Hemochromatosis

Hemochromatosis (pigmentary cirrhosis of the liver , bronze diabetes) is a hereditary disease characterized by increased absorption of iron in the intestine and deposition in organs and tissues of iron-containing pigments (mainly in the form of hemosiderin) with the development of fibrosis. In addition to hereditary (idiopathic, primary) hemochromatosis, there is also a secondary one, which develops against the background of certain diseases.

This disease was first described in 1886 as bronze diabetes. Hereditary hemochromatosis is an autosomal recessive metabolic disorder in which there is an increased absorption of iron in the intestine for many years. An excess amount of iron accumulates in the tissues, which can reach 20-60 g. If 5 mg of iron consumed with food is retained daily in the tissues, then it will take about 28 years to accumulate 50 g.

[1], [2], [3]

Causes of the hemochromatosis

Currently, the role of genetic factors in the development of idiopathic hemochromatosis has been proven. The prevalence of the gene for hereditary hemochromatosis (it is localized on the short arm of chromosome VI and is closely related to the region of antigens of the HLA histocompatibility system) is 0.03-0.07% with a frequency of heterozygosity in the European population of about 10%. Hemochromatosis develops in 3-5 cases per 1000 carriers of the hereditary hemochromatosis gene and is transmitted in an autosomal recessive manner. A relationship has been established between hereditary hemochromatosis, a congenital enzyme defect leading to the accumulation of iron in the internal organs, and the histocompatibility antigens of the HLA-A3, B7, B14, A11 system.

Molecular genetic mechanisms of hemochromatosis

Sheldon, in his classic monograph, described idiopathic hemochromatosis as a congenital metabolic disorder. The discovery of the genetic relationship of hemochromatosis with HLA antigens made it possible to establish that inheritance occurs in an autosomal recessive manner and that the gene is located on chromosome 6. Among the white population, the frequency of homozygosity (disease) is 0.3%, the frequency of heterozygous carriage is 8-10%.

The genetic link with HLA-A is stable, the recombination rate is 0.01 (1%). Therefore, at first, the defective gene regulating iron absorption was searched for in the area of the HLA-A gene, but it was not found there. Molecular genetics methods have made it possible to obtain DNA regions located closer to the telomere and to reveal new polymorphic markers. The study of linkage disequilibrium using these markers showed a relationship of hemochromatosis with D ₆ S ₁₀₅  and D ₆ S ₁₂₆₀. Further studies in this direction and analysis of haplotypes suggest that the gene is located between D ₆ S ₂₂₃₈  and D ₆ S ₂₂₄₁, 3-4 megabases from HLA-A towards the telomere. A careful search in a 250 kilobase region located between these markers revealed a new gene, designated HLA-H. A mutation of this gene (Cis282Tyr) occurs in the chromosomes of patients with hemochromatosis in 85% of cases, while in the control chromosomes its frequency was 3%. 83% of patients with hemochromatosis were homozygous for this mutation.

The putative hemochromatosis gene is homologous to HLA, and the mutation appears to affect a functionally important region. Nevertheless, the protein encoded by this gene remains to be studied, its role in iron metabolism and thus to confirm that this gene is a gene for hemochromatosis. Previously, the relationship between HLA antigens and iron metabolism was proven only in mice with beta ₂ -microglobulin deficiency, in which iron accumulated in parenchymal organs by an unknown mechanism.

Studies have shown that in about 50 % of cases, chromosomes with a defective gene causing hemochromatosis contain the same set of marker alleles between HLA-A and D ₆ S1 ₂ 60, which is rarely found in people without hemochromatosis. It was named the generic haplotype. It is believed to be the haplotype of the first person to develop hemochromatosis and to contain the recently described mutated gene. Comparison of the haplotype with the degree of iron accumulation showed that the generic haplotype is combined with a heavier excess iron deposition. In addition, the results of determining the level of iron suggest that heterozygotes may be protected from iron deficiency. This may provide greater survival and explains why hemochromatosis is one of the most common diseases associated with a single gene mutation.

Since hemochromatosis is closely associated with HLA antigens, their serotyping is important for the early (before iron accumulation) detection of hemochromatosis in the siblings of the patient. However, in the future, mutation analysis of the hemochromatosis gene will replace this study.

• Heterozygotes

A quarter of heterozygotes show a slight increase in serum iron, 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, for example, hemolytic anemia.

