Jaundice

Jaundice is yellow discoloration of the skin, sclerae and mucosa from bilirubin deposition. It usually becomes visible when serum bilirubin rises above about 2 to 2.5 mg/dL. The normal adult range is 0.3 to 1.2 mg/dL (Robbins & Kumar Basic Pathology, Pathophysiology of Jaundice).

Bilirubin metabolism

Heme from senescent red cells is converted to unconjugated bilirubin. This form is water-insoluble and bound to albumin, so it is not filtered by the kidney.
Hepatocytes take it up and conjugate it with glucuronic acid via UGT1A1, which makes it water-soluble. It is then excreted into bile.
Gut bacteria convert conjugated bilirubin to urobilinogen. Most is lost in stool, about 20% is reabsorbed, and a little appears in urine.

Any bilirubin found in urine is conjugated, and its presence implies hepatobiliary disease (Harrison's Principles of Internal Medicine 22E, p. 365).

Pathophysiology and classification

Hyperbilirubinemia results from overproduction, impaired uptake, conjugation or excretion, or regurgitation from damaged hepatocytes or ducts. The first step in assessment is to decide whether the raised fraction is unconjugated or conjugated (Harrison's, p. 365).

Type	Mechanism	Examples	Typical findings
Pre-hepatic (unconjugated)	Overproduction	Hemolysis, ineffective erythropoiesis, hematoma resorption	Normal ALT, AST and ALP. No bilirubinuria ("acholuric"). Raised urobilinogen.
Hepatic, defective uptake or conjugation (unconjugated)	Reduced UGT1A1 activity or hepatic uptake	Gilbert syndrome, Crigler-Najjar syndrome, neonatal immaturity, drugs	Isolated indirect hyperbilirubinemia with otherwise normal liver tests.
Hepatocellular (mixed, mostly conjugated)	Hepatocyte injury with impaired excretion	Viral, alcoholic, autoimmune and drug-induced hepatitis, cirrhosis, Wilson disease	ALT and AST much higher than ALP. Synthetic dysfunction may be present.
Cholestatic, intrahepatic (conjugated)	Impaired canalicular secretion	PBC, PSC, drugs, sepsis, pregnancy cholestasis	ALP and GGT disproportionately high.
Cholestatic, extrahepatic (conjugated)	Mechanical obstruction	Choledocholithiasis, pancreatic or biliary cancer, stricture, cholangitis	ALP and GGT high. Dark urine and pale stool. Dilated ducts on imaging.

A rough rule from the Quick Compendium of Clinical Pathology: hepatocellular jaundice has ALP below 3 times the upper limit of normal, and cholestatic jaundice has ALP above 3 times. Harrison's notes that biliary obstruction or hepatocellular cholestatic injury can sometimes present with predominantly conjugated hyperbilirubinemia, so labs alone cannot always separate intrahepatic from extrahepatic causes.

Delta bilirubin is conjugated bilirubin covalently bound to albumin. It has a long half-life, so bilirubin falls slowly during recovery. It is not filtered by the kidney, so urine dipstick can be falsely negative in prolonged cholestasis (Harrison's).

Clinical approach

History

Onset and tempo, and abdominal pain (biliary colic suggests stones).
Fever and rigors (cholangitis).
Pruritus, dark urine and pale stool (cholestasis).
Weight loss and painless jaundice (malignancy).
Alcohol, drugs and herbal supplements, transfusions, IV drug use, travel and sexual exposures.
Family history, including hemolysis or Gilbert syndrome.

Examination

Stigmata of chronic liver disease: spider naevi, ascites, splenomegaly, asterixis.
Courvoisier sign (a palpable, non-tender gallbladder suggests malignant obstruction).
Hepatomegaly, lymphadenopathy, Kayser-Fleischer rings.

Investigations

Fractionated bilirubin, ALT, AST, ALP, GGT, albumin, INR, CBC and smear. Add reticulocytes, LDH, haptoglobin and a Coombs test if hemolysis is suspected.
Abdominal ultrasound first for a cholestatic pattern. Look for duct dilatation and stones.
MRCP, EUS or CT if the cause is still unclear. ERCP is used for therapy. Reserve liver biopsy for unexplained hepatocellular or intrahepatic cholestasis.
For hepatocellular disease: viral serology, autoimmune markers, ceruloplasmin, iron studies and alpha-1 antitrypsin.

Emergencies

Ascending cholangitis (Charcot triad of fever, jaundice and RUQ pain): give antibiotics and arrange urgent biliary decompression.
Acute liver failure (jaundice with coagulopathy and encephalopathy): urgent hepatology and transplant referral.
Neonatal jaundice with high or rapidly rising bilirubin: risk of kernicterus.

Neonatal jaundice

Physiologic jaundice rises slowly (under 5 mg/dL per 24 h), peaks at 5 to 6 mg/dL on days 2 to 4, and falls below 2 mg/dL by days 5 to 7.

Jaundice in the first 24 hours is pathologic until proven otherwise. Think ABO or Rh hemolysis, congenital infection, or bruising.
Conjugated hyperbilirubinemia is always pathologic. Biliary atresia is the key diagnosis not to miss, especially with acholic stools.
Unconjugated bilirubin can cross the blood-brain barrier and cause kernicterus. Conjugated bilirubin is water-soluble and non-toxic (Robbins; Tintinalli's Emergency Medicine, Jaundice).

Recent evidence check

A PubMed search of the last 2 years found no meta-analysis or systematic review that contradicts the textbook framework above. Recent reviews cover neonatal screening: community assessment of neonatal jaundice (PMID 41966723, 2026) and non-invasive biosensors for neonatal jaundice detection (PMID 38785728, 2024).

I can go deeper on any one area: neonatal jaundice and phototherapy thresholds, hereditary hyperbilirubinemias (Gilbert, Crigler-Najjar, Dubin-Johnson, Rotor), the obstructive jaundice work-up, or a case-based approach. Tell me which you want.

Treatment

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