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Prolonged cholestasis due to trimethoprim sulfamethoxazole
GASTROENTEROLOGY
1992;102:2146-2150
Prolonged Cholestasis Due to Trimethoprim Sulfamethoxazole
KRIS V. KOWDLEY,
EMMET
B. KEEFFE,
and
KARIM
A. FAWAZ
Division of Gastroenterology, New England Medical Center, Boston, Massachusetts; and Oregon Health Sciences University, Portland, Oregon
Drug-induced liver injury due to trimethoprim sulfamethoxazole is rare and classified as an unpredictable or idiosyncratic type of hepatotoxic reaction. Early reports suggested that the pattern of liver injury in the majority of cases is mixed hepatocellular-cholestatic. The current report describes two cases of severe, prolonged cholestasis after treatment with trimethoprim sulfamethoxazole; intractable pruritus and abnormal liver test results lasted for 1-2 years after discontinuation of the drug. Liver biopsy specimens showed a cholestatic pattern of liver injury and only minimal hepatocellular necrosis or inflammation. Recent case reports suggest that cholestasis alone may occur after the use of trimethoprim sulfamethoxazole; these two additional cases show that cholestasis may be quite prolonged. rimethoprim sulfamethoxazole is a commonly used antibiotic for a variety of infections. Hepatic injury caused by this medication is rare and classified as an idiosyncratic reaction.le4 The pattern of trimethoprim sulfamethoxazole hepatotoxicity is variable but is usually characterized by cholestasis or a mixed hepatocellular-cholestatic reaction.5-7 Recent case reports document that trimethoprim sulfamethoxazole-induced intrahepatic cholestasis is associated with minimal hepatocellular inflammation or necrosis, usually self-limited, and resolves within 6 months.‘-l4 Recently Munoz et al. described a case of intrahepatic cholestasis caused by trimethoprim sulfamethoxazole associated with hepatic phospholipidosis; severe pruritus lasted 8 months but was responsive to plasmapheresis.* We describe two cases of severe, prolonged cholestasis lasting 1-2 years after treatment with trimethoprim sulfamethoxazole. In addition, one of the cases shows that severe pruritus resistant to cholestyramine, phenobarbital, corticosteroids, and plasmapheresis may be a complication of cholestasis associated with the use of trimethoprim sulfamethoxazole.
T
Case Reports Case 1 A 48-year-old woman was treated for dysuria with a lo-day course of trimethoprim sulfamethoxazole beginning on August 30, 1988. Toward the end of therapy, the patient noted light stools and dark urine. On September 30, 1988, her serum total bilirubin level was 82 pmol/L (4.8 mg/dL); direct bilirubin, 62 pmol/L (3.6 mg/dL); alkaline phosphatase, 229 U/L (normal, 41-130); y-glutamyltransferase (GGT), 372 U/L (normal, 7-59); aspartate aminotransferase (AST), 675 U/L (normal, 6-38); and alanine aminotransferase (ALT), 422 U/L (normal, 2-54). Serum total protein and albumin levels were normal. Hepatitis A and B serology was negative. White blood cell count was normal with no eosinophilia. Abdominal ultrasound examination showed cholelithiasis but no abnormalities of the liver or bile ducts. Six days later, serum total bilirubin level was 152 pmol/L (8.9 mg/dL); direct bilirubin, 150 umol/L (8.8 mg/dL); alkaline phosphatase, 399 U/L; ALT, 405 U/L; AST, 126 U/L; and GGT, 228 U/L. Repeat abdominal ultrasonographic results were unchanged. Over the next several weeks, serum total bilirubin level increased to a peak of 595 pmol/L (34.8 mg/dL) while alkaline phosphatase levels ranged from 150 to 170 U/L and AST from 60 to 100 U/L. On October 14, 1988, a percutaneous liver biopsy was performed and the specimen showed an intact architecture and cholestasis with bile staining of hepatocytes. There was mild lobular focal necrosis and mild portal inflammation. Bile ducts were normal in size and number. On referral to the Oregon Health Sciences University, the patient reported malaise, fatigue, anorexia, and a 30-lb weight loss. She denied rash, fever or chills, or previous history of liver disease. She had not drank alcohol 6 months before the onset of her illness. Her only other medical problem was mild hypertension, treated with atenolol for more than 5 years. Physical examination showed deep jaundice and scleral icterus. No spider angiomas or palmar erythema were noted. Additional laboratory data showed a weakly positive antinuclear antibody at a titer of 1:40, negative antimitochondrial antibody, and negative hepatitis C antibody. Pruritus was treated successfully with cho0 1992 by the American Gastroenterological 0016-5065/92/$3.00
