Granulomatous liver disease: A hepatic clue to a forgotten diagnosis

Case report

A 25-year old male presented with a one-month history of generalized pruritus, without rash or jaundice. He reported significant unintentional weight loss over the past few months, evident from loose clothing. There was no history of fever or constitutional symptoms. Notably, he had completed a full course of anti-tuberculosis therapy (ATT) six months earlier for presumed pulmonary tuberculosis, though no documentation was available.

On examination, discrete bilateral axillary lymphadenopathy and mild splenomegaly were noted, with a non-palpable liver. Initial laboratory investigations showed mild derangement of liver function tests (serum bilirubin 12.0 µmol/L; aspartate aminotransferase 46 IU/L, alanine aminotransferase 68 IU/L, alkaline phosphatase (ALP) 282 IU/L, gamma glutamyl transferase (GGT) 121 IU/L, and albumin 43 g/L.

He was started on ursodeoxycolic acid for one month, following which liver function tests demonstrated normalization of aminotransferase levels; however, ALP level remained persistently elevated, along with an increase in GGT. An abdominal ultrasound scan then showed mild splenomegaly without hepatic or biliary abnormality, and transient elastography indicated no significant fibrosis or steatosis (liver stiffness 6.5 kPa; CAP 156 dB/m).

Autoimmune testing showed a positive ANA with moderate intensity (2+), a mixed homogenous and speckled pattern at a titre of 1:100, and an IgG level of 22.8 g/L (reference range 7–16 g/L). Disease-specific antibodies for primary biliary cholangitis, including AMA-M2, anti-Sp100, and anti-gp210, were negative. Viral hepatitis screening was negative, angiotensin-converting enzyme level was normal, but erythrocyte sedimentation rate (ESR) remained markedly elevated (>100 mm/h). Contrast-enhanced CT scan confirmed mild splenomegaly and small axillary lymph nodes, with no signs of tuberculosis or sarcoidosis.

Given the constellation of persistently elevated ALP, splenomegaly, elevated ESR, and positive ANA, a liver biopsy was performed. Histopathological examination (Fig. 1A and B) revealed multiple non-necrotizing, well-formed epithelioid granulomas confined to the portal tracts, accompanied by moderate lymphoplasmacytic infiltration. The bile ducts were intact and mild hepatocellular cholestasis was noted. Additionally, the hepatic sinusoids were dilated and infiltrated by inflammatory cells and foamy histiocytes. Staining for acid-fast bacilli was negative. These findings were consistent with granulomatous hepatitis.

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Figure 1.

A & B: The portal tracts show moderate inflammation comprising lymphocytes and a few plasma cells, with intact bile ducts. The hepatic parenchyma reveals cellular cholestasis and the presence of non-necrotising, well-defined epithelioid granulomas along with foamy histiocytes. There is no evidence of interface hepatitis. The sinusoids are dilated and contain foamy macrophages and inflammatory cells; 1C: slit-skin smear microscopy with Ziehl-Neelsen staining revealing numerous acid-fast bacilli (arrow).

The possibility of hepatic tuberculosis was deemed unlikely due to the recent completion of ATT, and alternative causes such as autoimmune overlap, sarcoidosis, and lymphoma were reasonably excluded. On a more detailed re-examination, the patient was found to have subtle thickening of the greater auricular, transverse cervical, and ulnar nerves that had previously gone undetected. Subsequently, a slit-skin smear revealed numerous acid-fast bacilli consistent with Mycobacterium leprae (Fig. 1C). Dapsone-based multidrug therapy was initiated, which resulted in normalization of liver function tests within two months, with complete resolution of pruritus, and an increase in body weight of 4 kg.

Discussion

Granulomatous liver disease poses a considerable diagnostic challenge owing to its wide range of potential causes. ¹ As the initial and sole manifestation of lepromatous leprosy, this is unusual.^2,3 The classical skin lesions were absent despite pruritus being the predominant presenting symptom. Although cutaneous manifestations are considered a hallmark of leprosy, some 4–8% may present without. ⁴ In our case, pruritus was probably cholestatic in origin. Auto-antibodies are frequently detected in leprosy and are thought to reflect a reactive immune response rather than true auto-immune pathology. ⁵ Peripheral nerve thickening is not routinely checked for, but a thorough clinical examination is mandatory in granulomatous hepatitis.

In endemic settings, tuberculosis is the commonest cause. ⁶ The absence of necrotizing granulomas and a recent completion of ATT made this diagnosis untenable. Currently, leprosy is reported in hepatic granulomas in India in 21- 62% of liver biopsies. ⁷ This represents a host immune response to persistent antigenic stimulation rather than direct evidence of pathogen presence. While the national prevalence has markedly declined in recent decades, with India achieving leprosy elimination status as per WHO criteria in 2005, new cases continue to be reported from several districts. Sustained public health surveillance and awareness are therefore advised.