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Query: UMLS:C0018801 (heart failure)
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Haemochromatosis is an inherited disorder of iron metabolism characterized by a general iron over loading. Without diagnosis and early treatment, it is a serious and potentially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estimated at 0.06 in Brittany, so that haemochromatosis may be the most common genetic disease in this area. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption through duodenal mucosa is excessive. However we don't know if it is a primary event. The gene is also unknown but in 1975 it was located on the short arm of chromosome 6, closely linked to the HLA class I region, less than 1 cM from HLA-A. None of the genes coding for the known iron proteins could be the haemochromatosis gene because of their chromosomal localization. In order to locate this gene with precision, we have used a reverse genetic approach now called positional cloning. Characterization of new polymorphic markers and linkage disequilibrium analysis, have led us to locate the gene within a 350 kb region around HLA-A. We have then searched for all the structural genes in this region. Seven new genes have been so identified and located with precision. A structural analysis of these genes was undertaken to find an eventual abnormality in patients.
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PMID:[Molecular genetics of hemochromatosis]. 835 73

Dilated cardiomyopathy is a frequent and serious complication of idiopathic hemochromatosis. The mechanism by which disordered iron metabolism induces heart failure is not entirely understood, but myocardial dysfunction appears to be intimately related to the deposition of iron in myocytes. Cardiac function characteristically worsens or improves in proportion to the degree of iron accumulation in cardiac myocytes. The authors report the case of a 47-year-old man with idiopathic hemochromatosis and cirrhosis who developed symptoms of congestive heart failure and was found to have dilated cardiomyopathy 7 months after receiving a liver transplant. An initial endomyocardial heart biopsy demonstrated severe iron deposition in myocytes. The patient's heart failure worsened in the next 3 years and he eventually required a heart transplant. Examination of the explanted heart revealed dilated cardiomyopathy, but the previously demonstrated iron deposits in the cardiac myocytes were depleted. This "uncoupling" of cardiac function and cardiac iron load suggests that a threshold may be reached at which point the metabolic and ultrastructural derangements of iron deposition are no longer reversible, even with the removal of the inciting agent. Furthermore, displacement of myocyte iron stores after liver transplantation implicates altered hepatic iron metabolism as a primary or contributing mechanism in the pathophysiology of idiopathic hemochromatosis.
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PMID:Progressive hemochromatotic cardiomyopathy despite reversal of iron deposition after liver transplantation. 842 14

Cardiac hemochromatosis can cause heart failure and cardiac arrhythmias. Among these arrhythmias, ventricular tachycardia may be resistant to treatment. A case of cardiac hemochromatosis complicated with ventricular tachycardia that did not respond to intravenous lidocaine, procainamide or propafenone, nor to DC cardioversion, was successfully treated with amiodarone. Amiodarone, a class III antiarrhythmic drug, may be highly effective in similar cases.
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PMID:Sustained ventricular tachycardia in cardiac hemochromatosis treated with amiodarone. 914 11

Few reports exist concerning heart transplantation in recipients with end-stage myocardiopathy-associated heart failure caused by iron overload occurring with beta-thalassaemia, Diamond-Blackfan syndrome or haemochromatosis. Seven potential transplant candidates (six male, one female, mean age 26 years) with such heart failure, following desferrioxamine application subcutaneously over a number of years, and intravenously during their hospitalization before transplantation, were retrospectively analysed. Five were New York Heart Association (NYHA) class IV, three experienced one or more resuscitations immediately before transplantation could be performed. Continuous, high-volume, veno-venous haemofiltration was necessary in two patients. One of these two candidates additionally had to be bridged, first with a right ventricular, then with a biventricular assist device. Five of the seven patients survived, two with haemochromatosis, one with beta-thalassaemia major and one with Diamond-Blackfan syndrome following transplantation. One non-transplanted candidate with beta-thalassaemia major has been recompensated for 5 years. Survival was 14-74 months. Our results demonstrate the feasibility and indication of transplantation in patients with such heart failure and the satisfying outcome of immunosuppression is described.
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PMID:Heart transplantation for end-stage heart failure caused by iron overload. 916 90

Haemochromatosis is the most common genetic disease in individuals of Northern European origin. This disorder of iron metabolism, for which the molecular basis remains poorly understood, is characterized by an excessive absorption of dietary iron through the duodenal mucosa. Progressive iron loading of parenchymal organs results in the mid-life onset of clinical complications, and patients may succumb to cardiac failure and/or hepato-carcinoma. But patients who undergo early diagnosis and phlebotomy treatment before the development of organ damage have a normal life expectancy. The haemochromatosis gene was recently isolated and encodes a HLA class I related protein. A missense mutation (C282Y) in the homozygous configuration was observed in more than 92% of the patients. So diagnosis and genetic counselling are getting modified by this direct genotyping test.
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PMID:[Genetic hemochromatosis]. 923 20

