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PubMed2006

Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis.

The discovery in recent years of a plethora of new genes whose products are implicated in iron homeostasis has led to rapid expansion of our knowledge in the field of iron metabolism and its underlying complex regulation in both health and disease. Abnormalities of iron metabolism are among the most common disorders encountered in practical medicine and may have significant negative impact on physical condition and life expectancy. Basic insights into the principles of iron homeostasis and the pathophysiological and clinical consequences of iron overload, iron deficiency and misdistribution are thus of crucial importance in modern medicine. This review summarizes our current understanding of human iron metabolism and focuses on the clinically relevant features of hereditary and secondary hemochromatosis, iron deficiency anemia, anemia of chronic disease and anemia of critical illness. The interconnections between iron metabolism and immunity are also addressed, in as much as they may affect the risk and course of infections and malignancies.

Adolescent↗
PubMedDate not supplied

Neonatal hemochromatosis, renal tubular dysgenesis, and hypocalvaria in a neonate.

We report a neonate with neonatal hemochromatosis (NH), renal tubular dysgenesis (RTD), and hypocalvaria. NH is a fatal condition of the newborn, characterized by severe idiopathic liver failure of intrauterine onset and siderosis, intra- and extrahepatic, with sparing of the reticuloendothelial system. RTD is characterized by short, abnormally developed cortical tubules that lack proximal tubule differentiation. Although both NH and RTD have been reported as entities with a genetic component, similar findings can be secondary to in utero insults. Hypocalvaria has been reported in association with fetal hypoxia including that secondary to angiotensin converting enzyme inhibitors. This 38-week-old infant died at 8.5 h. The small nodular liver weighed 44 g. Grossly, the kidneys were normal. Hypocalvaria was present. Microscopically, the hepatic parenchyma was distorted by fibrous tracts, proliferation of bile ducts, and abundant iron deposition in hepatocytes. Extrahepatic siderosis in the pancreas, myocardium, and other organs was consistent with NH. Proximal convoluted tubules were not seen on routine stains and markers for proximal tubules were negative. Previous reports have linked NH with RTD and RTD with hypocalvaria. This infant had all three of these rare conditions, which have been hypothesized or shown to be due to genetic factors, hypoxia, or drugs. The etiology in this case is unknown.

Abnormalities, Multiple↗
PubMed1983

Cardiac hemochromatosis: beneficial effects of iron removal therapy. An echocardiographic study.

The echocardiographic (echo) features of idiopathic hemochromatosis (IH) were studied in 22 patients. Results were compared with a control group of 22 patients without heart disease. Statistically significant increases in left ventricular (LV) mass, end-diastolic and end-systolic diameters of the left ventricle and in left atrial dimension were observed in patients with IH; significant changes of systolic function indexes (decrease in fractional shortening and ejection fraction and increase in distance of the E point to the septum) were seen as well. These echo abnormalities were mainly seen in patients with abnormal electrocardiograms. In 11 patients with IH, iron removal therapy was carried out by means of periodic phlebotomies. In patients with impaired LV function at the beginning of therapy, comparison between measurements of the initial echo and posttreatment echo showed significant improvement in LV diameters, fractional shortening, ejection fraction, distance from the E point to the septum, LV mass and left atrial dimension.

Adult↗
PubMed1981

Myocardial involvement in idiopathic hemochromatosis. Morphologic and clinical improvement following venesection.

We describe a 31 year old male patient who presented with severe cardiomyopathy caused by primary hemochromatosis. After a stormy course, complicated by heart failure and severe ventricular arrythmias, improvement in clinical status and myocardial function occurred. Depletion of myocardial iron was documented by the technique of serial endomyocardial biopsy. Myocardial iron stores were not yet depleted when hypoferremia and iron deficiency anemia occurred. This is the first reported study of myocardial morphology in a successfully treated patient with hemochromatotic cardiomyopathy.

Adult↗
PubMed1993

Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases.