Association
June 1992
CHOLESTASIS DUE TO TRIMETHOPRIM
lestyramine 4 g three times a day. In December 1988, the serum total bilirubin level began to progressively decrease and reached normal levels in August 1989. Serial liver enzyme levels also gradually decreased, but mild abnormalities in alkaline phosphatase and GGT levels persisted as of July 1990. However, the patient has felt well, been free of pruritus, and regained 20 lb. Case 2 A 43-year-old-woman was treated with trimethoprim sulfamethoxazole for sinusitis in April 1990. One week after beginning treatment, she noted a confluent, macular rash over her trunk and extremities and stopped the medication. Two weeks later, her rash was improved, but light stools, dark urine, and jaundice appeared. Hepatitis A and B serology was negative. Abdominal ultrasound examination showed no abnormalities, and abdominal computed tomographic scan revealed a homogeneous liver and no dilated ducts. She was treated with cholestyramine without relief. Six weeks after the onset of jaundice, the patient was referred to the New England Medical Center. She reported intense pruritus, 25-lb weight loss, malaise, and fatigue. She denied neurological symptoms, arthritis, myalgias, headache, or diarrhea. On physical examination, the patient was thin and deeply jaundiced. The skin had extensive excoriations. Liver span was 8 cm, and there was no splenomegaly. Laboratory evaluation showed a white blood cell count 6100/mm3, with 2% eosinophils, and a hematocrit of 34%. Serum alkaline phosphatase level was 306 U/L (normal, O-117); ALT 63 U/L (normal, O-25); AST, 101 U/L (normal, O-35); and serum total bilirubin, 463 umol/L (27.1 mg/dL). Serum albumin level and prothrombin time were normal. Repeat abdominal ultrasound examination showed no abnormalities. A trial of 30 mg/day oral prednisone, 30 mg four times a day phenobarbital, and cimetidine failed to relieve either pruritus or biochemical cholestasis. On May 31, 1990, serum alkaline phosphatase level was 694 U/L; total bilirubin, 629 umol/L (36.8 mg/dL); ALT, 228 U/L; and AST, 124 U/L. Endoscopic retrograde cholangiopancreatography (ERCP) showed a normal biliary system. A liver biopsy specimen showed an intact lobular architecture and bile staining of hepatocytes; bile ducts were normal in appearance and number, and there was no significant portal or parenchyma1 inflammation. The patient had continued severe pruritus unresponsive to cholestyramine and hydroxyzine. A course of ultraviolet B therapy resulted in only minimal improvement of pruritus. On June 21,1990, she was readmitted to hospital with intractable pruritus and fatigue. The serum total bilirubin level was 496 pmol/L (29 mg/ dL); alkaline phosphatase 930 U/L; AST, 163 U/L; and ALT, 228 U/L. An antimitochondrial antibody test showed negative results. Ultraviolet B treatment was resumed, and ursodeoxycholic acid was administered orally. Plasmapheresis was begun, and six cycles were performed. There was no subjective improvement in pruritus, but excoriations diminished. Oral naloxone therapy also did not relieve the pruritus. On follow-up in August 1990, pruritus was slightly improved; serum total bilirubin was 121 umol/L (7.1 mg/dL); alkaline phosphatase, 678 U/L;
SULFAMETHOXAZOLE
2149
ALT, 169 U/L; and AST, 184 U/L. However, on October 11, 1990, pruritus was worse, and serum total bilirubin level increased to 251 umol/L (14.7 mg/dL). Alkaline phosphatase level was 415 U/L; ALT, 137 U/L; and AST, 138 U/L. Repeat liver biopsy on October 16, 1990 again revealed cholestasis and a moderate mixed mononuclear and polymorphonuclear inflammatory infiltrate in the portal areas with depletion of normal-looking bile ducts and duplication of atypical ones. Repeat ERCP again showed no abnormalities. Administration of prednisone was resumed at a dose of 60 mg/day; rifampicin at a dose of 150 mg orally twice a day was also added. Pruritus did not improve, and rifampicin was discontinued after 6 weeks of therapy. Over the next several months, liver function test results gradually improved. In late March 1991, pruritus had finally resolved; serum total bilirubin level was normal, although mild abnormalities in the other liver function test results, particularly the alkaline phosphatase, persisted.
