Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The term hemochromatosis is commonly used as synonymous with HFE-associated genetic iron overload but several rarer causes of an identical clinicopathological syndrome have been described in recent years. The most common symptoms are lethargy and arthralgia, and the major complications of end-stage disease are cirrhosis, diabetes, and cardiac and endocrine manifestations. However, with the development of cascade screening for family members of affected probands as well as screening for common diseases at health checks, hemochromatosis is being detected at increasingly early stages, often when there are only biochemical abnormalities. The available evidence from screening studies strongly suggests that approximately 75% of C282Y homozygous subjects have biochemical expression. Hepatic iron overload is present in approximately 56% and 34% of men and women, respectively, advanced hepatic fibrosis in 18.7% and 5.4%, respectively, and cirrhosis in 5.8% and 1.9%, respectively. In subjects with severe expression of the disease, additional modifying genetic mutations have been described including those in hepcidin and hemojuvelin. Treatment is by regular phlebotomy which, if instituted before the development of cirrhosis, results in normal life expectancy.
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PMID:Clinical aspects of hemochromatosis. 1631 32

Type 1 hereditary hemochromatosis is a common disorder of iron overload occurring in individuals homozygous for the C282Y HFE gene mutation. It can be a progressive and fatal condition. Early detection and phlebotomy prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with clinical features suggestive of iron loading. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified. Potential ethical, legal, and psychosocial issues arising through application of genetic screening programs also must be resolved prior to implementation of general population screening programs.
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PMID:Screening for HFE and iron overload. 1631 34

Iron is essential for cellular functions, but in excessive amounts it is toxic to cells. The harmful effects are related to increased oxidative stress and production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Heavy iron overload as occurs in primary and secondary hemochromatosis can cause fibrosis of various parenchymal organs such as the liver, heart, and pancreas. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. In this article we review selected nonhemochromatotic disorders in which iron can play an important comorbid role.
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PMID:Iron in nonhemochromatotic liver disorders. 1631 39

The aim of the present study was to describe the histopathologic features of hepatic iron accumulation in patients with chronic hepatitis C (CH-C) infection, the relation between HFE mutations and hepatic iron location and among iron distribution, HFE, and hepatic damage. We studied 206 patients with CH-C infection. Of 101 patients with hemosiderin deposits, 90.1% had iron deposits in hepatocytes (alone or with sinusoidal and/or portal involvement). The hepatic iron score increased significantly as iron accumulation involved sinusoidal and portal tract compartments and according to HFE genotypes. Severe fibrosis and cirrhosis were associated more markedly with the presence of hemosiderin iron in the 3 hepatic compartments, HFE mutations, and high alcohol intake. We suggest that part of the iron accumulation in CH-C infection derives from increased iron absorption and release from storage cells and that the amount and distribution of hepatic iron deposits is related to hepatic damage. HFE mutations favor both processes, but other factors, genetic or acquired, are involved.
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PMID:Iron accumulation in chronic hepatitis C: relation of hepatic iron distribution, HFE genotype, and disease course. 1641 33

Hereditary hemochromatosis has been redefined over the past century, from a rare (but often fatal) disorder of iron overload known as "bronzed diabetes" to only biochemical evidence of altered iron metabolism, and recently to mere expression of the C282Y homozygous genotype of the HFE gene. The variable definitions of the disease, as well as the variable degree of penetrance of the C282Y homozygous genotype, have made it difficult to determine optimal screening strategies. Multiple studies performed since discovery of the C282Y mutation have led to the conclusion that overall penetrance of the genotype is low and that screening of asymptomatic general populations for hereditary hemochromatosis is not recommended. Screening for HFE mutations among certain patient groups, including patients with cirrhosis, however, may help target those who would benefit most from iron removal. For most patients, phlebotomy is the preferred treatment option; iron chelation therapies are available for patients unable to tolerate phlebotomy.
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PMID:Hereditary hemochromatosis: screening and management. 1653 44

