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Cases of secondary hemochromatosis caused by excessive iron ingestion are very rare. In most instances there are associated factors known to cause iron overload, such as anemia, alcoholism or the presence of the hemochromatosis allele. We report a patient who developed secondary hemochromatosis, apparently due only to excessive iron ingestion.
The relationship between iron status and food iron absorption was evaluated in 75 normal volunteers, 15 patients with idiopathic hemochromatosis, and 22 heterozygotes by using double extrinsic radioiron tags to label independently the nonheme and heme iron components of a hamburger meal. In normal subjects, absorption from each of these pools was inversely correlated with storage iron, as measured by the serum ferritin concentration. In patients with hemochromatosis, absorption of both forms of iron was far greater than would be predicted from the relationship between absorption and serum ferritin observed in normal volunteers. Nevertheless, there was still a modest but statistically significant reduction in absorption of nonheme iron with increasing serum ferritin. This relationship could not be demonstrated in the case of heme iron absorption. In heterozygotes, nonheme iron absorption from a hamburger meal containing no supplementary iron did not differ significantly from that observed in normal volunteers. However, when this meal was both modified to promote bioavailability and supplemented with iron, absorption of nonheme iron was significantly elevated. These studies confirm the presence of excessive nonheme iron absorption even from unfortified meals in patients with idiopathic hemochromatosis and suggest in addition that they are particularly susceptible to iron loading from diets containing a high proportion of heme iron. Impaired regulation of nonheme iron absorption was also observed in heterozygous individuals, but a statistically significant abnormality was demonstrable only when the test meal contained a large highly bioavailable iron supplement.
Conventional ferrokinetic studies were done in patients with idiopathic hemochromatosis, secondary siderosis of the liver and iron overload in consequence of sideroblastic or aplastic anaemia. By means of the isotope 59Fe we determined the clearance of radioiron from the plasma, the plasma iron turnover, the utilization of iron by the erythropoesis and the iron uptake by the liver. The later value showed a good correlation with the iron content of the liver determined by atomic absorption spectrometry as well in patients with hemochromatosis as in patients with secondary siderosis of the liver. The 59Fe uptake by the liver was normal in treated hemochromatosis. There was no correlation between the degree of the iron overload and the 59Fe uptake by the liver in patients with anaemia.
Hemochromatosis is a disease in which the inappropriate absorption of iron over 30-40 yr results in tissue iron overload and the development of cirrhosis of the liver, diabetes, hypogonadism, arthropathy, and skin pigmentation. We present an infant who died at 2 days of age, and who was found to have massive iron overload in the liver. This case is consistent with a rare condition that has been called neonatal hemochromatosis. This disease is discussed in the context of an overview of iron metabolism and adult hemochromatosis.
Three sibling and two isolated-case perinates (4 newborn, 1 stillborn) died with siderotic cirrhosis and widespread parenchymal siderosis, the latter similar to that seen in both hereditary and secondary hemochromatosis. Reticuloendothelial siderosis was absent, as occurs in primary hemochromatosis. Studies of iron metabolism were performed antemortem in two of the siblings and ante-, post- and internatally in their mother, who showed hyperferremia antenatally. The only finding in the affected family suggestive of hereditary hemochromatosis was the commonly associated HLA haplotype (A3, B7) in the mother and an infant. Liver morphology, including immunocytochemistry and ultrastructure, was similar in the 5 infants and suggested that liver disease commenced as massive necrosis in midfetal life. Histologic grading and chemical assays for iron and copper on liver and spleen of the 5 index cases were compared with 26 controls; placentas were compared with 12 control placentas. Hepatic iron concentration, but not hepatic copper concentration, was significantly increased in index cases, compared with controls. Hepatic iron to copper ratio was significantly increased in index cases, compared with controls, but this ratio was unaltered in spleen and placenta. Total hepatic iron, but not total hepatic copper, was significantly increased in index cases, compared with a subgroup of 11 controls of low gestational age, similar to the fetal stage when liver disease commenced in utero. The results suggest that, irrespective of the fetal liver disease being genetic or acquired, hepatic iron overload was directly involved in pathogenesis.
A 56-year-old man, who had previously been treated for arthritis of the hands, was admitted to the hospital because of abdominal pain and fever. Physical examination, laboratory tests and liver biopsy led to the diagnosis of hemochromatosis. The patient's brother, who had also been treated for arthritis, was then found to have hemochromatosis. The patient's five children appeared to be well, but serum iron studies and HLA typing showed that four were affected with hemochromatosis.
Primary hemochromatosis is a genetic disorder rarely recognized in childhood; its long-term consequences include cirrhosis and liver cancer. We report a family with primary hemochromatosis affecting three generations, including a 7-year-old child and a 29-month-old child; these are the youngest children with primary hemochromatosis yet reported. The pathophysiology, genetics, and clinical findings of this disorder are reviewed. Serum ferritin and transferrin saturation are useful screening tests; definitive diagnosis, however, depends on determination of hepatic iron content. A plan for evaluating and treating affected patients is proposed. Physicians caring for children must learn to recognize this potentially treatable disorder.
