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PubMed1996

The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients.

We evaluate the relation between genotype and phenotype in 47 Italian male patients with homozygous genetic hemochromatosis (GH). Phenotype evaluation was based on the ratio of amount of iron removed (IR) by phlebotomy and age (IR/age). Patients were divided in two classes of phenotype expression: class I included 26 patients with less severe iron overload (IR/age <0.33) and class II included 21 patients with a more marked one (IR/age >0.33). Genetic variability was assessed by haplotype analysis combining alleles at HLA-B, D6S265, HLA-A, and D6S105 loci. A common ancestral haplotype carrying D6S265-1, HLA-A3, and D6S105-8 alleles was present in 13 of 52 (25%) chromosomes in class I and in 24 of 42 (57%) chromosomes in class II (P = .0027). Homozygotes and heterozygotes for the ancestral haplotype had higher iron indices than patients carrying two haplotypes other than the ancestral one. Seven of the eight patients homozygous for the ancestral haplotype were in class II, heterozygotes were equally distributed between the two classes, whereas 14 of 18 carriers of other haplotype combinations were in class I. Our results suggests that the gene defect linked to the ancestral haplotype is the result of a single, severe mutation. The high variability of phenotype expression in heterozygotes for the ancestral haplotype could be accounted for the contribution of the mutation carried by the second haplotype. Combination of different mutations could be responsible for the variable degrees of iron overload found in patients with GH.

Adult↗
PubMed2001

Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease.

It has been suggested that excess iron may facilitate the occurrence of cancer. Patients with hereditary hemochromatosis (HH) are at high risk of developing liver cancer, and studies of limited series reported a high frequency of nonhepatic cancers. To verify whether patients with HH are at higher risk of liver cancer and other malignancies as compared with patients with non-iron-related chronic liver disease (CLD), we analyzed the occurrence of neoplasms in 230 patients with HH and 230 with non-iron-related CLD. The patients were matched by sex, age, duration of follow-up (+/-5 years), and severity of liver disease. On enrollment, the following variables were considered: hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcohol abuse, smoking, and a family history of cancer (first-degree relatives). The diagnosis of primary cancers was confirmed by histology. During the follow-up, hepatocellular carcinoma (HCC) developed in 49 and 29 patients (all cirrhotic patients) with HH and non-iron-related CLD, respectively, with a relative risk of 1.8 (95% confidence interval [CI] 1.1-2.9); nonhepatic cancers occurred in 20 and 11 patients, respectively, with a relative risk of 1.8 (95% CI 0.8-4). Four patients with HH and 1 with non-iron-related CLD developed 2 different primary cancers during follow-up. The risk of cancer after adjustment for alcohol abuse, smoking, and family history of cancer was 1.9 (95% CI 1.1-3.1) in the patients with HH. In conclusion, patients with HH are at high risk of both liver cancer and other malignancies, which should be carefully sought during follow-up.

Adult↗
PubMed2002

Molecular aspects of iron absorption: Insights into the role of HFE in hemochromatosis.

Hereditary hemochromatosis is the most common genetic disorder occurring in persons of northern European descent, and the clinical hallmark of the disease is the gradual accumulation of iron in internal organs, especially the liver, heart, and pancreas, which ultimately leads to organ failure. HFE, the gene that is defective in the majority of cases, was identified in 1996 and, although the exact role that HFE plays in the uptake and utilization of iron is not yet clear, important aspects of HFE function are emerging. Identification and studies of new proteins involved in the absorption of iron in the gut and in somatic cells has led to a clearer picture of how humans absorb iron from the diet and regulate this absorption to meet metabolic needs and to balance body iron stores. This review focuses on the molecular aspects of iron absorption and the role that HFE may play in these processes.

Hemochromatosis↗
PubMed2002

Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis.

The aim of the present study was to examine the predictive accuracy of noninvasive clinical and biochemical variables associated with cirrhosis among patients with C282Y homozygous hemochromatosis. Sixteen clinical and laboratory variables were recorded at the time of diagnosis in 193 Canadian C282Y homozygous patients. All patients underwent percutaneous liver biopsy and 27 (14%) had biopsy specimen-proven cirrhosis. Prediction of cirrhosis was assessed first by univariate regression analysis. Variables significantly related to cirrhosis were then evaluated by stepwise linear multivariate regression. Receiver operating characteristic curve analysis of the most informative variables from multivariate analysis was then used to devise a clinically applicable index for the noninvasive prediction of cirrhosis. This index was then validated in 162 C282Y homozygous patients in France. Ferritin, blood platelets, and aspartate transaminase (AST) level were selected for the clinical index. The combination of ferritin levels of 1,000 microg/L or greater, platelet levels of 200 x 10(9)/L or less, and AST levels above the upper limit of normal led to a correct diagnosis of cirrhosis in 77% of Canadian patients. In the French patients, this led to a correct diagnosis of cirrhosis in 90%. In conclusion, in C282Y homozygous patients, a combination of easily measured laboratory variables (ferritin, platelets, AST) can be used to make the diagnosis of cirrhosis in approximately 81% of cases, reducing the need for liver biopsy.

