The hemochromatosis (from ancient Greek αἷμα Haima , German , Blood and ancient Greek χρῶμα Chroma , German , color ' ; Synonyms : Primary siderosis, hemosiderosis, siderophilia, hemochromatosis , bronze diabetes ; English: overload iron , hemochromatosis ) is a disease in which it through an increased absorption of iron in the upper small intestine and excessive iron storage (deposition), especially in parenchymal organs, leads to corresponding organ damage. The total body iron content increases from approx. 2–6 g (normal value) to up to 80 g. Over the years, the storage leads to damage, in particular to the liver , pancreas , heart , joints , spleen , pituitary gland , thyroid and skin .
In most cases, hemochromatosis is a hereditary condition that is usually inherited as an autosomal recessive trait. In this case, both parents must inherit the changed gene, but they do not have to have the disease themselves (recessive inheritance). The altered gene responsible for hemochromatosis is not on a sex chromosome (autosomal inheritance). In rarer cases, hemochromatosis is not hereditary. In men, the hemochromatosis has a much higher probability of occurrence than in women. The disease can be treated successfully if it is discovered early. When the disease progresses, irreversible damage occurs, particularly to the liver. The disease also increases the risk of developing liver cell carcinoma .
The disease is not notifiable, so no exact figures are available. It is estimated that over 200,000 people in Germany live with hemochromatosis.
The HFE gene is often affected by mutations , around 10% of the northern European population are heterozygous (mixed-breed) for such a gene defect. Around 0.3–0.5% of this population group are homozygous for this (purely hereditary), only with these the disease can occur. However, the penetrance is incomplete: around a third to half of the homozygous mutation carriers show no clinical signs of iron overload. The various mutations are distributed differently from region to region. Numerous mutations that do not occur in the western population have been detected in people of Asian descent. Hemochromatoses that are not associated with an HFE mutation are very rare. They occur more frequently in Italy .
Women naturally lose iron bound in the body through menstruation and pregnancy . As a result, genetically affected men are five to ten times more likely to get the disease. The latency period until the first symptoms appear varies depending on alcohol consumption, the iron content of the food and the number of blood donations received. The majority of sufferers develop the first symptoms between the fourth and sixth decades of life.
Signs of illness
Liver damage, diabetes, skin pigmentation
In addition to liver enlargement, the most common symptoms of hemochromatosis are the onset of diabetes mellitus and dark skin pigmentation, which is why hemochromatosis is sometimes referred to as bronze diabetes . Skin pigmentation is usually most pronounced in the armpit . The body hair is typically missing in the pigmented areas. Other preferred areas of skin discoloration are the extension sides of the arms and hands, the neck and face area, the lower legs and the genital region. Three quarters of the patients already have cirrhosis of the liver at the time of diagnosis .
Spleen enlargement, joint inflammation, atrial fibrillation
Less common symptoms are enlarged spleen and inflammatory swelling of the metatarsophalangeal joints . The joint inflammation can spread to larger joints as it progresses. In many cases it precedes the other symptoms. Around 15% of the initial diagnoses only become noticeable due to cardiac arrhythmias. Seizure-like palpitations, atrial flutter , atrial fibrillation and blockages in the conduction between atrium and ventricle are possible .
Mental symptoms and testicular changes
Lethargy and loss of libido can appear as signs of mental illness . Hypogonadism can also occur due to damage to the pituitary gland . The most important general diseases that cause functional and organic testicular changes (usually disorders of spermiogenesis ) include, in addition to cachexia (pathological, very severe emaciation):
- Liver cirrhosis: decreased estrogen inactivation as the cause of testicular atrophy (colloquially "shrunken testicles")
- Hemochromatosis: Iron deposits in the pituitary lead to panhypopituitarism and thus to secondary hypogonadism (testosterone deficiency). Panhypopituitarism is a disease in which there is a deficiency or an absence of all the hormones produced in the anterior pituitary.
