home Audience 5 Hemochromatosis is a genetic liver disease with serious complications, treatment and prognosis. Liver hemochromatosis: causes, symptoms, treatment Primary hemochromatosis

Hemochromatosis is a genetic liver disease with serious complications, treatment and prognosis. Liver hemochromatosis: causes, symptoms, treatment Primary hemochromatosis

Hemochromatosis is a disease that is inherited and causes a disorder of iron metabolism in the human body. With this disease, pigments that contain iron are absorbed by the intestines and accumulate in tissues and organs.

Hemochromatosis is most widespread in northern Europe - there 5% of the population is homozygous for the disease. Most often, men suffer from hemochromatosis (statistics indicate the ratio of sick men to sick women as 10:1). As a rule, the first symptoms of the disease appear in middle age (from 40 years to retirement age). Most often, hemochromatosis affects the liver, as it takes part in iron metabolism.

Signs of the disease

Hemochromatosis has the following symptoms:

the presence of weakness and constant fatigue;
decreased blood pressure;
sudden weight loss;
increased pigmentation. Provides for a change in skin color to a grayish-brown tint, as well as a change in the color of the sclera or mucous membranes;
development (a disease that involves increased blood sugar);
appearance . This complex of ailments includes all pathologies that are associated with the ability of the heart muscle to contract;
appearance (involves a change in liver tissue towards scar tissue);
(inability to cope with functions during digestion);
decreased libido;
the presence of edema and limited mobility of the limbs.

Forms and stages of the disease

The following types of illness are distinguished:

primary. Relates to the mutation of genes that are responsible for iron metabolism in the body;
neonatal. Appears due to high iron content in newborns. The reasons for this form of the disease have not yet been clarified by doctors;
secondary. Secondary hemochromatosis, as a rule, develops against the background of other diseases that are associated with blood circulation and skin problems. It also develops as a result of taking medications with high iron content.

Hemochromatosis has the following stages:

at stage 1, disturbances in iron metabolism are observed, but its amount remains below the permissible standard;
at stage 2, the patient experiences iron overload, which does not have any special clinical signs, but diagnostics show deviations from the norm;
at stage 3, the patient has all the signs of the disease due to the accumulation of large amounts of iron.

Causes of the disease

The main reasons for the development of the disease include:

factor of heredity. Usually this factor is the cause of the development of the primary form of pathology and appears due to damage to the gene that is responsible for iron metabolism;
metabolic disorders. Most often it manifests itself against the background of cirrhosis of the liver due to shunting to improve blood flow in the portal vein;
liver diseases of viral etiology. These include B and C, which are observed in the patient for more than six months;
steatohepatitis (overgrowth of liver tissue with fat);
blocking the opening of the pancreas;
the presence of tumor formations, for example, leukemia or liver tumor.

Diagnosis of the disease

Diagnosis of a disease such as secondary hemochromatosis is based on:

analysis of the patient's medical history and complaints. The doctor takes into account the time of onset of symptoms and what the patient associates their occurrence with;
analysis of family medical histories. It takes into account whether the disease was observed in family members of the sick person;
genetics test results. It helps detect the defective gene;
analysis of the properties of iron metabolism in the blood. It includes several tests to detect the presence of large amounts of iron;
information obtained from a biopsy (a test that involves collecting a small amount of liver tissue with a thin needle). This diagnosis shows whether there is damage to organ tissue.

Sometimes the diagnostic measure is to consult the patient with an endocrinologist.

Treatment of the disease

Treatment of hemochromatosis is complex and involves the patient taking the following measures:

diet prescription. It should take into account the reduction of iron-containing foods, as well as protein. It is worth reducing the intake of fruits and other products high in vitamin C, since its high content leads to increased absorption of iron. The diet includes avoiding alcohol, as it also increases the absorption of pigments into the liver tissue and has a detrimental effect on them. The patient needs to stop eating large amounts of bread made from buckwheat, rye flour, as well as other flour products. You should not eat kidneys and liver, and also exclude seafood (squid, shrimp, seaweed) from your diet. You can drink black tea and coffee, as they reduce the rate of iron metabolism due to their tannin content;
taking medications, which bind iron. They help to promptly remove excess iron from the patient’s organs;
phlebotomy. Bloodletting involves removing up to 400 ml of blood, which contains a large amount of iron, from the body every week. This reduces symptoms (eliminates pigmentation, reduces liver size);
treatment of related diseases(diabetes mellitus, tumors, heart failure) and their timely diagnosis.

Possible complications

Hemochromatosis may include the following complications for the body:

the appearance of liver failure. In this case, the organ stops coping with its responsibilities (participation in the digestion of food, metabolism and neutralization of harmful substances);
the appearance of other defects in the functioning of the heart muscle;
. This disease occurs as a result of serious circulatory disorders and involves the death of part of the heart muscle. Often appears against the background of developed heart failure;
bleeding from the veins located in the esophagus;
coma (hepatic or diabetic). This serious condition is caused by damage to the brain by toxic substances that accumulate in the body due to ineffective liver function;
the appearance of liver tumors.

To prevent all of these complications from developing, it is necessary to diagnose the disease in time so that the doctor can prescribe adequate treatment.

Treatment of hemochromatosis must be timely to prevent serious consequences for the patient’s organs. To do this, when the first symptoms appear, he should immediately consult a doctor. As for the prognosis during the course of the disease, with timely initiation of treatment within 10 years, more than 80% of patients remain alive. If the manifestations of the disease in a patient began about 20 years ago, then the probability of his survival is reduced to 60–70%. Doctors' predictions for a favorable outcome directly depend on the amount of iron-containing pigments in the patient's body. The more there are, the less chance of recovery. If the disease was diagnosed before the onset of cirrhosis, then the patient has a good chance of a normal life expectancy. It is worth noting that about 30% of patients die from complications of the disease, which include heart failure or malabsorption syndrome.

Disease prevention

Hemochromatosis is a serious disease that affects many tissues and organs. Prevention must take into account following several rules at once. Firstly, it involves following a diet (reducing the consumption of foods high in protein, as well as ascorbic acid and iron-containing products). Secondly, prevention takes into account the use of special medications that bind iron in the body and quickly remove it, under the strict supervision of a doctor. Thirdly, even in the absence of obvious symptoms, prevention is taking iron-containing medications, which are prescribed to the patient by a doctor.

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Diseases with similar symptoms:

Heart defects are anomalies and deformations of individual functional parts of the heart: valves, septa, openings between vessels and chambers. Due to their improper functioning, blood circulation is disrupted, and the heart ceases to fully perform its main function - supplying oxygen to all organs and tissues.

