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A 47 year old kidney transplant recipient who died from liver failure caused by hemochromatosis, is described. The diagnosis was established by post mortem examination. The question whether these findings are an extreme form of the common pathological changes seen in the liver in other transplant recipients, or were related to infectious hepatitis or were due to the use of immunosuppressive therapy, remains unanswered.
A 12-year-old girl with congenital dyserythropoietic anemia, type I, was diagnosed as having hemochromatosis. Deferoxamine was given subcutaneously for 14 months. Iron overload, as measured by liver iron and serum ferritin levels, was reduced substantially, liver function tests improved, and hepatomegaly decreased. Toxicity was negligible.
Anterior pituitary function, particularly the hypothalamus-pituitary gonadal axis, has been investigated in four patients with idiopathic hemochromatosis and in two potentially affected family members (sons) of one patient. All the patients presented a hypogonadotrophic hypogonadism. In one patient there was an associated primary testicular failure. Gonadotropin secretion was intact in the family members. The remaining pituitary functions were usually preserved, except a probable decrease of the glandular reserve of TSH in two patients, and of prolactin in one of them.
Idiopathic hemochromatosis (iH) is typically a disease of older males. The case presented here describes a 26-yr-old woman with problems presenting heart failure, insulin-dependent diabetes, hepatomegaly, and secondary amenorrhea. The diagnosis was established by serum iron and transferrin saturation measurements, liver biopsy, and bone marrow examination for iron. Twenty grams of iron were removed by phlebotomy over 30 mo, and the patient's symptoms improved. A review of the literature pertinent to people with symptomatic onset of IH before age 30 yr revealed 52 young people in addition to this case. In contrast to IH patients older than 30, there was an almost equal ratio between the sexes, a greater frequency of cardiomyopathy and hypogonadism, and a lower frequency of diabetes mellitus and hepatic involvement. An autosomal recessive mode of inheritance appears to be most likely in this young group.
Heart failure and hypogonadotropic hypogonadism are the most frequent clinical problems encountered in patients with juvenile idiopathic hemochromatosis (JIH). In this context, amenorrhea is one of the first symptoms in female patients, and hormone therapy must be added to phlebotomy to restore menstrual cycles. Here we report the case of a woman in childbearing age with hypogonadotropic hypogonadism due to JIH. Following therapy with gonadotropinic hormones the patient had a twin pregnancy with term delivery. The newborns presented a normal iron status. This confirms that early diagnosis and treatment of JIH are important to prevent irreversible organ damage and shows that the female reproductive function can be preserved in adequately treated patients.
Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.
We present a patient with hemochromatosis whose first sign of disease was an accidental finding of interstitial patterns on a chest film and whose transbronchial biopsy showed traces of iron (Fe) in alveolar macrophages and septal matter. We then looked for deposits in other locations, finding Fe ([+]: 6.964 micrograms) in the dry weight of a cylindrical sample of liver tissue. A Medline search on CD-ROM for 1989 through May of 1994 revealed no references to similar cases.
Hereditary hemochromatosis is a common genetic disorder. A large number of homozygous patients with early disease are asymptomatic, but with early diagnosis and treatment, their life expectancy is normal. The best screening test is determination of the percent saturation of transferrin or the transferrin index. Liver biopsy with measurement of hepatic iron concentration is required for definitive diagnosis. Once the diagnosis is confirmed, treatment by phlebotomy at regular intervals is straightforward.
A significant body of research over the last 10-20 years supports the hypothesis that screening for hereditary hemochromatosis (HH) may be cost-effective, given the low-cost, low-risk therapeutic options available for most homozygous individuals. The factors that confound a straightforward test of this hypothesis include the fact that the disease is not fully penetrant and that, to achieve the anticipated life-year gains, therapy must be instituted before disease complications become irreversible. Recent articles and editorials, as well as practice guidelines prepared by the College of American Pathologists, recommend screening for HH with transferrin saturation and ferritin testing, and with percutaneous liver biopsy for those with positive laboratory test results. Patients at risk would be treated with phlebotomy for life and monitored with ferritin testing. We present a cost-effectiveness analysis that evaluates the efficacy of using a screening strategy to accomplish the desired healthcare goals.