Adult↗
PubMed2001

Hemochromatosis (HFE) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens.

BACKGROUND: Hereditary hemochromatosis (HH) is a common disease predominantly characterized by mutations of the HFE gene. METHODS AND RESULTS: We investigated the utility of HFE gene sequence analysis in the diagnosis of HH in 61 prospectively accrued formalin-fixed, paraffin-embedded liver biopsy specimens with clinical or histologic features suggestive of HH. Mutations in codons 63 or 282 of the HFE gene were identified by direct sequencing; in 21 of these samples, quantitative hepatic iron testing was also performed. Changes characteristic of HH were present in 16 (26%) of the cases, and 54% of the cases showed HFE gene mutations. The most common alteration was homozygous mutation of codon 282 (11 cases, 18%), followed by the combined 63 + 282 heterozygous mutation (3 cases, 5%). Two cases (3%) showed biallelic mutation of codon 63. The other 28 cases (46%) showed no sequence abnormalities. Weak iron staining did not exclude HH; intense staining did not reliably predict HH. CONCLUSION: When HH is clinically and/or histologically suspected, HFE gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of HH.

Age Factors↗
PubMed1993

A 39-year-old man with chronic hepatitis, elevated serum ferritin values, and a family history of hemochromatosis.

The patient described is a heterozygote for hemochromatosis, and he has chronic hepatitis C. We have hypothesized that, because of chronic viral hepatitis, he could either have an increase in circulating NTBI or he could have up-regulation of hepatocyte TfR expression, perhaps caused by a viral effect on the IRE of TfR mRNA, or a combination of both. Either could result in an increase of his hepatocellular iron uptake, resulting in a redistribution of his total body iron burden (which is in the range seen for HHC heterozygotes) and, in effect, "concentrating" the iron in his liver, thus simulating homozygous HHC. It is likely that there are interrelationships between hepatic iron concentration, hepatocellular iron metabolism, and chronic viral hepatitis. Understanding of these interrelationships may be important in the understanding of some of the fundamental mechanisms of viral growth and replication and hepatocellular injury. A clearer understanding of these interactions is necessary to diagnose the cause of liver disease accurately in patients such as this one.

Adult↗
PubMed1983

Renal impairment in experimental hemochromatosis in rats.

Parenteral administration of iron as the complex with nitrilotriacetate resulted in moderate iron deposition in the renal cortex along with heavy deposition of iron in liver, heart, and exocrine pancreas. Iron treated rats exhibited slight but significant changes in serum chemistries consistent with mild renal insufficiency: increased chloride and creatinine and decreased sodium, calcium and CO2 content as a group with isolated increases in urea nitrogen (2/9) and phosphorus (3/9). Serum albumin was decreased and the normal correlation of serum calcium with serum albumin was abolished by iron overload. Although food intake/g body weight was similar in the two groups, both water intake and urine output relative to solute load were increased in iron-overloaded rats. We conclude that the renal insufficiency occasionally reported in human hemochromatosis may reflect a direct nephrotoxic action of iron.

Animals↗
PubMed1987

[Cardiomyopathy in idiopathic hemochromatosis. Diagnostic possibilities using proton spin tomography].

In idiopathic hemochromatosis, there is progressive deposition of iron in parenchymatous organs owing to a defect in iron absorption the nature of which is not so far known. This can result in cardiomyopathy with heart failure and arrhythmia which are refractory to therapy. Nuclear magnetic resonance tomography is a specific imaging technique for early detection of myocardial iron deposits. With quantitative determination of the T2 relaxation time of the myocardium, a progress control under venesection therapy is possible above and beyond diagnostics.

Bradycardia↗
PubMed1977

Hereditary hemochromatosis. Diagnosis in siblings and children.