We report the case of a man with severe X-linked sideroblastic anemia, severe iron overload, and hepatic cirrhosis who died of hepatocellular carcinoma. Evaluation of family members using DNA sequencing revealed that he was hemizygous for the novel ALAS2 mutation R452H (exon 9; nt 1407 G --> A). The proband's brother, an ALAS2 R452H hemizygote, had mild anemia and mild iron overload. Four female relatives were ALAS2 R452H heterozygotes, but they had mild or no anemia and no iron overload. Sequencing of TFR2, HFE, FPN1 (SLC40A1), HAMP, HJV, and the erythrocyte pyruvate kinase genes of family members was also performed. We thus detected the novel TFR2 missense mutation I449V (exon 10; nt 1345 A --> G) in the proband's wife and daughter, neither of whom had anemia or iron overload. Possible explanations for the disparate red blood cell and iron phenotypes of the proband and his family members are discussed.
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PMID:Disparate phenotypic expression of ALAS2 R452H (nt 1407 G --> A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. 1654 Mar 54

Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83% of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein. HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease. Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. This review gives the background and a model as to possible mechanisms of how HFE could exert different effects on iron homeostasis in different cell types.
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PMID:Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis. 1662 71

Levels of body iron should be tightly controlled to prevent the formation of oxygen radicals, lipoperoxidation, genotoxicity, and the production of cytotoxic cytokines, which result in damage to a number of organs. Enterocytes in the intestinal villae are involved in the apical uptake of iron from the intestinal lumen: iron is further exported from the cells into the circulation. The apical divalent metal transporter-1 (DMT1) transports ferrous iron from the lumen into the cells, while the basolateral transporter ferroportin extrudes iron from the enterocytes into the circulation. Patients with hereditary hemochromatosis display an accelerated transepithelial uptake of iron, which leads to body iron accumulation that results in cirrhosis, hepatocellular carcinoma, pancreatitis, and cardiomyopathy. Hereditary hemochromatosis, a recessive genetic condition, is the most prevalent genetic disease in Caucasians, with a prevalence of one in 300 subjects. The majority of patients with hereditary hemochromatosis display mutations in the gene coding for HFE, a protein that normally acts as an inhibitor of transepithelial iron transport. We discuss the different control points in the homeostasis of iron and the different mutations that exist in patients with hereditary hemochromatosis. These control sites may be influenced by gene therapeutic approaches; one general therapy for hemochromatosis of different etiologies is the inhibition of DMT1 synthesis by antisense-generating genes, which has been shown to markedly inhibit apical iron uptake by intestinal epithelial cells. We further discuss the most promising strategies to develop gene vectors and deliver them into enterocytes.
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PMID:Hereditary hemochromatosis: an opportunity for gene therapy. 1662 72

Recent advances in molecular genetics have led to a better understanding of hereditary iron overload syndromes, of which the most frequent are recessive HFE-hemochromatosis and, to a much lesser extent, dominant ferroportin disease. Acquired iron overload syndromes can be related to metabolic syndrome (insulin resistance syndrome), end-stage cirrhosis, or hematological disorders such as thalassemia and refractory anaemia.
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PMID:[Human hepatic iron overload syndromes]. 1673 93

Screening for hereditary hemochromatosis, although largely discussed, is not yet implemented in clinical practice. We evaluated the cost-effectiveness of 165 hemochromatosis population-screening algorithms involving two or three of several screening tests by developing a computer program that simulates all possible screening scenarios. Input data comprised government estimates of health services data and costs and a virtual population with user-defined demographic characteristics (including variable HFE mutation frequencies and penetrance values). We show that when C282Y homozygote prevalence is set at 3:1000, population screening appears cost-effective when penetrance of the biochemical phenotype is >0.70. When only hepatocellular carcinoma and cirrhosis are considered as the cost-driving complications, population-based screening is not significantly more cost-efficient than no screening, but life expectancy of individuals identified with hereditary hemochromatosis and treated is still improved by 7 years. Among the 165 screening algorithms tested in 91 different virtual populations of one million individuals, biochemical tests usually perform better as the initial test than genetic testing. Indeed, the genetic testing is most cost-effective as the final confirmatory test. Finally, for most combinations of prevalence and penetrance of HFE, one screening algorithm--unbound iron-binding capacity + transferrin saturation--appeared robust enough to be always within the top 5 most cost-effective strategies.
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PMID:Hereditary hemochromatosis screening: effect of mutation penetrance and prevalence on cost-effectiveness of testing algorithms. 1720 47


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