💡 Learning Outcomes:

1. Discuss the aetiology and pathogenesis of hepatic jaundice.
2. Discuss the clinical features of hepatic jaundice.
3. Describe the laboratory investigation and differential diagnosis of hepatic jaundice. 

1. Aetiology and Pathogenesis of Hepatic Jaundice

Definition

Jaundice is the accumulation of unconjugated or conjugated bilirubin in the skin, leading to a characteristic golden-yellow discoloration. Normal serum bilirubin levels range from 0.3 to 1.3 mg/dL, with 80% being unconjugated. Jaundice becomes evident when serum bilirubin levels reach 2.5–3 mg/dL or higher.

Classification of Jaundice

• Pre-Hepatic Jaundice (Haemolytic Jaundice): Caused by increased bilirubin production due to hemolysis.

• Hepatic Jaundice: Due to liver disease affecting bilirubin metabolism.

• Post-Hepatic Jaundice (Obstructive Jaundice): Caused by bile duct obstruction.

Aetiology of Hepatic Jaundice

• Inherited/Genetic Disorders:
• • Gilbert’s Syndrome
  • Crigler-Najjar Syndrome
  • Wilson’s Disease
  • Hemochromatosis

• Acquired Conditions:
• • Hepatitis: Various types, including viral, alcoholic, and autoimmune.
  • Alcoholic Liver Disease: Stages include hepatic steatosis, alcoholic hepatitis, and cirrhosis.
  • Non-Alcoholic Fatty Liver Disease (NAFLD): Associated with metabolic syndrome.
  • Cirrhosis: Resulting from chronic liver disease.
  • Hepatocellular Carcinoma: Often arising in the context of chronic liver disease.

Pathogenesis of Hepatic Jaundice

• Decreased Hepatic Uptake: Impaired uptake of bilirubin by liver cells.

• Impaired Conjugation: Defective conversion of unconjugated bilirubin to conjugated form.

• Decreased Hepatic Excretion: Failure to excrete conjugated bilirubin into bile.

2. Clinical Features of Hepatic Jaundice

General Symptoms

• Jaundice: Yellow discoloration of the skin and sclera (icterus).

• Malaise and Fatigability: General feelings of illness and tiredness.

• Loss of Appetite and Weight Loss: Common in chronic liver disease.

• Fever: Low-grade fever may accompany acute hepatitis.

• Abdominal Pain: Tenderness in the right upper quadrant due to liver enlargement.

Specific Symptoms

• Acute Hepatitis: May present with marked constitutional symptoms, including nausea, vomiting, and diarrhea.

• Chronic Hepatitis/Cirrhosis: Features of chronic liver failure such as ascites, variceal hemorrhage, and signs of portal hypertension.

• Hepatocellular Carcinoma (HCC): Symptoms may include worsening jaundice, palpable mass in the right hypochondrium, and features of liver failure. Paraneoplastic syndromes may also occur (e.g., hypoglycemia, hypercalcemia).

Clinical Signs

• Liver Function Tests: Abnormal liver function tests indicating hepatic dysfunction.

• Physical Examination: Mildly enlarged and tender liver, possible signs of portal hypertension.

3. Laboratory Investigation and Differential Diagnosis of Hepatic Jaundice

Laboratory Investigations

• Liver Function Tests:
• • Total Bilirubin: Increased levels of both unconjugated and conjugated bilirubin.
  • ALT and AST: Elevated liver enzymes indicate hepatocellular damage.
  • Total Protein: Decreased total protein levels, with a reverse albuminratio.
  • Prothrombin Time: Prolonged in liver dysfunction.

• Viral Serology: Tests to assess for hepatitis viruses (A, B, C, etc.) and to determine the viral load.

• Assessment of Aetiology:
• • Serum Ferritin/Ceruloplasmin: To evaluate iron overload or Wilson’s disease.
  • Liver Autoantibodies: (e.g., antinuclear antibody, smooth muscle antibody) to investigate autoimmune hepatitis.
  • Endoscopy: To assess for esophageal varices.

• Imaging:
• • Ultrasound/CT Scan: To detect underlying liver disease, cirrhosis, and HCC.
  • Fibroscan: To assess liver stiffness and fibrosis.

• Tumor Markers:
• • Serum Alpha-Fetoprotein (AFP): Increased in HCC, though false positives can occur in cirrhosis and chronic hepatitis.
  • Carcinoembryonic Antigen (CEA): Also increased but not specific to HCC.

Differential Diagnosis

• Pre-Hepatic Causes: Conditions leading to hemolysis such as sickle cell disease or autoimmune hemolytic anemia.

• Post-Hepatic Causes: Biliary obstruction due to gallstones, tumors, or strictures.

4. Conditions Related to Hepatic Jaundice

A. Hepatocellular Carcinoma (HCC)

• Epidemiology: Accounts for approximately 5% of all cancers worldwide, more common in Asian countries due to chronic HBV infection.