We studied five patients with clinically manifest hemochromatosis and 19 of their siblings and children to define better the diagnostic criteria for stages of the disease. The earliest detectable abnormalities were an increase in hepatic-parenchymal-cell stainable iron, hepatic iron concentration, transferrin saturation and serum iron concentration. In contrast, urinary iron excretion after deferoxamine and serum ferritin concentration were usually normal in early iron loading. In either latent or clinically manifest disease, hepatic-parenchymal-cell stainable iron was Grade 3 or 4; hepatic iron concentration was greater than 250 microng per 100 mg; serum iron was greater than 170 microng per 100 ml; transferrin saturation was greater than 70 per cent; urinary iron excretion exceeded 2.2 mg per 24 hours; and serum ferritin usually exceeded 1000 ng per ml. Estimation of liver iron is the most sensitive method for detecting early disease. Urinary iron excretion and serum ferritin estimate the total body burden of iron in latent and clinically manifest disease.

Adolescent↗
PubMed2002

The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis.

Although cardiac dysfunction in hereditary hemochromatosis (HHC) can be evaluated by conventional echocardiography, findings are often not specific. To test the hypothesis that the assessment of (1) conventional Doppler left ventricular filling indexes and (2) intrinsic elastic properties of the myocardium by Doppler tissue echocardiography can both enhance the accuracy of echocardiographic diagnosis of cardiac involvement in HHC, a group of 18 patients with HHC (mean age 50 +/- 17 years) and 22 age-matched healthy subjects were studied. The following indexes were characteristic for HHC: (1) the duration of atrial reversal measured from pulmonary venous flow (ms) was longer (118 +/- 20 vs 90 +/- 16; P <.001); (2) systolic lateral mitral, early-diastolic medial mitral, and early-diastolic lateral tricuspid annular velocities were reduced by 23%, 31%, and 13%, respectively; (3) late-diastolic mean myocardial velocity and myocardial velocity gradient (MVG) were also reduced by 22% and 34%, respectively. Late-isovolumic relaxation (late-IVR) MVG (s(-1)) was positive in HHC as opposed to negative in healthy subjects (1.72 +/- 0.85 vs -0.89 +/- 1.15; P <.001) indicating impaired early-diastolic subepicardial relaxation in HHC. The assessment of atrial reversal flow duration, the difference in duration between A-wave and atrial reversal flow, and the presence of positive late IVR-MVG findings were the most accurate variables to differentiate patients with HHC from healthy subjects (80%, 67%, 94% sensitivity and 90%, 95%, 86% specificity, respectively).

Adult↗
PubMed2000

Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite down-regulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the iron-responsive elements found in the 3' untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overload (2% carbonyl iron), dietary iron deficiency (gastric parietal cell ablation), and HH (HFE -/-). Northern blot analyses demonstrated distinct tissue-specific patterns of expression for TfR and TfR2, with TfR2 expressed highly only in liver where TfR expression is low. In situ hybridization demonstrated abundant TfR2 expression in hepatocytes. In contrast to TfR, TfR2 expression in liver was not increased in iron deficiency. Furthermore, hepatic expression of TfR2 was not down-regulated with dietary iron loading or in the HFE -/- model of HH. From these observations, we propose that TfR2 allows continued uptake of Tf-bound iron by hepatocytes even after TfR has been down-regulated by iron overload, and this uptake contributes to the susceptibility of liver to iron loading in HH.

Amino Acid Sequence↗
PubMed2005

The molecular basis of ferroportin-linked hemochromatosis.

Mutations in the iron exporter ferroportin (Fpn) (IREG1, SLC40A1, and MTP1) result in hemochromatosis type IV, a disorder with a dominant genetic pattern of inheritance and heterogeneous clinical presentation. Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes. We show that known human mutations introduced into mouse Fpn-GFP generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Studies using co-immunoprecipitation of epitope-tagged Fpn and size-exclusion chromatography demonstrated that Fpn is multimeric. Both WT and mutant Fpn participate in the multimer, and mutant Fpn can affect the localization of WT Fpn, its stability, and its response to hepcidin. The behavior of mutant Fpn in cell culture and the ability of mutant Fpn to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes.

Animals↗
PubMed2001

Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a common disorder of iron metabolism caused by mutation in HFE, a gene encoding an MHC class I-like protein. Clinical studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Serum transferrin saturations (percent saturation of serum transferrin with iron), hepatic and splenic iron concentrations, and hepatocellular iron distribution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/-), and knockout (Hfe -/-) mice from each strain. Although the Hfe -/- mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrate that heritable factors markedly influence iron homeostasis in response to Hfe disruption. Analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of HH.

