Jaundice

Pathophysiology of Jaundice

• Classic Definition: Serum bilirubin > 2.5 to 3 mg/dL (42.8 to 51.3 μmol/L) with yellow skin and sclera.
• Bilirubin Metabolism Phases:
  • Prehepatic Phase:
    • ~4 mg/kg of bilirubin produced daily from heme metabolism.
    • 80% from red blood cell catabolism, 20% from erythropoiesis, muscle myoglobin, and cytochromes.
    • Bilirubin transported to the liver for conjugation and excretion.
  • Intrahepatic Phase:
    • Unconjugated bilirubin is water-insoluble but fat-soluble.
    • Conjugated with a sugar in hepatocytes via glucuronosyltransferase.
    • Becomes water-soluble and excreted in bile.
  • Posthepatic Phase:
    • Conjugated bilirubin transported to gallbladder or duodenum via bile ducts.
    • In intestines, some excreted in stool; the rest metabolized to urobilinogens.
    • Urobilinogens reabsorbed, filtered by kidneys, and excreted in urine; some re-excreted into bile.

Clinical Presentation of Jaundice

• Symptomatic Variability:
  • May be asymptomatic (incidental finding) or present with severe symptoms.
  • Presentation depends on underlying cause and disease onset speed.
• Acute Illness (often infectious):
  • Fever, chills, abdominal pain, flu-like symptoms.
  • Skin color change may be secondary concern.
• Noninfectious Jaundice:
  • Symptoms: weight loss, pruritus, abdominal pain.
  • Abdominal pain common in pancreatic or biliary cancers.
  • Depression in chronic infectious hepatitis or alcoholism history.
• Extrahepatic Manifestations:
  • Chronic hepatitis: pyoderma gangrenosum.
  • Acute hepatitis B or C: polyarthralgias.

Differentials

1. Jaundice with Pain/Fever:
   • Hepatobiliary Disorders: Cholecystitis, cholangitis, gallstones.
   • Infectious Hepatitis: Hepatitis A, B, or C; often accompanied by fever, fatigue.
   • Pancreatitis: Especially if pain is in the upper abdomen, radiating to the back.
   • Liver Abscess: Can cause fever, pain, and jaundice.
   • Biliary Stricture: Obstruction leading to jaundice, pain, and possible fever.
2. Jaundice without Pain/Fever:
   • Hemolytic Anemia: Increased breakdown of red blood cells leading to jaundice.
   • Gilbert’s Syndrome: Mild, chronic jaundice without other significant symptoms.
   • Drug-Induced Liver Injury: Certain medications causing liver damage and jaundice.
   • Alcoholic Liver Disease: In the absence of acute exacerbation like alcoholic hepatitis.
   • Cancer: Pancreatic or liver cancers can cause obstructive jaundice.
   • Non-Alcoholic Fatty Liver Disease (NAFLD): Often asymptomatic.

Differential Diagnosis of Jaundice

Jaundice Causes: Malfunction in prehepatic, intrahepatic, or posthepatic phases of bilirubin production.

Pseudojaundice: From excessive ingestion of beta-carotene-rich foods; no scleral icterus or elevated bilirubin.

Prehepatic Causes

• Unconjugated Hyperbilirubinemia: Results from impaired bilirubin conjugation in hepatocytes.
  • Excessive Heme Metabolism: From hemolysis or large hematoma reabsorption.
  • Hemolytic Anemias: Typically mild bilirubin elevation (~5 mg/dL), may result from:
    • Membrane abnormalities (e.g., hereditary spherocytosis).
    • Enzyme abnormalities (e.g., glucose-6-phosphate dehydrogenase deficiency).
    • Autoimmune disorders, drugs, hemoglobin structure defects (e.g., sickle cell disease, thalassemias).

Intrahepatic Causes

• Unconjugated Hyperbilirubinemia:
  • Enzyme Metabolism Disorders: Affect bilirubin conjugation.
    • Gilbert Syndrome: Mild decrease in glucuronosyltransferase activity, incidental finding, transient jaundice during stress.
• Conjugated Hyperbilirubinemia:
  • Intrahepatic Cholestasis: Disrupted transport of conjugated bilirubin.
    • Hepatitis: Caused by viruses, alcohol, autoimmune disorders.
      • Hepatitis A: Acute onset of jaundice.
      • Hepatitis B and C: Jaundice in chronic infection stages.
      • Epstein-Barr Virus: Transient jaundice.
    • Alcohol Use: Fatty liver, hepatitis, cirrhosis; acute hepatitis with jaundice.
    • Autoimmune Hepatitis: Acute icteric hepatitis in older patients.
    • Primary Biliary Cirrhosis: Progressive, presents in middle-aged women, fatigue, pruritus, late jaundice.
    • Primary Sclerosing Cholangitis: Common in men, associated with inflammatory bowel disease, may lead to cholangiocarcinoma.
    • Metabolic Defects: Dubin-Johnson syndrome, Rotor’s syndrome.
    • Drug-induced Cholestasis: Caused by acetaminophen, penicillins, oral contraceptives, chlorpromazine, steroids.

