- Hereditary hemochromatosis (HH) is a genetic disorder that causes excess iron retention in the body. This disorder is a common among Caucasians of Northern European origin.
- In normal individuals, the balance of iron concentration in the body is regulated by the amount of iron stored in the body. Iron may be lost in the sweat, shed from the skin, and excreted from the cells in the intestines. Approximately 1 milligram of iron is lost from the body daily via these routes in a healthy individual. More iron can be lost in women during menstruation. Normally, 1 milligram of iron is regained daily by the intestines from dietary sources.
- In hemochromatosis, this regulatory mechanism is impaired and an excess amount of iron is absorbed from the intestines regardless of the iron stores already in the body, resulting in iron overload. Because the body does not have a mechanism to rid the excess iron, this imbalance between gains and losses results in accumulation of the extra iron in some of the organs in the body.
- The iron overload in hereditary hemochromatosis can affect many organs in the body including the:
- thyroid, and
- As a result of this excess iron build-up in the organs, hemochromatosis can be manifested by dysfunction of the involved organ(s). Signs may include:
- It is important to note that some individuals may not have any signs or symptoms associated with hemochromatosis.
- Hereditary hemochromatosis is an autosomal recessive genetic abnormality, meaning that both copies of the involved gene (one from each parent) are abnormal. The genetic abnormality in hereditary hemochromatosis affects the so-called HFE gene which was discovered in 1996.
As mentioned earlier, hemochromatosis is a genetic hereditary disorder. In each individual, there are 23 pairs of chromosomes (carrying genetic information) in every cell in their body. Each of these pairs contains one chromosome from each parent. Chromosomes contain DNA which carries the genetic blueprint of all the activities and functions in the human body. Small disturbances in the DNA structure (mutations) can potentially result in genetic conditions which can be passed on to offspring.
Hereditary hemochromatosis is thought be the result of a genetic mutation. This condition is inherited in an autosomal recessive fashion, meaning both genes (one from each parent) have a specific mutation. This is in contrast to conditions termed autosomal dominant, in which only one defective gene from a single parent needs to be inherited in order to manifest the condition.
The HFE gene responsible for hereditary hemochromatosis is located on chromosome number 6. The primary mutations for hereditary hemochromatosis are the C282Y, H63D, or S65C. These numbers specify the location of the mutation on the HFE gene. Based on genetic testing, a majority (up to 95%) of cases of hereditary hemochromatosis are caused by homozygote C282Y mutations, that is to say both genes (one from each parent) have inherited this specific mutation. Some cases may be inherited in a heterozygous pattern, meaning the C282Y abnormality comes from one parent and either the H63D or S65C mutation comes from the other parent.
Iron accumulation from hereditary hemochromatosis can affect many organs in the body, leading to a variety of possible symptoms. Many individuals with hemochromatosis may not have any symptoms or disease manifestations at all, especially early in the course of the disease or in those with heterozygous genes. Some heterozygotes (one C282Y with either H63D or S65C) may have mild iron overload without overt hemochromatosis.
Because the iron overload may occur over years, most men present with symptoms of hemochromatosis in the 5th or 6th decade of life. This may lag even longer in women by 10 to 20 years because of excess iron loss from menstruation during the premenopausal years.
Initial symptoms of hemochromatosis may be non-specific including:
The most commonly involved organs in hemochromatosis are the liver, pancreas, joints, skin, heart, testicles, and the thyroid gland. Some of the most common manifestations and symptoms of hemochromatosis are listed as follows:
- Hemochromatosis can cause liver disease of varying degrees, including cirrhosis and liver cancer. The liver is typically the first organ to be affected.
A majority of symptomatic (having symptoms) patients have liver involvement.
- Skin discoloration (from iron deposits in the skin) may be seen in hemochromatosis. The skin may have a bronze appearance. The skin is also involved very commonly in close to
most symptomatic patients.
- Diabetes mellitus may result because of hemochromatosis affecting the pancreas. This may be seen in more than half of the patients with hemochromatosis.
- Joint pain (arthralgia) and arthritis are also common in hemochromatosis.
- Hemochromatosis can sometimes involve the heart, causing heart failure or heart rhythm disturbances.