BACKGROUND: Although liver cancer arises frequently in the course of genetic hemochromatosis (GH), it has not been previously studied in a large series of patients with well-defined GH. METHODS: The bioclinical and pathological data from 1 cholangiocarcinoma and 53 hepatocellular carcinomas (HCCs) complicating GH in 32 untreated and 22 de-ironed patients are reported. RESULTS: This study (1) adds three new well-documented cases of HCC in noncirrhotic but only fibrotic hemochromatotic liver, (2) shows the high prevalence (83%) of proliferative and often dysplastic (70%) iron-free foci in the nontumorous liver of untreated patients, and (3) emphasizes the significant increase of cirrhosis (81% vs. 28%) and of associated noniron-related risk factors, mainly chronic alcoholism (48% vs. 25%) and tobacco smoking (50% vs. 18%) in patients with HCC compared with matched hemochromatotic patients without HCC. CONCLUSIONS: These data (1) suggest that iron-free foci may be markers of an early stage of HCC in GH and (2) supply the basis for defining a cost-effective policy for the screening of HCC in GH patients.

Female↗
PubMed1989

Perinatal hemochromatosis: entity or end result?

A clinicopathologic picture of severe neonatal liver disease associated with heavy stainable iron stores in a "hemochromatotic" distribution has been designated as neonatal or perinatal iron storage disease or hemochromatosis. In an attempt to determine the specificity of these findings, we determined the amount and distribution of stainable iron in four groups of autopsied infants: those with severe subacute/chronic liver disease of undetermined etiology, those with subacute/chronic liver disease of known etiology, those with severe acute liver disease, and those with no liver disease. Fourteen of 15 infants with severe subacute/chronic liver disease of unknown etiology showed heavy iron accumulation in a hemochromatotic distribution in more than one organ, in contrast to only one of 37 cases in the other three groups. The findings are compatible with the possibility that the combination of morphologic findings defines a single disease entity (of currently unknown etiology), and also with the possibility that this disease entity is specific only to the extent of establishing a relationship between severe early (in utero) liver injury and a hemochromatotic distribution of iron in multiple organs.

Hemochromatosis↗
PubMed1984

Hemochromatosis simulating hepatoma by computed tomography.

Computed tomography of the liver in hemochromatosis characteristically demonstrates diffusely increased attenuation. We report a patient with this disorder who presented with such a finding over the right lobe of the liver and a benign, large lower density area occupying the other lobe, closely simulating malignancy. Biopsies of the liver showed prominent fibrosis of the left lobe as compared with the right lobe, which probably accounts for the attenuation difference.

Adult↗
PubMed1994

Management of hereditary hemochromatosis.

Hereditary hemochromatosis is a common disorder of iron metabolism with a prevalence as high as 8 per 1000. Affected individuals absorb excessive amounts of dietary iron and over time, tissue iron deposition results in skin discoloration, arthropathy, hepatic cirrhosis, heart failure, diabetes mellitus and impotence. Early diagnosis and institution of phlebotomy treatments will prevent these manifestations and normalize life expectancy. Once organ damage is established many of the manifestations are irreversible. Since the early manifestations of the disease are subtle, a case can be made for routine screening. This conclusion is supported by cost-effectiveness analysis based on available data. A reasonable screening strategy would start with a serum transferrin saturation. A value > or = 55% should trigger a repeat transferrin saturation in a fasting state and a serum ferritin level. If both these tests are abnormal, a liver biopsy with quantitative iron determination is the currently accepted confirmatory test.

Adolescent↗
PubMed2004

Wilson's disease and hemochromatosis.

Wilson's disease (WD) and hereditary hemochromatosis (HH) are two inherited disorders with potentially devastating and life-threatening complications. Their eminent treatability makes diagnosis in adolescence or young adulthood critical. WD is the result of abnormal copper homeostasis, causing copper overload and end-organ damage. Chelation therapy can be highly efficacious in preventing manifestations of WD. HH is caused by inappropriate absorption of dietary iron, typically as the result of a specific mutation, C282Y, in the HFE gene. End-organ disease from iron accumulation is protean and includes progressive damage of the liver, pancreas, skin, heart, and pituitary. It is important to permit therapeutic phlebotomy to commence before the onset of complications.

Adolescent↗
PubMed2006

Left ventricular systolic function during stress echocardiography exercise in subjects with asymptomatic hereditary hemochromatosis.