Chronic mild liver enzyme abnormalities are attributable to hereditary hemochromatosis in at least 3% of cases. Hemochromatosis formerly was diagnosed late with diabetes and hepatic and cardiac failure. Only recently have the autosomal recessive inheritance and subtle early presentations been understood. However, patients still wait many years and see many physicians before receiving a correct diagnosis. Increased serum transferrin saturation is currently the best test for detection of those likely to accumulate iron. Serum ferritin identifies those requiring treatment. When liver biopsy (controversial in asymptomatic individuals) is indicated, chemical measurement of liver iron content is helpful and therapeutic phlebotomy is the only effective treatment. Caucasian-type hemochromatosis (prevalence of 0.005) is associated with genetic abnormalities in HLA-H but also occurs in other ethnic groups. Those of African descent may have a different but also heritable iron-loading disease. Caucasian-type and to a lesser extent African iron loading are detectable early by laboratory testing. Early treatment restores normal expectations of length and quality of life in the Caucasian disease. Long-term treatment data are not yet available in African iron loading. Laboratory-initiated screening programs using unsaturated iron-binding capacity can eliminate symptomatic hemochromatosis.
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PMID:Mild liver enzyme abnormalities: eliminating hemochromatosis as cause. 926 5

Although rare, amyloidosis and hemochromatosis are the infiltrative diseases in which the heart is more frequently involved. The most common clinical presentation is heart failure with hemodynamic features of restrictive heart disease in cardiac amyloidosis. The diagnosis is often made because of symptoms of other organ involvement, although sometimes cardiac symptoms may be the initial manifestation. The non-specific clinical presentation and the low prevalence of these cardiomyopathies make the diagnosis difficult if the clinician does not suspect it. Once symptoms develop, the evolution is fast. Usually, the unsatisfactory and ineffective treatment of amyloidosis and hemochromatosis contribute to the poor prognosis. The indication of cardiac transplantation in advanced cases is questionable because of the high recurrence of the illness.
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PMID:[Cardiac pathology of extracardiac origin (II). The cardiac repercussion of amyloidosis and hemochromatosis]. 942 3

Juvenile haemochromatosis (JH) is an autosomal recessive disorder which leads to early-onset, severe iron overload. The disease affects both sexes equally. Iron parameters and tissue iron distribution are similar to those in middle-life haemochromatosis (which is linked to the HFE gene). Endocrine manifestations, especially hypogonadism, and heart failure are the most prominent clinical features. Liver involvement, although present, is clinically less relevant. Genetic evidence indicates that JH is a disorder distinct from HFE-linked disease. Patients do not have mutations in the HFE gene, and the study of selected families has excluded a linkage to the interval of chromosome 6p where the HFE gene resides. The distinction between the two disorders raises the possibility that the different clinical presentation of JH is not only age-related but probably depends on a different biochemical defect. Early diagnosis of JH is important to avoid cardiac complications which can lead to premature death. As with HFE-linked disease, JH is responsive to phlebotomies.
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PMID:Juvenile haemochromatosis. 989 70

Juvenile haemochromatosis is a rare inborn error of iron metabolism with clinical manifestations before 30 years of age. Unlike adult haemochromatosis which principally affects men, juvenile haemochromatosis affects the sexes equally; it causes early endocrine failure, dilated cardiomyopathy and joint disease. We report four patients (two of each sex) from three pedigrees affected by juvenile haemochromatosis with a mean onset at 22 years (range 14-30). All had endocrine deficiency with postpubertal gonadal failure secondary to pituitary disease; two suffered near-fatal cardiomyopathy with heart failure. Mean time to diagnosis from the first clinical signs of disease was 9.8 years (range 0.5-20) but general health and parameters of iron storage responded favourably to iron-depletion therapy. A 24-year-old man listed for heart transplantation because of cardiomyopathy [left ventricular (LV) ejection fraction 16%] responded to intravenous iron chelation with desferrioxamine combined with phlebotomy (ejection fraction 31%). A 27-year-old woman with subacute biventricular heart failure refractory to medication required orthotopic cardiac transplantation before the diagnosis was established (LV ejection fraction 25%). Genetic studies showed that these two patients with cardiomyopathy from unrelated families were heterozygous for the HFE 845G-->A (C282Y) mutation and wild-type at the H63D locus: complete sequencing of the intron-exon boundaries and entire coding sequence of the HFE gene failed to identify additional lesions. Two siblings in a pedigree without cardiomyopathy were wild-type at the HFE C282Y locus; although the brother harboured a single copy of the 187C-->G (H63D) allele, segregation analysis showed that in neither sibling was the iron-storage disease linked to MHC Class I markers on chromosome 6p. Juvenile haemochromatosis is thus a genetically heterogenous disorder distinct from the common adult variant.
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PMID:Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron-storage disease. 1002 15

Hereditary hemochromatosis (HHC) is one of the most common inherited disorders in the Caucasian population. Diagnosis usually made after an elevation in ferritin and serum transferrin saturation is noted, often accompanied by asymptomatic hepatomegaly. Diagnosis is confirmed by genetic testing or liver biopsy. Damage to organs is due to excessive intestinal iron, which is transported to and then deposited in the liver parenchyma, and the heart, skin, and endocrine organs, causing skin pigmentation, development of cirrhosis and hepatic carcinoma, diabetes and endocrine failure, and heart failure. Bony changes can be manifested by arthritis, often in non-weight-bearing joints. The treatment of HHC is phlebotomy, which depletes iron stores. When diagnosis is made before organ damage occurs, treatment can prevent manifestations of the disease. Skin pigmentation and some cardiac damage may reverse on depletion of iron stores, but liver and endocrine damage is rarely reversible. Arthropathy is also not reversible, and often continues to progress even with effective treatment. When hemochromatosis is diagnosed, all first degree relatives of the patient should undergo genetic testing. With early detection and treatment this can be a manageable chronic disease. If undetected, it is potentially fatal.
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PMID:Hereditary hemochromatosis: diagnosis and treatment in primary care. 1054 25


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