Hemochromatosis

Content

Introduction

Introduction

Hemochromatosis is a hereditary disease that affects iron metabolism. It is generally recessive in transmission (a person must inherit the mutated gene from both parents to get sick) and is caused by increased absorption of iron in the intestine with consequent progressive accumulation in various organs and tissues, especially the liver, pancreas and heart.

It is not a contagious disease, it was described for the first time in 1865 by the doctor Trousseau and, for a long time, was known as "bronzed diabetes" due to the very dark color of the skin it causes and the onset of diabetes. due to the accumulation of iron in the pancreas.

It is an often underestimated disease for several reasons, including:

  • uncharacteristic initial disturbances (symptoms), such as chronic fatigue, abdominal pain, joint pain
  • relevant clinical manifestations with late onset, on average between 40-50 years of age with a male / female ratio of 5 to 1, particularly before menopause
  • little known disease and tests necessary to ascertain it
  • little difference with alcoholic liver disease, with which it is often confused

Hereditary hemochromatosis is one of the most frequent genetic diseases in Caucasians and in populations originating from Northern Europe reaches a frequency ranging from 1 case per 100 inhabitants, in Ireland, to 1 case per 400 inhabitants, in France.

In Italy, the frequency of the disease is subject to wide differences between the populations of the north, where it is higher (1 case per 500 inhabitants), and the central-southern populations in which it is lower (less than 1 case per 2000 inhabitants). .

It is a disease that, regardless of age, presents itself in an extremely variable way: some forms are completely free of disturbances (asymptomatic), others are very serious.

Environmental factors such as alcohol abuse, viral infections, other diseases, but also other genetic factors, can greatly change the severity of the disease.

Symptoms

Symptoms

The disorders (symptoms) of hereditary hemochromatosis develop slowly and progressively and the disease can go unnoticed until the body's iron accumulation becomes excessive.

Disorders usually begin between the ages of 30 and 60, although they can occur even earlier. They occur earlier in men than in women, especially in comparison with the period preceding menopause. In women of childbearing age, in fact, the loss of iron during the menstrual period and the increased demand for iron during pregnancy somehow compensate for the excessive amount present.

In cases where the disease does not cause disturbances, it can be discovered during periodic checks or carried out for other reasons.

Initial complaints

The most common initial complaints include:

  • chronic fatigue
  • weight loss
  • weakness
  • articolar pains
  • problems getting or maintaining an erection (erectile dysfunction), in men
  • irregular or absent menstruation (amenorrhea), in women

These disorders (symptoms) are quite non-specific as they may also depend on other causes or be simply linked to aging.

Late complaints

As the disease progresses, the following may appear:

  • decreased sexual desire(libido)
  • bronze-colored leather
  • stomach pain (abdomen) and bloating
  • yellowing of the skin and eyes(jaundice)
  • need to drink continuously and to pee frequently
  • severe pain and stiffness in the joints, especially in the fingers
  • chest pain
  • shortness of breath
  • swelling of the hands and feet
  • irregular heartbeat (arrhythmia)
  • smaller testicles, in men

These disorders (symptoms) often form part of the complications of hemochromatosis and, therefore, appear when the disease is not treated from its early stages.

It is important to contact your doctor in the presence of lasting and worrying disorders that could be caused by hemochromatosis, especially in the case of:

  • family origins in Northern Europe
  • siblings or relatives with hemochromatosis, even in the absence of specific disorders. In this case, it is possible to undergo simple tests to know if you are at risk of developing the disease
Causes

Causes

Hereditary hemochromatosis can be caused by various changes in the genetic material (genetic mutations). Depending on the mutated gene, it can occur:

  • type 1 hereditary hemochromatosis, most common form dependent on mutations in a gene called HFE. It is transmitted in an "autosomal recessive" way, which means that the person to be sick must inherit a mutated gene from both parents. The gene HFE it produces a protein that has the task of detecting the amount of iron in the body. If the gene is mutated, the protein it produces is defective and this can cause excessive absorption of iron from food.
    Those who inherit the mutated gene from a single parent, on the other hand, are a healthy carrier of the disease. Also in this case it absorbs more iron than normal but, in general, it does not develop an accumulation of iron such as to create damage to organs and tissues. Hemochromatosis type 1 is quite common in people of Northern Europe. It is uncommon in people of color and rare in the Asian population. However, for reasons not yet known, many people have inherited the mutated gene from both. the parents do not have the typical ailments of the disease
  • type 2 hereditary hemochromatosis, form known as juvenile hemochromatosis because it often occurs in adolescents. It is a rare form that is transmitted in an autosomal recessive way (the person must inherit a mutated gene from both parents to be sick) and is caused by mutations in a gene called HJV (hemogiuvelin) or from mutations in a gene called HAMP (hepcidin). It is a serious form that, if not treated in time, can lead to death by the age of thirty
  • type 3 hereditary hemochromatosis, caused by mutations in the gene for the transferrin receptor (protein that transports iron to all tissues) type 2 (TfR2), is rare and inherited in an autosomal recessive manner (the person must inherit a mutated gene from both parents to be ill )
  • type 4 hereditary hemochromatosis, the only form that is transmitted in an autosomal dominant way (it is enough to inherit a single mutated gene from a parent to get sick), is caused by mutations in the ferroportin gene (SLC40A1). It is more frequent in the population of South European origin

