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PubMed2005

Hepatic expression of hemochromatosis genes in two mouse strains after phlebotomy and iron overload.

BACKGROUND AND OBJECTIVES: Iron homeostasis is tightly regulated in mammals according to the needs of erythropoiesis and the iron stores present. This regulation is disrupted in hereditary hemochromatosis (HH), a genetic disorder characterized by increased intestinal iron absorption, leading to iron overload. The genes coding for HFE, transferrin receptor 2 (TFR2), ferroportin (SLC40A1 or FPN1), hepcidin (HEPC) and hemojuvelin (HJV or RGMC) are responsible for different types of genetic iron overload. All these genes are highly expressed in the liver and their protein products are likely components of a single hepcidin-related pathway. In order to gain insights into the molecular relationship among the HH proteins we evaluated the hepatic expression of HH genes in conditions of iron restriction or overload. DESIGN AND METHODS: Data were obtained after phlebotomy, to activate the erythroid regulators and following parenteral iron dextran loading, to activate the store regulators, in two mice strains (C57BL/6 and DBA/2). HH genes and proteins expression were analyzed by quantitative real time polymerase chain reaction and by Western blotting, respectively. RESULTS: Hepc RNA was reduced after phlebotomy and increased in iron overload. A statistically significant reduction of hepatic Fpn1 RNA expression was observed after phlebotomy; this effect was more evident in the DBA/2 strain. Fpn1 increased in C57BL/6 mice, but not in the DBA/2 ones in parenteral iron loading. Fpn1 protein did not change substantially in either condition. Hfe, Rgmc and Tfr2 expression was not influenced by phlebotomy. In parenteral iron overload, Tfr2 gene and protein expression decreased concomitant to the increase in Hepc, while Hfe RNA remained constant. INTERPRETATION AND CONCLUSIONS: Our results indicate that regulation of hepatic Fpn1 differs from that reported for duodenal Fpn1. Furthermore, taken the differences in gene expression in dietary overload (increased Hfe but not Tfr2), distinct roles are suggested for Hfe and Tfr2 in Hepc activation.

Animals↗
PubMed1991

[Perinatal hemochromatosis].

Neonatal hemochromatosis is responsible for death in utero or severe hepatic insufficiency in the newborn, generally with rapid progression to death. Recurrence in sibships is frequent. Necropsy findings are characterized by siderosis in the liver, pancreas, heart, thyroid, but not in the reticuloendothelial system. Urinary cytology, serum iron concentration, iron-binding capacity, ferritin, and magnetic resonance imaging allow a diagnosis to be made before death. Liver transplantation probably offers the best chance of survival. The pathophysiology is unknown; there may be a variety of etiologies.

Female↗
PubMed2006

Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency.

BACKGROUND AND OBJECTIVES: The functions of the iron regulatory proteins (IRP1 and IRP2), which control cellular iron homeostasis are similar but not identical. As an inappropriate up-regulation of total IRP activity has been found in the duodenum and monocytes of patients with hereditary hemochromatosis (HH), we investigated the respective roles of IRP1 and IRP2 in these settings. DESIGN AND METHODS: Specific antibodies were used in RNA-supershift, immunoblotting and immunohistochemistry assays to evaluate IRP1 and IRP2 separately in monocytes, macrophages and duodenum of control subjects, and patients with HH or iron-deficiency anemia. RESULTS: The activity of both IRP1 and IRP2 and the levels of IRP2 were: (i) higher in monocytes and macrophages of HH patients than in those of control subjects; (ii) increased in the duodenal samples of the patients with HH and iron-deficiency anemia. IRP2 levels increased when monocytes differentiated to macrophages. Under all of the examined conditions, IRP2 was induced to a greater extent. In the duodenum of HH and anemic patients, IRP1 was shifted from the aconitase form (present in controls) to the apoform, whereas the IRP1 in monocytes/macrophages was always in the apoform, in both the patients and controls. The RNA-bound fraction of IRP1 was small in all of the samples. Both IRP were expressed more in the villi than in the crypts of the duodenum, with no differences in localization or expression between the patients and controls. INTERPRETATION AND CONCLUSIONS: These findings of the first extensive investigation of the comparative expression of the two IRP in human tissues and blood cells indicate that IRP2 is the major regulator of intracellular iron homeostasis in humans.

Adult↗
PubMed2006

[A case of hemochromatosis diagnosed in a middle-aged patient with diabetes mellitus].

