- Email: [email protected]
Acute hepatitis induced by omeprazole
550
AMERICAN JOURNAL OF EMERGENCY MEDICINE [] Volume 16, Number 5 [] September 1998
nally comatose when found by his parent, he was extremely combative on arrival to our department. The patient was able to localize painful stimuli but was otherwise noncommunicative.The negative toxicology screen and the absence of physical findings suggestive of other toxidromes make the presence of other coingestants unlikely. Previous descriptions of metabolic acidosis in ibuprofen toxicity describe normal or minimally elevated lactic acid levels. The acidosis has been attributed to a direct effect of ibuprofen and its metabolites on serum pH in combination with lactic acidosis. 2,11,13 The etiology of the lactic acidosis is most likely hypoperfusion as mild to moderate hypotension is not unusual in ibuprofen intoxication. Our patient had an anion gap of 21 and a mild metabolic acidosis that can be explained by the lactic acidosis and the ibuprofen metabolites present in the serum. The acidosis persisted more than 12 hours despite appropriate intravenous hydration and rapid correction of hypotension prior to transfer to the intensive care unit. Failure of rapid correction of the acidosis with improved perfusion suggests that ibuprofen and its metabolites may have contributed to the acidosis. Another unusual aspect of this case was that the patient was hypothermic on arrival. Mild hyperthermia has been found previously in ibuprofen overdose, but hypothermia has been noted in only 2 cases, and was attributed to accompanying CNS depression. 2,9 However, our patient was extremely agitated and struggling against physical restraints on arrival. Exposure would be an unlikely etiology of hypothermia in this patient because he was found indoors and his depressed mental status was acute in onset (less than 1 hour). We are unable to explain this patient's hypothermia based on the known pharmacological properties of ibuprofen. The ibuprofen level of 160 gg/mL 7 hours postingestion is clearly above the therapeutic level (therapeutic range 10 to 50 ~g/mL; toxic range greater than 100 ~lg/mL).1,8 In addition to his altered mental status our patient also exhibited other signs of toxicity including metabolic acidosis and minimally elevated liver enzymes. Although the serum level has little bearing on clinical management of ibuprofen toxicity, this patient's elevated level is an indication of a significant ingestion. This case demonstrates that ibuprofen intoxication alone can cause agitation and combative behavior as well as hypothermia in addition to the previously reported manifestations of toxicity. ALBERTRITTER,MD BARNETESKIN,MD
Department of Emergency Medicine Emergency Medicine Residency Program Morristown Memorial Hospital Morristown, NJ
References 1. Hall AH, Smolinske SC, Conrad FL: Ibuprofen overdose: 126 cases. Ann Emerg Med 1986; 15:1308-1313 2. Le HT, Bosse GM, Tsai Y: Ibuprofen overdose complicated by renal failure, adult respiratory distress syndrome, and metabolic acidosis. CIin Toxicol 1994;32:315-320 3. Perry SJ, Streete PJ, Volans GN: Ibuprofen overdose: The first two years of over-the-counter sales. Hum Toxicol 1987;6:173-178 4. McEIwee NE, Veltri JC, Bradford DC, et al: A prospective, population-based study of acute ibuprofen overdose: Complications are rare and routine serum levels not warranted. Ann Emerg Med 1990; 19:657-662 5. Court H, Streete P, Volans GN: Acute poisoning with ibuprofen. Hum Toxicol 1983;2:381-384 6. Mills RF, Adams SS, Cliffe EE, et al: The metabolism of ibuprofen. Xenobiotica 1973;3:589-598 7. Insel PA: Analgesic-antipyretics and antiinflammatory agents; drugs employed in the treatment of rheumatoid arthritis and gout. In