We postulated that patients with hereditary hemochromatosis (HH) absorb increased quantities of lead, as do iron-deficient subjects. To test this hypothesis, whole blood lead concentration ([blood Pb]) was quantified by atomic absorption spectrometry in HH homozygotes (n = 44), obligate heterozygotes (n = 19), normal control subjects (n = 33), and abnormal controls, with transfusion-induced iron overload (n = 8). HH homozygotes had higher [blood Pb] than did normal control subjects (5.6 +/- 0.6 microgram/dl vs 3.6 +/- 0.5 microgram/dl; p < 0.005); significantly increased mean [blood Pb] was observed in both male and female homozygotes. In heterozygotes, the mean [blood Pb] 4.1 +/- 0.5 microgram/dl) was intermediate between that of homozygotes and normal control subjects. The mean [blood Pb] of subjects with transfusion-induced iron overload (22 +/- 0.6 microgram/dl) did not differ significantly from that of normal controls. The findings in homozygotes could to be related to age, serum ferritin concentration, presence or absence of iron loading, or the extent of therapeutic phlebotomy. Lead exposure in all of our subjects was due primarily to ambient sources. Analysis of our data, when using a mathematical biokinetic model of human lead metabolism, suggests that the most likely explanation for our findings is that homozygotes (and, to a lesser extent, heterozygotes) absorb increased quantities of lead, a conclusion that corresponds to the increased absorption of iron and cobalt previously documented in homozygotes.
Computed tomography (CT) was performed to estimate the density of the hepatic and splenic parenchyma in 18 patients with hemochromatosis. The mean CT density was 79 +/- 21 Hounsfield units compared with 61 +/- 9 (p < 0.01) in 31 controls without hepatic disease. Increased density above 79 Hounsfield units was found in eight patients out of 18 (44%). The highest density (125 Hounsfield units) was found in a patient with a serum ferritin of 6500 micrograms/l. There was an association between CT density and serum ferritin (r = 0.72, p < 0.01). The difference in density between liver and spleen gave better discrimination between patients and controls: 12 of 18 (67%) showed an increased difference in density between liver and spleen. We conclude that CT represents a non-invasive alternative to liver biopsy in cases where the latter is contraindicated. However, CT is not sensitive when serum ferritin is below 1,000 micrograms/l.
During the period 1986-93 22 patients were diagnosed as having primary hemochromatosis. Only 11 of them had elevated aminotransferases. Transferrin saturation was higher > 63% in 17 (77%) and serum-ferritin was higher in all the patients. (257 mumol/l to 6,500 mumol/l). A percutaneous liver biopsy was performed in 20 patients, all of whom showed a characteristic grading from 2 + to 4+ using Perls' stain. Two males had cirrhosis with simultaneous hepatocellular carcinoma, and another two had cirrhosis. One patient had diabetes mellitus type I. We conclude that fasting serum-iron and transferrin should be determined in all subjects over 40 years of age and in patients with chronic elevation of liver enzymes. If transferrin saturation is higher than 50% in females and 60% in males, serum ferritin should be determined. A percutaneous liver biopsy should be performed if both values are higher than normal. Screening of siblings is important because of the autosomal recessive pattern of inheritance.
A case of genetic hemochromatosis presented with asymptomatic hepatomegaly. The diagnosis was based on elevated serum iron, serum ferritin and transferrin saturation, a characteristic picture on magnetic resonance imaging, and liver biopsy showing cirrhosis with excessive iron deposits in the liver parenchyma. The extreme rarity of this disease in our country is perhaps determined by hereditary factors.
We compared hepatic morphology, hepatocellular siderosis, extrahepatic parenchymal siderosis, and (by chemical assay of liver and spleen) the amount of elemental iron and copper in 12 cases of perinatal hemochromatosis (PH) with 119 perinatal controls. Controls were subgrouped according to diagnoses based on clinical and autopsy findings; 37 had chronic liver disease, either hepatic fibrosis (17) or cirrhosis (20). Graded semiquantitatively, hepatocellular siderosis varied widely among controls, and some showed more than PH cases. By chemical assay, total hepatic iron in PH cases was not significantly greater than in any control group except the preterm. Therefore, our findings do not support an etiological role for iron in PH. Its distinctive hepatic morphology seems related to onset of liver disease during fetal life, when periportal hepatocytes normally contain hemosiderin (as in 71 of 82 controls without chronic liver disease). Environmental agents (such as hypoxia, virus, drug) that could damage a fetal liver would usually damage other fetal organs as well. They would be unlikely to recur in a subsequent pregnancy and thereby account for PH occurring in siblings. In initiating PH, therefore, putative environmental agents may need to interact with a factor or factors intrinsic to the developing fetal liver.
