Symptomatic Information and Courses from MediaLab, Inc.
These are the MediaLab courses that cover Symptomatic and links to relevant pages within the course.
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| Development of Iron Overload The amount of time needed for iron to increase to levels causing organ damage is variable and may be partially dependent on gender, dietary or other environmental factors, and unknown genetic factors. Blood loss through menstruation and pregnancy are thought to delay the onset of iron overload, and therefore symptoms of HH, in women. Similarly, regular blood donation may confer some degree of protection. The loss of hemoglobin within intact erythrocytes reduces the amount of iron available for recycling.As levels of storage iron increase, clinical features of iron overload, including hepatic dysfunction or failure, diabetes, hypogonadism, arthritis, cardiomyopathy, hyperpigmentation, and fatigue, may become evident.Symptomatic patients typically present in middle age between the ages of 30 and 60, although this is quite variable. Persons as young as 20 may show clinical signs and symptoms of HH.(6) In the US, males are more than twice as likely as females to be diagnosed with HH, and the majority of cases are found in Caucasians. | View Page |
| Epidemiology of HFE Mutations The prevalence of common HFE mutations among persons with hereditary hemochromatosis (HH) has been reported in numerous studies conducted in the US, France, Australia, and other countries. Homozygous C282Y mutation (C282Y/C282Y) is present in 82% to 90% of Caucasian patients diagnosed with iron overload due to HH.(7) This suggests a strong link between the genotype and the phenotypic presentation of clinical iron overload. Much lower percentages of persons diagnosed with HH do not have two C282Y mutations. A small percentage of persons diagnosed with HH are compound heterozygotes for C282Y and H63D (C282Y/H63D), are homozygous for H63D (H63D/H63D), heterozygous for C282Y (C282Y/wild type) or for H63D (H63D/wild type), or carry S65C or other HFE mutations.It may be that symptomatic heterozygotes are actually HFE-compound heterozygotes with additional unidentified mutations modifying the expression of the more severe known mutation. It is quite possible that more mutations of HFE and elucidation of other gene mutations modifying HFE will be discovered in the future enabling scientists to better explain the phenotypic heterogeneity of this disorder.In the US, the C282Y mutation is most prevalent in the non-Hispanic white population. It is much less common among Hispanics and African Americans. | View Page |
| General Clinical Considerations Hereditary hemochromatosis (HH) is frequently discovered only during management of associated illness or routine health evaluations. It has been estimated that only a small percentage of all affected persons are actually diagnosed. Individuals with HH may be symptomatic for several years prior to diagnosis and may have consulted multiple health care providers.Under-diagnosis of HH is thought to occur due to:• Lack of specificity of early signs and symptoms• Asymptomatic status of some patients until damage to organs and tissues has occurred• Confusion with liver disease due to other causes• Insufficient awareness and knowledge of HHEarly identification of persons with HH is essential to prevent serious and irreversible complications associated with severe iron overload. A classic triad of skin hyperpigmentation (bronzing), type 2 diabetes, and hepatic cirrhosis has long been recognized as evidence of advanced iron overload. However, persons with HH may present with a much wider variety of signs and symptoms, particularly if they are seen before significant iron accumulation has occurred. Age of presentation and disease severity are highly variable. A diagnosis of HH is based on laboratory evidence of iron overload, genetic mutations associated with HH, and presence of clinical signs and symptoms consistent with HH.(10) | View Page |
| Molecular Tests DNA tests for HFE mutations associated with hereditary hemochromatosis (HH) are available in some clinical laboratories and reference laboratories. Testing for the presence of the C282Y is essential, although most labs also test for H63D and S65C mutations. Molecular testing is most appropriate for confirmatory testing of symptomatic individuals with altered iron studies (increased TS and SF), in pre-symptomatic individuals (increased TS, normal SF and liver function tests), and in family members of individuals diagnosed with HH. The use of genetic tests alone for routine screening of asymptomatic persons is not recommended for several reasons. A positive test indicating the presence of HFE mutations does not guarantee that an individual will develop clinically significant iron overload or predict severity of symptoms. A negative result (no HFE mutations present) does not rule out a diagnosis of iron overload because of genetic heterogeneity. Compared to biochemical analyses for iron, molecular assays are expensive. Finally, molecular testing may result in the diagnosis of a genetic disease, thus opening up the possibility for discrimination in health insurance coverage. Using molecular methods, DNA is extracted from leukocytes in whole blood samples or from buccal cells and analyzed for specific HFE mutations using polymerase chain reaction (PCR) with melt curve analysis. Currently there are no FDA-cleared products for HFE testing, and testing laboratories are using "home brew" reagents. This situation is expected to change as manufacturers submit products for FDA approval. | View Page |
| Rationale for Treatment Treatment for hereditary hemochromatosis (HH) is typically indicated for iron overload in symptomatic patients. The goal of therapy is to reduce stored iron which may result in reversal or resolution of some symptoms and improve prognosis. Causes of death in patients with HH include serious medical conditions such as hepatocellular carcimoma, cirrhosis, cardiomyopathy, and diabetes. Ideally, treatment should begin before these conditions develop. The earlier HH is detected, before the onset of severe organ damage, the lower the risk of mortality. | View Page |