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Jaundice

Chapter 52 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 52

Key Clinical Points

  1. Scleral icterus indicates a serum bilirubin level of at least 51 μmol/L (3 mg/dL).
  2. In alcoholic hepatitis, the AST-to-ALT ratio is typically ≥ 2:1, and AST rarely exceeds 300 U/L.
  3. Gilbert's syndrome affects 3–7% of the population, with males predominating by a ratio of 1.5–7:1.
  4. Dubin-Johnson syndrome is caused by mutations in the gene for MRP2, leading to altered excretion of bilirubin into bile ducts.
  5. Rotor syndrome is caused by a deficiency of the major hepatic drug reuptake transporters OATP1B1 and OATP1B3.
  6. Crigler-Najjar type I is characterized by complete absence of bilirubin UDPGT activity, leading to severe jaundice and risk of kernicterus.
  7. Crigler-Najjar type II has reduced UDPGT activity (typically ≤ 10% of normal) and patients survive into adulthood.
  8. ERCP is the 'gold standard' for identifying choledocholithiasis and allows therapeutic interventions.
  9. MRCP has replaced ERCP as the initial diagnostic test in most cases for bile duct obstruction.
  10. Pathognomonic segmental strictures on cholangiography are characteristic of primary sclerosing cholangitis (PSC).
  11. Delta bilirubin is conjugated bilirubin covalently linked to albumin, with a half-life approximating albumin (18–20 days).
  12. Murphy's sign (severe right-upper-quadrant tenderness with respiratory arrest on inspiration) suggests cholecystitis.

DEFINITION & OVERVIEW

• Jaundice: A yellowish discoloration of body tissues resulting from the deposition of bilirubin. • Clinical Significance: Tissue deposition occurs only in serum hyperbilirubinemia; it is a sign of liver disease, hemolytic disorder, or disorder of bilirubin metabolism. • Scleral Icterus: Detection of bilirubin ≥ 51 μmol/L (3 mg/dL). • Bilirubinuria: Indicates the presence of conjugated bilirubin in urine, signifying liver or biliary disease.

Bilirubin Metabolism

• Formation: Heme → Biliverdin (via heme oxygenase) → Bilirubin (via biliverdin reductase). • Transport: Unconjugated bilirubin is insoluble in water; it must bind to albumin for transport to the liver. • Conjugation: Occurs in the endoplasmic reticulum via bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT). • Excretion: Conjugated bilirubin is transported into canalicular bile by MRP2. • Reuptake: Conjugated bilirubin can be reabsorbed into the portal circulation via OATP1B1 and OATP1B3. • Enterohepatic Circulation: Conjugated bilirubin is hydrolyzed to unconjugated bilirubin in the gut; 80–90% are excreted in feces, while 10–20% undergo enterohepatic cycling.

EPIDEMIOLOGY

• Gilbert's Syndrome: ◦ Prevalence: 3–7% of the population. ◦ Demographics: Males predominate (1.5–7:1). ◦ Clinical Impact: Generally no clinical consequence; may have protective effects. • Crigler-Najjar Type I: ◦ Frequency: Exceptionally rare, primarily in neonates. ◦ Presentation: Severe jaundice (>342 μmol/L [>20 mg/dL]) and high risk of kernicterus. • Crigler-Najjar Type II: ◦ Frequency: More common than Type I. ◦ Presentation: Patients survive into adulthood; bilirubin 103–428 μmol/L (6–25 mg/dL).

ETIOLOGY & PATHOPHYISIOLOGY

• Unconjugated Hyperbilirubinemia: ◦ Causes: Overproduction (hemolysis, ineffective erythropoiesis) or impaired hepatic uptake/conjugation (drug effects like rifampin and probenecid; genetic disorders). ◦ Hemolytic Disorders: Spherocytosis, sickle cell anemia, thalassemia, and enzyme deficiencies (pyruvate kinase, G6PD). ◦ Genetic Conjugation Defects: Crigler-Najjar (Type I & II) and Gilbert's syndrome. • Conjugated Hyperbilirubinemia: ◦ Dubin-Johnson Syndrome: Mutation in the MRP2 gene → altered excretion into bile ducts. ◦ Rotor Syndrome: Deficiency of OATP1B1 and OATP1B3 transporters.

Hepatocellular vs. Cholestatic Differentiation

• Hepatocellular Process: ◦ Characterized by a rise in aminotransferases (AST/ALT) disproportionate to alkaline phosphatase (ALP). ◦ Indicators: Low albumin suggests chronic process; elevated prothrombin time indicates significant dysfunction or prolonged jaundice. • Cholestatic Process: ◦ Characterized by a rise in ALP disproportionate to aminotransferases.