[4], [5], [6], [7]

Pathogenesis

To date, no structural abnormalities of ferritin or transferrin have been identified in hereditary hemochromatosis. However, a violation of the process of blocking transferrin receptors in the duodenum (but not in the liver) has been established. The defective gene is located on chromosome 6, which makes it possible to exclude the primary defect in ferritin subunits expressed by genes located on chromosome 11 (subunit H) and 19 (subunit L), transferrin and its receptor expressed by genes on chromosome 3, and a regulatory protein, the gene of which localized on chromosome 9. If it is proved that the gene located on chromosome 6 is responsible for the occurrence of hemochromatosis, the description of the protein encoded by it will allow a new look at the regulation of iron metabolism.

In idiopathic hemochromatosis, the primary functional defect is a dysregulation of iron uptake by cells of the gastrointestinal mucosa, which leads to unrestricted absorption of iron, followed by excessive deposition of the iron-containing pigment hemosiderin in the liver, pancreas, heart, testes and other organs (no "limitation of absorption" ). This causes the death of functionally active elements and the development of the sclerotic process. There are clinical symptoms of liver cirrhosis, diabetes mellitus, metabolic cardiomyopathy.

The body of a healthy person contains 3-4 g of iron, with hemochromatosis - 20-60 g. This is due to the fact that with hemochromatosis about 10 mg of iron is absorbed daily, while in a healthy adult it is about 1.5 mg (maximum 2 mg ). Thus, about 3 g of excess iron accumulates in the body of a patient with hemochromatosis per year. That is why the main clinical signs of hemochromatosis appear approximately 7-10 years after the onset of the disease.

Secondary hemochromatosis most often develops with cirrhosis of the liver, alcohol abuse, and inadequate protein nutrition.

With cirrhosis of the liver, the synthesis of transferrin decreases, which binds iron in the blood and delivers it to the bone marrow (for erythropoiesis), to tissues (for the activity of tissue respiration enzymes) and to the iron depot. With a lack of transferrin, there is an accumulation of iron that is not used for metabolism. In addition, with cirrhosis of the liver, the synthesis of ferritin, which is a form of iron depot, is disrupted.

Alcohol abuse leads to increased absorption of iron in the intestine, which contributes to the more rapid onset of symptoms of hereditary hemochromatosis or liver damage and the development of a secondary form of the disease.

The presence of anastomoses in the portal system enhances the deposition of iron in the liver.

In case of iron refractory (sideroachrsistic) anemia and thalassemia major, the absorbed iron is not used, it turns out to be excessive and is deposited in the liver, myocardium and other organs and tissues.

Pathomorphology of hemochromatosis

Wherever iron is deposited, it triggers a tissue reaction in the form of fibrosis.

In the  liver  in the early stages, only fibrosis of the portal zones with iron deposition in periportal hepatocytes and, to a lesser extent, in Kupffer's cells can be noted. Then fibrous septa surround groups of lobules and nodes of irregular shape (a picture resembling  a holly leaf). The architectonics of the liver is partially preserved, although as a result, large-nodular cirrhosis develops. Fatty changes are uncharacteristic, the glycogen content in hepatocytes is normal.

Patients with cirrhosis of the liver with iron-free areas are at increased risk of developing hepatocellular carcinoma.

In the  pancreas,  fibrosis and parenchymal degeneration with iron deposits in acinar cells, macrophages, islets of Langerhans and in fibrous tissue are detected.

Pronounced changes develop in the heart muscle  ,  in the fibers of which there are accumulations of iron-containing pigment. Degeneration of fibers is uncommon, and hardening of the coronary arteries is often observed.

Iron deposits cannot be detected in the spleen, bone marrow and duodenal epithelium. It is usually absent  in the brain  and  nervous tissue.

Atrophy of the epidermis can cause significant thinning of the  skin. Hair follicles and sebaceous glands are not expressed. An increase in the content of melanin in the basal layer is characteristic. In the epidermis, iron is usually absent, but is found in its deep layers, especially in the basal.

Iron deposition and fibrosis are found  in the endocrine glands,  including the adrenal cortex, the anterior pituitary gland, and the thyroid gland.

The eggs are small and soft in texture. They show atrophy of the embryonic epithelium without iron deposition, interstitial fibrosis, and iron is found in the walls of the capillaries.

• Link to alcoholism

Alcoholism often occurs in patients with clinical manifestations of hemochromatosis, but rarely in relatives with an asymptomatic course of the disease. Alcohol abuse can accelerate iron accumulation in individuals with a genetic predisposition to hemochromatosis. In patients with hemochromatosis, alcohol consumption worsens liver damage. In an experiment with alcoholic liver damage, the addition of iron to food led to cirrhosis.

