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Hemochromatosis is a complex hereditary disorder defined by the body’s inability to regulate iron absorption, leading to a toxic accumulation of this metal in vital organs. In a healthy physiological state, the human body is extremely efficient at conserving iron, absorbing only about one to two milligrams daily from the diet to replace what is naturally lost through sweat and shedding skin cells. This balance is tightly controlled because the body lacks an active mechanism to excrete excess iron. In individuals with hemochromatosis, this regulatory system malfunctions, causing the intestines to absorb iron at a rate two to four times higher than normal.Â
Over years and decades, this surplus iron, which has nowhere to go, is deposited in the liver, pancreas, heart, joints, and pituitary gland. If untreated, this iron overload acts as a slow poison, causing oxidative stress, cellular death, and fibrosis, which can eventually lead to organ failure and chronic disease. At Liv Hospital, we view hemochromatosis not just as a condition of blood chemistry, but as a systemic metabolic disorder that requires a deep understanding of genetics and physiology for effective management.
To understand hemochromatosis, one must first understand how the body normally manages iron. The central regulator of systemic iron balance is a peptide hormone called hepcidin, which is synthesized and secreted by the liver.
The Gatekeeper Function
Hepcidin functions as a negative regulator of iron entry into the plasma. It acts on a protein called ferroportin, which is the only known iron exporter on the surface of cells. Ferroportin is found on the cells that line the intestine (enterocytes) and on immune cells (macrophages) that recycle old red blood cells. When iron levels in the body are high, the liver produces more hepcidin. This hormone binds to ferroportin and degrades it, essentially locking the iron inside the cells and preventing it from entering the bloodstream.
In the most common form of hereditary hemochromatosis, the genetic defect prevents the liver from producing enough hepcidin, or it renders the hepcidin ineffective. As a result, the “gates” on the intestinal cells remain permanently open. The body perceives a false state of iron deficiency and continues to absorb dietary iron aggressively, regardless of how much iron is already stored in the tissues.
Hereditary hemochromatosis is primarily an autosomal recessive disorder linked to the HFE gene located on the short arm of chromosome 6.
This is the most clinically significant mutation. It involves a substitution of tyrosine for cysteine at amino acid position 282 of the protein. Individuals who inherit two copies of this mutation (homozygotes) are at the highest risk for developing severe iron overload. This specific genetic profile accounts for the vast majority of clinical cases in people of Northern European descent.
This is a more common but less severe mutation. It involves a substitution of aspartic acid for histidine at position 63. Being homozygous for H63D rarely leads to significant iron overload unless other risk factors, like fatty liver disease or alcohol use, are present.
Some individuals inherit one C282Y mutation from one parent and one H63D mutation from the other. These compound heterozygotes can develop iron overload, but it is typically milder and presents later in life compared to C282Y homozygotes.
Etiology of Iron Overload
It is crucial for clinicians to differentiate between genetic hemochromatosis and iron overload caused by external factors.
Primary Hemochromatosis
This is the classic genetic form where the defect lies within the DNA itself. It is a lifelong condition present from conception, though the accumulation of iron takes decades to reach toxic levels. The primary defect is the failure of the hepcidin ferroportin axis due to HFE or non HFE gene mutations.
Secondary Hemochromatosis
Also known as secondary hemosiderosis, this condition arises when the iron overload is a consequence of another disease or medical intervention. It is frequently seen in patients with erythropoietic disorders like thalassemia or sideroblastic anemia, where ineffective red blood cell production drives iron absorption. It is also the result of chronic blood transfusions, as each unit of blood delivers a substantial load of iron that the body cannot eliminate. Chronic liver diseases, such as alcoholic cirrhosis or non alcoholic steatohepatitis, can also disrupt hepcidin production, leading to secondary accumulation.
The clinical understanding of hemochromatosis has evolved significantly over the last century.
The disease was first described in the late 19th century by French pathologist Armand Trousseau and later by von Recklinghausen, who noted the triad of skin pigmentation, diabetes, and cirrhosis. The term “bronze diabetes” was coined to describe the darkening of the skin combined with pancreatic failure.
As genetic mapping advanced, researchers discovered a startlingly high prevalence of the HFE mutation in populations of Celtic and Viking origin. This has led to the nickname “The Celtic Curse” or “The Irish Illness.” It is believed that the mutation may have originally provided an evolutionary advantage, helping ancient populations survive on iron poor diets, before becoming a liability in the modern era of iron rich nutrition.
Hereditary hemochromatosis is one of the most common genetic disorders in the Western world.
Approximately one in every 200 to 300 people of Northern European ancestry is homozygous for the C282Y mutation. The carrier rate is even higher, with roughly one in ten people carrying a single copy of the defective gene.
While the genetic defect is inherited equally by men and women, the clinical expression of the disease shows a marked gender bias. Men typically present with symptoms in their 40s or 50s. Women, however, often have a delayed onset, usually presenting 10 to 20 years later than men. This is due to physiological iron losses through menstruation, pregnancy, and lactation, which act as a natural protective mechanism by offloading excess iron and delaying the threshold of toxicity.
While HFE related disease is the most common, there are rarer forms caused by mutations in other genes involved in iron metabolism.
This is a rare and severe form caused by mutations in the hemojuvelin (HJV) or hepcidin (HAMP) genes. Unlike the classic adult onset form, juvenile hemochromatosis causes rapid iron loading early in life. Symptoms often appear in the second or third decade, presenting with severe cardiomyopathy and hypogonadism rather than liver disease.
Mutations in the TFR2 gene cause a form of the disease that clinically mimics classic HFE hemochromatosis but often presents at a slightly younger age.
This is caused by a dominant mutation in the SLC40A1 gene, which encodes ferroportin itself. This form is unique because the iron tends to accumulate in the macrophages rather than the liver cells (hepatocytes), leading to a different pattern of organ damage and often presenting with high ferritin but lower transferrin saturation.
Iron is a transition metal that is vital for life but lethal in excess.
Normally, iron circulates in the blood bound to a protein called transferrin. In hemochromatosis, the transferrin becomes fully saturated, leaving “non transferrin bound iron” (NTBI) to circulate freely. This free iron is eagerly taken up by cells in the liver, heart, and pancreas. Once inside, it catalyzes the formation of reactive oxygen species (ROS) through the Fenton reaction.
These reactive molecules cause oxidative stress, damaging DNA, proteins, and cell membranes. In the liver, this leads to the activation of stellate cells, which produce collagen and scar tissue, resulting in fibrosis. In the pancreas, the iron is toxic to the beta cells, impairing insulin synthesis. In the heart, it disrupts the electrical conduction system and weakens the muscle fibers.
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Hepcidin acts as a hormonal brake that stops the intestines from absorbing too much iron from food.
The genetic mutation originated in Celtic or Viking populations thousands of years ago and was passed down through generations in Northern Europe.
A carrier has one mutated gene and usually stays healthy, while a person with the disease has two mutated genes and risks iron overload.
It is very rare for children to show symptoms of the classic form, but a rare type called juvenile hemochromatosis can affect young people.
No, secondary hemochromatosis is caused by other medical conditions like anemia or blood transfusions, not by an inherited gene defect.
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