Posthepatic Causes

• Conjugated Hyperbilirubinemia: Issues after bilirubin conjugation.
  • Obstruction of Duct System: Intrinsic or extrinsic.
    • Cholelithiasis: Gallstones, possible cholecystitis or cholangitis (fever, pain, jaundice – Charcot’s triad).
    • Cholangitis: Usually due to impacted gallstone, requires cholecystectomy or endoscopic removal.
    • Biliary Strictures/Infection: Consider in postoperative jaundice.
    • Biliary Tract Tumors:
      • Gallbladder Cancer: Presents with jaundice, hepatomegaly, RUQ mass (Courvoisier’s sign).
      • Cholangiocarcinoma: Jaundice, pruritus, weight loss, abdominal pain, ~50% survival rate.
    • Pancreatitis: Gallstones or alcohol use; can lead to secondary bile duct compression from pancreatic edema.

Physical Examination

• Signs of Liver Disease:
  • Bruising
  • Spider Angiomas
  • Gynecomastia
  • Testicular Atrophy
  • Palmar Erythema
• Abdominal Examination:
  • Assess liver size and tenderness
  • Check for the presence or absence of ascites

Red Flags in History and Examination

1. Severity and Duration of Jaundice:
   • Rapid onset or worsening jaundice might indicate acute liver failure or significant biliary obstruction.
2. Associated Symptoms:
   • Dark urine, pale stools, and itching suggest obstructive jaundice.
   • Abdominal pain, especially in the right upper quadrant or epigastrium, may indicate hepatobiliary disease.
   • Weight loss, particularly if unintentional, could be a sign of malignancy.
3. Fever and Systemic Illness:
   • Fever with jaundice is a concerning sign of infection or inflammation (hepatitis, cholangitis).
4. Alcohol and Drug Use:
   • History of significant alcohol intake or use of hepatotoxic drugs.
5. Medical History:
   • Previous liver or gallbladder disease, hepatitis, or pancreatitis.
   • Chronic conditions like diabetes or obesity, which can predispose to NAFLD or gallstones.
6. Travel History:
   • Exposure to endemic areas for viral hepatitis or parasitic infections.
7. Physical Examination Findings:
   • Hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), abdominal tenderness.
   • Signs of chronic liver disease: spider angiomas, palmar erythema, ascites, gynecomastia.
8. Laboratory and Imaging Studies:
   • Abnormal liver function tests (LFTs), particularly elevated bilirubin and liver enzymes.
   • Ultrasound or CT findings suggesting gallstones, biliary obstruction, or liver pathology.
9. Family History:
   • Hereditary conditions like hemochromatosis or Wilson’s disease.

Evaluation of Jaundice

Evaluation of Jaundice

Initial Work-up:

1. Determine if hyperbilirubinemia is conjugated (direct) or unconjugated (indirect)
2. Urinalysis:
   • Positive for bilirubin indicates conjugated hyperbilirubinemia.
   • Confirm with serum total and direct bilirubin levels.

Serum Testing:

Markers of Hepatocyte Metabolic/Catabolic Activities:

1. Elevated Serum Bilirubin:
   • Increased in liver diseases due to impaired uptake, impaired conjugation, or leakage from damaged hepatocytes or bile ducts.
2. Elevated Ammonia:
   • Increases because the liver fails to metabolize ammonia.

Markers Suggestive of Hepatocellular Injury:

1. Aminotransferases:
   • Aspartate Aminotransferase (AST):
     • More specific for other tissues (Liver, heart, muscle, kidney, brain).
     • Elevated in hepatic necrosis, muscle injury, congestive cardiac failure.
   • Alanine Aminotransferase (ALT):
     • Liver-specific (also found in skeletal muscle).
     • More indicative of liver disease.
     • Remains elevated longer than AST and LD due to a longer half-life.
     • Elevated ALT (>2-3 times normal range) in febrile illness, dehydration, viraemia.
2. AST/ALT Ratio:
   • 1 in alcoholic liver disease.
   • <1 in non-alcoholic liver disease.

Specific Liver Conditions:

1. Liver Disease:
   • ALT is approximately twice the AST level, with minor LD elevation.
2. Acute Viral Hepatitis:
   • ALT levels may rise to several thousand units per liter.
3. Acute Liver Injury (Drugs/Ischemia):
   • ALT levels >10,000 U/L.
4. Infectious Hepatitis:
   • Greater elevation in ALT than AST.
5. Acute Alcoholic Hepatitis:
   • AST and ALT rise to several hundred units per liter.
   • AST/ALT ratio >1, with AST > ALT and significantly elevated GGT.
6. Malignancy, Hemolysis, Severe Illness:
   • Elevated LD, AST >> ALT.
7. Muscle and Hematological Disorders:
   • Elevated LD, AST, ALT.
8. Abnormal LFTs in Healthy Individuals:
   • Repeat tests in 2-3 months to check for low-grade chronic liver disease.

