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Hemolytic anemia after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency
CORRESPONDENCE ADMINISTRATION OF HEME ARGINATE, BUT NOT HEMATIN, CAUSED ANAPHYLACTIC SHOCK To the Editor: Acute intermittent porphyria is inherited as an autosomal dominant trait and is due to a partial deficiency in porphobilinogen deaminase (1). The disease is characterized by acute attacks of neurologic dysfunction, with abdominal pain, peripheral neuropathy, and psychiatric symptoms (1). Treatment of these attacks is challenging because their course is unpredictable and sometimes fatal (1). Hypertonic glucose loading is often used, but heme compounds seem to be more effective. Such compounds are now available as heme arginate (Normosang; Leiras Oy Pharmaceuticals, Finland), which is the reaction product of hemin and Larginine in a mixture of propylene glycol, ethanol, and water; and as hematin (Panhematin; Abbott Laboratories), which is a lyophilized powder consisting of hemin, sodium carbonate, and sorbitol. Heme arginate remains stable in ampules for years (2). Hematin, on the other hand, is very unstable and should be administered within an hour after the powder has been dissolved in sterile water (2). Heme arginate does not affect coagulation, whereas hematin has often been associated with coagulopathy with occasional bleeding (3,4). Moreover, heme arginate irritates veins less than hematin does (4). Therefore, heme arginate seems to be safer and more beneficial than hematin. However, we report a case in which administration of hematin overcame a problem caused by heme arginate. A 29-year-old woman was admitted to our hospital with severe abdominal pain, vomiting, and constipation. She was diagnosed with acute intermittent porphyria and was first treated with hypertonic glucose 240
䉷2001 by Excerpta Medica, Inc. All rights reserved.
loading and chlorpromazine. Heme arginate was administered later when she developed severe acute porphyric attacks. Two years later, when we administered heme arginate for the 25th time, the patient developed dyspnea and severe urticaria and a decrease in blood pressure. We considered these to be symptoms of an acute anaphylactic reaction. After they were reproduced by readministration of heme arginate, we thought the reaction was anaphylactic shock caused by heme arginate. Because heme arginate contains other substances besides hemin, one of them might have caused the reaction. Therefore, we tried to administer hematin. Surprisingly, this greatly eased the acute porphyric attack without bringing on shock, which indicated that hemin itself was not the substance causing the shock. Heme arginate is very effective at easing the symptoms of acute porphyric attacks, and has been thought to be very safe. It has therefore been recommended as initial treatment (4). However, our case shows that heme arginate is not always safe, because frequent administration may lead to development of an immediate hypersensitivity reaction and anaphylactic shock. We recommend that anaphylactic shock be considered a side effect of heme arginate, and that hematin be used to treat acute porphyric attacks in such cases. Makoto Daimon, MD Shinji Susa, MD Masahiko Igarashi, MD Takeo Kato, MD Third Department of Internal Medicine Yamagata University School of Medicine Yamagata, Japan Wataru Kameda, MD Division of Internal Medicine Nihon-Kai Hospital Sakata, Japan
1. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Stanbury JB, Wyngaarden JB, Fredrikson DS, et al, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill International; 1989:1305–1365. 2. Herbert L, Bonkovsky MD. Advances in understanding and treating “the little imitator,” acute porphyria. Gastroenterology. 1993;105:590 –594. 3. Green D, Ts’ao C. Hematin: effects on hemostasis. J Lab Clin Med. 1990;115:144 – 147. 4. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Intern Med. 1993;153:2004 – 2008.