• Aetiology & Pathogenesis:
  • Chronic infection with HBV or HCV leading to genomic instability and neoplastic transformation.
  • Hepatocarcinogens like aflatoxin B1 and nitrosamines.
  • Pre-existing cirrhosis increases risk.

• Clinical Features:
  • Asymptomatic or present with abnormal liver function tests.
  • Constitutional symptoms: weight loss, jaundice, ascites, and signs of portal hypertension.

• Diagnosis: Elevated AFP, imaging studies (ultrasound, CT, MRI), and biopsy if needed.

• Management: Surgical resection, liver transplantation, and systemic therapies (e.g., sorafenib).

B. Non-Alcoholic Fatty Liver Disease (NAFLD)

• Definition: Characterized by fat accumulation in hepatocytes, not due to alcohol consumption.

• Presence of hepatic steatosis in individuals who do not consume alcohol, associated with metabolic syndrome.

• Etiology: Strongly associated with obesity, type 2 diabetes, hyperlipidemia, and metabolic syndrome.

• Pathogenesis: Insulin resistance and hepatocellular oxidative injury. Insulin resistance leads to increased lipogenesis and decreased fat oxidation. Histological features overlap with alcoholic hepatitis.

• Clinical Features: Often asymptomatic; may have mild elevation in liver enzymes.

• Diagnosis: Imaging studies (ultrasound) and liver biopsy may be needed to rule out NASH (non-alcoholic steatohepatitis).

• Management: Lifestyle modifications, weight loss, and control of metabolic risk factors.

C. Drug/Toxin Induced Hepatitis

• Injury may arise from direct toxicity, metabolic conversion to a toxic metabolite, or immune reactions.

• Etiology: Hepatotoxicity due to medications (e.g., acetaminophen, isoniazid, statins) or environmental toxins.

• Histology may show necrosis, cholestasis, inflammation, and eosinophilic infiltration.

• Pathogenesis: Direct toxicity or immune-mediated damage to hepatocytes.

• Clinical Features: Symptoms of hepatitis (nausea, vomiting, jaundice) appear after exposure to the offending agent.

• Diagnosis: History of drug exposure, elevated liver enzymes, and exclusion of other causes of hepatitis.

• Management: Discontinuation of the offending agent; N-acetylcysteine for acetaminophen toxicity.

D. Alcoholic Hepatitis

• Alcoholic liver disease comprises three stages: hepatic steatosis, alcoholic hepatitis, and cirrhosis.

• Pathogenesis: Alcohol metabolites lead to oxidative stress and inflammation in the liver, resulting in hepatocyte damage and potential fibrosis.

• Clinical Features:
  • Symptoms of liver failure: jaundice, ascites, and hepatic encephalopathy.
  • Tender hepatomegaly.

• Diagnosis: History of alcohol use, elevated liver enzymes (AST > ALT), and liver biopsy if necessary.

• Management: Alcohol cessation, nutritional support, and corticosteroids in severe cases.

E. Acute Hepatitis

• Definition: Inflammation of the liver lasting less than 6 months, often viral in origin.

• Characterized by less inflammation and more hepatocyte death. Causes include viral infections, toxins, and ischemia.

• Etiology: Commonly caused by hepatitis A, B, C, D, or E viruses.

• Clinical Features: Fatigue, nausea, vomiting, jaundice, and elevated liver enzymes.

• Histological Features:
  • Hepatocyte Swelling: Ballooning degeneration.
  • Cholestasis: Bile accumulation in hepatocytes.
  • Hepatocyte Necrosis: Isolated or in clusters.
  • Cytolysis or Apoptosis: Cell rupture or shrinkage.
  • Bridging Necrosis: Necrosis connecting portal areas.
  • Lobular Disarray: Loss of normal liver architecture.
  • Regenerative Changes: Proliferation of hepatocytes.
  • Inflammation: In portal tracts.

• Diagnosis: Serological testing for viral hepatitis markers.

• Management: Supportive care; most cases resolve spontaneously.

F. Chronic Hepatitis

• Definition: Chronic inflammation of the liver lasting longer than 6 months, often due to viral infection.

• Defined by ongoing inflammation and scarring. Causes include chronic viral infections, alcohol, and autoimmune diseases.

• Etiology: Most commonly caused by hepatitis B and C viruses.

• Clinical Features: Often asymptomatic; can progress to cirrhosis or HCC over time.

• Histological Features:

  • Similar to acute hepatitis but with:

    

  • Interface Hepatitis: Necrosis spilling into adjacent parenchyma.

  • Fibrosis: Progressive scarring of the liver.

  • Specific Findings:

    • HBV: Ground-glass hepatocytes (accumulation of HBsAg).

      

    • HCV: Bile duct proliferation and lymphoid aggregates.

      

• Diagnosis: Persistent elevation of liver enzymes and serological markers for hepatitis viruses.

• Management: Antiviral therapy for hepatitis B and C, monitoring for complications like cirrhosis and HCC.