Hemochromatosis

Hemochromatosis (pigmentary cirrhosis of the liver, bronze diabetes) is a hereditary disease characterized by increased absorption of iron in the intestine and deposition of iron-containing pigments in organs and tissues (mainly in the form of hemosiderin) with the development of fibrosis. In addition to hereditary (idiopathic, primary) hemochromatosis, there is also secondary hemochromatosis, 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 increased absorption of iron in the intestine over many years. Excessive amounts of iron accumulate in the tissues, which can reach 20-60 g. If 5 mg of iron consumed with food is retained in the tissues daily, then it will take about 28 years to accumulate 50 g.

[ 1 ], [ 2 ], [ 3 ]

Causes hemochromatosis

Currently, the role of genetic factors in the development of idiopathic hemochromatosis has been proven. The prevalence of the hereditary hemochromatosis gene (it is localized on the short arm of chromosome VI and is closely associated with the region of the HLA histocompatibility system antigens) is 0.03-0.07% with a heterozygosity frequency 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 link has been established between hereditary hemochromatosis - a congenital enzyme defect leading to the accumulation of iron in the internal organs, and the HLA histocompatibility system antigens - A3, B7, B14, A11.

Molecular genetic mechanisms of hemochromatosis

Sheldon, in his classic monograph, described idiopathic hemochromatosis as an inborn error of metabolism. The discovery of a genetic link between hemochromatosis and 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 frequency is 0.01 (1%). Therefore, at first the defective gene regulating iron absorption was searched for in the region of the HLA-A gene, but it was not found there. Molecular genetic methods made it possible to obtain DNA regions located closer to the telomere and to identify new polymorphic markers. A study of linkage disequilibrium using these markers showed an association of hemochromatosis with D ₆ S ₁₀₅ and D ₆ S ₁₂₆₀. Further studies in this direction and haplotype analysis allow us to consider that the gene is located between D ₆ S ₂₂₃₈ and D ₆ S ₂₂₄₁, 3-4 megabases from HLA-A in the direction of the telomere. A thorough search in a 250-kilobase-long region located between these markers revealed a new gene, designated HLA-H. The mutation of this gene (Cis282Tyr) is found 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 homozygotes for this mutation.

The putative hemochromatosis gene is homologous to HLA, and the mutation appears to affect a functionally important region. However, the protein encoded by this gene, its role in iron metabolism, and thus confirmation that this gene is the hemochromatosis gene remain to be elucidated. Previously, the association between HLA antigens and iron metabolism was demonstrated only in mice with beta ₂ -microglobulin deficiency, in which iron accumulated in parenchymatous organs by an unknown mechanism.

Studies have shown that in about 50% of cases, chromosomes with the defective gene causing hemochromatosis contain between HLA-A and D6S1260 the _{same setof} marker alleles, which is rarely found in people without hemochromatosis. This has been called the ancestral haplotype. It is thought to be the haplotype of the first person to develop hemochromatosis and to contain the recently described mutated gene. Correlating the haplotype with the degree of iron accumulation has shown that the ancestral haplotype is associated with more severe excess iron deposition. In addition, the results of iron level determination suggest that heterozygotes may be protected from iron deficiency. This may provide greater survival and help explain 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 early (before iron accumulation) detection of hemochromatosis in the patient's siblings. However, in the future, hemochromatosis gene mutation analysis will replace this test.

• Heterozygotes

A quarter of heterozygotes have slightly elevated serum iron levels but no excess iron accumulation or tissue damage. However, this may occur if heterozygotes also have other disorders that involve iron metabolism, such as hemolytic anemia.

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

Pathogenesis

To date, no abnormalities in the structure of ferritin or transferrin have been identified in hereditary hemochromatosis. However, a disorder in 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 allows us to exclude a primary defect in the 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 the regulatory protein, the gene for which is localized on chromosome 9. If it is proven that the gene located on chromosome 6 is responsible for the development of hemochromatosis, the description of the protein it encodes will allow us to take a new look at the regulation of iron metabolism.

