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PubMed2004

Pathogenesis of hereditary hemochromatosis.

Hereditary hemochromatosis comprises several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorpstion and resultant tissue iron deposition. The identification of HFE and other genes involved in iron metabolism has greatly expanded our understanding of hereditary hemochromatosis. Two major hypotheses have been proposed to explain the pathogenesis of HFE-related hereditary hemochromatosis: the hepcidin hypothesis and the duodenal crypt cell programming hypothesis.

Animals↗
PubMed2005

Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis.

OBJECTIVE: To report a case of complete reversibility of hypogonadotropic hypogonadism with intensive venesection treatment in juvenile hemochromatosis. DESIGN: Case report. SETTING: Endocrine department of Hippocrateion Hospital of Athens. PATIENT(S): A 25-year-old man who presented with hypogonadotropic hypogonadism and severe iron overload due to juvenile hemochromatosis and who was initially treated with phlebotomies and androgen substitution. INTERVENTION(S): Intensification of chelation therapy. MAIN OUTCOME MEASURE(S): Clinical evaluation, serum ferritin concentration, and biochemical assessment of pituitary function were performed periodically. RESULT(S): One year after normalization of serum ferritin levels and transferrin saturation was achieved, he became eugonadal. CONCLUSION(S): We believe that hypogonadotropic hypogonadism in juvenile hemochromatosis may be reversible by a consequent venesection therapy probably because treatment was intensive and promptly introduced at a young age.

Adult↗
PubMed2004

Cardiac phosphorus-31 two-dimensional chemical shift imaging in patients with hereditary hemochromatosis.

Hemochromatosis is a hereditary iron overload syndrome characterized by increased iron storage, followed by liver cirrhosis and is often associated with restrictive cardiomyopathy. The purpose of this study was to detect alterations of cardiac high-energy phosphate metabolism in patients with hereditary hemochromatosis (HHC) prior to the development of structural heart diseases. Therefore cardiac phosphorus-31 two-dimensional chemical shift imaging ((31)P 2D CSI) was employed. Twenty-four male patients (mean age 47.2 +/- 12 years) homozygous for the C282Y mutation in the hemochromatosis associated HFE gene and twenty-four male healthy volunteers (mean age 47 +/- 11 years) as age-matched controls were included in this study. Using a 1.5-Tesla whole-body magnetic resonance scanner, electrocardiograph-triggered transversal 31P 2D CSI was performed. Left ventricle mean phosphocreatine (PCr) to beta-adenosine triphosphate (beta-ATP) ratios of patients with HHC (1.60 +/- 0.41) were significantly decreased in comparison to healthy volunteers (1.93 +/- 0.36; p = 0.004). Furthermore, we detected moderate, negative correlations between left ventricular PCr to beta-ATP ratios and transferrin saturation, cholesterol, low-density lipoprotein as well as triglyceride. This study shows that 31P 2D CSI permits the detection of alterations of cardiac high-energy phosphate metabolism in patients with HHC, but without any evidence for heart disease. The decreased PCr to beta-ATP ratios in HHC might be caused by mitochondrial impairment due to cardiac iron overload.

Adenosine Triphosphate↗
PubMed1990

Secondary hypogonadism in hemochromatosis.

Hemochromatosis is a rare disorder of iron storage. This report illustrates a case of hypogonadotropic-hypogonadism in a female with biopsy-proven hemochromatosis. Dynamic pituitary and gonadal testing revealed subnormal gonadotropin responses to gonadotropin-releasing hormone (GnRH) but normal ovarian reserve, as shown by normal follicular stimulation with hMG. Thus, abnormalities of ovulation and menstruation in patients with hemochromatosis are most likely because of inadequate pituitary responsiveness to GnRH.

Adult↗
PubMed1999

Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury.