Iron overload is a major cause of morbidity and mortality in thalassemia major patients. All chronic liver diseases may be associated with such endocrine symptoms as diabetes mellitus, testicular failure or hypothyroidism. We studied 15 thalassemic patients (12 men and 3 women; age range: 10-50 years, mean: 22.5 years). All patients received blood transfusions, but only some were treated with iron chelation. Seven patients were splenectomized. MRI was performed with an 0.5 T superconducting magnet, using SE T1- and T2-weighted and IR sequences. We used these data with Bloch's equation to calculate T1 and T2 values. Quantitative analysis was made by calculating signal intensity and relaxation times in 8 hepatic regions of interest: marked reduction in hepatic signal intensity and a negative relationship between T1 and serum ferritin (r = 0.646, p < 0.01) and between T2 and serum ferritin (r = 0.688, p < 0.01) were observed. Moreover, a negative relationship was found between hepatic signal intensity and aspartic aminotransferase (r = 0.524, p < 0.05). Our results confirm the value of MRI in the diagnosis and evaluation of hepatic iron overload but an accurate quantitative analysis can be made only when hepatic iron levels are between 1 and 2 mg/g of liver. Even though it is below statistical significance, the negative relationship between signal intensity and aspartic aminotransferase suggests that hepatic hemochromatosis can influence pituitary-thyroid axis and interfere with peripheral hormone metabolism.
It has previously been shown that cDNA hybridization selection can identify and recover novel genes from large cloned genomic DNA such as cosmids or YACs. In an effort to identify candidate genes for hemochromatosis, this technique was applied to a 320-kb YAC containing the HLA-A gene. A short fragment cDNA library derived from human duodenum was selected with the YAC DNA. Ten novel gene fragments were isolated, characterized, and localized on the physical map of the YAC.
The hemochromatosis (HC) gene is known to be linked to HLA-A (6p21.3); however, its precise location has been difficult to determine because of a lack of additional highly polymorphic markers for this region. The recent identification of short tandem repeat sequences (microsatellites) has now provided this area with a number of markers with similar polymorphic index to the HLA serological polymorphisms. Using four microsatellites--D6S105, D6S109, D6S89, and F13A--together with the HLA class I loci HLA-A and HLA-B in 13 large pedigrees clearly segregating for HC, we have been able to refine the location of the HC gene. We identified no recombination between HC and HLA-A or D6S105, and two-point analyses placed the HC gene within one centimorgan (cM) of HLA-A and D6S105 (HLA-A maximum of the lod score [Zmax] of 9.90 at recombination fraction [theta] of 0.0, and D6S105 Zmax of 8.26 at theta of 0.0). The markers HLA-B, D6S109, D6S89, and F13A were separated from the HC locus by recombination, defining the centromeric and telomeric limits for the HC gene as HLA-B and D6S109, respectively. A multipoint map constructed using HLA-B, HLA-A, and D6S109 indicates that the HC gene is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A. These pedigree data indicate an association between HC and specific alleles at HLA-A and D6S105 (i.e., HLA-A3 and D6S105 allele 8).(ABSTRACT TRUNCATED AT 250 WORDS)
Skin manifestations of idiopathic hemochromatosis (IH) are presented in 100 cases with emphasis on the previously unrecognized high frequency of ichthyosis-like states and koilonychia. In 50 cases with treated and nontreated groups, histological siderosis and clinical skin pigmentation were found to decrease postphlebotomy whereas melanosis, histologically, did not. By skin biopsy in 50 cases versus controls, the location of siderosis in eccrine sweat glands seems specific for IH providing a strong basis for a probable diagnosis of the disease. There are correlations between skin manifestations and other signs of the disease.