Symptoms of the hemochromatosis

Mostly men suffer from hemochromatosis (the ratio of men and women is 20: 1), the detailed symptoms of hemochromatosis appear at the age of 40-60 years. The lower incidence of the disease in women is due to the fact that women lose iron through menstrual blood within 25-35 years. Excess iron in women is removed during menstruation and pregnancy. In women with hemochromatosis, menstruation is usually (but not always) absent or scanty, or there is a history of hysterectomy or prolonged (over many years) postmenopause. Observations of familial hemochromatosis are described, in which menstruation persisted in 2 women belonging to different generations. Familial juvenile hemochromatosis has also been described. In men, symptoms of hemochromatosis appear at a younger age than in women.

Hemochromatosis is rarely diagnosed in patients younger than 20 years old, most often it is detected between the ages of 40 and 60 years. In children, the disease hemochromatosis is more acute and is manifested by skin pigmentation, endocrine disorders and heart damage.

The classic symptoms of hemochromatosis: lethargy, apathy, skin pigmentation, enlarged liver, decreased sexual activity, hair loss in areas of secondary hair growth, often diabetes mellitus.

The possibility of hemochromatosis should be considered in all cases of asymptomatic hepatomegaly in a man with practically normal biochemical parameters of liver function. Given the high frequency of heterozygotes in the population, we believe that the disease develops more often than it is diagnosed. From the moment the first symptoms appear until the diagnosis is established, an average of 5-8 years pass.

The main symptoms of hemochromatosis:

1. Skin pigmentation (melasma) is observed in 52-94% of patients. It is caused by the deposition of iron-free pigments (melanin, lipofuscin) and hemosiderin in the epidermis. The severity of pigmentation depends on the duration of the disease. The skin has a smoky, bronze, grayish color, most noticeable on open areas of the body (face, hands), on previously pigmented areas, in the armpits, in the genital area.
2. An enlarged liver  is observed in 97% of patients in the advanced stage of the disease, the liver is dense, often painful.

In 37% of cases, abdominal pain is noted, usually dull, accompanied by soreness of the liver. However, the pain is sometimes so intense that it simulates a sharp abdomen and can collapse and lead to sudden death. The mechanism of these clinical manifestations is unclear. A certain role is attributed to the release of ferritin from the liver, which has vasoactive properties.

Signs of hepatocellular failure are usually absent, and ascites is rare. The spleen can be palpated, but it rarely reaches a significant size. Bleeding from varicose veins of the esophagus is not common.

Primary liver cancer develops  in  15-30% of patients with cirrhosis. It can be diagnosed at the first clinical manifestations of the disease, especially in elderly patients. It should be suspected when the patient's condition worsens, accompanied by a rapid increase in the liver, abdominal pain and ascites. Possibly increased serum alpha-fetoprotein levels

4. Endocrine Disorders.

Approximately two thirds of patients develop clinical manifestations of diabetes, which can be complicated by nephropathy, neuropathy, peripheral vascular disease and proliferative retinopathy. In some patients, diabetes is easily treatable; in others, even large doses of insulin have no effect. The development of diabetes can be promoted by hereditary predisposition, cirrhosis of the liver, which leads to impaired glucose tolerance, direct damage to the pancreas by iron deposits.

In about two-thirds of patients, there is a dysfunction of the pituitary gland of varying severity. It can be caused by iron deposition in the anterior pituitary gland and not depend on the severity of liver damage or the degree of iron metabolism disorder. Cells that produce gonadotropic hormones are selectively affected, which is manifested in a decrease in the basal level of prolactin and luteinizing hormone in the serum and a reduced response to the administration of thyro- and gonadotropin and clomiphene intake. Insufficiency of the gonadotropic function of the pituitary gland leads to testicular atrophy, impotence, loss of libido, skin atrophy and hair loss in areas of secondary hair growth. The level of testosterone with the introduction of gonadotropins increases, which indicates the preserved sensitivity of the testicles to these hormones.

Less common is panhypopituitarism with hypothyroidism and adrenal insufficiency.

5. Heart failure.

Cardiomyopathy is  accompanied by an enlargement of the heart, rhythm disturbances, and the gradual development of heart failure that is resistant to treatment with cardiac glycosides. 35% of patients with hemochromatosis die from congestive heart failure.