Studies in experimental animals have indicated that enhanced lipid peroxidation may play a role in the hepatic injury produced by iron overload or by excessive alcohol consumption. The aim of this study was to compare the formation of lipid peroxidation-derived aldehydes in the liver of patients with hereditary hemochromatosis (HH) and alcohol abuse. Liver biopsy specimens from 10 nondrinking patients with HH were evaluated. These patients were classified as having HH based on hepatic iron index or human leukocyte antigen identity with a known proband. All patients were homozygous for the Cys282Tyr mutation. In addition, 8 patients with alcoholic liver disease were examined, 2 of whom also had hemochromatosis. For comparison, 17 patients with liver diseases unrelated to iron overload or alcohol abuse were studied. Liver biopsy specimens were immunostained for protein adducts with malondialdehyde and 4-hydroxynonenal. Both malondialdehyde- and 4-hydroxynonenal-protein adducts were found from liver specimens of patients with HH and alcohol abuse in more abundant amounts than from patients in a control group. In alcoholics the adducts were primarily in zone 3, whereas in hemochromatosis staining had an acinar zone 1 predominance, which followed the localization of iron. The most abundant amounts of protein adducts were noted in patients with alcohol abuse plus iron overload. The data support the concept that both chronic alcohol use and iron overload induce hepatic lipid peroxidation. Through formation of reactive aldehydic products, excessive alcohol consumption and iron overload may have additive hepatotoxic effects.

Adult↗
PubMed1987

Influence of phlebotomy treatment on abnormal hypothalamic-pituitary function in genetic hemochromatosis.

To test the hypothesis that deficiencies in hypothalamic-pituitary function in genetic hemochromatosis result from cellular injury by iron deposits, we conducted provocative tests in 11 men with genetic hemochromatosis before and after iron depletion by serial phlebotomy and in 10 control subjects. We gave combination intravenous injections of insulin (0.15 U/kg), luteinizing hormone releasing hormone (LHRH, 100 micrograms), and thyrotropin releasing hormone (400 micrograms) and then measured plasma glucose, growth hormone, corticosteroids, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone at 30-minute intervals for 90 minutes. Phlebotomy caused a substantial decrease in median values for serum ferritin, deferoxamine-chelatable iron, and hepatic iron concentration. Before phlebotomy, stimulation by hypoglycemia and thyrotropin releasing hormone caused significantly less secretion of growth hormone (P = 0.004) and prolactin (P = 0.03) in patients than in control subjects. No significant improvement was noted, however, in growth hormone or prolactin secretion after phlebotomy. Of the 11 patients, 7 had secondary hypogonadism, and phlebotomy did not improve the serum testosterone, follicle-stimulating hormone, luteinizing hormone, or responses to LHRH in any case. Chlorpromazine injections failed to elevate serum prolactin in all patients, and administration of levodopa caused a partial reduction in serum prolactin; thus, the hypothalamus may be an important locus of endocrine malfunction in these patients. We conclude that abnormal hypothalamic-pituitary function in genetic hemochromatosis is not substantially improved by iron-depletion therapy.

Adult↗
PubMed1989

Hemochromatosis.

This article discusses the pathophysiology and clinical manifestations of idiopathic and secondary hemochromatosis. Pedigree studies documenting the hereditary evidence for hemochromatosis are discussed. Current theories for the molecular mechanisms that result in iron overload are presented. Diagnostic strategies for assessing hemochromatosis and therapeutic modalities are reviewed.

Bloodletting↗
PubMed2001

[Analysis of the HFE gene in a large Spanish kindred with hereditary hemochromatosis].

BACKGROUND: Hereditary hemochromatosis (HH) is an inborn error of iron metabolism that is inherited as an autosomal recessive trait. Recently, it has been shown that the HFE gene, located telomeric to HLA-A on chromosome 6 is mutated in most patients with HH. Moreover, the phenotypic expression of hereditary hemochromatosis is influenced by sex and environmental agents such as alcohol and dietary iron intake. SUBJECTS AND METHOD: We have studied 40 subjects from a family some of which members have HH. DNA was obtained from nucleated peripheral blood cells, and exons 2 and 4 and intron 5 of the HFE gene were amplified by PCR and digested with specific restriction enzymes. RESULTS: Analysis of the HFE gene revealed that 29 members of the family carry some of the three HFE mutations (C282Y, H63D and S65C). Nevertheless, only those homozygous for the C282Y mutation develop HH. In this family, the allele 187G of exon 2 mutation is cosegregated with the allele IVS5-47 A in intron 5. CONCLUSIONS: Analysis of the HFE gene in the members of a large Spanish kindred, living in the same geographical area, shows that only those homozygous for the C282Y mutation develop hemochromatosis.