Discussion Hepatic toxicity due to sulfonamides has been recognized since their introduction.5 Zimmerman classified sulfonamide hepatotoxicity as mixed hepatocellular-cholestatic.15 The associated findings of rash, fever, peripheral blood eosinophilia, and hepatic eosinophils and granulomas point to a hypersensitivity phenomenon5” Rarely, chronic liver disease occurs after treatment with sulfonamides.15 Although there have been occasional case reports of hepatotoxicity due to trimethoprim sulfamethoxazo1e,8-‘4 this medication appears to be associated with a very low incidence of liver damage.’ The pattern of liver abnormality that occurs with trimethoprim sulfamethoxazole has been described as cholestatic or mixed type with both cholestasis and parenchymal injury. ‘3’ Review of the English language literature identified at least 10 other cases of cholestasis associated with trimethoprim sulfamethoxazole treatment.5’8-‘4”6 The onset of symptoms can occur from a few days to a month after beginning therapy. Liver biopsy specimens characteristically show centrilobular cholestasis with minimal inflammation.’ The clinical course is one of resolution within 6 months.8-‘4 There are no reports of cholestasis due to trimethoprim sulfamethoxazole lasting as long as seen in our two patients, who had pruritus and abnormal liver tests lasting up to 1-2 years after discontinuation of the medication. The etiologic role of trimethoprim sulfamethoxazole was confirmed by deliberate or inadvertent rechallenge in four cases.g~‘2~13 It is generally believed that hepatic toxicity is caused by sulfamethoxazole and not trimethoprim. However, an isolated case report challenges this theory; Tanner described a patient in whom cholestasis developed with trimetho-
2150
KOWDLEY ET AL.
prim alone after an earlier episode of jaundice associated with trimethoprim sulfamethoxazo1e.l’ Munoz et al. reported a case of intrahepatic cholestasis caused by trimethoprim sulfamethoxazole associated with prominent lysosomal inclusions suggestive of phospholipidosis by electron microscopy. They speculate that inhibition of lysosomal phospholipase A, or generation of lipid-soluble metabolites with the formation of drug-lipid complexes play a role in trimethoprim sulfamethoxazole toxicity.* This theory is supported by their observation that the metabolite of sulfamethoxazole, IV’-acetylsulfametoxazole is very highly lipid soluble. Genetically susceptible individuals who are “fast-acetylators” may form this metabolite at a higher rate leading to phospholipidosis. The cases described in this report had the longest recorded duration of cholestasis associated with trimethoprim sulfamethoxazole, i.e., l-2 years after beginning treatment. Case 2 was characterized by cholestasis with pruritus refractory to plasmapheresis or any other form of therapy.‘* The prognosis of cholestatic jaundice caused by trimethoprim sulfamethoxazole is good. No fatalities have been reported in patients with a purely cholestatic presentation; only one death has been documented in a patient with acute hepatocellular form of hepatotoxicity.*’ We conclude that intrahepatic cholestasis after trimethoprim sulfamethoxazole may be severe, with pruritus resistant to all forms of therapy, and may also be prolonged, lasting >l year. References I. Wormer GP, Keusch GT. Trimethoprim-sulfamethoxazole
in the United States. Ann Intern Med 1979;91:420-429. 2. Beard K, Belie L, Aselton P, Perera D, Jick H. Outpatient drug induced parenchymal liver disease requiring hospitalization. J Clin Pharmacol 1986;26:633-637. 3. Frisch JM. Clinical experience with adverse reactions to trimethoprim sulfamethoxazole. J Infect Dis 1973;128(Suppl): S607-S611.
