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Classical Case Studies

HepatologyLiver diseases

Granulomatous liver diseases

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Daniel R Gaya, Karen Oien & Adrian J Stanley Hepatic granulomas and polymyalgia rheumatica
Daniel R Gaya, Karen Oien & Adrian J Stanley, 18 August 2003
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Summary

We present a patient with subsequently proven of polymyalgia rheumatica (PMR) who was initially referred to the liver clinic with abnormal liver function tests. Liver biopsy revealed hepatic epithelioid granulomas. The diagnosis of PMR was only considered after typical signs and symptoms of the condition appeared after cessation of corticosteroid for presumed idiopathic granulomatous hepatitis. We propose that PMR should be considered in patient with epithelioid granulomas on liver biopsy in the absence of a known etiology. It is possible that PMR accounts for a significant proportion of those labeled as having steroid-responsive idiopathic granulomatous hepatitis.

Case Report

History

A 60-year-old gentleman was initially referred to the liver clinic with abnormal liver function tests and a 12 month history of weight loss, lethargy, and night sweats. He also described clear sputum production on most days, although he specifically denied hemoptysis.

There was no significant alcohol intake and he had given up smoking 20 years earlier. His past medical history was notable for an episode of pulmonary tuberculosis treated with antituberculous chemotherapy 45 years earlier. He was on no regular medications and there was no family history of note.

Examination

On examination he appeared pale and thin. He was apyrexial and there was no lymphadenopathy. Cardiorespiratory examination was unremarkable and there was no abdominal organomegaly. There were no focal neurological deficits and no mypoathy was apparent on musculoskeletal examination.

Investigation

Investigations revealed, hemoglobin 11 g/dL (12.5–16.5), white blood cells 12.9x109(4–11), platelets 550x109/L (150–450), erythrocyte sedimentation rate (ESR) 108 mm/h (<20), ferritin 660mcg/L (15–300). The B12, folate and prothrombin time were all normal, as were the urea and electrolytes.

Liver function tests (LFTs) revealed albumin 36 g/L (34–48), alkaline phosphatase 1230 iu/L (25–150), gamma-glutamyl transferase 165 i/L (11–50). The bilirubin and transaminases were normal.

The C-reactive protein (CRP) was 64mg/dL (<10). Serum immunoglobulins, auto-antibodies, angiotensin converting enzyme, calcium, sputum for acid/alcohol fast bacilli, hepatitis B/C were all normal or negative.

A chest radiograph revealed apical changes consistent with old tuberculous infection, and a CT of chest and abdomen confirmed the above, with no evidence of lymphadenopathy or abdominal organomegaly. Liver biopsy was performed (Figure 1).

Figure 1

The most striking feature was the presence of numerous well-defined epithelioid granulomas, which lacked necrosis but contained occasional giant cells. Special stains for microorganisms were negative.

The granulomas were found mainly in portal tracts, although most did not appear to be centred on bile ducts, but granulomas were also present in the parenchyma. A small number of bile ducts showed epithelial injury. There was no ductopenia or vasculitis. The portal tracts also contained a mild chronic inflammatory infiltrate with occasional lymphoid aggregates. There was mild interface hepatitis. The periportal hepatocytes did not show histological features of chronic cholestasis by hematoxyln and eosin staining, but there was minimal deposition of copper-associated protein. Otherwise, the liver biopsy showed preservation of the liver architecture and no fibrosis.

The features were therefore of a granulomatous hepatitis. The differential diagnoses are obviously extensive, but from the histology would have included primary biliary cirrhosis, sarcoidosis, tuberculosis, and drug reactions.

Management and outcome

After multiple negative sputa samples for AAFB, the patient was commenced on an empirical course of corticosteroids for presumed idiopathic hepatic granulomas. This resulted in an immediate symptomatic and biochemical improvement.

The steroids were gradually reduced and he remained on a maintenance dose of 5 mg oral prednisolone for over 3 years with good symptomatic control and suppression of his LFTs and ESR (Figure 2).

Figure 2

Subsequently, an attempt was made to wean him off his steroids. However 4 weeks after discontinuing the corticosteroids, he was unable to walk upstairs or get up from a sitting position; complained of marked proximal muscle aching and stiffness. His lethargy and sweats also returned, although he specifically denied any headaches or visual upset.

On examination he had a marked proximal myopathy and his ESR and alkaline phosphatase had both markedly risen once more (Figure 2). With the reassurance of a normal creatinine kinase, the clinical and laboratory findings were compatable with an underlying diagnosis of polymyalgia rheumatica (PMR). This was supported by the fact that within a day of recommencing his prednisolone at a dose of 30 mg/day, he was able to walk normally again and his symptoms resolved.

After 6 weeks of steroid therapy, his LFTs and inflammatory indices had all returned to normal and a repeat liver biopsy was performed to monitor the disease. This second biopsy showed an appearance very similar to the first, with persisting granulomas, a similar mild degree of inflammation but no evidence of the development of fibrosis.

