Hepatotoxicity caused by the combined action of isoniazid and rifampicin.

Abstract

Most antituberculous drugs, with the notable exception of streptomycin, are prone to cause liver injury. The hepatotoxic potential of isoniazid given alone is well established,' while data on the hepatotoxicity of rifampicin, pyrazinamide, and ethambutol are difficult to interpret since these drugs are almost always used in different combinations.2 The evidence supporting possible hepatotoxic interaction between rifampicin and isoniazid is circumstantial.3The requirement of a hepatotoxic drug interaction is the absence of hepatotoxicity when the drugs are administered separately and the presence ofhepatotoxicity when given together. We report the first case where a hepatotoxic drug interaction between rifampicin and isoniazid is firmly documented. This interpretation proved to be essential for optimal treatment of our patient.Case report A 35 year old black woman from Somalia was admitted to our department with a seven month history of dry cough, night sweats, and weight loss of 15 kg. A chest radiograph revealed diffuse fine nodular shadowing, and a diagnosis of miliary tuberculosis was confirmed by the presence of acid fast bacilli in the bronchoalveolar lavage fluid.Treatment was initiated with the Danish four drug routine regimen of isoniazid 300 mg, rifampicin 450 mg, ethambutol 1 g, and pyrazinamide 1 5 g (body weight 46 kg) daily. Five days before the start of treatment the serum level of aspartate aminotransferase (ASAT) was slightly raised at 59 units/l (upper limit of normal (ULN) 35 units/l), whereas the bilirubin level was normal at 11 jtmol/l (ULN 17 1imol/l) (fig 1). After four days of antituberculous treatment the patient developed abdominal pain, nausea, and malaise and ASAT levels started to increase (fig 1). Bilirubin rose to 26,mol/I and alkaline phosphatase to 1-5 times ULN. The patient was not on any other potentially hepatotoxic drug and did not consume alcohol. IgM anti-HAV, HBsAg, and IgM anti-CMV were negative. An ultrasound scan of the liver was normal.Drug treatment was discontinued and bilirubin and ASAT levels fell (fig 1). Treatment was reinstituted seven days later with a daily dose of 100 mg isoniazid, increased to 300 mg after three days. The liver profile remained stable and a dose of 150 mg rifampicin was added. After four days (the day after the dose of rifampicin was doubled to 300 mg) a steep increase in ASAT levels was observed (fig 1). Bilirubin levels reached 31 itmol/l and alkaline phosphatase rose to almost twice the ULN. The patient developed abdominal pain, nausea, and vomiting. Rifampicin was withdrawn and isoniazid treatment was supplemented by a daily dose of streptomycin 1 g, followed one week later by ethambutol. ASAT, bilirubin, and alkaline phosphatase levels returned to normal (fig 1).The general condition of the patient did, however, gradually worsen, and 26 days after rifampicin withdrawal (58 days after starting antituberculous therapy) the isolated Mycobacterium tuberculosis proved to be resistant to isoniazid. Accordingly, isoniazid was withdrawn and rifa...

Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity

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Efficacy and Safety of Anti-Tubercular Regimens in Cirrhosis of Liver with Tuberculosis: A Randomised Controlled Trial

“…The first human case of proven hepatotoxic interaction between INH and RMP has recently been reported by Askgaard et al [12] A 35-yearold black Somalian patient with miliary tuberculosis developed hepatotoxicity after a few days of treatment with INH, RMP, PZA and EMB. On withdrawing all the drugs, the liver profile normalised and remained so after INH challenge.…”

Hepatoprotective Effect of Calotropis procera in Isoniazid and Rifampicin Induced Hepatotoxicity

“…26,27 The mechanism of hepatotoxicity has been suggested by these two drugs is mediated via oxidative damage, 28 the additive or synergistic hepatotoxic effect has been reported to the caused by monoacetyl hydrazine, hydrazine and other related compounds produced from hepatic biotransformation through enzyme induction; 29 therefore, a regular weekly or biweekly monitoring of liver enzyme is required for initial 2 months, 30 according to the guidelines of American thoracic society a rapid increase in liver enzyme like ALT is one of the most prominent indicator for development of hepatic injury. 31,32 In order to manage the ATT induced hepatotoxicity it is recommended to hold the treatment when the hepatotoxicity is evident, until the liver enzymes normalize.…”