Gilman AG, Rail TW, Nies AS, et al (eds): The Pharmacological Basis of Therapeutics (ed 8). New York, NY, McGraw-Hill, 1990, pp 665-666 8. Hall AH, Smolinske SC, Stover B, et al: Ibuprofen overdose in adults. Clin Toxico11992;30:23-37 9. Chelluri L, Jastremski MS: Coma caused by ibuprofen overdose. Crit Care Med 1986; 14:1078-1079 10. Jenkinson ML, Fitzpatrick R, Streete PJ, et al: The relationship between plasma ibuprofen concentrations and toxicity in acute ibuprofen overdose. Hum Toxicol 1988;7:319-324 11. Lee CY, Finkler A: Acute intoxication due to ibuprofen overdose. Arch Pathol Lab Med 1988;110:747-749 12. Hunt DP, Leigh RJ: Overdose with ibuprofen causing unconsciousness and hypotension. BMJ 1980;281:1458-1459 13. Linden CH, Townsend PL: Metabolic acidosis after acute ibuprofen overdosage. J Pediatr 1987;111:922-925
ACUTE HEPATITISINDUCED BY OMEPRAZOLE To the Editor: With the increased use of omeprazole for the treatment of conditions such as Zollinger-Ellisonsyndrome, reflux esophagitis, and peptic ulcer disease, several sequelae have been documented in the literature, but there has been limited evidence of significant hepatotoxicity. We present a unique case of acute hepatitis secondary to the use of Omeprazole that resolved spontaneously with discontinuationof the drug. A 34-year-old black woman with a history of insulin-dependent diabetes mellitus, hypertension, and peptic ulcer disease was seen in our emergency department because of a complaint of 2 weeks of mid-epigastric abdominal pain associated with nausea and vomiting. She reported no recent medical problems and no history of toxin exposure, intravenous drug use, alcohol ingestion, iron ingestion, or acetaminophen ingestion. The patient reported that she had been told 11 years earlier that she had presumed hepatitis C; however, she had recovered without complications or exacerbations. Her regular medications included Vasotec (enalapril maleate; Merck, West Point, PA), NPH insulin, and amitryptiline. Four weeks earlier, she had been started on Omeprazole for presumed peptic ulcer disease. The patient was afebrile, her vital signs were stable, and the physical examination was significant only for mild tenderness in the epigastric and right upper quadrant regions without rebound tenderness or guarding. Laboratory data revealed a white blood cell count of 9,980/~tL with no left shift, hemoglobin was 11.2 g/L, platelets were 369,000/pL, and prothrombin time was 12.3 seconds. Liver function test results were as follows: bilirubin, 0.3 mg/dL; alkaline phosphatase, 149 U/L; lactate dehydrogenase, 1,207 U/L; aspartate transarninase, 1,059 U/L. Amylase level was 84 U/L. Other levels were as follows: glucose, 160 mg/dL; blood urea nitrogen, 23 mg/dL; creatinine, 1.6 mg/dL; sodium, 136 mEq/L; potassium, 4.1 mEq/L, and carbon dioxide, 18.6 mEq/L. Urinalysis and toxicologic screen were negative. Abdominal ultrasound revealed a surgically absent gall bladder and no other abnormalities. The patient had undergone routine laboratory screening as an outpatient 4 weeks earlier before starting the omeprazole. Values were as follows: hemoglobin, 10.3 g/dL; platelets, 255,000/gL, gammaglutamyl transferase, 8 U/L; lactate dehydrogenase, 222 U/L; alanine transaminase, 49 U/L; aspartate transaminase, 44 U/L; alkaline phosphatase, 103 U/L; bilirubin, 0.5 mg/dL; blood urea nitrogen, 21 mg/dL; and creatinine, 1.6 mg/dL. The patient was admitted for presumed omeprazole-induced hepatitis. The omeprazole was discontinued and she was given intravenous hydration. During her hospital course, she had one temperature elevation, but all cultures were negative. A full hepatitis serum screen was performed. Hepatitis B surface antibody, hepatitis B surface antigen, hepatitis B core antibody, and hepatitis A antibody (IgM) were all negative. Hepatitis C virus antibody was positive and this was confirmed with the radioimmune blot assay. The patient continued to do very well and had a
CORRESPONDENCE
