4 mg/dl, DB 18.5 mg/dl

Pattern of liver injury?

Impression

.. Cholestatohepatitis ..

Differential causes?
Investigation?

Differential causes

Autoimmune liver diseases

Overlapping syndrome PBC + autoimmune hepatitis PSC + autoimmune hepatitis

Drugs

Amoxycillin/clavulanic acid (Augmentin) Chlorpromazine Erythromycin

Investigation

AMA, ASMA, ANA Ultrasound abdomen

Investigation
AST 60 U/L, ALT 132 U/L, ALP 333 U/L (50-136) GGT 559 U/L (15-85) TB 23.4 mg/dl, DB 18.5 mg/dl ANA (-), AMA (-) Ultrasound abdomen No bile duct dilatation

Diagnosis: Drug-induced hepatoxicity

Criteria for Drug-induced Hepatotoxicity

Very suggestive Suggestive Time since drug intake Liver enzymes after drug cessation 590 d by 50% of by 50% of excess excess above above ULN ULN within 8 within 30 days days (hepatocellular) and 180 days (cholestatic) Positive Compatible <5 or >90 d

Rechallenge

Alternative cause Excluded

Further Investigation

ERCP? MRCP? Liver biopsy? No further work-up?

Liver Biopsy
: Intrahepatic Cholestasis

Hepatotoxicity & Hypolipidemic drug

Statins 22.7% 22.7% Reported Fibrates Niacin Binding resins Fish oil

Asymptomatic Hepatocellular Cholestatic

Reported Reported Reported

Up to 8.3% Reported Reported

Reported Reported NR

NR NR NR

Fulminant
Cirrhosis

0.2/100,000
Reported

NR
NR

Reported
Reported

NR
NR

NR
NR

NR = No report

(Parra JL, Reddy KR. Clin Liver Dis 2003)

Drugs, Herbs & Substances of Abuse Causing Elevations in Liver Enzymes

Drugs
Antibiotics (penicillins, isoniazid) Antiepileptic drugs (phenytoin, carbamazerpine) HMG-co A reductase inhibitors (simvastatin, atorvastatin) NSAIDs Sulfonylureas

Herbs
Chaparral, Ji bu huan, mahuang

Drugs and substances of abuse

Anabolic steroids Cocaine MDMA (ectasy) Glue containing toluene Trichloroethylene, chloroform

Drug-induced Hepatotoxicity
Hepatocellular pattern
Isoniazid Methyldopa Acetaminophen

Cholestatic pattern
Chlorpromazine Erythromycin Anabolic steroids

Mixed pattern
Sulfonamides Nitrofurantoins

Troglitazone
Diclofenac

Thiabendazole
Imipramine

Causes of Conjugated Hyperbilirubinemia

Bile duct obstruction Hepatitis Cirrhosis Medications / toxins Primary biliary cirrhosis

Primary sclerosing cholangitis

Sepsis Total parenteral nutrition

Dubin-Johnson syndrome
Rotor syndrome

Causes of Isolated Unconjugated Hyperblirubinemia

Hemolysis Blood transfusion (hemolysis) Ineffective erythropoiesis Resorption of large hematoma

Criggler-Najjar syndrome type II

Gilberts syndrome Shunt hyperbilirubinemia Neonatal jaundice

Contraindication for Liver Biopsy

Absolute Contraindication
Uncooperative patient Tendency to bleed

PT 3-5 sec more than control Platelet count < 50,000 /mm3 Prolonged bleeding time ( 10 min) Use of NSAID drug within 7-10 days

Unavailable blood for transfusion Suspected hemangioma or vascular tumor Inability to identify a suitable site for biopsy

Contraindication for Liver Biopsy

Relative contraindication
Morbid obesity
Ascites Hemophilia Infection in the right pleural cavity or below the right hemidiaphragm

(Bravo AA. N Eng J Med 2001;344:495)

Helpful Hints for Interpreting LFT (1)

Situation
Mildly elevated ALT (less than 1.5 xULN)
Alcoholic hepatitis

Comments
ALT level can be normal for gender, ethnicity or body mass index. Consider muscle injury or myopathy.
LFT can appear as cholestatic Minimal elevation of AST and ALT often occur. AST elevation is unlikely to result from alcohol intake alone. In a heavy drinker, consider alcoholic-acetaminophen syndrome