With active absorption of iron in the intestine with subsequent accumulation of the substance in other organs, hemochromatosis of the liver develops. The disease belongs to hereditary multisystem pathologies, but can be acquired against the background of other diseases. The clinic is pronounced, intense and manifests itself in a bronze tint of the mucous membranes and skin. Complications – cirrhosis, cardiomyopathy, diabetes mellitus, arthralgia, sexual dysfunction. To make a diagnosis, specific laboratory tests are performed. Treatment is based on bloodletting, the principles of diet therapy and symptomatic therapy. According to indications, transplantation of the affected organ or arthroplasty is performed.

Failure in the metabolism of iron in the blood can cause a liver disease called hemochromatosis.

What it is?

What is hemochromatosis? This is a severe pathology, which is also called bronze diabetes, pigmentary cirrhosis due to the specific clinical picture characterized by pigmentation of the skin and internal organs. The disease is a semi-systematic genetic disease caused by a mutation in the HFE gene. The disease is most often associated with a transmitted mutation of the HFE gene on chromosome 6, which is why it is called hereditary hemochromatosis.

Idiopathic hemochromatosis is manifested by a violation of the process of iron metabolism against the background of a gene mutation, as a result of which the substance is absorbed into the intestines with its further accumulation in other organs (heart, pituitary gland, liver, joints, pancreas), in tissues. Against the background of the ongoing process, multiple organ failure develops. The disease is always accompanied by cirrhosis, diabetes mellitus and pigmentation of the dermis.

Prevalence

Among genetic pathologies, hereditary hemochromatosis is one of the most common. The maximum number of cases was recorded in northern Europe. A specific mutated hemochromatosis gene, which is present in the DNA of 5% of people on Earth, is responsible for the appearance of the disease, but the disease develops in only 0.3% of the population. The prevalence among men is 10 times higher than among women. In 70% of patients, the first symptoms appear at 40-60 years of age.

Forms and stages of hemochromatosis

According to etiological factors, there are:

Primary hemochromatosis, that is, hereditary type. The primary form is associated with a congenital malfunction of enzyme systems, which provokes the accumulation of iron on internal organs, which causes a gene mutation on the 6th DNA chromosome. There are 4 subforms of the hereditary disease, which differ in severity and location:

Hemochromatosis can be congenital or occur during life.

autosomal recessive, HFE-associated (develops in 95% of patients);
juvenile;
congenital HFE-unassociated;
autosomal dominant.

Secondary disease, that is, acquired generalized hemosiderosis. The disease appears as a result of damage to another serious disease. Acquired enzyme deficiency, which accelerates the accumulation of iron, occurs:

post-transfusion;
nutritional;
metabolic;
neonatal;
mixed.

Only the third degree of hemochromatosis has characteristic symptoms.

According to the nature of the process, there are 3 stages of congenital and secondary disease:

I – light, without load, that is, iron metabolism is impaired, but its concentration does not exceed the norm;
II – moderate, with overload, but asymptomatic;
III – with intense symptoms: pigmentation, dysfunction of the heart, kidneys, liver, pancreas, etc.

Causes and pathogenesis

There are a number of reasons that provoke the development of hemochromatosis:

Poor heredity is the cause of the idiopathic form of hemochromatosis. The disease develops due to the degeneration of a gene that corrects metabolic processes involving iron. A disease such as the HFE gene mutation is inherited.
Other pathologies, such as cirrhosis, hepatitis B and C untreated for more than six months, malignant tumors in the liver tissues or hematopoietic system.
Vascular operations associated with portocaval shunting in the portal vein.
Accumulation of fat in the “filter” parenchyma, not associated with alcohol intoxication.
Blockage of the main channel of the pancreas.
Introduction of specific intravenous drugs that provoke an increase in iron concentration.
Transfusion. Red blood cells foreign to the body are destroyed faster than our own. As a result of their death, iron is formed.
Continuous hemodialysis.
Diseases associated with increased hemoglobin. When it is destroyed, a large number of metabolites and iron are formed.

All points, except the first, provoke the development of secondary pathology.

With hemochromatosis, excessive accumulation of iron occurs in organ tissues, which begins to gradually destroy them. The inflammatory process begins at the site of the lesion. Local immunity, in order to suppress the lesion, activates the process of fibrin scarring. As a result, fibrosis of the affected organ and its failure develops. The first to suffer is the liver, which subsequently becomes affected by cirrhosis.

Symptoms and course

Primary hemochromatosis does not manifest itself in the initial stages. General weakness and malaise may develop. As the disease progresses, symptoms of dysfunction of other organs appear, expressed by:

Hemochromatosis provokes pigmentation, abdominal pain, gastrointestinal disorders, and headaches.

pigmentation of the dermis in the facial part, in front of the forearm, on top of the hand, near the navel, nipples and genitals, which is associated with the deposition of hemosiderin and a small amount of melanin;
lack of hair growth on the face and body;
non-localized abdominal pain of varying strength;
gastrointestinal disorders, including nausea with vomiting, diarrhea, lack of appetite;
dizziness;
limitation of the motor ability of joints due to their damage and deformation.

The most common symptom complex for hemochromatous changes are symptoms of cirrhosis of the parenchyma, diabetes mellitus against the background of strong pigmentation of the dermis. Symptoms appear when iron levels exceed 20 g, which is 5 times the physiological norm.

The course of the disease is characterized by constant progression. In the absence of therapy, symptoms of irreversible changes and severe complications that threaten death immediately appear.

Complications and consequences

As the disease progresses, the following complications develop:

Liver dysfunction, when basic functions are not performed.
Any heart rhythm disturbances and congestive cardiac dysfunction.
Infectious complications of various types.
Myocardial infarction.
Bleeding from varicose veins, most often in the esophagus and gastrointestinal tract.
Diabetic and hepatic coma with progression of diabetes and cirrhosis, respectively.
Development of tumors, most often in liver tissues.
Diabetes mellitus, which develops in 75% of cases.
Hepatomegaly, when the liver increases in size.
Splenomegaly is an increase in the volume of the spleen.
Diffuse progressive cirrhosis of the parenchyma.
Arthralgia, when the joints hurt severely. The interphalangeal joints on the second and third fingers are especially affected.
Sexual disorders such as impotence (in men). Women develop amenorrhea, as a result, decreased libido.
Lesions of the pituitary gland and associated hormonal deficiency.

Diagnostics

Since hemochromatosis provokes different diseases, the clinical picture may vary. Consequently, different specialists are capable of diagnosing pathology, such as:

A final diagnosis of iron metabolism failure can only be made by undergoing a comprehensive examination by a dermatologist, urologist, cardiologist and other specialists.

But all doctors will use the same approach in diagnosing a pathological condition, regardless of the cause and clinical picture. After a visual examination and assessment of the patient’s complaints, a complex of complex laboratory and instrumental studies is prescribed to clarify the diagnosis and determine the severity of damage to the body.

