Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
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One of the most common genetic causes of iron overload is hereditary hemochromatosis (HHC), a condition characterized by overabsorption of dietary iron from the gastrointestinal tract. This condition can lead to excessive iron accumulation with resulting dysfunction in multiple organs, including the liver, skin, heart,joints, pancreas, and testes. The clinical consequences of HHC if undetected and untreated can be severe and include liver cirrhosis,hepatocellular carcinoma, diabetes mellitus, cardiac arrhythmias and failure, arthritis, and hypogonadism. HHC is one of the most common heritable conditions in white populations of Northern European origin. This article presents a case study of HHC, describing inheritance and genetics, disease characteristics and natural history, diagnosis, differential diagnosis, and management.
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PMID:Clinical consult: iron overload--hereditary hemochromatosis. 1533 Dec 58

Intrahepatic iron overload is commonly seen in chronic hepatitis C infection. High levels of intrahepatic iron may lead to accelerated liver injury and development of fibrosis and cirrhosis. This is frequently seen in hereditary hemochromatosis, which in most of the cases is caused by homozygous mutations in the HFE gene. In patients suffering from chronic hepatitis C, the presence of heterozygous HFE mutations associates with higher hepatic iron scores and advanced stages of fibrosis. HFE mutations must therefore be considered as important comorbidity factors in chronic hepatitis C infection.
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PMID:Iron, the HFE gene, and hepatitis C. 1546 55

Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising in some developed countries, whereas mortality from non-HCC complications of cirrhosis is decreasing or is stable. Cohort studies indicate that HCC is currently the major cause of liver-related death in patients with compensated cirrhosis. Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively), followed by hereditary hemochromatosis (5-year cumulative incidence, 21%). In hepatitis B virus (HBV)-related cirrhosis, the 5-year cumulative HCC risk is 15% in high endemic areas and 10% in the West. In the absence of HCV and HBV infection, the HCC incidence is lower in alcoholic cirrhotics (5-year cumulative risk, 8%) and subjects with advanced biliary cirrhosis (5-year cumulative risk, 4%). There are limited data on HCC risk in cirrhosis of other causes. Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC, independent of etiology of cirrhosis. In viral-related cirrhosis, HBV/HCV and HBV/HDV coinfections increase the HCC risk (2- to 6-fold relative to each infection alone) as does alcohol abuse (2- to 4-fold relative to alcohol abstinence). Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate other viral factors (eg, HBV genotype/mutant, occult HBV, HIV coinfection) and preventable or treatable comorbidities (eg, obesity, diabetes) in the HCC risk in cirrhosis.
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PMID:Hepatocellular carcinoma in cirrhosis: incidence and risk factors. 1550 1

Iron overload diseases are due to a progressive increase in total body iron stores that leads to deposition of iron in parenchymal organs and to subsequent damage to these organs. The commonest inherited form of iron overload is hereditary hemochromatosis (HH), an autosomal recessive disorder affecting the white population. Although in the western world and in northern Europe the majority of cases of HH are associated with an HFE gene mutation (C282Y and H63D), there are families with a familial iron overload disorder in whom neither the C282Y nor the H63D mutations were found. Recently, other forms of HH that are not related to HFE, but are due to mutations in genes coding iron transport proteins (ferroportin-1, TfR2, hepcidin) have been described. The clinical presentation of the disorder is highly variable, depending on the severity of iron overload. In fact, the inappropriate absorption and deposition of dietary iron may result in the development of hepatic and non-hepatic end-organ injury, leading to liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, skin pigmentation and cardiac diseases. HH and its sequelae are preventable with an early diagnosis and treatment. Patients with evidence of iron overload, a family history of HH or other risk factors should be screened by genotype testing for the HFE mutation. Nowadays, HH is recognized as being a complex genetic disease with probable significant environmental and genetic modifying factors, such as hepatitis C virus infection and alcohol abuse, and it has been shown that HFE mutations represent an independent risk factor for fibrosis and cirrhosis in chronic hepatitis C.
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PMID:[Iron overload disease: recent findings]. 1552 41