Changes in the ECG at the time of diagnosis are observed in 88% of patients with hereditary hemochromatosis. Sometimes, especially in young patients, the disease may first manifest itself as signs of heart failure. Heart damage is characterized by progressive failure of the right sections, rhythm disturbances, and sometimes leads to sudden death. It may resemble constrictive pericarditis or cardiomyopathy. The heart is often spherical. "Iron heart" is a weak heart.

Dysfunction of the heart is mainly associated with the deposition of iron in the myocardium and the conducting system.

6. Metabolic malabsorption syndrome  is caused by dysfunction of the small intestine and pancreas due to the deposition of iron-containing pigment in these organs.
7. Arthropathy

Approximately two thirds of patients develop characteristic arthropathy that affects the metacarpophalangeal joints. The hip and wrist joints can also be affected. Arthropathy may be the first manifestation of hemochromatosis and is caused by acute synovitis caused by the deposition of calcium pyrophosphate crystals. X-ray examination reveals a picture of hypertrophic osteoarthritis, chondrocalcinosis of the menisci and articular cartilage.

Symptoms of hemochromatosis can manifest themselves for a long time (15 years or more), with the development of liver cirrhosis, life expectancy does not exceed 10 years. With secondary hemochromatosis, life expectancy is shorter.

[8], [9], [10], [11]

Forms

1. Hereditary (idiopathic, primary) hemochromatosis.
2. Secondary hemochromatosis, forms:
   1. Post-transfusion (for chronic anemia, in the treatment of which blood transfusions are used for a long time).
   2. Alimentary (hemochromatosis of the African Bantu tribe due to excessive intake of iron with food and water; alcoholic cirrhosis of the liver; probably Kashin-Beck disease, etc.).
   3. Metabolic (violation of iron metabolism in intermediate B-thalassemia, in patients with cirrhosis of the liver with the development or imposition of a portocaval anastomosis, with blockage of the pancreatic duct, cutaneous porphyria, etc.).
   4. Mixed origin (thalassemia major, some types of dyserigropoietic anemia - iron refractory, sideroachrestic, sideroblastic).

[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24],

Diagnostics of the hemochromatosis

• Laboratory data for hemochromatosis

1. Complete blood count: signs of anemia (not in all patients), increased ESR.
2. General urine analysis: moderate proteinuria, urobilinuria, glucosuria are possible; the excretion of iron in the urine increases to 10-20 mg per day (the norm is up to 2 mg / day).
3. Biochemical blood test: the level of serum iron is more than 37 μmol / L, serum ferritin is more than 200 μmol / L, the percentage of transferrin saturation with iron is more than 50%, an increase in ALT, gamma globulins, thymol test, impaired glucose tolerance or hyperglycemia.
4. Decrease in blood levels of 11-OCS, 17-OCS, sodium, chlorides, hydrocortisone, decrease in daily urinary excretion of 17-OCS, 17-KS, decrease in blood and urine levels of sex hormones.
5. Sternal puncture: the punctate has a high iron content.
6. In biopsies of the skin - excessive deposition of melanin, in biopsies of the liver - deposition of hemosiderin, lipofuscin, a picture of micronodular cirrhosis of the liver. According to research data, the iron content in the liver in primary hemochromatosis increases by almost 40 times compared to the norm, and by 3-5 times in secondary hemochromatosis.
7. Desferal test - based on the ability of desferal to bind iron ferritin and hemosiderin and remove it from the body. The test is considered positive if, after intramuscular administration of 0.5-1 g of desferal per day, more than 2 mg of iron is excreted in the urine.
8. F erritin serum

Ferritin is the main cellular protein that stores iron. Normally, serum ferritin contains small amounts of iron, and its function is unknown. Its concentration is proportional to the body's iron stores. However, it has diagnostic value only with an uncomplicated excess of iron and does not allow to reliably diagnose the pre-cirrhotic stage of hemochromatosis. Normal values do not exclude excess iron accumulation. This indicator can be used to monitor the effectiveness of treatment.

With severe necrosis of hepatocytes, the serum ferritin level increases due to its release from liver cells. In addition, high serum ferritin levels are observed in some cancers.

9. Puncture liver biopsy

Puncture liver biopsy is the best method for confirming the diagnosis, and also allows you to determine the severity of fibrosis or cirrhosis of the liver and the degree of iron accumulation. The amount of iron in the biopsy specimen correlates with the total iron storage in the body. Puncture biopsy can be difficult with dense fibrosed liver, but if biopsy is obtained, it can reveal characteristic pigmentary cirrhosis.

