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)

Hemochromatosis is the most common genetic disorder known in man and results in progressive tissue deposition of iron leading to cirrhosis of the liver, hepatic carcinoma, congestive heart failure, endocrinopathies, and premature death. SFT (stimulator of Fe transport) is a newly discovered transport protein that facilitates uptake of iron. Recent studies have demonstrated that although SFT expression is reciprocally regulated in response to cellular iron levels, it is aberrantly upregulated in the liver of hemochromatosis patients, indicating that enhanced SFT expression contributes to the etiology of this disease. Here we report the molecular cloning and characterization of the human gene for SFT. FISH analysis maps the SFT gene to human chromosome 10q21. PCR analysis indicates 1000 nucleotides of intervening intron sequence near the 3' end of the coding region for SFT. Based on DNA sequence analysis of the additional 5' untranslated region obtained from the genomic clone, SFT lacks known metal-regulated transcriptional or translational control elements. These studies provide the basis for future elucidation of the mechanisms that control SFT expression in order to discover how this regulation is lost in hemochromatosis.
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PMID:Characterization and chromosomal mapping of the human gene for SFT, a stimulator of Fe transport. 991 97

A case of cryptogenic cirrhosis in a patient with Turner's syndrome is presented. The individual was admitted for upper gastrointestinal bleeding due to oesophageal varices. After failure of medical treatment, a transjugular intra-hepatic portal systemic shunt was used to control the bleeding. A liver biopsy revealed cirrhosis with minimal necro-inflammatory activity and no steatosis. Immunohistochemical staining for HCV, HBsAg and HBcAg was negative. No other risk factor for liver disease was recognized and none of the known causes of chronic liver disease was identified after a thorough evaluation for such. Turner's syndrome is a genetic disorder due to X chromosome monosomy in which a wide range of congenital anomalies can occur. Cardiac, renal and skeletal anomalies are all well recognized. The possible association of Turner's syndrome with cirrhosis is herein discussed along with a review of the published literature.
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PMID:Cirrhosis in Turner's syndrome: case report and literature review. 1091 94

Juvenile hemochromatosis is a rare genetic disorder that causes iron overload. Clinical complications, which include liver cirrhosis, heart failure, hypogonadotropic hypogonadism and diabetes, appear earlier and are more severe than in HFE-related hemochromatosis. This disorder, therefore, requires an aggressive therapeutic approach to achieve iron depletion. We report here the case of a young Italian female with juvenile hemochromatosis who was unable to tolerate frequent phlebotomy because of coexistent ss-thalassemia trait. The patient was successfully iron-depleted by combining phlebotomy with recombinant human erythropoietin.
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PMID:Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin. 1094 34

Iron overload in body tissues can cause complications such as cirrhosis, cardiomyopathy, diabetes, hypogonadism and arthritis. In populations of northern European descent, most iron overload is due to hereditary haemochromatosis (HHC), a genetic condition that causes increased iron absorption. HHC can be treated or prevented by regular phlebotomy treatments. Some experts have called for population screening for HHC, so that early phlebotomy treatment can be initiated. Two screening tests are available: measurement of the serum iron transferrin saturation (Tf%) and genetic testing for HFE mutations. However, both methods have low positive predictive values. Current data suggest that most people at risk are unlikely to develop clinical symptoms and that the population prevalence of clinical complications of HHC is low, arguing against population screening. Two other prevention strategies are available. (1) Health provider education, to heighten awareness of HHC as an explanation for symptoms and signs seen in early iron overload including unexplained fatigue, joint pain, palpitations, abdominal pain, elevated liver function tests, hepatomegaly and elevated serum ferritin. (2) Family-based testing after a diagnosis of HHC, to ensure that relatives are evaluated for evidence of iron overload. More research is also needed to identify the factors that increase risk for disease in persons with excess iron uptake, to determine whether moderate iron overload is a health risk and to evaluate the causes of iron overload other than HHC.
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PMID:Hereditary haemochromatosis: a realistic approach to prevention of iron overload disease in the population. 1240 10

Hereditary hemochromatosis (HHC) is a condition characterized by excess iron in body tissues, resulting in complications such as cirrhosis, cardiomyopathy, diabetes, and arthritis. These complications usually manifest during adulthood. Two methods of screening for the detection of early stage of HHC are available: serum iron measures and molecular testing to detect mutations in the gene. These phenotypic and genotypic screening tests are of particular interest because a simple treatment-periodic phlebotomy-can be used to prevent iron accumulation and clinical complications. HHC might represent the first adult-onset genetic disorder for which universal population-based screening would be appropriate. Therefore, HHC has been proposed as a paradigm for the introduction of adult genetic diseases into clinical and public health practice. However, universal screening for HHC has not been recommended because of the uncertainty about the natural history of the iron overload or HHC and, in particular, uncertainty about the prevalence of asymptomatic iron overload and the likelihood that it will progress to clinical complications. If universal screening is not appropriate based on current data, what other measures might reduce the disease burden of iron overload? New studies provide more systematic information about the penetrance of the C282Y mutation and shed further light on the natural history of the disorder. The authors review these data and consider their implications for public health, medical genetics, and primary care.
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PMID:Hereditary hemochromatosis: perspectives of public health, medical genetics, and primary care. 1254 69