Classification of hemochromatosis
Primary hemochromatosis (congenital forms)
Hereditary (hereditary) hemochromatosis is the most common form and is usually inherited as an autosomal recessive trait. But there are also less common genetic defects. In addition to genetic defects, other diseases can also cause iron overload.
Depending on the age of onset and the underlying genetic modification, a distinction can be made:
- Type 1 : classic form, synonyms: symptomatic form of classic hemochromatosis; Symptomatic form of the HFE gene-associated hereditary hemochromatosis , mutations in the HFE gene ( chromosome 6 gene locus p21.3) gene product : hereditary hemochromatosis protein, the most common mutation with 90%
Rare forms of hemochromatosis
Rare forms include:
- Type 2 : juvenile form, synonyms: juvenile form, hemochromatosis, juvenile
- Type 3 : Synonyms: hemochromatosis, TFR2 gene-associated , mutations in the TFR2 gene ( chromosome 7 gene locus q22) gene product: transferrin receptor 2
- Type 4 , synonyms: hemochromatosis, autosomal dominant; Hemochromatosis due to ferroportin defect; Hemochromatosis, hereditary, autosomal dominant , mutations in the SLC40A1 gene ( chromosome 2 gene locus q32) gene product: ferroportin -1
- Type 5
- Neonatal form , very rare, occurs as early as childhood or newborn, its course is usually very difficult.
Other congenital diseases with iron overload
- Hereditary atransferrinaemia and hypotransferrinaemia
- with as an essential feature of the GRACILE syndrome
Types 1–3 are inherited in an autosomal recessive manner and are associated with the clinical symptoms that are typical of hemochromatosis. Types 1, 2A and 2B are associated with a decrease in the hepcidin level. By binding to ferroportin in intestinal mucosal cells, hepcidin inhibits the absorption of iron into the bloodstream. Type 1 with the classic HFE mutation has a lower risk of organ damage than types 2A and 2B.
Types 2A and 2B differ from the other forms of hemochromatosis in their early onset of symptoms and organ damage. They occur in the second to third decade of life and are therefore also referred to as juvenile (adolescent) hemochromatosis. The classic type 1 and also type 4 only manifest themselves in the fourth to fifth decade of life.
Type 4 has a special position within hemochromatosis. It is inherited in an autosomal dominant manner, has a lower potential for organ damage and can only be detected in the later course by laboratory tests for ferritin and transferrin. Some authors therefore suggest type 4 as a separate disease entity.
Secondary hemochromatosis (acquired iron overload)
Several different causes of acquired iron overload are known, such as increased iron intake in the body. For example, people who receive a large number of blood transfusions can develop secondary hemochromatosis. Acquired iron overload can also occur with very high levels of iron absorption via the gastrointestinal tract. This form is mainly found in Africa south of the Sahara, as there are spirits that are distilled in iron vessels. Long -term hemolysis can also result in iron overload, as the body overloads itself with the iron collected from the destroyed red blood cells. Genetic causes are very rare, such as B. a lack of transferrin . Long hemodialysis therapy can also lead to hemochromatosis in some cases. Treatment of the secondary forms is often the same as treatment of hereditary hemochromatosis. However, if anemia occurs at the same time, no bloodletting can be performed as a therapy.
The human body has no mechanism for actively excreting iron. A "breakdown" only takes place in the event of blood loss. However, further absorption of iron can be prevented if the ferroportin transport of iron into the blood is stopped by hepcidin in the intestine and the iron thus collected in the intestinal mucosa cells is released back into the intestinal lumen with the exfoliated cells. This inhibition of absorption can be prevented by disrupting individual components of the iron balance and the body consequently accumulates iron in various body organs, especially the liver.
The excessively high iron content damages the genetic information of the cells and also ensures the formation of harmful free radicals. Due to the constant cell damage, the affected organs lose their function. As a result, liver damage and liver cancer develop. In addition to liver damage, hemochromatosis can also damage the brain areas for sex hormones or cause diabetes. A connection with Parkinson's disease has also been suggested.
