Severe coagulopathy caused by rifampicin in patients with primary sclerosing cholangitis and refractory pruritus

Introduction

Pruritus is one of the most disabling clinical manifestations of cholestatic liver disease. Antipruritic agents are effective only in a proportion of patients [1], [2]. Rifampicin is an antituberculous agent recommended for relieving pruritus refractory to bile acid sequestrants [3]–[6]. This is the first report of severe, reversible prolongation of prothrombin time in patients with primary sclerosing cholangitis (PSC), following the introduction of rifampicin.

Case reports

Two patients with PSC were assessed for consideration of liver transplantation at our unit, in view of intractable pruritus and a high United Kingdom endstage liver disease (UKELD) score [7]. Patient A was a 59-year-old man with no comorbidities, receiving ursodeoxycholic acid, cholestyramine and omeprazole. Patient B was a 69-year-old woman. Comorbidity included type II diabetes mellitus, hypertension and chronic kidney disease. Medication included ursodeoxycholic acid, cholestyramine, propranolol, ramipril, omeprazole, subcutaneous insulin and metformin.

Patient A was accepted for transplantation; however, patient B was deemed unsuitable. Rifampicin 300 mg daily in divided doses was started as an antipruritic agent to ameliorate symptoms in both patients. Prior to commencing rifampicin, the prothrombin time was 12.7 (9.8–12.6) and 13.8 s, respectively.

At outpatient review, 2 weeks later, patient A's pruritus had improved significantly. However, whilst the rest of the laboratory values remained unchanged, the prothombin time was found to be significantly prolonged at 114.7 s, confirmed on repeat testing. Coagulation factor quantification revealed very low levels of the vitamin K-dependent factors II (0.06 IU ml⁻¹; 0.5–1.3), VII (0.03 IU ml⁻¹; 0.6–1.2), IX (0.09 IU ml⁻¹; 0.7–1.5) and X (0.04 IU ml⁻¹; 0.6–1.4).

Patient B presented 3 weeks later with symptoms of cystitis. There was no clinical evidence of further decompensation. All laboratory values remained stable apart from the prothombin time, which was now significantly prolonged at 99.6 s, confirmed on repeat testing.

Rifampicin was withdrawn and 10 mg intravenous vitamin K administered in both cases. The prothrombin time normalized within 24 h.

Discussion

This is the first time the use of rifampicin for the management of pruritus has been associated with reversible hypoprothrombinaemia, in patients with PSC. Rifampicin-induced coagulopathy has been described, sporadically, in patients with low vitamin K levels [8]–[11]. Quantification of coagulation factors in patient A revealed very low levels of the vitamin K-dependent factors (II, VII, IX and X). The hypoprothrombinaemia was reversed fully with administration of parenteral vitamin K. These data suggest that rifampicin-induced hypoprothrombinaemia is mediated by vitamin K deficiency.

Toxic hepatitis is a well-described complication of rifampicin treatment [12]. It is associated with hypoprothrombinaemia secondary to hepatic synthetic impairment. In both cases described, the patients' blood biochemistry revealed no deviation from their baseline liver function. The coagulopathy was reversed entirely with vitamin K replacement. Toxic hepatitis as a cause for prothrombin time prolongation is therefore excluded.

The pathogenesis of rifampicin-induced vitamin K deficiency is most likely to be multifactorial. Intestinal decontamination by rifampicin may impair vitamin K production by gut flora [13]. Rifampicin, similar to warfarin, may inhibit vitamin K epoxide reductase [8]. It may also increase the oxidative degradation of vitamin K as a result of hepatic microsomal enzyme stimulation [9].

We conclude that the use of rifampicin as an antipruritic agent in cholestatic liver disease may precipitate marked hypoprothrombinaemia. Vitamin K deficiency appears to be a prerequisite. Malabsorption of fat-soluble substances is likely to render such patients vitamin K deficient, despite a normal or near-normal prothrombin time. Measurement of vitamin K levels or empirical replacement therapy should be considered before administration of rifampicin for pruritus. Furthermore, the prothrombin time should be monitored closely because there is a theoretical risk of severe haemorrhage.

Competing Interests

There are no competing interests to declare.