Diagnostics is aimed at identifying the disease itself using specific methods, since the standard list of tests is uninformative. Today, a step-by-step scheme for diagnosing a pathological condition is proposed, which includes the following steps:

Determination of the level of transferrin, a specific protein involved in the transfer of iron throughout the body. The norm is no more than 44%.
Ferritin calculation. The norm of the substance in women outside and after menopause is 200 and 300 units, respectively.
Diagnostic bloodletting. The essence of the method is the extraction of a small amount of blood and the calculation of iron in the serum. Typically, the patient feels better when the level of iron in the general bloodstream drops by 3 grams.

Laboratory methods

Hemochromatosis is also diagnosed based on the results of blood and urine tests.

Clinical tests necessary to diagnose the disease are based on determining the level of iron itself and the substances involved in its metabolism and transport throughout the body. The following laboratory diagnostic methods are used:

specific analysis for the concentration of iron, ferritin, transferrin;
positive desferal test - urine tests with calculation of excreted iron;
assessment of the decline in the general iron-binding property of blood.

To confirm the diagnosis, a puncture or dermal puncture is performed, followed by examination for the presence/absence of hemosiderin deposits. The hereditary form of the disease is determined on the basis of data obtained from molecular genetic research.

To assess the severity of damage to other organs and determine the prognosis, the following is carried out:

liver tests;
analyzes of biological fluids for sugar and glycosylated hemoglobin.

Instrumental techniques

In addition to clinical studies of the patient’s biological fluids, an instrumental examination is carried out, which allows one to obtain a more accurate picture of the course and extent of the pathological process, and to determine the damage caused to the body. For this purpose the following are assigned:

x-ray of joints;
Ultrasound of the peritoneum;
ECG, EchoCG;
MRI, .

Hemochromatosis was first described as a separate disease in 1889. However, it was possible to accurately establish the causes of the disease only with the development of medical genetics.

This rather late classification was facilitated by the nature of the disease and its rather limited distribution.

Thus, according to modern data, 0.33% of the planet’s inhabitants are at risk of developing hemochromatosis. What causes the disease and what are its symptoms?

Hemochromatosis - what is it?

This disease is hereditary and is characterized by a multiplicity of symptoms and a high risk of serious complications and associated pathologies.

Research has shown that hemochromatosis is most often caused by a mutation in the HFE gene.

As a result of a gene failure, the mechanism of iron uptake in the duodenum is disrupted. This leads to the fact that the body receives a false message about a lack of iron in the body and begins to actively and in excess quantities synthesize a special protein that binds iron.

This leads to excessive deposition of hemosiderin (glandular pigment) in the internal organs. Simultaneously with the increase in protein synthesis, the gastrointestinal tract is activated, leading to excessive absorption of iron from food in the intestines.

So even with a normal diet, the amount of iron contained in the body is many times higher than normal. This leads to the destruction of tissues of internal organs, problems with the endocrine system, and immunity.

Classification by types, forms and stages

In medical practice, primary and secondary types of the disease are divided. In this case, primary, also called hereditary, is the result of manifestation. Secondary hemochromatosis is a consequence of the development of abnormalities in the functioning of enzyme systems involved in glandular metabolism.

There are four known forms of hereditary (genetic) type of disease:

classical;
juvenile;
ancestral HFE-unassociated species;
autosomal dominant.

The first type is associated with a classic recessive mutation of a region of the sixth chromosome. This type is diagnosed in the vast majority of cases - more than 95 percent of patients suffer from classic hemochromatosis.

The juvenile type of the disease occurs as a result of a mutation in another gene – HAMP. Under the influence of this change, the synthesis of hepcidin, the enzyme responsible for the deposition of iron in organs, increases significantly. The disease usually appears between the ages of ten and thirty.

The HFE-unassociated type develops when the HJV gene fails. This pathology involves the mechanism of hyperactivation of transferrin-2 receptors. As a result, hepcidin production is activated. The difference with the juvenile type of the disease is that in the first case there is a malfunction of the gene directly responsible for the production of the iron-binding enzyme.

Whereas in the second case, a state characteristic of an excess of iron in food is created in the body, which leads to the production of the enzyme.

The fourth type of hereditary hemochromatosis is associated with a malfunction of the SLC40A1 gene.

The disease manifests itself in old age and is associated with improper synthesis of the protein ferroportin, which is responsible for transporting iron compounds into cells.

Causes of missense mutations and risk factors

A genetic mutation in a hereditary type of disease is a consequence of a person’s predisposition.

Studies show that the majority of patients are white residents of North America and Europe, with the largest number of patients suffering from hemochromatosis observed among immigrants from Ireland.

At the same time, different parts of the globe are characterized by the prevalence of different types of mutation. Men are susceptible to the disease several times more often than women. In the latter, symptoms usually develop after hormonal changes in the body that occur as a result of menopause.

Among registered patients, there are 7-10 times fewer women than men. The reasons for the changes are still unclear. Only the hereditary nature of the disease has been irrefutably proven, and a connection can be traced between the presence of hemochromatosis and.

While the proliferation of connective tissue cannot be directly explained by the accumulation of iron in the body, up to 70% of patients with hemochromatosis had liver fibrosis.

However, genetic predisposition does not necessarily lead to the development of the disease.

In addition, there is a secondary form of hemochromatosis, which is observed in people with initially normal genetics. Risk factors also include some pathologies. Thus, previous steatohepatitis (non-alcoholic deposition of adipose tissue), the development of chronic hepatitis of various etiologies, as well as blockage contribute to the manifestation of the disease.

Some malignant neoplasms can also become a catalyst for the development of hemochromatosis.

Symptoms of hemochromatosis in women and men

In the past, only the development of a number of serious symptomatic manifestations allowed the diagnosis of this disease.

A patient with excess iron accumulation feels chronic fatigue and weakness.

This symptom is characteristic of 75% of those suffering from hematochromatosis. Skin pigmentation increases, and this process is not associated with the production of melanin. The skin acquires a dark shade due to the accumulation of iron compounds there. Darkening is observed in more than 70% of patients.

The negative impact of accumulated iron on immune cells leads to weakened immunity. Therefore, as the disease progresses, the patient’s susceptibility to infections increases - from quite serious to banal and harmless under normal conditions.

About half of the patients suffer, which is expressed in the occurrence of pain.

There is also a deterioration in their mobility. This symptom occurs because an excess of iron compounds catalyzes the deposition of calcium in the joints.

Attacks of arrhythmia and the development of heart failure are also possible. A negative effect on the pancreas often leads to. Excess iron causes dysfunction of the sweat glands. In fairly rare cases they are observed.

The development of the disease leads to impotence in men. Decreased sexual function indicates signs of poisoning of the body with iron compounds. Women may experience heavy bleeding during regulation.

An important symptom is liver enlargement, as well as quite severe abdominal pain, the appearance of which cannot be identified as systematic..

