Hemochromatosis is a disease that affects the metabolism of iron, which causes excess iron in the body. Find out what causes it, symptoms and treatment.

There is no doubt that the liver is one of the most important organs of our body. Among its main functions, one can mention the storage and release of sugar in the blood, the synthesis of glycogen, the processing of alcoholic beverages and various drugs, the elimination of impurities from the blood ...

However, there are a number of liver diseases that can clearly affect the liver, especially directly. A good example is hemochromatosis, a disease that can be hereditary or acquired.

What is hemochromatosis?

Hemochromatosis is a change characterized by poor metabolism of iron in our body. Needless to say, it is an essential component of our body if we want all of our organs to function properly. It is estimated that the correct amount of iron in the blood should be at least about 4 or 5 grams, the amount that is released from hemoglobin.

However, this condition is characterized by the fact that the body is unable to break down this element and therefore causes an excessive increase in the level of iron throughout the digestive tract. This is something that can have a very negative impact on our health and especially on the functioning of the liver.

Hemochromatosis is a disease that occurs in people of all ages. It can affect about one in 200-300 people and is much more common in men because women have other ways to get rid of iron through pregnancy.

What are the causes of hemochromatosis?

Now that we already know what hemochromatosis consists of, we are going to explain what its causes are:

• Excessive consumption of wine. This alcoholic beverage characterized by the presence of large doses of iron. Therefore, if it is taken in too much, it is possible that the person is suffering from hemochromatosis.
• Hepatitis C. This liver virus can also cause an increase in the level of iron in the blood.
• Blood transfusion. When a person receives multiple transfusions for any reason, this process also causes iron deposits to begin to accumulate.
• Transferrin production deficit. Transferrin is a protein that is responsible for transporting all iron through the body. However, problems arise when a person is unable to secrete this protein naturally, causing a clear case of hemochromatosis.

Symptoms of hemochromatosis

The symptoms of hemochromatosis can vary depending on how advanced the disease is. Therefore, it is very important to determine it as soon as possible. Among the most common symptoms are:

• Liver damage: One of the most common symptoms of hemochromatosis is what is known as hepatomegaly. This means that the left side of the liver is inflamed, which can subsequently cause ascites, edema, and even jaundice.
• Excess iron can also build up through various heart muscles, which can subsequently cause mild heart failure. Extreme tiredness and swelling of the legs are prominent symptoms of this condition.
• Hyperpigmentation of the skin: Most cases of hemochromatosis usually translate later in cases of hyperpigmentation of the skin to very dark tones. It's also normal to see pictures of baldness or hair loss.

Types of hemochromatosis

As stated at the beginning of this post, there are two different types of hemochromatosis: one hereditary (the most common) and one acquired. Below we will find out the main differences.

Hereditary hemochromatosis

Hereditary hemochromatosis is genetic disease autosomal recessive type (or recessive inheritance), which means that for its manifestation, it must be inherited from the father and mother; that is, both parents must carry the gene.

It is estimated that every 20-25 people carry a gene, which means that we have a hereditary liver disease that is very common.

In the case of hereditary hemochromatosis, two mutations have been identified in the HFE protein genes, known as C282Y and H63D. Studies show that in Europe, it is estimated that 60 to 100% of affected patients inherit the C282Y gene from both parents (homozygous C282Y) or inherit the H63D gene from one and the C282Y gene from the other (double heterozygotes).

Acquired hemochromatosis

Also known as secondary hemochromatosis, it is caused by a wide variety of disorders and conditions, and there is no single or specific cause that leads to increased iron deposits in the body.

Among the reasons that most often cause the appearance of this hemochromatosis, you can mention:

• Liver diseases such as alcoholic liver disease or hepatitis C.
• Chronic alcohol consumption affecting the liver.
• Performing multiple blood transfusions.
• Congenital transferrin deficiency.
• Porphyria cutaneous tarda.
• Neonatal hemochromatosis.
• Aceruloplasminemia.
• Excessive iron intake

What treatment is there for hemochromatosis?

Since hemochromatosis is characterized by too high a dose of iron in our body, it is obvious that it will be necessary to reduce the levels of this component. To do this, you must take into account the following signs:

• Reducing alcohol consumption. The consumption of certain beverages, such as red or rosé wine, can cause hemochromatosis. Therefore, it is strongly recommended that you stop taking them from the moment the first symptoms appear.
• Avoid white fish and seafood. Fish is also an inexhaustible source of iron. Therefore, you will need to stop taking it for a while to lower your iron levels. The same goes for shellfish or vitamin supplements that contain iron or vitamin C.
• Stay away from utensils made of iron. And the fact is that processing or manipulating it can lead to the fact that later we borrow this element by accident.

Hemochromatosis is a hereditary disease that affects almost all systems and organs. This is a severe pathology, which is also called bronze diabetes or pigmentary cirrhosis.

Among genetic abnormalities, this disease is recognized as one of the most common. The maximum number of cases was recorded in the Nordic countries.

Statistics and medical history

A mutated gene is responsible for the development of the disease, which 5% of the population has, but the disease develops only in 0.3%. The prevalence in men is 10 times higher than in women. In most patients, the first symptoms appear at the age of 40-60 years.

The disease code according to ICD-10 is U83.1.

For the first time information about the disease appeared in 1871. M. Troisier was described as a complex with symptoms of diabetes mellitus, cirrhosis, skin pigmentation.

In 1889, the term "hemochromatosis" was introduced. It reflects one of the features of the disease: the dermis and internal organs acquire an unusual color.

