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Hepatotoxicity of rifampicin and isoniazid in children
Volume 86 Number 5
1. Intrathecal administration of h u m a n leukocyte interferon (8 x 600,000 units) into the n e w b o r n infant did not lead to overt toxicity. Even with the crude interferon available for this study, the only adverse effect noticed was a moderate rise of body temperature. 2. Relatively high interferon titers were maintained in the CSF (800-8,000 units/ml) at 12-24 hours after intrathecal administration of 600,000 units of interferon. 3. Interferon did not freely cross the blood-brain barrier since interferon levels in the serum were approximately 40- to 80-fold lower than the corresponding CSF titers. 4. The intrathecal route may not be the optimal single route for delivering interferon to all parts of the central nervous system in which virus is actively multiplying, i n a s m u c h as virus was recovered from b r a i n tissue postmortem. We are indebted to Dr. K. Cantell for providing the human leukocyte interferon, to Drs. W. E. Stewart II, M. Casteels-Van Daele, E. Eggermont, and L. Corbeel for helpful suggestions, to Dr. W.T. Liu for electron microscopic examination of the virus samples, to Dr. B. Van Damme for performing the autopsy studies, to Francine Cornette and Gaby Lenaerts for technical assistance, and to Janine Putzeys for editorial help. REFERENCES 1. Nahmias AJ, Alford CA, and Korones SB: Infection of the newborn with Herpesvirus hominis, Adv Pediatr 17:185, 1970. 2. Partridge JW, and Millis RR: Systemic herpes simplex infection in a newborn treated with intravenous idoxuridine, Arch Dis Child 43:377, 1968. 3. Golden B, Bell WE, and McKee AP: Disseminated herpes simplex with encephalitis in a neonate, J A M A 209:1219, 1969. 4. Tuffii GA, and Nahmias AJ: Neonatal herpetic infection.
Hepatotoxicity of rifampicin and isoniazid in children M. Casteels-Van Daele, M.D.,*
Brief clinical and laboratory observations
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
739
Report of two premature infants treated with systemic use of idoxuridine, Am J Dis Child 118:909, 1969. Charnock EL, and Cramblett HG: 5-Iodo-2'-deoxyuridine in neonatal herpes virus hominis encephalitis, J PEDIATR 76:459, 1970. Strander H, Cantell K, CarlstrOm G, and Jakobsson PA: Clinical and laboratory investigations on man : Systemic administration of potent interferon to man, J Natl Cancer Inst 51:733, 1973. Nahmias AJ, Dowdle WR, Josey WE, Naib ZM, Painter LM, and Luce C: Newborn infection with herpes virus hominis types 1 and 2, J PEDIATR75:1194, 1969. Finter NB: Dye uptake methods of assessing viral cytopathogenicity and their application to interferon assays, J Gen Virol 5:419, 1969. Figueroa MA, and Rawls WE: Biologicalmarkers for differentiation of herpes strains of oral and genital origin, J Gen Virol 4:259, 1968. Bellanti JA, Catalano LW Jr, and Chambers RW: Herpes simplex encephalitis : Virologic and serologic study of a patient treated with an interferon inducer, J PED1ATR 78:136, 1971. Ho M, Nash C, Morgan CW, Armstrong JA, Carroll RG, and Postic B: Interferon administered in the cerebrospinal space and its effect on rabies in rabbits, Infect Immun 9:286, 1974. Cathala F, and Baron S: Interferon in rabbit brain, cerebrospinal fluid and serum following administration of polyinosinicrpolycytidylic acid, J Immunol 104:1355, 1970. Cesario TC, Mandell A, and Tilles JG: Inactivation of human interferon by body fluids, Proc Soc Exp Biol Med 144:1030, 1973. Fishman MA, Haymond MW, and Middelkamp JN: Failure of idoxuridine treatment in herpes simplex encephalitis, Am J Dis Child 122:250, 1971. Kern ER, Overall JC Jr, and Glasgow LA: Herpes virus hominis infection in newborn mice. I, An experimental model and therapy with iododeoxyuridine, J Infect Dis 128:290, 1973.
THERE HAVE BEEN REPORTS of hepatotoxicity related to therapy with rifampicin, especially in association with isoniazid, in adults. 1, 2 As far as we know, there have been no reports of serious and life-threatening side effects in children in conjunction with this therapy. This report is of a boy who developed hepatic coma while receiving antituberculous therapy.