The presence of several symptoms indicates the need for accurate laboratory diagnosis of the disease.

A sign of the disease is a high, with simultaneous low content in red blood cells. Transferrin iron saturation levels below 50% are considered a laboratory sign of hemochromatosis.

The presence of complex heterozygotes or homozygous mutations of a certain type in the HFE gene with clinical evidence of excess iron accumulation indicates the development of hemochromatosis.

A significant enlargement of the liver with a high density of its tissue is also a sign of the disease. In addition, with hemochromatosis, a change in the color of the liver tissue is observed.

How does it manifest in a child?

Early hemochromatosis has a number of features - from the mutations of the corresponding chromosome sections that caused it to the characteristic clinical picture and manifestations.

First of all, the symptoms of the disease at an early age are polymorphic.

Children typically develop symptoms indicating the presence of a portal. A disturbance in the absorption of food develops, with a simultaneous enlargement of the spleen and liver.

With the development of pathology, severe and treatment-resistant ascites begins - dropsy that forms in the abdominal region. The development of varicose veins of the esophagus is characteristic.

The course of the disease is severe, and the prognosis for treatment is almost always unfavorable. In almost all cases, the disease provokes a severe form of liver failure.

What tests and diagnostic methods help identify pathology?

Several different laboratory diagnostic methods are used to identify the disease.

Initially, blood is drawn to study the level of hemoglobin in red blood cells and plasma.

Iron metabolism is also assessed.

The Desferal test helps confirm the diagnosis. To do this, an injection of a glandular preparation is administered, and after five hours a urine sample is taken. Additionally, a CT scan is performed, as well as an MRI of internal organs, which makes it possible to determine their pathological changes - an increase in size, pigmentation, changes in tissue structure.

Molecular genetic scanning allows you to determine the presence of a damaged part of a chromosome. This study, conducted on the patient’s family members, also allows us to assess the possibility of the disease occurring even before the appearance of its clinical manifestations that worry the patient.

Principles of treatment

The main methods of treatment are to normalize iron levels in the body and prevent damage to internal organs and systems. Unfortunately, modern medicine does not know methods for normalizing the gene apparatus.

Bloodletting

A common method of treatment is to perform bloodletting. Initial therapy involves removing 500 mg of blood weekly. After normalization of iron levels, they move on to maintenance therapy, when blood sampling occurs every three months.

Intravenous administration of iron-binding drugs is also practiced. Thus, chelators allow you to remove excess substances through urine or feces. However, the short period of action makes it necessary to regularly inject medications subcutaneously using special pumps.

Laboratory control is carried out once every three months. It includes calculating iron content, as well as diagnosing signs of anemia and other consequences of the disease.

Possible complications and prognosis

With early diagnosis, the disease can be effectively controlled.

The length and quality of life of patients who receive regular care are practically no different from those of healthy people.

In this case, untimely treatment leads to serious complications. These include the development of cirrhosis and liver failure, diabetes, damage to veins, even bleeding.

The risk of developing cardiomyopathy and liver cancer is high, and intercurrent infections are also observed.

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About what hemochromatosis is and how to treat it:

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Hemochromatosis

What is Hemochromatosis -

Primary hemochromatosis (PHC) is an autosomal recessive, HLA-associated disease caused by a genetic defect characterized by a metabolic disorder 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, and liver cirrhosis associated with the accumulation of iron in the body. In 1889, Reclinghausen introduced 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 first 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 understanding of PHC as a rare disease. The prevalence of the PHC gene is 0.03-0.07% - so, until recently, 3-8 cases were observed per 100 thousand population. Among the white population, the frequency of homozygosity is 0.3%, the frequency of heterozygous carriage is 8-10%. Due to improved diagnostics, there is an increase in incidence. The incidence rate among residents of the European community averages 1: 300. According to WHO, 10% of the population is predisposed to hemochromatosis. Men get sick approximately 10 times more often than women.

Pathogenesis (what happens?) during Hemochromatosis:

Normally, the body contains about 4 g of iron, of which g is contained in hemoglobin, myoglobin, catalase and other respirator-bix pigments or enzymes. Iron reserves are 0.5 g, some of which are in the liver, but they are not visible during histological examination of iron using conventional methods. Normally, the human 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 iron absorbed depends on its reserves in the body: the higher the need, the more iron is absorbed. Absorption occurs primarily 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 found in the cytosol. Some of it is bound and stored as ferritin, which is subsequently either used or lost as a result of desquamation of epithelial cells. Some of the iron intended for metabolism in other tissues is transported across the basolateral membrane of the cell and binds to transferrin, the main transport protein for iron in the blood. In cells, iron is deposited in the form of ferritin - a complex of the protein apoferritin with iron. Clumps of broken down ferritin molecules are hemosiderin. Approximately a third of the body's iron stores are in the form of hemosiderin, the amount of 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 approximately 1 g. Ultimately, the intra- and extracellular pools of the body become oversaturated with iron, which allows free iron to enter toxic intracellular reactions. Being a strong redox substance, iron creates free hydroxyl radicals, which, in turn, destroy macromolecules of lipids, proteins and DNA.

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, pituitary gland.
Increased absorption of iron, which leads to its adsorption and accumulation.

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

The genetic nature of PGC was confirmed by M. Simon et al. in 1976, who revealed a close association of the disease with certain antigens of the major histocompatibility complex in representatives of the European population. For clinical expression, the patient must have two PHC alleles (homozygosity). The presence of one HLA haplotype common to the patient indicates heterozygous carriage of the PHC allele. Such individuals may show indirect signs indicating increased iron levels in the body, and the absence of clinically significant symptoms. Heterozygous carriage of the gene predominates over homozygous carriage. If both parents are heterozygotes, a pseudodominant type of inheritance is possible. In heterozygotes, iron absorption is usually slightly increased, a slight increase in iron in the blood serum is detected, but a life-threatening overload of the microelement is not observed. At the same time, if heterozygotes suffer from other diseases accompanied by disorders of iron metabolism, then clinical and morphological signs of the pathological process may appear.

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

Hereditary hemochromatosis was initially considered a simple monogenic disease. Currently, based on the gene defect and clinical picture, 4 forms of PGC are distinguished:

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

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 a protein structure consisting of 343 amino acids, the structure of which is similar to the molecule of the MHC class I system. Mutations in this gene have been identified in individuals suffering from hemochromatosis. Carriers of the C282Y allele in a homozygous state among ethnic Russians number at least 1 per 1000 people. The role of HFE in iron metabolism is demonstrated 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 C282U mutation, HFE is not able to bind to TfR at all, and with the H63D mutation, the affinity for TfR decreases to a lesser extent. The three-dimensional structure of HFE was studied 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 C282U mutation leads to the rupture 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 HFE protein is produced in the deep crypts of the duodenum. Normally, the role of the HFE protein in krypton cells is to modulate the uptake of iron bound to transferrin. In a healthy person, increasing serum iron levels leads to increased iron uptake by deep crypt cells (a process mediated by TfR and modulated by HFE). The C282Y mutation may impair TfR-mediated iron uptake by crypt cells and thus generate a false signal of low iron status in the body.