Development reasons

Primary hereditary hemochromatosis is an autosomal recessive transmission. It is based on HFE mutations. This gene is located on the short arm of chromosome 6.

The defect leads to a violation of the capture of iron by cells duodenum... Therefore, a false signal appears about the occurrence of iron deficiency in the body.

This leads to an increase in the formation of iron-binding protein and an increase in the absorption of iron in the intestine. Subsequently, pigment is deposited on many organs, followed by the death of active elements and the development of sclerotic processes.

The disease can manifest itself at any age. There are certain prerequisites:

• Metabolic disorders. Often, the disease is detected against the background of cirrhosis of the liver or during bypass surgery.
• Liver disease. Especially if they are of a viral nature, for example, hepatitis B and C, which have not been treated for more than 6 months.
• Overgrowth of liver tissue with fat.
• Availability or.
• The introduction of specific intravenous drugs that provoke an increase in the concentration of iron.
• Permanent hemodialysis.

Forms of the disease

There are three types of ailment:

• Hereditary (primary). In the primary case, we are talking about the mutation of genes responsible for iron metabolism. This form is the most common. A link has been established between hereditary hemochromatosis and congenital enzyme defects that lead to iron accumulation.

Photo of diagnosis of hereditary hemochromatosis

• Neonatal appears in newborn babies. The reasons for the development of such a pathology have not been clarified to this day.
• Secondary develops against the background of other diseases that are associated with blood circulation and skin problems. It develops on the background of taking a large number of preparations containing iron.

The latter type can be post-transfusion, alimentary, metabolic and mixed origin.

Stages

There are three main stages:

• First. Disorders in iron metabolism are observed, but its amount remains below the permissible level.
• Second. Excessive accumulation of iron by the body occurs. Special clinical signs no, but thanks to laboratory research methods, it becomes possible to quickly establish a deviation from the norm.
• Third. All symptoms of the disease begin to progress. The disease affects most organs and systems.

Symptoms of hemochromatosis

The disease manifests itself most clearly in people of mature age, when the content total iron reaches critical values.

Depending on the prevailing symptoms, several forms of hemochromatosis differ:

• liver,
• hearts,
• endocrine system.

First, the patient complains of increased fatigue, decreased libido. Not very strong ones may appear. Gradually, the skin becomes drier, disorders appear in large joints.

In the expanded stage, a symptom complex is formed, represented by a change in skin color to a bronze tint, the development of cirrhosis of the liver, diabetes mellitus. Pigmentation mainly affects the face, upper hand, navel and nipples. Hair gradually falls out.

Excessive accumulation of iron in tissues and organs leads to testicular atrophy in men. The limbs become swollen, and a sharp weight loss appears.

Complications

The liver ceases to cope with its functions. Therefore, it begins to take part less in digestion, neutralization, and metabolism. There are violations of the heart rate, a decrease in the contractility of the heart muscle.

The body becomes predisposed to other diseases, since the immune system cannot cope with the stress.

Common complications are:

• ... There is a death of part of the heart area due to circulatory disorders. Pathology can occur against the background of heart failure.
• Diabetic and. Due to toxins, brain damage occurs, which accumulate in diabetes.
• The appearance of tumors in the liver.

If bacteria enter the bloodstream, sepsis can develop. It leads to severe intoxication of the whole body and a significant deterioration in the patient's condition. As a result of sepsis, the likelihood of death is high.

Some patients have hypogonadism as a complication. This is a disease associated with a decrease in the production of sex hormones. This pathology leads to sexual dysfunction.

Diagnostics

Diagnostic measures are prescribed for multiple organ lesions and for the disease of several members of the same family. Attention is paid to the age of onset of the disease.

When hereditary form symptoms appear between the ages of 45-50. With an earlier appearance of signs, they speak of hemochromatosis of the second type.

Among non-invasive methods, it is often used. There is a decrease in the signal intensity of the liver, which is overloaded with iron. Moreover, its strength depends on the amount of trace element.

When there is an abundant deposition of Fe, giving a positive Perls reaction. With a spectrophotometric study, it can be established that the iron content is more than 1.5% of the dry mass of the liver. The staining results are assessed visually depending on percentage stained cells.

Additionally, they can carry out:

• x-ray of the joints,
• EchoCG.

Blood test

A complete blood count is not indicative. It is needed only to exclude anemia. The most often rented, which is shown:

1. Increase in bilirubin above 25 μmol per liter.
2. Increase in ALAT above 50.
3. With diabetes mellitus, the amount of glucose in the blood increases 5.8.

If you suspect hemochromatosis, a special scheme is used:

• First, a transferrin concentration test is performed. The specificity of the test is 85%.
• Ferritin dosing test. If the result is positive, then proceed to the next steps.
• Phlebotomy. This is a medical and diagnostic method aimed at extracting a certain amount of blood. It aims to remove 3 gr. gland. If after this the patient becomes better, then the diagnosis is confirmed.

Treatment

Therapeutic methods depend on the characteristics of the clinical picture. It is imperative to follow a diet in which there is no food with iron and other substances that contribute to the absorption of this trace element.

Therefore, under a strict ban:

• kidney and liver dishes,
• alcohol,
• flour products,
• seafood.

In small quantities, you can eat meat, foods fortified with vitamin C. It is possible to use coffee and tea in the diet, since tannins slow down the absorption and accumulation of iron.

Phlebotomy, described just above, also has a therapeutic effect. The duration of bloodletting for medicinal purposes is at least 2 years, until ferrin is reduced to 50 units. Simultaneously with this, the dynamics of hemoglobin is monitored.