L. Igodt-Ameye, M.D., L. Corbeel, M.D., and R. Eeekels, M.D., Leuven,Belgium From the Department of Pediatrics, University of Leuven. *Reprint address: Department of Pediatrics, St. Raphael Academisch Ziekenhuis, Universityof Leuven, B-3OOOLeuven, Belgium.
CASE REPORT Ph., a 13-year-old boy, was admitted to our department in a comatose state. Two weeks before admission pleurisy of tuberculous origin was diagnosed. The patient was treated with isoniazid 500 mg/day (12 mg/kg), ethambutol 800 mg (20 rag/ kg), and rifampicin 450 mg/day (11 mg/kg). On the seventh
740
Brief clinical and laboratory observations
The Journal of Pediatrics May 1975
Table I. Evolution of liver function tests Day 11 * (on admission) Bilirubin (mg/dl) SGOT (U/I) SGPT (U/l) Alkaline phosphotase (lUll) NH 4(/zg/ml) Prothrombin (%)
5.2 2,722 1,500 302 1.78 (10
Day 13 8 282 590 1.18 35
Day 15 9.1 6.2 155 294 232 0.67 45
Day 18 7.2 4.8 36 139 160 0.8
Day 23 4.27 2.45 23 75 130 0.65 100
Day 29 1.9 22.5 35
After 3 months 0.3 17 18 267
*Day 1 : start of antituberculoustherapy.
day after starting therapy, he became lethargic and confused; on Day 11, he was transferred to our department. Physical examination revealed a well-developed boy who was icteric and unconscious. Height was 150.5 cm; weight, 40 kg. The edge of the liver was barely palpable. The diagnosis of tuberculous pleurisy was confirmed. Electroencephalogram was compatible with encephalitis or severe metabolic disorder. The most important laboratory data are summarized in Table. I. Australian antigen and the lymphocyte transformation test with rifampicin were negative. A percutaneous needle biopsy of the liver was performed on the eighteenth day. Histopathologically the changes resembled a "hepatitis-like" lesion. The clinical diagnosis was hepatic coma, most probably due to the antituberculosis therapy. This medication was discontinued on the eleventh day of treatment. The patient received several exchange transfusions, intravenous fluids, and vitamines B and K. He regained consciousness on Day 13. Recovery was progressive and complete. On Day 24, therapy with isoniazid was resumed (10 mg/kg). After six months the boy was examined as an outpatient. The pleural effusion had disappeared, and evidence of hepatic dysfunction had subsided. DISCUSSION Our patient developed hepatic coma while receiving antituberculous treatment with rifampicin, isoniazid, and ethambutol. No evidence could be found to support a viral origin of the hepatitis. Several features suggest that the hepatitis was due to the antituberculous drugs: the first s y m p t o m s of lethargy and c o n f u s i o n were noted on the seventh day of treatment, which correlates q u i t e well w i t h t h e o b s e r v a t i o n s of M a r c h e 3 a n d Lesobre 1and their colleagues. Furthermore, clinical and biochemical remission in our patient promptly followed cessation of antituberculous therapy. In our patient, r i f a m p i c i n was a d m i n i s t e r e d with isoniazid and ethambutol, which makes the evaluation of side-effects difficult. Ethambutol is known to cause
ocular toxicity, which is dose related, 4 but it has not been implicated as a cause of liver disease. Isoniazid and r i f a m p i c i n are k n o w n to be hepatotoxic w h e n adm i n i s t e r e d separately, and especially w h e n used in combination. This was first reported by Lesobre and colleagues ~in 1969, and subsequently by Lees and associates 2 from Great Britain. Histologic changes were observed in the liver of rats after combined treatment with isoniazid and rifampicin, but not when the drugs were given separateiy. 5 It has been assumed that the handling of these two drugs t o g e t h e r m a y place some strain on liver capacity, particularly in subjects whose acetylator p h e n o t y p e indicates that they metabolize isoniazid slowly.6 The exact mechanism of liver damage from rifampicin is at present obscure. The increased lymphocyte transformation in the presence of rifampicin, observed by Hollins and Simmons, 7 could suggest allergy. In our case, however, the lymphocyte transformation test with rifampicin was negative: Dieu s has s t u d i e d the hepatotoxicity of c o m b i n e d rifampicin and isoniazid therapy in children in relation to dosage. W h e n the dose of rifampicin was kept constant at 10-15 mg/kg/day, and the dose of isoniazid varied from 20 to 8 mg/kg, the degree of hepatotoxicity was found to be related to excessive doses of isoniazid. Our patient, however, who received isoniazid in a dose of 12 mg/kg/day, and rifampicin at 11 mg/kg/day developed a nearly fatal complication. The lack of reports in the pediatric literature on the toxicity of rifampicin and the general assumption that the patients most at risk are elderly persons with liver disease make it necessary to alert pediatricians to the possible hepatic side effects of these antituberculous drugs, even in healthy children. W h e n prescribing a combination of rifampicin and isoniazid, one should bear in mind the potential hepatotoxicity of this combination and keep strictly within the "safer" dosage
Volume 86 Number 5
B r i e f clinical and laboratory observations
limits of rifampicin (10-15 mg/kg/day) and of isoniazid (8-10 mg/kg/day). Even at these doses the patient must be followed for evidence of hepatotoxicity. Nausea and anorexia are important alerting symptoms. Serum transa m i n a s e s and p r o t h r o m b i n values s h o u l d be d e t e r mined, especially during the first two weeks of treatment; abnormal values of these two determinations are an indication for a change in therapy. We thank Dr. L. Vanden Bulcke, Dr. J. Fevery, Professor V. Desmet and Professor H. Van den Berghe for their valuable help and advice. REFERENCES 1. Lesobre R, Ruffino J, Teyssier L, Achard F, and Brefort G: Les ict~res au cours du traitement par la Rifampicine, Rev Tuberc Pneumol 33:393, 1969.