HEMOLYTIC ANEMIA AFTER ACETAMINOPHEN OVERDOSE IN A PATIENT WITH GLUCOSE-6PHOSPHATE DEHYDROGENASE DEFICIENCY To the Editor: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common clinically significant enzyme deficiencies, affecting approximately 200 million people worldwide. Among African Americans, the gene frequency is 0.11 (1). Affected patients are predisposed to developing hemolytic anemia when oxidant stress depletes reduced glutathione within red blood cells, thereby limiting the reduction of reactive oxygen species. G6PD is the only source of nicotinamide adenine dinucleotide phosphate (NADPH) in erythrocytes for regenerating reduced glutathione, and thereby has a critical function in protecting the cell from oxidative damage (2). Many drugs are known to precipitate hemolytic episodes in patients with G6PD deficiency. Acetaminophen is generally considered safe for use in these patients (1). We report the case of a 16-year-old African-American boy with previously undiagnosed G6PD deficiency 0002-9343/01/$–see front matter PII S0002-9343(00)00723-3
Letters to the Editor
who ingested an unknown quantity of acetaminophen, fluvoxamine, and clomipramine in a suicide attempt. An acetaminophen level obtained 6 hours after the time of ingestion was 680 ug/mL (therapeutic level 10 to 30 ug/mL; toxic level ⬎115 /mL at 6 hours). The patient was treated with intravenous N-acetylcysteine, which has not been reported to cause hemolysis and which prevents decreases in whole-blood glutathione concentrations in feline models of acetaminophen toxicity (3). Two days after his suicide attempt, the patient developed scleral icterus, and his unconjugated bilirubin level was elevated. His hemoglobin and hematocrit decreased from initial concentrations of 13.7 g/dL and 40.0%, respectively, to 9.7 g/dL and 27.9%. Plasma freehemoglobin was 148 mg/dL (normal ⬍7 mg/dL). The patient’s hemolysis continued for 8 days; his hemoglobin and hematocrit reached nadirs of 7.6 g/dL and 22.1%. Although testing for G6PD deficiency optimally should be done several weeks after a hemolytic episode to avoid false negative results, a qualitative G6PD assay was obtained from our patient during the crisis. The deficiency of G6PD activity in our patient suggested he had one of the more severe variants. The combination of a severe variant of G6PD deficiency and massive acetaminophen overdose may have put him at increased risk for hemolysis. There has been only one case report of an isolated acetaminophen overdose leading to hemolysis in a patient with known G6PD deficiency (4). The other medications he ingested have not been reported to produce hemolysis. The metabolite of acetaminophen responsible for oxidant stress-induced hemolysis in G6PD-deficient patients remains unknown. Our case is unique in that our patient’s enzyme deficiency had been previously undiagnosed. We recommend that patients with acetaminophen toxicity whose ethnic backgrounds place them at risk for G6PD
deficiency be monitored for hemolysis during their hospitalizations. In addition, acetaminophen toxicity should be recognized as a potential cause of hemolytic anemia in susceptible patients. Anne-Michelle Ruha, MD Brad Selden, MD Steven Curry, MD Department of Medical Toxicology Good Samaritan Regional Medical Center Phoenix, Arizona 1. Beutler E. G6PD Deficiency. Blood. 1994;84: 3613–3636. 2. Mason PJ. New insights into G6PD deficiency. Br J Haematol. 1996;94:585–591. 3. Savides MC, Oehme FW, Leipold HW. Effects of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats. Am J Vet Res. 1985;46: 1485–1489. 4. Wright RO, Perry HE, Shannon MW. Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol. 1996;34:731–734.
DIAGNOSING OSTEOPOROSIS IN JAPANESE AMERICAN WOMEN To the Editor: A significant difference in the bone mineral density (BMD) of Asian and Caucasian women has been reported previously (1). However, the magnitude of this discrepancy as it relates to the clinical diagnosis of osteoporosis is likely underappreciated. We therefore sought to estimate and compare the prevalence of osteoporosis in older Japanese-American women by utilizing Asian and Caucasian reference groups. Letters of invitation were sent to a randomly selected sample of women enrolled in a prospective cohort study of dementia incidence in Japanese Americans aged 65⫹ living in King County, Washington (the Kame Project) (2). The Kame Project identified subjects from King County teleFebruary 15, 2001
phone directories, Medicare recipient lists, Japanese-American organizational lists, and by word of mouth, and enrolled 1,985 men and women between May 1992 and September 1994. Hip BMD was measured in 273 Japanese-American women aged 65 to 93 years (mean [⫾ SD] 73 ⫾ 5) using dual energy x-ray absorptiometry (Norland, Fort Atkinson, Wisconsin) between October 1995 and May 1997. All participants were of 100% Japanese ancestry. Participants were more likely than nonparticipants to be born in the United States (84% versus 75%), and therefore, were more representative of older US-born Japanese-American women living in King County. Absolute values of femoral neck BMD were compared with two ethnic-specific references supplied by the manufacturer. Based on the World Health Organization criteria for osteopenia and osteoporosis, which utilizes T scores, 22.3% of these older Japanese-American women were diagnosed as normal (BMD ⬎0.739 g/cm2), 57.1% were diagnosed as osteopenic (BMD 0.577 to 0.739 g/cm2), and 20.5% were diagnosed as osteoporotic (BMD ⬍0.577 g/cm2), when femoral neck BMD was compared with the young-adult normal Asian-American reference. The number of women diagnosed as osteoporotic dramatically increased when femoral neck BMD was compared with the young-adult normal Caucasian-American reference (2.9% normal, BMD ⬎0.899 g/cm2; 23.4% osteopenic, BMD 0.715 to 0.899 g/cm2; and 73.6% osteoporotic, BMD ⬍0.715 g/cm2). Should the clinical diagnosis of osteoporosis for older Japanese-American women be based on an Asian or Caucasian reference? The answer to this question depends on whether ethnic-adjusted or absolute BMD best predicts future fractures. Japanese-American women, compared with Caucasian American women, have lower BMD at most
THE AMERICAN JOURNAL OF MEDICINE威
Volume 110 241
䉷2001 by Excerpta Medica, Inc. All rights reserved.