Cytophoresis is sometimes used. The essence of the method consists in passing blood through a closed cycle. In this case, the serum is purified. After that, the blood returns. To obtain the desired result, 10 procedures are carried out in one cycle.

For treatment, chelators are used, which help the gland to be excreted from the body faster. Such an effect is carried out only under the watchful guidance of a doctor, since with prolonged use or use without control, there is a clouding of the lens of the eye.

If hemochromatosis is complicated by the growth of a malignant tumor, then surgery... With progressive cirrhosis, liver transplantation is prescribed. Arthritis is treated with joint plastic surgery.

Forecast and prevention

When a disease appears, to prevent complications, you need:

1. Follow a diet.
2. Take iron-binding medications.

If there is no hemochromatosis, but there are hereditary preconditions, then it is necessary to strictly follow the doctor's recommendations when taking iron preparations. Prevention also boils down to family screening and early detection of the onset of the disease.

The disease is dangerous and has a progressive course. With timely therapy, life can be extended by several decades.

With absence medical care survival is rarely more than 5 years. In the presence of complications, the prognosis is poor.

Video lecture about hemochromatosis of the liver:

Hemochromatosis of the liver (bronze diabetes, pigmentary cirrhosis) is a disease associated with impaired absorption of iron in the body. The first signs in most patients appear after reaching the age of 40. The most common hereditary hemochromatosis (3-4 cases per 1000 patients). In the absence of timely competent treatment, the disease leads to the development of severe complications, including liver cancer.

What is g emochromatosis

Hemochromatosis of the liver is one of the most common hereditary diseases. Its code in ICD-10 is E83. 1 (disorders of iron metabolism).

Hemochromatosis is also called bronze diabetes, because the genetic cells in this disease work in such a way that human body absorbs iron in excess, not allowing cells to get rid of excess iron in a timely manner. This provokes the accumulation of pigments and iron-containing elements in the internal organs, which leads to the appearance of a characteristic color of the skin and organs. With an excess amount of iron in the tissues, cells die.

This disease develops most often in men, and women suffer from it three times less often.

Forms of the disease

Specialists distinguish two forms of hemochromatosis: primary and secondary. The primary form is more common and is hereditary, associated with a gene defect. In this case, bronze diabetes develops mainly in people who have received the defective gene from the mother and father.

The primary form is divided into several types:

• autosomal recessive classic;
• juvenile;
• autosomal dominant;
• hereditary unassociated.

The secondary form of bronze diabetes develops due to acquired dysfunction of the systems involved in the process of iron metabolism, and occurs in rare cases. It is also divided into the following types:

• alimentary;
• metabolic;
• neonatal;
• post-transfusion;
• mixed.

Neonatal hemochromatosis develops only in newborns. In this case, the main symptoms of the disease appear in the first hours after birth. At risk are premature boys, who have the disease twice as often as girls. Drug treatment in such cases, it does not bring the desired results, and a liver transplant is resorted to to save the child's life.

Development reasons

Hereditary or primary bronze diabetes can develop due to a mutation in a gene located on the 4th chromosome, the left shoulder. There are many more reasons for the appearance of the secondary form and most often the following diseases provoke the appearance of hemochromatosis:

• thalassemia;
• alcoholic cirrhosis of the liver;
• hepatitis;
• anemia;
• liver cancer;
• cutaneous porphyria.

The secondary form can also develop after transfusion, because donor blood contains foreign red blood cells that die before their own and secrete iron. Among other reasons for the occurrence of bronze diabetes, it is worth highlighting the excessive intake of iron-containing drugs and adherence to a low-protein diet.

Symptoms and stages

The first signs of hemochromatosis appear when up to 40 g of iron accumulates in the human body. The most obvious symptom of this disease is pigmentation.The skin on the face, neck, arms, genitals and armpits of the patient takes on a grayish and bronze tint. Moreover, the brightness of this symptom depends on the duration of the course of hemochromatosis.

A clear sign of hemochromatosis is a bronze skin tone

Stages of bronze diabetes and the symptoms characterizing it: table

Features of the course in men and women

The appearance of the characteristic signs of bronze diabetes depends not only on the stage of the disease, but also on the gender of the patient. So, in men, atrophic changes in the testes and a decrease in potency are initially observed. As hemochromatosis develops, complete impotence and gynecomastia (an increase in the volume and growth of the mammary glands) occur.

In women at the advanced stage of bronze diabetes, infertility and amenorrhea (absence of menstruation for six months or more) are often diagnosed.

Diagnostics

Upon detection characteristic symptoms of bronze diabetes, you should immediately make an appointment with a hepatologist. To confirm the diagnosis, the clinic will conduct a visual examination and prescribe a number of the following procedures:

1. Analysis of urine, blood. They are necessary for detecting the level of iron, proteins and enzymes in the body, detecting infection and inflammation.
2. Ultrasound of the affected organs. Ultrasound examinations help assess the health of the heart, liver and intestines.
3. MRI. During this procedure, the condition of the liver and the degree of damage to its tissues are examined.
4. Genetic testing. It is required to determine if a defective gene is present in the body.
5. Biopsy. During the procedure, a fragment of the liver is examined for cirrhosis and malignant neoplasms.

If complications are suspected, an X-ray of the joints and the determination of blood sugar levels are additionally prescribed.