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

Further research in this direction and analysis of haplotypes suggest that the gene is located between D6 S2238 and D6 S2241. The putative hemochromatosis gene is HLA homologous, and the mutation appears to affect a functionally important region. The gene that controls 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 transferrin-iron complex. Thus, the HFE gene mutation disrupts the transferrin-mediated uptake of iron by duodenal enterocytes, resulting in the formation of a false signal about the presence of low iron content in the body, which, in turn, leads to increased production of the iron-binding protein DCT-1 in the villi of enterocytes and how the consequence is increased iron uptake.

Potential toxicity is explained by its ability, as a variable-valence metal, 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 no excess iron accumulation or tissue damage.

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

Secondary hemochromatosis often develops against the background of blood diseases, porphyria cutanea tarda, frequent blood transfusions, and taking iron-containing drugs.

Symptoms of Hemochromatosis:

Features of clinical manifestations:

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

There are three stages in the development of the disease:

without iron overload due to genetic predisposition;
iron overload without clinical manifestations;
stage of clinical manifestations.

The onset of the disease is gradual. In the initial stage, over a number of years, complaints of severe 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, liver cirrhosis and diabetes.

Pigmentation is one of the common and early symptoms of hemochromatosis. Its severity depends on the duration of the process. Bronze, smoky skin tone is more visible on exposed parts of the body (face, neck, HANDS), on previously pigmented areas, in the armpits, and on the genitals.

In most patients, iron is deposited primarily in the liver. Liver enlargement is observed in almost all patients. The consistency of the liver is dense, the surface is smooth, and in some cases it is painful on palpation. Splenomegaly is detected in 25-50% of patients. Extrahepatic signs are rare. Paired diabetes is observed 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) and gonads. Various types of endocrinopathies occur in more than 80% of patients. The most common form of pathology is diabetes mellitus.

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

A combination of hemochromatosis with arthropathy, chondrocalcinosis, osteoporosis with calciuria, neuropsychiatric disorders, tuberculosis, and porphyria cutanea tarda is possible.

There are latent (including patients with a genetic predisposition and minimal iron overload), with pronounced clinical manifestations, and terminal hemochromatosis. The most common are hepapathic, cardiopathic, and endocrinological forms: respectively, slowly progressive, rapidly progressive, 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 people in the older age group have minimal symptoms in the form of slight weakness, increased fatigue, a feeling of heaviness in the right hypochondrium, pigmentation of the skin on open areas of the body, decreased libido, and slight 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, and impaired pancreatic function (insulin-dependent diabetes mellitus).

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

Such patients have a predisposition to developing a tumor process (the risk of its development in people over 55 years of age increases 13 times compared to 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.

Diagnosis of Hemochromatosis:

Diagnostic features:

Diagnosis is based on multiple organ lesions, cases of the disease in several members of the same family, elevated iron levels, urinary iron excretion, high concentrations of transferrin, ferritin in the blood serum. The diagnosis is likely when combined with diabetes mellitus, cardiomyopathy, hypogonadism and typical skin pigmentation. Laboratory criteria include hyperferremia, increased transferrin saturation index (more than 45%). Serum ferritin levels and urinary iron excretion (desferal test) sharply increase. After intramuscular administration of 0.5 g of desferal, iron excretion increases to 10 mg/day (at a norm of 1.5 mg/day), the IF ratio (iron/TIB) 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 conducted for the presence of C282Y/H63D mutations in a group at risk for developing 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, microelement deposition in the liver can be determined using MRI. The method is based on reducing the signal intensity of the liver overloaded with iron. In this case, the degree of reduction in signal intensity is proportional to iron reserves. The method allows you to determine excess iron deposition in the pancreas, heart and other organs.

On liver biopsy, abundant iron deposition is observed, giving a positive Perls reaction. In a spectrophotometric study, the iron content is over 1.5% of the dry weight of the liver. Importance is attached to the quantitative measurement of iron levels in liver biopsies using atomic absorption spectrometry with subsequent calculation of the liver iron index. The index represents the ratio of iron concentration in the liver (in µmol/g dry weight) to the patient’s age (in years). In case of PHC, already in the early stages, this indicator is equal to or exceeds 1.9-2.0 and does not reach the specified value in other conditions characterized by hemosiderosis of the liver.

In the latent stage of the disease, functional liver tests practically do not change, and according to histological examination, grade 4 hemosiderosis and 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 deposits in macrophages and bile duct epithelium.

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 iron overload:

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

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

Treatment of Hemochromatosis:

Features of the treatment of hemochromatosis:

A diet rich in proteins, without foods containing iron, is indicated.

The most accessible way to remove excess iron from the body is bloodletting. Usually 300-500 ml of blood is removed with a frequency of 1-2 times a week. The number of bloodlettings 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 hemoglobin of red blood cells. Bloodletting is continued 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 cells, CA has a detoxifying effect and helps reduce the severity of degenerative-inflammatory processes. Each patient undergoes 8-10 sessions of CA with further transition to maintenance 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. The drug has high specific activity towards Fe3+ ions. At the same time, 500 mg of desferal can remove 42.5 mg of iron from the body. The duration of the course is 20-40 days. At the same time, cirrhosis, diabetes and heart failure are treated. The frequently observed anemic syndrome in patients with PHC in the presence of excess iron in the liver tissue limits the use of efferent therapy. Our clinic has developed a regimen for the use of recombinant erythropoietin against the background of CA. The drug promotes increased utilization of iron from the body's depot, resulting in a decrease in the total reserves of the microelement and an increase in hemoglobin levels. Reombinant erythropoietin is administered at a dose of 25 mcg/kg body weight during CA sessions performed 2 times a week for 10-15 weeks.

