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Fatal hepatitis with leflunomide and itraconazole
Letters to the Editor
cobalamin malabsorption (2), which is characterized by the inability to release vitamin B12 from food or its binding protein (3). Patients have low serum vitamin B12 levels, normal Schilling test results, and atrophic gastritis. To date, only case reports or small studies have described this condition in elderly patients. We report our findings in a cohort of 50 elderly patients with cobalamin deficiency due to food-cobalamin malabsorption. Between 1995 and 2002, 127 patients with cobalamin deficiency (serum vitamin B12 level ⬍200 pg/mL) were enrolled in a prospective cohort study at our institution (2), of whom 50 who were older than 65 years had food-cobalamin malabsorption. The median age was 78 years (range, 65 to 91 years), and 40% were women. Clinical characteristics included mild peripheral neuropathy, with decrease in or loss of reflexes (n ⫽ 14) and paresthesia of the legs (n ⫽ 4); mental confusion or cognitive dysfunction (n ⫽ 8); and ischemic stroke (n ⫽ 4). Other features related to the anemia included asthenia (n ⫽ 11), lower limb edema (n ⫽ 8), and jaundice (n ⫽ 2). The mean (⫾ SD) serum vitamin B12 level was 136 ⫾ 45 pg/mL (range, 35 to 200 pg/mL), and mean total homocysteine level was 22 ⫾ 15 mol/L (range, 13 to 97 mol/L). Serum folate and creatinine levels were normal; no patients had anti–intrinsic factor antibodies. Hematologic abnormalities included mild anemia (n ⫽ 15), with typical features of megaloblastic anemia on bone marrow biopsy (n ⫽ 14); thrombocytopenia (n ⫽ 8); and leukopenia (n ⫽ 8). The mean hemoglobin level was 108 ⫾ 26.4 g/L (range, 33 to 132 g/L), and the mean erythrocyte cell volume was 95.5 ⫾ 14 fL (range, 55 to 140 fL). All patients had normal Schilling test results. None had a nutritional cobalamin deficiency. Other conditions associated with the disorder (3) included atrophic gastritis (n ⫽ 18), with 1 case of Helicobacter pylori infection; metformin 352
September 2002
intake for diabetes mellitus (n ⫽ 4) or long-term acid-suppressive drugs (n ⫽ 4); and alcohol abuse (n ⫽ 3), with 1 case of partial pancreatic insufficiency. Ten patients had idiopathic food-cobalamin malabsorption, wherein no associated condition was found. All patients were treated with intramuscular or oral cyanocobalamin (mean dose, 500 ⫾ 260 g/d), of whom 24 were evaluable for treatment response. In the 24 patients, serum vitamin B12 levels and blood count abnormalities were corrected during the first 3 months of treatment. Symptom recovery was observed in 15 patients; 8 with asthenia, 5 with peripheral neuropathy, and 2 with jaundice. All our patients had food-cobalamin malabsorption according to the criteria reported by Carmel (3), as well as established cobalamin deficiency (4). More than 80% of the patients had nonspecific mild symptoms or moderate hematologic abnormalities. However, we also observed severe neurologic conditions in 12 patients (24%), pancytopenia not attributable to other conditions or disorders in 5 (10%), and severe anemia in 3 (6%). The relation between vitamin B12 deficiency and neurologic symptoms such as confusion, dementia, or ischemic stroke is not known; however, these patients had increased serum total homocysteine levels, which is a potential risk factor for vascular disease (5). Our data suggest that atrophic gastritis was the main cause of food-cobalamin malabsorption in at least 40% of elderly patients. In the 10 patients with “idiopathic” food-cobalamin malabsorption, older age may have been a factor (5). Our data also confirm the efficacy of oral crystalline cyanocobalamin in correcting serum vitamin B12 levels and hematologic abnormalities (6). We used cyanocobalamin, at a mean dose of 600 g/d, although in some patients, doses be-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113
tween 250 to 500 g/d were sufficient to correct the cobalamin deficiency. Emmanuel Andre`s, MD Georges Kaltenbach, MD Anne-Elisabeth Perrin, MD Jean-Emmanuel Kurtz, MD, PhD Jean-Louis Schlienger, MD Hoˆpitaux Universitaires de Strasbourg Strasbourg, France 1. Lindenbaum J, Rosenberg IH, Wilson PWF, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60:2–11. 2. Andre`s E, Goichot B, Schlienger JL. Foodcobalamin malabsorption: a usual cause of vitamin B12 deficiency. Arch Intern Med. 2000;160:2061–2062. 3. Carmel R. Malabsorption of food-cobalamin. Baillie`res Clin Haematol. 1995;8:639 – 655. 4. Snow C. Laboratory diagnosis of vitamin B12 and folate deficiency. A guide for the primary cares physician. Arch Intern Med. 1999;159:1289 –1298. 5. Matthews JH. Cobalamin and folate deficiency in the elderly. Baille`res Clin Haematol. 1995;54:245–253. 6. Andre`s E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med. 2001;111:126 –129.