Adolescent↗
PubMed1998

Hemochromatosis and male infertility.

BACKGROUND: The clinical association of hemochromatosis and infertility is rare. Hemochromatosis may affect fertility through a variety of mechanisms. CASE: A 44-year-old man and his 36-year-old wife presented with primary infertility of 7 years' duration. The husband was diagnosed as having idiopathic hemochromatosis, abnormal glucose tolerance, and hypogonadism accompanied by impotence, retrograde ejaculation, and azoospermia. Treatment consisted of phlebotomies followed by gonadotropins, which corrected retrograde ejaculation and improved semen characteristics. Concomitant pelvic factors in the woman were corrected endoscopically. After failure of pregnancy with ovulation stimulation and intrauterine inseminations, a singleton pregnancy was achieved by in vitro fertilization, augmented with intracytoplasmic sperm injection. CONCLUSION: This case underscores the need to consider advanced reproductive technologies after the failure of specific, first-line therapeutic options in infertile couples.

Adult↗
PubMed2002

Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients.

BACKGROUND/AIMS: Several abnormalities in the immune status of hereditary hemochromatosis patients have been reported. We evaluated the peripheral blood lymphocytes phenotype and cytokine profile of CD8(+) and CD4(+) T cells in C282Y homozygous hereditary hemochromatosis patients compared to control subjects. METHODS: Peripheral blood lymphocytes from 17 asymptomatic patients and 14 control subjects were analyzed. We determined the distribution of lymphocyte subsets and investigated at single-cell level by flow-cytometry the potential of cytokines production. The frequency of cytokine (interferon gamma, tumor necrosis factor alpha, interleukin 2 (IL-2), IL-4, IL-5, IL-10 and IL-13) producing cells was assessed in total T-lymphocytes, CD3(+)CD8(+) and CD3(+)CD4(+) subsets. RESULTS: The patients studied showed a significant decrease of total lymphocyte count, T CD4(+)CD3(+), CD28(+), CD8(+)CD28(+) lymphocytes and natural killer (NK) CD56(+)CD16(+)CD3(-) cells. The reduction of CD28(+) and CD8(+)CD28(+) lymphocyte count was inversely related to transferrin saturation index. An increase in the ability of T-cells to produce all the cytokines studied and a major increase in IL-4 and IL-10 production in the CD3(+)CD8(+) subset was found. Our results demonstrate that activated Th1 and Th2 lymphocytes coexist in the peripheral blood of hereditary hemochromatosis patients and that T-cytotoxic (Tc) 2 subset is more expanded than in control population. CONCLUSIONS: The association of a decreased number of T CD8(+) cytotoxic lymphocytes and NK cells, and the development of Tc2 cells in asymptomatic C282Y homozygous patients represents an imbalance in their immune function that might contribute to the high incidence of hepatocarcinoma.

Adult↗
PubMed1997

Ultrastructural sequences during liver iron overload in genetic hemochromatosis.