GASTROENTEROLOGYVol.102,No.6
4. Dossing M, Andreasen PB. Drug-induced liver disease in Denmark: analysis of 572 cases of hepatotoxicity reported to the Danish board of adverse reactions to drugs. Stand J Gastroenterol 1982;17:205-211. 5. Dujovne CA, Chan CH, Zimmerman HJ. Sulfonamide hepatic injury. N Eng J Med 1967;277:785-788. 6. Zimmerman HJ. Hepatotoxicity from drugs in common use. Semin Liver Dis 1990;10:322-338. 7. Zimmerman HJ. In: Schiff L, Schiff ER, eds. Diseases of the liver. 6th ed. Philadelphia: Lippincott, 1987:64X 8. Munoz SJ, Martinez-Hernandez A, Maddrey WC. Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim sulfamethoxazole. Hepatology 1990;12:342347. 9. Coto H, McGowan WR, Pierce EH, Thomas E. Intrahepatic cholestasis due to trimethoprim sulfamethoxazole. South Med J 1981;74:897-898. 10. Nair SS, Kaplan JM, Levine LH, Geraci K. Trimethoprim-sulfamethoxazole-induced intrahepatic cholestasis. Ann Intern Med 1980;92:511-512. intra11. Ghishan FK. Trimethoprim-sulfamethoxazole-induced hepatic cholestasis. Clin Pediatr 1983;22:212-214. UP, Mishkin S. Sulfamethoxazole-induced he12. Steinbrecher patic injury. Dig Dis Sci 1981;26:756-759. 13. Ogilvie AL, Toghill PJ. Cholestatic jaundice due to co-trimoxazole. Postgrad Med J 1980;56:202-204. 14. Abi-Mansur P, Ardiaca MC, Allam C, Shamma’a M. Trimethoprim-sulfamethoxazole-induced cholestasis. Am J Gastroenterol 1981;76:356-359. 15. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century-crofts, 1978. 16. Thies PW, Dull WL. Trimethoprim-sulfamethoxazole-induced cholestatic hepatitis. Arch Intern Med 1984;144:16911692. 17. Tanner AR. Hepatic cholestasis induced by trimethoprim. Br Med J 1986;293:1072-1073. 18. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology 1990;11:884-887. 19. Ransohoff DF, Jacobs G. Terminal hepatic failure following a small dose of sulfamethoxazole-trimethoprim. Gastroenterology 1981;80:816-819.
Received July 9, 1991. Accepted November 13,1991. Address requests for reprints to: Karim A. Fawaz, M.D., Box 002, Division of Gastroenterology, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111.
1992;102:2146-2150
Prolonged Cholestasis Due to Trimethoprim Sulfamethoxazole
KRIS V. KOWDLEY,
EMMET
B. KEEFFE,
and
KARIM
A. FAWAZ
Division of Gastroenterology, New England Medical Center, Boston, Massachusetts; and Oregon Health Sciences University, Portland, Oregon
Drug-induced liver injury due to trimethoprim sulfamethoxazole is rare and classified as an unpredictable or idiosyncratic type of hepatotoxic reaction. Early reports suggested that the pattern of liver injury in the majority of cases is mixed hepatocellular-cholestatic. The current report describes two cases of severe, prolonged cholestasis after treatment with trimethoprim sulfamethoxazole; intractable pruritus and abnormal liver test results lasted for 1-2 years after discontinuation of the drug. Liver biopsy specimens showed a cholestatic pattern of liver injury and only minimal hepatocellular necrosis or inflammation. Recent case reports suggest that cholestasis alone may occur after the use of trimethoprim sulfamethoxazole; these two additional cases show that cholestasis may be quite prolonged. rimethoprim sulfamethoxazole is a commonly used antibiotic for a variety of infections. Hepatic injury caused by this medication is rare and classified as an idiosyncratic reaction.le4 The pattern of trimethoprim sulfamethoxazole hepatotoxicity is variable but is usually characterized by cholestasis or a mixed hepatocellular-cholestatic reaction.5-7 Recent case reports document that trimethoprim sulfamethoxazole-induced intrahepatic cholestasis is associated with minimal hepatocellular inflammation or necrosis, usually self-limited, and resolves within 6 months.‘-l4 Recently Munoz et al. described a case of intrahepatic cholestasis caused by trimethoprim sulfamethoxazole associated with hepatic phospholipidosis; severe pruritus lasted 8 months but was responsive to plasmapheresis.* We describe two cases of severe, prolonged cholestasis lasting 1-2 years after treatment with trimethoprim sulfamethoxazole. In addition, one of the cases shows that severe pruritus resistant to cholestyramine, phenobarbital, corticosteroids, and plasmapheresis may be a complication of cholestasis associated with the use of trimethoprim sulfamethoxazole.