Single-peak insulin in the treatment of insulin-induced fat atrophy L. Ferland, M.D., and R. M. Ehrlich, M.D.,
F.R.C.P.(C),* Toronto, Ont., Canada T HE DISAPPEARANCE of subcutaneous adipose tissue (fat atrophy or lipoatrophy) is the most c o m m o n local complication of insulin therapy. It was first described by Depisch I in 1926 and further reports quickly followed. 2, 3 A l t h o u g h less s e r i o u s t h a n o t h e r c o m p l i c a t i o n s , it results in an undesirable cosmetic effect. Thirty to 50% o f all c h i l d r e n t a k i n g i n s u l i n are affected to s o m e degree, girls more frequently than boys. With current fashion trends, the skin changes are unsightly and embarrassing. T h e fat a t r o p h y d e v e l o p s w i t h i n a few m o n t h s o f s t a r t i n g i n s u l i n t h e r a p y and can last for many years. The cause is unknown and until recently no truly effective treatment was available. However, in 1973 W e n t w o r t h a n d his associates 4 r e p o r t e d that purified i n s u l i n (called s i n g l e - p e a k i n s u l i n ) i n j e c t e d directly into the atrophic patches produced significant From the Department o f Paediatrics, The Hospital for Sick Children. *Reprintaddress: The Hospitalfor Sick Children, 555 University A re., Toronto,OntarioMSG 1X8, Canada.
741
2. Lees AW, Asgher B, Hashem MA, and Sinha BN: Jaundice after rifampicin, Br J Dis Chest 64:90, 1970. 3. Marche J, Hugues F C, Graisely B, and Marche C: L'h6patite provoqu6e par l'association de rifampicine et l'isoniazide, Ann Med Intern 10:1045, 1971. 4. Leibold JE: The ocular toxicity of ethambutol and its relation to dose, Ann NY Acad Sci 135:904, 1966. 5. Hugues FC, Marche C, and Marche J: Effects h6patobiliaries de l'association rifampicine-isoniazide, Th~rapie 24:899, 1969. 6. Smith J, Tyrrell WF, Gow A, Allen MB, and Lees AW: Hepatotoxicity in rifampicin-isoniazid treated patients related to their rate of isoniazid inactivation, Chest 61:587, 1972. 7. Hollins PJ, and Simmons AV: Jaundice associated with rifampicin, Tubercle 51:328, 1970. 8. Dieu MC: R61e de l'Isoniazide dans l'h6patotoxicit~ de l'association INH-Rifampicine dans la tuberculose de l'enfant, M6d Lyon 53:1, 1972.
i m p r o v e m e n t and reaccumulation of fat. This paper d o c u m e n t s our experience with single-peak insulin in a group of 46 children with diabetes mellitus. CLINICAL
MATERIAL
We studied 21 children 5 to 16 years of age, with known diabetes and significant fat atrophy, who were attending th~ Diabetic Clinic at The Hospital for Sick Children (Group 1). In all cases diabetes had been present for more than two years and fat atrophy for at least six months. The children were instructed to change to single peak insulin and to inject directly into or around the edge of one of the atrophic areas on their body.