CLINICAL FEATURES

• Physical Examination Findings: ◦ Scleral Icterus: Indicates bilirubin ≥ 51 μmol/L (3 mg/dL). ◦ Carotenoderma: Yellowing of skin due to high carotene intake; spares the sclerae. Associated with diabetes, hypothyroidism, and anorexia nervosa. ◦ Drug-induced Discoloration: Quinacrine (4–37%), sunitinib, and sorafenib. ◦ Murphy's Sign: Severe RUQ tenderness with respiratory arrest on inspiration → suggests cholecystitis. • Symptoms: ◦ General: Pruritus, abdominal pain, fever, arthralgias, myalgias, rash, anorexia, weight loss. ◦ Specific Patterns: → Arthralgias/myalgias predating jaundice → suggests viral or drug-related hepatitis. → Sudden RUQ pain + shaking chills → suggests choledocholithiasis and ascending cholangitis.

DIFFERENTIAL DIAGNOSIS

• Isolated Unconjugated Hyperbilirubinemia: ◦ Hemolytic disorders (Spheroderma, Sickle cell, Thalassemia). ◦ Ineffective erythropoiesis (Cobalamin, folate, iron deficiencies). ◦ Drug effects (Rifampin, Probenecid). ◦ Genetic: Gilbert's, Crigler-Najjar. • Isolated Conjugated Hyperbilirubinemia: ◦ Dubin-Johnson syndrome. ◦ Rotor syndrome. • Combined/Conjugated with Liver Test Abnormalities: ◦ Hepatocellular: Viral hepatitis (A, B, C, D, E), EBV, CMV, HSV; Alcoholic hepatitis; Drug toxicity (Acetaminophen, Isoniazid); Wilson's disease; Autoimmune hepatitis. ◦ Cholestatic: Primary biliary cholangitis (PBC), Sclerosing cholangitis (PSC), Vanishing bile duct syndrome, Gallstones, Malignancy.

DIAGNOSTIC APPROACH

  1. Initial Laboratory Evaluation: • Measure total and direct serum bilirubin. • Assess liver enzymes: AST, ALT, ALP. • Assess liver function: Albumin, Prothrombin Time (PT). • Interpretation of PT: Failure to correct with Vitamin K indicates severe hepatocellular injury.
  2. Categorization of Hyperbilirubinemia: • Determine if conjugated ≥ 15% of total bilirubin.
  3. Determination of Site (if Conjugated): • Imaging: Ultrasound, CT, or MRCP to assess for dilation of intra- and extrahepatic biliary tree. → No dilation → suggests intrahepatic cholestasis. → Dilation present → suggests extrahepatic cholestasis.
  4. Advanced Imaging & Procedures: • MRCP: Initial diagnostic test for bile duct obstruction. • ERCP: Gold standard for identifying choledocholithiasis; allows therapeutic intervention (stone removal, stenting). • EUS: High sensitivity/specificity for bile duct obstruction and biopsy of malignant lesions.
  5. Specific Testing based on Pattern: • Viral: H1, H2, H3, HEV, EBV, CMV, HSV. • Autoimmune: AMA, ANA, SMA. • Metabolic: Ceruloplasmin (Wilson's), α1-antitrypsin (if <40 years old).
  6. Flowchart: Evaluation of the patient with jaundice: • Step 1: Determine Bilirubin Type → If Unconjugated (≤ 15% direct): ◦ Assess for Inherited (Gilbert, Crigler-Najjar) vs. Acquired (Hemolysis, Ineffective erythropoiesis). → If Conjugated (≥ 15% direct): ◦ Proceed to Liver Function and Imaging. • Step 2: Determine Location of Obstruction → If Extrahepatic: Evaluate for biliary obstruction (gallstones, malignancy). → If Intrahepatic: Perform specific testing: ◦ Viral etiology (H1, H2, H3, HEV). ◦ Autoimmune/Other (AMA, ANA, SMA). ◦ Genetic/Metabolic (α1-antitrypsin, Wilson disease).

MANAGEMENT & TREATMENT

  1. General Management: • Assess nutritional status and identify signs of chronic liver disease.
  2. Drug-Induced Cholestasis: → Identify specific agents (e.g., anabolic/contraceptive steroids, chlorpromazine).
  3. Primary Biliary Cholangitis (PBC): → Management based on clinical diagnosis.
  4. Primary Sclerosing Cholangitis (PSC): → Identification of characteristic segmental strictures via cholangiography.
  5. Cholestasis of Pregnancy: → Specific management for pregnancy-related cholestasis.
  6. Intensive Care Unit (ICU) Cholestasis: → Management of acute, severe cases.
  7. Transplant/Transfusion Related: → Manage complications such as Graft-versus-host disease or Vanishing bile duct syndrome.
  8. Specific Conditions requiring management (Table 52-3): • Intrahepatic: Viral hepatitis, Alcoholic hepatitis, Drug toxicity, PBC, PSC, Vanishing bile duct syndrome, Congestive/Ischemic hepatopathy, Inherited conditions, Cholestasis of pregnancy, TPN, Nonhepatobiliary sepsis, Benign postoperative cholestasis, Paraneoplastic syndrome, Veno-occlusive disease, Graft-versus-host disease, Infiltrative disease (TB, Lymphoma, Amyloidosis), Infections (Malaria, Leptospirosis). • Extrahepatic: Malignant (Cholangiocarcinoma, Pancreatic cancer, Gallbladder cancer, Ampullary cancer), Benign (Choledocholithiasis, Postoperative biliary strictures, PSC, Chronic pancreatitis, AIDS cholangiopathy, Mirizzi's syndrome, Parasitic disease).

