Brit. aY. Dis. Chest (t97o) 64, 9o.

Jaundice after Rifampicin A. W. LEEs, B. ASOHER, M. A. HASHEM AND B. N. SINHA

Chest Department, Ruchill Hospital, Glasgow

LABORATORY studies (Pallanza et al. I967; Clark & Wallace, 1967; Hobby & Lenert 1968; Verbist & Gyselen i968), animal experiments (Hobby & Lenert 1968; Verbist & Gyselen 1968 ) and clinical investigations (Virchow & Flemming 1967; Pines et ah 1967; Lucchesi et al. i967) indicate that rifam- picin is likely to prove a highly active antituberculosis drug. Moreover, in preliminary trials unwanted effects have apparently been notably infrequent. The occurrence of jaundice in four elderly men (mean age 72 years) who were among the first fifty patients treated with the drug at this hospital was there- fore unexpected.

A male aged 75 years was admitted on 20.6.69 with newly diagnosed, previously untreated pulmonary tuberculosis. Acid and alcohol-fast organisms were demonstrated in the sputum. He had chronic bronchitis, but his general condition was good for his age. Apart from bronchitis and tuberculosis no other significant disease was detected. He weighed 44 kg. There was no history of alcoholism, exposure to infective hepatitis, ingestion of potentially hepato- toxic drugs or other factors which might have predisposed to hepatic disease. The liver was not palpable and there was no evidence of hepatic dysfunction. Liver function tests showed: S.G.O.T. 13 units per ml; S.G.P.T. 9 units per ml; serum bilirubin o. 4 mg per I oo ml; thymol turbidity 4 units per ml; alkaline phosphatase 13 K.A. units; total protein 7"4 g per Ioo ml. Urinalysis revealed no albumin, blood, sugar or bile. Examination of blood showed: Hb I2"7 g per Ioo ml; W.B.C. 4,7oo/mmS; polys 787o; lymphs 97o; eos. 3Yo; monos Io7o. Serum urea and electrolytes were normal.

On 21.6.69 treatment was started with rifampicin 6oo mg (I 4 mg per kg) and isoniazid 3oo mg daily, both drugs being given in one pre-breakfast dose. No other drugs were given except ampicillin. On I4.7.69 jaundice was noted and the patient complained of loss of appetite and some malaise. Liver function tests showed: S.G.O.T. 63 units per ml; S.G.P.T. 76 units per ml; serum bili- rubin 4"9 mg per i oo ml; thymol turbidity 4 units per ml; alkaline phosphatase 8- 5 K.A. units; total protein 7"7 g per ioo ml. The liver was not palpable. Drug treatment was stopped. On i7.7.69 S.G.O.T. was 99 units per ml; S.G.P.T. 73 units per ml; serum bilirubin 7"5 mg per Ioo ml; thymol turbidity 5 units per ml; alkaline phosphatase 8 K.A. units; total protein 7"3 g per Ioo ml. By 22.7.69 jaundice was not apparent, serum bilirubin was i- 4 mg per Ioo ml and transaminases were normal. On 25.7.69 rifampicin and isoniazid therapy

(Received for publication, oTanuary x97o )

JAUNDICE AFTER RIFAMPICIN 9I

was recommenced in the same dosage as before. Jaundice was again noted on 1.8.69 and liver function tests showed: S.G.O.T. lO2 units per ml; S.G.P.T. 69 units per ml; serum bilirubin 2-2 mg per IOO ml; thymol turbidity 2 units per ml; alkaline phosphatase 8 K.A. units; total protein 6.1 g per IOO ml. Treatment was stopped and by I 1.8.69 the jaundice had again almost gone. Liver function tests then showed: S.G.O.T. 33 units per ml; S.G.P.T. 26 units per ml; serum bilirubin o. 9 mg per IOO ml; thymol turbidity 3 units per ml; alkaline phosphatase 7 K.A. units; total protein 7"4 g per I oo ml. It appeared clear from the sequence of events that rifampicin had been responsible for the jaundice and on 12.8.69 the patient was put on a daily regimen of ethambutol i IOO mg and isoniazid 3oo mg. Up to the present (November 1969) the patient has felt well, liver function tests have remained normal, and progress of the pulmonary disease has been satisfactory.