In idiopathic hemochromatosis, the primary functional defect is a violation of the regulation of iron uptake by the cells of the gastrointestinal mucosa, which leads to unlimited absorption of iron with subsequent excessive deposition of the iron-containing pigment hemosiderin in the liver, pancreas, heart, testicles and other organs (absence of "absorption limitation"). This causes the death of functionally active elements and the development of a sclerotic process. Clinical symptoms of liver cirrhosis, diabetes mellitus, and metabolic cardiomyopathy occur.

A healthy person's body contains 3-4 g of iron, while in hemochromatosis it is 20-60 g. This is due to the fact that in hemochromatosis about 10 mg of iron is absorbed daily, while in a healthy adult it is about 1.5 mg (maximum 2 mg). Thus, in a year, about 3 g of excess iron accumulates in the body of a patient with hemochromatosis. This 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 liver cirrhosis, alcohol abuse, and inadequate protein nutrition.

In liver cirrhosis, the synthesis of transferrin, which binds iron in the blood and delivers it to the bone marrow (for erythropoiesis), to the tissues (for the activity of tissue respiration enzymes) and to the iron depot, is reduced. With a lack of transferrin, iron that is not used for metabolism accumulates. In addition, in liver cirrhosis, 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 a 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 iron deposition in the liver.

In iron-refractory (sideroachrosis) anemia and thalassemia major, the absorbed iron is not used, 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 causes a tissue reaction in the form of fibrosis.

In the early stages of the liver, only fibrosis of the portal zones may be observed, with iron deposition in periportal hepatocytes and, to a lesser extent, in Kupffer cells. Then, fibrous septa surround groups of lobules and irregularly shaped nodes (a picture resembling a holly leaf). The architecture of the liver is partially preserved, although eventually large-nodular cirrhosis develops. Fatty changes are uncommon, and the glycogen content in hepatocytes is normal.

Patients with cirrhosis of the liver with areas of the liver that do not contain iron have an increased risk of developing hepatocellular carcinoma.

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

Pronounced changes develop in the heart muscle, in the fibers of which accumulations of iron-containing pigment are noted. Degeneration of fibers is uncharacteristic, sclerosis of the coronary arteries is often observed.

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

Epidermal atrophy can cause significant thinning of the skin. Hair follicles and sebaceous glands are not expressed. Increased melanin content in the basal layer is characteristic. Iron is usually absent in the epidermis, but is found in its deep layers, especially in the basal layer.

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

The testicles are small and soft. They show atrophy of the germinal epithelium without iron deposition, interstitial fibrosis, and iron is found in the capillary walls.

• Link to alcoholism

Alcoholism is common in patients with clinical manifestations of hemochromatosis, but is rare in relatives with asymptomatic disease. Alcohol abuse can accelerate iron accumulation in individuals genetically predisposed to hemochromatosis. In patients with hemochromatosis, alcohol consumption aggravates liver damage. In an experiment with alcoholic liver damage, adding iron to food led to cirrhosis.

Symptoms hemochromatosis

Hemochromatosis predominantly affects men (the ratio of men to women is 20:1), with full-blown symptoms appearing at the age of 40-60 years. The lower incidence of the disease in women is explained by the fact that women lose iron with menstrual blood over the course of 25-35 years. Excess iron in women is removed during menstruation and pregnancy. Women with hemochromatosis usually (but not always) have no or scanty menstruation, or have a history of hysterectomy or prolonged (over many years) postmenopause. Cases of familial hemochromatosis have been described, in which menstruation was maintained in two women from 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 under 20 years of age, most often it is detected at the age of 40 to 60 years. In children, hemochromatosis is more acute and manifests itself as skin pigmentation, endocrine disorders and heart damage.

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

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

The main symptoms of hemochromatosis:

1. Skin pigmentation (melasma) is observed in 52-94% of patients. It is caused by the deposition of non-iron 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 exposed areas of the body (face, hands), in previously pigmented areas, in the armpits, in the genital area.
2. Liver enlargement is observed in 97% of patients in the advanced stage of the disease; the liver is dense and often painful.