Fig. 1. Area of insulin-induced fat atrophy in a 7-year-old boy.
1. Intrathecal administration of h u m a n leukocyte interferon (8 x 600,000 units) into the n e w b o r n infant did not lead to overt toxicity. Even with the crude interferon available for this study, the only adverse effect noticed was a moderate rise of body temperature. 2. Relatively high interferon titers were maintained in the CSF (800-8,000 units/ml) at 12-24 hours after intrathecal administration of 600,000 units of interferon. 3. Interferon did not freely cross the blood-brain barrier since interferon levels in the serum were approximately 40- to 80-fold lower than the corresponding CSF titers. 4. The intrathecal route may not be the optimal single route for delivering interferon to all parts of the central nervous system in which virus is actively multiplying, i n a s m u c h as virus was recovered from b r a i n tissue postmortem. We are indebted to Dr. K. Cantell for providing the human leukocyte interferon, to Drs. W. E. Stewart II, M. Casteels-Van Daele, E. Eggermont, and L. Corbeel for helpful suggestions, to Dr. W.T. Liu for electron microscopic examination of the virus samples, to Dr. B. Van Damme for performing the autopsy studies, to Francine Cornette and Gaby Lenaerts for technical assistance, and to Janine Putzeys for editorial help. REFERENCES 1. Nahmias AJ, Alford CA, and Korones SB: Infection of the newborn with Herpesvirus hominis, Adv Pediatr 17:185, 1970. 2. Partridge JW, and Millis RR: Systemic herpes simplex infection in a newborn treated with intravenous idoxuridine, Arch Dis Child 43:377, 1968. 3. Golden B, Bell WE, and McKee AP: Disseminated herpes simplex with encephalitis in a neonate, J A M A 209:1219, 1969. 4. Tuffii GA, and Nahmias AJ: Neonatal herpetic infection.
Hepatotoxicity of rifampicin and isoniazid in children M. Casteels-Van Daele, M.D.,*
Brief clinical and laboratory observations
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
739
Report of two premature infants treated with systemic use of idoxuridine, Am J Dis Child 118:909, 1969. Charnock EL, and Cramblett HG: 5-Iodo-2'-deoxyuridine in neonatal herpes virus hominis encephalitis, J PEDIATR 76:459, 1970. Strander H, Cantell K, CarlstrOm G, and Jakobsson PA: Clinical and laboratory investigations on man : Systemic administration of potent interferon to man, J Natl Cancer Inst 51:733, 1973. Nahmias AJ, Dowdle WR, Josey WE, Naib ZM, Painter LM, and Luce C: Newborn infection with herpes virus hominis types 1 and 2, J PEDIATR75:1194, 1969. Finter NB: Dye uptake methods of assessing viral cytopathogenicity and their application to interferon assays, J Gen Virol 5:419, 1969. Figueroa MA, and Rawls WE: Biologicalmarkers for differentiation of herpes strains of oral and genital origin, J Gen Virol 4:259, 1968. Bellanti JA, Catalano LW Jr, and Chambers RW: Herpes simplex encephalitis : Virologic and serologic study of a patient treated with an interferon inducer, J PED1ATR 78:136, 1971. Ho M, Nash C, Morgan CW, Armstrong JA, Carroll RG, and Postic B: Interferon administered in the cerebrospinal space and its effect on rabies in rabbits, Infect Immun 9:286, 1974. Cathala F, and Baron S: Interferon in rabbit brain, cerebrospinal fluid and serum following administration of polyinosinicrpolycytidylic acid, J Immunol 104:1355, 1970. Cesario TC, Mandell A, and Tilles JG: Inactivation of human interferon by body fluids, Proc Soc Exp Biol Med 144:1030, 1973. Fishman MA, Haymond MW, and Middelkamp JN: Failure of idoxuridine treatment in herpes simplex encephalitis, Am J Dis Child 122:250, 1971. Kern ER, Overall JC Jr, and Glasgow LA: Herpes virus hominis infection in newborn mice. I, An experimental model and therapy with iododeoxyuridine, J Infect Dis 128:290, 1973.
THERE HAVE BEEN REPORTS of hepatotoxicity related to therapy with rifampicin, especially in association with isoniazid, in adults. 1, 2 As far as we know, there have been no reports of serious and life-threatening side effects in children in conjunction with this therapy. This report is of a boy who developed hepatic coma while receiving antituberculous therapy.