Case 2

A male aged 71 years was admitted on 9.4.69 with newly diagnosed, pre- viously untreated pulmonary tuberculosis. Acid and alcohol-fast organisms were demonstrated in the sputum and culture was subsequently positive for Myco. tuberculosis. His general condition was fairly good for his age and apart from tuberculosis no significant disease was found. He weighed 6o kg. There was no history of alcoholism, exposure to infective hepatitis, ingestion of potentially hepato-toxic drugs or other factors which might have predisposed to hepatic disease. The liver was not palpable and there was no clinical evidence of hepatic dysfunction. Liver function tests showed: serum bilirubin o.2 mg per IOO ml; thymol turbidity 3 units per ml; alkaline phosphatase 13 K.A. units; serum albumin 4"2 g per ioo ml; serum globulin 2"8 g per IOO ml. (Trans- aminases not estimated.) Urinalysis revealed no albumin, blood, sugar or bile. Serum urea and electrolytes were normal. Examination of the blood showed: Hb Io- 3 g per ioo ml; W.B.C. 5,ooo/mm3; polys 93~o; lymphs 7~o-

On 22.4.69 treatment was started with rifampicin 6oo mg (IO mg per kg) and isoniazid 3oo mg. daily, both drugs being given in one pre-breakfast dose. The patient received no other drugs except triclofos. On 23.4.69 he developed a morbilliform rash and treatment was stopped. The rash disappeared and treatment was recommenced on 3o.4.69 . Progress was satisfactory, but on 28.5.69 liver function tests showed: S.G.O.T. 49 ° units per ml; S.G.P.T. 6oo units per ml; serum bilirubin o'4 mg per IOO ml; thymol turbidity, 4 units per ml; alkaline phosphatase, 29"5 K.A. units; total protein 7-6 g per Ioo mh On 2.6.69 the patient became jaundiced and complained of loss of appetite and some malaise. The liver was enlarged 5 cm below the costal margin and was firm and tender. Liver function tests on 2.6.69 showed: S.G.O.T. 55 ° units per ml; S.G.P.T. 68o units per ml; serum bilirubin 4"9 mg per IOO ml; thymol turbidity 7 units per ml; alkaline phosphatase 25 K.A. units; serum albumin 4"2 g per IOO ml; serum globulin 4"2 g per IOO ml. Treatment was stopped. By 22.7.69 the jaundice had disappeared and liver function tests were normal. Treatment was restarted on 15.8.69. On 22.8.69 liver function tests were normal except for S.G.O.T. and S.G.P.T. which had risen to 97 units and 67 unit

9 2 LEES~ ASGHER~ HASHEM AND SINHA

respectively. On 2.9.69, S.G.O.T. was i46 units and S.G.P.T. I44 units. Thereafter the transaminase levels declined, and by 26.9.69 were: S.G.O.T. 27 units, S.G.P.T. 20 units. The transaminase levels have remained normal up to the time of writing (November I969). The patient has felt well since re- starting the drugs and progress of the pulmonary disease has been satisfactory.

Case 3 A male aged 66 years was admitted on 11.7.69 with newly diagnosed,

previously untreated pulmonary tuberculosis. Alcohol and acid-fast organisms were demonstrated in the sputum and culture was subsequently positive for Myeo. tuberculosis. His general condition was fairly good for his age. He weighed 58 kg. There was no history of alcoholism, exposure to infective hepatitis, ingestion of potentially hepato-toxic drugs or other factors which might have predisposed to hepatic disease. The liver was palpable 4 cm below the costal margin in the mid-clavicular line and was firm and smooth. Liver function tests showed: S.G.O.T. 28 units per ml; S.G.P.T. 18 units per ml; serum bili- rubin 0. 5 mg per I oo ml; thymol turbidity I unit per ml; alkaline phosphatase i6 K.A. units; total protein 7"3 g per IOO ml. Urinalysis revealed no albumin blood, sugar or bile. Examination of blood showed: Hb IO g per IOO ml; W.B.C. 8,2oo/mm3; polys 75~o; lymphs I6~o ; eos. 4~o; monos 5~o. Serum urea and electrolytes were within normal limits.