There is no information available on left ventricular (LV) systolic function and the response to stress echocardiography in asymptomatic subjects with hereditary hemochromatosis (HH). To evaluate this topic, 43 asymptomatic subjects with HH homozygous for the C282Y HFE gene mutation (22 untreated subjects [group A] and 21 long-term treated subjects [group B]) were compared with 21 age- and gender-matched normal volunteers negative for HFE mutations. Contractile reserve, as a measure of LV systolic function, was assessed using continuous echocardiographic imaging and electrocardiography during supine bicycle exercise. Nineteen subjects in group A had repeat tests after 6 months of induction phlebotomy therapy to assess the effect of iron removal. Exercise performance and hemodynamic variables of supine bicycle exercise were comparable between subjects with HH and controls. LV contractile reserve of asymptomatic subjects with HH was not impaired at either a 75-W submaximal exercise level (mean +/- SD difference in ejection fraction from baseline 13.8 +/- 6.2%, 11.5 +/- 6.8%, and 13.4 +/- 7.8% in groups A, B, and C, respectively; p = NS for all by analysis of variance) or at peak exercise (difference in ejection fraction from baseline 18.9 +/- 6.9%, 18.4 +/- 7.8%, and 20.3 +/- 8.1% in groups A, B, and C, respectively; p = NS for all by analysis of variance). However, the incidence of abnormal ischemic stress electrocardiographic responses was more frequent in subjects with HH as a whole (33%) compared with normal subjects (10%). Stress imaging revealed no regional wall motion abnormalities, suggesting that these were false-positive results. Iron removal by induction phlebotomy did not affect stress echocardiographic performance. In conclusion, LV systolic function during exercise in asymptomatic subjects with HH is preserved, and 6-month induction phlebotomy does not affect stress echocardiographic performance.

Echocardiography, Stress↗
PubMed2006

Significance of left atrial contractile function in asymptomatic subjects with hereditary hemochromatosis.

Patients with hereditary hemochromatosis (HH) have been reported to develop diastolic functional abnormalities detectable by echocardiography, but it is unknown whether these occur in asymptomatic subjects. Thus, this study tested whether echocardiographic left ventricular (LV) relaxation abnormalities are detectable in subjects with asymptomatic HH. Forty-three asymptomatic subjects with HH (C282Y homozygosity in the HFE gene) and 21 age- and gender-matched control subjects without known HFE mutations underwent echocardiography with comprehensive diastolic functional evaluations. Subjects with HH were in New York Heart Association functional class I and consisted of 22 newly diagnosed patients (group A) and 21 chronically phlebotomized subjects with stable iron levels (group B). Group A subjects showed significant iron overload compared with group B subjects and controls (group C) (ferritin 1,164 +/- 886 [p <0.05 vs groups B and C], 128 +/- 262, and 98 +/- 76 microg/L and transferrin saturation 79 +/- 19% [p <0.05 vs groups B and C], 42 +/- 21%, and 26 +/- 10% for groups A, B, and C, respectively). Echocardiographic evaluation revealed (1) no statistically significant abnormalities of Doppler LV relaxation in HH groups; (2) significant augmentation of atrial contractile function in subjects with HH compared with controls, which was not correlated with iron levels and treatment status; and (3) the preservation of overall LV systolic function in HH groups. In conclusion, the results of this study suggest that the augmentation of atrial contraction appears to be an early detectable echocardiographic cardiac manifestation of abnormal diastolic function in asymptomatic subjects with HH, which may reflect undetectable subclinical LV relaxation abnormalities.

Atrial Function, Left↗
PubMed2006

Serum non-transferrin-bound iron and low-density lipoprotein oxidation in heterozygous hemochromatosis.

UNLABELLED: Non-transferrin-bound iron (NTBI) is implicated in lipid peroxidation but the relation with oxidative modification of low-density lipoprotein (LDL) is not known. We assessed variables reflecting in vitro and in vivo LDL oxidation in two age- and sex-matched groups (n=23) of hereditary hemochromatosis heterozygotes (C282Y), characterized by a clear difference in mean serum NTBI (1.55+/-0.57 micromol/L vs 3.70+/-0.96 micromol/L). Plasma level of oxidized LDL (absolute and relative to plasma apolipoprotein B), and IgG and IgM antibodies to oxidized LDL, markers of in vivo LDL oxidation, did not differ between the groups with low and high serum NTBI. Mean lag-phase of in vitro LDL oxidation was also not significantly different between both study groups. CONCLUSION: these findings do not support the hypothesis that NTBI promotes oxidative modification of plasma LDL.

Adult↗
PubMedDate not supplied

DMT1 genetic variability is not responsible for phenotype variability in hereditary hemochromatosis.