A case of hemochromatosis--a disease in which iron is deposited in parenchymatous organs in the form of hemosiderin leading to fibrosis and functional impairment of these organs--is reported. The classical triad of symptoms seen in hemochromatosis (cirrhosis of the liver, diabetes mellitus, and skin pigmentation) are often supplemented by cardiomyopathy. In this case, postmortem examination revealed pigmentary cirrhosis of the liver and pancreas and hemosiderin deposits in the myocardium and other organs. The leading cause of death was concluded to be hemochromatosis of the heart.
We report a case of idiopathic hemochromatosis presenting clinically, biochemically, and histopathologically with features of chronic active hepatitis. Liver biopsy demonstrated excessive iron deposition as well as a striking inflammatory process. Progressive deterioration of hepatic function led to death despite return of iron levels to values seen in phlebotomy-treated patients with idiopathic hemochromatosis. This case suggests that patients with idiopathic hemochromatosis are not immune to other liver disorders and demonstrates the value of serum tissue iron studies in patients with liver disease of uncertain etiology.
Rare cases of hemochromatosis have been reported in patients who underwent prolonged oral iron therapy for hemolytic anemia or prolonged self-treatment with iron pills. A proportionately large segment of the South African Bantu tribe, who ingest large quantities of an alcoholic beverage brewed in iron pots, are found to have the disease. Reports of health fadists developing hemochromatosis due to excessive dietary iron intake, however, are extremely rare. This report presents clinical considerations and pathologic findings in a compulsive health fadist who consumed large numbers of vitamins containing iron. Clinical findings included the development and progression of cirrhosis of the liver, bronzing of the skin, and diabetes mellitus, all consistent with a diagnosis of hemochromatosis. Light microscopy of liver biopsies taken late in the course of the disease revealed a massive buildup of iron in the hepatocytes, less in the Kupffer cells, and sparse deposition in the epithelial cells of the bile duct. Minimal periportal fibrosis was noted. Electron microscopy showed numerous pleomorphic siderosomes with varying degrees of crystallization and ferritin attached at uniform intervals to the membranes of residual bodies. Abundant free ferritin was observed in most cells. The aggregated and membrane-associated ferritin was verified by non-dispersive x-ray analysis. An additional finding, noted only by electron microscopy, was the presence of many fat-storing cells of Ito, which are thought to be involved in the onset of fibrosis.
A large Mormon pedigree of a proband with hemochromatosis was studied, using transferrin saturation as the quantitative phenotypic trait. The analysis indicated that the inheritance of hemochromatosis was recessive, with partial expression in some heterozygotes. The lod score of 6.88 (theta = .0) was strongly indicative of linkage between the hemochromatosis locus and the human major histocompatibility (HLA) loci.
Deferoxamine-chelatable iron was measured in 103 patients with known or suspected iron overload. All of 34 patients with untreated hemochromatosis had distinctly elevated values for deferoxamine-chelatable iron. The mean value in these cases was significantly greater than that in patients with cirrhosis, who had little or no stainable hepatic iron. In 15 patients with hemochromatosis who were tested sequentially during the course of phlebotomy therapy, deferoxamine-chelatable iron proved a reliable index of the degree of reduction of storage iron. In 22 additional patients with partially treated hemochromatosis and 14 with iron overload accompanying chronic anemia, this test correlated well with the magnitude of iron deposits in liver or bone marrow. In patients with unexplained elevations of serum iron, normal or only slightly elevated deferoxamine-chelatable iron correctly indicated that storage (hepatic) iron was not excessive. The test was more reliable than determination of serum iron or transferrin saturation as an indicator of increased storage iron. Elevated values could not be attributed to disturbed liver function. Determination of deferoxamine-chelatable iron is a safe, practical, and useful procedure for identifying persons with increased iron stores and for assessing the effect of phlebotomy therapy.
The binding of 125I-diferric transferrin to cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes was studied in cells derived from individuals homozygous for hereditary hemochromatosis and from normal individuals. Receptors with a high affinity for diferric transferrin were present on all cells. Transferrin receptor number decreased by more than 50% when fibroblasts from both normal and hemochromatotic subjects were maintained in iron-supplemented medium. The number of transferrin receptors expressed by normal and hemochromatotic lymphocytes after mitogen stimulation in iron-supplemented media was less than 50% that of lymphocytes which were mitogen stimulated in standard medium. No change in the affinity of the receptors for diferric transferrin was seen in cells maintained in iron-supplemented medium. Competition experiments in the presence of deferoxamine suggested that the transferrin receptors of fibroblasts and mitogen-stimulated lymphocytes have a 70- to 100-fold higher affinity for diferric transferrin than for apotransferrin. No differences in the properties of transferrin receptors were found between patients with hereditary hemochromatosis and normal individuals. Although transferrin binding decreases when cells are exposed to high levels of iron in the medium, the failure to totally abolish transferrin binding to the receptor suggests that the concentration of diferric transferrin to which cells are exposed may be a major determinant of cellular iron loading in hereditary hemochromatosis.