On 12.7.69 treatment with rifampicin 600 mg (x o mg per kg) and isoniazid 300 mg daily, both drugs being given in one pre-breakfast dose. He received no other drugs. On 29.7.69 jaundice was noted and the patient complained of slight loss of appetite and some malaise. Liver function tests showed: S.G.O.T. 134 units per ml; S.G.P.T. 600 units per ml; serum bilirubin 3.8 mg per i oo ml; thymol turbidity, 2 units per ml ; alkaline phosphatase 12. 5 K.A. units; total protein 6. 9 g per Ioo ml. Treatment was stopped. On 6.8.69 liver function tests showed: S.G.O.T. 135 units per ml; S.G.P.T. 116 units per ml; serum bilirubin 3"8 mg per lOO ml; thymol turbidity I unit per ml; alkaline phos- phatase 19. 5 K.A. units; total protein 6.2 g per IOO ml; albumin 3.2 g per ioo ml; globulin 3 g per lOO ml. On 11.8.69 liver function tests showed: S.G.O.T. 65 units per ml; S.G.P.T. 79 units per ml; serum bilirubin I.I mg per lOO ml; thymol turbidity 2 units per ml; alkaline phosphatase i6. 5 K.A. units; total protein 6 g per lOO ml. In another week jaundice had disappeared and liver function tests were normal: S.G.O.T. 17 units per ml; S.G.P.T. i I units per ml; serum bilirubin 0. 5 mg per IOO ml; thymol turbidity 2 units per ml; alkaline phosphatase IO" 5 K.A. units; total protein 5-8 g per lOO ml. Rifampicin and isoniazid therapy was restarted on 19.8.69. On 26.8.69 liver function tests showed: S.G.O.T. 66 units per ml; S.G.P.T. 31 units per ml; serum bilirubin 0. 5 mg per 1oo ml; thymol turbidity 2 units per ml; alkaline phosphatase 16 K.A. units; total protein 7-I g per IOO ml. On 1.9.69 liver function tests showed: S.G.O.T. 75 units per ml; S.G.P.T. 39 units per ml; serum bilirubin I. 3 mg per Ioo ml; thymol turbidity I unit per ml; alkaline phosphatase x 3 K.A. units; total protein 6.8 g per ioo ml. On 9.9.69, S.G.O.T. was 24 units per ml; S.G.P.T. 19 units per ml; serum bilirubin 0.2 mg per xoo

JAUNDICE AFTER RIFAMPICIN 93

ml; thymol turbidity I unit per ml; alkaline phosphatase 13. 5 K.A. units; total protein 5.8 g per IOO ml. A liver biopsy carried out on I2.9.6 9 reported: 'There is no suggestion of undue fibrosis of the portal tracts or linkages between them. The possibility of macronodular cirrhosis cannot be excluded'. Liver function tests have remained normal to the time of writing (November 1969) and progress of the pulmonary disease has been satisfactory.

Case 4 A male aged 77 years was admitted on 2.6.69 with newly diagnosed, pre-

viously untreated pulmonary tuberculosis. Acid and alcohol-fast organisms were demonstrated in the sputum and culture was subsequently positive for Myco. tuberculosis. His general condition was fairly good for his age and apart from tuberculosis no significant disease was found. He weighed 79 kg. There was no history of alcoholism, exposure to infective hepatitis, ingestion of potentially hepato-toxic drugs or other factors which might have predisposed to hepatic disease. The liver was not palpable and there was no clinical evidence of hepatic dysfunction. Liver function tests showed: S.G.O.T. 20 units per ml; S.G.P.T. 9 units per ml; serum bilirubin 0. 5 mg per IOO ml; thymol turbidity I unit per ml; alkaline phosphatase 18 K.A. units; total protein 7"3 g per IOO ml. Urinalysis revealed no albumin, blood, sugar or bile. Examination of the blood showed: Hb 12"9 g per IOO ml; W.B.C. 6,ooo/mma; polys 85°7o ; lymphs i4~o; eos. I ~o. Serum urea and electrolytes were within normal limits.

On lO.6.69 treatment was started with rifampicin 6oo mg (7.6 mg per kg) and isoniazid 3oo mg daily, both drugs being given in one pre-breakfast dose. Apart from antituberculosis drugs the patient received ampicillin for a week. On 18.7.69 liver function tests showed: S.G.O.T. 6oo units per ml; S.G.P.T. 21o units per ml; serum bilirubin 1. 5 mg per IOO ml; thymol turbidity IO units per ml; alkaline phosphatase 32"5 K.A. units; total protein 7"3 g per IOO ml; albumin 2" 5 g per ioo ml; globulin 4.8 g per ioo ml. Apart from some loss of appetite and slight malaise the patient made no complaints, but jaundice was noted on 29.7.69. Liver function tests showed: S.G.O.T. 425 units per ml; S.G.P.T. 275 units per ml; serum bilirubin 3"1 mg per IOO ml; thymol tur- bidity 4 units per ml; alkaline phosphatase i4. 5 K.A. units; total protein 5"3 g per ioo ml. Treatment was continued. By 22.8.69 the jaundice had dis- appeared and liver function tests were normal except for the S.G.O.T. which was 67 units per ml. On 9.9.69 liver function tests were all within normal limits. At the time of writing (November 1969) the rffampicin and isoniazid treatment continues. The general condition of the patient has remained good and progress with respect to the pulmonary disease has been satisfactory.

