African iron overload is a condition that involves absorption of too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the liver, bone marrow, and spleen. Humans cannot increase the excretion of iron, although some iron is lost through bleeding or when cells of the intestine (enterocytes) are shed at the end of the cells' lifespan. Iron levels in the body are primarily regulated through control of how much iron is absorbed from the diet.

African iron overload results from a diet high in iron. It is particularly associated with consumption of a traditional African beer that contains dissolved iron from the metal drums in which it is brewed. Some evidence suggests that a genetic predisposition to absorbing too much iron may also be involved.

In African iron overload, excess iron typically accumulates primarily in certain immune cells called reticuloendothelial cells. Reticuloendothelial cells include macrophages in the bone marrow and spleen and Kupffer cells, which are specialized macrophages found in the liver that help protect the body against foreign invaders such as viruses and bacteria. Later in the course of the condition, iron also accumulates in liver cells (hepatocytes). This pattern differs from that seen in a similar iron overload disorder called hereditary hemochromatosis, in which the excess iron accumulates primarily in the hepatocytes.

When too much iron is absorbed, the resulting iron overload can eventually damage tissues and organs. Iron overload in the liver can lead to chronic liver disease (cirrhosis). Cirrhosis increases the risk of developing a type of liver cancer called hepatocellular carcinoma. Iron overload in immune cells may affect their ability to fight infections. African iron overload is associated with an increased risk of developing infections such as tuberculosis. The excess iron also leads to a faster-than-normal breakdown of vitamin C in the body, so affected individuals are at increased risk of vitamin C deficiency problems such as scurvy.

People with African iron overload may have a slightly low number of red blood cells (mild anemia), possibly because the iron that accumulates in the liver, bone marrow, and spleen is less available for production of red blood cells. Affected individuals also have high levels of a protein called ferritin in their blood, which can be detected with a blood test. Ferritin stores and releases iron in cells, and cells produce more ferritin in response to excess amounts of iron.

African iron overload was first noted in rural central and southern African populations among people who drink a traditional beer brewed in uncoated steel drums that allow iron (a component of steel) to leach into the beer. However, not all individuals who drink the beer develop African iron overload, and not all individuals of African descent with iron overload drink the beer. Therefore, researchers are seeking genetic differences that affect the risk of developing this condition.

Some studies have indicated that a variation in the SLC40A1 gene increases the risk of developing increased iron stores in people of African descent. This variation is found in 5 to 20 percent of people of African descent but is not generally found in other populations.

The SLC40A1 gene provides instructions for making a protein called ferroportin. This protein is involved in the process of iron absorption in the body. Iron from the diet is absorbed through the walls of the small intestine. Ferroportin then transports iron from the small intestine into the bloodstream, and the iron is carried by the blood to the tissues and organs of the body. Ferroportin also transports iron out of reticuloendothelial cells in the liver, spleen, and bone marrow. The amount of iron absorbed by the body depends on the amount of iron stored and released from intestinal cells and macrophages.

The SLC40A1 gene variation that some studies have associated with increased iron stores in people of African descent may affect the way ferroportin helps to regulate iron absorption in the body. However, researchers suggest that this variation is not associated with most cases of African iron overload.

Normal Function

The SLC40A1 gene provides instructions for making a protein called ferroportin. This protein is involved in the process of absorbing iron that the body receives from food. Ferroportin transports iron obtained from the diet that is absorbed through the walls of the small intestine into the bloodstream. The iron is carried by the blood to the tissues and organs of the body. Ferroportin also transports iron out of specialized immune system cells (called reticuloendothelial cells) that are found in the liver, spleen, and bone marrow. The amount of iron absorbed during digestion depends on the amount of iron transported from intestinal and reticuloendothelial cells.

The amount of ferroportin available to transport iron is controlled by another iron regulatory protein, hepcidin. Hepcidin attaches (binds) to ferroportin and causes it to be broken down when the body's iron supplies are normal. When the body is low on iron, hepcidin levels decrease and more ferroportin is available to transport iron into the bloodstream so it can be delivered to tissues throughout the body.

Health Conditions Related to Genetic Changes

Hereditary hemochromatosis

Researchers have identified more than 37 mutations in the SLC40A1 gene that cause a form of hereditary hemochromatosis called ferroportin disease, which is also sometimes referred to as type 4 hemochromatosis. This form of the disorder usually begins during adulthood. Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron accumulates in, and eventually damages, the body's tissues and organs.

Almost all SLC40A1 gene mutations change a single protein building block (amino acid) in ferroportin. Abnormal ferroportin proteins cannot transport and release iron from intestinal or reticuloendothelial cells. As a result, the regulation of iron levels in the body is impaired, resulting in iron overload and damage to tissues and organs in the body that is characteristic of hereditary hemochromatosis.

African iron overload

Some studies have indicated that a particular variation in the SLC40A1 gene slightly increases the risk of increased iron stores in people of African descent, which may lead to African iron overload. This effect seems to be more pronounced in men, which may be related to sex differences in the processing of iron.

The SLC40A1 gene variation associated with increased iron stores replaces the amino acid glutamine with the amino acid histidine at position 248 in the ferroportin protein sequence and is written as Gln248His or Q248H. It is found in 5 to 20 percent of people of African descent but is not generally found in other populations. The Q248H variation may affect the way ferroportin helps to regulate iron levels in the body, resulting in an increased risk of African iron overload. People with the variation may inherit an increased risk of this condition, but not the condition itself. Not all people with this condition have the variation in the gene, and not all people with the variation will develop the disorder.

Other Names for This Gene

• Ferroportin 1
• FPN1
• HFE4
• IREG1
• Iron regulated gene 1
• Iron-regulated transporter 1
• MTP1
• S40A1_HUMAN
• SLC11A3
• Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 3
• solute carrier family 40 (iron-regulated transporter), member 1

Genomic Location

African iron overload seems to run in families, and high iron in a family's diet seems to be the major contributor to development of the condition. There also may be a genetic contribution, but the inheritance pattern is unknown. People with a specific variation in the SLC40A1 gene may inherit an increased risk of this condition, but not the condition itself. Not all people with this condition have the variation in the gene, and not all people with the variation will develop the disorder.

African iron overload is common in rural areas of central and southern Africa; up to 10 percent of the population in these regions may be affected. Men seem to be affected more often than women, possibly due to some combination of differences in dietary iron consumption and women's shedding of excess iron through blood loss in menstruation and childbirth.

The prevalence of increased iron stores in people of African descent in other parts of the world is unknown; however, these individuals may be at higher risk of developing mildly increased iron stores than are people of European background.