Jaundice & LFT Patterns: Hepatocellular vs Cholestatic vs Hemolytic
Gastrointestinal · 8 min read · 2026-06-03
Introduction
Jaundice is a common presenting complaint on Step 1 and Step 2 CK, and the exam rewards a systematic approach rather than pattern memorization alone. The key skill is using bilirubin fractionation and liver enzyme ratios to localize the problem to the hepatocyte, the biliary tree, or the red blood cell before ordering further imaging or serology. This article walks through the reasoning framework tested repeatedly on both exams.
Step 1: Fractionate the Bilirubin
Before anything else, determine whether hyperbilirubinemia is unconjugated (indirect) or conjugated (direct).
- Unconjugated hyperbilirubinemia: overproduction (hemolysis) or impaired conjugation (Gilbert syndrome, Crigler-Najjar)
- Conjugated hyperbilirubinemia: impaired excretion, implies hepatocellular or cholestatic disease
Unconjugated bilirubin is not water-soluble, so it does not appear in urine. Conjugated bilirubin is water-soluble and causes dark urine. This single fact lets you separate hemolysis from true liver/biliary disease at the bedside.
Step 2: Use the AST/ALT vs ALP Ratio
Once you know the process is hepatobiliary (conjugated bilirubin elevated), compare transaminases to alkaline phosphatase.
- Hepatocellular pattern: AST/ALT rise disproportionately to ALP (ratio of enzyme elevation favors transaminases)
- Cholestatic pattern: ALP and GGT rise disproportionately to AST/ALT
GGT confirms that an elevated ALP is hepatic in origin rather than bony, since GGT is not produced by bone.
Hepatocellular Injury: Key Causes and Clues
- Viral hepatitis: AST/ALT often in the thousands, ALT usually greater than AST except in advanced cirrhosis
- Alcoholic hepatitis: AST greater than ALT, typically both under 500, AST:ALT ratio at least 2:1
- Acetaminophen toxicity: AST/ALT can exceed 3000-5000, out of proportion to bilirubin early on
- Ischemic hepatitis (shock liver): rapid, massive transaminase rise with rapid resolution once perfusion restored
- Autoimmune hepatitis: elevated transaminases with positive ANA, anti-smooth muscle antibody
Cholestatic Injury: Key Causes and Clues
- Extrahepatic obstruction (choledocholithiasis, pancreatic head mass, cholangiocarcinoma): dilated ducts on ultrasound, conjugated bilirubin, elevated ALP/GGT
- Primary biliary cholangitis: middle-aged woman, pruritus, elevated ALP, positive antimitochondrial antibody
- Primary sclerosing cholangitis: young man, ulcerative colitis history, beaded appearance on MRCP
- Drug-induced cholestasis: oral contraceptives, anabolic steroids
Hemolytic Causes: The Prehepatic Pattern
Hemolysis produces unconjugated hyperbilirubinemia with normal AST, ALT, and ALP. Supporting labs distinguish it clearly from liver disease.
- Elevated LDH
- Decreased haptoglobin
- Increased reticulocyte count
- Peripheral smear findings (schistocytes in microangiopathic hemolysis, spherocytes in autoimmune hemolysis)
Because unconjugated bilirubin is not excreted in urine, patients with pure hemolysis have normal-colored urine despite scleral icterus, a classic exam distractor.
Comparison Table
Common Pitfall
Do not equate an elevated ALP with liver disease automatically. ALP is also produced by bone, placenta, and intestine. Always confirm hepatic origin with a GGT before pursuing a cholestatic workup, especially in patients with a history of bone disease, pregnancy, or recent fracture. Another frequent error is ordering an abdominal ultrasound before fractionating bilirubin; the fractionation should guide whether imaging is even indicated, since pure unconjugated hyperbilirubinemia points away from the biliary tree entirely.
Clinical Pearl
In a patient with jaundice, dark urine, and pale stools, think biliary obstruction: conjugated bilirubin is being shunted into urine while blocked bile cannot reach the gut to be converted to urobilinogen and stercobilin. Conversely, a patient with jaundice and normal-colored stool and urine, but scleral icterus, should prompt you to check a reticulocyte count and haptoglobin before ordering liver-specific tests.
Summary
Approach jaundice by first fractionating bilirubin to separate hemolytic and conjugation disorders from true hepatobiliary disease. Within hepatobiliary disease, compare transaminases to ALP/GGT to distinguish hepatocellular injury from cholestasis. Layer in urine bilirubin, urobilinogen, LDH, haptoglobin, and imaging only after this initial localization step, and you will efficiently narrow the differential on exam vignettes and in clinical practice.