Liver sections are stained with Perls reagent. The degree of iron accumulation is assessed visually (from 0 to 4+) depending on the percentage of stained parenchymal cells (0-100%). The amount of iron is also determined by chemical methods. If there is no fresh specimen, you can examine the tissue embedded in the paraffin block. Knowing the iron content (in micrograms or micromoles per 1 g of dry weight), the hepatic iron index is calculated (the iron content in micromoles per 1 g of dry weight, divided by age in goals). In patients with hemochromatosis, the iron content in the liver depends on age. It has been shown that the hepatic iron index makes it possible to differentiate homozygotes (index above 1.9) from heterozygotes (index below 1.5) and patients with alcoholic liver disease. Both heterozygotes and patients with alcoholic liver disease may experience an increase in ferritin levels and / or percent satiety.

In the absence of other pathology (for example, iron overload caused by blood transfusions, alcoholism, viral hepatitis C, blood diseases), moderate and severe siderosis (from 3+ to 4+) indicates hereditary hemochromatosis. To confirm the diagnosis, the amount of iron is determined by chemical methods and the hepatic iron index. With mild siderosis (from 1+ to 2+) or the presence of any concomitant disease (alcoholism, viral hepatitis C), in order to exclude hereditary hemochromatosis, it is necessary to determine the hepatic iron index.

However, in patients with blood transfusion-induced iron overload, this index has no diagnostic value.

Liver biopsy is not necessary to monitor for iron deficiency during treatment. It is sufficient to determine serum iron metabolism parameters.

• Instrumental data

1. Ultrasound and radioisotope scanning: enlargement of the liver, pancreas, diffuse changes in them, splenomegaly.
2. FEGDS: with the development of liver cirrhosis, varicose veins of the esophagus and stomach are revealed.
3. Echocardiography: an increase in the size of the heart, a decrease in the contractile function of the myocardium.
4. ECG: diffuse changes in the myocardium (decreased T wave, ST interval), lengthening of the QT interval, heart rhythm disturbances.
5. With single-photon emission computed tomography (CT), the degree of signal attenuation by the liver correlates with the level of serum ferritin, but this method of investigation does not reveal an overload of the liver with iron in cases where its content is less than 5 times the norm (40% of patients).

The accuracy of the determination is significantly improved with CT using two energy levels.

Iron, which is a naturally occurring paramagnetic contrast agent, can be detected by magnetic resonance imaging. With iron overload, the relaxation time is significantly reduced when examining in the T2 mode.

Although CT and MRI can detect significant iron overload, they do not accurately determine its concentration in the liver.

Differential diagnosis

In cirrhosis not associated with hereditary hemochromatosis (for example, alcoholic liver disease and viral hepatitis C), serum iron and ferritin levels and the saturation of transferrin with iron may sometimes increase. The clinical picture also does not always allow a diagnosis to be made, since the combination of diabetes mellitus with cirrhosis of the liver is often found and patients with cirrhosis may experience impotence, a decrease in hairiness and skin pigmentation. However, in hemochromatosis, the manifestations of hepatic cell failure are usually minimal. All doubts are resolved with a liver biopsy. Although alcoholic patients often (57%) have liver siderosis, it is rarely significant (7%). Determination of the hepatic iron index makes it possible to differentiate hereditary hemochromatosis (in which the index is higher than 1.9) and other causes of excessive accumulation of iron in the liver.

Treatment of the hemochromatosis

Iron can be removed by bloodletting; at the same time, up to 130 mg per day is removed from tissue reserves. Blood regeneration occurs extremely quickly, hemoglobin synthesis is accelerated 6-7 times compared to the norm. It is necessary to remove large volumes of blood, since only 250 mg of iron is excreted from 500 ml of blood, and the tissues contain 200 times more. Depending on the original stock, it is required to remove from 7 to 45 g of iron. Bloodletting of 500 ml is performed once a week, and with the consent of the patient - 2 times a week until the levels of iron and ferritin in the serum, as well as the degree of saturation of transferrin with iron, decrease to the lower limit of the norm. The average life expectancy of patients who were treated with bloodletting turned out to be significantly longer than that of patients who did not produce bloodletting, and amounted to 8.2 and 4.9 years, respectively, and mortality over 5 years - 11 and 67%, respectively. Bloodletting helps to improve well-being and increase body weight. Decreases pigmentation and hepatosplenomegaly. Biochemical indicators of liver function are improved. Some people get better diabetes treatment. The course of arthropathy does not change. The severity of heart failure may decrease. If the disease in men is diagnosed before the age of 40, phlebotomy can lead to a weakening of the manifestations of hypogonadism. There are described 2 observations, when patients with hemochromatosis with repeated biopsies in the course of treatment revealed the reverse development of cirrhosis. This, apparently, is explained by the type of fibrosis in hemochromatosis, in which the liver architectonics is preserved.