complete and uneventful recovery. Laboratory values on discharge were as follows: white blood cell count, 8,500/gL, aspartate transaminase, 31 U/L; alanine transaminase, 360 U/L; alkaline phosphatase, 107 U/L; lactate dehydrogenase, 194 U/L; bilirubin, 0.4 mg/dL; amylase, 31 U/L; lipase, 8 U/L; and ammonia, 34 U/L. Follow-up laboratory values 3 weeks later revealed completely normal liver function test results. A problem that we encountered in this case was the previous history of hepatitis C that was confirmed by antibody testing. However, the clinical course of hepatitis C varies from this presentation. The liver enzymes typically remain elevated for longer periods of time than the 2 weeks we observed and recovery tends to be more gradual, even with interventions. Hepatitis C exacerbations are not known to resolve in days without specific therapy (ie, interferon treatments). Furthermore, the patient had been symptom-free for 11 years from her initial bout of hepatitis C with no prior exacerbations. Increasing numbers of side effects are becoming evident with the increased use of omeprazole. Common side effects include constipation, diarrhea, headaches, and nausea) -4 Mild increases in liver enzymes have been reported, as well as acute fulminant hepatic failure, the development of acute interstitial nephritis, and a case of reversible hemolytic anemia.2,5-7 In conclusion, we reported a case of omeprazole as the etiology of acute hepatitis. With the increased use of omeprazole, health
551
care professionals should be aware of the possible associated hepatotoxicity, even with therapeutic doses. SHAHEEDI. KOURY,MD C. KEITHSTONE,M.D DI~SIRI~ED. LA CHARITE
Department of Emergency Medicine University of Kentucky College of Medicine Lexington, KY References 1. Nelis GF: Safety profile of omeprazole. Adverse events with short-term treatment. Digestion 1989;44:68-76 (suppl I) 2. Arnold R, Koop H: Omeprazole: Long-term safety. Digestion 1989;44:77-86 (suppl I) 3. Joelson S, Joelson IB, Lundborg P, et al: Safety experience from long-term treatment with omeprazole. Digestion 1992;51:93101 (suppl I) 4. Lloyd-Davies KA, Rutgerson K, Solvell L: Omeprazole in the treatment of Zollinger-Ellison syndrome. Aliment Pharmacol Ther 1988;2:13-32 5. Marks DR, Joy JV, Bonheim NA: Hemolytic anemia associated with the use of omeprazole. Am J Gastroenterol 1991 ;86:217-218 6. Ruffenach SJ, Siskind MS, Lien YH: Acute interstitial nephritis due to omeprazole. Am J Med 1992;93:472-473 7. Jochem V, Kirkpatrick R, Greenson J, eta[: Fulminant hepatic failure related to omeprazole. Am J Gastroentero11992;87:523-525
AMERICAN JOURNAL OF EMERGENCY MEDICINE [] Volume 16, Number 5 [] September 1998
nally comatose when found by his parent, he was extremely combative on arrival to our department. The patient was able to localize painful stimuli but was otherwise noncommunicative.The negative toxicology screen and the absence of physical findings suggestive of other toxidromes make the presence of other coingestants unlikely. Previous descriptions of metabolic acidosis in ibuprofen toxicity describe normal or minimally elevated lactic acid levels. The acidosis has been attributed to a direct effect of ibuprofen and its metabolites on serum pH in combination with lactic acidosis. 2,11,13 The etiology of the lactic acidosis is most likely hypoperfusion as mild to moderate hypotension is not unusual in ibuprofen intoxication. Our patient had an anion gap of 21 and a mild metabolic acidosis that can be explained by the lactic acidosis and the ibuprofen metabolites present in the serum. The acidosis persisted more than 12 hours despite appropriate intravenous hydration and rapid correction of hypotension prior to transfer to the intensive care unit. Failure of rapid correction of the acidosis with improved perfusion suggests that ibuprofen and its metabolites may have contributed to the acidosis. Another unusual aspect of this case was that the patient was hypothermic on arrival. Mild hyperthermia has been found previously in ibuprofen overdose, but hypothermia has been noted in only 2 cases, and was attributed to accompanying CNS depression. 2,9 However, our patient was extremely agitated and struggling against physical restraints on arrival. Exposure would be an unlikely etiology of hypothermia in this patient because he was found indoors and his depressed mental status was acute in onset (less than 1 hour). We are unable to explain this patient's hypothermia based on the known pharmacological properties of ibuprofen. The ibuprofen level of 160 gg/mL 7 hours postingestion is clearly above the therapeutic level (therapeutic range 10 to 50 ~g/mL; toxic range greater than 100 ~lg/mL).1,8 In addition to his altered mental status our patient also exhibited other signs of toxicity including metabolic acidosis and minimally elevated liver enzymes. Although the serum level has little bearing on clinical management of ibuprofen toxicity, this patient's elevated level is an indication of a significant ingestion. This case demonstrates that ibuprofen intoxication alone can cause agitation and combative behavior as well as hypothermia in addition to the previously reported manifestations of toxicity. ALBERTRITTER,MD BARNETESKIN,MD