FATAL HEPATITIS WITH LEFLUNOMIDE AND ITRACONAZOLE To the Editor: Leflunomide, an immunomodulatory prodrug, is indicated for the treatment of patients with active rheumatoid arthritis (1). It is associated with several life-threatening adverse effects, including agranulocytosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatitis (1,2). We describe a patient who developed fatal liver lesions while receiving leflunomide and itraconazole. The patient was a 68-year-old woman with a 30-year history of rheumatoid arthritis complicated by corticoid-induced diabetes and recurrent infections. Unsuccessful treatment with cyclosporine and methotrexate led to the introduction of leflunomide in January 2001. She
Letters to the Editor
received a loading dose, followed by a 10-mg/d dose for 5 months. Several months earlier, she was taking furosemide for hypertension, nadroparin for recurrent thrombophlebitis, insulin for diabetes, methylprednisolone plus omeprazole for rheumatoid arthritis, and domperidone. She was hospitalized 1 month after starting leflunomide for poorly controlled diabetes. In May, she was readmitted for fungal osteitis (Scedosporium apiospermum) of the second metatarsus, which was treated with surgery and itraconazole (300 mg/d). In June, leflunomide was increased to 20 mg/d. Liver function tests were normal. In July, she was admitted to the hospital for abdominal pain, vomiting, and weakness. On clinical examination, blood pressure was 95/42 mm Hg, heart rate was 109 beats per minute, respiratory rate was 19 breaths per minute, and temperature was 36.6°C. Liver function tests revealed cytolytic hepatitis with a serum aspartate aminotransferase (AST) level of 577 U/L (reference, 6 to 25 U/L), an alanine aminotransferase (ALT) level of 1111 IU/L (reference, 5 to 35 U/L), an alkaline phosphatase level of 62 U/L (reference, 45 to 145 U/L), a ␥-glutamyl transpeptidase level of 16 U/L (reference, 6 to 20 U/L), and prothrombin time of 43%. Albuminemia was 17 g/L.
Despite symptomatic treatment and washout with cholestyramine, fulminant hepatic failure occurred (AST, 5940 U/L; ALT, 6950 U/L; ammonemia, 163 mol/L [reference, 14 to 38 mol/L]; prothrombin time, 11%) that led to death. Serologic tests were negative for hepatitis A, B, and C viruses, cytomegalovirus, EpsteinBarr virus, and human immunodeficiency virus. Liver biopsy revealed necrosis that was mainly pericentrolobular, microvesicular steatosis, with canalicular cholestasis and very mild portal and lobular inflammation. Although some of the drugs (omeprazole, domperidone, nadroparin, and insulin) prescribed for this patient can increase liver enzyme levels, leflunomide and itraconazole were more likely to have led to this fatal hepatitis because of their known toxicity. Cytolytic and cholestatic hepatitis have been reported with itraconazole at certain doses (3,4). The temporal relation between leflunomide and the occurrence of hepatic injury is suspected because the leflunomide dose had been increased, severe hypoalbuminemia increased hepatotoxicity, and itraconazole had been introduced recently. Hepatotoxicity of leflunomide has been reported in 10% of cases (1), and the European Agency for the Evaluation of Medicinal Products has received more than 250 reports of hepatic reactions, in-
September 2002
cluding cirrhosis (2 patients) and liver failure (15 patients), with death occurring in 9 patients (5). The majority of serious hepatic reactions was associated with other confounding factors, including concomitant use of hepatotoxic agents (n ⫽ 101) (5). Hepatotoxicity is dose dependent and seems to be induced by the active metabolite of leflunomide (A771726), which is strongly related to plasma proteins, the blood levels of which are presumed to be increased in patients with hypoprotidemia (1). Annick Legras, MD Anne-Marie Bergemer-Fouquet, MD Annie-Pierre Jonville-Bera, MD Hoˆpital Bretonneau Tours, France 1. Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999;58:1137–1164. 2. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet. 1999; 353:259 –266. 3. Garcia-Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999;48:847–852. 4. Lavrijsen APM, Balmus KJ, Nugteren-Huying WM, et al. Hepatic injury associated with itraconazole. Lancet. 1992;340:251– 252. 5. The European Agency for the Evaluation of Medicinal Products. EMEA issues public statement on leflunomide. Reactions Weekly. March 24, 2001;844:2.
