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PubMed2006

A diagnostic approach to hemochromatosis.

In the present clinical review, a diagnostic approach to hemochromatosis is discussed from the perspective of two clinicians with extensive experience in this area. The introduction of genetic testing and large-scale population screening studies have broadened our understanding of the clinical expression of disease and the utility of biochemical iron tests for the detection of disease and for the assessment of disease severity. Liver biopsy has become more of a prognostic test than a diagnostic test. The authors offer a stepwise, diagnostic algorithm based on current evidence-based data, that they regard as most cost-effective. An early diagnosis can lead to phlebotomy therapy to prevent the development of cirrhosis.

Hemochromatosis↗
PubMed2004

Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer.

Individuals with the major hemochromatosis (HFE) allele C282Y and iron overload develop hepatocellular and some extrahepatic malignancies at increased rates. No association has been previously reported between the C282Y allele and breast cancer. We hypothesized that due to the pro-oxidant properties of iron, altered iron metabolism in C282Y carriers may promote breast carcinogenesis. Because 1 in 10 Caucasians of Northern European ancestry carries this allele, any impact it may have on breast cancer burden is potentially great. We determined C282Y genotypes in 168 patients who underwent high-dose chemotherapy and blood cell transplantation for cancer: 41 with breast cancer and 127 with predominantly hematological cancers (transplant cohort). Demographic, clinical, and tumor characteristics were reviewed in breast cancer patients. The frequency of C282Y genotypes in breast cancers was compared with the frequency in nonbreast cancers, an outpatient sample from Tennessee (n = 169), and a published United States national sample. The frequency of at least one C282Y allele in breast cancers was higher (36.6%, 5 homozygotes/10 heterozygotes) than frequencies in Tennessee (12.7%, P < 0.001), the general population (12.4%, P < 0.001), and similarly selected nonbreast cancers (17.0%, P = 0.008). The likelihood of breast cancer in the transplant cohort increased with C282Y allele dose (P(trend) = 0.010). These results were supported by the finding in a nontransplant cohort of a higher frequency of C282Y mutations in Caucasian (18.4%, P = 0.039) and African-American (8.5%, P = 0.005) women with breast cancer than race-specific national frequency estimates. A high prevalence of C282Y alleles in women with breast cancer with and without poor risk features suggests that altered iron metabolism in C282Y carriers may promote the development of breast cancer and/or more aggressive forms of the disease.

Adult↗
PubMed2000

Erythrocytapheresis with recombinant human erythropoietin in hereditary hemochromatosis therapy: a new alternative.

BACKGROUND AND OBJECTIVES: The purposes of this study were to evaluate the tolerance, efficacy and safety of isovolemic erythrocytapheresis (EA) in nonanemic patients with hereditary hemochromatosis (HH), and to assess the usefulness of recombinant human erythropoietin (rHuEPO) associated with EA to reduce treatment duration. MATERIALS AND METHODS: In 10 asymptomatic patients with serum ferritin >400 microg/l, transferrin saturation >50%, and GPT elevation, EA with rHuEPO and folic acid was performed. RESULTS: Red cell indices, serum ferritin, and other iron metabolism parameters (serum iron, transferrin, and transferrin saturation); GPT and other laboratory data were considerably improved. CONCLUSION: This method offers better results in less time than traditional phlebotomy. EA with rHuEPO is an effective therapeutic alternative for patients with HH.

Adult↗
PubMed2003

Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease.

The H63D mutation in the hemochromatosis gene (HFE) has recently been considered as a risk factor in Alzheimer's disease (AD) with advancing age at onset of the disease, independently of the apolipoprotein E (ApoE) epsilon4 allele effect. We examined the distribution of the H63D mutation and ApoE genotypes as a function of age at AD onset in 328 patients with sporadic AD. Our data show that the mutant H63D allele potentially interacts with the ApoE epsilon4 allele to significantly reduce age at onset of AD compared to ApoE epsilon4 carriers alone, but has no effect on age at onset in ApoE epsilon4 non-carriers.

Age of Onset↗
PubMed2003

High incidence of hemochromatosis gene mutations in the myelodysplastic syndrome: the Budapest Study on 50 patients.

Genotypic testing of nonselected patients with the myelodysplastic syndrome (MDS) for the C282Y and H63D mutations of the HFE gene responsible for hereditary hemochromatosis revealed a significantly increased frequency of these mutations when compared to healthy blood donors reflecting the average population. Among the 50 patients examined [26 refractory anemia (RA), 9 refractory anemia with ring sideroblasts (RARS), 2 refractory anemia with excess of blasts (RAEB) and 13 refractory anemia with excess of blasts in transformation (RAEB-t)] there were 24 heterozygotes (20 for H63D and 4 for C282Y), 1 homozygote for H63D and 1 compound heterozygote. The difference between the HFE-positive and HFE-negative MDS patients as regards initial serum iron and transferrin saturation was not significant. Inevitably the iron overload syndrome eventually develops in MDS patients due to intrinsic characteristics of the disease as well as an escalating need for blood transfusion therapy in the course of the disease. The high incidence rate of HFE gene mutations among MDS patients may also contribute to this vicious circle.