T
Case Reports Case 1 A 48-year-old woman was treated for dysuria with a lo-day course of trimethoprim sulfamethoxazole beginning on August 30, 1988. Toward the end of therapy, the patient noted light stools and dark urine. On September 30, 1988, her serum total bilirubin level was 82 pmol/L (4.8 mg/dL); direct bilirubin, 62 pmol/L (3.6 mg/dL); alkaline phosphatase, 229 U/L (normal, 41-130); y-glutamyltransferase (GGT), 372 U/L (normal, 7-59); aspartate aminotransferase (AST), 675 U/L (normal, 6-38); and alanine aminotransferase (ALT), 422 U/L (normal, 2-54). Serum total protein and albumin levels were normal. Hepatitis A and B serology was negative. White blood cell count was normal with no eosinophilia. Abdominal ultrasound examination showed cholelithiasis but no abnormalities of the liver or bile ducts. Six days later, serum total bilirubin level was 152 pmol/L (8.9 mg/dL); direct bilirubin, 150 umol/L (8.8 mg/dL); alkaline phosphatase, 399 U/L; ALT, 405 U/L; AST, 126 U/L; and GGT, 228 U/L. Repeat abdominal ultrasonographic results were unchanged. Over the next several weeks, serum total bilirubin level increased to a peak of 595 pmol/L (34.8 mg/dL) while alkaline phosphatase levels ranged from 150 to 170 U/L and AST from 60 to 100 U/L. On October 14, 1988, a percutaneous liver biopsy was performed and the specimen showed an intact architecture and cholestasis with bile staining of hepatocytes. There was mild lobular focal necrosis and mild portal inflammation. Bile ducts were normal in size and number. On referral to the Oregon Health Sciences University, the patient reported malaise, fatigue, anorexia, and a 30-lb weight loss. She denied rash, fever or chills, or previous history of liver disease. She had not drank alcohol 6 months before the onset of her illness. Her only other medical problem was mild hypertension, treated with atenolol for more than 5 years. Physical examination showed deep jaundice and scleral icterus. No spider angiomas or palmar erythema were noted. Additional laboratory data showed a weakly positive antinuclear antibody at a titer of 1:40, negative antimitochondrial antibody, and negative hepatitis C antibody. Pruritus was treated successfully with cho0 1992 by the American Gastroenterological 0016-5065/92/$3.00
Association
June 1992
CHOLESTASIS DUE TO TRIMETHOPRIM
lestyramine 4 g three times a day. In December 1988, the serum total bilirubin level began to progressively decrease and reached normal levels in August 1989. Serial liver enzyme levels also gradually decreased, but mild abnormalities in alkaline phosphatase and GGT levels persisted as of July 1990. However, the patient has felt well, been free of pruritus, and regained 20 lb. Case 2 A 43-year-old-woman was treated with trimethoprim sulfamethoxazole for sinusitis in April 1990. One week after beginning treatment, she noted a confluent, macular rash over her trunk and extremities and stopped the medication. Two weeks later, her rash was improved, but light stools, dark urine, and jaundice appeared. Hepatitis A and B serology was negative. Abdominal ultrasound examination showed no abnormalities, and abdominal computed tomographic scan revealed a homogeneous liver and no dilated ducts. She was treated with cholestyramine without relief. Six weeks after the onset of jaundice, the patient was referred to the New England Medical Center. She reported intense pruritus, 25-lb weight loss, malaise, and fatigue. She denied neurological symptoms, arthritis, myalgias, headache, or diarrhea. On physical examination, the patient was thin and deeply jaundiced. The skin had extensive excoriations. Liver span was 8 cm, and there was no splenomegaly. Laboratory evaluation showed a white blood cell count 6100/mm3, with 2% eosinophils, and a hematocrit of 34%. Serum alkaline phosphatase level was 306 U/L (normal, O-117); ALT 63 U/L (normal, O-25); AST, 101 U/L (normal, O-35); and serum total bilirubin, 463 umol/L (27.1 mg/dL). Serum albumin level and prothrombin time were normal. Repeat abdominal ultrasound examination showed no abnormalities. A trial of 30 mg/day oral prednisone, 30 mg four times a day phenobarbital, and cimetidine