Lactate Dehydrogenase (LD):

1. Source:
   • All tissues; isoenzymes assist with specificity.
2. Elevated Levels:
   • 5 times normal (>500 U/L): Extensive hepatocellular injury (acute hepatitis, drug-induced liver injury, profound ischemia, hepatic necrosis, severe autoimmune hepatitis).
   • <5 times normal (<500 U/L): Chronic hepatitis, nonhepatic causes, smoldering inflammation (autoimmune disorders, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, alcoholic liver disease, nonalcoholic fatty liver disease, drug-induced liver injury).

Markers of Liver Injury Secondary to Cholestasis:

1. Cholestatic Enzymes:
   • Takes 5-6 days for enzymes to peak.
2. Common Causes:
   • Choledocholithiasis, malignancy, primary biliary cirrhosis, primary sclerosing cholangitis.
3. Alkaline Phosphatase (ALP):
   • Sources: Canalicular & sinusoidal membranes of liver, bone, intestine, placenta.
   • Elevated in cholestasis (intrahepatic or extrahepatic).
4. Gamma Glutamyl Transpeptidase (GGT):
   • Sources: Liver, biliary epithelium, smooth endoplasmic reticulum (indicative of smooth ER proliferation due to drug, hormone, or chemical detoxification, e.g., alcohol), pancreas, renal tubules, intestinal mucosa.
   • Biliary obstruction results in elevated ALP and GGT, indicating proliferation of biliary ducts within the liver.

Bilirubin & Urobilinogen:

1. Urine Dipstick Test:
   • Bilirubinuria indicates conjugated bilirubin present in urine → hepatobiliary disease.
   • Absence of bilirubinuria suggests jaundice is due to increased unconjugated bilirubin.
2. Urobilinogen:
   • Suggests hemolysis or hepatic dysfunction of any cause.
   • Not very valuable clinically.

Markers of synthetic function 

Elevated Prothrombin time (PT): 

• Marker of synthetic function of the vitamin K-dependent coagulation factors (II, VII, IX, X).
• Sensitive indicator of acute and chronic liver disease
• Pts usually given bolus of Vit K prior to test – exclude deficiency as cause for ↓PT
• Prolongation of the international normalized ratio (INR) more than 1.5 is considered a poor prognostic sign and a key component to make a diagnosis of acute liver failure 
• Prolongation of PT/INR occurs within hours to days of liver injury, making it a better marker than albumin to determine the liver’s synthetic function.

Decreased albumin: 

• indicative of protein synthesis function
• useful in grading severity of liver disease
  • ↓albumin in liver disease – bad prognostic sign
• N.B. in acute liver disease – serum albumin levels may be normal

Chronic Hepatitis

• Haemochromatosis = Iron studies, gene test if indicated
• Autoimmune Hepatitis =  ANA, anti-smooth muscle, anti-mitochondrial Ab  anti-LKM
• Alpha-1-antitrypsin deficiency = Alpha-1-antitrypsin level,phenotype
• Wilson’s disease (if < 40 years): – Ceruloplasmin, Serum and urine (24-hour) copper

Imaging in Jaundice Evaluation

• Ultrasonography:
  • First Test Ordered: Due to lower cost, wide availability, no radiation exposure.
  • Sensitivity: Most sensitive for detecting biliary stones.
  • Usage: Initial test, especially important for pregnant patients.
• Computed Tomographic (CT) Scanning:
  • Information Provided: Detailed view of liver and pancreatic parenchymal disease.
  • Limitations: Less effective for intraductal stones compared to ultrasonography.
• Advanced Imaging Techniques:
  • Endoscopic Retrograde Cholangiopancreatography (ERCP): Performed by gastroenterologists.
  • Percutaneous Transhepatic Cholangiography (PTC): Performed by interventional radiologists.

Liver Biopsy

• Purpose:
  • Provides information on liver architecture.
  • Helps determine prognosis.
  • Useful for diagnosis when serum and imaging studies are inconclusive.
• Applications:
  • Autoimmune Hepatitis Diagnosis.
  • Biliary Tract Disorders:
    • Primary biliary cirrhosis: Antimitochondrial antibody positive.
    • Primary sclerosing cholangitis: Antineutrophil cytoplasmic antibodies positive.
• Risks:
  • Fatal Hemorrhage:
    • Malignant Disease: 0.4% risk.
    • Nonmalignant Disease: 0.04% risk.