Adult↗
PubMed1994

Mapping recombinant events with molecular markers in hemochromatosis pedigrees.

The gene responsible for hereditary hemochromatosis (HH) is tightly linked to the class I region of the human leukocyte antigen (HLA) complex. Initial studies designed to map the disease locus have relied on serological markers for the class I antigens. Molecular markers from this region can now be used in combination with HLA serotyping for mapping studies. We previously reported two pedigrees in which serological data indicated recombinant events within the class I region. These data suggested a location for the HH locus between HLA-A and HLA-B. Molecular mapping studies have allowed us to demonstrate that an apparent recombination in one pedigree did not occur. This approach has also produced a more precise centromeric boundary for the region containing the disease locus, telomeric of HLA-C. These results emphasize the importance of including both serological and molecular markers in pedigree studies aimed at fine mapping the HH locus.

Cells, Cultured↗
PubMedDate not supplied

Liver transplantation for hereditary hemochromatosis.

Although the experience of orthotopic liver transplantation (OLT) for hereditary hemochromatosis (HHC) is limited, the existing data indicate that it carries a higher mortality when compared to transplantation for other causes of end-stage liver disease. Posttransplantation deaths are usually related to infectious or cardiac complications. HHC is often not diagnosed prior to OLT and one series has shown a high incidence of primary liver cancer diagnosed incidentally only at the time of transplantation. Factors that may account for the increase in postoperative mortality for HHC are the extent of iron deposition in extrahepatic sites in patients undiagnosed and thus untreated prior to transplantation. A high index of suspicion in subjects with end-stage liver disease should lead to improved diagnosis and allow for the prompt institution of either phlebotomy therapy or iron chelation therapy prior to transplantation. It is expected that these changes would reduce postoperative complications as well as improve long-term survival.

Female↗
PubMed1977

alpha-Fetoprotein screening in patients with idiopathic hemochromatosis and liver cirrhosis.

The serum alpha-fetoprotein level was measured by radioimmunoassay in 200 patients when admitted to hospital, 63 with idiopathic hemochromatosis and 137 with liver cirrhosis. In addition, repeated controls were performed in 19 subjects of each group for a mean period of 11 months (range 3--18 months). Elevated alpha-fetoprotein levels were observed initially or during the study period in 15 patients, a malignant liver tumor being demonstrated in 12 of them. In 4 of these patients, the abnormal alpha-fetoprotein concentration was the clue to the diagnosis of an unsuspected malignant hepatoma, but in none of these cases could the tumor be resected. The present results indicate that screening the serum alpha-fetoprotein level may contribute to the detection of malignant hepatoma in high-risk clinical groups, but the practical interest of such screenings may keep limited until more efficient therapeutic methods are developed.

Adult↗
PubMed1984

Effect of ascorbic acid on desferrioxamine-induced urinary iron excretion in idiopathic hemochromatosis.

The effect on urinary iron excretion (UIE) of vitamin C administered orally 2 h after the start of an 8-hour desferrioxamine (DF) i.v. infusion was studied in 12 patients with untreated idiopathic hemochromatosis (IH). Mean +/- SEM basal UIE of 324.6 +/- 84.6 micrograms/24 h increased after a 1-gram i.v. DF infusion to 8,778.5 +/- 1,191.4 micrograms/24 h; when vitamin C 1 or 2 g were added to DF i.v. infusion, there were further increases to 11,241.5 +/- 1,486.1 (p less than 0.01) and 13,531.2 +/- 1,697.2 micrograms/24 h (p less than 0.05 versus the last value), respectively. Basal UIE did not significantly increase after oral vitamin C administration alone. No side effects were observed.

Adult↗
PubMed1978

Influence of food iron absorption on the plasma iron level in idiopathic hemochromatosis.

The relationship between food iron absorption, iron stores, and plasma iron level was studied. On a low iron diet subjects with idiopathic hemochromatosis (IH) during reaccumulation of iron after phlebotomies showed a fall in plasma iron. Fortification of the diet with 22--135 mg of iron/day for 3 days caused little or no change in the plasma iron in subjects with normal iron stores, whereas in subjects with iron deficiency a significant rise in plasma iron occurred with the addition of 45 mg of iron/day. In subjects with IH with normal iron stores, plasma iron increased with the addition of 22.5 mg/day. These studies indicate that iron absorption is an important determinant of the elevated plasma iron in IH and that the plasma iron tolerance test combined with the serum ferritin may be used to detect excessive absorption of iron.

Bloodletting↗
PubMed1994

Hunting the hemochromatosis gene: progress and problems.

Hereditary hemochromatosis (HFE) is an inherited recessive disorder which causes progressive iron overload. Homozygotes for the affected gene develop symptoms of parenchymal organ damage and especially liver cirrhosis in midlife. Early diagnosis is important in order to prevent symptoms. The protein responsible for the increased iron absorption is unknown. The tight association of the disease gene with HLA-A has been known for nearly 20 years, but its precise localization remains uncertain. Linkage and linkage disequilibrium analyses in different populations have focussed on two possible locations of the gene either very close to HLA-A, or at the telomeric site of 6p in the vicinity of the D6S105 marker.