How hemochromatosis is inherited

Genes are present in pairs and one copy is inherited from the mother and one from the father. In the case of hemochromatosis types 1, 2 and 3, all autosomal recessively inherited forms, the disease develops only when the mutated gene is inherited from both parents. This can only happen if both parents carry the mutated gene. If one of the two is a healthy carrier but the other is not, there is no possibility of having a sick child. If, on the other hand, both parents carry the mutated gene, we have:

  • 25% chance (1 in 4) that each child will not inherit the defective genes, does not have hemochromatosis and cannot pass it on
  • 50% chance (1 in 2) that each child will inherit only one copy of the defective gene, from one of the parents and is, therefore, a healthy carrier
  • 25% chance (1 in 4) that each child will inherit copies of the mutated gene from both parents and is, therefore, at risk of developing the disease

In some populations, such as those of Celtic origin (Ireland, Scotland and Wales), it is quite common to be a healthy carrier of a gene HFE mutated (hemochromatosis type 1). However, it should be remembered that being born with two mutated copies of the gene HFE it certainly does not mean developing the disease since, for reasons not yet known, this occurs only in a small percentage of individuals.

Diagnosis

Diagnosis

Identifying hereditary hemochromatosis on the basis of the disorders (symptoms) present can be difficult as they may also be caused by other causes. The assessment (diagnosis) of hemochromatosis is usually done through specific blood tests.

Blood tests

Specific blood tests to ascertain (diagnose) hereditary hemochromatosis are:

  • transferrin saturation, a test that indicates how much iron is present in the blood. It is measured as a percentage and a value greater than 50% indicates accumulation of iron in the body. Transferrin is the protein that transports iron to all tissues, in particular to the bone marrow
  • ferritin, a test that indicates the amount of iron accumulated in the body. Ferritin is a protein that stores iron. Values ​​above 200 micrograms per liter (microg / L) in women and 300 microg / L in men indicate the disease
  • genetic test, performed to identify the mutations responsible for the disease. If the values ​​of the percentage of transferrin saturation and the ferritin level are high, once other causes that can alter these tests have been excluded, the doctor may prescribe a genetic test. Genetic testing is recommended for people with suspected hemochromatosis and should undergo checks to ascertain (diagnose) the disease, that is, to measure iron levels, including all first degree relatives (siblings, parents and children). Genetic analysis allows us to ascertain the most common form of hereditary hemochromatosis, that caused by mutations in the gene HFE (type 1). Hemochromatosis types 2 to 4 are suspected when ferritin and other specific blood tests show iron overload while genetic analysis does not reveal gene mutations HFE (negative result), especially if they are young people

Further investigation

If the results of blood tests indicate the presence of hemochromatosis, to see if the disease has caused damage to organs and tissues, especially the liver, it is necessary to undergo further investigations which include:

  • specific blood tests, to evaluate the functioning of the liver
  • liver biopsy, needed to check for liver damage
  • magnetic resonance, non-invasive technique used to measure the iron content in the liver, very important since liver damage is one of the main complications of hemochromatosis

Other causes of high iron levels

High levels of iron in the body can also be caused by:

  • liver disease, present for a long time
  • thalassemia and sickle cell anemia, diseases that require frequent transfusions
  • drinking beer brewed in iron containers
  • excessive iron intake through supplements or injections
  • dialysis, for an extended time
  • hereditary atransferrinemia, very rare blood disease caused by the deficiency of transferrin, a protein necessary for the transport of iron to all tissues, in particular to the bone marrow, where red blood cells are produced. It is an autosomal recessively inherited disease due to gene mutations TF which contains the indications (coding) for the production of transferrin. It is characterized by severe microcytic anemia (small red blood cells) and is associated with iron overload in the liver and other organs and tissues. If left untreated it can lead to death
  • aceruloplasminemia, an iron storage neurodegenerative disease in the brain that appears in adulthood. Characterized by anemia, retinal degeneration, diabetes and various neurological disorders, it is a very rare inherited disease with autosomal recessive transmission, caused by the complete absence of ceruloplasmin ferroxidase activity due to alterations (mutations) of the ceruloplasmin (CP) gene
Therapy

Therapy

There is no cure for hereditary hemochromatosis, but some treatments are available to reduce the amount of iron that builds up in the body, relieve some ailments, and reduce the risk of developing damage to organs and tissues, particularly the heart, liver, and pancreas.