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 353
cobalamin malabsorption (2), which is characterized by the inability to release vitamin B12 from food or its binding protein (3). Patients have low serum vitamin B12 levels, normal Schilling test results, and atrophic gastritis. To date, only case reports or small studies have described this condition in elderly patients. We report our findings in a cohort of 50 elderly patients with cobalamin deficiency due to food-cobalamin malabsorption. Between 1995 and 2002, 127 patients with cobalamin deficiency (serum vitamin B12 level ⬍200 pg/mL) were enrolled in a prospective cohort study at our institution (2), of whom 50 who were older than 65 years had food-cobalamin malabsorption. The median age was 78 years (range, 65 to 91 years), and 40% were women. Clinical characteristics included mild peripheral neuropathy, with decrease in or loss of reflexes (n ⫽ 14) and paresthesia of the legs (n ⫽ 4); mental confusion or cognitive dysfunction (n ⫽ 8); and ischemic stroke (n ⫽ 4). Other features related to the anemia included asthenia (n ⫽ 11), lower limb edema (n ⫽ 8), and jaundice (n ⫽ 2). The mean (⫾ SD) serum vitamin B12 level was 136 ⫾ 45 pg/mL (range, 35 to 200 pg/mL), and mean total homocysteine level was 22 ⫾ 15 mol/L (range, 13 to 97 mol/L). Serum folate and creatinine levels were normal; no patients had anti–intrinsic factor antibodies. Hematologic abnormalities included mild anemia (n ⫽ 15), with typical features of megaloblastic anemia on bone marrow biopsy (n ⫽ 14); thrombocytopenia (n ⫽ 8); and leukopenia (n ⫽ 8). The mean hemoglobin level was 108 ⫾ 26.4 g/L (range, 33 to 132 g/L), and the mean erythrocyte cell volume was 95.5 ⫾ 14 fL (range, 55 to 140 fL). All patients had normal Schilling test results. None had a nutritional cobalamin deficiency. Other conditions associated with the disorder (3) included atrophic gastritis (n ⫽ 18), with 1 case of Helicobacter pylori infection; metformin 352
September 2002
intake for diabetes mellitus (n ⫽ 4) or long-term acid-suppressive drugs (n ⫽ 4); and alcohol abuse (n ⫽ 3), with 1 case of partial pancreatic insufficiency. Ten patients had idiopathic food-cobalamin malabsorption, wherein no associated condition was found. All patients were treated with intramuscular or oral cyanocobalamin (mean dose, 500 ⫾ 260 g/d), of whom 24 were evaluable for treatment response. In the 24 patients, serum vitamin B12 levels and blood count abnormalities were corrected during the first 3 months of treatment. Symptom recovery was observed in 15 patients; 8 with asthenia, 5 with peripheral neuropathy, and 2 with jaundice. All our patients had food-cobalamin malabsorption according to the criteria reported by Carmel (3), as well as established cobalamin deficiency (4). More than 80% of the patients had nonspecific mild symptoms or moderate hematologic abnormalities. However, we also observed severe neurologic conditions in 12 patients (24%), pancytopenia not attributable to other conditions or disorders in 5 (10%), and severe anemia in 3 (6%). The relation between vitamin B12 deficiency and neurologic symptoms such as confusion, dementia, or ischemic stroke is not known; however, these patients had increased serum total homocysteine levels, which is a potential risk factor for vascular disease (5). Our data suggest that atrophic gastritis was the main cause of food-cobalamin malabsorption in at least 40% of elderly patients. In the 10 patients with “idiopathic” food-cobalamin malabsorption, older age may have been a factor (5). Our data also confirm the efficacy of oral crystalline cyanocobalamin in correcting serum vitamin B12 levels and hematologic abnormalities (6). We used cyanocobalamin, at a mean dose of 600 g/d, although in some patients, doses be-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113
tween 250 to 500 g/d were sufficient to correct the cobalamin deficiency. Emmanuel Andre`s, MD Georges Kaltenbach, MD Anne-Elisabeth Perrin, MD Jean-Emmanuel Kurtz, MD, PhD Jean-Louis Schlienger, MD Hoˆpitaux Universitaires de Strasbourg Strasbourg, France 1. Lindenbaum J, Rosenberg IH, Wilson PWF, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60:2–11. 2. Andre`s E, Goichot B, Schlienger JL. Foodcobalamin malabsorption: a usual cause of vitamin B12 deficiency. Arch Intern Med. 2000;160:2061–2062. 3. Carmel R. Malabsorption of food-cobalamin. Baillie`res Clin Haematol. 1995;8:639 – 655. 4. Snow C. Laboratory diagnosis of vitamin B12 and folate deficiency. A guide for the primary cares physician. Arch Intern Med. 1999;159:1289 –1298. 5. Matthews JH. Cobalamin and folate deficiency in the elderly. Baille`res Clin Haematol. 1995;54:245–253. 6. Andre`s E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med. 2001;111:126 –129.
