Hereditary hemochromatosis is a genetic disease; it is characterized by the excessive accumulation of iron in the tissues, leading to tissue damage. The clinical presentation includes systemic symptoms, liver disease, cardiomyopathy, diabetes, erectile dysfunction and joint diseases. The diagnosis is made by an elevated serum ferritin and transferrin saturation increased and confirmed by genetic testing. Treatment is usually in repeated phlebotomy.
Hereditary hemochromatosis is a genetic disease; it is characterized by the excessive accumulation of iron in the tissues, leading to tissue damage. The clinical presentation includes systemic symptoms, liver disease, cardiomyopathy, diabetes, erectile dysfunction and joint diseases. The diagnosis is made by an elevated serum ferritin and transferrin saturation increased and confirmed by genetic testing. Treatment is usually in repeated phlebotomy. Depending etiology of the mutated gene, the hereditary hemochromatosis type 1 -4 be distinguished. Type 1: mutations in the HFE gene type 2 (juvenile hemochromatosis): Mutations in the genes HAMP HJV- and Type 3: TFR2 mutations in the gene type 4 (Ferroportinkrankheit): Mutations in the SLC40A1 gene are more clearly rare genetic associated diseases with hepatic iron overload, but the clinical picture is generally determined by symptoms and complaints of failure of other organs (eg. as anemia in hypotransferrinemia or atransferrinemia or neurological defects in aceruloplasminemia). Even though these types vary greatly on the age of onset, the clinical consequences of iron overload are always the same. Hereditary hemochromatosis Type 1 Type 1 is the classic hereditary hemochromatosis and will HFE-related hemochromatosis referred. Over 80% of cases are due to the homozygous C282Y mutation or the combined heterozygous mutation C282Y / H63D caused. The disease is inherited as an autosomal recessive trait. In individuals with Northern European ancestry the Homozygotenfrequenz is 1: 200, and the heterozygote 1: 8. In dark-skinned people, the disease is uncommon and people of Asian origin they rarely occurs. Of patients with clinical hemochromatosis 83% are homozygous. But for unknown reasons, it is much rarer for phenotypic disease manifestations, as this suggests the frequency of the gene (ie, in numerous homozygous individuals, the disease does not manifest) .Hereditäre hemochromatosis type 2 Hereditary hemochromatosis type 2 (juvenile hemochromatosis) is a rare autosomal recessive disorder to mutations in HJV gene (influences the transcription of the protein hemojuvelin) or in HAMP gene (encoding directly hepcidin) is based. It manifests itself especially during the Adoleszenz.Hereditäre hemochromatosis type 3 mutations in the transferrin receptor 2 (TFR2), a protein that is likely to control the transferrin saturation, a rare autosomal recessive form of hemochromatosis hervorrufen.Hereditäre hemochromatosis type 4 may Hereditary hemochromatosis type 4 (Ferroportinkrankheit) occurs primarily in persons with southern European ancestry. It is due to an autosomal dominant mutation in SLC40A1 gene and affects the binding ability of ferroportin to Hepcidin.Transferrin- and ceruloplasmin When transferrin deficiency (hypotransferrinemia or atransferrinemia) resorbed iron that enters into the portal venous system and not bound to transferrin is in the liver deposited. Due to this lack of subsequent transferrin iron transport is restricted to sites of red cell production. The absence of the ferroxidase when ceruloplasmin (Aceruloplasminemia) is not Fe2 + + Fe3 converted into, which is, however, necessary for the binding of iron to transferrin. By defective transferrin binding the iron transport from intracellular stores is limited in the plasma, which leads to iron accumulation in tissues. Pathophysiology The normal value of total body iron content is about 2.5 g in women and in men, 3.5 g. Symptoms occur late, d. H. only at a significantly excessive iron accumulation on (z. B.> 10-20 g), so that hemochromatosis is detected only in middle age, although it is a hereditary anomaly. In women symptoms before menopause are unusual in that iron accumulation is to some extent compensated by the iron loss during menstruation (and occasionally pregnancies and births). In the iron overload enhanced iron absorption from the gastrointestinal tract takes place both at HFE as well as non-HFE-dependent Hämosiderosen, which leads to chronic iron deposition in tissues. The peptide hepcidin produced in the liver plays a crucial role in the regulation of iron absorption. Hepcidin is upregulated in general, if iron stores are elevated, and the inhibitory effect on ferroportin (contributing towards the absorption of iron) it prevents the excessive iron absorption and storage in healthy people. The hemochromatosis Type 1 to Type 4 have the same pathogenic basics (eg. as lack of Hepcidinsynthese or activity) and important clinical characteristics. The iron deposits in organs catalyzes the formation of reactive hydroxyl free radicals; generally it seems thereby cause tissue damage. Other mechanisms may affect certain organs (eg. As may be due to increased melanin hyperpigmentation of the skin and iron accumulation). Symptoms and signs The clinical consequences of iron overload are the same, regardless of the etiology and pathophysiology of overload. Initially it was assumed that symptoms unless develop until there has been a significant organ damage. However, an organ is damaged only gradually, fatigue and nonspecific systemic symptoms often occur early. In hereditary hemochromatosis type 1 (HFE) Other symptoms depend on the organs with the largest iron deposits (see Table: Common features of hereditary hemochromatosis). In men, hypogonadism and erectile dysfunction caused by iron deposits in the gonads may be the initial manifestation. As another feature common to glucose intolerance or diabetes mellitus may show. Some patients show up for the first time