KEY PEARLS & CLINICAL TRAPS

• Scleral Icterus: Threshold is ≥ 51 μmol/L (3 mg/dL). • Bilirubinuria: Indicates conjugated bilirubin; always suggests liver or biliary disease. • Carotenoderma vs. Jaundice: Carotenoderma spares the sclerae and concentrates on palms/soles; jaundice is uniform. • ERCP: Gold standard for choledocholithiasis; allows therapeutic intervention. • MRCP: Preferred initial test for bile duct obstruction over ERCP. • Dubin-Johnson vs. Rotor: Dubin-Johnson = MRP2 mutation; Rotor = OATP1B1/OATP1B3 deficiency. • Hepatocellular vs. Cholestatic: Use AST/ALT vs. ALP ratio to differentiate. • Murphy's Sign: Specific for cholecystitis. • Crigler-Najjar I: Complete absence of UDPGT; high risk of kernicterus. • PSC: Characterized by pathognomonic segmental strictures on cholangiography.

Reference Tables

Table 52-1 Drugs

Harrison's 22e, p.322

  • Drugs
    Rifampicin
    Probenecid
  • Inherited disorders
    Gilbert’s syndrome
    Crigler-Najjar syndromes
  • Hemolytic disorders
    Ineffective erythropoiesis

TABLE 52-2 Hepatocellular Conditions That May Produce Jaundice Viral hepatitis

Harrison's 22e, p.324

  • Viral hepatitis
  • Hepatitis A, B, C, D, and E
  • Epstein-Barr virus
  • Cytomegalovirus
  • Herpes simplex virus
  • Alcoholic hepatitis
  • Chronic liver disease and cirrhosis
  • Drug toxicity
  • Predictable, dose-dependent (e.g., acetaminophen)
  • Unpredictable, idiosyncratic (e.g., isoniazid)
  • Environmental toxins
  • Vinyl chloride
  • Jamaica bush tea—pyrrolizidine alkaloids
  • Kava kava
  • Wild mushrooms—Amanita phalloides, A. verna
  • Wilson’s disease
  • Autoimmune hepatitis

TABLE 52-3 Cholestatic Conditions That May Produce Jaundice I. Intrahepatic

Harrison's 22e, p.325

  • I. Intrahepatic
    A. Viral hepatitis
    1. Fibrosing cholestatic hepatitis—hepatitis B and C
    2. Hepatitis A, Epstein-Barr virus infection, cytomegalovirus infection
    B. Alcoholic hepatitis
    C. Drug toxicity
    1. Pure cholestasis—anabolic and contraceptive steroids
    2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate
    3. Chronic cholestasis—chlorpromazine and prochlorperazine
    D. Primary biliary cholangitis
    E. Sclerosing cholangitis, primary and secondary
    F. Vanishing bile duct syndrome
    1. Chronic rejection of liver transplants
    2. Sarcoidosis
    3. Drugs
    G. Congestive hepatopathy and ischemic hepatitis
    H. Inherited conditions
    1. Progressive familial intrahepatic cholestasis
    2. Benign recurrent intrahepatic cholestasis
    I. Cholestasis of pregnancy
    J. Total parenteral nutrition
    K. Nonhepatobiliary sepsis
    L. Benign postoperative cholestasis
    M. Paraneoplastic syndrome
    N. Veno-occlusive disease
    O. Graft-versus-host disease
    P. Infiltrative disease
    1. Tuberculosis
    2. Lymphoma
    3. Amyloidosis
    Q. Infections
    1. Malaria
    2. Leptospirosis
    II. Extrahepatic
    A. Malignant
    1. Cholangiocarcinoma
    2. Pancreatic cancer
    3. Gallbladder cancer
    4. Ampullary cancer
    5. Malignant involvement of the porta hepatis lymph nodes
    B. Benign
    1. Choledocholithiasis
    2. Postoperative biliary strictures
    3. Primary sclerosing cholangitis
    4. Chronic pancreatitis
    5. AIDS cholangiopathy
    6. Mirizzi’s syndrome
    7. Parasitic disease (ascariasis)