L. Igodt-Ameye, M.D., L. Corbeel, M.D., and R. Eeekels, M.D., Leuven,Belgium From the Department of Pediatrics, University of Leuven. *Reprint address: Department of Pediatrics, St. Raphael Academisch Ziekenhuis, Universityof Leuven, B-3OOOLeuven, Belgium.
CASE REPORT Ph., a 13-year-old boy, was admitted to our department in a comatose state. Two weeks before admission pleurisy of tuberculous origin was diagnosed. The patient was treated with isoniazid 500 mg/day (12 mg/kg), ethambutol 800 mg (20 rag/ kg), and rifampicin 450 mg/day (11 mg/kg). On the seventh
740
Brief clinical and laboratory observations
The Journal of Pediatrics May 1975
Table I. Evolution of liver function tests Day 11 * (on admission) Bilirubin (mg/dl) SGOT (U/I) SGPT (U/l) Alkaline phosphotase (lUll) NH 4(/zg/ml) Prothrombin (%)
5.2 2,722 1,500 302 1.78 (10
Day 13 8 282 590 1.18 35
Day 15 9.1 6.2 155 294 232 0.67 45
Day 18 7.2 4.8 36 139 160 0.8
Day 23 4.27 2.45 23 75 130 0.65 100
Day 29 1.9 22.5 35
After 3 months 0.3 17 18 267
*Day 1 : start of antituberculoustherapy.
day after starting therapy, he became lethargic and confused; on Day 11, he was transferred to our department. Physical examination revealed a well-developed boy who was icteric and unconscious. Height was 150.5 cm; weight, 40 kg. The edge of the liver was barely palpable. The diagnosis of tuberculous pleurisy was confirmed. Electroencephalogram was compatible with encephalitis or severe metabolic disorder. The most important laboratory data are summarized in Table. I. Australian antigen and the lymphocyte transformation test with rifampicin were negative. A percutaneous needle biopsy of the liver was performed on the eighteenth day. Histopathologically the changes resembled a "hepatitis-like" lesion. The clinical diagnosis was hepatic coma, most probably due to the antituberculosis therapy. This medication was discontinued on the eleventh day of treatment. The patient received several exchange transfusions, intravenous fluids, and vitamines B and K. He regained consciousness on Day 13. Recovery was progressive and complete. On Day 24, therapy with isoniazid was resumed (10 mg/kg). After six months the boy was examined as an outpatient. The pleural effusion had disappeared, and evidence of hepatic dysfunction had subsided. DISCUSSION Our patient developed hepatic coma while receiving antituberculous treatment with rifampicin, isoniazid, and ethambutol. No evidence could be found to support a viral origin of the hepatitis. Several features suggest that the hepatitis was due to the antituberculous drugs: the first s y m p t o m s of lethargy and c o n f u s i o n were noted on the seventh day of treatment, which correlates q u i t e well w i t h t h e o b s e r v a t i o n s of M a r c h e 3 a n d Lesobre 1and their colleagues. Furthermore, clinical and biochemical remission in our patient promptly followed cessation of antituberculous therapy. In our patient, r i f a m p i c i n was a d m i n i s t e r e d with isoniazid and ethambutol, which makes the evaluation of side-effects difficult. Ethambutol is known to cause
ocular toxicity, which is dose related, 4 but it has not been implicated as a cause of liver disease. Isoniazid and r i f a m p i c i n are k n o w n to be hepatotoxic w h e n adm i n i s t e r e d separately, and especially w h e n used in combination. This was first reported by Lesobre and colleagues ~in 1969, and subsequently by Lees and associates 2 from Great Britain. Histologic changes were observed in the liver of rats after combined treatment with isoniazid and rifampicin, but not when the drugs were given separateiy. 5 It has been assumed that the handling of these two drugs t o g e t h e r m a y place some strain on liver capacity, particularly in subjects whose acetylator p h e n o t y p e indicates that they metabolize isoniazid slowly.6 The exact mechanism of liver damage from rifampicin is at present obscure. The increased lymphocyte transformation in the presence of rifampicin, observed by Hollins and Simmons, 7 could suggest allergy. In our case, however, the lymphocyte transformation test with rifampicin was negative: Dieu s has s t u d i e d the hepatotoxicity of c o m b i n e d rifampicin and isoniazid therapy in children in relation to dosage. W h e n the dose of rifampicin was kept constant at 10-15 mg/kg/day, and the dose of isoniazid varied from 20 to 8 mg/kg, the degree of hepatotoxicity was found to be related to excessive doses of isoniazid. Our patient, however, who received isoniazid in a dose of 12 mg/kg/day, and rifampicin at 11 mg/kg/day developed a nearly fatal complication. The lack of reports in the pediatric literature on the toxicity of rifampicin and the general assumption that the patients most at risk are elderly persons with liver disease make it necessary to alert pediatricians to the possible hepatic side effects of these antituberculous drugs, even in healthy children. W h e n prescribing a combination of rifampicin and isoniazid, one should bear in mind the potential hepatotoxicity of this combination and keep strictly within the "safer" dosage
Volume 86 Number 5
B r i e f clinical and laboratory observations
limits of rifampicin (10-15 mg/kg/day) and of isoniazid (8-10 mg/kg/day). Even at these doses the patient must be followed for evidence of hepatotoxicity. Nausea and anorexia are important alerting symptoms. Serum transa m i n a s e s and p r o t h r o m b i n values s h o u l d be d e t e r mined, especially during the first two weeks of treatment; abnormal values of these two determinations are an indication for a change in therapy. We thank Dr. L. Vanden Bulcke, Dr. J. Fevery, Professor V. Desmet and Professor H. Van den Berghe for their valuable help and advice. REFERENCES 1. Lesobre R, Ruffino J, Teyssier L, Achard F, and Brefort G: Les ict~res au cours du traitement par la Rifampicine, Rev Tuberc Pneumol 33:393, 1969.