BACKGROUND/AIMS: The pathway through which iron contributes to liver cell damage and cirrhosis in genetic hemochromatosis is not clear. The objective of the present study was to describe the ultrastructural changes in liver biopsies of patients in various stages of this condition and to correlate these with clinical, histopathological and biochemical data. METHODS: Liver biopsies from 20 patients with genetic hemochromatosis were examined by transmission electron microscopy. The use of unstained thin (60 nm) sections facilitated the identification and localization of the electron-opaque compounds ferritin and hemosiderin in various liver cells. Stained thin sections permitted evaluation of the concomitant subcellular damage and collagen deposition. The ultrastructural observations were corroborated with the histopathological findings and biochemical data. RESULTS: All patients had liver iron overload, which was classified as mild, moderate or severe. In the stage of mild overload (hepatic iron concentration HIC 93.5+/-23.3 micromol/g and hepatic iron index HII 2.3+/-0.7), cytosolic ferritin and scarce pericanalicular lysosomes (siderosomes) were seen in periportal hepatocytes (acinar zone 1), without evidence of organelle damage, and in the absence of sinusoidal cell siderosis. In moderate overload (HIC 190.8+/-41.5 micromol/g and HII 4.3+/-1.9), ferritin was identified in hepatocytes of all acinar zones, and the pericanalicular siderosomes were abundant, especially in acinar zone 1. Single hepatocytes showed organelle damage and occasional sinusoidal cells showed siderosis. In severe overload (HIC 308+/-49.0 micromol/g and HII 7.5+/-1.7), hepatocytes of all acinar zones were filled with large, hemosiderin-containing siderosomes, and changes in mitochondria, smooth and rough endoplasmic reticulum and nuclei were conspicuous. Marked sinusoidal cell siderosis and collagen deposition were observed predominantly in this stage. CONCLUSIONS: Electron microscopy has shown that during the long, latent stage of "compensated" genetic hemochromatosis, hepatocytes display only minimal subcellular changes, other than iron overload. "Decompensated" overload, characterized by extensive subcellular pathology and focal necrosis, is reached when 1) the hepatocytic siderosis is generalized (i.e. beyond pericanalicular polarization of siderosomes in hepatocytes, and beyond zone 1 in the acinus); and 2) there is evidence of massive siderosis of sinusoidal cells. These findings support the concept of a critical level of hepatic iron concentration beyond which organelle damage is conspicuous and liver cell injury may become irreversible.

Adult↗
PubMed2001

[Hepatocellular carcinoma in a patient with hereditary hemochromatosis without cirrhosis].

Hepatocellular carcinoma in patients with hereditary hemochromatosis in the cirrhotic phase is one of the complications causing greatest mortality and may present in spite of removal of excess iron by bloodletting. Hepatocellular carcinoma is usually considered to occur in cirrhotic livers and consequently measures for the early diagnosis of this complication are only recommended in this type of patient. We present the case of a 69-year-old female patient with non-cirrhotic hemochromatosis who, 6 years after undergoing successful treatment, developed hepatocellular carcinoma. This observation should be added to the 12 cases published in the literature. Criteria should be established for the early diagnosis of hepatocellular carcinoma in patients with hereditary hemochromatosis, irrespective of whether they have cirrhosis.

Aged↗
PubMed2001

[Ventricular tachycardia and cardiac hemochromatosis].

Hemochromatosis is characterized by an excessive iron deposit in different tissues. Cardiac involvement may be observed in one third of the patients due to hemochromatosis and occurs as a consequence of ferritin accumulation in the heart which on one hand induces alterations in systolic and diastolic ventricular function and on the other hand, an arrythmogenic substrate. The clinical manifestations can be indistinctly related to atrial tachyarrhythmia, ventricular tachyarrhythmia, atrio-ventricular blockade and congestive heart failure, with the first being the most frequent. We present the case of one patient with secondary hemochromatosis to repeated transfusions due to sideroblastic anemia with cardiac involvement, whose initial heart manifestations were recurrent atrial tachyarrhythmia and sustained ventricular tachycardia with syncope for which an automatic defibrillator was implanted.

Adult↗
PubMed2005

Phenotype variation in C282Y homozygotes for the hemochromatosis gene.

BACKGROUND & AIMS: Typical hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, approximately 50% of women and 20% of men do not have an increase in serum ferritin level. This study assessed factors, genetic and otherwise, that may modify biochemical expression in C282Y homozygotes. METHODS: Hemochromatosis families that each had at least 2 untreated C282Y homozygotes were included. Nonexpressors were defined as having a ferritin level less than 300 microg/L for a male and a ferritin level less than 200 microg/L for a female. A multivariate linear stepwise regression analysis was performed to assess the contribution of sex, age, and the presence of a nonexpressor in the family on serum ferritin level. Heritability calculations were performed using variance component analysis. RESULTS: Fifty-three pedigrees consisting of 148 C282Y homozygotes (92 males, 56 females) were identified. Twenty-nine homozygotes were nonexpressors (19.6%), of which 11 of 29 were male (37.9%) (P=.0054). Based on multivariate analysis, highly significant associations with increased ferritin levels in C282Y homozygotes were male sex (P=.00005), increasing age (P=.009), and absence of a nonexpressor in the family (P=.01). Variance component modeling using age, sex, and C282Y genotype as covariates in 39 pedigrees (n=296) showed a residual heritability for serum ferritin of .35+/-.10 (P<.001). CONCLUSIONS: These findings suggest that male sex is the major clinical factor associated with an increased serum ferritin level in hemochromatosis. In addition, these results support the hypothesis that other genes contribute to the variance in serum ferritin concentration among C282Y homozygotes.