Female↗
PubMed1989

Duodenal iron proteins in idiopathic hemochromatosis.

This study was undertaken to assess the relationship between iron absorption and the concentration of duodenal iron proteins in normal subjects and patients with idiopathic hemochromatosis (IH). Biopsies were obtained endoscopically from the duodenum in 17 normal subjects, 3 of whom were mildly iron deficient, and 7 patients with untreated IH. The absorption of both heme and nonheme iron was increased in IH despite a 20-fold elevation in serum ferritin. Immunoassays using MAb were used to measure transferrin, H-rich ferritin, and L-rich ferritin in mucosal samples. Mucosal transferrin concentrations in normal subjects did not correlate with either iron status or iron absorption, indicating that mucosal transferrin plays no physiological role in iron absorption. Mucosal transferrin was significantly lower in IH, presumably because of a decrease in mucosal transferrin receptors. Mucosal H and L ferritin concentrations were directly related to body iron stores and inversely related to iron absorption in normal subjects. In IH, mucosal H and L ferritin failed to increase in parallel with the serum ferritin, but were appropriate for the level of iron absorption. The relationship of mucosal H/L ferritin in IH did not differ from that observed in normal subjects. Our findings indicate that the major abnormality in duodenal iron proteins in IH is a parallel decrease in the concentration of H- and L-rich ferritin. It is not evident whether this is the result or the cause of the absorptive abnormality.

Adult↗
PubMed1982

Diagnostic workup bias in the evaluation of a test. Serum ferritin and hereditary hemochromatosis.

Two studies report markedly divergent results about the usefulness of serum ferritin in diagnosing iron overload in relatives of patients with hereditary hemochromatosis. One study found the sensitivity of elevated serum ferritin to be 0%; another study found a sensitivity of 100%. Although different genetic abnormalities in iron or ferritin metabolism may explain the different results, our examination of these studies suggests that diagnostic workup bias also may explain the difference. In the study reporting a sensitivity of 100%, relatives with normal serum tests may have been excluded from consideration for liver biopsy, thus preventing detection of iron overload. The controversy may provide an empirical illustration of diagnostic workup bias.

Adolescent↗
PubMed2003

Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R).

Juvenile or type 2 hemochromatosis (JH) is a genetic disease caused by increased intestinal iron absorption that leads to early massive iron overload. The main form of the disease is caused by mutations in a still unknown gene on chromosome 1q. Recently, we recognized a second type of JH with clinical features identical to the 1q-linked form, caused by mutations in the gene encoding hepcidin (HEPC). Hepcidin is a hepatic antimicrobial-like peptide whose role in iron homeostasis was first defined in animal models; deficiency of hepcidin in mice leads to iron overload, whereas its hepatic overexpression in transgenic animals causes iron deficiency. To define the prevalence of HEPC mutations in JH we screened the HEPC gene for mutation in 21 unrelated JH subjects. We identified a new mutation (C70R), which affects 1 of the 8 conserved cysteines that form the disulfide bonds and are critical for the stability of the polypeptide.

Amino Acid Sequence↗
PubMed2004

Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P <.001; mean +/- SEM; n = 7). Ferrous ion chelators, bathophenanthroline disulfonate, and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately 2-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by divalent metals and up-regulation of DMT1 expression suggested that NTBI uptake was mediated by DMT1.

Animals↗
PubMed2005

In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.

Type IV hemochromatosis is associated with dominant mutations in the SLC40A1 gene encoding ferroportin (FPN). Known as the "ferroportin disease," this condition is typically characterized by high serum ferritin, reduced transferrin saturation, and macrophage iron loading. Previously FPN expression in vitro has been shown to cause iron deficiency in human cell lines and mediate iron export from Xenopus oocytes. We confirm these findings by showing that expression of human FPN in a human cell line results in an iron deficiency because of a 3-fold increased export of iron. We show that FPN mutations A77D, V162delta, and G490D that are associated with a typical pattern of disease in vivo cause a loss of iron export function in vitro but do not physically or functionally impede wild-type FPN. These mutants may, therefore, lead to disease by haploinsufficiency. By contrast the variants Y64N, N144D, N144H, Q248H, and C326Y, which can be associated with greater transferrin saturation and more prominent iron deposition in liver parenchyma in vivo, retained iron export function in vitro. Because FPN is a target for negative feedback in iron homeostasis, we postulate that the latter group of mutants may resist inhibition, resulting in a permanently "turned on" iron exporter.

Antigens, CD↗
PubMed2024

SLC40A1-related hemochromatosis associated with a p.Y333H mutation in mainland China: a pedigree report and literature review.

BACKGROUND: Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete. CASE PRESENTATION: We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T&#x2009;>&#x2009;C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level&#x2009;>&#x2009;1000&#xa0;&#xb5;g/L, transferrin saturation&#x2009;>&#x2009;90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin. CONCLUSIONS: This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

Humans↗