Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron deficiency is the most common disorder of iron metabolism worldwide, but there is concern that iron accumulation resulting from enhanced iron absorption may also be a cause of morbidity. In patients with genetic haemochromatosis the clinical manifestations of iron overload are well-known. In northern Europe 90% of such patients are homozygous for the C282Y mutation of the HFE gene and this genotype is found in 1 in 200 of the population. Heterozygosity for C282Y occurs in 15% of the population and 25% carry another mutation, H63D. Population studies have revealed (i) the serum transferrin saturation is strongly influenced by HFE genotype, being lowest in subjects lacking mutations and highest in those homozygous for C282Y; (ii) most subjects homozygous for C282Y accumulate iron but do not present with the clinical manifestations of iron overload. Testing for HFE mutations in clinics for diabetes, liver disease and cardiovascular disease has shown that homozygosity for C282Y is not commonly found. Heterozygosity for either C282Y or H63D does not appear to be a risk factor for these common conditions.
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PMID:HFE Mutations as risk factors in disease. 1240 9

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

Genetic haemochromatosis is an autosomal recessive inherited disorder of iron metabolism due to mutation of the HFE gene. In homozygotes (1 in 300 of the UK population), this results in excessive iron absorption from the gut and its deposition in major body organs. This may give rise to fatigue, arthritis, cardiac failure, diabetes mellitus, hepatic cirrhosis or skin pigmentation, occurring predominantly in males over 50 years of age. Identification uses measurement of serum iron, iron-binding capacity (or transferrin) and ferritin, together with initial or confirmatory genetic DNA studies.
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PMID:Genetic haemochromatosis. 1242 71

The presence of steatosis and inflammatory infiltrate in liver biopsies is essential for the diagnosis of non-alcoholic steatohepatitis (NASH). These findings are similar to those with alcoholic liver disease. However, in the NASH-situation alcohol doesn't play an important role. Risk factors for the development of NASH are obesity and diabetes. Most of the patients are clinically asymptomatic. This means, that a diagnosis of NASH is a diagnosis of exclusion: Viral induced, autoimmune, metabolic and toxic liver disease have to be excluded. The disease has a benign clinical course. The risk of cirrhosis is low. So far, there is no established treatment. Preliminary reports suggest a positive effect of weight-loss and ursodeoxycholic acid. Wilson's disease, a copper storage disorder, in which biliary copper excretion is reduced, is inherited as an autosomal recessive trait. Most patients with Wilson disease become symptomatic between the ages of 6 and 15. In about 90% of patients serum ceruloplasmin levels and serum copper concentrations are reduced. Copper excreation is increased. Histologic examination of liver biopsy specimens reveals fatty infiltration, Mallory bodies and ballooned glycogen nuclei, abnormalities which are also found in alcoholic liver disease. The definitive diagnostic parameter is the quantitative determination of liver copper content (> 250 micrograms/g dryweight). Untreated Wilson disease is always fatal. Lifelong treatment with anti-copper drugs are essential, D-penicillamine being the firstline therapy. Hereditary hemochromatosis (HH) is an iron overload disease inherited as an autosomal recessive trait. The frequency of the disease is high. The first symptoms usually can be found at the age of 20-50 years. Arthralgia develops in up to 50% of the patients. Many organs are involved, most often the liver. The organ is usually enlarged, transaminases are always moderately elevated. Laboratory findings disclose a marked elevation in serum ferritin and transferrin saturation. More than 80% of HH-patients are homozygous for the C282Y-mutation in the HFE-gene. The firstline treatment of HH is phlebotomy. Treatment is lifelong. When serum ferritin drops below 50 micrograms/l, the frequency of phlebotomy should be reduced (4-12 per year). If the patient already has cirrhosis, the risk of HCC is very high.
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PMID:[Rare, but important chronic liver diseases]. 1250 71

