A multisystem granulomatous disease: necrobiotic xanthogranuloma with hepatic involvement.

Clinical record A 51-year-old woman was referred to hospital after an incidental fi nding of abnormal liver function test results (γ-glutamyl transpeptidase, 271 U/L [reference interval (RI), < 60 U/L]; alkaline phosphatase, 220 U/L [RI, 30–110 U/L]; hepatic transaminases, normal), acute renal impairment (urea, 11.7 mmol/L [RI, 2.7–8.0 mmol/L]; creatinine, 207 μmol/L [RI, 50–100 μmol/L]) and elevated globulin levels of 44 g/L (RI, 21–41 g/L). She was otherwise well and asymptomatic. Her past medical history included resistant hypertension with renal denervation 8 months earlier, and chronic macrocytic anaemia secondary to alcohol. Physical examination was largely unremarkable apart from several skin nodules and hepatomegaly (4 cm below the costal margin). She underwent an abdominal ultrasound, which showed multiple hypoechoic liver lesions suspicious for metastasis. An abdominal computed tomography (CT) scan (Box 1) confi rmed the presence of hypovascular liver lesions suggestive of metastasis. Malignancy screening, including mammography, colonoscopy and CT of the chest, abdomen and pelvis, was negative. A subsequent liver biopsy specimen showed necrotising granulomas with no evidence of malignancy. The initial histopathological impression was of mycobacterial infection, despite negative Ziehl–Neelsen and Gram stains and the absence of infective organisms. Further assessment found no risk factors for tuberculosis exposure and no symptoms of underlying infection. Dermatology consultation was requested and the skin nodules were closely examined. These included a 1 2 cm violaceous nodule on the left side of the woman’s neck, a 2 5 cm yellowish plaque on her left fl ank, and a large violaceous-yellow plaque exhibiting Koebner phenomenon along the scar from her left total knee replacement surgery (Box 2). The patient reported that they had been present for 8–12 months and were asymptomatic. Biopsy specimens from the lesions on her neck and fl ank showed identical histological features to the liver specimen, again negative for Mycobacterium tuberculosis on Ziehl–Neelsen stain, culture and polymerase chain reaction (PCR) testing. A previous biopsy sample of the plaque overlying her kneereplacement scar had been taken by a dermatologist and showed non-discrete granulomatous infl ammation and necrobiosis (Box 3, A). In retrospect, this was consistent with her current skin sample. Thorough investigations were performed for causes of systemic granulomatous diseases. Infective causes that were investigated included histoplasmosis, brucellosis and mycobacterial infections. However, results from extensive serological testing, cultures, tuberculosis PCR testing of the skin and liver biopsy samples, and an interferon-γ release assay were negative. Non-infective differential diagnoses included sarcoidosis or vasculitis. However, angiotensin-converting enzyme concentration was low and no hilar lymphadenopathy was found on CT of the chest. Results of autoimmune and vasculitic screening were unremarkable except for low-titre antinuclear antibody (ANA) (titre, 1 : 80; pattern, speckled) and type 1 monoclonal cryoglobulinaemia (1.2 g/L). Elevation of the patient’s erythrocyte sedimentation rate (ESR) was also noted (> 120 mm/h [RI, 1–20 mm/h]). The patient was assessed for multiple myeloma, given that she had anaemia (haemoglobin, 106 g/L [RI, 115–155 g/L]), renal impairment, elevated globulin and hypercalcaemia (corrected calcium, 2.72 mmol/L [RI, 2.10–2.55 mmol/L]). She was found to have paraproteinaemia (11 g/L), with raised levels of immunoglobulin G (IgG) kappa light chains (36 mg/L [RI, 3–19 mg/L]) and 2-microglobulin (6.9 mg/L [RI, 0.6–2.9 mg/L]), and positive urine Bence Jones protein of 0.01 g/L. Urine sediment was otherwise bland. A skeletal survey was normal and a bone marrow