D i s c u s s i o n

The comparative frequency of jaundice in this series of rifampicin treated patients was unexpected, but Lesobre et al. (1969) have recently reported twelve cases of jaundice with four deaths in fifty patients treated with rifam- picin. Three of their four patients who had jaundice and died were known to be chronic alcoholics, and of the eight patients who survived some were chronic

94 LEES~ ASGHER~ HASHEM AND SINHA

alcoholics or had impaired liver function from some other cause. Some of the patients were given, in addition to rifampicin, prothionamide or other drug which might have been wholly or partly responsible for the hepatic toxicity: yet it seems clear from the experience of these authors that rifampicin may be dangerously hepato-toxic in patients who have impaired liver function. In the present series none of the four patients developing jaundice were addicted to alcohol or had received drugs or had suffered from diseases likely to impair liver function. One of the patients had initially a slightly enlarged smooth liver but he had no history of hepatic disorder and liver function tests were normal before and after the development of the jaundice.

In the series of Lesobre et al. (i 969) jaundice developed from the 6th to the 17th day of treatment: in the present series jaundice was noted from the 17th to the 49th day of treatment.

There appears to be no doubt from the sequence of events and from the fact that jaundice did not occur except in patients treated with rifampicin, that its occurrence in the four cases in the present series was caused by the drug. Whether the accompanying drug, isoniazid, played any role is open to specula- tion. From the studies of Keberle et al. (i968) it may be inferred that rifam- picin competes with bilirubin for excretion in the bile and this is a possible mechanism for the production of jaundice. But it is not the only mechanism and probably not the main one, since the development of jaundice was heralded by elevated transaminase levels indicating damage to the liver cells. Moreover, in several cases in this series where jaundice did not develop, transaminase levels became elevated but returned to normal despite the continuation of treatment. It may be that in some instances the liver finds it initially difficult to deal with the load ofrifampicin but after a period of adjustment is capable of doing so. I f rising transaminases indicate that this may be the case, perhaps a temporary reduction in dosage would permit adaptation to take place. On the other hand, it would not seem advisable in the absence of further experience to start t reatment in all cases with a lower daily dose than the recommended 600 mg since in the four cases with jaundice the dose per kg bodyweight ranged from 7.6 mg to 14 rag.

Although there was nothing to indicate initial sub-normal liver function in the cases with jaundice in this series, it is noteworthy that three of the patients were over 7 ° years of age and the other was 69. None of these patients had more than mild malaise, but it is clear that rifampicin should be used with great caution in those who have demonstrable or suspected hepatic dysfunction.

Summary The occurrence of jaundice in four patients in a group of 5 ° with pulmon-

ary tuberculosis treated with 600 mg rifampicin and 300 mg isoniazid daily is reported. In one case, resumption of treatment after jaundice had disappeared provoked its re-appearance: an ethambutol-isoniazid regimen was then sub- stituted, and progress was subsequently uneventful. In two cases, after jaundice had disappeared and liver function tests had returned to normal the rifampicin- isoniazid regimen was reinstituted: serum transaminase levels became elevated

JAUNDICE AFTER RIFAMPICIN 95

bu t eventually re turned to normal . In the remaining case rifampicin-isoniazid t rea tment was cont inued despite the occurrence of j aundice : j aundice subse- quent ly disappeared and liver function tests became normal . The daily dose of r ifampicin varied from 7.6 mg per kg to 14 mg per kg bodyweight . Al though none of these patients was seriously ill, evidence of hepato-toxicity should be looked for in patients t reated with rifampicin, and especially in those who m a y initially have impaired liver function.

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rifampicin. Tubercle (Lond.), 48, x44. HOBBY, G. L. & LENERT, T. F. (I968) The antimycobacterial activity of rifampin. Araer. Rev.

resp. Dis., 97, 713 • KEBERL~, H., SCHMID, K. & MEYER-BRuNOT, H. G. (x968) The metabolic fate of Rimactane

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occurring during treatment with rifampicin. Rev. Tubercl., 33, 393. LUCCHESI, M., PALLOTTA, G., & Rossx, P. (x967) L'Azione terapeutica della rifampicina de-

rivato 3-(4-metil-x-piperazinil-iminometil)- rifamlclna SV nalla tuberculosi polmonare. Cit. no. 3xxi233 . Ann. Ist. Fodnnini, 27, x99.

PALLANZA, R., ARXOLX, V., FuR~sZ, S. & BOLSONI, G. (x967) Rifampicin: A new rifamycin. Arzneimlttel-Forsch., xT, 529 •

PINES, A., RAAFAT, H. & BUNDI, R. (I967) The rifamycins with other drugs in the treatment of pulmonary tuberculosis: A report of nlne cases. Tubercle (Land.), 48, 28i.

VERBIST, L. & GYSELEN, A. (I968) Antituberculosis activity of rifampin in vitro and in vivo and the concentrations attained in human blood. Amer. Rev. resp. Dis., 98, 723.

VIRCHOW~ CHR. & FLEMMING, J. (t967) Rifampizin ais tuberkulostatikum. Dtsch. raed. Wschr. 92, 22t7.