Biochemical Liver Function Tests

• Harrison's Principles of Internal Medicine 22E, p. 2677
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease

1. Serum Bilirubin

• Isolated unconjugated hyperbilirubinemia (<15% direct): Rarely due to liver disease. Causes include hemolytic disorders and genetic syndromes (Gilbert's, Crigler-Najjar). Work up for hemolysis; if negative, consider Gilbert's syndrome.
• Conjugated hyperbilirubinemia (>15% direct): Almost always implies liver or biliary tract disease. The rate-limiting step in bilirubin metabolism is transport into the bile canaliculi, not conjugation - so conjugated bilirubin can be elevated in any liver disease.
• In most liver diseases, both fractions are elevated.
• Bilirubinuria - because unconjugated bilirubin is bound to albumin and cannot be filtered, any bilirubin in urine is conjugated, indicating liver disease or obstructive jaundice.

2. Serum Aminotransferases (Transaminases)

• Liver cell necrosis is not required for release - increased membrane permeability is enough.
• In acute hepatitis, ALT levels can reach 500-5000 IU/L; ALT > AST is the typical pattern.
• AST:ALT ratio >2 is characteristic of alcoholic hepatitis or cirrhosis.
• In acute fulminant hepatic failure, AST and ALT may exceed 10,000 IU/L, with a disproportionate rise of AST over ALT.
• Because ~80% of liver tissue must be destroyed before protein synthesis or ammonia metabolism fails, aminotransferases are often the first and only abnormal test in hepatitis.
• Harrison's Principles of Internal Medicine 22E, p. 2678
• Henry's Clinical Diagnosis and Management by Laboratory Methods

3. Alkaline Phosphatase (ALP)

• Intra- or extrahepatic cholestasis: elevation often >4× normal
• Infiltrative diseases (hepatic metastases, granulomata): elevation often >4× normal - ALP is the most sensitive marker of hepatic metastases
• Bone disease (Paget disease, osteoblastic activity) - bone origin
• Normal growth in children and pregnancy

• Normal childhood growth and pregnancy
• Ingesting a meal can raise ALP by 30% for up to 12 hours (intestinal isoenzyme)
• Oral contraceptives

• Quick Compendium of Clinical Pathology 5th ed.

4. Gamma-Glutamyl Transferase (GGT)

• Located on biliary epithelial cells and hepatocyte limiting plates
• Highly sensitive indicator of hepatobiliary injury, principally biliary tract
• Used to confirm that an elevated ALP is of hepatic origin
• Not specific - elevated by many chemical exposures: warfarin, barbiturates, phenytoin, valproate, methotrexate
• Alcohol marker: GGT elevated in up to 70% of chronic alcoholics; levels correlate with alcohol consumption; can be elevated to 2-3× the upper limit of normal (ULN) in heavy drinkers
• • Quick Compendium of Clinical Pathology 5th ed.

5. 5'-Nucleotidase (5'-NT)

• An adjunct to ALP to confirm biliary/hepatic origin of ALP elevation
• More specific than ALP for liver disease
• If 5'-NT and GGT are within normal range, an elevated ALP is most likely of bone origin
• Used alongside GGT in biliary obstruction workup

6. Serum Albumin

• Synthesized exclusively by the liver
• Reflects hepatic synthetic function
• Half-life ~20 days, so levels fall slowly and are a marker of chronic rather than acute liver injury
• Reduced when >80% of liver tissue is destroyed (cirrhosis, fulminant hepatic failure)
• Hypoalbuminemia in liver disease also contributes to ascites (reduced oncotic pressure)
• • Henry's Clinical Diagnosis and Management by Laboratory Methods

7. Prothrombin Time (PT) / INR

• Reflects synthesis of clotting factors I, II, V, VII, X - all made in the liver
• Factor VII has the shortest half-life (~6 hours), so PT is a sensitive marker of acute changes in hepatic synthetic function
• PT is prolonged in both acute and chronic liver disease
• Key differential: if PT corrects with parenteral vitamin K, the cause is cholestasis (fat malabsorption reducing vitamin K absorption), not hepatocellular failure; if it fails to correct, it suggests poor synthetic function (parenchymal disease)
• PT >5× control that fails to correct with vitamin K in acute hepatitis suggests poor prognosis
• Also used in MELD score

8. Serum Ammonia

• The liver is the only tissue that can metabolize ammonia via the urea cycle (Krebs-Henseleit cycle)
• Ammonia rises only when >80% of liver tissue is destroyed
• Elevated in cirrhosis and fulminant hepatic failure
• Causes hepatic encephalopathy

9. Total Protein and Serum Protein Electrophoresis (SPEP)

• Liver synthesizes >90% of serum proteins including all albumin
• Levels fall only in severe parenchymal disease (>80% destruction)
• In cirrhosis, gamma globulins are elevated (polyclonal) - reflecting immune activation

Patterns of LFTs in Disease

Diagnostic Algorithm for Abnormal Liver Tests

• Isolated unconjugated bilirubin: Fractionate → hemolysis workup or Gilbert's syndrome
• Isolated conjugated bilirubin: Dubin-Johnson or Rotor syndrome if no other abnormality
• Hepatocellular pattern (high aminotransferases): Review drugs, check viral hepatitis serology, iron studies, ANA, ceruloplasmin (if <40 years), ultrasound for fatty liver
• Cholestatic pattern (high ALP + bilirubin): Ultrasound first - dilated ducts → CT/MRCP/ERCP; non-dilated → check AMA (antimitochondrial antibody for primary biliary cholangitis)
• Isolated ALP elevation: Fractionate or confirm hepatic origin with GGT/5'-NT; if bone origin → bone evaluation; if hepatic origin → ultrasound, review drugs, check AMA

Summary: Grouping the Tests by Function

• Harrison's Principles of Internal Medicine 22E (2025), Ch. 348
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Quick Compendium of Clinical Pathology 5th ed.
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease