Granulomatous hepatitis from disseminated Mycobacterium bovis infection: shift of an intended local towards a detrimental systemic infection.

An 80-year-old male presented with worsening fever, chills and night sweats 10 days after he received his fifth intravesical BCG instillation for his recurrent low-grade transitional cell carcinoma of the bladder. Review of systems was remarkable for mild dysuria and hematuria. Physical examination revealed a temperature of 102F. He had no hepatosplenomegaly or lymphadenopathy. Laboratory evaluation was significant for leukopenia (3000/μL) and elevated LFTs (alkaline phosphatase (ALP)-378 U/L, AST-70 U/L, ALT-26 U/L). Prior to presentation, isoniazid was initiated by his urologist for presumptive BCG infection. Rifampin and levofloxacin were added upon admission to the hospital. Routine blood and urine cultures did not yield any pathogens and the results of serologic tests to assess virus, bacteria, and fungus were negative. Chest Xray was unremarkable but the chest-CT revealed diffuse, miliary nodular infiltrates suspicious for Mycobacterium infection (Figure 1). A USG-guided liver biopsy was performed for a persistently elevated ALP and revealed granulomatous hepatitis with non-caseating epithelioid granulomas (Figure 2). Gram stain, AFB, GMS, FITE and immunohistochemical stains did not detect any organisms and tissue culture was negative. Worsening pancytopenia prompted a bone marrow biopsy that revealed multiple large granulomas. The patient gradually improved and his fever subsided within several days of anti-tuberculous therapy. Liver abnormalities resolved during the following week. He completed a 6-month course of isoniazid and rifampin, and continues to do well at 1-year follow-up. Intravesical BCG is an effective treatment for superficial bladder cancer with a success rate varying between 63 and 100%. Minor complications including hematuria, cystitis, fever (<38.5C) and malaise are quite common, whereas major complications such as both local (granulomatous prostatitis, epididymo-orchitis, ureteral obstruction, bladder contracture) and systemic reactions (fever >39.5C, sepsis, pancytopenias, granulomatous hepatitis and pneumonitis) occur occasionally. BCG complications generally result from contiguous and hematogenous spread of intravesical mycobacteria through inflamed and/or disrupted urothelium most frequently caused by traumatic catheterization, bladder perforation, or by extensive tumor resection. Granulomatous hepatitis is a rare (<0.4%) and serious complication after BCG instillation, with unclear pathogenesis. It has been considered a hypersensitivity reaction to BCG based on negative staining and cultures of liver tissue. However, cases have been reported in which mycobacteria were present on staining and mycobacterial DNA was detected in liver tissue suggesting a liver infection after hematogenous dissemination of BCG, rather than hypersensitivity. There have been no prospective studies to evaluate the optimal treatment for BCG infection. In severe systemic cases, some data supports the administration of three anti-tuberculous drugs including isoniazid, rifampin and ethambutol for at least Figure 2: Histopathology of liver biopsy specimen showing granulomatous hepatitis with multinucleated-giant cell epitheliod granulomas