Treatment methods

After confirming the diagnosis, the doctor will develop a treatment regimen. Regardless of the form of bronze diabetes, therapy is complex and includes:

• taking medications;
• adherence to a special diet;
• the use of traditional medicine.

In the treatment of hemochromatosis, a procedure such as bloodletting is often used. It is necessary to remove excess iron from the body. In advanced cases, the doctor decides to resort to surgery.

Drug therapy

Medical treatment of bronze diabetes is aimed at reducing the amount of iron in the liver, restoring the tissues of this internal organ and eliminating the cause of the development of the disease. Specialists most often prescribe drugs belonging to the following groups medicines:

1. Chelators. Medicines are aimed at removing iron from the liver. Most often, for bronze diabetes, Deferoxamine is prescribed.
2. Hepatoprotectors. Medicines improve the condition of the affected organ and normalize its work.

The use of drugs from other groups depends on the patient's condition. In some cases, the specialist additionally prescribes antibiotic therapy and taking medications aimed at improving the functioning of the heart and increasing immunity.

Duration of use of any medications and their dosage is determined by the attending physician.

Diet

Most iron-containing foods will have to be eliminated from the diet.

An important role in the treatment of bronze diabetes is played by diet therapy, which implies the exclusion of foods with a high iron content from the diet. This group includes:

• pork and beef (the darker the meat, the more iron it contains);
• seafood;
• buckwheat;
• pistachios;
• apples;
• spinach;
• legumes;
• parsley;
• corn.

During treatment, you should also stop drinking alcohol, eggs and foods with a high content of vitamin C, which contributes to the accumulation of iron. With hemochromatosis, it is recommended to drink coffee and black tea, since these drinks reduce the amount of trace element in the body.

Using folk remedies

As an additional therapy, traditional medicine is used. The following are most effective in treating bronze diabetes:

Before using traditional medicine, you should consult with your doctor.

Surgical intervention

The cardinal method of treating bronze diabetes is surgery... The doctor resorts to it if the patient is diagnosed with cirrhosis of the liver or joint damage. In case of impaired mobility, the patient is shown an operation to install a prosthesis.

With progressive cirrhosis, a transplant of the affected organ is required, which is necessary to save the patient's life. Surgical intervention is carried out under general anesthesia after compliance with certain conditions for preparation.

Possible complications

Timely treatment will help avoid serious complications. Disturbances in the body occur in advanced cases, and the patient develops the following diseases:

• liver failure;
• heart attack;
• liver cancer;
• diabetes;
• cirrhosis of the liver;
• joint diseases;
• arrhythmia.

In the absence of qualified assistance, the patient dies from peritonitis, hepatic or diabetic coma.

Prevention measures

Prevention of hemochromatosis includes adherence to the following general recommendations:

• refusal to take medications that increase hemoglobin;
• exclusion from the diet of foods high in iron;
• eating protein foods.

If one or both parents are diagnosed with hemochromatosis, children need to regularly donate blood to control the level of iron in the body and be examined at the clinic.

If the treatment of hemochromatosis is started immediately after the characteristic symptoms are detected, then the development of complications can be avoided, and the prognosis will be favorable. If the signs of the disease are ignored, the patient's condition is rapidly deteriorating, and his life expectancy is significantly reduced. Due to metabolic disorders in the body, the patient develops diseases that are incompatible with life. On initial stage bronze diabetes responds well complex treatment, and the patient does not require surgical intervention.

Hemochromatosis

What is Hemochromatosis -

Primary hemochromatosis (PHC) is an autosomal recessive, HLA-associated disease caused by a genetic defect characterized by metabolic disorders in which there is increased absorption of iron in the gastrointestinal tract.

What provokes / Causes of Hemochromatosis:

The disease was first described by M. Troisier in 1871 as a symptom complex characterized by diabetes mellitus, skin pigmentation, liver cirrhosis associated with the accumulation of iron in the body. In 1889, Reclinghausen coined the term "hemochromatosis", reflecting one of the features of the disease: the unusual coloration of the skin and internal organs. It was found that iron initially accumulates in the parenchymal cells of the liver, and then can be deposited in other organs (pancreas, heart, joints, pituitary gland).

Prevalence.Population genetic studies have changed the perception of PHC as a rare disease. The prevalence of the PHC gene is 0.03-0.07% - so, until recently, there were 3-8 cases per 100 thousand of the population. Among the white population, the frequency of homozygosity is 0.3%, the frequency of heterozygous carriage is 8-10%. In connection with the improvement of diagnostics, an increase in the incidence is noted. The incidence rate among residents of the European community is on average 1: 300. According to WHO, 10% of the population have a predisposition to hemochromatosis. Men get sick about 10 times more often than women.

Pathogenesis (what happens?) During Hemochromatosis:

Normally, the body contains about 4 g of iron, of which g in the composition of hemoglobin, myoglobin, catalase and other respiratory-bix pigments or enzymes. Iron reserves are 0.5 g, part of them are in the liver, but they are not visible during histological examination for iron by conventional methods. Normally, a person's daily diet contains about 10-20 mg of iron (90% in free standing, 10% in combination with heme), of which 1-1.5 mg is absorbed.

The amount of absorbed iron depends on its reserves in the body: the higher the need, the more iron absorbed. Absorption occurs mainly in the upper small intestine and is an active process in which iron can be transported further against a concentration gradient. However, the transfer mechanisms are unknown.