- Impotence (erectile dysfunction) can be seen in hemochromatosis due to testicular or pituitary involvement.
- Hypothyroidism may result because of hemochromatosis affecting the thyroid gland.
One of the possible late manifestations of hereditary hemochromatosis is referred to as "bronze diabetes". This condition occurs when the disease involves the skin (bronze appearance) and the pancreas (diabetes).
Many of these conditions are commonly seen in the general population and are not related to hereditary hemochromatosis. In addition, they may be present in varying degrees in individuals with hemochromatosis. Because of these factors, delay in making the diagnosis of hereditary hemochromatosis is not uncommon.
Hemochromatosis Genetic Screening
Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron. This causes iron to build up in the blood, liver, heart, pancreas, joints, skin, and other organs.
In its early stages, hemochromatosis can cause joint and belly pain, weakness, lack of energy, and weight loss. It can also cause scarring of the liver (cirrhosis), darkening of the skin, diabetes, infertility, heart failure, irregular heartbeats (arrhythmia), and arthritis. But many people do not have symptoms in the early stages.
In men, hereditary hemochromatosis is usually found at ages 40 to 60. In women, it is not usually found until after menopause because, until that time, women regularly lose blood and iron during their monthly periods.
When to Seek Medical Care for Hemochromatosis
When a person is diagnosed with hereditary hemochromatosis, they are advised to see their physician routinely for management of the associated conditions and general care and treatment. Many types of physicians may be involved in the treating patients with this condition. Internal medicine doctors (internists), endocrinologists, cardiologists, and gastroenterologists are some of the common specialists who treat patients with hemochromatosis.
Genetic specialists may also play an important role in counseling and testing of the patient and their family members. Because of the hereditary nature of hemochromatosis, screening of the first degree relatives of these patients is strongly recommended, and its importance cannot be overemphasized.
Exams and Tests for Hemochromatosis
The diagnosis of hereditary hemochromatosis primarily requires a clinical suspicion by the doctor. In cases in which one family member already carries this diagnosis, the chance for another blood relative to have hemochromatosis is higher.
A complete medical history and a thorough physical examination are key components in the evaluation of a person suspected to have hemochromatosis. Particular attention to their family history and their personal history of the conditions associated with hereditary hemochromatosis is prudent.
Measurement of indices of iron in the blood plays an important role in making the diagnosis of hemochromatosis. There are a number of measurements that can be made to assess the amount iron in the blood and stored in the body. Normal levels of these tests may vary in different laboratories, and the numbers quoted in this article denote the general range.
Ferritin is a protein that correlates with the amount of iron stored in the body. In hemochromatosis, ferritin levels tend to be very high (900-6000 micrograms per liter), whereas, in iron deficiency anemia, these levels are usually low. Normal range for ferritin may range from 10-200 microgram per liter. Ferritin may also be elevated in any infection or inflammation (it is an acute phase reactant) and, therefore, this test is not totally specific.
Transferrin is a protein that carries iron from one part of the body to another. The iron level of the blood can also be measured, signifying the amount of iron circulating in the blood (normal 50-150 microgram per deciliter or one tenth of a liter). Total iron binding capacity or TIBC (normal 250-370 microgram per deciliter) is the total amount of iron that is carried in the blood by transferrin. Transferrin saturation is the percentage of transferrin in the blood that is used to carry oxygen and it is derived by dividing the serum iron level by TIBC.
Transferrin saturation in normal individuals runs between 25%-45%. In people with hemochromatosis, transferrin can be up to 100% saturated (range of 50%-100%), whereas, in people with iron deficiency anemia, it can be lower than 25%. The combination of elevated ferritin level and high transferrin saturation is a reliable test to screen for suspected hemochromatosis.
Biopsy of the liver can also be done in evaluating people with hemochromatosis. This test is especially useful if the diagnosis is still in doubt or if there is existing evidence of liver disease. This is the definitive test of hemochromatosis, by measuring the hepatic (liver) iron index. This number is derived from the measurement of the liver iron weight (the weight of iron in micrograms divided by the weight of liver in grams) divided by the age of the person. In normal people, the hepatic iron index is less than 1. In hemochromatosis, the index is greater than 2.