The authors present the case of a 60-year-old patient admitted for diabetes mellitus. Primary (hereditary) hemochromatosis was diagnosed as the pathological background of diabetes as well as the associated symptoms (weight loss, arthrosis, erectile dysfunction, supraventricular arrhythmia, hepatic cirrhosis). To eliminate the accumulated excess iron, phlebotomy cycles were started. Family screening revealed two other affected patients who contrary to the index-patient were free of complaints. Phlebotomy was, however, started in one of these patients because of abnormal laboratory values consistent with iron-overload. For the prevention of the symptoms early diagnosis is important. Although some of the symptoms can disappear, the most severe changes (cirrhosis, diabetes) are irreversible. Latest knowledge about the pathophysiology including the genetic background and the practice of diagnosis and treatment of the disease are discussed as well.

Diabetes Complications↗
PubMed2006

Searching for hereditary hemochromatosis.

OBJECTIVE: To detect hereditary hemochromatosis (HH) in low-income residents of a medically underserved region through free screening and confirmatory laboratory testing and to raise awareness of HH in the general population. DESIGN: Two-tiered reflexive laboratory testing was used to screen for HH. Participants evaluated the project by written survey upon its conclusion. Data were analyzed by descriptive techniques. SETTING: Local public health departments in 18 counties in western North Carolina (WNC). PARTICIPANTS/SUBJECTS: Phase 1: adult volunteers age > or = 20 without previous diagnosis of HH; Phase 2: Phase 1 participants with elevated screening results and adult family members of Phase 2 participants found to have HFE mutations; Phase 3: randomly-selected Phase 1 participants (Survey A) and all Phase 2 participants with HFE mutations (Survey B). INTERVENTIONS: Phase 1 (initial screening): non-fasting blood collection by venipuncture with testing for transferrin saturation (TS). Phase 2 (confirmatory testing): fasting blood collection by venipuncture for TS, serum ferritin (SF), and cheek swab for DNA analysis for two HFE mutations (C282Y and H63D). Phase 3: written Surveys A and B. MAIN OUTCOME MEASURES: Total number participants screened for HH; prevalence of elevated TS in Phase 1 participants; prevalence of HFE genotypes consistent with HH (C282Y/C282Y and C282Y/H63D) in Phase 2 participants; prevalence of elevated SF in subjects with HFE mutations; number of family members tested; number of participants being treated for HH as a result of screening; increase in awareness of HH among Phase 1 participants. RESULTS: 2,034 total subjects participated in screening events and/or family member testing. Of the 1,976 Phase 1 participants, 130 (6.6%) had elevated TS (> or = 45%). Twenty of 130 (15.4%) Phase 2 subjects were homozygotes for C282Y. The prevalence of the C282Y/C282Y genotype among the Phase 1 participants who were tested in Phase 2 was 20/1976 (1.0%). Fourteen of 20 (70%) C282Y homozygotes had elevated SE Eleven of 130 (8.5%) Phase 2 subjects were compound heterozygotes for C282Y and H63D, and none had elevated SE Of 58 family members tested, two (3.4%) were homozygotes for C282Y and eight (13.8%) were compound heterozygotes for C282Y and H63D. One of two (50%) family members homozygous for C282Y had an elevated SE No compound heterozygotes had elevated SE Sixty-four of 120 (54.2%) Phase 1 subjects responded to Survey A. 53.1% of respondents were unaware of HH prior to the screening event. 92.1% of respondents told their family and friends about HH after participating. 73.4% discussed their laboratory results with their healthcare provider. Twenty of 41 participants (48.8%) found to have HFE mutations associated with HH responded to Survey B. Eleven of 20 (55.0%) stated that they were being treated for HH. CONCLUSION: The prevalence of the major genetic mutation, C282Y/C282Y, associated with HH among Phase 1 study participants in WNC was 1%, more than three times the national prevalence of approximately 0.33%. Results suggest that free screening using laboratory tests in a two-tiered reflexive approach may be an effective means of detecting HH, especially in high-risk populations. Early detection through free laboratory screening tests may reduce morbidity and, ultimately, healthcare costs for low-income individuals. Awareness of HH as a health concern may increase as a result of publicity generated by screening events.

Adult↗
PubMed1975

[Idiopathic hemochromatosis and primary cancer of the liver].