Animals↗
PubMed2003

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80-90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y/H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y/H63D and H63D/H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D/C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y/C294Y > C294Y/H67D > H67D/H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.

Amino Acid Substitution↗
PubMed1987

Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis.

Genetically hypotransferrinemic mice accumulate iron in the liver and pancreas. A similar pattern of tissue iron accumulation occurs in humans with hereditary hemochromatosis. In both disorders, there is a decreased plasma concentration of apotransferrin. To test the hypothesis that nontransferrin-bound iron exists and is cleared by the parenchymal tissues, the tissue distribution of 59Fe was studied in animals lacking apotransferrin. Two groups of animals were used: normal rats and mice whose transferrin had been saturated by an intravenous injection of nonradiolabeled iron, and mice with congenital hypotransferrinemia. In control animals, injected 59Fe was found primarily in the bone marrow and spleen. In the transferrin iron-saturated animals, injected 59Fe accumulated in the liver and pancreas. Gastrointestinally absorbed iron in hypotransferrinemic or transferrin iron-saturated mice was deposited in the liver. This indicates that newly absorbed iron is released from mucosal cells not bound to transferrin. Clearance studies demonstrated that transferrin-bound 59Fe was removed from the circulation of rats with a half-time of 50 min. In transferrin iron-saturated animals, injected 59Fe was removed with a half-time of less than 30 s. Analysis of the distribution of 59Fe in serum samples by polyacrylamide gel electrophoresis demonstrated the presence of 59Fe not bound to transferrin. These results demonstrate the existence of and an uptake system for non-transferrin-bound iron. These observations support the hypothesis that parenchymal iron overload is a consequence of reduced concentrations of apotransferrin.

Animals↗
PubMed1999

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE-/- mice have increased duodenal expression of the divalent metal transporter (DMT1). By 4 weeks of age, the HFE-/- mice demonstrated iron loading when compared with HFE+/+ littermates, with elevated transferrin saturations (68.4% vs. 49.8%) and elevated liver iron concentrations (985 micrograms vs. 381 micrograms). By using Northern blot analyses, we quantitated duodenal expression of both classes of DMT1 transcripts: one containing an iron responsive element (IRE), called DMT1(IRE), and one containing no IRE, called DMT1(non-IRE). The positive control for DMT1 up-regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1(IRE) mRNA. HFE-/- mice also demonstrated an increase in duodenal DMT1(IRE) mRNA (average 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, up-regulation of DMT1, and increased absorption of dietary iron.

Animals↗
PubMed1998

Expression of SFT (stimulator of Fe transport) is enhanced by iron chelation in HeLa cells and by hemochromatosis in liver.

SFT (stimulator of Fe transport) is a novel transport protein that has been found to facilitate uptake of iron presented to cells as either Fe(II) or Fe(III). When HeLa cells are exposed to the iron chelator desferrioxamine, levels of SFT mRNA increase in an actinomycin D-sensitive manner. In contrast, cells exposed to high levels of iron down-regulate SFT expression in a time-dependent and reversible fashion. Thus, homeostatic regulation of SFT expression not only ensures that sufficient levels of iron are maintained but also limits excessive assimilation to prevent potentially harmful effects of this toxic metal. The unexpected observation that SFT transcript levels are up-regulated in hemochromatosis patients therefore suggests that enhanced SFT expression contributes to the etiology of this iron overload disorder.

Biological Transport↗
PubMed2002

The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis.

The antibacterial and antifungal peptide hepcidin (LEAP-1) is expressed in the liver. This circulating peptide has recently been found to also act as a signaling molecule in iron metabolism. As such, it plays an important role in hereditary hemochromatosis, a serious iron overload disease. In this study, we report the solution structures of the hepcidin-20 and -25 amino acid peptides determined by standard two-dimensional (1)H NMR spectroscopy. These small cysteine-rich peptides form a distorted beta-sheet with an unusual vicinal disulfide bridge found at the turn of the hairpin, which is probably of functional significance. Both peptides exhibit an overall amphipathic structure with six of the eight Cys involved in maintaining interstrand connectivity. Hepcidin-25 assumes major and minor conformations centered about the Pro residue near the N-terminal end. Further NMR diffusion studies indicate that hepcidin-20 exists as a monomer in solution, whereas hepcidin-25 readily aggregates, a property that may contribute to the different activities of the two peptides. The nuclear Overhauser enhancement spectroscopy spectra of the hepcidin-25 aggregates indicate an interface for peptide interactions that again involves the first five residues from the N-terminal end.

Amino Acid Sequence↗