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PubMed2001

Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis?

OBJECTIVE: The relationship between the degree of iron overload and the presence of cirrhosis has not been clearly established in hemochromatosis. Severe iron overload occurs without cirrhosis and moderate iron overload can occur with cirrhosis. Previous estimates may have overestimated the problem because of the overdiagnosis of hemochromatosis in patients with alcoholic liver disease and chronic viral hepatitis. The objective of this study was to determine if a threshold for hepatic iron concentration leads to the development of cirrhosis in C282Y hemochromatosis. METHODS: This study included only hemochromatosis patients who were homozygotes for the C282Y mutation of the HFE gene and had undergone liver biopsy with hepatic iron concentration. Analysis of the thresholds for cirrhosis were determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Data were available on 100 C282Y homozygotes (62 men, 38 women; mean age 51, range 18-74 yr). ROC curve analysis showed an area under the curve for hepatic iron concentration versus cirrhosis of 0.85 (95% CI = 0.75-0.96). The threshold for the prediction of cirrhosis was 283 micromol/g. At that threshold, the sensitivity was 85% and specificity 84%. CONCLUSIONS: From this analysis, it appears that a hepatic iron concentration >283 micromol/g is associated with cirrhosis. However, the low sensitivity of this threshold suggests that other cofactors contribute to the development of cirrhosis in hemochromatosis. Early diagnosis is encouraged to initiate iron depletion before the development of cirrhosis.

Case-Control Studies↗
PubMedDate not supplied

Eligibility and exclusion of hemochromatosis patients as voluntary blood donors.

BACKGROUND: Hereditary hemochromatosis patients are excluded in many countries as voluntary blood donors. In 1991, changes in the Canadian Red Cross policy allowed healthy hemochromatosis patients to become voluntary donors. STUDY DESIGN AND METHODS: The medical histories of 208 hemochromatosis patients were evaluated for eligibility for blood donation from a large prospective database of hemochromatosis patients. A survey that determined the success or exclusion of 81 patients for blood donation and the reasons for their exclusion based on Canadian Red Cross donor exclusion criteria was analyzed. RESULTS: Of 208 hemochromatosis patients, 140 (67%) were eligible for blood donation. Criteria for exclusion were other illnesses excluded by Canadian Red Cross criteria and the use of contraindicated medications. Fifty-one per cent of patients had attempted to donate blood, with only 7% being successful. CONCLUSIONS: A large number of potential blood donors are excluded from blood donation inappropriately despite changes in eligibility criteria to the contrary. Further public and health education is needed to increase awareness and, thus, increase blood donation by potential donors.

Blood Donors↗
PubMed2005

Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer.

Iron overload has been noticed as a feature of human breast cancer. Cellular iron uptake is regulated by the hemochromatosis and transferrin receptor system, mutations of which cause the iron storage disease hereditary hemochromatosis. To understand the role of hemochromatosis and transferrin receptor system mutations in breast cancer, we analyzed 19 sequence variations at HFE, TFR1, TFR2, and FPN1 and compared genotype frequencies between cases and controls in a German population. There were 688 breast cancer patients and 724 population-based and age-matched controls. For genotyping, we applied the Hemochromatosis Strip Assay and TaqMan allelic discrimination analyses. In addition to genotype frequencies, we established frequencies of compound genotypes. The frequencies of HFE at His63Asp, Ser65Cys, and Cys282Tyr, and of TFR1 at Ser142Gly minor alleles in this German population were 15.9%, 1.8%, 5.6%, and 46.0%, respectively. No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients. There were no significant differences of allele and genotype frequencies between cases and controls. Triple and quadruple compound genotypes at HFE_His63_Cys282-TFR1_Ser142Gly and HFE_His63_Ser65_Cys282-TFR1_Ser142Gly showed a nonsignificant increase in cases. Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032). Our data suggest that variants of the hemochromatosis-transferrin receptor system have no direct effect on the incidence of breast cancer in Germany. Possible effects on tumor progression and prognosis remain elusive.

Adult↗
PubMed1978

Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis. Role of retinol-binding protein and zinc.