In the cells of the intestinal mucosa, iron is in the cytosol. Some of it is bound and stored in the form of ferritin, which is subsequently either used or lost as a result of desquamation of epithelial cells. Part of the iron destined for metabolism in other tissues is transported across the basolateral membrane of the cell and binds to transferrin, the main transport protein of iron in the blood. In cells, iron is deposited in the form of ferritin, a complex of the protein apoferritin with iron. Clusters of decayed ferritin molecules are hemosiderin. Approximately one third of the body's iron stores is in the form of hemosiderin, which increases in diseases associated with excess iron accumulation.

With hemochromatosis, the absorption of iron in the digestive tract increases to 3.0-4.0 mg. Thus, within 1 year, its excess amount deposited in the cells of the liver, pancreas, heart and other organs and tissues is about 1 g. Ultimately, the intra- and extracellular pools of the body become supersaturated with iron, which allows free gland to enter into toxic intracellular reactions. As a strong redox agent, iron creates free hydroxyl radicals, which in turn destroy lipid, protein and DNA macromolecules.

Increased accumulation of iron in the liver is characterized by:

• Fibrosis and cirrhosis of the liver with an initial predominant accumulation of iron in parenchymal cells, to a lesser extent in stellate reticuloendotheliocytes.
• Iron deposition in other organs, including the pancreas, heart, and pituitary gland.
• Increased absorption of iron, which leads to its adsorption and accumulation.

The disease is associated with the so-called missense mutations, i.e. mutations that cause a change in the meaning of the codon and lead to the arrest of protein biosynthesis.

The genetic nature of PHC was confirmed by M. Simon et al. in 1976, who revealed in representatives of the European population a close association of the disease with certain antigens of the main histocompatibility complex. For clinical expression, the patient must have two alleles of PHC (homozygosity). The presence of one common HLA haplotype with the patient indicates the heterozygous carriage of the PHC allele. In such persons, indirect signs may be found that indicate an increased content of iron in the body, and the absence of clinically significant symptoms... Heterozygous carriage of a gene predominates over homozygous one. If both parents are heterozygotes, a pseudo-dominant type of inheritance is possible. In heterozygotes, iron absorption is usually slightly increased, a slight increase in serum iron is detected, but there is no life-threatening trace element overload. At the same time, if heterozygotes suffer from other diseases accompanied by disorders of iron metabolism, then clinical and morphological signs of a pathological process may appear.

The close relationship of the disease with HLA antigens made it possible to localize the gene responsible for PHC, located on the short arm of chromosome 6, near the A locus of the HLA system and associated with the A3 allele and A3 B7 or A3 B14 haplotypes. This fact served as the basis for research aimed at its identification.

Hereditary hemochromatosis was originally considered a simple, monogenic disease. Currently, for a gene defect and clinical picture 4 forms of PHC are distinguished:

• classic autosomal recessive HFE-1;
• juvenile HFE-2;
• HFE-3 associated with a type 2 transferrin receptor mutation;
• autosomal dominant hemochromatosis HFE-4.

The identification of the HFE gene (associated with the development of hemochromatosis) was an important point in understanding the essence of the disease. The HFE gene encodes the structure of a protein consisting of 343 amino acids, the structure of which is similar to the MHC class I molecule. In persons suffering from hemochromatosis, mutations in this gene have been identified. Carriers of the C282Y allele in a homozygous state among ethnic Russians are at least 1 per 1000 people. The role of HFE in iron metabolism is evidenced by the interaction of HFE with the transferrin receptor (TfR). The association of HFE with TfR reduces the affinity of this receptor for iron-bound transferrin. With the C282Y mutation, HFE is generally unable to bind to TfR, and with the H63D mutation, the affinity for TfR decreases to a lesser extent. The three-dimensional structure of HFE was investigated using X-ray crystallography, which made it possible to establish the nature of the interaction between HFE and the 2m light chain, as well as to determine the localization of mutations characteristic of hemochromatosis.

The C282Y mutation leads to the breaking of the disulfide bond in the domain, which is important in the formation of the correct spatial structure of the protein and its binding to 2m. The largest amount of the HFE protein is produced in the deep crypts of the duodenum. Normally, the role of the HFE protein in cryptone cells is to modulate transferrin-associated iron uptake. Have healthy person level up serum iron leads to an increase in its uptake by deep crypt cells (the process is mediated by TfR and modulated by HFE). The C282Y mutation can disrupt TfR-mediated iron uptake by crypt cells and, thus, generate a false signal about the presence of low iron in the body.

Due to a decrease in the content of intracellular iron, differentiating enterocytes migrating to the apex of the villi begin to produce an increased amount of DMT-1, as a result of which iron uptake is enhanced. The main link in pathogenesis is a genetic defect in enzyme systems that regulate the absorption of iron in the intestine during normal intake of it with food. The genetic link with the HLA-A system has been proven. The study of linkage disequilibrium using these markers showed a relationship of hemochromatosis with Az, B7, Bt4, D6 Siosh D6 S126O.

Further studies in this direction and analysis of haplotypes suggest that the gene is located between D6 S2238 and D6 S2241. The putative hemochromatosis gene is homologous to HLA, and the mutation appears to affect a functionally important region. The gene that controls the iron content in the body is located at the A3HLA locus on chromosome 6. This gene encodes the structure of a protein that interacts with the transferrin receptor and reduces the receptor's affinity for the transferring-iron complex. Thus, the mutation of the HFE gene disrupts the transferrin-mediated capture of iron by the enterocytes of the duodenum, as a result of which a false signal is formed about the presence of a low iron content in the body, which, in turn, leads to an increased production of the iron-binding protein DCT-1 in the villi of enterocytes and how the consequence is an increased capture of iron.