failed to relieve either pruritus or biochemical cholestasis. On May 31, 1990, serum alkaline phosphatase level was 694 U/L; total bilirubin, 629 umol/L (36.8 mg/dL); ALT, 228 U/L; and AST, 124 U/L. Endoscopic retrograde cholangiopancreatography (ERCP) showed a normal biliary system. A liver biopsy specimen showed an intact lobular architecture and bile staining of hepatocytes; bile ducts were normal in appearance and number, and there was no significant portal or parenchyma1 inflammation. The patient had continued severe pruritus unresponsive to cholestyramine and hydroxyzine. A course of ultraviolet B therapy resulted in only minimal improvement of pruritus. On June 21,1990, she was readmitted to hospital with intractable pruritus and fatigue. The serum total bilirubin level was 496 pmol/L (29 mg/ dL); alkaline phosphatase 930 U/L; AST, 163 U/L; and ALT, 228 U/L. An antimitochondrial antibody test showed negative results. Ultraviolet B treatment was resumed, and ursodeoxycholic acid was administered orally. Plasmapheresis was begun, and six cycles were performed. There was no subjective improvement in pruritus, but excoriations diminished. Oral naloxone therapy also did not relieve the pruritus. On follow-up in August 1990, pruritus was slightly improved; serum total bilirubin was 121 umol/L (7.1 mg/dL); alkaline phosphatase, 678 U/L;
SULFAMETHOXAZOLE
2149
ALT, 169 U/L; and AST, 184 U/L. However, on October 11, 1990, pruritus was worse, and serum total bilirubin level increased to 251 umol/L (14.7 mg/dL). Alkaline phosphatase level was 415 U/L; ALT, 137 U/L; and AST, 138 U/L. Repeat liver biopsy on October 16, 1990 again revealed cholestasis and a moderate mixed mononuclear and polymorphonuclear inflammatory infiltrate in the portal areas with depletion of normal-looking bile ducts and duplication of atypical ones. Repeat ERCP again showed no abnormalities. Administration of prednisone was resumed at a dose of 60 mg/day; rifampicin at a dose of 150 mg orally twice a day was also added. Pruritus did not improve, and rifampicin was discontinued after 6 weeks of therapy. Over the next several months, liver function test results gradually improved. In late March 1991, pruritus had finally resolved; serum total bilirubin level was normal, although mild abnormalities in the other liver function test results, particularly the alkaline phosphatase, persisted.
Discussion Hepatic toxicity due to sulfonamides has been recognized since their introduction.5 Zimmerman classified sulfonamide hepatotoxicity as mixed hepatocellular-cholestatic.15 The associated findings of rash, fever, peripheral blood eosinophilia, and hepatic eosinophils and granulomas point to a hypersensitivity phenomenon5” Rarely, chronic liver disease occurs after treatment with sulfonamides.15 Although there have been occasional case reports of hepatotoxicity due to trimethoprim sulfamethoxazo1e,8-‘4 this medication appears to be associated with a very low incidence of liver damage.’ The pattern of liver abnormality that occurs with trimethoprim sulfamethoxazole has been described as cholestatic or mixed type with both cholestasis and parenchymal injury. ‘3’ Review of the English language literature identified at least 10 other cases of cholestasis associated with trimethoprim sulfamethoxazole treatment.5’8-‘4”6 The onset of symptoms can occur from a few days to a month after beginning therapy. Liver biopsy specimens characteristically show centrilobular cholestasis with minimal inflammation.’ The clinical course is one of resolution within 6 months.8-‘4 There are no reports of cholestasis due to trimethoprim sulfamethoxazole lasting as long as seen in our two patients, who had pruritus and abnormal liver tests lasting up to 1-2 years after discontinuation of the medication. The etiologic role of trimethoprim sulfamethoxazole was confirmed by deliberate or inadvertent rechallenge in four cases.g~‘2~13 It is generally believed that hepatic toxicity is caused by sulfamethoxazole and not trimethoprim. However, an isolated case report challenges this theory; Tanner described a patient in whom cholestasis developed with trimetho-
2150
KOWDLEY ET AL.