Single-peak insulin in the treatment of insulin-induced fat atrophy L. Ferland, M.D., and R. M. Ehrlich, M.D.,
F.R.C.P.(C),* Toronto, Ont., Canada T HE DISAPPEARANCE of subcutaneous adipose tissue (fat atrophy or lipoatrophy) is the most c o m m o n local complication of insulin therapy. It was first described by Depisch I in 1926 and further reports quickly followed. 2, 3 A l t h o u g h less s e r i o u s t h a n o t h e r c o m p l i c a t i o n s , it results in an undesirable cosmetic effect. Thirty to 50% o f all c h i l d r e n t a k i n g i n s u l i n are affected to s o m e degree, girls more frequently than boys. With current fashion trends, the skin changes are unsightly and embarrassing. T h e fat a t r o p h y d e v e l o p s w i t h i n a few m o n t h s o f s t a r t i n g i n s u l i n t h e r a p y and can last for many years. The cause is unknown and until recently no truly effective treatment was available. However, in 1973 W e n t w o r t h a n d his associates 4 r e p o r t e d that purified i n s u l i n (called s i n g l e - p e a k i n s u l i n ) i n j e c t e d directly into the atrophic patches produced significant From the Department o f Paediatrics, The Hospital for Sick Children. *Reprintaddress: The Hospitalfor Sick Children, 555 University A re., Toronto,OntarioMSG 1X8, Canada.
741
2. Lees AW, Asgher B, Hashem MA, and Sinha BN: Jaundice after rifampicin, Br J Dis Chest 64:90, 1970. 3. Marche J, Hugues F C, Graisely B, and Marche C: L'h6patite provoqu6e par l'association de rifampicine et l'isoniazide, Ann Med Intern 10:1045, 1971. 4. Leibold JE: The ocular toxicity of ethambutol and its relation to dose, Ann NY Acad Sci 135:904, 1966. 5. Hugues FC, Marche C, and Marche J: Effects h6patobiliaries de l'association rifampicine-isoniazide, Th~rapie 24:899, 1969. 6. Smith J, Tyrrell WF, Gow A, Allen MB, and Lees AW: Hepatotoxicity in rifampicin-isoniazid treated patients related to their rate of isoniazid inactivation, Chest 61:587, 1972. 7. Hollins PJ, and Simmons AV: Jaundice associated with rifampicin, Tubercle 51:328, 1970. 8. Dieu MC: R61e de l'Isoniazide dans l'h6patotoxicit~ de l'association INH-Rifampicine dans la tuberculose de l'enfant, M6d Lyon 53:1, 1972.
i m p r o v e m e n t and reaccumulation of fat. This paper d o c u m e n t s our experience with single-peak insulin in a group of 46 children with diabetes mellitus. CLINICAL
MATERIAL
We studied 21 children 5 to 16 years of age, with known diabetes and significant fat atrophy, who were attending th~ Diabetic Clinic at The Hospital for Sick Children (Group 1). In all cases diabetes had been present for more than two years and fat atrophy for at least six months. The children were instructed to change to single peak insulin and to inject directly into or around the edge of one of the atrophic areas on their body.
Fig. 1. Area of insulin-induced fat atrophy in a 7-year-old boy.