Adolescent↗
PubMed2000

Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.

Porphyria cutanea tarda is a skin disease caused by photosensitization by porphyrins whose accumulation is caused by deficiency of hepatic uroporphyrin- ogen decarboxylase activity. Mutations in the uroporphyrinogen decarboxylase gene are present in the low-penetrant, autosomal dominant familial form but not in the commoner sporadic form of porphyria cutanea tarda. We have investigated the relationship between age of onset of skin lesions and mutations (C282Y, H63D) in the hemochromatosis gene in familial (19 patients) and sporadic porphyria cutanea tarda (65 patients). Familial porphyria cutanea tarda was identified by mutational analysis of the uroporphyrinogen decarboxylase gene. Five previously described and eight novel mutations (A80S, R144P, L216Q, E218K, L282R, G303S, 402-403delGT, IVS2 + 2 delTAA) were identified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda, the effect being more marked in familial porphyria cutanea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation has much less effect on the development of the disease.

Adolescent↗
PubMed2002

Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.

BACKGROUND & AIMS: The progression of fibrosis to cirrhosis is the most significant prognostic factor in hereditary hemochromatosis. We aimed to determine the range of hepatic iron concentration associated with cirrhosis in the absence of alcohol and other pro-fibrogenic cofactors and to quantify the contribution of excess alcohol consumption to the development of cirrhosis. METHODS: Liver biopsy data were evaluated on 224 C282Y homozygous hemochromatosis subjects. To determine the effect of alcohol alone on the development of fibrosis, subjects with viral hepatitis or nonalcoholic steatohepatitis were excluded. Subjects were divided into those who consumed less than 60 g alcohol per day and those who consumed 60 g per day or more. RESULTS: Seven percent of subjects who consumed less than 60 g per day had severe fibrosis/cirrhosis compared with 61% of excess alcohol consumers. CONCLUSIONS: Hemochromatosis subjects who drink more than 60 g alcohol per day are approximately 9 times more likely to develop cirrhosis than those who drink less than this amount, and the range of hepatic iron concentration associated with cirrhosis in the absence of cofactors was 233-675 micromol/g dry weight.

Adult↗
PubMed2004

Multigenic control of hepatic iron loading in a murine model of hemochromatosis.

BACKGROUND & AIMS: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. METHODS: To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. RESULTS: We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. CONCLUSIONS: Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.

Animals↗
PubMed2000

Radial artery wall alterations in genetic hemochromatosis before and after iron depletion therapy.

Iron overload is believed to have an adverse influence on the cardiovascular system and animal studies have shown that iron may be involved in the events that lead to atherosclerosis via an enhancement of smooth muscle cell proliferation, lipid oxidation, and free radical production. There are no data on the effect of iron overload on arterial structural and mechanical properties in humans. We measured wall thickness and distensibility (D) by ultrasonography of the radial artery in 12 patients with uncomplicated genetic hemochromatosis (GH) who were normotensive and without atherosclerotic plaques. Twelve age- and sex-matched patients were taken as controls. Nine patients were evaluated also after iron depletion. Wall thickness was greater in patients with GH than in controls (+50%, P <.01) whereas D was slightly reduced in the former group compared with the latter group, though the difference was not statistically significant. After iron depletion, a significant reduction of wall thickness and a significant increase in D were observed (-24% and +33%, P <.05 for both). Thus, in patients with hemochromatosis, arterial wall thickness is increased before the onset of cardiovascular complications. This alteration is reverted by iron depletion, which also can improve the initial and modest radial artery wall stiffening associated with this condition. Thus, functional and structural alterations in midsize muscle arteries may be an early abnormality of hemochromatosis.

Adult↗