Serum levels of vitamin A, its specific carrier protein retinol-binding protein (RBP), and zinc were determined in 34 cases of idiopathic hemochromatosis, 33 cases of alcoholic cirrhosis, 10 cases of non-alcoholic cirrhosis, and in 35 normal controls. In both alcoholic and non-alcoholic cirrhosis, vitamin A and RBP levels were very significantly reduced, whereas a significantly low zinc was observed only in the alcoholic cirrhosis group. In idiopathic hemochromatosis, vitamin A values were significantly lower compared to normals, whereas serum RBP levels were normal and serum zinc was very close to that of the controls. A significant correlation was found between vitamin A and RBP levels in the entire group of 112 patients. These results, (1) in alcoholic and non-alcoholic cirrhosis, confirm a dramatic vitamin A deficiency and the major role played by decreased RBP, but tend to deemphasize the possible role of zinc deficiency; (2) in idiopathic hemochromatosis, affirm a significant serum vitamin A deficiency supposedly by a different mechanism from that of alcoholic cirrhosis since in idiopathic hemochromatosis plasma RBP levels are normal. The role of this vitamin A disorder should be considered in the interpretation of clinical signs of idiopathic hemochromatosis such as ichthyosis and visual disorders.

Adult↗
PubMed1980

Association of HLA-linked hemochromatosis with idiopathic refractory sideroblastic anemia.

Five of seven patients with idiopathic refractory sideroblastic anemia carried an HLA-A3 alloantigen (relative risk, 7.3; P = 0.02). The significance of this association was strengthened by study of two pedigrees. An abnormality in iron metabolism was found in two siblings who had an HLA-A3,B14 haplotype in common with the first proband. A second proband with idiopathic refractory sideroblastic anemia had clinically manifest hemochromatosis. His brother had clinically manifest hemochromatosis but not sideroblastic anemia. This proband and his brother shared only the HLA-A3,B12 haplotype. Our findings infer that patients with idiopathic refractory sideroblastic anemia carry a single allele for hemochromatosis, that this allele accounts for the increased iron loading in this form of anemia, and that clinically manifest hemochromatosis may develop in an occasional patient with only one allele for hemochromatosis in the presence of the sideroblastic factor.

Adult↗
PubMed2003

Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron.

Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron.

Antimicrobial Cationic Peptides↗
PubMed2005

Hereditary hemochromatosis is reflected in the iron isotope composition of blood.

It has recently been shown that the iron isotopic composition of blood differs between individuals and sexes, which is supposed to reflect individual differences in iron metabolism. We hypothesized that patients suffering from hereditary hemochromatosis would demonstrate alterations in the iron isotopic composition of blood due to persistent up-regulation of intestinal iron absorption. Blood from 30 patients with homozygous C282Y hemochromatosis was analyzed for iron isotopic composition by a newly developed technique using multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS). Blood of patients with hemochromatosis is characterized by a higher 56Fe/54Fe isotope ratio than blood of healthy individuals, which are either members of an age-matched control group (n = 10; P < .001) or young adults (n = 36; P < .001). In patients with hereditary hemochromatosis, the 56Fe/54Fe isotope ratio of blood significantly correlates with total-body iron accumulation, severity of clinical disease, and the need for regular phlebotomies to prevent iron reaccumulation. We conclude that blood of patients with hereditary hemochromatosis contains more of the heavier iron isotopes than blood of healthy individuals. The primary determinant of the iron isotopic composition of blood appears to be isotope-sensitive iron absorption in the intestine and the efficiency of this process.

Adult↗
PubMed2001

Cardiac dysfunction because of secondary hemochromatosis caused by congenital non-spherocytic hemolytic anemia.

Most patients diagnosed with secondary hemochromatosis have had repeated blood transfusions. Cardiac failure accounts for approximately one-third of the deaths associated with hemochromatosis. Liver dysfunction or hormonal disorders such as diabetes generally precede cardiac failure. A 23-year-old woman with hemochromatosis had, despite significant left ventricular dysfunction, liver function within the normal range on biochemical evaluation. She was treated for congestive heart failure and given desferoxamine intravenously. She did not have primary hemochromatosis, and had not received multiple blood transfusions or iron supplement. As a child the patient had been diagnosed with congenital non-spherocytic hemolytic anemia not requiring transfusion; thus, this is a unique case of secondary hemochromatosis.

Adult↗
PubMed2006

Neonatal hemochromatosis: long-term experience with favorable outcome.