In 74 patients admitted to hospital for primary hemochromatosis, the authors observed in 5 cases, the development of primary carcinoma of the liver. The frequency of this complication was definitely greater than in alcoholic or post-hepatitic cirrhosis, whether one considers patients in hospital or on autopsy. The best signs of malignant change are alterations in the surface of the liver and the development of hemorrhagic ascites. Using modern methods of clinical investigation, it is possible to make the diagnosis during the patient's life. Laparoscopy, permitting biopsy under direct vision, is the best investigation but it is not always possible. A search for alpha 1 foeto-protein was positive in one third of cases and the demonstration by hepatic arteriography of characteristic vascular abnormalities and, perhaps in future, information supplied by ultra-sonic echography, usually permit one to make the diagnosis. The course was fatal within a few months, and it seems that metastases and vascular spread are less frequent than in carcinoma developing on cirrhosis due to other causes.

Aged↗
PubMed1991

[Idiopathic hemochromatosis: association with antigens of the HLA system].

HLA-A3 and HLA-B7 antigens were detected significantly more frequently in a group of 59 patients with idiopathic hemochromatosis than in a general population. The haplotype most commonly associated with the disease was A3B7. No differences in disease severity were to be found between homozygotic and heterozygotic carriers of this haplotype and patients with other haplotypes. An increased prevalence was also found for the HLA-A9 antigen. The haplotypes A9B7 and A9B27 were significantly more common among the patients investigated than among the general population.

Chromosome Aberrations↗
PubMed1991

[The clinical characteristics of the course of hemochromatosis].

Eight patients with hemochromatosis (HC) were followed up. For a long time HC ran a latent course. Throughout many years, the symptoms occurred at varying succession. In many cases, the first manifest symptoms included skin itch, arthropathy, and diabetes mellitus. They may be dominant in the clinical picture for a long time, masking the genuine cause of the disease. The correct diagnosis was established, as a rule, at the pronounced stage of HC. Before that event the patients were followed up and treated by the endocrinologist (3 persons), by the infectionist (2 persons), dermatologist and traumatologist (2 persons), and by the internist (1 person). Appearance of one of the symptoms of the classical triad can be regarded as the onset of HC. The cardinal symptoms that determine the clinical picture progressed for the most part: liver cirrhosis, diabetes mellitus, and melanoderma. The first two require appropriate correction. Melanoderma presents a cosmetic and social and psychological problem. In HC patients, disorders occurring by the type of liver porphyria are recordable. They are of secondary nature, being an unfavourable prognostic sign. Investigation of iron metabolism in patients suffering from chronic liver diseases should be carried out by all means, since it can be regarded a specific enough test in the diagnosis of HC. Emphasis is laid on the importance of early diagnosis of HC.

Aged↗
PubMed1991

[The characteristics of the clinical course of hereditary hemochromatosis].

The authors describe 32 patients with hemochromatosis observed from 1965 through 1990 (28 men and 4 women). The diagnostic role of serum iron determination and liver biopsy is emphasized. The therapeutic results of bloodletting (500 ml weekly for several years) dyspheral (1-1.2 g intramuscularly daily for 1-2 years and longer). This treatment did not essentially influence the course of diabetes mellitus, liver cirrhosis as well as the articular and endocrine syndromes. The clinical effect of this treatment lasted for 6-8 years.

Bloodletting↗
PubMed1991

Hemochromatosis, iron and septicemia caused by Vibrio vulnificus.

Vibrio vulnificus is killed by normal human blood but grows rapidly in blood from patients with hemochromatosis. It also grows in normal blood if the saturation of the transferrin is increased or if hematin, which contains iron, is added. It is suggested that the increased availability of iron in the blood of patients with chronic iron overload is responsible for their enhanced susceptibility to infection with V vulnificus.

Female↗
PubMed1991

Idiopathic hemochromatosis.

Hemochromatosis is a rare disorder in which about four times the normal amount of iron is absorbed in the intestine, resulting in the accumulation of iron in the skin, liver, pancreas and heart. Radiographic features may include a small liver on plain abdominal films, increased hepatic density on computed tomographic imaging, and loss of liver signal on magnetic resonance imaging as a result of the strong paramagnetic effect of iron. Management includes phlebotomy and supportive treatment of damaged organs.

Bloodletting↗
PubMed1991

Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis.

