Hemochromatosis: Symptoms and Treatment

Brief overview

  • What is hemochromatosis? Disease in which too much iron is stored in the body (iron storage disease).
  • Causes: The primary form is based on gene mutations in proteins that regulate iron metabolism. Secondary hemochromatosis is based on other diseases (congenital or acquired) or on excessive iron intake (especially as infusion).
  • Symptoms: e.g. severe fatigue, irritability, reduced sexual desire, upper abdominal cramps, joint pain
  • Late effects: diabetes mellitus, liver damage, brown discoloration of the skin, severe joint problems and heart damage, impotence, absence of menstruation.
  • Treatment: bloodletting or erythrocytapheresis, medication (iron chelators), organ transplantation if necessary, avoidance of iron-rich foods (such as offal), no alcohol if possible.
  • Prognosis: Normal life expectancy with early treatment. If late damage already exists, the prognosis worsens.

Hemochromatosis: Definition

Depending on the origin, physicians distinguish:

  • primary hemochromatosis: It is genetically determined and thus congenital (also called hereditary hemochromatosis).
  • secondary hemochromatosis: It is acquired due to another disease.

Hemosiderosis

Hemosiderosis is the term used to describe increased iron deposition in the body as a result of increased iron concentration in the blood. The term is sometimes used as a synonym for hemochromatosis or is considered a kind of precursor of it. It is derived from hemosiderin – an iron-containing protein complex: iron can be stored in the body in the form of hemosiderin, primarily in special immune cells called macrophages.

Hemosiderosis does not always have to affect the whole body – it can also occur only locally, for example on the lower legs.

Frequency

Overall, hemochromatosis is found in one to five out of every 1,000 people. The first signs of hemochromatosis are detectable in men between the ages of 20 and 40 and in women usually after menopause.

The disease is responsible for up to two percent of new cases of diabetes mellitus and for up to 15 percent of all liver cirrhosis (shrinking liver).

Hemochromatosis: Symptoms

If hemochromatosis is not treated early, the first obvious iron excess symptoms usually appear between the ages of 40 and 60, and often earlier in men than in women: Diabetes mellitus, liver damage and browning of the skin (hyperpigmentation, bronze diabetes). But heart problems, joint damage and hormone disorders are also among the important hemochromatosis symptoms. However, these are late symptoms. They have become rarer in the meantime because hemochromatosis is now usually detected earlier.

Hemochromatosis symptoms at a glance

In the early stages of iron storage disease, symptoms appear that are primarily nonspecific. These include:

  • severe fatigue
  • irritability, depressive mood
  • susceptibility to infections
  • decreasing sexual desire (libido)
  • change in length and intensity of menstrual bleeding
  • gray-brown discoloration of the skin, increased formation of red spots
  • hair loss or premature graying of the hair
  • cramps in the upper abdomen
  • chest pain (especially on the right side of the body)
  • shortness of breath
  • irregular heartbeat
  • joint pain (especially in knees, hips, and fingers)

Symptoms and late effects in detail

Joints

How joint pain develops in iron storage disease is still unclear.

Liver

The liver is one of the main storage sites for iron and the first organ reached by the blood after passing through the intestine (where iron is absorbed). Iron overload over a long period of time leads to connective tissue remodeling of the liver (hepatic fibrosis) and then to the loss of liver tissue (cirrhosis). The typical symptoms of this are:

  • Loss of performance
  • Loss of appetite
  • Feeling of fullness
  • weight loss
  • in late stages: yellowing of skin and eyes (jaundice), vascular spiders (spider nevi), redness and itching

In about 30 percent of hemochromatosis cases with liver cirrhosis, a malignant liver tumor (liver carcinoma, hepatocellular carcinoma) develops. Thus, the risk of liver cancer is increased 100-fold in hemochromatosis. Other liver diseases such as liver inflammation (hepatitis) can increase the progression of liver damage.

Skin

Pancreas

The pancreas is also stressed by the excess iron in hemochromatosis. Initially, the body cells no longer respond to the blood sugar-lowering pancreatic hormone insulin (insulin resistance). Later, the insulin-producing cells of the pancreas are so damaged by the iron that they can no longer produce sufficient insulin. As a result, diabetes mellitus develops.

Heart

Heart damage is a common cause of death in young hemochromatosis patients. Iron deposits in the heart lead to muscle damage (cardiomyopathy) and cardiac arrhythmias. This can result in heart failure and weakness with risk to life. If heart muscle damage occurs as part of hemochromatosis, transplantation may be required.

Endocrine system

Iron metabolism

The body needs iron for the production of red blood cells (erythrocytes) and for cell survival and growth. In larger quantities, however, the heavy metal is toxic. For this reason, the body must control the iron balance according to need and keep absorption and excretion in equilibrium – so that neither an iron deficiency nor an iron overload occurs.

