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Iron Overload and Hepatic Fibrosis: In Response
Mayo Clin Proc, June 2004, Vol 79
Letters to the Editor
Arthur Purdy Stout, the doyen of American soft tissue pathologists, expressed the opinion that the lesions were simply benign, if exuberant, fibroblastic proliferations. I was, at that time, assigned to the US Army 406th Medical Laboratory in Japan. It occurred to me that intravenous iron dextran might be toxic to the liver, inducing fibrosis similar to that seen in hemochromatosis and cirrhosis and at injection sites. My commanding officer provided helpful support and supervision. I injected a series of rabbits intravenously with very large amounts of iron dextran (up to 500,000 µg/kg). Initially, the blood iron levels were extremely high, up to 250,000 µg/dL, and even 6 months later, they were in the 2000- to 3000-µg/dL range. After 6 months, I detected no fibrosis in the rabbits’ livers. Therefore, I attempted the same study with mice, made alcoholic by adding 5% ethanol to their drinking water. The mice lost weight and their hair fell out, but no fibrosis was induced. I had failed to find an animal model for the well-known fibroblastic effect of iron on the liver. It didn’t occur to me that there wasn’t much fibroblastic effect. Claude O. Burdick, MD Medical Director Spectra Laboratories Fremont, Calif 1. 2. 3.
Beutler E. Natural history of hemochromatosis [editorial]. Mayo Clin Proc. 2004;79:305-306. Chandra RK. The risk of sarcomatous change after iron-dextran therapy. Indian J Pediatr. 1965;32:75-77. Grasso P. Sarcoma after intramuscular iron injection. BMJ. 1973;2: 667.
In reply: Almost universally, experience has shown that “loading” normal animals with iron does not result in hepatic fibrosis. In experimental animals, fibrosis generally has been produced by iron overload only when some other toxic variable, such as a choline-deficient high-fat diet,1 is superimposed, although rare successes in producing liver damage by iron overloading in rats2 and gerbils3 have been reported. At one time it was generally believed that the apparent resistance of experimental animals to the hepatotoxic effect of iron overload was due entirely to species differences. However, as Dr Burdick suggests, the same seems to be true in humans. Saven and I4 reported the case of a 63-year-old patient who, according to our calculations, had received a total of 52 g of iron in the form of iron dextran over a period of 20 years but had no cirrhosis evident on liver biopsy. It may well be that most humans tolerate massive iron overload well and that additional genetic factors or hepatotoxic environmental factors are needed to produce the severe cirrhosis that occurs in only a small proportion of patients homozygous for the C282Y mutation. Ernest Beutler, MD The Scripps Research Institute La Jolla, Calif 1.
MacDonald RA, Pechet GS. Experimental hemochromatosis in rats. Am J Pathol. 1965;46:85-109.
2. 3. 4.
831 832
Park CH, Bacon BR, Brittenham GM, Tavill AS. Pathology of dietary carbonyl iron overload in rats. Lab Invest. 1987;57:555-563. Pietrangelo A, Gualdi R, Casalgrandi G, Montosi G, Ventura E. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents. J Clin Invest. 1995;95:1824-1831. Saven A, Beutler E. Iron overload after prolonged intramuscular iron therapy [letter]. N Engl J Med. 1989;321:331-332.
Incidence of Bronchiolitis-Associated Hospitalization Among Children in Olmsted County, Minnesota To the Editor: Respiratory syncytial virus (RSV) is the most frequent cause of severe respiratory infections in young children. It is responsible for 80% of cases of bronchiolitis, particularly during the winter months.1 The incidence of RSV hospitalization varies among different population groups.2-4 Targeting the use of currently available prophylactic agents5 will require knowledge of local hospitalization rates. We describe a study of bronchiolitis-associated hospitalization among children in Olmsted County, Minnesota. Patients and Methods.—We performed a retrospective cohort study of all children younger than 24 months old residing in Olmsted County, Minnesota, from January 1990 to December 1999. The medical records of all children hospitalized during RSV season (defined as November to April each year) with a diagnosis of RSV infection or bronchiolitis were reviewed. Birth hospitalizations and nosocomial infections were excluded. Age- and sex-specific incidence rates were calculated for the entire study period. The change in bronchiolitis incidence over the time period of the study was assessed by fitting a generalized linear model assuming a Poisson error distribution with use of the SAS GENMOD procedure (SAS Institute Inc, Cary, NC). Results.—From 1990 to 1999, 280 children younger than 2 years old were hospitalized for bronchiolitis or RSV-related infection in Olmsted County. Of these, 252 (90%) were younger than 12 months old, and 28 (10%) were between 12 and 23 months old. The median age at diagnosis was 4 months. Nearly two thirds (63%) of the patients were male. During the first year of life, the incidence of bronchiolitis hospitalization was significantly higher among male infants, who had a rate of 17.8 per 1000 (95% confidence interval [CI], 15.0-20.6), compared with the rate in female infants of 11.8 per 1000 (95% CI, 9.4-14.2). The sex-adjusted incidence among children younger than 12 months old was 14.9 per 1000 (95% CI, 13.016.7). Among children 12 to 23 months old, the sex-adjusted incidence was 1.5 per 1000 (95% CI, 0.9-2.0). Among our cases, 40 children (14%) had a history of premature birth (<36 weeks of gestation), and 47 (17%) had a birth weight of less than 2500 g. Fifteen children (5%) had congenital heart disease, and 5 (2%) had bronchopulmonary dysplasia. Thirty-five children (12%) were diagnosed as having asthma or reactive airways disease before their hospitalization. Oxygen therapy was administered to 185 children (66%), 76 (27%) were admitted to the intensive care unit, and 17 (6%) required mechanical ventilation. The mean hospital stay was 2.7 days (range, 1-15 days). The peak of bronchiolitis hospi-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Letters to the Editor
Arthur Purdy Stout, the doyen of American soft tissue pathologists, expressed the opinion that the lesions were simply benign, if exuberant, fibroblastic proliferations. I was, at that time, assigned to the US Army 406th Medical Laboratory in Japan. It occurred to me that intravenous iron dextran might be toxic to the liver, inducing fibrosis similar to that seen in hemochromatosis and cirrhosis and at injection sites. My commanding officer provided helpful support and supervision. I injected a series of rabbits intravenously with very large amounts of iron dextran (up to 500,000 µg/kg). Initially, the blood iron levels were extremely high, up to 250,000 µg/dL, and even 6 months later, they were in the 2000- to 3000-µg/dL range. After 6 months, I detected no fibrosis in the rabbits’ livers. Therefore, I attempted the same study with mice, made alcoholic by adding 5% ethanol to their drinking water. The mice lost weight and their hair fell out, but no fibrosis was induced. I had failed to find an animal model for the well-known fibroblastic effect of iron on the liver. It didn’t occur to me that there wasn’t much fibroblastic effect. Claude O. Burdick, MD Medical Director Spectra Laboratories Fremont, Calif 1. 2. 3.