In hereditary hemochromatosis (HH), increased intestinal iron absorption leads to the development of iron overload. To examine the abnormal regulation of iron absorption in this disorder, we analyzed mucosal iron kinetics in six patients with HH and in five normal subjects by using a compartmental model of intestinal iron absorption and systemic ferrokinetics. Subjects were given simultaneous oral and intravenous tracer doses of iron 59-labeled citrate and iron 55-labeled transferrin, respectively. Plasma and whole-body radioactive iron levels were then monitored serially during the next 2 weeks, and mucosal iron transport rate constants were estimated by non-linear least-squares fit of the model to these data. Iron absorption was inversely related to serum ferritin concentration in both normal subjects and patients with HH but was higher in relation to serum ferritin level among the latter (p less than 0.0002). Analysis of mucosal iron kinetics demonstrated a similar inverse relationship between the rate constant for mucosal iron uptake and serum ferritin among all subjects combined, but the mean uptake rate constant in patients with HH did not differ from that of normal subjects (p = 0.71). The mean rate constant for incorporation of iron into the mucosal storage pool in patients with HH also was comparable to that of normal subjects (p = 0.94). In contrast, the rate constant for transfer of mucosal iron to the plasma was higher in patients with HH than in normal subjects for any given serum ferritin level (p less than 0.0001), and the transfer rate constant accounted for 87% of the variability in iron absorption among all subjects. We conclude that the increased iron absorption in HH is mediated primarily by an increase in the rate constant for transfer of mucosal iron to the plasma.

Ferritins↗
PubMed1990

Hypoechoic focal liver lesions in granulomatous hepatitis and hemochromatosis.

Hypoechoic focal liver lesions are described, for the first time, in two patients with granulomatous hepatitis and hemochromatosis, and presenting a 'bright liver pattern' at ultrasonography. CT-scan was not able to make evident such areas in both cases, while hepatoscintigraphy revealed them only in the patient with granulomatous hepatitis. Echoguided fine-needle biopsies on the focal lesions were suitable for the correct final diagnoses. The finding of such areas was probably due to different intensity of the diseases in contiguous zones of liver parenchyma.

Adult↗
PubMed1990

[Primary hemochromatosis with cardiac involvement].

An autopsy case is described of a primary hemochromatosis in a 33-year-old man which was not diagnosed clinically. The peculiar feature of the disease was the absence of skin discolorations, definite symptoms of diabetes mellitus and a hepatic cirrhosis against the background of pigment cardiomyopathy. It's suggested that the progression of the heart pathology was due to the use of certain antibacterial preparations.

Acute Disease↗
PubMed1990

[Perinatal hemochromatosis].

Perinatal hemochromatosis (PHC) is a rare disorder presumably autosomal recessive, responsible for foetal death or severe liver failure during the neonatal period. It is fatal in nearly all cases. Diagnosis relies on histologic examination, generally post mortem, which shows numerous iron deposits in the liver as well as other organs (pancreas, heart, thyroid...). The study of iron and of its ligands may have a diagnostic interest. The authors report 2 cases of PHC in one family, of whom one concerned child presented with biological signs evoking PHC on foetal blood at 31 weeks of pregnancy.

Female↗
PubMed1990

[Myocardial function in patients with hereditary hemochromatosis based on echocardiographic data].

In order to reveal changes in the myocardium at the preclinical stage of heart failure, 34 patients with hereditary hemochromatosis (HHC) underwent echocardiography in the M-mode. There were 26 men and 8 women aged 24 to 59 years. The control group was made up of 20 healthy persons. The HHC patients over 35 years of age (49.5 years on the average) manifested enlargement of the left ventricular cavity, an increase of the thickness of the interventricular septum and of the posterior heart wall, and reduction of pump function of the left ventricle.

Adult↗
PubMedDate not supplied

Prevalence of idiopathic hemochromatosis in Italy: study of 1301 blood donors.

Idiopathic hemochromatosis (IH) was considered a rare hereditary disease until population studies in the U.S.A. and Northern Europe indicated an unexpectedly high frequency. In this study we estimated the prevalence of IH in Italy by testing 1301 presumably healthy blood donors. Transferrin saturation (TS) and serum ferritin (SF) levels were used as screening methods. The subjects with TS greater than 50% and/or SF greater than 300 micrograms/l in men and greater than 160 micrograms/l in women were given a complete medical and laboratory examination and those with evidence of iron overload were asked to undergo liver biopsy. Five male donors but no female donors presented increased iron indexes. Diagnosis of homozygous IH in two of them was confirmed by liver biopsy, indicating a prevalence of the disease in this population of 0.2%; that is a gene frequency of 4.5% and a heterozygote frequency of 9%. Since our study might underestimate the true prevalence of the disease because blood donors are at high risk of iron depletion, IH could be one of the most frequent hereditary diseases in Italy. Large-scale screening of young adults based on TS and SF determinations should be proposed for early diagnosis and treatment.

Adolescent↗