The body needs 25 milligrams of iron per day. Most of this is obtained from the breakdown of old red blood cells. The rest of the requirement is covered by iron-rich food. Healthy people absorb about ten percent of the iron contained in food in the intestine (about 1 to 2 milligrams per day). In the case of genetic hemochromatosis, on the other hand, up to 20 percent of dietary iron is absorbed.

Absorption and storage of iron

The main part of the body’s iron is stored in the red blood cells (hemoglobin), liver and immune cells (reticuloendothelial system) – for example in the form of ferritin (an iron-protein complex), which can be detected in the blood. Normally, the body stores one to four grams of iron – in hemochromatosis, however, more than twice that amount.

Hemochromatosis: Causes and risk factors

Most often, excess iron is congenital (primary hemochromatosis). Less common is the acquired (secondary) form of iron storage disease.

Congenital (primary) hemochromatosis

The HFE protein presumably binds to the docking sites (receptors) of transferrin on the surface of the cells and blocks them. The transport protein for iron can then no longer bind to its receptor. This promotes the release of hepcidin. This protein in turn inhibits iron absorption from the intestine.

Due to the gene mutation in type 1 primary hemochromatosis, the HFE protein is absent or present in insufficient amounts. As a result, hepcidin is missing as a brake on iron absorption. As a result, too much iron is absorbed in the intestine.

The transport protein transferrin in the blood can no longer transport the increased amount of iron, and the cells can no longer store the excess iron in a stable form. Unstable iron builds up in the blood and damages the body’s cells. This puts a great strain on the affected organs and can result in serious complications. However, it usually takes decades for such organ damage to result.

Acquired (secondary) hemochromatosis

Other possible causes of secondary hemochromatosis are a malformation of the red blood pigment (thalassemia) and abnormal deformability of the red blood cells (sickle cell anemia). Both are genetic disorders.

Acquired diseases that can cause hemochromatosis include myelodysplastic syndrome (MDS; a disorder of blood formation in the bone marrow) and myelofibrosis (connective tissue remodeling of the bone marrow). Both diseases have in common that the turnover of (red) blood cells and thus also of iron is significantly increased.

Hemochromatosis: examinations and diagnosis

Taking your medical history

To clarify a possible hemochromatosis, your doctor will first take your medical history (anamnesis). During the interview, he will ask you the following questions, among others:

  • Were previous blood tests abnormal?
  • Are there any known iron storage diseases in your family?
  • Do you suffer from joint complaints or fatigue?
  • Do you have abdominal or heart complaints?

Physical examination

During the physical examination, your doctor will pay particular attention to signs of heart and liver damage, as well as increased pigmentation of the skin (bronzed diabetes). Joint pain in the index and middle fingers is also typical of hemochromatosis.

Blood tests

Very important for the diagnosis of an iron storage disease are blood values that allow a statement about the iron balance (iron values). In addition, various hormone values can be informative.

Iron values

  • Iron level: If there is too much iron in the blood, the suspicion of hemochromatosis becomes stronger. However, even with normal iron levels, iron storage disease cannot be ruled out with certainty.
  • Ferritin: Low values signal iron deficiency, increased values an enlarged iron store – but not always, because there are other causes for a high ferritin value: dangerous ones like cancer and less dangerous ones like inflammations. In fact, the latter are often the reason for elevated ferritin. Therefore, the ferritin value cannot be evaluated if inflammatory parameters (such as CRP) are elevated at the same time.
  • Transferrin saturation: This indicates how much of the existing transferrin (the most important transport protein for iron) is loaded with the heavy metal. If the saturation exceeds 45 percent, hemochromatosis is suspected. If the saturation is more than 60 percent, the suspicion is even very strong. Normal saturation virtually rules out hemochromatosis.

If a patient has both an elevated ferritin concentration and a high transferrin saturation, iron storage disease is suspected. The patient has too much iron in the blood, so to speak. To confirm the suspicion, a hemochromatosis genetic test should be performed (see below).

Hormone levels

In the case of initial diagnosis or indications of disorders of the endocrine system, appropriate tests should be made. For example, if the physician suspects impaired thyroid function, he or she will determine the thyroid hormones in the blood. Similarly, if there is a suspicion of hypofunction of the sex glands or the adrenal cortex, the corresponding hormones will also be measured.

Genetic test

  • HFE mutation on both gene copies: The patients are homozygous carriers of the gene mutation. The diagnosis of hemochromatosis is thus confirmed, so that the removal of a tissue sample from the liver (liver biopsy) can be dispensed with.
  • HFE mutation on one gene copy only: The patients are heterozygous carriers and usually healthy. However, they should have regular check-ups. If symptoms of hemochromatosis or liver damage develop, either a liver biopsy or further genetic testing is advisable. If the biopsy shows evidence of iron storage disease, other known mutations in iron metabolism can be searched for (i.e. other type of genetic hemochromatosis).