Medical Treatment for Hemochromatosis
Treatment of hemochromatosis typically involves removal of excess iron, any supportive measures for the involved organs, and treatment of hemochromatosis-related conditions.
The removal of iron is usually initiated by weekly or twice weekly phlebotomy (removal of blood from the body) of 500cc of blood from a vein. Transferrin saturation and ferritin levels can be monitored routinely, and once the levels become normal, then the phlebotomies can be done less frequently (every few months). The normalization of these levels can sometimes take up to one to two years. Phlebotomy can be done in the physician's office, blood banks, or hospitals.
If hemochromatosis is diagnosed or treated early, most of the complications of the disease may be prevented by doing routine phlebotomy.
- Some of the manifestations of hemochromatosis can be prevented or reversed, such as skin discoloration, heart rhythm problems, diabetes mellitus, or early liver disease.
- Cirrhosis (scarring) of the liver, liver cancer, and advanced heart failure are manifestations of advanced hereditary hemochromatosis which may not be reversed. Arthritis and testicular dysfunction are also usually not reversible.
Routine treatment of diabetes mellitus, heart failure, and liver insufficiency may be done similar to the conventional therapy of these conditions. Loss of libido may be partially corrected withtestosterone treatment.
In severe cases of advanced liver failure due to cirrhosis, liver transplantation may be a recommended option.
Chelating agents (deferoxamine) have been used to remove iron from the body in patients with hemochromatosis. These agents bind to the iron and remove it from the body. They are not as effective as phlebotomy and are rarely used; however, they can be an option in patients who may suffer concomitantly from anemia and may not tolerate phlebotomy.
People with hemochromatosis are encouraged to consume a balanced diet. However, there are certain important precautions that warrant mentioning.
- A large alcohol intake (for example, 60gram of alcohol or four glasses of wine or beer daily) was shown to increase the risk of liver cirrhosis by nine fold in patients with hemochromatosis. Alcohol can also promote theabsorption of iron from the intestines, resulting in further iron overload. Occasional social drinking, however, may not add any further risk in patients with hemochromatosis.
- Ingestion of large doses of vitamin C (ascorbic acid) may lead to increased iron uptake. Therefore, vitamin C supplementation is discouraged in patients with hemochromatosis. It is worth noting that there is no reason to discourage the usual consumption of fruits (citrus) and vegetables containing vitamin C in people with hemochromatosis.
- Uncooked seafood may induce bacterial infections that thrive in the iron-rich environment, and their ingestion is not recommended in people who have hemochromatosis.
Patients with hemochromatosis need routine follow-up with their treating physicians. Blood draws to monitor iron, ferritin, and transferrin saturation are typically done every few months in those undergoing phlebotomy. Hemochromatosis-related diseases require regular follow-up depending on their severity, as recommended by the treating doctor.
Once the diagnosis of hemochromatosis is made in an individual, screening of the first-degree relatives is of utmost importance. This is the most significant step in preventing the disease manifestations in family members of the affected person, and it is considered the standard of care.
Screening of the first-degree relatives of the patient with hemochromatosis may be done by measuring serum ferritin and transferrin saturation. Genetic testing for the HFE gene mutation has also been recommended in this population for both screening and confirmation of the diagnosis. The ages between 20-30 are generally recommended for screening of the first degree relatives.
Routine screening for hemochromatosis in the general population has undergone considerable debate. Despite its relatively significant prevalence, a population-based genetic screening (testing the entire population) for hereditary hemochromatosis is not advocated based on recent studies.
Recent studies promote screening tests for at-risk individuals who may have clinical suggestion of iron overload, such as elevated liver enzymes or early arthritis, in people of Northern European ancestry. This approach is not an established recommendation as of yet.
Outlook for Hemochromatosis
The outlook for hereditary hemochromatosis is favorable if it is diagnosed early and treated promptly. Life expectancy, in general, is a significantly improved survival rate with removal of excess iron and its maintenance in the normal range.
The main causes of death in untreated patients with hemochromatosis are heart failure, cirrhosis of the liver, and liver cancer.
Reviewed on 11/17/2017
Medically reviewed by Avrom Simon, MD; Board Certified Preventative Medicine with Subspecialty in Occupational Medicine
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