The rate of iron accumulation varies from 1.4 to 4.8 mg / day, therefore, after the normalization of the level of iron, to prevent its accumulation, it is necessary to perform bloodletting every 3 months with the removal of 500 ml of blood. A diet low in iron is impossible to find.

Gonadal atrophy can be treated with intramuscular replacement of long-acting testosterone preparations. Human chorionic gonadotropin injections can increase testicular volume and sperm count.

To treat diabetes, in addition to diet, insulin is prescribed if necessary. In some patients, diabetes is not amenable to correction.

Complications from the heart do not respond well to conventional treatment, but may reverse with bloodletting.

• Liver transplant

The survival rate after liver transplantation with hereditary hemochromatosis is lower than with other diseases (53% versus 81% after 25 months). Lower survival is associated with cardiac complications and sepsis, highlighting the importance of early diagnosis and treatment.

When observing patients with hemochromatosis who underwent healthy liver transplantation, and patients with other pathologies who received liver transplants from donors with undiagnosed hemochromatosis, it was not possible to establish whether the liver is the site of a metabolic defect.

• Examination of relatives for early detection of hemochromatosis

For early treatment (before tissue damage develops), it is important to examine the patient's immediate family, especially siblings. Normal iron and serum ferritin levels and transferrin saturation are matched by normal iron stores. The screening test for hemochromatosis, based on a combination of increased transferrin saturation (more than 50%) and serum ferritin levels (more than 200 μg / L in men and 150 μg / L in women) in young homozygotes, has a sensitivity of 94%, and specificity equal to 86%. If elevated values of at least one of these indicators persist for a long time, a liver biopsy is indicated with the determination of the content and hepatic iron index. When the diagnosis of hemochromatosis (homozygosity) is confirmed in a relative, it must be treated with bloodletting even in the absence of symptoms.

The disease can also be detected by comparing the HLA-A serotype of the relatives and the patient. Brothers and sisters of a patient who have the same serotype with him have an increased risk of developing hemochromatosis. In the not too distant future, it will be possible to perform mutation analysis instead of HLA typing. Heterozygotes do not develop progressive iron overload.

The risk of developing hemochromatosis in the patient's children is small, since the likelihood that the second parent will be heterozygous (carrier) is approximately 1:10. However, for early detection of iron overload in all adolescents, it is necessary to measure serum iron and ferritin levels and the degree of transferrin saturation with iron. When the defective gene responsible for the development of hemochromatosis is accurately identified, it will be possible to diagnose the disease using mutation analysis.

• Mass survey

Mass determination of the degree of transferrin saturation with iron in representatives of the Caucasian race to identify patients with hereditary hemochromatosis turned out to be economically profitable. A sample survey of the population is also justified. Among the patients admitted to the rheumatological clinic, hereditary hemochromatosis was found in 1.5%. Another positive aspect of the study was the identification of iron deficiency in 15% of patients.

[25], [26], [27], [28], [29], [30]

Forecast

The prognosis of hemochromatosis is largely determined by the degree and duration of iron overload. Therefore, early diagnosis and treatment are essential.

The disease does not affect life expectancy if treatment is started in the pre-cirrhotic stage, before the onset of diabetes mellitus, and if normal iron levels are maintained with bloodletting. It is important to consider this when insuring the life of such patients.

Heart failure worsens the prognosis, and untreated patients with this complication rarely live more than one year. The terminal sign in such patients is rarely liver failure or bleeding from varicose veins of the esophagus.

The prognosis in patients with hemochromatosis is better than in patients with alcoholic cirrhosis who have stopped drinking alcohol. However, the severity of the disease in patients with hemochromatosis is significantly aggravated if they abuse alcohol.

The risk of developing hepatocellular carcinoma in patients with hemochromatosis in the presence of liver cirrhosis increases by about 200 times and does not decrease when iron is excreted from the body. In a small proportion of patients with hemochromatosis (about 15%), hepatocellular carcinoma develops in the absence of cirrhosis, i.e. With a frequency similar to the incidence of hepatocellular carcinoma due to other causes.

[31], [32], [33], [34], [35], [36]