Download PDF

The Hyperbilirubinemias¶

Chapter 349 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders · Chapter 349

Key Clinical Points¶

Gilbert syndrome is the most common cause of unconjugated hyperbilirubinemia, characterized by mild elevation (≤70 μmol/L; ≤4 mg/dL) and normal liver tests.
Crigler-Najjar syndrome Type I presents with severe unconjugated hyperbilirubinemia (>345 μmol/L; >20 mg/dL) and high risk of kernicterus; Type II has lower levels (≤345 μmol/L; ≤20 mg/dL) and responds to phenobarbital.
Dubin-Johnson syndrome is characterized by conjugated hyperbilirubinemia, a black liver due to lipofuscin accumulation, and elevated urinary coproporphyrin isomer I (>80% of total).
Rotor syndrome presents with conjugated hyperbilirubinemia but lacks the characteristic black liver pigmentation of Dubin-Johnson.
Bilirubin metabolism involves four distinct steps: hepatocellular uptake, intracellular binding (ligandins), conjugation (UGT1A1), and biliary excretion (MRP2).
Hemolysis alone cannot result in a sustained hyperbilirubinemia exceeding 68 μmol/L (4 mg/dL); values above this indicate concurrent hepatic dysfunction.
Drug-induced hyperbilirubinemia (e.g., atazanavir, irinotecan) should be considered in patients with preexisting Gilbert syndrome.
Phenobarbital induces UGT1A1 activity, reducing bilirubin in both Gilbert and Crigler-Najjar Type II syndromes.
Bilirubin conjugates are filtered by the kidneys; renal failure can act as an 'overflow valve,' potentially amplifying jaundice in conjugated hyperbilirubinemia.
PFIC3 is associated with severe cholestasis in childhood and elevated GGT.

DEFINITION & OVERVIEW¶

• Definition: Disorders characterized by elevated serum bilirubin levels resulting from perturbations in bilirubin metabolism and transport. • Clinical Context: ◦ Diagnosis often requires repeating tests over days or weeks to establish a clear pattern. ◦ Regional Variation: In developing nations, infectious diseases are more common causes of abnormal liver tests than in developed nations.

Liver Test Patterns (Table 348-1)¶

• Hemolysis/Gilbert's syndrome: ◦ Bilirubin: Normal to 86 μmol/L (5 mg/dL); 85% is indirect fraction; No bilirubinuria. ◦ Other tests: Aminotransferases, ALP, Albumin, and PT are all normal. • Acute hepatocellular necrosis (viral, ischemic, drug/toxin-induced): ◦ Bilirubin: Both fractions may be elevated; peak usually follows aminotransferases; Bilirubinuria present. ◦ Aminotransferases: Elevated, often >500 IU; ALT > AST. ◦ ALP: Normal to <3× normal elevation. ◦ Albumin: Normal. ◦ PT: Normal. (Note: If >5× and fails to correct with parenteral Vitamin K, suggests poor prognosis). • Chronic hepatocellular disorders: ◦ Bilirubin: Both fractions may be elevated; Bilirubinuria present. ◦ Aminotransferases: Normal to <3× normal elevation. ◦ ALP: Normal to <3× normal elevation. ◦ Albumin: Often decreased. ◦ PT: Often prolonged; fails to correct with parenteral Vitamin K. • Alcoholic hepatitis, cirrhosis: ◦ Bilirubin: Both fractions may be elevated; Bilirubinuria present. ◦ Aminotransferases: AST:ALT >2 suggests alcoholic etiology or cirrhosis. ◦ ALP: Normal to <3× normal elevation. ◦ Albumin: Often decreased. ◦ PT: Often prolonged; fails to correct with parenteral Vitamin K. • Intra- and extrahepatic cholestasis (obstructive jaundice): ◦ Bilirubin: Both fractions may be elevated; Bilirubinuria present; Rarely >500 IU. ◦ Aminotransferases: Normal to moderate elevation. ◦ ALP: Elevated, often >4× normal elevation. ◦ Albumin: Normal (unless chronic). ◦ PT: Normal (unless chronic); if prolonged, corrects with parenteral Vitamin K. • Infiltrative diseases (tumor, granulomata): ◦ Bilirubin: Usually normal. ◦ Aminotransferases: Normal to slight elevation. ◦ ALP: Elevated, often >4× normal elevation; confirm liver origin with 5′-nucleotidase or γ-glutamyl transpeptidase. ◦ Albumin: Normal. ◦ PT: Normal.

EPIDEMIOLOGY¶

• Gilbert Syndrome (GS): ◦ Prevalence: High, up to 8% in some series. ◦ Sex Distribution: Males predominate (1.5:1 to >7:1 ratio). ◦ Note: Higher male prevalence may be partly due to higher mean bilirubin levels in normal males compared to females. • Regional Variation: ◦ Developing nations: Infectious diseases are more common causes of abnormal liver tests than in developed nations.

