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Among specific diabetes subtypes secondary to pancreatopathies, hereditary hemochromatosis is an inherited disorder of iron metabolism resulting in excessive iron overload and tissue damage in various organs. We here report the case of a man with the young-onset form of the disease and describe his glycaemic status before and during venesection therapy. A 25-year old man visited our clinic in Athens, Greece, with hypogonadotropic hypogonadism due to hereditary hemochromatosis. Genetic analysis revealed that he was suffering from the juvenile aggressive form and treatment was initiated with frequent phlebotomies in conjunction with androgen substitution. Within 18 months of therapy ferritin level was normalized and hypogonadism was fully restored. Despite severe iron overload, glucose tolerance remained normal during the various stages of the disease, although alterations in both insulin secretion and sensitivity were detected. Present data indicate that in juvenile hemochromatosis, the efficacy of the chelation therapy and probably the chronic interval required to restore normal iron concentration both play important roles in the formation of glucose metabolism characteristics.
Exp Clin Endocrinol Diabetes 2007 Mar
PMID:Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature. 1742 10

We studied the relationship between iron removed by venesection, sex, age, and clinical characteristics in a group of 100 Spanish probands with hereditary hemochromatosis (HH), all C282Y homozygous in the HFE gene. Iron overload was higher in men than in women (P < 0.0001) and increased with age (P = 0.02). Forty-four patients presented with liver disease (28 had fibrosis-cirrhosis of the liver), 24 with diabetes, 18 with arthropathy, and 13/73 men with impotence. No clinical consequences of hemochromatosis were observed in 43 patients. The number of clinical complications was higher in men (P = 0.01) and increased with age (P = 0.006) and with the amount of iron removed (P < 0.0001). The amount of iron removed was significantly higher by univariate analysis in patients with liver disease (P < 0.0001), diabetes (P = 0.007), arthropathy (P = 0.006), and impotence (P = 0.003) than in patients without these complications. In the multivariant analysis, only liver disease maintained a significant relationship with the amount of iron removed (P < 0.0001). Diabetes and arthropathy were closely related with previous liver disease, and impotence appeared mainly in hemochromatosic men with diabetes and alcoholism.
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PMID:The relationship between iron overload and clinical characteristics in a Spanish cohort of 100 C282Y homozygous hemochromatosis patients. 1763 89

Palmar erythema (PE), an often overlooked physical finding, is due to several physiologic or systemic pathologic states. PE can exist as a primary physiologic finding or as a secondary marker of systemic pathology. Primary or physiologic PE can be due to heredity, occurs in at least 30% of pregnant women as a result of associated alterations in the function of the skin and its microvasculature, or may be a diagnosis of exclusion (i.e. idiopathic PE). Secondary PE from systemic pathology encompasses a wide range of disease states. Twenty-three percent of patients with liver cirrhosis, from varying causes, can manifest PE as a result of abnormal serum estradiol levels. Patients with a rare neonatal liver disease such as Wilson disease and hereditary hemochromatosis may exhibit PE along with the other systemic manifestations of the genodermatoses. PE has been reported to occur in >60% of patients with rheumatoid arthritis and is associated with a favorable prognosis. Up to 18% of patients with thyrotoxicosis and 4.1% of patients with diabetes mellitus can have PE. This cutaneous manifestation of diabetes occurs more often than the more classic diseases such as necrobiosis lipoidica diabeticorum (0.6%). PE can be seen in early gestational syphilis and among patients with human T-lymphotrophic virus-1-associated myelopathy. Drug-induced PE with hepatic damage has been documented with use of amiodarone, gemfibrozil, and cholestyramine, while topiramate and albuterol (salbutamol) have been reported to cause PE in the setting of normal liver function. Fifteen percent of patients with both metastatic and primary brain neoplasms may have PE. Increased levels of angiogenic factors and estrogens from solid tumors have been postulated as the cause of PE in such cases. Erythema ab igne can mimic PE, and patients with atopic diathesis are more likely to have PE than matched control subjects. Smoking and chronic mercury poisoning are environmental causes of PE.No treatment of primary PE is indicated. If medication is the cause of PE, the drug responsible should be discontinued if possible. Identification of PE related to underlying disorders should be followed by treatment of the underlying condition. In light of the numerous etiologies of PE, this article reviews the current literature and provides a framework to help guide the clinician in determining the cause of PE in patients presenting with this finding.
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PMID:Palmar erythema. 1803 17

