Aim: To evaluate the current aetiologies of hepatic granulomas and to assess the prognosis for the “idiopathic” group, in which all investigations for a recognised cause were negative or normal.

Methods: A retrospective review of patient case notes between 1991 and 2001; all patients who had a liver biopsy at Glasgow Royal Infirmary revealing epithelioid granulomas had their case notes and liver biopsies reviewed and a standard proforma completed.

Results: Over the study period, 1662 liver biopsies were performed. Hepatic granulomas were found in 63. Of those identified, 47 were female, with a mean age of 42 years (range, 17–81). Underlying aetiologies were as follows: primary biliary cirrhosis (PBC; 23.8%), sarcoidosis (11.1%), idiopathic (11.1%), drug induced (9.5%), HCV (9.5%), PBC/autoimmune hepatitis (AIH) overlap (6.3%), Hodgkin lymphoma (6.3%), AIH (4.8%), tuberculosis (4.8%), resolving biliary obstruction (3.2%), and other single miscellaneous causes (9.5%). Of the seven patients with idiopathic hepatic granulomas, one was lost to follow up, one died of stroke, and the remaining five were well with no liver related morbidity at a mean follow up of 6.2 years.

Epithelioid granulomas have been reported in 2–15% of unselected liver biopsies^1–8 with a large number of underlying aetiologies. Unfortunately, only rarely do granulomas possess distinct histological features—for example, caseous necrosis containing acid fast bacilli (tuberculosis; TB) or ova of Schistosoma mansoni (schistosomiasis), which enable such clinical conditions to be diagnosed.^9,10 Thus, a specific aetiological agent often cannot be identified despite serological, immunological, microbiological, and radiological investigations, leading to a diagnosis of “idiopathic” hepatic granulomas; there is a consistent cohort of such patients, accounting for approximately 15% of hepatic granuloma series.^1–8

The only published series from the UK, including one from this centre, largely included patients diagnosed before the discovery of the hepatitis C virus (HCV), now recognised as a common cause of hepatic epithelioid granulomas.^4,7,8,10 We undertook a further analysis of all liver biopsies revealing hepatic granulomas over a 10 year period, after the introduction of HCV antibody testing, to establish whether, with advances in immunological and virological testing, there has been an alteration in the distribution of diagnoses in patients identified with hepatic granulomas. In addition, we were interested to see whether there had been a resulting reduction in the proportion of “idiopathic” cases. Because few data exist regarding the characteristics and outcome of this group, we aimed to document the presentation and outcome of this “idiopathic” group.

Chronic HCV has only been recognised as a cause of hepatic granulomas since the availability of routine serological testing in 1991, and was therefore not described as a cause of hepatic granulomas in the previous large UK series.^4,7,8,10 Hepatic granulomas have been described in up to 10% of liver biopsies from HCV infected patients,^12–15 although the clinical relevance of this finding is unknown.^16,17

Thus, we expected that there would have been a smaller proportion of “idiopathic” cases in our series. Interestingly, this was not the case because we identified a subgroup of patients (11.1%) in our study in whom an underlying aetiology could not be found, despite extensive investigations. The most likely explanation for this is that those patients with HCV, most of whom were infected through intravenous drug abuse, were rarely investigated for abnormal liver function tests before 1990 (when widespread HCV serology testing became available), and certainly rarely underwent liver biopsy before the HCV era. Thus, the HCV granuloma group probably represents a new cohort of previously undiagnosed hepatic granulomas.

In our experience, those patients with so called idiopathic hepatic granulomas tend to be middle aged women with cholestatic liver function tests who have an excellent outcome. The benign prognosis of this patient group has been noted previously.^7,18 Earlier publications on this subset of patients^19,20 have highlighted the systemic upset, with fever, myalgia, weight loss, and weakness that may accompany the deranged liver function. In our “idiopathic” cohort, no patient exhibited such a clinical picture and, in addition, the fact that nine of the 10 patients in our study¹⁹ were male suggests this may represent a distinct disorder. Indeed, it is possible that these cases may represent underlying polymyalgia rheumatica, a recognised cause of hepatic granulomas and systemic upset. This is supported by the reported good clinical/laboratory response of such patients to corticosteroids.¹⁹

PBC remains the most common diagnosis in patients with hepatic granulomas and is consistent with previous granuloma series from the UK.⁸ However, it should be noted that PBC may be underestimated as a cause in our series because we do not routinely biopsy all patients with presumed PBC, particularly if they are middle aged women with positive AMA and cholestatic liver function test derangement.

In sarcoidosis, the histological findings are not diagnostic, and a wide range of pathological features is recognised.^21–23 Thus, a combination of multisystem involvement, chest radiograph abnormalities, raised serum calcium, and raised angiotensin converting enzyme values were used to make the diagnosis.

In our drug induced group, all of the patients had a favourable outcome and none developed acute liver failure. Many other medications have been reported to be associated with hepatic granulomas.²⁴

It has long been recognised that Hodgkin disease is associated with the development of hepatic granuloma, and a study in 1974²⁵ revealed that 8% of staging liver biopsies in 103 patients with Hodgkin disease contained granulomas. An earlier study had suggested a figure of 17%.²⁶ The presence of hepatic granulomas does not appear to be related to disease outcome or prognosis in Hodgkin lymphoma. Cases of hepatic granulomas associated with non-Hodgkin lymphoma,²⁷ polmyalgia rheumatica,^28,29 and jejuno–ileal bypass surgery^30,31 have previously been described.

In our series, similar to that reported by McGluggage and Sloan,⁸ infections accounted for only a small proportion of cases. This is in sharp contrast to other parts of the world. A series from Turkey³² revealed that infectious agents including TB, hydatid disease, brucella, and typhoid fever accounted for over half of their hepatic granuloma cases. In addition, in a series from Saudi Arabia,⁵ schistosomiasis accounted for over half of the cases, with TB the next most common cause. We noted one case that was caused by systemic BCG infection after an intravesicular BCG injection for a bladder tumour, which has been described previously.^33–36 We may have expected some opportunistic infections (for example, Mycobacterium avium intracellulare, toxoplasmosis) to account for some cases in human immunodeficiency virus infected patients, but these patients are exclusively cared for in a dedicated infectious diseases unit at another hospital in our city.

Perhaps surprisingly, in none of our cases of hepatic granuloma was inflammatory bowel disease the underlying aetiology, despite our hospital having a cohort of approximately 1000 patients with inflammatory bowel disease. For many years, it has been recognised that hepatic granulomas are associated with this disease, and are particularly prevalent in patients with Crohn’s disease.^37,38 The series of McGluggage and Sloan,⁸ carried out in Northern Ireland during the 1980s, revealed three (1.8%) cases of underlying Crohn’s disease. It is possible that endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography are being performed in preference to liver biopsy for the investigation of abnormal liver function tests in our patient cohort.

As previously mentioned, steroids have been advocated in the treatment of idiopathic granulomatous hepatitis; some believe their benefit depends on the fact that a proportion of these are cases of undiagnosed sarcoid. However, this course of action risks exacerbating underlying TB, and an earlier paper⁴ described a patient who died from miliary TB after empirical steroids in this setting. Therefore, caution must be exercised, particularly in parts of the world with a high incidence of TB, where empirical antituberculous treatment should be considered as a first line treatment. Of our three cases of TB, one showed central caseation and none had acid fast bacilli revealed on Ziehl-Neelsen staining. This is consistent with earlier studies,^1,4 highlighting the poor diagnostic yield for TB on hepatic histology, and underlines the need to consider this diagnosis.