OBJECTIVE: Neonatal hemochromatosis is a severe, often fatal multiorgan disorder of iron metabolism. Liver transplantation can be curative; the benefit of antioxidant treatment is discussed controversially. We summarize our experience with neonatal hemochromatosis over the past 13 years. METHODS: A retrospective study was performed of 16 patients with acute liver failure attributable to neonatal hemochromatosis between 1992 and 2004. RESULTS: Median age at the onset of neonatal hemochromatosis was 2 days (range: 0-21 days). Median weight at the time of diagnosis was 2900 g (range: 1520-4200 g). All patients had elevated ferritin levels (median: 4179 microg/L), and transferrin saturation (median: 99%). Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 children had additional iron deposition in extrahepatic tissue. Four patients were diagnosed by MRI. Seven infants received liver transplants, 5 of them in combination with a preceding antioxidant treatment. Four children (25%) received antioxidants without the necessity of liver transplantation and were in good clinical condition at the time of this evaluation. Five patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In September 2005, 68.7% of the patients were still alive after a median follow-up of 5 years. CONCLUSIONS: Neonatal hemochromatosis is a severe metabolic disease, but early antioxidant treatment and liver transplantation in addition to optimal medical care can improve the outcome dramatically. Children with moderate liver failure can survive without liver transplantation, but should be monitored closely for deterioration.

Antioxidants↗
PubMed1976

Hemochromatosis: a disease often silent but not invisible.

Hemochromatosis is a disorder characterized by the association of portal cirrhosis with deposition of excess amounts of iron in the parenchymal cells of many organs. Arthralgia and arthritis occur in about 50% of patients. The role of the radiologist is often significant in the recognition of this condition because hemochromatosis may be unsuspected clinically since the hepatic cirrhosis is frequently inactive at the time the arthritis develops. The possibility of hemochromatosis should be considered when the characteristic involvement of the metacarpophalangeal, radiocarpal, and proximal interphalangeal joints of the hand and wrist is present. In addition, articular and fibrocartilage calcification is often noted, particularly in the knee, triangular cartilage of the wrist, hip, elbow, symphysis pubis, and shoulder. Although localized chondrocalcinosis may be seen in association with many disorders, as well as in asymptomatic elderly persons, generalized chondrocalcinosis is a significant finding and is commonly associated with hemochromatosis. Recognition of the typical distribution of the arthropathy plus its characteristic roentgenographic features should aid in the identification of patients with the disorder who do not demonstrate the typical clinical features of hemochromatosis.

Arthritis↗
PubMed1997

Clinical features of genetic hemochromatosis in women compared with men.

BACKGROUND: The clinical expression of hemochromatosis is presumed to be less frequent and less severe in women than in men because of the iron loss associated with menses and pregnancy, but this hypothesis has not been validated. OBJECTIVE: To compare the clinical features of women who have genetic hemochromatosis with those of men who have the disease. DESIGN: Cross-sectional study. SETTING: Tertiary referral centers for hemochromatosis in France and Canada. PATIENTS: 176 women and 176 men with hemochromatosis, matched for year of birth. MEASUREMENTS: Age at presentation, clinical symptoms, transferrin saturation, serum ferritin level, hepatic iron concentration, and hepatic iron index. RESULTS: Hepatic iron concentration and hepatic iron index were similar in men and women. Women had lower serum ferritin levels than men did (911 micrograms/L compared with 1911 micrograms/L; mean difference, 1000 micrograms/L [95% CI, 669 micrograms/L to 1331 micrograms/L]) and less iron removed by venesections (5.5 g and 8.6 g; mean difference, 3.1 g [CI, 1.5 g to 4.8 g]). Compared with women, men had a higher incidence of cirrhosis (25.6% and 13.8%; mean difference, 11.8 percentage points [CI, 3.2 to 20.4 percentage points]) and diabetes (15.9% and 7.4%; mean difference, 8.5 percentage points [CI, 1.9 to 5.2 percentage points]). Compared with men, women had a higher incidence of fatigue (64.8% and 42%; mean difference, -22.8 percentage points [CI, -32.9 to -12.5 percentage points]) and pigmentation (48% and 44.9%; mean difference, -13.1 percentage points [CI, -23.4 to 2.7 percentage points]). Hepatic iron concentration and hepatic iron index were greater in women in whom menstruation had stopped before 50 years of age. Serum ferritin levels and transferrin saturation were normal in 6.2% of women and 0% of men. CONCLUSIONS: Women with genetic hemochromatosis can have full phenotypic expression of the disease, including cirrhosis. Recognizing the nonspecific nature of presenting symptoms in women is essential for early diagnosis and treatment.

Age Factors↗
PubMedDate not supplied

Hereditary hemochromatosis.