Various mutations in genes that control the human iron balance can cause hemochromatosis. The HFE gene codes for a protein structurally related to the major class 1 histocompatibility complex . In healthy people, the HFE protein HLA-H forms a complex with β2-microglobulin and is expressed on the outer side of the cell membrane. The HLA-H-β2 complex enables the binding of transferrin , the main iron transport protein in the blood. The complex is absorbed by endocytosis . The resulting lysosome is dissolved by acidification and iron is released. The epithelial cells of the small intestine, through which iron is absorbed, increase their iron absorption in the opposite direction to the iron level in their cell plasma. In addition, another regulatory circle on hepcidin and ferroportin has recently been discussed. This is also affected in type 1 hemochromatosis, since the HFE mutation is also associated with a lack of hepcidin. The exact mechanism has not yet been clarified.
Hemochromatosis type 2A is caused by a mutation of the hemojuvelin and is also associated with decreased hepcidin levels. Here, hemojuvelin acts as a positive regulator of hepcidin transcription, which transmits its signal via the BMP protein signaling pathway.
Hemochromatosis type 2B leads to a hepcidin deficiency via a mutation in the gene for hepcidin. This leads to a reduced discharge of iron from the intestinal cells, macrophages and the cells of the affected organs. In type 4, ferroportin - a protein that is used to remove iron directly from the cells - is defective. However, this only affects liver cells, cells of the placenta and macrophages.
The healthy human body contains around 2–6 grams of iron. 98% of this is stored in the liver cells ( hepatocytes ). The annual iron intake in hemochromatosis patients is around 0.5–1.0 grams, depending on gender, alcohol consumption and food composition. The first symptoms appear from a cumulative iron intake of 20 grams. The first main storage site is the liver cells, which are damaged by several mechanisms due to the increased iron content. Iron itself is DNA-damaging and can oxidize fats through the formation of radicals . In addition, iron stimulates the formation of collagen fibers in the extracellular space via a hitherto unknown mechanism and is still stored in the pancreas , the heart and the pituitary gland .
Hemochromatosis is inherited as an autosomal recessive trait. The disease usually only becomes manifest if both versions of the gene have the defect ( homozygous mutation ). However, weaker forms of hemochromatosis are also possible with heterozygous mutations. The penetrance of the mutation is low, around 30% of men with a homozygous mutation and only around 1% of homozygous women develop a clinically relevant clinical picture; the occurrence of a disease is very rare in heterozygous carriers of traits.
Mutations in the HFE gene can also cause pathological changes independent of the hemochromatosis. Among other things, increases in blood triglycerides have been described.
An examination of removed liver tissue can reveal the iron overload in the liver cells. However, it does not provide any indication of whether the disease has genetic causes or is caused by another underlying disease.
The pathological iron deposit can be determined with a light microscope . The deposits show up in the HE staining as coarse rust-brown granules in the cell plasma . The deposits typically begin on the liver cells around the portal fields. As iron storage continues, the granules also appear in the rest of the liver lobule. Later on, the Kupffer stellate cells and the bile duct cells also show corresponding abnormalities. As soon as iron storage leads to tissue damage, fibrosis and cirrhosis of the liver become visible. The iron deposits can be specifically detected by coloring with Prussian blue .
The suspicion of hemochromatosis should be made in the case of elevated levels of ferritin (> 200 μg / l in women,> 300 μg / l in men) and transferrin saturation (> 45% in women,> 50% in men) in the blood. In this case, a genetic test should be performed for the presence of genetic hemochromatosis. If negative, a liver biopsy should be considered.
