Iron overload syndrome is a pathological condition in which excessive accumulation of iron ions (Fe) occurs in the human body, which leads to damage to internal organs. It may have a primary nature due to a genetic mutation or occur a second time against the background of blood and liver diseases, multiple blood transfusions. The clinical picture consists of hyperpigmentation of the skin, arthralgia, disorders of reproductive function. Diabetes mellitus and cardiomyopathy develop. Diagnosis is carried out by determining the level of serum iron, ferritin and transferrin. As a treatment, bloodletting and chelating drugs are prescribed.
E83.1 Iron metabolism disorders
Iron overload syndrome (hemochromatosis) was first described by the French pediatrician A. Trousseau in 1865. The prevalence of the hereditary form of IOS is 1:1,000 people. Mostly men are ill, the ratio with women is 1.8-3:1. Men are more likely to have severe forms of the disease with complications. The average age of the manifestation is from 30 to 50 years. Secondary iron overload occurs in 30-35% of people with liver diseases and in 90-95% with hemoglobinopathies. There are no more accurate epidemiological data on secondary hemochromatosis.
Iron overload syndrome causes
Hereditary hemochromatosis develops due to mutation of the HFE gene. The most common mutations are C282Y and H63D. The HFE gene is located on chromosome 6, at the 6p21.3 locus, encodes the synthesis of a protein that regulates iron metabolism in the gastrointestinal tract. A pronounced clinical manifestation of the disease occurs with a homozygous mutation. Heterozygous carriers have an almost asymptomatic course with a slight increase in the level of Fe. The causes of secondary iron overload are:
- Liver diseases. With non-alcoholic fatty liver disease, chronic viral hepatitis, cirrhosis, hepatocytes die, which suppresses the production of the protein hepsidin, which reduces the level of iron in the blood.
- Chronic alcoholism. In addition to liver damage, prolonged alcohol consumption leads to an increase in the Fe content in the body due to stimulation of its absorption in the small intestine.
- Blood transfusion. Multiple transfusions of blood and its components (erythrocyte mass), which are often performed in patients with hematological diseases (hemolytic anemia, bleeding diathesis, leukemia), are almost always accompanied by iron overload.
- Hemolytic anemia. The development of the syndrome in people with hereditary microspherocytosis, paroxysmal nocturnal hemoglobinuria and hemoglobinopathies is caused by 3 mechanisms: constant hemotransfusions, destruction of erythrocytes with the release of free iron into the blood and incomplete use of iron in the synthesis of hemoglobin, which leads to an increase in the plasma concentration of free Fe.
- Taking iron preparations. Since there are no effective mechanisms for the rapid utilization of excess iron from the body, non-compliance with dosages and the frequency of administration of parenteral forms of iron-containing drugs is often complicated by IOS The development of IOS when taking oral pharmaceuticals with Fe is possible only in heterozygous or homozygous carriers of the HFE mutation.
- Rare reasons. Sideroblastic anemia, porphyria cutanea tarda.
The excess amount of free iron, which is not associated with the transferrin carrier protein, begins to accumulate actively in tissues and organs. The liver, heart muscle and endocrine glands (pancreas, pituitary gland, gonads) are most severely affected. The high reactivity of Fe ions induces oxidative stress and triggers the processes of lipid peroxidation. Cell membranes, organelles and DNA are damaged.
Connective tissue (fibrosis) is actively growing in the liver. Toxic cardiomyopathy develops in the heart. The defeat of beta cells of the pancreas leads to diabetes mellitus. In the pituitary gland, cells that produce hormones that regulate reproductive function (gonadotropins) are mainly damaged. In the epidermis, iron stimulates the formation of the pigment melanin.
By the nature of the origin , there are two types of iron overload syndrome:
- Primary: hereditary hemochromatosis caused by a genetic mutation of proteins involved in Fe metabolism.
- Secondary: develops against the background of other diseases and conditions, is divided into posttransfusion, alimentary, metabolic and mixed.
Symptoms of iron overload syndrome
From the beginning of the pathological accumulation of iron in the internal organs to the appearance of clinical signs, several years pass. With hereditary hemochromatosis, iron overload is more pronounced, so the clinical picture is brighter. Initially, there are nonspecific symptoms – general weakness, increased fatigue, slight weight loss. Then aching pains in the joints join. Proximal interphalangeal, wrist and knee joints are more often affected.
The skin darkens, gradually acquires a brownish or bronze hue. Pigmentation is more clearly represented on the skin of the face, neck and back of the hands. Due to a decrease in the level of sex hormones, libido decreases. Men develop erectile dysfunction, women have a menstrual cycle. Diabetes mellitus is manifested by thirst, increased urination and muscle weakness.