BACKGROUND: The understanding of hereditary hemochromatosis, along with the availability of genetic testing, is changing the approach to diagnosis of the disease. METHODS: A MEDLINE search was performed using multiple key words related to hemochromatosis and iron metabolism. RESULTS: Most cases of hereditary hemochromatosis are caused by a single mutation to the HFE gene, resulting in unregulated dietary iron uptake. The signs and symptoms of hereditary hemochromatosis are nonspecific and common in family practice settings. Measuring the transferrin saturation level is a cost-effective way to screen for suspected disease. Subsequent workup includes serum ferritin levels, hepatic enzyme levels, and HFE gene testing, or liver biopsy. HFE gene testing can provide a definitive diagnosis in many patients. Liver biopsy is useful and indicated when liver disease is clinically evident. CONCLUSION: For many patients, hereditary hemochromatosis can be diagnosed and treated in the physician's office. After iron mobilization with therapeutic phlebotomy, most patients will require phlebotomy 2 to 4 times each year throughout their lifetime. Treatment before organ toxicity occurs leads to a normal life span. Treatment after symptoms appear is less effective but can improve some signs and symptoms of iron toxicity.

Hemochromatosis↗
PubMedDate not supplied

Liver ferritin subunit ratios in neonatal hemochromatosis.

Neonatal hemochromatosis is an enigmatic disease. Little is known about iron metabolism in this disease, including the tissue concentration of ferritin or its H and L subunit ratio. The authors report the tissue iron, ferritin, and ferritin subunit content of a child who died at 5 weeks of neonatal hemochromatosis. The child was born at 29 weeks gestation to a mother with lupus, sickle cell trait, and gestational diabetes. The child's severe liver dysfunction led to the clinical diagnosis of neonatal hemochromatosis at 1 week of age. Despite aggressive support, including red cell transfusions and chelation, the child died of an intracranial hemorrhage. Autopsy showed liver fibrosis and iron staining characteristic of neonatal hemochromatosis. Autopsy liver tissue was compared to age-matched control tissue. Soluble protein was analyzed by the Bradford method. Soluble iron (over 90% of total iron) was analyzed by the o-phenanthroline complex. Tissue ferritin and human ferritin controls (Calzyme) were analyzed by Western blotting after SDS-PAGE, identified with sheep anti-human ferritin antibodies (The BindingSite) secondary antibody-fluorescence for detection, and quantified using the Molecular Dynamics Storm 840 phosphorimager and ImageQuant software. Protein, iron, and total ferritin were similar in the normal and neonatal hemochromatosis liver tissues. Ferritin subunits, however, showed an increased H/L-subunit ratio compared to an age-matched control. This first report of a marked increase in the ferritin H/L-subunit ratio may point to an underlying mechanism of disease in this enigmatic disorder.

Biopsy↗
PubMed2005

Inherited hemochromatosis: from genetics to clinics.

Hereditary hemochromatosis is one of the most common autosomal recessive disorder among Caucasians since the genotype at risk for hemochromatosis accounts for 1:200-400 individuals of Northern European ancestry. The disease is characterized by an inappropriately increased intestinal iron absorption leading to early abnormalities of iron parameters followed by iron deposition in different organs. Excessive iron causes tissue damage and fibrosis, leading to organ failure. Clinical complications appear late in life and include liver cirrhosis, diabetes, cardiomyopathy, hypogonadism, arthropathy, skin pigmentation and susceptibility to liver cancer. Clinical symptoms develop only in homozygotes. Heterozy-gotes may show abnormalities of iron parameters, but are not clinically affected, unless carriers of other conditions which modify iron metabolism, such as chronic liver diseases, beta-thalassemia trait or other haemolytic anemias. The phenotypic expression of the disease is variable even within the same family, due to the effect of modifier genes or to environmental factors. Recent progress of genetics and molecular biology have shown that hemochromatosis is an heterogeneous disease, that may result from the inactivation of different genes. The identification of mutations of HFE and of other genes involved in the disease has allowed to develop molecular tests to support early diagnosis, allowing also to ameliorate the differential diagnosis with other iron loading disorders. In addition, the increased knowledge acquired from the study of hemochromatosis has contributed to clarify the pathophysiology of iron metabolism. For this reason hemochromatosis is considered a typical example of molecular medicine.

Hemochromatosis↗
PubMed1987

Stainable iron in gastric and duodenal mucosa of primary hemochromatosis patients and alcoholics.