BACKGROUND/AIMS: Homozygosity for a cysteine to tyrosine translocation at position 282 within the HFE gene (C282Y) is responsible for over 90% of hereditary hemochromatosis (HH) in Celtic populations. Determining those C282Y homozygotes at greatest risk for iron overload is a major clinical concern as only a small percentage will develop clinically significant iron overload. Divalent metal transport protein (DMT1) on the apical surface of duodenal enterocytes is recognised as the major iron import protein. We investigated whether genetic variability within the DMT1 gene may partly explain the phenotypic variability seen amongst a group of C282Y homozygotes with iron overload. METHODS: One hundred and one unrelated C282Y homozygotes and 103 C282Y negative controls were analysed for the presence of four specific mutations/polymorphisms within the DMT1 gene (1245T/C, 1303C/A, IVS4 + 44C/A, IVS15Ex16-16C/G) using standard PCR techniques. Hepatic iron deposition was determined in 32 HH patients following Perls Prussian blue staining (0-4+). Estimations of the haplotype frequencies were performed utilising the program Arlequin version 2. RESULTS: There were no significant differences in the allele frequencies of the IVS4 + 44C/A, 1303C/A, 1254T/C and IVS15Ex16-16C/G polymorphisms in the patient cohort compared to those observed in the control cohort. The commonest haplotypes identified were CCTC: IVS4C + 44C, 1303C, 1254T, IVS15ex16-16C; ACCC: IVS4C + 44A, 1303C, 1254C, IVS15ex16-16C and ACTG: IVS4C + 44A, 1303C, 1254T, IVS15ex16-16G. Similarly, there were no significant differences in the frequencies of these three haplotypes in the patient cohorts (regardless of the degree of hepatic iron deposition) compared to the control cohort. CONCLUSIONS: Polymorphisms within DMT1 gene do not influence penetrance of the HH phenotype.

Adolescent↗
PubMedDate not supplied

Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients.

Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non-HFE dependent mechanism of primary iron overload dominates in Russian population.

Gene Frequency↗
PubMed2006

The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: an update of clinical and immunological data from 70 C282Y homozygous subjects.

Hereditary hemochromatosis (HH) is a clinically heterogeneous disease. Among other factors, the individual immunological profile of CD8+ T-lymphocytes has been described to influence the severity of iron overload, with low numbers being negatively correlated with the total amount of body iron stored. With the objective of testing the modifier effect of the individual CD8+ T-lymphocyte profile on the levels of iron stores with age in HH, we reviewed the clinical and immunological data from a group of well-characterized C282Y homozygous HH subjects, regularly followed-up for a period of 20 years. A total of 70 subjects were analyzed. Sixty-four were adults (> or = 18 years): 42 males (mean age 47 +/- 14; range 22-75 years) and 22 females (mean age 46 +/- 14; range 19-65 years). Six were younger than 18 years, 5 males (mean age 9 +/- 4; range 5-14 years) and 1 female (15 years). The characterization of subjects included measurements, at diagnosis, of the iron parameters, transferrin saturation (TfSat) and serum ferritin, quantification of total body iron stores (TBIS) removed by phlebotomies, presence of associated clinical manifestations, and the T-cell immunophenotype (CD4+ and CD8+ T-lymphocytes) determined by flow cytometry. In general, statistically significant lower values of TfSat (67 +/- 17% vs. 89 +/- 14%, P = 0.0006) and ferritin levels (58 +/- 9 vs. 949 +/- 233 ng/ml, P = 0.02) were found in the young subjects in comparison to adults. After the age of 18, however, no further effect of age was significantly found on the biochemical iron parameters either in males or females. A modifier effect of the individual CD8+ T-lymphocyte profile on the association between iron stores and age was demonstrated by multiple regression analysis, where a significant correlation between TBIS and age was found only in males with low (< or = 0.41 x 10(6)/ml) CD8+ T-cell numbers (R2 = 0.43, P < 0.0001). In conclusion, in the present population of C282Y homozygous subjects, the CD8+ T-lymphocyte profile could be considered a modifier of the iron overload with increasing age in males, with low numbers predicting a severe outcome.

Adult↗
PubMed2005

Antisense gene delivered by an adenoassociated viral vector inhibits iron uptake in human intestinal cells: potential application in hemochromatosis.

