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.

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.

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