ETIOLOGY & PATHOPHYSIOLOGY¶

• General Principles: ◦ Bilirubin is the end product of heme degradation (70–90% from senescent RBCs). ◦ Transport: Bound to albumin in plasma due to insolubility. ◦ Metabolism Steps: Transition from blood to bile involves 4 distinct steps.

Bilirubin Metabolism Steps¶

Hepatocellular uptake: ◦ Mechanism: Carrier-mediated kinetics; specific transporter identity remains elusive.
Intracellular binding: ◦ Mechanism: Bound to glutathione-S-transferases (formerly ligandins) as a non-substrate ligand.
Conjugation: ◦ Process: Conjugated with 1–2 glucuronic acid moieties by UDP-glucuronosyltransferase (UGT1A1). ◦ Result: Formation of bilirubin mono- and diglucuronides. ◦ Transport: Actively transported across canalicular membrane; some enter portal circulation (via MRP3) and are re-taken up by OATP1B1/OATP1B3.
Biliary excretion: ◦ Mechanism: Active transport across canalicular membrane via MRP2 (ABCC2). ◦ Clinical Note: Mutations in MRP2 result in Dubin-Johnson syndrome.

Extrahepatic Aspects of Bilirubin Disposition¶

• Bilirubin in the Gut: ◦ Conversion: Conjugated bilirubin converted by bacteria to water-soluble urobilinogen. ◦ Circulation: Urobilinogen undergoes enterohepatic circulation; some reaches systemic circulation and is cleared by kidneys. ◦ Unconjugated Bilirubin: Usually does not reach gut except in neonates or severe unconjugated hyperbilirubinemia (e.g., Crigler-Najjar Type I) → leads to increased reabsorption. • Renal Excretion of Bilirubin Conjugates: ◦ Unconjugated Bilirubin: Not excreted in urine (bound to albumin; no tubular secretion). ◦ Conjugated Bilirubin: Readily filtered at glomerulus; can appear in urine in conjugated hyperbilirubinemia. ◦ Clinical Note: Kidney acts as an "overflow valve" for conjugates → renal failure may amplify jaundice.

Disorders of Bilirubin Metabolism Leading to Unconjugated Hyperbilirubinemia¶

• Increased Bilirubin Production: ◦ Hemolysis: ◦ Mechanism: Increased destruction of RBCs → increased turnover. ◦ Limit: Bone marrow can only sustain 8-fold increase in production; hemolysis alone cannot cause sustained hyperbilirubinemia >68 μmol/L (4 mg/dL). ◦ Diagnosis: If bilirubin is purely unconjugated (direct fraction ≤15%), it suggests normal liver function. ◦ Complication: Prolonged hemolysis can lead to pigment gallstones (bilirubin-rich) → cholecystitis or biliary obstruction. ◦ Ineffective Erythropoiesis: ◦ Mechanism: Loss of hemoglobin during maturation/destruction in marrow. ◦ Conditions: Thalassemia major, megaloblastic anemias (B12/folate deficiency), lead poisoning, dyserythropoietic anemias. ◦ Result: Can produce modest unconjugated hyperbilirubinemia. ◦ Miscellaneous: ◦ Mechanism: Breakdown of extravascular RBC collections (e.g., tissue infarction, hematomas) → transient unconjugated hyperbilirubinemia.

DIAGNOSTIC APPROACH¶

Initial Assessment: Determine if hyperbilirubinemia is conjugated or unconjugated to differentiate liver, hemolysis, or transport issues.
Liver Function Test (LFT) Analysis: Evaluate Aminotransferases, ALP, Albumin, and PT to determine the site of pathology (e.g., cholestasis vs. hepatocellular injury).
Specific Differentiation Criteria: • Dubin-Johnson vs. Rotor: Both present with conjugated hyperbilirubinemia; Dubin-Johnson is distinguished by a black liver (lipofuscin) and elevated urinary coproporphyrin isomer I (>80% of total). • Hemolysis Assessment: If unconjugated bilirubin >68 μmol/L (4 mg/dL), assume concurrent hepatic dysfunction. • Cholestasis Identification: Elevated ALP (>4x normal) and presence of conjugated bilirubin suggest cholestatic processes; use 5′-nucleotidase or γ-glutamyl transpeptidase to confirm liver origin in infiltrative diseases.

MANAGEMENT & TREATMENT¶

Identify Underlying Cause: Determine if the cause is hemolysis, liver disease, or a genetic transport defect.
Pharmacological Intervention: • Crigler-Najjar Type II: Phenobarbital → induces UGT1A1 activity → reduces bilirubin levels. • Gilbert Syndrome: No specific treatment required for mild cases; phenobarbital may reduce levels but is not standard primary therapy.
Monitoring and Risk Mitigation: • Neonatal Care: Monitor for kernicterus in neonates with unconjugated bilirubin >345 μmol/L (>20 mg/dL). • Renal Management: Assess renal function in patients with conjugated hyperbilirubinemia to manage the "overflow" of conjugates into the urine.