Department of Emergency Medicine Emergency Medicine Residency Program Morristown Memorial Hospital Morristown, NJ
References 1. Hall AH, Smolinske SC, Conrad FL: Ibuprofen overdose: 126 cases. Ann Emerg Med 1986; 15:1308-1313 2. Le HT, Bosse GM, Tsai Y: Ibuprofen overdose complicated by renal failure, adult respiratory distress syndrome, and metabolic acidosis. CIin Toxicol 1994;32:315-320 3. Perry SJ, Streete PJ, Volans GN: Ibuprofen overdose: The first two years of over-the-counter sales. Hum Toxicol 1987;6:173-178 4. McEIwee NE, Veltri JC, Bradford DC, et al: A prospective, population-based study of acute ibuprofen overdose: Complications are rare and routine serum levels not warranted. Ann Emerg Med 1990; 19:657-662 5. Court H, Streete P, Volans GN: Acute poisoning with ibuprofen. Hum Toxicol 1983;2:381-384 6. Mills RF, Adams SS, Cliffe EE, et al: The metabolism of ibuprofen. Xenobiotica 1973;3:589-598 7. Insel PA: Analgesic-antipyretics and antiinflammatory agents; drugs employed in the treatment of rheumatoid arthritis and gout. In
Gilman AG, Rail TW, Nies AS, et al (eds): The Pharmacological Basis of Therapeutics (ed 8). New York, NY, McGraw-Hill, 1990, pp 665-666 8. Hall AH, Smolinske SC, Stover B, et al: Ibuprofen overdose in adults. Clin Toxico11992;30:23-37 9. Chelluri L, Jastremski MS: Coma caused by ibuprofen overdose. Crit Care Med 1986; 14:1078-1079 10. Jenkinson ML, Fitzpatrick R, Streete PJ, et al: The relationship between plasma ibuprofen concentrations and toxicity in acute ibuprofen overdose. Hum Toxicol 1988;7:319-324 11. Lee CY, Finkler A: Acute intoxication due to ibuprofen overdose. Arch Pathol Lab Med 1988;110:747-749 12. Hunt DP, Leigh RJ: Overdose with ibuprofen causing unconsciousness and hypotension. BMJ 1980;281:1458-1459 13. Linden CH, Townsend PL: Metabolic acidosis after acute ibuprofen overdosage. J Pediatr 1987;111:922-925
ACUTE HEPATITISINDUCED BY OMEPRAZOLE To the Editor: With the increased use of omeprazole for the treatment of conditions such as Zollinger-Ellisonsyndrome, reflux esophagitis, and peptic ulcer disease, several sequelae have been documented in the literature, but there has been limited evidence of significant hepatotoxicity. We present a unique case of acute hepatitis secondary to the use of Omeprazole that resolved spontaneously with discontinuationof the drug. A 34-year-old black woman with a history of insulin-dependent diabetes mellitus, hypertension, and peptic ulcer disease was seen in our emergency department because of a complaint of 2 weeks of mid-epigastric abdominal pain associated with nausea and vomiting. She reported no recent medical problems and no history of toxin exposure, intravenous drug use, alcohol ingestion, iron ingestion, or acetaminophen ingestion. The patient reported that she had been told 11 years earlier that she had presumed hepatitis C; however, she had recovered without complications or exacerbations. Her regular medications included Vasotec (enalapril maleate; Merck, West Point, PA), NPH insulin, and amitryptiline. Four weeks earlier, she had been started on Omeprazole for presumed peptic ulcer disease. The patient was afebrile, her vital signs were stable, and the physical examination was significant only for mild tenderness in the epigastric and right upper quadrant regions without rebound tenderness or guarding. Laboratory data revealed a white blood cell count of 9,980/~tL with no left shift, hemoglobin was 11.2 g/L, platelets were 369,000/pL, and prothrombin time was 12.3 seconds. Liver