Excess iron accumulation and liver damage

Fibrosis and damage to liver cells are directly related to their iron content. The nature of the damage does not depend on the cause of iron accumulation, be it hereditary hemochromatosis or frequent blood transfusions. Fibrosis is most pronounced in the periportal zones - the sites of predominant iron deposition. Feeding rats with iron carbonyl leads to chronic liver damage and fibrosis.

When iron reserves are small, it is stored as ferritin. When there is an excess of iron entering the cell, it is deposited as hemosiderin.

Removal of iron by bloodletting or administration of chelators leads to an improvement in the condition of patients and biochemical indicators of liver function, and a reduction or prevention of its fibrosis.

There are several possible mechanisms of the damaging effect of iron on the liver. Under the influence of iron, lipid peroxidation of organelle membranes increases, which leads to disruption of the function of lysosomes, mitochondria and microsomes, and a decrease in the activity of mitochondrial cytochrome C oxidase. The stability of lysosome membranes is disrupted with the release of hydrolytic enzymes into the cytosol. Animal experiments have shown that iron overload leads to the activation of hepatic stellate cells (lipocytes) and increased synthesis of type I collagen. Currently, the mechanisms of stellate cell activation are being studied. Administration of antioxidants to animals prevents liver fibrosis, despite iron overload.

Other diseases associated with increased iron accumulation

Transferrin deficiency

A case is described in which a child with excessive iron accumulation lacked this iron-binding protein. Hematological changes were consistent with severe iron deficiency, while the tissues contained excess iron. The parents were heterozygous, and the child was homozygous.

Iron overload caused by cancer

It is believed that primary bronchial cancer, which produces abnormal ferritin, may cause excess iron deposition in the liver and spleen.

Porphyria cutanea tarda

The cause of increased iron content in the liver in late cutaneous porphyria is considered to be its combination with heterozygosity for the hemochromatosis gene.

Erythropoietic siderosis

Siderosis is combined with an extremely high level of erythropoiesis. Bone marrow hyperplasia may somehow lead to the absorption of excess amounts of iron by the intestinal mucosa, which continues even with significant iron reserves. Iron is initially deposited in the macrophages of the reticuloendothelial system, then in the parenchymatous cells of the liver, pancreas, and other organs.

Thus, siderosis can develop in diseases accompanied by chronic hemolysis, especially in beta-thalassemia, sickle cell anemia, hereditary spherocytosis and hereditary dyserythropoietic anemia. The risk group also includes patients with chronic aplastic anemia. The development of siderosis is possible even in patients suffering from a mild form of sideroblastic anemia and not receiving blood transfusions.

Siderosis is aggravated by blood transfusions, since iron introduced with blood cannot be eliminated from the body. Clinical signs of siderosis appear after transfusion of more than 100 units of blood. Erroneously prescribed iron therapy increases siderosis.

Siderosis is clinically characterized by increased skin pigmentation and hepatomegaly. In children, growth and development of secondary sexual characteristics are slowed. Liver failure and overt portal hypertension are rare. Fasting glucose levels increase, but clinical signs of diabetes develop extremely rarely.

Although relatively little iron is deposited in the heart, myocardial damage is the major determinant of prognosis, especially in young children. In children, symptoms begin when 20 g of iron (100 units of blood transfusion) accumulate in the body; when 60 g accumulate, death from heart failure is likely.

Treatment of siderosis is difficult. The need for blood transfusions decreases after splenectomy. It is almost impossible to find a well-balanced diet with low iron content. Subcutaneous administration of 2-4 g of deferoxamine into the anterior abdominal wall for 12 hours using a portable syringe pump is effective. However, due to the high cost, this treatment is available only to a few children with hemoglobinopathies. The possibility of treatment with oral iron chelators has been studied experimentally.

Bantu siderosis

This condition occurs in blacks in South Africa who eat porridge fermented in an acidic environment in iron pots. Acidic foods and malnutrition increase iron absorption. In rural areas of sub-Saharan Africa, siderosis still occurs due to the tradition of drinking beer brewed in steel vessels. Studies have shown that both genetic (non-HLA) and environmental factors influence the degree of iron overload in these patients.

Alcoholic cirrhosis

Increased iron deposition in the liver depends on many factors. One of the most common factors is protein deficiency. Increased intestinal iron absorption is found in patients with liver cirrhosis regardless of its etiology. In cirrhosis with pronounced portosystemic collaterals, iron absorption is somewhat enhanced.

Alcoholic beverages, especially wine, contain large amounts of iron. Chronic pancreatitis, which develops in alcoholism, apparently promotes increased iron absorption. Iron overload can also be caused by iron-containing drugs and hemolysis, while gastrointestinal bleeding reduces it.

Iron accumulation rarely reaches the degree characteristic of hereditary hemochromatosis. In alcoholic cirrhosis, iron deficiency develops soon after repeated bloodletting, indicating only a moderate increase in its accumulation in the body. Histologically, signs of alcoholism are detected in the liver along with iron deposition. Determination of the liver iron index allows us to distinguish early hemochromatosis from alcoholic siderosis. The advent of diagnostic methods based on genetic analysis will help to establish that some patients with alcoholic siderosis of the liver may be heterozygotes for hereditary hemochromatosis.

Siderosis due to portocaval shunting

After the application of a portosystemic shunt, as well as with the spontaneous development of portosystemic anastomoses, rapid accumulation of iron in the liver is possible. Shunting is probably the cause of the increased severity of siderosis, often observed in cirrhosis.

Hemodialysis

Significant iron overload of the liver and spleen during hemodialysis treatment can be caused by blood transfusions and hemolysis.

The influence of the pancreas on iron metabolism

In experimental damage to the pancreas, as well as in patients with cystic fibrosis and chronic calcifying pancreatitis, increased absorption and accumulation of iron was found; in patients with cystic fibrosis, absorption of inorganic iron was increased, but not iron bound to hemoglobin. This suggests the presence of a factor in pancreatic secretion that can reduce iron absorption.

Hemochromatosis of the newborn

Neonatal hemochromatosis is a very rare, fatal disease characterized by the development of liver failure in the prenatal period, iron overload of the liver and other parenchymatous organs. The question of whether this is due to a primary disorder of iron accumulation or is the result of some other liver disease, physiologically already saturated with iron, remains unclear. Neonatal hemochromatosis is not related to hereditary hemochromatosis.

Chronic viral hepatitis

Almost half of patients with chronic hepatitis B and C have elevated iron saturation of transferrin and/or serum ferritin levels. Currently, the only reliable method for diagnosing hereditary hemochromatosis is liver biopsy, which allows detecting iron deposition and determining the liver iron index. With high iron content in the liver, the effectiveness of treatment with interferon-a for chronic hepatitis C is reduced. Determining the appropriateness of bloodletting to improve treatment effectiveness requires prospective studies.

Non-alcoholic steatohepatitis

Plasma iron metabolism parameters were altered in 53% of those with alcoholic steatohepatitis, but none of them had hemochromatosis according to the night iron index.

Excessive iron accumulation associated with aceruloplasminemia

Aceruloplasminemia is a very rare syndrome caused by a mutation in the ceruloplasmin gene and accompanied by excess iron deposition, mainly in the brain, liver, and pancreas. Patients develop extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus.

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