Phlebotomy

The classic therapy to remove excess iron is simple, well tolerated, effective and consists in removing a quantity of blood (phlebotomy) that varies according to the person's weight, generally around 500 milliliters. Phlebotomy is initially performed once or twice a week until the iron level and the percentage of iron in the transferrin are normalized. In less severe cases, the frequency can be every fortnight or monthly. Thereafter, phlebotomy is performed periodically to keep iron stores within normal levels. The procedure is similar to that of donating blood.

Chelation therapy

To eliminate excess iron, drug-based therapies can also be used to facilitate its elimination through the urine. The treatment is known as chelation therapy and the drugs used are known as chelating agents. A commonly used drug is deferasirox to be taken as soluble tablets once a day. Chelation therapy is considered in a small number of cases, i.e. when regular phlebotomies are not possible due to the difficulty of removing blood frequently, for example in the case of very thin and fragile veins. Your doctor will evaluate and recommend this type of therapy as the drug has not been approved for the treatment of hemochromatosis. This means that there are still no in-depth clinical studies on its use in this type of disease. Your doctor can recommend it if you think so. that the possible benefits outweigh the risks.

Diet and alcohol

Hereditary hemochromatosis occurs in people who follow a normal diet.There are no particular preventive indications, therefore, other than to follow a balanced diet in the quantity, composition and quality of foods, including those containing iron.
Instead, they should be avoided:

  • foods fortified with iron, such as breakfast cereals
  • iron and vitamin C supplements, can be dangerous for people with high iron levels
  • excessive alcohol consumption, alcohol should be consumed in moderation because it can increase iron absorption and, in high quantities, the risk of cirrhosis
  • raw oysters and clams, because they may contain a type of bacterium that can cause very serious infections in people with high iron levels
Complications

Complications

If the hemochromatosis is detected (diagnosed) and treated quickly, complications can be avoided and a normal life can be led. , the person should be kept under close surveillance, however, even at this stage, therapies can improve clinical conditions and survival.

Liver damage

The liver is a very sensitive organ to the effects of iron accumulation and many people with hemochromatosis have varying levels of liver damage, from mild to severe. At the beginning there may be no obvious disturbances (symptoms) but the prescription of specific tests for hemochromatosis can highlight the presence of damage even in the initial phase.

If the liver is damaged and cirrhosis is present, you may have the following disorders:

  • tiredness and weakness
  • loss of appetite
  • weight loss
  • feeling unwell
  • itchy skin
  • pain around the liver area
  • yellowing of the eyes and skin (jaundice)

It is very important to remember that cirrhosis increases the risk of developing liver cancer. In severe cases, surgery and therapies can alleviate the disorders of cirrhosis but, to date, the only way to a complete recovery is a liver transplant.

Diabetes

Diabetes is a disease characterized by too high a level of sugar (glucose) in the blood. It can occur in people with hemochromatosis if the high levels of iron have damaged the pancreas, the organ that produces insulin, the hormone used to transform the glucose introduced in the diet into energy. If the pancreas is damaged, there is not enough insulin production and, as a result, the blood sugar level rises.

Disorders (symptoms) can include:

  • need to urinate more often at night
  • intense thirst
  • tiredness

Lifestyle changes, such as eating healthily and balancedly and exercising regularly, can help, although some people may need to take medications to control their blood sugar levels.

Arthritis

In severe cases of hemochromatosis joint damage, or arthritis, can occur due to high iron levels. Arthritis disorders (symptoms) include:

  • articolar pains
  • joint stiffness
  • joint inflammation

Disorders can be alleviated, where necessary, with pain relievers and steroid medications. In the case of very severe joint damage, it may be necessary to replace the damaged joint with an artificial prosthesis, such as that of the hip or knee.

Heart problems

If iron is deposited in the heart, heart muscle damage, cardiomyopathy and an increased risk of having a heart attack can occur. Heart attack disorders (symptoms) include:

  • shortness of breath
  • extreme tiredness and weakness
  • swelling in the legs, ankles and feet
Bibliography

Bibliography

Hollerer I, Bachmann A and Muckenthaler MU. Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Hematological. 2017, 102: 809-817

Association for the Study of Hemochromatosis and Iron Overload Diseases - ONLUS

Brissot P, Pietrangelo A, Adams PC, De Graaff B, McLuren E and Loreal O. Hemochromatosis [Summary]. Nature Reviews Disease Primers. 2018, 4  

In-depth link

In-depth link

Association for the Study of Hemochromatosis and Iron Overload Diseases - ONLUS

Humanitas research Hospital. Hemochromatosis

Orphanet. Hemochromatosis

NHS. Haemochromatosis (English)

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