The presence of iron in gastric and duodenal mucosa was investigated with Perl's stain in endoscopic biopsies from 13 patients with overt primary hemochromatosis, 10 chronic heavy alcohol abusers, and 10 patients with nonulcer dyspepsia. In the primary hemochromatosis patients marked iron deposition was found in cells at the base of glands in the gastric body and antrum in nine cases, and in crypt cells and Brunner gland cells of the duodenum in six. Iron was detected in the lamina propria of the stomach in five and duodenum in four cases. A similar distribution of iron overload, usually of lesser degree, was also observed in five alcoholics. Serum ferritin levels and the degree of gastric and/or duodenal iron deposits did not correlate in either hemochromatosis patients or alcoholics. No gastric or duodenal siderosis was observed in nonulcer dyspepsia cases. The absence of gastric and duodenal stainable iron in some hemochromatosis patients and its presence in some alcoholics suggests that the diagnostic value of upper gastrointestinal biopsy in primary hemochromatosis is limited.

Adult↗
PubMed1980

Hepatic and serum ferritin concentrations in patients with idiopathic hemochromatosis.

Hepatic iron and ferritin concentrations have been measured in needle biopsy specimens from patients with idiopathic hemochromatosis and from patients with other liver diseases. There was an excellent correlation between liver iron and ferritin concentrations in patients with miscellaneous liver diseases, but this was not found for the patients with hemochromatosis either before or after treatment. The proportion of liver iron bound to ferritin was lower in treated and untreated hemochromatosis than in the other patients. This probably reflects the formation of increasing amounts of hemosiderin with increasing iron deposition. Three patients in the early stage of idiopathic hemochromatosis were studied. These patients had high concentrations of hepatic iron and ferritin, but had serum ferritin concentrations within, or just above, the normal stage. These results suggest that, in the early stage of hemochromatosis, there is no failure of ferritin synthesis in the liver and that normal levels of serum ferritin are present either because the total body iron content is within the normal range or because the liver parenchymal cells are not, in the absence of liver damage, an important source of plasma ferritin.

Adult↗
PubMed1994

Genetic discrimination and screening for hemochromatosis.

Recent advances in tests for the genotype for hemochromatosis and suggestions that the tests be used in mass screening programs for the disease raise the possibility of a large increase in the incidence of discrimination against people who are found to be homozygous for hemochromatosis. This paper presents cases of genetic discrimination drawn from a study of discrimination against people with a variety of genetic conditions. The cases discussed here involve employment and several types of insurance discrimination against people diagnosed with hemochromatosis who either are currently asymptomatic or whose condition is controlled by means of phlebotomies. There is no justification for these types of discrimination since people with controlled hemochromatosis suffer no excess mortality or morbidity. Our study suggests that genetic discrimination is already a serious problem and that any proposed screening program for hemochromatosis or other genetic condition must consider and attempt to mitigate its effects.

Adult↗
PubMed1994

Cost-effectiveness of screening for hereditary hemochromatosis.

BACKGROUND: Recent studies have estimated the prevalence of hereditary hemochromatosis to be 3 to 8 per 1000. Early detection and treatment can prevent disease manifestations and normalize life expectancy. We used decision analysis techniques to determine whether screening the population at large for hereditary hemochromatosis would be cost-effective. METHODS: We constructed a model to compare the cost and outcome of a strategy of performing screening transferrin saturation tests on cohorts of 30-year old men with that of awaiting symptomatic disease. Baseline estimates of disease prevalence and complication rates were based on the published literature. Costs of treatment were estimated based on prevailing local costs. Sensitivity analyses were then conducted to determine which variables had the most significant impact on the decision to screen. RESULTS: At our baseline estimates, the decision to screen was found to be a dominant strategy and resulted in cost saving. Sensitivity analysis showed that four variables had the most significant impact on the decision to screen: (1) the prevalence of hereditary hemochromatosis, (2) the probability of developing disease manifestations, (3) the cost of the screening test, and (4) the discount rate. Screening was a dominant strategy for asymptomatic men provided that the prevalence of hereditary hemochromatosis was at least 3 per 1000, the probability of developing disease manifestations was greater than 0.4, the test cost was less than $12, and the discount rate was less than 3%. Using more pessimistic estimates, the cost per life year saved was still less than that considered acceptable for many common medical interventions. CONCLUSION: Screening for hereditary hemochromatosis has a favorable cost-effectiveness ratio over a wide range of assumptions. We recommend that practitioners consider including a serum transferrin saturation test in their routine screening for asymptomatic white men.

Adult↗