function test results were as follows: bilirubin, 0.3 mg/dL; alkaline phosphatase, 149 U/L; lactate dehydrogenase, 1,207 U/L; aspartate transarninase, 1,059 U/L. Amylase level was 84 U/L. Other levels were as follows: glucose, 160 mg/dL; blood urea nitrogen, 23 mg/dL; creatinine, 1.6 mg/dL; sodium, 136 mEq/L; potassium, 4.1 mEq/L, and carbon dioxide, 18.6 mEq/L. Urinalysis and toxicologic screen were negative. Abdominal ultrasound revealed a surgically absent gall bladder and no other abnormalities. The patient had undergone routine laboratory screening as an outpatient 4 weeks earlier before starting the omeprazole. Values were as follows: hemoglobin, 10.3 g/dL; platelets, 255,000/gL, gammaglutamyl transferase, 8 U/L; lactate dehydrogenase, 222 U/L; alanine transaminase, 49 U/L; aspartate transaminase, 44 U/L; alkaline phosphatase, 103 U/L; bilirubin, 0.5 mg/dL; blood urea nitrogen, 21 mg/dL; and creatinine, 1.6 mg/dL. The patient was admitted for presumed omeprazole-induced hepatitis. The omeprazole was discontinued and she was given intravenous hydration. During her hospital course, she had one temperature elevation, but all cultures were negative. A full hepatitis serum screen was performed. Hepatitis B surface antibody, hepatitis B surface antigen, hepatitis B core antibody, and hepatitis A antibody (IgM) were all negative. Hepatitis C virus antibody was positive and this was confirmed with the radioimmune blot assay. The patient continued to do very well and had a
CORRESPONDENCE
complete and uneventful recovery. Laboratory values on discharge were as follows: white blood cell count, 8,500/gL, aspartate transaminase, 31 U/L; alanine transaminase, 360 U/L; alkaline phosphatase, 107 U/L; lactate dehydrogenase, 194 U/L; bilirubin, 0.4 mg/dL; amylase, 31 U/L; lipase, 8 U/L; and ammonia, 34 U/L. Follow-up laboratory values 3 weeks later revealed completely normal liver function test results. A problem that we encountered in this case was the previous history of hepatitis C that was confirmed by antibody testing. However, the clinical course of hepatitis C varies from this presentation. The liver enzymes typically remain elevated for longer periods of time than the 2 weeks we observed and recovery tends to be more gradual, even with interventions. Hepatitis C exacerbations are not known to resolve in days without specific therapy (ie, interferon treatments). Furthermore, the patient had been symptom-free for 11 years from her initial bout of hepatitis C with no prior exacerbations. Increasing numbers of side effects are becoming evident with the increased use of omeprazole. Common side effects include constipation, diarrhea, headaches, and nausea) -4 Mild increases in liver enzymes have been reported, as well as acute fulminant hepatic failure, the development of acute interstitial nephritis, and a case of reversible hemolytic anemia.2,5-7 In conclusion, we reported a case of omeprazole as the etiology of acute hepatitis. With the increased use of omeprazole, health
551
care professionals should be aware of the possible associated hepatotoxicity, even with therapeutic doses. SHAHEEDI. KOURY,MD C. KEITHSTONE,M.D DI~SIRI~ED. LA CHARITE
Department of Emergency Medicine University of Kentucky College of Medicine Lexington, KY References 1. Nelis GF: Safety profile of omeprazole. Adverse events with short-term treatment. Digestion 1989;44:68-76 (suppl I) 2. Arnold R, Koop H: Omeprazole: Long-term safety. Digestion 1989;44:77-86 (suppl I) 3. Joelson S, Joelson IB, Lundborg P, et al: Safety experience from long-term treatment with omeprazole. Digestion 1992;51:93101 (suppl I) 4. Lloyd-Davies KA, Rutgerson K, Solvell L: Omeprazole in the treatment of Zollinger-Ellison syndrome. Aliment Pharmacol Ther 1988;2:13-32 5. Marks DR, Joy JV, Bonheim NA: Hemolytic anemia associated with the use of omeprazole. Am J Gastroenterol 1991 ;86:217-218 6. Ruffenach SJ, Siskind MS, Lien YH: Acute interstitial nephritis due to omeprazole. Am J Med 1992;93:472-473 7. Jochem V, Kirkpatrick R, Greenson J, eta[: Fulminant hepatic failure related to omeprazole. Am J Gastroentero11992;87:523-525