Three hundred forty-seven (96.4%) of all persons aged 30 to 39 years were screened with serum iron and iron binding capacity measurements to determine the incidence of hemochromatosis in a population. No women had signs of iron overload; however, nine men (5%) had persistenly elevated serum iron levels. In four men (2%), increased iron stores was found with a distribution like that in the early stages of hemochromatosis. In combination with recent findings of clinical hemochromatosis at our hospital, this study suggests that this condition is not as rare as has been reported earlier.
To evaluate the roles of alcohol and genetic factors in hepatic iron overload, we studied prospectively 61 patients selected solely on the basis of increased stainable hepatic iron (grade 3 or 4). Independent comparisons were made between alcoholic (n = 20) and nonalcoholic (n = 41) patients, and between patients wih affected relatives (n = 25) and those without (n = 36). For the entire group, the mean value for mobilizable iron was 19.6 g and the prevalence of HLA-A3 was 69.6%, both findings compatible with genetic hemochromatosis. Subgroups were no different in clinical features (diabetes, pigmentation, cardiomyopathy, hypogonadism, or arthropaty), histologic findings (fat, inflammation, fibrosis), indexes of iron metabolism (serum iron, transferrin saturation, chelatable iron, and mobilizable iron stores), or frequency of HLA-A3 and HLA-B7. The only exception was that mean hepatic iron concentration was lower in alcoholic patients than in nonalcoholic patients (17,344 vs. 28,553 micrograms/g dry wt, p less than 0.001). Similarity between subgroups in almost all parameters examined is consistent with the hypothesis that heavy deposition of hepatic iron, as observed in our patients, is an indication of genetic hemochromatosis, regardless of alcohol consumption or the findings of affected relatives. The lower concentrations of hepatic iron in alcoholic patients, despite equal body stores in both groups, suggest that alcohol may alter the distribution of storage iron in genetic hemochromatosis.
In three patients arthropathy was the earliest symptom of hemochromatosis. Two of these patients had a precirrhotic stage of hemochromatosis. The liver histology of the third patient showed a beginning cirrhosis. The serum iron ranged from 212 to 260 micrograms/dl. The transferrin saturation was 95-100%. Serum iron and transferrin should be determined in all patients with arthralgias, since arthropathy may be the first clinical sign of hemochromatosis.
A 24-year-old women suffering from primary sterility was diagnosed in 1971 as having idiopathic hemochromatosis (IH). The diagnosis was made on the basis of high serum iron and high transferrin saturation, ferrokinetic studies, including iron absorption, liver biopsy showing heavy deposits of iron in the parenchymatous cells, and a family history. Except for slight elevations in the serum transaminases, there were no clinical or laboratory findings of liver pancreatic, myocardial, or dermal involvement by hemochromatosis. Endocrine evaluation revealed gonadotropin insufficiency as the cause of sterility. The patient was treated with periodic phlebotomies for seven years, and the mount of iron withdrawn during that time was calculated to be approximately 27 g. A repeat liver biopsy showed complete disappearance of the iron excess of the fibrotic changes that had been present in 1971. Repeated relevant clinical and laboratory studies did not reveal any pathological findings consistent with hemochromatosis. A complete endocrine evaluation, including stimulatory tests (luteinizing hormone releasing hormone, thyrotropin-releasing hormone, insulin, and metyrapone), disclosed only findings consistent with hypophyseal gonadotropin insufficiency, and these were attributed to iron deposition. It can be assumed that the prolonged treatment with phlebotomies prevented the development of liver, pancreatic, myocardial, or other clinical endocrine disease, but had no effect on the already damaged pituitary. The patient's clinical course followed the pattern recently described in other young patients with IH.
The hypothesis has been advanced that the two genes on chromosome 6 determining idiopathic hemochromatosis are not identical alleles and therefore that the disease is not recessively inherited, but rather that two different genes are involved. A study of 63 families points to: (a) the rarity with which a single hemochromatosis gene finds biochemical expression (in only 1 of 5 cases), as revealed through determinations of serum iron, serum ferritin and the desferrioxamine test; (b) no difference in HLA-antigen marking between genes with and those without biochemical expression: (c) no difference other than that produced by chance in the biochemical expression of the two genes in families; and (d) the finding in one highly informative family of identical expression of the two genes. It is concluded that idiopathic hemochromatosis is determined by two homologous alleles in accordance with the classical mode of recessive inheritance.