Potential toxicity is explained by its ability, as a metal with variable valence, to trigger valuable free radical reactions, leading to toxic damage to organelles and genetic structures of the cell, increased collagen synthesis and the development of tumors. Heterozygotes show a slight increase in serum iron levels, but do not show excessive iron accumulation or tissue damage.

However, this can happen if heterozygotes suffer from other diseases accompanied by disorders of iron metabolism.

Secondary hemochromatosis often develops against a background of blood diseases, late cutaneous porphyria, frequent blood transfusions, and the intake of iron-containing drugs.

Symptoms of Hemochromatosis:

Features of clinical manifestations:

Clinical manifestations of the disease develop after the onset of adulthood, when iron stores in the body reach 20-40 g or more.

There are three stages in the development of the disease:

• without the presence of iron overload with a genetic predisposition;
• iron overload without clinical manifestations;
• stage of clinical manifestations.

The onset of the disease is gradual. In the initial stage, for a number of years, complaints of pronounced weakness, fatigue, weight loss, and decreased sexual function in men predominate. Often there is pain in the right hypochondrium, joints due to chondrocalcinosis of large joints, dryness and atrophic changes in the skin and testicles.

The advanced stage of the disease is characterized by the classic triad. pigmentation of the skin, mucous membranes, cirrhosis of the liver and diabetes.

Pigmentation is one of the common and early symptoms of hemochromatosis. Its severity depends on the age of the process. A bronze, smoky skin tone is more visible on open parts of the body (face, neck, hands), on previously pigmented areas, in the armpits, on the genitals.

In most patients, iron is primarily deposited in the liver. An enlarged liver is observed in almost all patients. The consistency of the liver is dense, the surface is smooth, in some cases it is painful on palpation. Splenomegaly is diagnosed in 25-50% of patients. Extrahepatic signs are rare. Paired diabetes occurs in 80% of patients. He is often insulin dependent.

Endocrine disorders are observed in the form of hypofunction of the pituitary gland, pineal gland, adrenal glands, thyroid gland (1/3 of patients) of the gonads. Different kinds endocrinopathies occur in more than 80% of patients. The most frequent form pathology is diabetes mellitus.

Iron deposition in the heart with PHC is observed in 90-100% of cases, however, clinical manifestations of heart damage are found only in 25-35% of patients. Cardiomyopathy is accompanied by an increase in the size of the heart, rhythm disturbances, and the gradual development of refractory heart failure.

Possible combination of hemochromatosis with arthropathy, chondrocalcinosis, osteoporosis with calciuria, neuropsychiatric disorders, tuberculosis, tardive cutaneous porphyria.

Allocate latent (including patients with a genetic predisposition and minimal iron overload), with severe clinical manifestations, and terminal hemochromatosis. More often there are hepatopathic, cardiopathic, endocrinological forms: respectively, slowly progressing, rapidly progressing and a form with a fulminant course.

The latent stage of PHC is observed in 30-40% of patients, which is detected during family genetic examination of patients' relatives or during population screening. Some of these persons of the older age group have minimal symptoms in the form of slight weakness, increased fatigue, a feeling of heaviness in the right hypochondrium, pigmentation skin in open areas of the body, decreased libido, minor hepatomegaly.

The stage of advanced clinical manifestations is characterized by the presence of asthenovegetative syndrome, abdominal pain, sometimes quite intense, arthralgia, decreased libido and potency in 50% of men and amenorrhea in 40% of women. In addition, weight loss, cardialgia, and palpitations may occur. An objective examination reveals hepatomegaly, melasma, dysfunction of the pancreas (insulin-dependent diabetes mellitus).

In the terminal stage of PHC, there are signs of decompensation of organs and systems in the form of portal hypertension, development of hepatocellular, as well as right and left ventricular heart failure, diabetic coma, and exhaustion. The causes of death of such patients, as a rule, are bleeding from varicose veins of the esophagus, hepatocellular and heart failure, aseptic peritonitis, diabetic coma.

In such patients, there is a predisposition to the development of a tumor process (the risk of its development in persons over 55 years of age is 13 times higher than in the general population).

Juvenile hemochromatosis is a rare form of the disease that occurs at a young age (15-30 years) and is characterized by severe iron overload, accompanied by symptoms of liver and heart damage.

Diagnostics of the Hemochromatosis:

Diagnostic features:

Diagnosis is based on multiple organ lesions, cases of the disease in several members of the same family, increased iron content, urinary iron excretion, high transferrin concentration, and serum ferritin. The diagnosis is likely when combined with diabetes mellitus, cardiomyopathy, hypogonadism, and typical skin pigmentation. Laboratory criteria are hyperferremia, an increase in the transferrin saturation index (more than 45%). The level of ferritin in the blood serum and the excretion of iron in the urine (desferal test) sharply increase. After intramuscular injection 0.5 g of desferal, the excretion of iron increases to 10 mg / day (at a rate of 1.5 mg / day), the NTH ratio (iron / TIBC) increases. With the introduction of genetic testing into practice, the number of people with hemochromatosis without clinical signs of iron overload has increased. A study is carried out for the presence of C282Y / H63D mutations in the risk group for the development of iron overload. If the patient is a homozygous carrier of C282Y / H63D, the diagnosis of hereditary hemochromatosis can be considered established.

Among non-invasive research methods, the deposition of a trace element in the liver can be determined using MRI. The method is based on a decrease in the signal intensity of the liver overloaded with iron. In this case, the degree of decrease in the signal intensity is proportional to the iron stores. The method allows you to determine the excessive deposition of iron in the pancreas, heart and other organs.