Discussion

We describe a patient with PMR who presented with systemic upset and deranged LFT's which were at first thought to be due to "idiopathic" hepatic granulomas. The diagnosis of PMR was not considered initially due to the lack of myalgia or myopathy. The latter symptoms and signs only became apparent after the cessation of corticosteroid treatment for the presumed "idiopathic" hepatic granulomas.

Granulomas are found in approximately 3 to 10% of unselected liver biopsy series [1] and in most cases represent an unexpected finding. Only rarely are they present in association with distinct histological or clinical features to enable a firm diagnosis to be made.

Common causes include sarcoidosis, drugs, or infection with tuberculosis, Q fever, brucella, or HIV [2–4]. If investigations for recognized etiologies are negative, the patient is usually labeled with the diagnosis of "idiopathic" hepatic granulomas.

An empirical trial of steroids or antituberculous chemotherapy is often given, depending on the clinical picture and degree of liver dysfunction.

The association of PMR and abnormal LFTs was described in the literature in the early 1960s, with an increased serum alkaline phosphatase being the commonest abnormality. In addition, a case series from 1973 illustrated that these abnormalities resolved with steroid therapy [5].

The data from this series suggested that in the majority of cases, liver biopsy reveals essentially normal hepatic histology. However 2 separate case series in the 1970s described hepatic granulomas in association with PMR [6,7].

The presence of hepatic granulomas in patients with polmyalgia is probably grossly underestimated since abnormal LFTs in this context are only rarely investigated with liver biopsy.

The pathophysiological mechanism of the liver dysfunction in PMR remains unknown. Although giant cell arteritis is strongly associated with PMR, arteritis has never been reported in the liver biopsy of such a patient.

The identification of PMR as the cause of our patient's symptoms and liver dysfunction allowed appropriate therapy with steroids to be reintroduced. This led to a rapid resolution of the patient's symptoms, signs, and abnormal liver function tests. In addition, repeat liver biopsy (3 and a half years later) revealed no evidence of progression of inflammatory activity and no fibrosis. This is in the context of the patient having been on steroid therapy for all but 4 weeks of the 3-year period.

To our knowledge, this case represents the only published report of serial liver biopsies in a patient with PMR-related hepatic granulomas and suggests a relatively good prognosis with respect to liver disease in PMR if corticosteroid therapy is undertaken.

The benign prognosis of patients with idiopathic hepatic granulomas has been noted previously [4,8]. Earlier publications on this subset of patients [9,10] have highlighted the systemic upset, with fever, myalgia, weight loss, and weakness, which may accompany the deranged liver function and hepatic histopathology, which led to the term "granulomatous hepatitis". Indeed it is possible that these cases may represent underlying polymyalgia rheumatica—a recognized cause of hepatic granulomas and systemic upset. This is supported by the reported good clinical/laboratory response of such patients to corticosteroids [9].

As mentioned above, 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 tuberculosis and an earlier paper [3] 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 higher incidence of TB, where empirical antituberculous therapy should be considered as a first line therapy.

Earlier studies [3,11] have highlighted the poor diagnostic yield for TB on hepatic histology, and this underlines the need to always consider this diagnosis.

It is possible that PMR accounts for a significant proportion of the patients with steroid responsive "idiopathic" hepatic granulomas and we suggest that the diagnosis of PMR be considered in all patients diagnosed with this condition.

This article was first published on GastroHep.com on 18 August 2003.

References

  1. Guckian JC, Perry JE. Granulomatous hepatitis. An analysis of 63 cases and a review of the literature. Ann Intern Med 1966; 65(5): 1081–100.
  2. McCluggage WG, Sloan JM. Hepatic granulomas in Northern Ireland: a thirteen year review. Histopathology 1994; 25(3): 219–28. PubMed
  3. Cunningham D, Mills PR, Quigley EMM et al. Hepatic granulomas: experience over a 10-year period in the West of Scotland. Q J Med 1982; 202: 162–72.
  4. Anderson C, Nicholls J, Rowland R, LaBrooy JT. Hepatic granulomas: a 15-year experience in the Royal Adelaide Hospital. Med J Australia 1988; 148: 71–4. PubMed
  5. Dickson ER, Maldonado JE, Sheps SG, Cain JA. Systemic giant cell arteritis with polmyalgia rheumatica: reversible abnormalities of liver function. JAMA 1973; 224 (11): 1496–8. PubMed
  6. Long R, James O. Polymyalgia rheumatica and liver disease. Lancet 1974; 1: 77–9. PubMed
  7. Calamia KT, Hunder GG. Giant cell arteritis presenting as fever of unknown origin. Arthritis Rheumatism 1981; 24(11): 1414–8. PubMed
  8. Neville E, Piyasena KHG, Geraint JD. Granulomas of the liver. Postgrad Med J 1975; 51: 361–5. PubMed
  9. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin. a study of 13 patients. Medicine 1973; 52: 1–21. PubMed
  10. Terplan M. Hepatic granulomas of unknown origin presenting with fever. Am J Gastroenterol 1971; 55: 43–9. PubMed
  11. 11  Wagoner GP, Anton AT, Gall EA et al. Needle biopsy of the liver. Experiences with hepatic granulomas. Gastroenterology 1963; 25: 487–94.

 
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