Forecast:

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

The course of the disease is long, especially in older people. Timely therapy prolongs life by several decades. Survival over 5 years in treated patients is 2.5-3 times higher than in untreated patients. The risk of developing HCC in patients with HCC 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 Gastrointestinal tract diseases:

Grinding (abrasion) of teeth

Abdominal trauma

Abdominal surgical infection

Oral abscess

Edentia

Alcoholic liver disease

Alcoholic cirrhosis of the liver

Alveolitis

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Anesthetic management and intensive care

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Anomalies of teeth position

Anomalies of the esophagus

Anomalies in tooth size and shape

Atresia

Autoimmune hepatitis

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Budd-Chiari disease and syndrome

Veno-occlusive liver disease

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Hairy leukoplakia

Gastroduodenal bleeding

Geographic language

Hepatolenticular degeneration (Westphal-Wilson-Konovalov disease)

Hepatolienal syndrome (hepatosplenic syndrome)

Hepatorenal syndrome (functional renal failure)

Hepatocellular carcinoma (hcc)

Gingivitis

Hypersplenism

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Esophageal diverticula

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Esophageal dyskinesia

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Liver dystrophy

Sphincter of Oddi dysfunction (postcholecystectomy syndrome)

Benign nonepithelial tumors

Benign neoplasms of the gallbladder

Benign liver tumors

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Cholelithiasis

Fatty hepatosis (steatosis) of the liver

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Malignant tumors of the bile ducts

Foreign bodies of the stomach

Candidal stomatitis (thrush)

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Xanthogranulomatous cholecystitis

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Malocclusion

Impaired development and eruption of teeth

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Non-alcoholic steatohepatitis

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Examination of patients in emergency surgery

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Acute intestinal obstruction

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Acute gynecological diseases in the practice of a surgeon

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Acute esophagitis

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Acute appendicitis

Acute apical periodontitis

Acute acalculous cholecystitis

Acute viral hepatitis A (AVHA)

Acute viral hepatitis B (AVHB)

Acute viral hepatitis B with delta agent

Patients have the A77D mutation (conversion of alanine to aspartic acid) in the SLC40A1 gene (2q32 locus), which encodes the synthesis of the transport protein ferroportin. The age of onset of the disease exceeds 60 years in men and 70 in women. Distinctive clinical features are: early accumulation of iron in reticuloendotheliocytes and a significant increase in serum ferritin levels even before the increase in transferrin iron saturation coefficient.

Iron overload in newborns.

Neonatal hemochromatosis is a disease of unknown etiology. A characteristic feature of the clinical picture of this type of hemochromatosis is liver failure in newborns. In addition, intrauterine growth retardation is observed.

The disease progresses rapidly, leading to death soon after birth.

Secondary hemochromatosis.

Secondary hemochromatosis occurs when excess iron enters the body (with long-term uncontrolled treatment with iron supplements, with repeated frequent blood transfusions).

There are several types of secondary hemochromatosis:

Post-transfusion secondary hemochromatosis.
Develops in people who undergo repeated massive blood transfusions for chronic anemia.
Nutritional secondary hemochromatosis.
This group includes patients with alcoholic cirrhosis of the liver, hemochromatosis of the African Bantu tribe. The latter was previously called Bantu hemosiderosis. Its cause is the prolonged and excessive intake of iron into the body with alcoholic beverages made in special iron vessels.
Metabolic secondary hemochromatosis.
It develops as a result of disorders of iron metabolism in thalassemia intermedia, in patients with liver cirrhosis after portacaval shunt surgery, in chronic viral hepatitis B and C, in non-alcoholic steatohepatitis, in blockage of the pancreatic duct, cutaneous porphyria, in malignant neoplasms.
Secondary hemochromatosis of mixed origin.
Occurs with thalassemia major and some types of dyserythropoietic anemia.

Epidemiology of hemochromatosis
The incidence of hemochromatosis among residents of the European community ranges from 1:300 to 1:10-12 people.

The incidence rates of hemochromatosis among representatives of the black race are lower than among people of other ethnic groups (0.14:1000 population); at the same time, for example, among the Spaniards these values are higher: 0.27:1000 population.

Hereditary hemochromatosis occurs with a frequency of 1.5-3:1000 in the population. The most common form of hereditary hemochromatosis (more than 95% of all cases) is mediated by two mutations in the HFE gene located on chromosome 6 (hemochromatosis type I): C282Y and H63D.

In the United States, the incidence of primary hemochromatosis is 1:200-500 in the population. In 5.4% of cases, the C282Y mutation is detected in the HFE gene; in 13.5% - the H63D mutation. Homozygotes for the C282Y mutation are 0.25% of the population; homozygous for the H63D mutation - 1.89%.

In the world, 1.9 and 8.1% of the population, respectively, are homozygous for the C282Y and H63D mutations. Hemochromatosis type I is common in Northern Europeans. Thus, approximately 93% of the Irish population are homozygous for the C282Y mutation.

Over the past 20 years, a high prevalence of hereditary hemochromatosis has been revealed in people with human leukocyte antigen HLA-A3, -B7, -B14, -A11 (72-78% HLA-A3 and 20-22% HLA-B14).

Men (mostly aged 40-60 years) are affected more often than women (1.8-3:1). In the United States, the incidence of the disease is 0.034% in women and 0.68% in men.

Men are more likely than women to experience such serious complications of hereditary hemochromatosis as: diabetes mellitus (15.9 and 7.4%, respectively), liver cirrhosis (25.6 and 13.8%, respectively). Women are more likely than men to experience fatigue (64.8 and 425, respectively) and skin hyperpigmentation (48 and 44.9%, respectively).

Clinical symptoms of hemochromatosis develop in men over 40 years of age (average age of onset of the disease is 51 years); in women - after 50 years (the average age of onset of the disease is 66 years).

The mortality rate from hemochromatosis is 1.7:10 thousand deaths. According to autopsy results, this figure is higher: 3:210 thousand deaths.

Mortality rates from hemochromatosis are higher in children and in patients over 50 years of age (5.6: 1 million population). The main causes of death are: cirrhosis, liver cancer, heart failure.

Iron metabolism
The important role of iron for the human body was established back in the 18th century. Iron is indispensable in the processes of hematopoiesis and intracellular metabolism. This element is part of blood hemoglobin, which is responsible for oxygen transport and oxidative reactions. Iron, being a component of myoglobin and hemoglobin, is part of cytochromes and enzymes that take part in redox reactions. Read more: Iron.

Normal body iron stores are 300–1000 mg for adult women and 500–1500 mg for adult men.

The daily requirement for iron is 10 mg in men and 20 mg in women. It is believed that the optimal intensity of iron intake is 10-20 mg/day. Iron deficiency can develop if the intake of this element into the body is less than 1 mg/day.

The amount of iron in the body varies depending on weight, hemoglobin concentration, gender and size of the depot. The largest depot is hemoglobin, in particular in circulating red blood cells. Iron reserves here vary according to body weight, gender and blood hemoglobin concentration and account for approximately 57% of the total iron contained in the human body. For example, a person weighing 50 kg, whose blood hemoglobin concentration is 120 g/l, has a heme iron content of 1.1 g. The amount of non-heme iron stored in the form of ferritin and hemosiderin also depends on age, gender, body size, and in addition , from its loss (from bleeding), pregnancy or iron overload (with hemochromatosis). The tissue iron pool includes myoglobin and a tiny but essential fraction of iron in enzymes. Approximately 9% of iron is contained in myoglobin. There is a “labile pool,” a rapid recycling component that has no specific anatomical or cellular location.