Due to the enlarged liver, the patient is concerned about the severity or pulling pains in the right hypochondrium. Liver damage in patients with primary iron overload syndrome progresses rapidly enough to cirrhosis, the development of which is indicated by an increase in the size of the abdomen due to fluid accumulation in the abdominal cavity (ascites).
The main sign of toxic cardiomyopathy is cardiac arrhythmias, manifested by palpitations and a feeling of heart failure. Arrhythmias are accompanied by dizziness, darkening of the eyes. The continued accumulation of iron in the myocardium leads to a violation of its contractility and the occurrence of congestive heart failure. The patient is concerned about shortness of breath, which increases with exercise, walking and in a horizontal position, swelling on the legs.
Iron overload syndrome is characterized by a wide range of adverse effects. The most common of them are associated with liver damage. These include acute liver failure, massive bleeding from dilated esophageal veins. Almost a third of patients with hereditary hemochromatosis develop hepatocellular carcinoma. A marked decrease in the content of sex hormones can lead to infertility.
Cardiovascular complications include acute heart failure, myocardial infarction, life-threatening arrhythmias (ventricular tachycardia, ventricular fibrillation). Due to diabetes mellitus, acute conditions such as ketoacidosis and hyperosmolar coma may occur. People with a high concentration of Fe in the blood are more sensitive to certain infections, for example, yersiniosis.
Patients are supervised by hematologists or gastroenterologists, depending on the type of pathology and the disease that served as the background for its development. At the survey stage, the primary and secondary IOS are differentiated. When collecting anamnesis, it is clarified which medications the patient takes, whether he drinks alcohol, whether he has had blood transfusions, etc. To confirm the diagnosis , the following procedures are prescribed:
- Laboratory test. In a general blood test, a combination of a high level of total hemoglobin and its low concentration in red blood cells is often determined. Cirrhosis of the liver is characterized by a decrease in the number of all shaped elements (cytopenia). A biochemical blood test reveals hyperglycemia, an increase in glycated hemoglobin and hepatic transaminases (ALT, AST).
- Study of iron metabolism. There is an increase in the content of serum Fe and ferritin, a decrease in the total iron-binding capacity of serum and transferrin. The most objective laboratory indicator of IOS is the percentage of transferrin saturation, the threshold value is > 45%. An increased excretion of Fe in the urine during a desferal test is typical.
- Liver biopsy. The main histological signs of hereditary hemochromatosis are the presence of fibrous strands surrounding the hepatic lobules, the proliferation of cells of small bile ducts. A high concentration of iron (more than 3 mg/g of dry weight) is detected in liver cells.
- Molecular genetic research. If a hereditary form of IOS is suspected, polymerase chain reaction analysis is performed for H63D and C282Y mutations of the HFE gene.
Iron overload syndrome treatment
Hospitalization is mandatory regardless of the form of the syndrome. Diet is of particular importance. Patients need to limit iron–rich foods as much as possible – meat, buckwheat, apples. It is not recommended to take multivitamin complexes containing iron. Do not abuse ascorbic acid, as it increases the absorption of iron in the intestine.
- You need to completely give up alcohol. Due to the frequent development of diabetes mellitus, it is necessary to limit the consumption of easily digestible carbohydrates – chocolate, cakes, cakes. In addition to diet therapy, the treatment of IOS includes the following methods:
- Bloodletting. The most effective procedure for removing excess iron from the systemic circulation. Phlebotomies continue until the target values of laboratory parameters of iron metabolism are reached (ferritin up to 50 ng / ml and transferrin saturation below 50%).
- Chelating therapy. With contraindications to bloodletting (severe liver disease, severe anemia, the need for blood transfusions), medications are prescribed that bind and remove Fe ions from the body – deferoxamine, deferasirox.
Prognosis and prevention
The outcome of iron overload depends on the duration of the disease. The prognosis is directly determined by the timeliness of diagnosis. The life expectancy of patients receiving adequate treatment reaches 20-30 years from the moment of diagnosis, without treatment – about 4-5 years. In the structure of mortality, the main causes of death are liver cirrhosis with hepatic cell insufficiency and toxic cardiomyopathy. Less often, death occurs from decompensation of diabetes mellitus, hepatocellular carcinoma.
There are no effective methods to prevent primary IOS. When a mutation is detected, regular monitoring of serum indicators of iron metabolism is necessary. Prevention of secondary IOS is reduced to the treatment of liver diseases, compliance with dosages of iron preparations, preventive administration of chelators for long-term blood transfusions.
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