Hereditary hemochromatosis is a prevalent genetic disorder of iron hyperabsorption leading to hyperferremia, tissue iron deposition and complications including cirrhosis, hepatocarcinoma, cardiomyopathy and diabetes. Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200). Mice lacking Hfe or producing a C282Y mutant Hfe protein develop hyperferremia and have high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells; however, this model is unproven and controversial. Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE. Although expression of mouse Hamp is normally greater during iron overload, Hfe-/- mice have inappropriately low expression of Hamp. We crossed Hfe-/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe-/- mice. This argues against the crypt programming model and suggests that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease.
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PMID:Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. 1270 88

The consumption of excess alcohol in patients with liver iron storage diseases, in particular the iron-overload disease hereditary haemochromatosis (HH), has important clinical consequences. HH, a common genetic disorder amongst people of European descent, results in a slow, progressive accumulation of excess hepatic iron. If left untreated, the condition may lead to fibrosis, cirrhosis and primary hepatocellular carcinoma. The consumption of excess alcohol remains an important cause of hepatic cirrhosis and alcohol consumption itself may lead to altered iron homeostasis. Both alcohol and iron independently have been shown to result in increased oxidative stress causing lipid peroxidation and tissue damage. Therefore, the added effects of both toxins may exacerbate the pathogenesis of disease and impose an increased risk of cirrhosis. This review discusses the concomitant effects of alcohol and iron on the pathogenesis of liver disease. We also discuss the implications of co-existent alcohol and iron in end-stage liver disease.
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PMID:Effect of alcohol on iron storage diseases of the liver. 1282 61

Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.
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PMID:Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency. 1459 26

Alpha-1-antitrypsin (alpha1-AT) is a member of the serine protease inhibitor family regulating numerous proteolytic processes. The genetic disorder, alpha1-AT deficiency, is well known as a cause of hereditary pulmonary emphysema and liver cirrhosis. To create an animal model of human alpha1-AT deficiency, we disrupted the major murine isoform PI2, which is similar to human alpha1-AT and is one of 7 alpha1-AT isoforms found in the mouse. The ability of the serum to inhibit the activities of human leukocyte elastase (HLE) and human chymotrypsin (CYT) was significantly lower in heterozygous mice (alpha1-AT/PI2 -/+) than wild-type (alpha1-AT/PI2 +/+) mice (73.2% vs. 100% for HLE and 67.8% vs.100% for CYT, respectively; P<0.05). The distribution of genotypes among F(2) progeny was not in accordance with Mendelian distribution (P<0.01), as the percentages of wild-type, heterozygotes and homozygotes were 47.8%, 37.3% and 14.9%, respectively. Thus, it is likely that impairment of the protease inhibitor had a critical effect on fetus development. The alpha1-AT/PI2 deficient mouse will be a useful animal model for elucidating the function of alpha1-AT in fetal development, studying the mechanisms of chronic inflammatory disease and evaluating therapeutic candidates for the treatment of inflammatory disease.
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PMID:Disruption of the murine alpha1-antitrypsin/PI2 gene. 1551 92

Iron overload causes impaired function of tissues and organs due to the increased iron storage in them. Hereditary hemochromatosis is the most frequent hereditary metabolic disorder, with lethal outcome without treatment. The genetic disorder is a mutation on the short arm of the 6. chromosome, which resulted a cysteine-tyrosine substitution on the 282. amino acid position (C282Y). This mutation is less frequent in the non-Caucasian population, in opposition to the other reported mutation (H63D). The risk of the development of the disease is the highest in people who are C282Y homozygotes or C282Y/H63D compound heterozygotes. The prevalence of hemochromatosis is 1.5-5.9 per thousand. Liver disease/cirrhosis, diabetes mellitus and hyperpigmentation are the classic signs of the disease. Primer hepatocellular cancer occurs in 30% of patients with liver cirrhosis, that it is the most common cause of death among them. The diagnosis is based on the detection of iron overload (transferrin saturation, serum ferritin level, iron concentration of the liver tissue) and on the genetic examinations. Early diagnosis makes the causal therapy possible, which is the removal of the iron excess by phlebotomy. Furthermore, the early detection of iron overload allows of prevention of the development of the disease. Based in these facts population screening seems to be necessary and cost-effective, but further studies are required to determine the exact screening strategy.
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PMID:[Iron storage disease]. 1555 8


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