Beutler E. Natural history of hemochromatosis [editorial]. Mayo Clin Proc. 2004;79:305-306. Chandra RK. The risk of sarcomatous change after iron-dextran therapy. Indian J Pediatr. 1965;32:75-77. Grasso P. Sarcoma after intramuscular iron injection. BMJ. 1973;2: 667.
In reply: Almost universally, experience has shown that “loading” normal animals with iron does not result in hepatic fibrosis. In experimental animals, fibrosis generally has been produced by iron overload only when some other toxic variable, such as a choline-deficient high-fat diet,1 is superimposed, although rare successes in producing liver damage by iron overloading in rats2 and gerbils3 have been reported. At one time it was generally believed that the apparent resistance of experimental animals to the hepatotoxic effect of iron overload was due entirely to species differences. However, as Dr Burdick suggests, the same seems to be true in humans. Saven and I4 reported the case of a 63-year-old patient who, according to our calculations, had received a total of 52 g of iron in the form of iron dextran over a period of 20 years but had no cirrhosis evident on liver biopsy. It may well be that most humans tolerate massive iron overload well and that additional genetic factors or hepatotoxic environmental factors are needed to produce the severe cirrhosis that occurs in only a small proportion of patients homozygous for the C282Y mutation. Ernest Beutler, MD The Scripps Research Institute La Jolla, Calif 1.
MacDonald RA, Pechet GS. Experimental hemochromatosis in rats. Am J Pathol. 1965;46:85-109.
2. 3. 4.
831 832
Park CH, Bacon BR, Brittenham GM, Tavill AS. Pathology of dietary carbonyl iron overload in rats. Lab Invest. 1987;57:555-563. Pietrangelo A, Gualdi R, Casalgrandi G, Montosi G, Ventura E. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents. J Clin Invest. 1995;95:1824-1831. Saven A, Beutler E. Iron overload after prolonged intramuscular iron therapy [letter]. N Engl J Med. 1989;321:331-332.
Incidence of Bronchiolitis-Associated Hospitalization Among Children in Olmsted County, Minnesota To the Editor: Respiratory syncytial virus (RSV) is the most frequent cause of severe respiratory infections in young children. It is responsible for 80% of cases of bronchiolitis, particularly during the winter months.1 The incidence of RSV hospitalization varies among different population groups.2-4 Targeting the use of currently available prophylactic agents5 will require knowledge of local hospitalization rates. We describe a study of bronchiolitis-associated hospitalization among children in Olmsted County, Minnesota. Patients and Methods.—We performed a retrospective cohort study of all children younger than 24 months old residing in Olmsted County, Minnesota, from January 1990 to December 1999. The medical records of all children hospitalized during RSV season (defined as November to April each year) with a diagnosis of RSV infection or bronchiolitis were reviewed. Birth hospitalizations and nosocomial infections were excluded. Age- and sex-specific incidence rates were calculated for the entire study period. The change in bronchiolitis incidence over the time period of the study was assessed by fitting a generalized linear model assuming a Poisson error distribution with use of the SAS GENMOD procedure (SAS Institute Inc, Cary, NC). Results.—From 1990 to 1999, 280 children younger than 2 years old were hospitalized for bronchiolitis or RSV-related infection in Olmsted County. Of these, 252 (90%) were younger than 12 months old, and 28 (10%) were between 12 and 23 months old. The median age at diagnosis was 4 months. Nearly two thirds (63%) of the patients were male. During the first year of life, the incidence of bronchiolitis hospitalization was significantly higher among male infants, who had a rate of 17.8 per 1000 (95% confidence interval [CI], 15.0-20.6), compared with the rate in female infants of 11.8 per 1000 (95% CI, 9.4-14.2). The sex-adjusted incidence among children younger than 12 months old was 14.9 per 1000 (95% CI, 13.016.7). Among children 12 to 23 months old, the sex-adjusted incidence was 1.5 per 1000 (95% CI, 0.9-2.0). Among our cases, 40 children (14%) had a history of premature birth (<36 weeks of gestation), and 47 (17%) had a birth weight of less than 2500 g. Fifteen children (5%) had congenital heart disease, and 5 (2%) had bronchopulmonary dysplasia. Thirty-five children (12%) were diagnosed as having asthma or reactive airways disease before their hospitalization. Oxygen therapy was administered to 185 children (66%), 76 (27%) were admitted to the intensive care unit, and 17 (6%) required mechanical ventilation. The mean hospital stay was 2.7 days (range, 1-15 days). The peak of bronchiolitis hospi-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.