Hereditary hemochromatosis is a common disorder of iron metabolism that increasingly is diagnosed and treated prior to the development of cirrhosis or diabetes. The discovery of a candidate gene for hereditary hemochromatosis undoubtedly will result in improved diagnosis of hereditary hemochromatosis and to a better understanding of certain aspects of iron absorption, hepatic iron uptake and release, and whole body iron metabolism. In turn, this enhanced understanding of iron biology can be applied to the observations seen in patients with other hepatic diseases such as chronic viral hepatitis.
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PMID:Iron overload states. 1556 46

Hypogonadism, usually hypogonadotropic in origin, is the most common nondiabetic endocrinopathy in hereditary hemochromatosis (HH). Early studies, usually evaluating small numbers of patients with advanced HH, report prevalence rates of 10-100%. The clinical presentation of HH has changed in recent years as a result of increased awareness and screening. We assessed the prevalence of hypogonadism in a large group of patients with HH diagnosed in a single center over the past 20 yr, the period of follow-up spanning the time before and after widespread screening was introduced and the HFE gene was recognized. Abnormally low plasma testosterone levels, with low LH and FSH levels, were found in nine of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; three of nine (33%) had diabetes. Inappropriately low LH and FSH levels were found in two of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. This is the largest detailed study of hypogonadism reported in HH. The lower prevalence of hypogonadism compared with other reported series reflects the earlier diagnosis of HH in an unselected group of patients attending a single center. Patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism.
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PMID:Hypogonadism in hereditary hemochromatosis. 1565 76

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

The occurrence of primary hepatocellular carcinoma (HCC) in patients with hereditary hemochromatosis (HH) is well known. Thereby, the development of liver cirrhosis seems to be a prerequisite. Whether or not a hepatic iron overload in the context of hereditary hemochromatosis is an independent risk factor for HCC remains unclear. To date there are only a few reports about HCC arising in non-cirrhotic livers in the presence of HH. We report the case of a 64-year-old man who presented to our outpatient clinic with HCC. Liver cirrhosis could be excluded. Detailed exploration of the patient's history revealed that he had been treated by venesection for about 10 years up to 15 years ago. Subsequent investigations showed an elevated serum ferritin and transferrin saturation. The diagnosis of HH was confirmed by genetic testing, with homozygosity for the Cys282Tyr mutation. The patient received palliative chemotherapy and finally died 15 months after initial diagnosis of HCC.
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PMID:Hepatocellular carcinoma associated with hereditary hemochromatosis occurring in non-cirrhotic liver. 1639 38

Iron-mediated organ damage is common in patients with iron overload diseases, namely, hereditary hemochromatosis. Massive iron deposition in parenchymal organs, particularly in the liver, causes organ dysfunction, fibrosis, cirrhosis, and also hepatocellular carcinoma. To obtain deeper insight into the poorly understood and complex cellular response to iron overload and consequent oxidative stress, we studied iron overload in liver-derived HepG2 cells. Human hepatoma HepG2 cells were exposed to a high concentration of iron for 3 days, and protein expression changes initiated by the iron overload were studied by two-dimensional electrophoresis and mass spectrometry. From a total of 1,060 spots observed, 21 spots were differentially expressed by iron overload. We identified 19 of them; 11 identified proteins were upregulated, whereas 8 identified proteins showed a decline in response to iron overload. The differentially expressed proteins are involved in iron storage, stress response and protection against oxidative stress, protein folding, energy metabolism, gene expression, cell cycle regulation, and other processes. Many of these molecules have not been previously suggested to be involved in the response to iron overload and the consequent oxidative stress.
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PMID:Proteomic analysis of iron overload in human hepatoma cells. 1641 Mar 66

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


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