Granulomatous Hepatitis

A. Definition

Presence of granulomas on liver biopsy; usually indicative of underlying systemic disease.

B. Types of Granulomas

• Caseating granulomas: Central necrosis; associated with an infectious etiology.
• Noncaseating granulomas: No central necrosis; associated with a noninfectious cause.
• Fibrin-ring granulomas: Fibrin ring surrounding the epithelioid cells; may be seen in Q fever.
• Lipogranulomas: Central lipid vacuole; associated with mineral oil ingestion.

C. Epidemiology

• Incidence: 2%–15%; recent data suggest only 3%–6% due to decreasing opportunistic infections in HIV/AIDS and hepatitis C.

D. Etiologies

1. Autoimmune/Immunologic

• Sarcoidosis:
  • Systemic disease of unknown etiology; may be autoimmune.
  • One of the most common causes of hepatic granulomas in the United States.
  • Incidence varies by ethnic group; high in African Americans and Scandinavians.
  • Hepatic involvement uncommon, but noncaseating epithelioid granulomas often found microscopically in portal tracts.
  • Biochemical findings: ↑ alkaline phosphatase and GGT.
  • Most hepatic sarcoidosis has a benign course; ~1% develop cirrhosis and portal hypertension.
  • Steroid treatment not recommended unless portal hypertension or cirrhosis is present.
• Primary biliary cirrhosis:
  • Autoimmune disorder with destruction of intrahepatic biliary epithelium and chronic cholestasis.
  • Primarily affects middle-aged women.
  • Biochemical findings: elevated alkaline phosphatase and GGT, positive antimitochondrial antibodies, elevated serum IgM.
  • Treatment: Ursodeoxycholic acid (UDCA).
• Other: Crohn disease and Wegener granulomatosis.

2. Systemic Infections

• Tuberculosis (TB):
  • Mycobacterium tuberculosis causes hepatic granulomas, especially in miliary TB.
  • Granulomas may be caseating.
  • Biochemical findings: elevated alkaline phosphatase ± elevated transaminases.
• Other bacterial infections:
  • Brucellosis (Brucella abortus, B. canis, B. melitensis): acquired from infected cattle; noncaseating granulomas seen in ~70%.
  • Q fever (Coxiella burnetii): causes fibrin-ring granulomas in liver.
  • Other: Lyme disease (Borrelia burgdorferi), cat scratch disease (Bartonella henselae), Listeria, Salmonella (typhoid fever), Yersinia, BCG disease.
• AIDS-related/immunocompromised:
  • Mycobacterium avium complex associated with hepatic granulomas.
• Fungal infections:
  • Candida: causes suppurative granulomas.
  • Histoplasmosis (Histoplasma capsulatum): endemic in Ohio and Mississippi River valleys; liver involvement reported.
  • Coccidioidomycosis (Coccidioides immitis): endemic in southwestern U.S.; hepatic disease may occur in disseminated infection.
• Viral infections:
  • Hepatitis C and B viruses have been reported to cause hepatic granulomas.
  • HCV granulomas are epithelioid and noncaseating.
• Parasitic infections:
  • Schistosomiasis: associated with granulomatous hepatitis; granulomas contain abundant eosinophils.

3. Drug-Induced

• Drugs implicated: sulfa drugs, allopurinol, isoniazid, quinidine, chlorpropamide, etanercept.
• Granulomas may vary in size and location within the liver.
• Presence of eosinophils is a clue to drug-related etiology.

4. Malignancy

• Hodgkin lymphoma may be associated with hepatic granulomas.
• Granulomas also described in non-Hodgkin’s lymphoma and renal cell carcinoma.

5. Idiopathic

• Diagnosis considered when extensive workup fails to identify a cause.
• Symptoms: fever, weight loss, myalgias, arthralgias, hepatosplenomegaly.
• Laboratory findings: nonspecific; usually ↑ erythrocyte sedimentation rate.
• Noncaseating granulomas present in all cases and randomly distributed.
• Treatment: short course of steroids and/or methotrexate.
• Important: TB and other infections must be ruled out before starting immunosuppressive therapy.