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

Signs of hepatocellular insufficiency are usually absent, ascites is rare. The spleen can be palpated, but it rarely reaches significant sizes. Bleeding from esophageal varices is uncommon.

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 rapid liver enlargement, abdominal pain and ascites. An increase in serum alpha-fetoprotein levels is possible.

4. Endocrine disorders.

Approximately two-thirds of patients develop clinical manifestations of diabetes, which may be complicated by nephropathy, neuropathy, peripheral vascular disease, and proliferative retinopathy. In some patients, diabetes is easily treated, while in others, even large doses of insulin are ineffective. The development of diabetes may be facilitated by hereditary predisposition, liver cirrhosis, which leads to impaired glucose tolerance, and direct damage to the pancreas by iron deposits.

Approximately two thirds of patients have varying degrees of pituitary dysfunction. This may be due to iron deposition in the anterior pituitary gland and is independent of the severity of liver damage or the degree of iron metabolism disorder. Cells producing gonadotropic hormones are selectively affected, which is manifested by a decrease in the basal level of prolactin and luteinizing hormone in the serum and a reduced response to the introduction of thyro- and gonadotropin-releasing hormone and the intake of clomiphene. 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. Testosterone levels increase with the introduction of gonadotropins, which indicates that the testicles remain sensitive to these hormones.

Less common is panhypopituitarism with hypothyroidism and adrenal cortex insufficiency.

5. Heart failure.

Cardiomyopathy is accompanied by an enlarged heart, rhythm disturbances, and gradual development of heart failure resistant to treatment with cardiac glycosides. Congestive heart failure is the cause of death for 35% of patients with hemochromatosis.

ECG changes at diagnosis are observed in 88% of patients with hereditary hemochromatosis. Sometimes, especially in young patients, the disease may first manifest itself with signs of heart failure. Heart disease 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.

Impaired cardiac function is mainly associated with iron deposition in the myocardium and conduction 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 a characteristic arthropathy affecting the metacarpophalangeal joints. The hip and wrist joints may also be affected. Arthropathy may be the first manifestation of hemochromatosis and is due to 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 (in 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 consumption of iron with food and water; alcoholic cirrhosis of the liver; probably Kashin-Beck disease, etc.).
   3. Metabolic (iron metabolism disorder in intermedia B-thalassemia, in patients with liver cirrhosis during the development or imposition of a portocaval anastomosis, during obstruction of the pancreatic duct, cutaneous porphyria, etc.).
   4. Mixed origin (thalassemia major, some types of dyserythropoietic anemia - iron refractory, sideroachrestic, sideroblastic).

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

Diagnostics hemochromatosis

• Laboratory data in hemochromatosis

1. Complete blood count: signs of anemia (not in all patients), increased ESR.
2. General urine analysis: moderate proteinuria, urobilinuria, glucosuria are possible; iron excretion in urine increases to 10-20 mg per day (normal - up to 2 mg/day).
3. Biochemical blood test: serum iron level over 37 μmol/l, serum ferritin over 200 μmol/l, transferrin saturation percentage over 50%, increased ALT, gamma globulins, thymol test, impaired glucose tolerance or hyperglycemia.
4. Decreased blood levels of 11-OCS, 17-OCS, sodium, chlorides, hydrocortisone, decreased daily urinary excretion of 17-OCS, 17-KS, decreased blood and urine levels of sex hormones.
5. Sternal puncture: the puncture fluid contains a high iron content.
6. In skin biopsies - excessive melanin deposition, in liver biopsies - hemosiderin, lipofuscin deposition, picture of micronodular liver cirrhosis. According to research data, the iron content in the liver in primary hemochromatosis increases compared to the norm by almost 40 times, in secondary - by 3-5 times.
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, more than 2 mg of iron is excreted in urine per day.
8. Serum ferritin

Ferritin is the main cellular protein that accumulates iron. Normally, ferritin, detected in the blood serum, contains a small amount of iron, and the function it performs is unknown. Its concentration is proportional to the iron reserves in the body. However, it has diagnostic value only in uncomplicated iron excess and does not allow for a reliable diagnosis of the precirrhotic stage of hemochromatosis. Normal values do not exclude excessive iron accumulation. This indicator can be used to monitor the effectiveness of treatment.