Adequate nutrition and therapy should not only correct the deficiency of iron intake, but also replenish lost iron stores. Safe intake of iron in diet is up to 45 mg/day.

Daily iron loss is approximately 1 mg per day. They are mainly carried out through the digestive tract: desquamation of intestinal epithelial cells (0.3 mg/day), microbleeding and bile losses. Iron is also lost during desquamation of skin epithelial cells and, to a lesser extent, in urine (less than 0.1 mg/day).

In healthy people, compensation for these losses occurs by absorbing iron from food. The normal balance of iron is maintained largely by regulating its absorption. Incoming inorganic iron is solubilized and ionized by acidic gastric juice, and is also reduced to ferrous and chelate forms. Substances that form low molecular weight chelated iron (such as ascorbic acid, sugar and amino acids) promote iron absorption. Normal gastric secretion contains a stabilizing factor and probably an endogenous complex that helps slow the precipitation of dietary iron into the alkaline pH of the small intestine.

The divalent form of iron is more soluble than the trivalent form. Thus, ferrous iron more easily crosses the mucous layer to reach the brush border of the small intestine. There it is oxidized to ferric iron before entering the enterocyte.

In the epithelial cell membrane, iron binds to a receptor protein that moves it into the cell. Apotransferrin from the cytosol of intestinal epithelial cells may accelerate iron absorption. The rate increases with iron deficiency and likely plays a regulatory role by facilitating iron absorption when demand increases.

Most of the iron that is absorbed from the intestinal lumen quickly crosses the epithelial cells in the form of small molecules. Iron entering the plasma is oxidized by ceruloplasmin, which functions as a ferroxidase, and is then taken up by transferrin. 20–30 mg of iron per day usually passes through this route. The portion of cytosolic iron that exceeds the rapid transport capacity combines with apoferritin to form ferritin. Some iron from ferritin may later be released into circulation, but more remains in the mucosal cells until they are shed into the intestinal lumen. The direct entry of iron into the lymphatic vessels is negligible. Ferritin is synthesized by many types of cells, but mainly by the cells of the liver and spleen, which are the main iron stores in the body. The rate of ferritin synthesis is regulated by the intracellular iron content, and part of the formed ferritin enters the circulation through active secretion or reverse endocytosis, and the amount of ferritin circulating in the blood corresponds to iron reserves.

Thus, the transport and storage of iron is carried out by transferrin, transferrin receptor and ferritin.

Extracellular iron compounds also include lactoferrin, which is similar in structure to transferrin, and the heme-binding protein hemopexin.

The main regulator of iron balance is the level of iron absorption in the gastrointestinal tract. When there is a deficiency of iron in the body, the absorption process increases, and when there is an excess, it decreases. Iron absorption occurs in the small intestine and is especially intense in the enterocytes of the duodenum.

The process of iron absorption begins with the migration of pluripotent precursor cells located inside the intestinal crypts to the villi. At the final stage, the precursor cells turn into mature red blood cells capable of transporting iron.
Metabolism of iron in the body of a healthy person.
Only 1 mg/day of iron is absorbed in the gastrointestinal tract. Therefore, the basic need for iron is satisfied through its reutilization from decaying red blood cells, maintaining a constant iron balance in the body, and the reutilization processes are quite intensive.

After absorption from the gastrointestinal tract, iron is transported into the plasma mainly in the form of iron bound to transferrin. The iron-transferrin complex subsequently interacts with transferrin receptor 1 (RTf1), which is present in various organs, particularly the liver and erythropoietic cells.

The half-life of the iron-transferrin complex does not exceed 60-90 minutes. With enhanced erythropoiesis, the half-life of the complex is reduced to 10-15 minutes. Under normal conditions, most of the iron (coming from the intestine (5%) and from the recycling of old red blood cells of the mononuclear macrophage system (95%)) transported by troansferrin is transferred to the bone marrow, where it participates in the synthesis of hemoglobin.

In the bone marrow, the iron-transferrin complex penetrates the cytoplasm of red blood cell precursors, in which iron is released from the complex and incorporated into the heme porphyrin ring. Heme is included in hemoglobin and iron leaves the bone marrow as part of a new red blood cell.

The process of transporting iron by transferrin to the bone marrow occurs 10-20 times a day. Every day, 0.8% of circulating red blood cells are renewed in the adult body. Every 1 ml of blood contains 1 mg of elemental iron. Iron that is not utilized by red blood cell precursors is stored in the spleen, liver and bone marrow in the form of ferritin.

With an excess of dietary or medicinal iron, despite a decrease in its absorption in percentage terms, iron overload develops, the consequences of which are clinically manifested in hemolytic conditions, frequent blood transfusions and in patients with hemochromatosis.

The dominance of one of them (usually cirrhosis of the liver) is characteristic of the early stage of the disease; full-blown symptoms are usually observed in the terminal stage.

As the disease progresses, the following clinical syndromes develop:

Complications of hemochromatosis
As the disease progresses, after the patient develops cirrhosis of the liver, the course of hemochromatosis may be complicated by the occurrence of liver failure.

Almost 30% of patients with hemochromatosis develop liver cancer. The incidence of this complication increases with age. Hepatocellular carcinoma is a common cause of death in hemochromatosis. And the risk of its occurrence in patients with hemochromatosis is 200 times higher than the average in the population. Liver cancer is found in patients with already developed cirrhosis. However, the likelihood of cancer occurring does not correlate with either the degree of liver damage or the effectiveness of treatment.

Complications of hemochromatosis also include: arrhythmias, myocardial infarction, congestive heart failure, bleeding from dilated veins of the esophagus, diabetic and hepatic coma (rarely observed).

Patients with hemochromatosis are prone to various infections (including the development of sepsis), which can be caused by microorganisms that rarely affect healthy people (for example, Yersenia enterocolitica and Vibrio vulnificus).

The liver in patients with hemochromatosis is enlarged, dense, smooth and often painful. The liver can be enlarged in the absence of complaints or with unchanged liver function tests.

In the final stage of the disease, macronodular cirrhosis develops; Splenomegaly is observed in 30-50% of patients.

Signs of skin damage.

In 25% of cases, skin pigmentation is the first sign of the disease. With hemochromatosis, the skin is pale gray in color (due to the deposition of melanin), and areas of brown pigmentation appear on it (bronze skin). At the same time, it is dry and shiny.

Skin pigmentation is diffuse, but most pronounced on the face, neck, extensor surface of the lower forearms, dorsum of the hands, lower legs, genital area and skin scars. The folds of the skin and palms are devoid of pigmentation.

Characteristic is the depletion of hair on the face and torso (in 62% of cases).

In 20% of patients, pigmentation is noted not only of the skin, but also of the mucous membranes (for example, the hard palate).

In 42% of patients, skin atrophy is observed (on the anterior surface of the lower extremities).