with hypothyroidism. The most common complications liver diseases occur which can turn into cirrhosis. In 20-30% of patients with cirrhosis, a further development into a hepatocellular carcinoma occurs. The most common cause of death include liver disease. Cardiomyopathy with congestive heart failure is the second most common fatal complication. Hyperpigmentation ( “bronze diabetes”) and symptomatic arthropathy are common. Symptoms of Type 2 disease include a progressive hepatomegaly and hypogonadotropic hypogonadism. The symptoms and complaints of the type 3 disease are similar to those in hereditary (HFE) hemochromatosis type first During the first decade of life, the type 4 disorder manifested by elevated serum ferritin levels are low or normal transferrin saturation; an increasing transferrin saturation occurs at the age of 20 to 30 years. The clinical manifestations are less pronounced than in the case of type 1 disease. The liver is usually affected only moderately, and mild anemia may occur. Common features of hereditary hemochromatosis feature prevalence (approximately) Systemic symptoms (eg. B. weakness, lethargy) 75% Pathological liver 75% 70% hyperpigmentation Diabetes 50% 45% arthropathy Erectile dysfunction 45% (men) cardiomyopathy 15% diagnostic serum ferritin and transferrin saturation genetic testing The symptoms and complaints may be nonspecific and insidious onset, so the diagnosis should be made generous. A primary hemochromatosis should be suspected when typical manifestations, in particular simultaneous occurrence of multiple characteristics, can not be explained by a routine examination. Although the family history are more precise indications, it is unproductive in general. The determination of serum ferritin is the simplest and most basic test. Elevated levels (> 200 ng / ml in women or> 300 ng / ml in men) are usually from primary hemochromatosis before, but can also come from other disorders, such as (inflammatory liver diseases such. As chronic viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease), malignant tumors, certain systemic inflammatory diseases (eg., rheumatoid arthritis, hemophagocytic lymphohistiocytosis) or obesity. At elevated ferritin followed by other tests, including measurement of serum iron (usually> 300 mg / dl) and iron binding capacity (transferrin saturation; values ??usually> 50%). The ferritin in type 2 disease are> 1000 ng / ml and the transferrin saturation> 90%. In transferrin or ceruloplasmin deficiency serum transferrin (i.e. iron binding capacity) and the Ceruloplasminspiegel are extremely low. The diagnosis of hereditary hemochromatosis by HFE gene mutations on the basis of genetic testing. A hemochromatosis of type 2 to type 4 (especially in younger patients) adopted in the rare cases where ferritin, and iron parameters indicate an iron overload and the genetic test on the HFE gene mutation is negative. The confirmatory tests concerning these diagnoses are evolving. As cirrhosis affects the prognosis is often performed a liver biopsy and (if available), the iron content is determined in tissue. A special “high-intensity” MRI of the liver is a non-invasive alternative to estimate the iron content in the liver that is always accurate. In first degree relatives of people with hereditary hemochromatosis the serum ferritin level should be obtained and C282Y and H63D genetic testing be performed. Bloodletting therapy treatment is indicated in patients with clinical symptoms, elevated serum ferritin levels (in particular, values> 1000 ng / ml) or elevated transferrin saturation. Asymptomatic patients should be evaluated clinically only periodically (eg. As a year) and are determined ferritin, serum iron and transferrin saturation. Bloodletting is the easiest and most effective way to remove excess iron. He delayed the progression of fibrosis to cirrhosis, can occasionally even reverse the cirrhotic changes and prolongs survival, but does not protect against the development of hepatocellular carcinoma. about 500 ml of blood (approximately 250 mg iron) are removed a week. This is continued until the serum iron levels have returned to normal and the transferrin saturation is <50%. The weekly phlebotomy may be necessary for many months (if z. B. 250 mg of iron to be removed a week, it takes 40 weeks to remove 10 g of iron). After normalization of iron levels phlebotomy can be made inter-center rend to maintain transferrin saturation <30%. If indicated, diabetes, cardiomyopathy, erectile dysfunction and other secondary manifestations be treated. Patients should eat a balanced diet; it is not necessary, the consumption of iron-containing foods (eg. as red meat, liver) limit. Alcohol should be consumed in moderation because it can iron absorption and increase the risk of cirrhosis of the liver in high quantities. The tolerance to repeated phlebotomy is low in patients with type 4 disease; hemoglobin levels and transferrin saturation should be monitored regularly. The treatment of transferrin and ceruloplasmin deficiency is experimental; z. B. diie treatment with iron chelators may be better tolerated than bloodletting, because patients often have anemia. Summary There are four types of hereditary hemochromatosis, in which, because of mutations the body's ability is impaired, to inhibit the absorption of iron with increased filling of the iron stores. The consequences of iron overload are similar for all types and include liver disease (leading to cirrhosis), skin pigmentation, diabetes, joint disease, erectile dysfunction, and occasionally heart failure. The diagnosis is made by determining the Serumferritinspiegels; it is increased, the confirmation is done by increased serum iron and transferrin saturation increased. Following diagnosis of a liver biopsy is performed to detect cirrhosis and determine the prognosis; Genetic testing and screening of first-degree relatives should be considered. Treatment with phlebotomy and restriction of alcohol consumption.