prim alone after an earlier episode of jaundice associated with trimethoprim sulfamethoxazo1e.l’ Munoz et al. reported a case of intrahepatic cholestasis caused by trimethoprim sulfamethoxazole associated with prominent lysosomal inclusions suggestive of phospholipidosis by electron microscopy. They speculate that inhibition of lysosomal phospholipase A, or generation of lipid-soluble metabolites with the formation of drug-lipid complexes play a role in trimethoprim sulfamethoxazole toxicity.* This theory is supported by their observation that the metabolite of sulfamethoxazole, IV’-acetylsulfametoxazole is very highly lipid soluble. Genetically susceptible individuals who are “fast-acetylators” may form this metabolite at a higher rate leading to phospholipidosis. The cases described in this report had the longest recorded duration of cholestasis associated with trimethoprim sulfamethoxazole, i.e., l-2 years after beginning treatment. Case 2 was characterized by cholestasis with pruritus refractory to plasmapheresis or any other form of therapy.‘* The prognosis of cholestatic jaundice caused by trimethoprim sulfamethoxazole is good. No fatalities have been reported in patients with a purely cholestatic presentation; only one death has been documented in a patient with acute hepatocellular form of hepatotoxicity.*’ We conclude that intrahepatic cholestasis after trimethoprim sulfamethoxazole may be severe, with pruritus resistant to all forms of therapy, and may also be prolonged, lasting >l year. References I. Wormer GP, Keusch GT. Trimethoprim-sulfamethoxazole
in the United States. Ann Intern Med 1979;91:420-429. 2. Beard K, Belie L, Aselton P, Perera D, Jick H. Outpatient drug induced parenchymal liver disease requiring hospitalization. J Clin Pharmacol 1986;26:633-637. 3. Frisch JM. Clinical experience with adverse reactions to trimethoprim sulfamethoxazole. J Infect Dis 1973;128(Suppl): S607-S611.
GASTROENTEROLOGYVol.102,No.6
4. Dossing M, Andreasen PB. Drug-induced liver disease in Denmark: analysis of 572 cases of hepatotoxicity reported to the Danish board of adverse reactions to drugs. Stand J Gastroenterol 1982;17:205-211. 5. Dujovne CA, Chan CH, Zimmerman HJ. Sulfonamide hepatic injury. N Eng J Med 1967;277:785-788. 6. Zimmerman HJ. Hepatotoxicity from drugs in common use. Semin Liver Dis 1990;10:322-338. 7. Zimmerman HJ. In: Schiff L, Schiff ER, eds. Diseases of the liver. 6th ed. Philadelphia: Lippincott, 1987:64X 8. Munoz SJ, Martinez-Hernandez A, Maddrey WC. Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim sulfamethoxazole. Hepatology 1990;12:342347. 9. Coto H, McGowan WR, Pierce EH, Thomas E. Intrahepatic cholestasis due to trimethoprim sulfamethoxazole. South Med J 1981;74:897-898. 10. Nair SS, Kaplan JM, Levine LH, Geraci K. Trimethoprim-sulfamethoxazole-induced intrahepatic cholestasis. Ann Intern Med 1980;92:511-512. intra11. Ghishan FK. Trimethoprim-sulfamethoxazole-induced hepatic cholestasis. Clin Pediatr 1983;22:212-214. UP, Mishkin S. Sulfamethoxazole-induced he12. Steinbrecher patic injury. Dig Dis Sci 1981;26:756-759. 13. Ogilvie AL, Toghill PJ. Cholestatic jaundice due to co-trimoxazole. Postgrad Med J 1980;56:202-204. 14. Abi-Mansur P, Ardiaca MC, Allam C, Shamma’a M. Trimethoprim-sulfamethoxazole-induced cholestasis. Am J Gastroenterol 1981;76:356-359. 15. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century-crofts, 1978. 16. Thies PW, Dull WL. Trimethoprim-sulfamethoxazole-induced cholestatic hepatitis. Arch Intern Med 1984;144:16911692. 17. Tanner AR. Hepatic cholestasis induced by trimethoprim. Br Med J 1986;293:1072-1073. 18. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology 1990;11:884-887. 19. Ransohoff DF, Jacobs G. Terminal hepatic failure following a small dose of sulfamethoxazole-trimethoprim. Gastroenterology 1981;80:816-819.
Received July 9, 1991. Accepted November 13,1991. Address requests for reprints to: Karim A. Fawaz, M.D., Box 002, Division of Gastroenterology, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111.