KEY PEARLS & HIGH-YIELD POINTS¶

• Gilbert Syndrome: Most common; ≤70 μmol/L (≤4 mg/dL); normal LFTs. • Crigler-Najjar Type I: Severe; >345 μmol/L (>20 mg/dL); no phenobarbital response; high kernicterus risk. • Dubin-Johnson vs. Rotor: Both have conjugated hyperbilirubinemia; DJS has black liver and high urinary coproporphyrin; Rotor does not. • Hemolysis Limit: If unconjugated bilirubin >68 μmol/L (4 mg/dL), assume concurrent hepatic dysfunction. • Bilirubin Metabolism Pathway: 1. Hepatocellular uptake → 2. Binding (Ligandins) → 3. Conjugation (UGT1A1) → 4. Biliary excretion (MRP2).

Reference Tables¶

TABLE 348-1 Liver Test Patterns in Hepatobiliary Disorders¶

Harrison's 22e, p.2637

TYPE OF DISORDER	BILIRUBIN	AMINOTRANSFERASES	ALKALINE PHOSPHATASE	ALBUMIN	PROTHROMBIN TIME
Hemolysis/Gilbert’s syndrome	Normal to 86 μmol/L (5 mg/dL) 85% due to indirect fractions No bilirubinuria	Normal	Normal	Normal	Normal
	Both fractions may be elevated Peak usually follows aminotransferases Bilirubinuria	Elevated, often >500 IU, ALT > AST	Normal to <3× normal elevation	Normal
Chronic hepatocellular disorders	Both fractions may be elevated Bilirubinuria	Elevated, but usually <300 IU	Normal to <3× normal elevation	Often decreased	Often prolonged Fails to correct with parenteral vitamin K
	Both fractions may be elevated Bilirubinuria	AST:ALT >2 suggests alcoholic hepatitis or cirrhosis	Normal to <3× normal elevation	Often decreased
Intra- and extrahepatic cholestasis (obstructive jaundice)	Both fractions may be elevated Bilirubinuria	Normal to moderate elevation Rarely >500 IU	Elevated, often >4× normal elevation	Normal, unless chronic	Normal If prolonged, will correct with parenteral vitamin K
	Usually normal	Normal to slight elevation	Elevated, often >4× normal elevation Fractionate, or confirm liver origin with 5′-nucleotidase or γ-glutamyl transpeptidase	Normal

TABLE 349-1 Principal Differential Characteristics of Gilbert and Crigler-Najjar Syndromes FEATURE Total serum…¶

Harrison's 22e, p.2639

FEATURE	CRIGLER-NAJJAR SYNDROME		GILBERT SYNDROME
	TYPE I	TYPE II
Total serum bilirubin, μmol/L (mg/dL)	310–755 (usually >345) (18–45 [usually >20])	100–430 (usually ≤345) (6–25 [usually ≤20])	Typically ≤70 μmol/L (≤4 mg/dL) in absence of fasting or hemolysis
	Normal None Usual Normal	Normal Decreases bilirubin by >25% Rare Normal
Bile characteristics Color Bilirubin fractions	Pale or colorless >90% unconjugated	Pigmented Largest fraction (mean: 57%) monoconjugates	Normal dark color Mainly diconjugates but monoconjugates increased (mean: 23%)
	Typically absent; traces in some patients Recessive	Markedly reduced: 0–10% of normal Predominantly recessive

TABLE 349-2 Principal Differential Characteristics of Inheritable Disorders of Bile Canalicular Function Gene Protein…¶

Harrison's 22e, p.2641

	DJS	ROTOR	PFIC1	BRIC1	PFIC2	BRIC2	PFIC3
Gene Protein Cholestasis	ABCCA MRP2 No	SLCO1B1/SLCO1B3 OATP1B1/1B3 No	ATP8B1 FIC1 Yes	ATP8B1 FIC1 Episodic	ABCB11 BSEP Yes	ABCB11 BSEP Episodic	ABCB4 MDR3 Yes
	Normal Normal	Normal Normal	Normal ↑↑	Normal ↑↑ during episodes	Normal ↑↑	Normal ↑↑ during episodes
Clinical features	Mild conjugated hyperbilirubinemia; otherwise, normal liver function; dark pigment in liver; characteristic pattern of urinary coproporphyrins	Mild conjugated hyperbilirubinemia; otherwise, normal liver function; liver without abnormal pigmentation	Severe cholestasis beginning in childhood	Recurrent episodes of cholestasis beginning at any age	Severe cholestasis beginning in childhood	Recurrent episodes of cholestasis beginning at any age	Severe cholestasis beginning in childhood; decreased phospholipids in bile