In severe hepatocyte necrosis, serum ferritin levels increase due to its release from liver cells. In addition, high serum ferritin levels are observed in some malignant tumors.

9. Liver biopsy

A liver biopsy is the best method to confirm the diagnosis and can also determine the extent of liver fibrosis or cirrhosis and the degree of iron accumulation. The amount of iron in the biopsy correlates with the total iron stores in the body. In dense fibrotic livers, a liver biopsy can be difficult to perform, but if a biopsy is obtained, it can reveal the characteristic pigmented 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 parenchymatous cells (0-100%). The amount of iron is also determined chemically. If a fresh preparation is not available, tissue embedded in a paraffin block can be examined. Knowing the iron content (in micrograms or micromoles per 1 g of dry weight), the liver iron index is calculated (the iron content in micromoles per 1 g of dry weight divided by the age in years). In patients with hemochromatosis, the iron content in the liver depends on age. It has been shown that the liver iron index allows differentiating 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 have an increase in the ferritin level and/or the saturation percentage.

In the absence of other pathologies (e.g., iron overload caused by blood transfusions, alcoholism, viral hepatitis C, blood diseases), moderate and severe siderosis (3+ to 4+) indicates hereditary hemochromatosis. To confirm the diagnosis, the amount of iron is determined by chemical methods and the liver iron index. In case of mild siderosis (1+ to 2+) or the presence of any concomitant disease (alcoholism, viral hepatitis C), the liver iron index must be determined to exclude hereditary hemochromatosis.

However, in patients with iron overload caused by blood transfusions, this index has no diagnostic value.

To monitor the decrease in iron content during treatment, liver biopsy is not necessary. It is sufficient to determine serum iron metabolism indices.

• 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 detected.
3. Echocardiography: enlarged heart, decreased myocardial contractility.
4. ECG: diffuse changes in the myocardium (decreased T wave, ST interval), prolongation of the QT interval, cardiac arrhythmia.
5. In single-photon emission computed tomography (CT), the degree of liver attenuation correlates with serum ferritin levels, but this method of examination does not allow detection of liver iron overload in cases where its content is less than 5 times the norm (40% of patients).

The accuracy of detection is significantly increased by CT using two energy levels.

Iron, which is a natural paramagnetic contrast agent, can be detected by magnetic resonance imaging. Iron overload significantly reduces the relaxation time in T2 imaging.

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

Differential diagnosis

In cirrhosis not associated with hereditary hemochromatosis (e.g., alcoholic liver disease and viral hepatitis C), serum iron and ferritin levels, as well as transferrin saturation with iron, may sometimes be elevated. The clinical picture also does not always allow for a diagnosis, since the combination of diabetes mellitus and cirrhosis of the liver is not uncommon, and patients with cirrhosis may experience impotence, decreased hairiness, and skin pigmentation. However, in hemochromatosis, the manifestations of hepatocellular insufficiency are usually minimal. Any doubts are resolved by liver biopsy. Although siderosis of the liver is common (57%) in patients with alcoholism, it is rarely significant (7%). Determination of the liver iron index allows differentiation between hereditary hemochromatosis (in which the index is above 1.9) and other causes of excess iron accumulation in the liver.