Hereditary hemochromatosis (HH) is a condition in which intestinal iron absorption is greatly elevated. Present treatment is weekly phlebotomy, affecting quality of life and leading to recurrent infections. The iron transporter divalent metal transporter-1 (DMT-1) of enterocytes is responsible for iron uptake from the intestinal lumen; iron is further extruded into the blood by the basolateral transporter ferroportin-1. A therapeutic approach for HH could start with a long-term reduction of iron transport by reduction of DMT-1 levels. We designed an AAV vector coding for a short antisense RNA (AAV-DMT-1-AS) against DMT-1, which reduced iron uptake by 50-60% in human intestinal cells (Caco-2). At low infection levels, DMT-1 mRNA virtually disappeared, suggesting RNAi-like and/or RNase H antisense effects. DMT-1 mRNA levels returned to normal at higher infection levels, indicating that an additional mechanism of mRNA occupation, able to block DMT-1 translation and to avoid feedback regulation by iron responsive elements (IRE), also exists. Cell morphology was normal in all cases and no increases in the interferon-related responses, measured by (a) 2'-5' A oligo synthetase (b) IFITM1 and (c) ISGF3gamma mRNA levels, were observed. Studies presented herein indicate that enterocyte targeting with a gene coding for a short antisense against iron transport blocks enterocyte iron uptake, which may have therapeutic value.

Caco-2 Cells↗
PubMed2005

TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis.

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism with variable penetrance. Only a minority of C282Y homozygotes develop clinical overt disease and cirrhosis. The phenotypic heterogeneity of HHC may be due to host genetic factors influencing fibrogenesis such as cytokine gene polymorphisms. In this respect, we investigated the impact of functional genetic polymorphisms of TGF-beta1 (codon 10 Leu/Pro, codon 25 Arg/Pro), TNF-alpha (-308 G/A, -238 G/A) and angiotensinogen (-6 G/A) on the development of cirrhosis in HHC. One hundred and forty-nine (111 male, mean age: 51.0+/-12.9) C282Y homozygotes who underwent liver biopsy were studied. Genotyping was performed by RFLP analysis. TGF-beta1 codon 25 genotypes Arg/Pro and Pro/Pro were more common in patients with cirrhosis than in those without (23.6% vs. 7.4%, p = 0.005). In contrast, the distribution of TGF-beta1 codon 10, TNF-alpha and angiotensinogen genotypes was not different. Logistic regression analysis identified male sex, age, serum ferritin and TGF-beta1 codon 25 Arg/Pro and Pro/Pro as independent predictors for the presence of cirrhosis. The adjusted odds ratio for TGF-beta1 codon 25 Arg/Pro and Pro/Pro was 2.8 (95% CI 1.4-5.7, p = 0.004). In conclusion, C282Y homozygotes carrying TGF-beta1 genotypes Arg/Pro and Pro/Pro are more likely to develop cirrhosis than those with genotype Arg/Arg.

Adult↗
PubMed2004

Biventricular diastolic behaviour in patients with hypertrophic and hereditary hemochromatosis cardiomyopathies.

AIM: To define biventricular diastolic behaviour in patients with cardiomyopathies with predominant diastolic left ventricular (LV) dysfunction. METHODS AND RESULTS: Doppler tissue echocardiography and both mitral and tricuspid Doppler inflow profiles were investigated in hypertrophic (n = 17), hereditary hemochromatosis (n = 12) cardiomyopathies and age-matched normals (n = 31). The cardiomyopathy group had both lower early diastolic mitral lateral annular (El), cm/s (13.9 +/- 6.5) and medial (Em) (10.0 +/- 4.5) velocities compared with normals (19.5 +/- 5.5, 15.9 +/- 3.4, p < 0.01, respectively). In the cardiomyopathy group, late isovolumic relaxation myocardial velocity gradient (IVR-MVG) (s(-1)) was positive compared with negative in normals (1.3 +/- 1.3 vs. -0.7 +/- 1.4, p < 0.01, respectively). In both the cardiomyopathy group and in normals the onset of the tricuspid E-wave preceded the onset of the mitral E-wave. However, the onset of early diastolic tricuspid annular (Et) motion preceded the onset of El (ms) only in normals, but not in the cardiomyopathies (43 +/- 26 vs. -8 +/- 44, p < 0.01, respectively). In the cardiomyopathy group there was a positive correlation between the onset of Et and abnormally positive late IVR-MVG (r = 0.51, p = 0.002). CONCLUSIONS: Biventricular early diastolic behaviour is abnormal in the selected group of cardiomyopathy patients. The delay in the Et (early diastolic longitudinal right ventricular relaxation) may have a negative effect on LV diastolic function.

Adult↗