loading and chlorpromazine. Heme arginate was administered later when she developed severe acute porphyric attacks. Two years later, when we administered heme arginate for the 25th time, the patient developed dyspnea and severe urticaria and a decrease in blood pressure. We considered these to be symptoms of an acute anaphylactic reaction. After they were reproduced by readministration of heme arginate, we thought the reaction was anaphylactic shock caused by heme arginate. Because heme arginate contains other substances besides hemin, one of them might have caused the reaction. Therefore, we tried to administer hematin. Surprisingly, this greatly eased the acute porphyric attack without bringing on shock, which indicated that hemin itself was not the substance causing the shock. Heme arginate is very effective at easing the symptoms of acute porphyric attacks, and has been thought to be very safe. It has therefore been recommended as initial treatment (4). However, our case shows that heme arginate is not always safe, because frequent administration may lead to development of an immediate hypersensitivity reaction and anaphylactic shock. We recommend that anaphylactic shock be considered a side effect of heme arginate, and that hematin be used to treat acute porphyric attacks in such cases. Makoto Daimon, MD Shinji Susa, MD Masahiko Igarashi, MD Takeo Kato, MD Third Department of Internal Medicine Yamagata University School of Medicine Yamagata, Japan Wataru Kameda, MD Division of Internal Medicine Nihon-Kai Hospital Sakata, Japan
1. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Stanbury JB, Wyngaarden JB, Fredrikson DS, et al, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill International; 1989:1305–1365. 2. Herbert L, Bonkovsky MD. Advances in understanding and treating “the little imitator,” acute porphyria. Gastroenterology. 1993;105:590 –594. 3. Green D, Ts’ao C. Hematin: effects on hemostasis. J Lab Clin Med. 1990;115:144 – 147. 4. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Intern Med. 1993;153:2004 – 2008.
HEMOLYTIC ANEMIA AFTER ACETAMINOPHEN OVERDOSE IN A PATIENT WITH GLUCOSE-6PHOSPHATE DEHYDROGENASE DEFICIENCY To the Editor: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common clinically significant enzyme deficiencies, affecting approximately 200 million people worldwide. Among African Americans, the gene frequency is 0.11 (1). Affected patients are predisposed to developing hemolytic anemia when oxidant stress depletes reduced glutathione within red blood cells, thereby limiting the reduction of reactive oxygen species. G6PD is the only source of nicotinamide adenine dinucleotide phosphate (NADPH) in erythrocytes for regenerating reduced glutathione, and thereby has a critical function in protecting the cell from oxidative damage (2). Many drugs are known to precipitate hemolytic episodes in patients with G6PD deficiency. Acetaminophen is generally considered safe for use in these patients (1). We report the case of a 16-year-old African-American boy with previously undiagnosed G6PD deficiency 0002-9343/01/$–see front matter PII S0002-9343(00)00723-3
Letters to the Editor
who ingested an unknown quantity of acetaminophen, fluvoxamine, and clomipramine in a suicide attempt. An acetaminophen level obtained 6 hours after the time of ingestion was 680 ug/mL (therapeutic level 10 to 30 ug/mL; toxic level ⬎115 /mL at 6 hours). The patient was treated with intravenous N-acetylcysteine, which has not been reported to cause hemolysis and which prevents decreases in whole-blood glutathione concentrations in feline models of acetaminophen toxicity (3). Two days after his suicide attempt, the patient developed scleral icterus, and his unconjugated bilirubin level was elevated. His hemoglobin and hematocrit decreased from initial concentrations of 13.7 g/dL and 40.0%, respectively, to 9.7 g/dL and 27.9%. Plasma freehemoglobin was 148 mg/dL (normal ⬍7 mg/dL). The patient’s hemolysis continued for 8 days; his hemoglobin and hematocrit reached nadirs of 7.6 g/dL and 22.1%. Although testing for G6PD deficiency optimally should be done several weeks after a hemolytic episode to avoid