Liver biopsy shows abundant iron deposition, giving a positive Perls reaction. In a spectrophotometric study, the iron content is over 1.5% of the dry weight of the liver. Of great importance is the quantitative measurement of the level of iron in liver biopsies by atomic absorption spectrometry with the subsequent calculation of the hepatic iron index. The index represents the ratio of the concentration of iron in the liver (in μmol / g dry weight) to the patient's age (in years). With PHC, already in the early stages, this indicator is equal to or exceeds 1.9-2.0 and does not reach the indicated value in other conditions characterized by liver hemosiderosis.

In the latent stage of the disease, liver function tests practically do not change, and according to histological examination, grade 4 hemosiderosis, fibrosis of the portal tracts without pronounced signs of inflammatory infiltration are observed.

At the stage of advanced clinical manifestations, histological changes in the liver usually correspond to pigmented septal or small-nodular cirrhosis with massive deposits of hemosiderin in hepatocytes and less significant in macrophages, epithelium bile ducts.

Histological examination in the terminal stage of the disease reveals a picture of generalized hemosiderosis with damage to the liver (like mono- and multilobular cirrhosis), heart, pancreas, thyroid, salivary and sweat glands, adrenal glands, pituitary gland and other organs.

Iron overload is observed in a number of congenital or acquired conditions with which it is necessary to differentiate PHC.

Classification and reasons for the development of an iron overload condition:

• Familial or congenital forms of hemochromatosis:
  • Congenital HFE-associated hemochromatosis:
    • homozygosity for C282Y;
    • mixed heterozygosity for C282Y / H63D.
  • congenital HFE-unassociated hemochromatosis.
  • Juvenile hemochromatosis.
  • Iron overload in newborns.
  • Autosomal dominant hemochromatosis.
• Acquired Iron Overload:
  • Hematological diseases:
    • iron overload anemia;
    • greater thalassemia;
    • sideroblastic anemia;
    • chronic hemolytic anemias.
• Chronic liver disease:
  • hepatitis C;
  • alcoholic liver disease;
  • non-alcoholic steatohepatitis.

The disease must also be differentiated with blood pathology (thalassemia, sideroblastic anemia, hereditary atransferrynemia, microcytic anemia, porphyria cutaneous tarda), liver diseases (alcoholic liver damage, chronic viral hepatitis, non-alcoholic steatohepatitis).

Treatment of Hemochromatosis:

Features of the treatment of hemochromatosis:

Shown is a protein-rich diet, no iron-rich foods.

The most affordable way to remove excess iron from the body is bloodletting. Usually, 300-500 ml of blood is removed at a frequency of 1-2 times a week. The number of bloodletting is calculated depending on the level of hemoglobin, blood hematocrit, ferritin, and the amount of excess iron. It is taken into account that 500 ml of blood contains 200-250 mg of iron, mainly in the composition of erythrocyte hemoglobin. Bloodletting continues until the patient develops mild anemia. A modification of this extracorporeal technique is cytapheresis (CA) (removal of the cellular part of the blood with the return of autoplasma in a closed circuit). In addition to the mechanical removal of blood corpuscles, CA has a detoxifying effect and helps to reduce the severity of degenerative-inflammatory processes. Each patient undergoes 8-10 sessions of CA with a further transition to supportive therapy using CA or hemoexfusion in the amount of 2-3 sessions for 3 months.

Drug treatment is based on the use of deferoxamine (desferal, desferin), 10 ml of a 10% solution intramuscularly or intravenously drip. The drug has a high specific activity for Fe3 + ions. At the same time, 500 mg of desferal is able to remove 42.5 mg of iron from the body. The duration of the course is 20-40 days. At the same time, cirrhosis, diabetes mellitus and heart failure are treated. The frequently observed anemic syndrome in patients with PHC in the presence of excess iron content in the liver tissue limits the use of efferent therapy. In our clinic, a scheme for the use of recombinant erythropoietin against the background of CA has been developed. The drug promotes increased utilization of iron from the body's depot, due to which there is a decrease in the total reserves of the trace element, an increase in the level of hemoglobin. Reombinant erythropoietin is administered at a dose of 25 μg / kg of body weight against the background of CA sessions, carried out 2 times a week for 10-15 weeks.

Forecast:

The forecast is determined by the degree and duration of congestion.

The course of the disease is long, especially in the elderly. Timely therapy prolongs life by several decades. The survival rate for 5 years in treated patients is 2.5-3 times higher than in untreated patients. The risk of developing HCC in patients with PHC in the presence of liver cirrhosis increases 200 times. Most often, death occurs due to liver failure.

Which doctors should you contact if you have Hemochromatosis:

• Gastroenterologist
• Nutritionist

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Other diseases from the group Diseases of the gastrointestinal tract:

The disease can manifest itself in systemic symptoms, liver disease, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Diagnosis is based on serum ferritin levels and gene analysis. It is usually treated with phlebotomy.

Causes of primary hemochromatosis

Until recently, the cause of the disease in almost all patients with primary hemochromatosis considered a mutation in the HFE gene. Other causes have recently been identified: various mutations leading to primary hemochromatosis and occurring in ferroportin diseases, juvenile hemochromatosis, neonatal hemochromatosis (iron storage disease in newborns), hypotransferrinemia and aceruloplasminemia.

