Granulomatous liver disease

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Chapter 43 GRANULOMATOUS LIVER DISEASE

KEY POINTS

• The hallmark of granulomatous liver inflammation is the epithelioid granuloma.
• The aetiology is multifactorial: infections (e.g. tuberculosis), sarcoidosis, primary biliary cirrhosis, drugs, Crohn’s disease and neoplasms.
• The cause is unknown in approximately 50% of cases.
• Work-up for hepatic granulomas includes a detailed history (including drugs), biochemical and serologic testing (alkaline phosphatase, angiotensin converting enzyme and antimitochondrial antibodies are particularly important) and microbiological evaluation.

INTRODUCTION

Often granulomas are found on liver biopsy and the clinical case needs to be reviewed to try and find the cause. The causes of granulomas are multifactorial and include tuberculosis, sarcoidosis, primary biliary cirrhosis, various drugs, neoplasms (e.g. Hodgkin’s lymphoma) and Crohn’s disease. The cause is unknown in approximately 50% of cases.

PRESENTATION AND CLINICAL EXAMINATION

Typical presentations include pyrexia of unknown origin or incidental abnormal liver function tests. Often the clinical examination is normal, though there may be symptoms and signs of an associated systemic disease (Figure 43.1). Infrequently, hepatomegaly, splenomegaly or lymphadenopathy may be detected.

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FIGURE 43.1 Diagnosis of granulomas.

AIDS = aquired immunodeficiency syndrome; CMV = cytomegalovirus; LFTs = liver function tests; TB = tuberculosis; PBC = primary biliary cirrhosis.

Biochemical liver tests

Generally, liver function testing is non-specific, but a predominant alkaline phosphatase (ALP) elevation may be present.

Histopathology

Hepatic granulomas are found in 0.8%–15% of liver biopsies. The epithelioid granuloma may be associated with distinguishing morphological pathological features. These can include duct involvement (primary biliary cirrhosis), periductal location with acute inflammatory changes (large duct obstruction with cholangitis), parenchymal and perivenular location (tuberculosis), caseation (tuberculosis), fibrin-ring pattern with central fat vacuole (Q fever), schistosome ova (schistosomiasis) or a positive fungal stain.

Lipogranulomas should be differentiated from epithelioid granulomas. Lipogranulomas are found in non-steatotic livers as a response to ubiquitous exogenous mineral oils used in food preparation.

CAUSES OF GRANULOMAS

The most common causes of hepatic granulomas where primary biliary cirrhosis has been excluded are sarcoidosis, chronic liver disease, biliary tract disease, tuberculosis, Q fever, other infections, drug hepatotoxicity, neoplasms and idiopathic (Table 43.1).

TABLE 43.1 Causes of granulomas

Associated with pyrexia of unknown origin Sarcoidosis, tuberculosis (miliary and pulmonary, caseation important), atypical mycobacterium, Q fever, brucellosis, cat-scratch disease, mycoses, drugs, idiopathic granulomatous hepatitis
Human immunodeficiency virus (HIV) Mycobacterium avium complex, idiopathic, other mycobacteria, Mycobacterium tuberculosis, Cryptococcus, Histoplasma, medications (trimethoprim-sulfamethoxazole)
Infectious diseases Bacteria: actinomycosis, brucellosis, cat-scratch disease, listeriosis, syphilis, tularaemia, Whipple’s disease
Mycobacteria: tuberculosis, leprosy (lepromatous and tuberculoid)
Rickettsia: Q fever
Chlamydia: lymphopathia venereum, psittacosis
Fungi: aspergillosis, blastomycosis, candidiasis, cryptococcosis, histoplasmosis
Viruses: cytomegalovirus, Epstein-Barr virus, infectious mononucleosis
Parasites: amoebiasis, capillariasis, fascioliasis, schistosomiasis, toxoplasmosis, visceral leishmaniasis (kala-azar)
Hypersensitivity and immunological diseases Metals: beryllium, copper, gold
Hypogammaglobulinaemia, primary biliary cirrhosis, primary sclerosing cholangitis, systemic lupus erythematosus
Vascular diseases: disseminated visceral giant cell arteritis, polyarteritis nodosa, temporal arthritis, Wegener’s granulomatosis
Foreign materials Anthracotic pigments, barium, cement and mica dust; mineral oil—radiocontrast media, food additives; silica, suture material, talc
Neoplasms Hodgkin’s disease, non-Hodgkin’s lymphoma
Miscellaneous diseases Biliary tract obstruction, bile granulomas, chronic inflammatory bowel disease, eosinophilic gastroenteritis, jejunoileal bypass, porphyria cutanea tarda, sarcoidosis, idiopathic
Drugs Allopurinol, amiodarone, amoxicillin/clavulanic acid, chlorpromazine, chlorpropamide, diltiazem, gold salts, halothane, hydralazine, methyldopa, benzylpenicillin, phenoxymethylpenicillin, phenylbutazone, phenytoin, procainamide, quinidine, quinine, sulfonamides