Nonalcoholic fatty liver disease (NAFLD) has emerged as a ubiquitous liver disorder with occasional serious overtones. Although diabetes and obesity were initially held culpable, insulin resistance (IR) is now considered the fundamental operative mechanism. IR is probably the "first step" in nonalcoholic steatohepatitis (NASH). Oxidative stress may be the elusive "second" of possibly multiple steps in the progression of steatosis to fibrosing steatohepatitis. Because hepatic iron promotes oxidative stress, it was mooted as a contributory cofactor in NASH. This proposal was strengthened by an association with hepatic fibrosis. Subsequent studies have shown neither a significant increase in hepatic iron nor an association between hepatic iron and any of the histologic determinants in NASH. Likewise, the increased prevalence of hemochromatosis gene (HFE) mutations in some studies appears to be largely irrelevant to the development of hepatic fibrosis. Excess hepatic iron may occur in insulin resistance-associated iron overload (IRHIO), characterized by hyperferritinemia with normal to mild increases in transferrin saturation. Although patients with IRHIO have a high prevalence of IR-related metabolic disorders, the relationship of IRHIO to NASH is unclear. A recent study showed improvement in insulin sensitivity with the use of venesection in patients with NAFLD, but this approach cannot be implemented without extensive review.
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PMID:Interaction of iron, insulin resistance, and nonalcoholic steatohepatitis. 1253 Sep 44

Hereditary hemochromatosis is classically inherited as a recessive trait but is genetically heterogeneous. Mutations in the HFE and the TFR2 genes account for about 80% of patients and a third locus on chromosome 1q is responsible for juvenile hemochromatosis. We describe here the clinical and biological characteristics of autosomal dominant form of iron overload due to the N144H mutation of the SLC11A3 gene. Clinical signs of iron overload in patients include joint pains, cardiomyopathies, liver fibrosis and hormonal disorders including diabetes mellitus. The main and most common clinical symptoms in this family were joint complaints and early signs of arthrosis. Serum ferritin levels in iron overloaded subjects varied from 31 to 2179 ng/ml and the transferrin saturation from 13 to 88.6%. The iron overload is moderate compared to patients with type 1 hemochromatosis but the deferoxamine test was normal in all patients. The disease in this family segregated as a dominant trait. None of the patients was homozygous or compound heterozygous for any known mutation in the HFE or TFR2 genes. The disease in this family represents a non-classical form of iron overload caused by the N144H mutation in the SLC11A3 gene. The reports of other distinct mutations in SLC11A3 suggest that this gene may be of interest for further etiologic research.
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PMID:Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics. 1254 33

Since the discovery of a candidate gene (HFE) thought to be involved in the development of hereditary hemochromatosis, there has been much interest in the potential use of genetic testing as a screening tool for the disease in the general population. However, a recent study suggests that less than 1% of subjects who are homozygous for the gene mutations will go on to develop the full-blown disease of hereditary hemochromatosis, historically termed "bronzed diabetes." The study also suggests that homozygotes have no higher risk of mortality or of any clinically significant morbidity than normal control subjects. This conclusion contradicts earlier findings that linked iron overload and HFE mutations to a number of devastating diseases, including cardiovascular disease, diabetes, and cancer.
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PMID:Current directions in hemochromatosis research: towards an understanding of the role of iron overload and the HFE gene mutations in the development of clinical disease. 1263 63

Four types of hereditary haemochromatosis have been identified. Type 1 is due to a point mutation in the HFE gene (C282Y) and leads via an increase in intestinal iron absorption to iron overload and organ damage. Type 2 is a juvenile form with manifestation before age 30; it affects both gender and is associated with severe cardiomyopathy and hypogonadism. The genetic defect of type 3 is located on chromosome 7q22 and affects the transferrin receptor 2. The consequences of type 3 are similar to those of type 1. The autosomal-dominant type 4 is located on chromosome 2q32 and affects the basolateral iron carrier ferroportin 1. In contrast to types 1 and 3 iron deposits in type 4 are seen predominantly in macrophages; in type 4 serum ferritin is significantly increased although transferrin saturation is only slightly abnormal. The prognosis of haemochromatosis is normal when phlebotomy therapy is started prior to manifestation of cirrhosis or diabetes. Screening strategies should be implemented to improve early detection.
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PMID:[Hereditary hemochromatosis]. 1267 39

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

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.
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PMID:[Diagnosis of 5 patients with possible primary hemochromatosis]. 1271 48


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