About half of patients have koilonychia (spoon-shaped, concave nails).

Diabetes.

Approximately 80% of patients develop non-insulin-dependent diabetes mellitus. Therefore, its symptoms can be detected in patients: thirst, polyuria.

Dysfunction of the endocrine glands.

Hemochromatosis is characterized by dysfunction of the gonads (due to insufficiency of the gonadotropic function of the pituitary gland), which manifests itself in men as testicular atrophy, decreased libido, impotence, azoospermia, gynecomastia, and female-type hair growth; in women - amenorrhea, infertility.

Arthropathy.

Arthropathy develops in 25-50% of patients; most often in patients over 50 years of age. Most often, the small joints of the hands are involved in the pathological process, especially the II and III metacarpophalangeal joints. In the future, progressive polyarthritis can spread to the wrist, hip and knee joints. Joint stiffness gradually develops. Persistent arthralgia caused by chondrocalcinosis of large joints (in most cases, the knee) is often observed.

Symptoms of heart damage.

Signs of heart disease are detected in 20-30% of patients with hemochromatosis: cardiomyopathy and its complications (chronic heart failure, arrhythmias) are the most common causes of death in young patients.

Congestive heart failure (right or left ventricular) develops most often. The heart becomes diffusely enlarged.

A variety of heart rhythm disturbances may be observed: for example, supraventricular extrasystoles and paroxysmal tachyarrhythmias; sometimes - atrial fibrillation, atrial fibrillation and atrioventricular block of varying degrees.

Symptoms of hemochromatosis most often detected during physical examination

Symptoms	Frequency (%)
Hepatomegaly	60-85
Cirrhosis of the liver	50-95
Skin pigmentation	40-80
Arthritis	40-60
Diabetes	10-60
Splenomegaly	10-40
Hair loss	10-30
Testicular atrophy	10-30
Dilated cardiomyopathy	0-30

A decrease in ferritin reflects iron deficiency in iron deficiency anemia.

Carrying out molecular genetic analysis
Molecular genetic diagnosis of hemochromatosis is based on the identification of two common HFE gene mutations - C282Y and H63D, associated with an increased risk of the disease. Diagnosis is carried out within 2-4 weeks. Allows you to confirm the hereditary nature of hemochromatosis and exclude the secondary nature of iron overload.

The diagnosis of hereditary hemochromatosis is established in the presence of homozygous mutations of the HFE gene (C282Y or H63D) or in the identification of complex heterozygotes (a combination of heterozygous mutations C282Y and H63D) in patients with laboratory signs of iron overload. Isolated heterozygous mutations C282Y and H63D occur in a population of healthy people with a frequency of 10.6% and 23.4% of cases, respectively; the presence of these mutations is not a basis for diagnosing hereditary hemochromatosis.

Molecular genetic diagnosis of hemochromatosis is carried out in patients with clinical symptoms of hemochromatosis and/or typical abnormalities in iron metabolism to confirm/clarify the diagnosis, as well as in relatives of such patients in order to diagnose their disease at the preclinical stage and timely start its treatment.

More than 90% of homozygotes with the C282Y mutation develop severe iron overload, which corresponds to an iron content in liver tissue of more than 4500 μg (or 80 mmol) per 1 g of dry weight in an adult patient. This overload occurs in less than 5% of complex heterozygotes.

- X-ray examination of joints.
  X-ray examination of the joints reveals signs of hypertrophic osteoarthritis (cystic changes in sclerotic subchondral bone surfaces, loss of articular cartilage with narrowing of the articular spaces, diffuse demineralization, hypertrophic bone proliferation and calcification of synovial membranes), chondrocalcinosis of the menisci and articular cartilage.
- CT scan of the abdominal organs.
  The study may reveal increased density of liver tissue due to iron deposits or suspect the presence of hemochromatosis. However, if serum iron levels are less than 5 times normal, this method cannot detect signs of iron overload. A CT scan of the liver is also performed to exclude the diagnosis of hepatocellular carcinoma.
- MRI of the abdominal organs.
  The liver of a patient with hemochromatosis in the photographs has a dark gray or black color. MRI is informative in the diagnosis of hemochromatosis with significant overload of internal organs with iron. However, this study cannot eliminate the need to perform a liver biopsy followed by histological examination of the resulting tissue samples. MRI of the liver is also performed to exclude the diagnosis of hepatocellular carcinoma.
  
  On an MRI image of a patient with hemochromatosis, the liver is visualized as a black area of reduced density.
- Evaluation of liver biopsy results.

Survey tactics
Diagnosis of hemochromatosis is based on determining indicators of iron metabolism, since biochemical liver tests for a long time, even at the stage of liver cirrhosis, remain normal and do not correlate with the level of iron accumulation in the liver.

The following changes in laboratory parameters are considered pathognomonic for hemochromatosis:
- Increase in serum iron content to 54-72 µmol/l.
- Increased ferritin content - more than 900 µg/l.
- Decrease in total iron-binding capacity of serum less than 40 µmol/l.
- Decrease in serum transferrin content to less than 2.6 g/l.
- An increase in the transferrin iron saturation coefficient of more than 60% (is a non-invasive informative screening test for the presence of iron overload).
If the coefficient of transferrin saturation with iron is more than 45%, then the next stage of diagnosis should be genetic testing of the patient for the presence of the C282Y and/or H63D mutations.

If the patient is a homozygous carrier of the C282Y, H63D mutations or a compound heterozygous carrier of the C282Y/H63D mutations, then the diagnosis of hereditary hemochromatosis is considered established. To verify the diagnosis in these cases, a liver biopsy is not required.

If the patient’s liver enzyme levels are within normal limits, ferritin levels are less than 1000 mcg/l, and the patient’s age is less than 50 years, then it is necessary to perform a liver biopsy to determine the liver iron index, which is calculated as the ratio of the iron content in liver tissue (in μmol/g dry weight) to the patient's age (in years). If the liver iron index exceeds 1.9, then the diagnosis of hereditary hemochromatosis can be considered established.

Differential diagnosis of hemochromatosis

Differential diagnosis of hemochromatosis must be carried out with the following diseases:

Disease	Overload mechanism
Thalassemia, sideroblastic anemia, congenital dyserythropoietic anemia	Ineffective erythropoiesis + blood transfusion
Blood transfusion, iron supplementation, Bounty syndrome	Excessive iron intake + genetic factor
Atransferrinemia, ceruloplasmin deficiency	Defects in iron transport and metabolism
Porphyria cutanea tarda
Hereditary hemolytic anemia	Inherited linked to the HFE gene
Alcoholism, non-alcoholic steatohepatitis, portacaval shunt	Increased absorption of dietary iron
Local siderosis (pulmonary, hepatic)	Diapedesis of erythrocytes, chronic intravascular hemolysis