This communication explores the temporal link between the age-associated increase in body iron stores and the age-related incidence of Alzheimer's disease (AD), the most prevalent cause of senile dementia. Body iron stores that increase with age could be pivotal to AD pathogenesis and progression. Increased stored iron is associated with common medical conditions such as diabetes and vascular disease that increase risk for development of AD. Increased stored iron could also promote oxidative stress/free radical damage in vulnerable neurons, a critical early change in AD. A ferrocentric model of AD described here forms the basis of a rational, easily testable experimental therapeutic approach for AD, which if successful, would be both widely applicable and inexpensive. Clinical studies have shown that calibrated phlebotomy is an effective way to reduce stored iron safely and predictably without causing anemia. We hypothesize that reducing stored iron by calibrated phlebotomy to avoid iron deficiency will improve cerebrovascular function, slow neurodegenerative change, and improve cognitive and behavioral functions in AD. The hypothesis is eminently testable as iron reduction therapy is useful for chronic diseases associated with iron excess such as nonalcoholic steatohepatitis (NASH), atherosclerosis, hereditary hemochromatosis and thalassemia. Testing this hypothesis could provide valuable insight into the causation of AD and suggest novel preventive and treatment strategies.
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PMID:Getting the iron out: phlebotomy for Alzheimer's disease? 1919 95

In populations of northern European descent, the p.C282Y mutation in the HFE gene is highly prevalent, and HFE-associated hereditary hemochromatosis is the most common type of inherited iron overload disorder. Inappropriate low secretion of hepcidin, which negatively regulates iron absorption, is postulated to be the mechanism for iron overload in this condition. The characteristic biochemical abnormalities are elevated serum transferrin-iron saturation and serum ferritin. Typical clinical manifestations include cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated serum aminotransferase levels, diabetes mellitus, restrictive cardiomyopathy and arthropathy of the second and third metacarpophalangeal joints. Most patients are now diagnosed before the development of these clinical features. Molecular genetic tests are currently available for genotypic diagnosis. In selected individuals, diagnosis might require liver biopsy or quantitative phlebotomy. Iron depletion by phlebotomy is the mainstay of treatment and is highly effective in preventing the complications of iron overload if instituted before the development of cirrhosis. Genetic testing is currently not recommended for population screening because of low yield as the majority of the healthy, asymptomatic p.C282Y homozygotes do not develop clinically significant iron overload. HFE gene testing remains an excellent tool for the screening of first-degree relatives of affected probands who are p.C282Y homozygotes.
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PMID:HFE-associated hereditary hemochromatosis. 1944 13

Although chronic infection with hepatitis B virus and/or hepatitis C virus are the most important risk factors for hepatocellular carcinoma (HCC) worldwide, other causes of cirrhosis can also lead to HCC. Given the high prevalence of alcoholism and the worldwide obesity epidemic, the relevant importance of nonviral liver disease-related HCC is expected to increase in the future. Some evidence supports mechanistic interactions between host or environmental factors and chronic viral hepatitis in the development of HCC. For example, food- and water-borne carcinogens have contributed to unusually high rates of HCC in parts of China and sub-Saharan Africa. With some of these conditions, appropriate public health measures to reduce the population's exposure to known etiologic agents, or early therapeutic intervention for 'at-risk' individuals before development of cirrhosis (e.g. hereditary hemochromatosis) can prevent HCC. Community-based programs to discourage and deal with excessive alcohol intake, to promote tobacco smoking awareness, to avoid exposure to aflatoxin and other food toxins, and measures to reduce the pandemic of obesity and diabetes are vital for effective interruption of the rising tide of HCC from nonviral liver disease.
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PMID:Prevention of hepatocellular carcinoma in nonviral-related liver diseases. 1964 14

Diabetes mellitus (DM) affects 30% to 60% of patients with hereditary hemochromatosis (HH). The underlying pathophysiology of DM in patients with hemochromatosis has not been fully elucidated. We studied both insulin secretion and insulin sensitivity in a cohort of patients with HH. We studied glucose metabolism in 53 newly diagnosed HH patients using a standard 75-g oral glucose tolerance test. Basal and stimulated insulin sensitivities were calculated using the quantitative insulin sensitivity check index and oral glucose insulin sensitivity index, respectively. beta-Cell function was assessed using C-peptide concentrations during the oral glucose tolerance test after adjusting for ambient insulin sensitivity. Twenty healthy subjects served as the control group. Fifteen subjects (28%) with HH had abnormal glucose tolerance (AGT). Seven (13%) had DM, and 8 (15%) had impaired glucose tolerance. As well as higher fasting glucose and glycated hemoglobin, those with AGT had a higher fasting insulin and C-peptide levels compared with those with normal glucose tolerance (NGT) (all Ps < .05). Insulin sensitivity measurements showed that the subjects in HH group with AGT were more insulin resistant than the subjects with NGT and controls subjects (P < .05). No significant changes were observed between the groups with NGT and AGT regarding hepatic insulin extraction and both indices related to insulin release in subjects with HH. Our cohort of patients with hemochromatosis and AGT had features similar to typical type 2 DM patients. These findings challenge the traditional view that DM in hemochromatosis is due primarily to iron-induced beta-cell failure.
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PMID:Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. 1981 42