Treatment hemochromatosis

Iron can be removed by bloodletting; up to 130 mg per day is removed from tissue reserves. Blood regeneration occurs extremely quickly, hemoglobin synthesis accelerates 6-7 times compared to the norm. Large volumes of blood must be removed, since only 250 mg of iron is excreted from 500 ml of blood, while tissues contain 200 times more. Depending on the initial reserves, 7 to 45 g of iron must be removed. Bloodletting of 500 ml is performed once a week, and with the patient's consent - twice 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 treated with bloodletting was significantly higher than that of patients who did not undergo bloodletting and amounted to 8.2 and 4.9 years, respectively, and the mortality rate over 5 years was 11 and 67%, respectively. Bloodletting improves well-being and increases body weight. Pigmentation and hepatosplenomegaly decrease. Biochemical indices of liver function improve. In some patients, diabetes treatment is facilitated. The course of arthropathy does not change. The severity of heart failure may decrease. If the disease is diagnosed in men under 40 years of age, bloodletting may lead to a weakening of the manifestations of hypogonadism. Two observations have been described, when in patients with hemochromatosis, repeated biopsies during treatment revealed a reverse development of cirrhosis. This is apparently explained by the type of fibrosis in hemochromatosis, in which the liver architectonics is preserved.

The rate of iron accumulation ranges from 1.4 to 4.8 mg/day, so after normalizing the iron level, bloodletting with the removal of 500 ml of blood every 3 months is necessary to prevent its accumulation. It is impossible to choose a diet with a low iron content.

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

In addition to diet, insulin is prescribed if necessary to treat diabetes. In some patients, diabetes cannot be corrected.

Cardiac complications are difficult to treat with conventional treatment, but can be reversed with bloodletting.

• Liver transplantation

Survival after liver transplantation in hereditary hemochromatosis is lower than in other diseases (53% vs. 81% at 25 months). Lower survival is associated with cardiac complications and sepsis, which emphasizes the importance of early diagnosis and treatment.

In studies of patients with hemochromatosis who received a healthy liver transplant and patients with other pathologies who received livers from donors with undiagnosed hemochromatosis, it was not possible to establish whether the liver is the site of a metabolic defect.

• Screening of relatives for early detection of hemochromatosis

For early treatment (before tissue damage develops), it is important to screen the patient's immediate family, especially siblings. Normal serum iron and ferritin levels, as well as the degree of transferrin saturation, correspond to normal iron stores. A screening test for hemochromatosis based on a combination of elevated 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 a specificity of 86%. If elevated values of at least one of these parameters persist for a long time, a liver biopsy with determination of the iron content and liver index is indicated. If the diagnosis of hemochromatosis (homozygosity) is confirmed in a relative, he or she should be treated with bloodletting even in the absence of symptoms.

The disease can also be detected by comparing the HLA-A serotype of relatives and the patient. Siblings of the patient who have the same serotype have an increased risk of developing hemochromatosis. In the near future, mutation analysis may be used instead of HLA typing. Heterozygotes do not develop progressive iron overload.

The risk of developing hemochromatosis in the offspring of an affected individual is low, as the odds of a second parent being heterozygous (a carrier) are approximately 1 in 10. However, serum iron and ferritin levels, as well as transferrin saturation, should be measured in all adolescents to detect iron overload early. Once the defective gene responsible for hemochromatosis has been accurately identified, the disease can be diagnosed by mutation analysis.

• Mass screening

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 cost-effective. A selective examination of the population is also justified. Among patients admitted to the rheumatology clinic, hereditary hemochromatosis was detected in 1.5%. Another positive aspect of the study was the detection of iron deficiency in 15% of patients.

[ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ]

Forecast

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

The disease does not affect life expectancy if treatment is started in the precirrhotic stage, before diabetes develops, and if normal iron levels are maintained with bloodletting. This is important to consider when insuring the lives of such patients.

Heart failure worsens the prognosis, and patients with this complication who are not treated rarely survive more than one year. The terminal symptom in such patients is rarely liver failure or bleeding from esophageal varices.

The prognosis for patients with hemochromatosis is better than for 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 approximately 200-fold and does not decrease with the removal of iron 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 frequency of hepatocellular carcinoma due to other causes.

[ 30 ], [ 31 ], [ 32 ], [ 33 ], [ 34 ], [ 35 ]