Various laboratory parameters can provide an indication of iron overload. The concentration of iron itself in the blood plasma is usually increased. In contrast, the iron-binding capacity is usually reduced in homozygosity or in the normal range. In heterozygous people, on the other hand, it is sometimes elevated, sometimes normal. In the case of manifest disease, transferrin saturation and ferritin are also increased. Ferritin itself is usually below 500 μg / l in symptomatically healthy people. In the symptomatically ill, it can be increased to 6,000 μg / l. The ferritin level can provide an indication of the distinction from advanced liver disease caused by alcohol consumption, since the ferritin level should be below 500 μg / l in alcoholic liver disease. The laboratory changes are not entirely specific, however, as other liver diseases can also increase the iron level in the liver. Ferritin is an acute phase protein and as a result is generally increased in inflammatory processes. Transferrin saturation is the most sensitive laboratory parameter for detecting hemochromatosis in the asymptomatic stage. The final diagnosis should be made through genetic testing of the HFE gene. If the genetic test is negative, the diagnosis can be made through a tissue examination (liver biopsy, histology with Berlin blue staining ).
A further diagnostic method is the quantitative determination of the iron content from unfixed liver tissue. The normal value is below 1,000 μg / g dry matter . People with hereditary hemochromatosis have levels above 10,000 μg / g. Irreversible liver damage and cirrhosis are to be expected from 22,000 μg / g, but due to the low penetrance of the disease, this is only meaningful when viewed in conjunction with the clinical and laboratory findings.
The iron content of the liver can also be determined non-invasively by computed tomography or magnetic resonance imaging . However, these methods are only semiquantitative and therefore only meaningful to a limited extent. The establishment of hepcidin as a diagnostic test for hemochromatosis is currently being discussed.
In specialist circles, hemochromatosis was named as a possible disease for which a general examination of the general population would be useful. More recent studies, however, now cast this into doubt.
In 2003, the German Medical Association identified hemochromatosis as a disease for which, in their opinion, general screening of the population would be beneficial. A genotyping is now starting a transferrin saturation recommended by 45% in two different tests. Other publications recommend a cutoff of 55%. In 2006, the Preventive Services Task Force established by the US government came to the conclusion that the genetic basis of hemochromatosis had not been researched enough to recommend general screening. A Canadian research group spoke out in 2009, after a test screening of 100,000 people, against general screening. She also came to the conclusion that transferrin saturation or ferritin levels were insufficiently specific and therefore not suitable for screening.
The therapy of choice is bloodletting and consists of two phases, which are usually structured as follows:
- Phase 1 (initial therapy): weekly bloodletting of 500 ml until the ferritin level has fallen below 50 μg / l;
- Phase 2 (long-term therapy): lifelong bloodletting of 500 ml in order to keep the ferritin level between 50 and 100 μg / l in the further course (about 4–12 per year).
The aim of therapy is to empty or at least reduce iron stores, which is most effectively achieved through bloodletting therapy. Initially, bloodletting of 500 ml should be performed once or twice a week. Half a liter of blood contains around 200–250 mg iron. Treatment should be carried out weekly until serum ferritin levels drop below 50 μg / L. This can take up to several years, depending on age and iron load. Three-monthly bloodletting can be performed for maintenance therapy. These are usually sufficient to maintain a plasma ferritin level of 50 to 100 μg / l, which is the long-term therapeutic goal. Other information also recommend a target level below 50 μg / l. It should be noted that the bloodletting is carried out as regularly as possible so that a constant regeneration of the lost amount of blood occurs. Iron deficiency anemia occurs characteristically in types 1 to 3 not to. People with type 4 should be closely monitored, as they are more likely to have anemia. Bloodletting therapy also has less of an effect on them.
Another form of therapy is erythroapheresis , whereby more erythrocytes can be removed per treatment, which can reduce the frequency of treatment and the ferritin value drops faster than with simple bloodletting therapy. This form of therapy is more complex, however, and the coverage of costs by the health insurance companies has not yet been clarified.
Proton pump inhibitors have an inhibiting effect on the absorption of non-haem-bound iron and can reduce the necessary amount and frequency of bloodletting.