Sarcoidosis

Between 50%–90% of patients with sarcoidosis have hepatic involvement with granulomas. The frequency of granulomas is greatest in lymph nodes followed by lung and liver. There is no evidence of liver dysfunction in the majority of cases. Portal hypertension is rare but may occur without cirrhosis. The granulomas may recur following liver transplantation.

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive form of autoimmune liver disease that predominantly affects middle-aged women.

Epidemiological, clinical and biochemical features

• Female to male ratio is 9:1
• Peak incidence in fifth decade of life
• High serum alkaline phosphatase levels should raise suspicion
• Patients may be asymptomatic in the early phase of the disease
• Fatigue and pruritus may become troublesome
• Once symptoms develop, patients have a limited life expectancy with a median survival time around 10 years
• High serum bilirubin, low serum albumin and prolonged prothrombin time are all associated with a poor prognosis
• There is a strong association with other autoimmune diseases including Sjögren’s syndrome, scleroderma, CREST syndrome, autoimmune thyroiditis
• Patients may have associated histological feature of autoimmune hepatitis and, in these situations, the term ‘overlap syndrome’ is used

Investigations

• The presence of anti-mitochondrial antibodies in the serum is characteristic
• A liver biopsy is vital for both diagnostic and prognostic purposes
• Histologically is characterised by inflammatory destruction of the interlobular and septal bile ducts, which leads to chronic cholestasis and biliary cirrhosis Ultimately non-caseating granulomas will develop

Management issues

• Ursodeoxycholic acid (UDCA) is the only proven medical therapy
• May require medical attention for the associated complications of pruritus, osteoporosis, fat-soluble vitamin deficiency, hypercholesterolaemia and steatorrhoea
• There is a substantial increased risk of hepatocellular carcinoma
• Patients may require liver transplantation for end-stage liver disease
• Overlap syndrome patients will require a combination of UDCA and corticosteroid therapy

Idiopathic granulomatous hepatitis

This group accounts for 5%–10% of hepatic granulomas.

Presentation

• Prolonged or recurrent fever
• Weight loss
• Myalgia and arthralgia
• Vague abdominal pain

There is seldom hepatocellular damage. It is usually a diagnosis of exclusion.

TREATMENT

Identified or suspected drugs or toxins should be withdrawn and the patient monitored. Specific infective diseases should be treated with appropriate antibiotics, antifungals or other specific drugs.

Patients diagnosed with idiopathic granulomatous hepatitis can be treated with corticosteroids starting with prednisolone 40 mg daily and steroids should be weaned over 2–4 weeks depending on the observed response. Most patients can be treated with a defined course of steroids and retreated as necessary if symptomatic relapse occurs. Treatment should be dictated by symptoms rather than biochemical response or relapse.

Patients refractory to steroid therapy can be treated with other immunosuppressive therapy, such as methotrexate at a dose of 0.20 mg/kg/week, and steroids gradually withdrawn. Methotrexate should be discontinued over a 12–18-month period.

SUMMARY

Hepatic granulomas are found in 0.8%–15% of liver biopsies. The causes of granulomas are multifactorial and include tuberculosis, sarcoidosis, primary biliary cirrhosis, various drugs, neoplasms (e.g. lymphoma) and Crohn’s disease. The cause is unknown in approximately 50% of cases. A detailed history is essential in establishing the cause. The hallmark of granulomatous inflammation is the epithelioid granuloma. The clinical manifestations, treatment and prognosis are those of the underlying disease.

FURTHER READING

Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261-1273.

Knox TA, Kaplan MM, Golfand JA, et al. Methotrexate treatment of idiopathic granulomatous hepatitis. Ann Int Med. 1995;122:592-595.

Lefkowitch JH. Hepatic granulomas. J Hepatol. 1999;30:40-45.

Matheus T, Muñoz S. Granulomatous liver disease and cholestasis. Clin Liver Dis. 2004;8:229-246.

Sandor M, Weinstock JV, Wynn TA. Granulomas in schistosome and mycobacterial infections: a model of local immune responses. Trends Immunol. 2003;24:44-52.

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