Granulomatous hepatitis

Granulomatous hepatitis is a condition characterized by the presence of liver granulomas and is detected in 1–15% of liver biopsies. Granulomatous hepatitis is idiopathic in approx. 10–36% of patients. Nonidiopathic causes are broad and include infectious diseases (e.g., tuberculosis), systemic conditions (e.g., sarcoidosis), and drugs. In Western countries, granulomatous hepatitis is most commonly caused by noninfectious conditions; in Middle Eastern and Asian countries, it is most commonly caused by infectious diseases. Patients are typically asymptomatic, but nonspecific symptoms (e.g., fever, fatigue, abdominal pain) may be present. Liver biopsy is required for diagnostic confirmation and to identify granuloma characteristics. Management differs based on the underlying cause. Complications include fibrosis, cirrhosis, and portal hypertension.

• Granulomatous hepatitis is detected in 1–15% of liver biopsies. ^[1][2]
• The prevalence of causes of granulomatous hepatitis vary worldwide. ^[1]
  • In Western countries, granulomatous hepatitis is most commonly caused by noninfectious conditions.
  • In Middle Eastern and Asian countries, granulomatous hepatitis is most commonly caused by infectious diseases.

Epidemiological data refers to the US, unless otherwise specified.

See also "Overview of granulomatous diseases."

• Idiopathic: ∼ 10–36% of cases ^[2]
• Infectious causes ^[1][2]
  • Bacterial, e.g.:
    • Tuberculosis (most common)
    • Q fever
    • Bartonellosis
    • Syphilis
  • Fungal, e.g.:
    • Histoplasmosis
    • Coccidioidomycosis
    • Blastomycosis
  • Parasitic, e.g.:
    • Ascariasis
    • Leishmaniasis
    • Toxoplasmosis
  • Viral, e.g.:
    • Hepatitis A, hepatitis B, and hepatitis C
    • CMV infection
    • Epstein-Barr virus
• Noninfectious causes, e.g.: ^[1][2]
  • Systemic and autoimmune conditions
    • Sarcoidosis (most common)
    • Primary biliary cholangitis
    • Inflammatory bowel disease (especially Crohn disease)
    • Vasculitides: e.g., granulomatosis with polyangiitis (GPA)
  • Drugs, e.g.:
    • Acetaminophen
    • Allopurinol
    • Sulfasalazine
    • Phenytoin
    • Anti-TNF agents (e.g., infliximab, etanercept)
    • Immune checkpoint inhibitors (e.g., ipilimumab, nivolumab)
  • Malignant neoplasms (e.g., Hodgkin lymphoma)
  • Foreign body reaction (e.g., caused by sutures, talc, prosthetic devices)
  • Congenital immunodeficiency disorders
    • Common variable immunodeficiency
    • Chronic granulomatous disease

Granuloma formation is caused by a delayed hypersensitivity reaction and can be idiopathic or triggered by a drug or infection. ^[1]

• Macrophages activate Th1 cells.
• Th1 cells release IFN-γ, which stimulates the formation of epithelioid cells and multinucleated giant cells.
• Epithelioid cells produce angiotensin-converting enzyme and release cytokines that recruit more immune cells.

Patients may be asymptomatic or present with the following: ^[1][2]

• Constitutional symptoms
• Hepatobiliary features (e.g., abdominal pain, pruritus, jaundice, hepatomegaly)
• Features of the underlying cause (e.g., pulmonary symptoms in sarcoidosis, tuberculosis; ENT involvement in GPA)

General principles

• Granulomatous hepatitis may be an incidental finding.
• Granulomatous hepatitis may be suspected in patients with unexplained abnormal liver chemistries and other systemic symptoms.
• A thorough history and physical examination is essential to narrow down potential causes and assess for complications.
• Refer all patients to hepatology and/or gastroenterology.

Sarcoidosis, tuberculosis, and PBC are the most common causes of granulomatous hepatitis. ^[1][2]

Initial studies ^[1][2]

• CBC: may show leukocytopenia
• Liver chemistries
  • ↑ ALP, ↑ GGT, ↑ ALT, AST, ↑ bilirubin
  • A cholestatic injury pattern is most common; mixed or hepatocellular patterns may also occur.
• Infectious disease screening: guided by clinical suspicion and epidemiology
  • TB screening: interferon-γ release assay
  • Viral hepatitis panel
  • Other serologies (e.g., EBV serology, CMV serology)

Imaging studies ^[1][2]

• Liver imaging: Findings are usually nonspecific but may show complications.
  • Ultrasound: increased liver echogenicity, hypoechoic and irregular lesions
  • CT or MRI: liver nodularity or nonspecific lesions
  • Specific findings depend on underlying cause.
• Chest imaging: May show specific findings depending on the underlying cause. See "Chest x-ray" in "Sarcoidosis."

Liver biopsy ^[1][2]

• Required for diagnostic confirmation
• Granuloma characteristics depend on the underlying cause.

Additional studies ^[1]

The following may be ordered based on clinical suspicion and in consultation with specialists, e.g.:

• Serum calcium and vitamin D for the diagnosis of sarcoidosis
• Antimitochondrial antibodies for PBC
• Blood and/or biopsy cultures if fungal or bacterial infections are suspected

Refer all patients to hepatology for appropriate management and follow-up; see "Management" in "Chronic liver disease."

Treatment of the underlying cause ^[1][2]

Management depends on the underlying cause, e.g.:

• Treatment of infectious conditions (e.g., treatment of tuberculosis)
• Treatment of systemic and/or autoimmune conditions (e.g., treatment of sarcoidosis, treatment of PBC)
• Treatment of drug-induced Iiver injury

Idiopathic granulomatous hepatitis ^[1][2]

• Asymptomatic patients: regular clinical assessment with liver chemistries
• Symptomatic patients
  • Glucocorticoids: may be considered tuberculosis has been excluded
  • Empiric antituberculosis therapy: if there is strong clinical suspicion of tuberculosis
  • Methotrexate: may be considered for relapses or if adverse effects to glucocorticoids are present

• Hepatic metastases
• Primary liver tumors (e.g., cholangiocarcinoma, hepatocellular carcinoma)
• Hepatic inflammatory pseudotumor
• Liver abscess

The differential diagnoses listed here are not exhaustive.

• Progressive hepatic fibrosis
• Cirrhosis
• Portal hypertension
• Liver failure
• See also "Complications" in "Chronic liver disease."

We list the most important complications. The selection is not exhaustive.