FATAL HEPATITIS WITH LEFLUNOMIDE AND ITRACONAZOLE To the Editor: Leflunomide, an immunomodulatory prodrug, is indicated for the treatment of patients with active rheumatoid arthritis (1). It is associated with several life-threatening adverse effects, including agranulocytosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatitis (1,2). We describe a patient who developed fatal liver lesions while receiving leflunomide and itraconazole. The patient was a 68-year-old woman with a 30-year history of rheumatoid arthritis complicated by corticoid-induced diabetes and recurrent infections. Unsuccessful treatment with cyclosporine and methotrexate led to the introduction of leflunomide in January 2001. She
Letters to the Editor
received a loading dose, followed by a 10-mg/d dose for 5 months. Several months earlier, she was taking furosemide for hypertension, nadroparin for recurrent thrombophlebitis, insulin for diabetes, methylprednisolone plus omeprazole for rheumatoid arthritis, and domperidone. She was hospitalized 1 month after starting leflunomide for poorly controlled diabetes. In May, she was readmitted for fungal osteitis (Scedosporium apiospermum) of the second metatarsus, which was treated with surgery and itraconazole (300 mg/d). In June, leflunomide was increased to 20 mg/d. Liver function tests were normal. In July, she was admitted to the hospital for abdominal pain, vomiting, and weakness. On clinical examination, blood pressure was 95/42 mm Hg, heart rate was 109 beats per minute, respiratory rate was 19 breaths per minute, and temperature was 36.6°C. Liver function tests revealed cytolytic hepatitis with a serum aspartate aminotransferase (AST) level of 577 U/L (reference, 6 to 25 U/L), an alanine aminotransferase (ALT) level of 1111 IU/L (reference, 5 to 35 U/L), an alkaline phosphatase level of 62 U/L (reference, 45 to 145 U/L), a ␥-glutamyl transpeptidase level of 16 U/L (reference, 6 to 20 U/L), and prothrombin time of 43%. Albuminemia was 17 g/L.
Despite symptomatic treatment and washout with cholestyramine, fulminant hepatic failure occurred (AST, 5940 U/L; ALT, 6950 U/L; ammonemia, 163 mol/L [reference, 14 to 38 mol/L]; prothrombin time, 11%) that led to death. Serologic tests were negative for hepatitis A, B, and C viruses, cytomegalovirus, EpsteinBarr virus, and human immunodeficiency virus. Liver biopsy revealed necrosis that was mainly pericentrolobular, microvesicular steatosis, with canalicular cholestasis and very mild portal and lobular inflammation. Although some of the drugs (omeprazole, domperidone, nadroparin, and insulin) prescribed for this patient can increase liver enzyme levels, leflunomide and itraconazole were more likely to have led to this fatal hepatitis because of their known toxicity. Cytolytic and cholestatic hepatitis have been reported with itraconazole at certain doses (3,4). The temporal relation between leflunomide and the occurrence of hepatic injury is suspected because the leflunomide dose had been increased, severe hypoalbuminemia increased hepatotoxicity, and itraconazole had been introduced recently. Hepatotoxicity of leflunomide has been reported in 10% of cases (1), and the European Agency for the Evaluation of Medicinal Products has received more than 250 reports of hepatic reactions, in-
September 2002
cluding cirrhosis (2 patients) and liver failure (15 patients), with death occurring in 9 patients (5). The majority of serious hepatic reactions was associated with other confounding factors, including concomitant use of hepatotoxic agents (n ⫽ 101) (5). Hepatotoxicity is dose dependent and seems to be induced by the active metabolite of leflunomide (A771726), which is strongly related to plasma proteins, the blood levels of which are presumed to be increased in patients with hypoprotidemia (1). Annick Legras, MD Anne-Marie Bergemer-Fouquet, MD Annie-Pierre Jonville-Bera, MD Hoˆpital Bretonneau Tours, France 1. Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999;58:1137–1164. 2. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet. 1999; 353:259 –266. 3. Garcia-Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999;48:847–852. 4. Lavrijsen APM, Balmus KJ, Nugteren-Huying WM, et al. Hepatic injury associated with itraconazole. Lancet. 1992;340:251– 252. 5. The European Agency for the Evaluation of Medicinal Products. EMEA issues public statement on leflunomide. Reactions Weekly. March 24, 2001;844:2.
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 353