AST level > 500 U/L

Helpful Hints for Interpreting LFT (1)

Situation
Mildly elevated ALT (less than 1.5 xULN)
Alcoholic hepatitis

Comments
ALT level can be normal for gender, ethnicity or body mass index. Consider muscle injury or myopathy.
LFT can appear as cholestatic Minimal elevation of AST and ALT often occur. AST elevation is unlikely to result from alcohol intake alone. In a heavy drinker, consider alcoholic-acetaminophen syndrome

AST level > 500 U/L

Helpful Hints for Interpreting LFT (1)

Situation
Mildly elevated ALT (less than 1.5 xULN)
Alcoholic hepatitis

Comments
ALT level can be normal for gender, ethnicity or body mass index. Consider muscle injury or myopathy.
LFT can appear as cholestatic Minimal elevation of AST and ALT often occur. AST elevation is unlikely to result from alcohol intake alone. In a heavy drinker, consider Alcoholic-acetaminophen syndrome

AST level > 500 U/L

Helpful Hints for Interpreting LFT (2)

Situation
Common bile duct stone

Comments
LFT can simulate acute hepatitis. AST and ALT become elevated immediately with delay elevation of AP and GGT. This situation may be induced by alcohol and medication, usually with no actual liver disease. Consider bone growth or injury, or pregnancy. Consider Gilbert syndrome or hemolysis.

Isolated elevation of GGT

Isolated elevation of AP (asymptomatic patient with normal GGT) Isolated elevation of unconjugated bilirubin

Helpful Hints for Interpreting LFT (2)

Situation
Common bile duct stone

Comments
LFT can simulate acute hepatitis. AST and ALT become elevated immediately with delay elevation of AP and GGT. This situation may be induced by alcohol and medication, usually with no actual liver disease. Consider bone growth or injury, or pregnancy. Consider Gilbert syndrome or hemolysis.

Isolated elevation of GGT

Isolated elevation of AP (asymptomatic patient with normal GGT) Isolated elevation of unconjugated bilirubin

Helpful Hints for Interpreting LFT (2)

Situation
Common bile duct stone

Comments
LFT can simulate acute hepatitis. AST and ALT become elevated immediately with delay elevation of AP and GGT. This situation may be induced by alcohol and medication, usually with no actual liver disease. Consider bone growth or injury, or pregnancy. Consider Gilbert syndrome or hemolysis.

Isolated elevation of GGT

Isolated elevation of AP (asymptomatic patient with normal GGT) Isolated elevation of unconjugated bilirubin

Helpful Hints for Interpreting LFT (2)

Situation
Common bile duct stone

Comments
LFT can simulate acute hepatitis. AST and ALT become elevated immediately with delay elevation of AP and GGT. This situation may be induced by alcohol and medication, usually with no actual liver disease. Consider bone growth or injury, or pregnancy. Consider Gilbert syndrome or hemolysis.

Isolated elevation of GGT

Isolated elevation of AP (asymptomatic patient with normal GGT) Isolated elevation of unconjugated bilirubin

Non-hepatic Causes of Abnormal Liver Function Test

Test result Non-hepatic causes Discriminating test
Serum globulin, antitrypsin clearance Urinalysis, 24-hr urine protein CK-MB, troponin, EKG CK, ESR GGT, 5-nucleotidase GGT, 5-nucleotidase, hCG Alkaline phosphatase electrophoresis Reticulocyte count, peripheral smear, LDH, haptoglobin Sepsis Ineffective erythropoiesis Shunt hyperbilirubinemia Elevated PT Antibiotic, anticoagulant use Steatorrhea, dietary deficiency Clinical setting, blood culture Peripheral smear, urine bilirubin, Hemoglobin electrophoresis Clinical setting Response to vitamin K

Decreased albumin Protein-losing enteropathy Nephrotic syndrome Elevated AST level Myocardial infarction Muscle disorder Elevated ALP level Bone disease Pregnancy Malignant tumor Elevated bilirubin Hemolysis