false negative results, a qualitative G6PD assay was obtained from our patient during the crisis. The deficiency of G6PD activity in our patient suggested he had one of the more severe variants. The combination of a severe variant of G6PD deficiency and massive acetaminophen overdose may have put him at increased risk for hemolysis. There has been only one case report of an isolated acetaminophen overdose leading to hemolysis in a patient with known G6PD deficiency (4). The other medications he ingested have not been reported to produce hemolysis. The metabolite of acetaminophen responsible for oxidant stress-induced hemolysis in G6PD-deficient patients remains unknown. Our case is unique in that our patient’s enzyme deficiency had been previously undiagnosed. We recommend that patients with acetaminophen toxicity whose ethnic backgrounds place them at risk for G6PD
deficiency be monitored for hemolysis during their hospitalizations. In addition, acetaminophen toxicity should be recognized as a potential cause of hemolytic anemia in susceptible patients. Anne-Michelle Ruha, MD Brad Selden, MD Steven Curry, MD Department of Medical Toxicology Good Samaritan Regional Medical Center Phoenix, Arizona 1. Beutler E. G6PD Deficiency. Blood. 1994;84: 3613–3636. 2. Mason PJ. New insights into G6PD deficiency. Br J Haematol. 1996;94:585–591. 3. Savides MC, Oehme FW, Leipold HW. Effects of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats. Am J Vet Res. 1985;46: 1485–1489. 4. Wright RO, Perry HE, Shannon MW. Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol. 1996;34:731–734.
DIAGNOSING OSTEOPOROSIS IN JAPANESE AMERICAN WOMEN To the Editor: A significant difference in the bone mineral density (BMD) of Asian and Caucasian women has been reported previously (1). However, the magnitude of this discrepancy as it relates to the clinical diagnosis of osteoporosis is likely underappreciated. We therefore sought to estimate and compare the prevalence of osteoporosis in older Japanese-American women by utilizing Asian and Caucasian reference groups. Letters of invitation were sent to a randomly selected sample of women enrolled in a prospective cohort study of dementia incidence in Japanese Americans aged 65⫹ living in King County, Washington (the Kame Project) (2). The Kame Project identified subjects from King County teleFebruary 15, 2001
phone directories, Medicare recipient lists, Japanese-American organizational lists, and by word of mouth, and enrolled 1,985 men and women between May 1992 and September 1994. Hip BMD was measured in 273 Japanese-American women aged 65 to 93 years (mean [⫾ SD] 73 ⫾ 5) using dual energy x-ray absorptiometry (Norland, Fort Atkinson, Wisconsin) between October 1995 and May 1997. All participants were of 100% Japanese ancestry. Participants were more likely than nonparticipants to be born in the United States (84% versus 75%), and therefore, were more representative of older US-born Japanese-American women living in King County. Absolute values of femoral neck BMD were compared with two ethnic-specific references supplied by the manufacturer. Based on the World Health Organization criteria for osteopenia and osteoporosis, which utilizes T scores, 22.3% of these older Japanese-American women were diagnosed as normal (BMD ⬎0.739 g/cm2), 57.1% were diagnosed as osteopenic (BMD 0.577 to 0.739 g/cm2), and 20.5% were diagnosed as osteoporotic (BMD ⬍0.577 g/cm2), when femoral neck BMD was compared with the young-adult normal Asian-American reference. The number of women diagnosed as osteoporotic dramatically increased when femoral neck BMD was compared with the young-adult normal Caucasian-American reference (2.9% normal, BMD ⬎0.899 g/cm2; 23.4% osteopenic, BMD 0.715 to 0.899 g/cm2; and 73.6% osteoporotic, BMD ⬍0.715 g/cm2). Should the clinical diagnosis of osteoporosis for older Japanese-American women be based on an Asian or Caucasian reference? The answer to this question depends on whether ethnic-adjusted or absolute BMD best predicts future fractures. Japanese-American women, compared with Caucasian American women, have lower BMD at most
THE AMERICAN JOURNAL OF MEDICINE威
Volume 110 241