More than 80% of HFE-related hemochromatosis is caused by homozygous C282Y or C282Y / H65D interfering with heterozygous mutations. This disease is autosomal recessive, with a homozygous frequency of 1: 200 and a heterozygous frequency of 1: 8 in people of northern European descent. The disease rarely occurs in black people and people of Asian descent. 83% of patients with clinical hemochromatosis are homozygous. However, for unknown reasons, phenotypic (clinical) disease occurs much less frequently than predicted by gene frequency (i.e., many homozygous people do not report this disorder).

Pathophysiology of primary hemochromatosis

The normal level of iron in the human body is 2.5 g in women and 3.5 g in men. Hemochromatosis cannot be established until the total iron content in the body exceeds 10 g, and most often even several times more, since symptoms can be delayed until the accumulation of iron becomes excessive. In women, clinical manifestations are rare before menopause, since the iron loss associated with menstruation (and sometimes pregnancy and childbirth) is sought by the body to compensate for the accumulation of iron.

The mechanism of iron overload is increased absorption of iron from the gastrointestinal tract, which leads to chronic accumulation of iron in the tissues. Hepcidin, a liver-synthesized peptide, is a critical mechanism for controlling iron absorption. Hepcidin, together with the normal HFE gene, prevents iron over-absorption and accumulation in normal people.

In most cases, tissue damage results from the effects of free hydroxyl radicals, which are formed when iron deposition in tissues catalyzes their structure. Other mechanisms may affect individual organs (for example, skin hyperpigmentation may result from increased melanin as well as iron accumulation).

Symptoms and signs of primary hemochromatosis

The consequences of iron overload remain the same regardless of the etiology and pathophysiology of the iron overload.

Doctors believe that symptoms do not appear until organ damage occurs. However, organ damage is slow and difficult to detect. Fatigue and nonspecific systemic symptoms usually occur first.

Other symptoms are associated with the functioning of organs with high iron accumulation. In men initial symptoms there may be hypogonadism and erectile dysfunction caused by gonadal iron accumulation. Impaired glucose sensitivity or diabetes mellitus are also early signs. Some patients develop hypothyroidism.

Cardiomyopathy with heart failure is the second most common cause. Hyperpigmentation (bronze diabetes) is common, as is symptomatic arthropathy.

Common manifestations of primary hemochromatosis

Diagnosis of primary hemochromatosis

• Serum ferritin levels.
• Genetic tests.

Symptoms and signs can be nonspecific, subtle, and onset gradually, so be alert. Primary hemochromatosis should be suspected when typical manifestations of diseases, in particular combinations of such manifestations, remain unexplained after a routine examination. Although a history of familial illness is a more specific answer, it is usually not presented.

Elevated ferritin levels (\u003e 200 ng / ml in women and\u003e 300 ng / ml in men) are usually seen in primary hemochromatosis, but can also be due to other disorders such as inflammatory diseases liver, cancer, certain systemic inflammatory diseases (eg, refractory anemia, hemophagocytic lymphohistiocytosis) or obesity. Follow-up tests are done if ferritin levels are outside the normal range. They are aimed at assessing serum iron levels (usually\u003e 300 mg / dL) and iron binding capacity (transferrin saturation; levels usually\u003e 50%). Genetic analysis is performed to detect primary hemochromatosis caused by mutations in the HFE gene. In very rare cases, other types of primary hemochromatosis (eg, ferroportin disease, juvenile hemochromatosis, neonatal hemochromatosis, transferrin deficiency, ceruloplasmin deficiency) are suspected, in which ferritin and blood iron tests indicate iron overload and genetic test results for gene mutation HFEs are negative, especially in younger patients. Confirmation of such diagnoses is progressing.

Because the presence of cirrhosis affects the prognosis, a liver biopsy is usually done and the iron content of the tissue is measured (if possible). High-intensity MRI is a non-invasive alternative for assessing liver iron (high accuracy).

For the immediate family of people with primary hemochromatosis, a serum ferritin screening test and testing for the 282Y / H63D gene should be performed.

Treatment of primary hemochromatosis

• Phlebotomy (phlebotomy).

Patients with clinical manifestations of the disease, increased level serum ferritin or increased transferrin saturation treatment is necessary. Patients who do not have symptoms of the disease require periodic (eg, annually) clinical examinations.

Phlebotomy delays the development of fibrosis into cirrhosis, sometimes even reverses cirrhotic changes and prolongs life, but does not prevent hepatocellular carcinoma. About 500 ml of blood is removed weekly until serum iron levels return to normal and transferrin saturation is<50%. Еженедельная флеботомия может быть необходима в течение многих месяцев. Для поддержания сатурации трансферина на уровне <30% при нормальном уровне железа, можно проводить периодические флеботомии.

Diabetes, cardiomyopathy, erectile dysfunction, and other secondary manifestations are treated as indicated.

Patients should adhere to a balanced diet, there is no need to limit the intake of iron-containing foods (for example, red meat, liver). Alcohol should only be consumed in moderation. it can increase iron absorption and increase the risk of cirrhosis.

Juvenile hemochromatosis

Juvenile hemochromatosis is a rare autosomal recessive disorder caused by a mutation in the HJV gene that affects the transcription of the hemouvelin protein. This is often seen in adolescents. Ferritin levels are\u003e 1000 ng / ml and transferrin saturation is\u003e 90%.

Transferrin receptor gene mutations

Mutations in the transferrin receptor 2, a protein that appears to control transferrin saturation, can cause rare autosomal recessive hemochromatosis. Symptoms and signs are similar to HFE hemochromatosis.