Incidence and timing of hepatotoxicity due to anti-tuberculous treatment

Hepatotoxicity is a life threatening complication of anti-tuberculous treatment. It is unclear how closely to monitor liver enzymes during treatment. In the absence of liver risk factors, the American Thoracic Society advises checking them if symptoms develop. The aim of this study was to assess the timing and causative factors associated with hepatotoxicity. We reviewed patients treated for TB in Leeds between 2006 and 2010. Elevations of aminotransferase (ALT) greater than two times the upper limit of normal (ULN) were considered abnormal. Our local policy recommends that patients should have ALT checked at weeks 0, 2, 4 and 8. 634 patents underwent treatment for TB during this period. 46 (7.3%) patients had ALT rises two times ULN and 14 (2.2%) five times ULN. Interestingly, hepatotoxicity was more common in Caucasians (p=0.02) and increasing age (p=0.07). Gender, HIV status, pregnancy, and organs affected by TB did not predict hepatotoxicity. The average time for the hepatotoxicity to develop was 28 days (range 3-306); however, this time was increased to 42 days (4-306) in patients with ALT rises greater than five times ULN. Only one patient presented with clinical symptoms of hepatitis, this patient subsequently died from liver failure. In the 14 patients with rises five times ULN, the cause was felt to be pyrazinamide in 8, isoniazid in 3, rifampicin in 1, and not established in 2. It is unknown whether identifying an elevated ALT and stopping treatment prior to symptoms reduces the severity of liver injury. We feel that careful biochemical monitoring and prompt cessation of treatment is appropriate. Only 2 patients developed hepatitis with ALT five times ULN at a time point beyond our 8 week protocol.