Hereditary HFE-linked hemochromatosis is a frequent recessive disorder among individuals of northern European ancestry. The clinical characteristic of this disease is the gradual accumulation of iron in internal organs, which ultimately may lead to organ damage and death. Three allelic variants of HFE gene have been correlated with hereditary hemochromatosis: C282Y is significantly associated with hereditary hemochromatosis in populations of Celtic origin, H63D and S65C are associated with milder form of iron overload. In this study we performed mutation analysis to identify allele frequency of the three variants of HFE gene in Jordanian Arab population, to assess deviations of these frequencies from those detected elsewhere, and to determine if there is an increased frequency of these variants in a diabetic population (Type 2 diabetes) from the same area. DNA was extracted from blood samples of 440 individuals attending King Abdullah University Hospital for ambulatory services. We used polymerase chain reaction (PCR) to amplify exons 2 and 4 of the HFE gene then restriction fragment length polymorphism (RFLP) method to detect the variants. There were neither homozygous nor heterozygous for C282Y variant. For the H63D variant, 0.68% were homozygous and 21.1% were heterozygous. For the S65C variant, there were no homozygous and 0.23% were heterozygous. Allelic frequencies were, 0%, 11.25%, and 0.11% for C282Y, H63D, and S65C, respectively. Our samples were subdivided into two categories of type 2 diabetic (89 cases) and controls (blood donors, 204 cases) and compared with regard to the H63D variant. Both groups did not have homozygous H63D variant. H63D heterozygous in diabetics were 23.60% and in blood donor controls 22.55%. Allelic frequency of the mutant H63D allele was 11.80% in diabetics and 11.27% for the blood donor controls. This is the first study to show the frequency of the three hemochromatosis gene variants in Jordan with the interesting finding of no C282Y allele detected in 440 samples. Additionally, no significant difference was observed in H63D variant frequency in type 2 diabetics as compared to controls.
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PMID:Frequency of the hemochromatosis gene (HFE) variants in a Jordanian Arab population and in diabetics from the same region. 1982 54

Hereditary hemochromatosis is one of the most common autosomal recessive diseases; it is characterized by excess absorption of iron. Clinically, the major challenge is to diagnose increased iron deposition before irreversible tissue damage has occurred. C282Y and H63D are the main mutations related to hereditary hemochromatosis; these mutations have been reported to be associated with increased risk of developing diabetes mellitus type 2 (DM2). We investigated whether these mutations are associated with increased risk for the development of DM2 in women in Brazil. Seventy-two women with clinical diagnosis of DM2 under treatment with hypoglycemic agents and a control group composed of 72 women with no clinical history of diabetes were studied. The C282Y and H63D mutations were determined by PCR-RFLP. Significant differences were not observed for C282Y and H63D, when we compared diabetic and non-diabetic women. We suggest that mutations C282Y and H63D in the HFE gene are not significant risk factors for the development of DM2 in Brazilian women.
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PMID:Lack of association of C282Y and H63D mutations in the hemochromatosis (HFE) gene with diabetes mellitus type 2 in a case-control study of women in Brazil. 1987 70

Bone morphogenetic protein-6 (BMP-6) is produced by bone marrow-mesenchymal (BMSC) and hematopoietic stem cells, which can differentiate into bone, cartilage, adipose, muscle, hematopoietic, synovial and other tissues. Bmp6-/- null mice have low hepcidin serum levels and an iron overload, resembling hereditary hemochromatosis, which may cause a reduced number of pancreatic beta-cells, increased serum glucose and diabetes. BMP-6 circulates in the normal human plasma and is produced by BMSC prior to differentiation into osteoblasts. Moreover, it is also released by osteoclasts as a key bone coupling factor recruiting osteoblasts to the resorption site. Due to unique structural, receptor binding and signaling characteristics much smaller amounts of BMP-6 than BMP-7 are needed in vivo to induce regeneration of bone defects in animals.
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PMID:BMP-6 and mesenchymal stem cell differentiation. 1990 Aug 32


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