The administration of deferoxamine also serves to reduce iron, but this therapy is not as effective. It is only used if there is anemia (anemia) or advanced heart failure (cardiomyopathy). Deferoxamine treatment is time-consuming (continuous infusion 5–7 days a week), often has side effects (visual and hearing impairments) and is less effective than bloodletting or apheresis. Meanwhile, a preparation for swallowing ( deferasirox ) is also available. If bloodletting therapy does not seem justifiable due to advanced heart failure , iron binders must be used. The two different active ingredients should be administered in combination. Since they differ in their diffusion strength into the cell interior, the iron stores can be emptied more quickly. Another substance used to reduce iron is deferiprone (trade name Ferriprox). It is quickly absorbed and reaches the highest serum level after 45 minutes. 85% are made urinary through glucuronization (connection with glucuronic acid ). The glucuronide of deferipron binds iron and excretes this with the urine. Possible side effects are nausea, abdominal pain, vomiting, increased liver values, joint pain, and neutropenia (decrease in white blood cells).
Dietary measures can aid healing. Specifically, foods with a high iron content should be consumed cautiously. Black tea or milk , drunk with meals, reduces iron absorption. Conversely, beverages containing vitamin C (e.g. orange juice ) should be avoided for about two hours before to two hours after meals, as vitamin C promotes the absorption of iron from food. Since the consumption of alcohol increases iron absorption, it makes sense to abstain from alcohol.
In advanced liver damage in the event of a can liver failure , a liver transplant can be performed. In some cases, this is also possible if the patient has developed liver cell carcinoma . Transplanted hemochromatosis patients, however, have a worse prognosis than transplant recipients with other underlying diseases because of the accompanying diseases caused by their underlying disease.
“Hemochromatosis can lead to life-threatening situations due to damage to the liver. It also greatly increases the risk of liver cell cancer if not detected before symptoms start. If the disease is discovered and treated before the symptoms appear, it is considered curable without any consequential damage. Without therapy, however, the prognosis is poor . "
If the disease is treated before irreversible organ changes occur, it does not have a negative effect on life expectancy. Liver fibrosis and liver cirrhosis can no longer be reversed and require independent treatment. The likelihood of long-term complications, including hepatocellular carcinoma, increases with the duration and extent of iron overload. As a result, early diagnosis is critical. Structural damage to the joints and genital organs that already exists at the time of diagnosis is considered irreversible. However, therapy can slow the progression of changes. Around 35% of people suffering from overt hemochromatosis develop liver cell carcinoma later.
Due to further such descriptions from the year 1871 by Charles Émile Troisier and 1882 by Victor Charles Hanot and Anatole Chauffard , the historical name Troisier-Hanot-Chauffard syndrome became common.
In 1889 Friedrich Daniel von Recklinghausen coined the term hemochromatosis. In 1935, Joseph H. Sheldon recognized the hereditary component of the disease. Until then, hemochromatosis had been wrongly attributed to alcohol abuse. In the 1970s, the autosomal recessive inheritance of types 1 to 3 was recognized. A US research team sequenced 1996 the HFE gene and introduced its connection is to hemochromatosis. It is believed that the HFE C282Y mutation about 4000 years ago when a man in Central Europe, which is probably of Celtic origin has been, has occurred and , proceeding from there, with its offspring has spread in the European population. One possible hypothesis for the spread of the mutation is the assumption that excessive iron storage in the event of a prolonged deficiency of iron could offer a survival advantage.
Hemochromatosis in animals
Hemochromatosis is very rare in animals. Individual cases of secondary hemochromatosis in dogs with pyruvate kinase deficiency and after repeated blood transfusions have been observed. Bedlington Terriers, however, have genetic predispositions. In cattle there were some cases of haemochromatosis in animals of the French Salers cattle breed and their crossbreeds. In birds, iron overload with a hemochromatosis-like clinical picture occurs, especially in starlings . A case of iron overload with liver damage has also been described in horses. In addition, there are some animal models with genetically modified laboratory rodents as well as with excessive iron intake.
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- Who named it
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