In genetic forms of hemochromatosis, family members should also be screened for hemochromatosis.

Liver examinations

The iron content of the liver can be expressed as liver iron concentration or liver iron index. The latter is obtained by dividing the liver iron concentration by the patient’s age.

Today, biopsy can be replaced by modern technical procedures that do not require tissue removal. These include:

  • Liver susceptometry: this examination method takes advantage of the magnetic properties of iron. However, the procedure is very expensive and rarely used.
  • Magnetic resonance imaging (MRI) of the liver: MRI (also called magnetic resonance imaging) can also be used to estimate the iron content of the liver, but only in late stages of the disease.

Heart function and iron

Damage to the heart muscle and cardiac arrhythmias that can lead to heart failure are a possible cause of death in hemochromatosis. Cardiac function should therefore be checked by cardiac ultrasound (echocardiography) and measurement of cardiac electrical activity (ECG). MRI allows the doctor to assess the iron content (heart iron) and the condition of the heart.

Hemochromatosis: Treatment

The excess iron in the body becomes dangerous if it is not treated. Therefore, the goal of hemochromatosis therapy is to reduce the body’s iron load and thus prevent the progression of hemochromatosis. The following therapies are available for this purpose:

  • Bloodletting or erythrocytapheresis
  • Iron chelators

An adapted diet can also help with iron excess.

In the advanced state of hemochromatosis, severe organ damage may also necessitate organ transplantation.

Bloodletting therapy

In symptomatic hemochromatosis, there are approximately 10 to 30 grams of iron in the body. To bring the iron stores back to normal (up to four grams of iron), 40 to 120 phlebotomies are therefore necessary over a period of one to two years:

  • Initially, phlebotomies are performed once or twice a week. Blood concentrations of ferritin and the red blood pigment (hemoglobin) are measured regularly to monitor progress. A low hemoglobin value indicates anemia. In that case, therapy may need to be interrupted.
  • When the ferritin concentration in the blood has normalized, four to six phlebotomies per year are sufficient.

If family members of a patient with genetic hemochromatosis have elevated ferritin levels, they may be given preventive phlebotomy treatment.

Erythrocytapheresis

This procedure is used, among other things, for patients with anemia due to red blood cell defects. Compared to phlebotomy, erythrocytapheresis allows more red blood cells to be collected per treatment appointment, so patients need to come in for treatment less frequently.

Iron chelators

Drug therapy for hemochromatosis is designed to increase iron excretion via urine and stool. This is achieved with so-called chelating agents or chelators. are substances that bind iron and are then excreted with it. In the past, the active ingredient deferoxamine was administered as a continuous infusion. Today, the active ingredient deferasirox is taken daily as a tablet.

Intensified treatment

If therapy with iron chelators does not respond adequately, severe cardiac damage exists, or rapid iron elimination is necessary for other reasons, drug therapy can be intensified. Such intensive treatment should be carried out in specialized centers. The chelating agents are then administered continuously under the skin or into the vein for 24 hours. Longer intensive administration via this route is also possible.

Risks and side effects

The benefits and risks of treatment with chelation agents should always be carefully weighed up. The active substances are suspected of inhibiting the growth of children.

In adults, gastrointestinal complaints, skin rashes and an increase in liver enzyme concentrations in the blood are typical side effects of iron chelators. Inner ear and visual disturbances, fever, headaches and joint complaints may also occur.

Pregnant women with hemochromatosis should seek advice from specialized centers.

Hemochromatosis: Diet

A strict low-iron diet is very difficult to follow and is also not very effective. For this reason, no specific hemochromatosis diet is recommended.

However, it is advisable to avoid iron-rich foods such as offal. It should also be noted that coffee and tea can reduce iron absorption, while more iron is absorbed in the intestine through the consumption of alcohol. Red wines can also be rich in iron. Therefore, affected individuals should avoid alcohol as much as possible.

Taking vitamin supplements is not recommended.

The best beverage to drink with meals is black tea to reduce iron absorption from food.

Organ transplantation

Hemochromatosis: disease course and prognosis

If hemochromatosis is detected and treated early – before late complications such as cirrhosis of the liver, cardiomyopathy or diabetes mellitus occur – affected individuals have a normal life expectancy.

The prognosis is significantly worse if hemochromatosis is detected late or is not treated. Also, if anemia necessitates frequent blood transfusions, iron overload can progress more rapidly. Most feared is severe heart damage, which can lead to (sudden) heart failure resulting in death. Regular monitoring of organ functions, especially the heart and liver, are therefore absolutely essential.