## Hemochromatosis, the most common form of iron overload disease, http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm
Hemochromatosis, the most common form of iron overload disease, is an inherited disorder that causes the body to absorb and store too much iron. The extra iron builds up in organs and damages them. Without treatment, the disease can cause these organs to fail.
Iron is an essential nutrient found in many foods. The greatest amount is found in red meat and iron-fortified bread and cereal. In the body, iron becomes part of hemoglobin, a molecule in the blood that transports oxygen from the lungs to all body tissues.
Healthy people usually absorb about 10 percent of the iron contained in the food they eat to meet the body needs. People with hemochromatosis absorb more than the body needs. The body has no natural way to rid itself of the excess iron, so it is stored in body tissues, especially the liver, heart, and pancreas.
Genetic or hereditary hemochromatosis is mainly associated with a defect in a gene called HFE, which helps regulate the amount of iron absorbed from food. There are two known important mutations in HFE, named C282Y and H63D. C282Y is the most important. When C282Y is inherited from both parents, iron is overabsorbed from the diet and hemochromatosis can result. H63D usually causes little increase in iron absorption, but a person with H63D from one parent and C282Y from the other may rarely develop hemochromatosis.
The genetic defect of hemochromatosis is present at birth, but symptoms rarely appear before adulthood. A person who inherits the defective gene from both parents may develop hemochromatosis. A person who inherits the defective gene from only one parent is a carrier for the disease but usually does not develop it. However, carriers might have a slight increase in iron absorption.
Scientists hope that further study of HFE will reveal how the body normally metabolizes iron. They also want to learn how iron injures cells and whether it contributes to organ damage in other diseases, such as alcoholic liver disease, hepatitis C, porphyria cutanea tarda, heart disease, reproductive disorders, cancer, autoimmune hepatitis, diabetes, and joint disease. Scientists are also working to find out why only some patients with HFE mutations get the disease.
Juvenile hemochromatosis and neonatal hemochromatosis are two forms of the disease that are not caused by an HFE defect. Their cause is unknown. The juvenile form leads to severe iron overload and liver and heart disease in adolescents and young adults between the ages of 15 and 30, and the neonatal form causes the same problems in newborn infants.
# Risk Factors
Hereditary hemochromatosis is one of the most common genetic disorders in the United States. It most often affects Caucasians of Northern European descent, although other ethnic groups are also affected. About 5 people in 1,000 (0.5 percent) of the U.S. Caucasian population carry two copies of the hemochromatosis gene and are susceptible to developing the disease. One person in 8 to 12 is a carrier of the abnormal gene. Hemochromatosis is less common in African Americans, Asian Americans, Hispanic Americans, and American Indians.
Although both men and women can inherit the gene defect, men are about five times more likely to be diagnosed with the effects of hereditary hemochromatosis than women. Men also tend to develop problems from the excess iron at a younger age.
Joint pain is the most common complaint of people with hemochromatosis. Other common symptoms include fatigue, lack of energy, abdominal pain, loss of sex drive, and heart problems. Symptoms tend to occur in men between the ages of 30 and 50 and in women over age 50. However, many people have no symptoms when they are diagnosed.
If the disease is not detected early and treated, iron may accumulate in body tissues and may eventually lead to serious problems such as:
· liver disease, including an enlarged liver, cirrhosis, cancer, and liver failure
· damage to the pancreas, possibly causing diabetes
· heart abnormalities, such as irregular heart rhythms or congestive heart failure
· early menopause
· abnormal pigmentation of the skin, making it look gray or bronze
· thyroid deficiency
· damage to the adrenal gland
A thorough medical history, a physical examination, and routine blood tests help rule out other conditions that could be causing the symptoms. This information often provides helpful clues, such as a family history of arthritis or unexplained liver disease.
Blood tests can determine whether the amount of iron stored in the body is too high. The transferrin saturation test determines how much iron is bound to the protein that carries iron in the blood. The total iron binding capacity (TIBC) test measures how well your blood can transport iron. The serum ferritin test shows the level of iron in the liver. If either of these tests shows higher than normal levels of iron in the body, doctors can order a special blood test to detect the HFE mutation, which will help confirm the diagnosis. (If the mutation is not present, hereditary hemochromatosis is not the reason for the iron buildup, and the doctor will look for other causes.) A liver biopsy, in which a tiny piece of liver tissue is removed and examined under a microscope, may be needed. It will show how much iron has accumulated in the liver and whether the liver is damaged.
Hemochromatosis is often undiagnosed and untreated. It is considered rare and doctors may not think to test for it. The initial symptoms can be diverse and vague and can mimic the symptoms of many other diseases. Also, doctors may focus on the conditions caused by hemochromatosis-arthritis, liver disease, heart disease, or diabetes-rather than on the underlying iron overload. However, if the iron overload caused by hemochromatosis is diagnosed and treated before organ damage has occurred, a person can live a normal, healthy life.
Hemochromatosis is usually treated by a specialist in liver disorders (hepatologist), digestive disorders (gastroenterologist), or blood disorders (hematologist). Because of the other problems associated with hemochromatosis, several other specialists may be on the treatment team, such as an endocrinologist, cardiologist, or rheumatologist. Internists or family practitioners can also treat the disease.
Treatment is simple, inexpensive, and safe. The first step is to rid the body of excess iron. The process is called phlebotomy, which means removing blood the same way it is drawn from donors at blood banks. Depending on how severe the iron overload is, a pint of blood will be taken once or twice a week for several months to a year, and occasionally longer. Blood ferritin levels will be tested periodically to monitor iron levels. The goal is to bring blood ferritin levels to the low end of normal and keep them there. Depending on the lab, that means 25 to 50 micrograms of ferritin per liter of serum. Depending on the amount of iron overload at diagnosis, reaching normal levels can take many phlebotomies.
Once iron levels return to normal, maintenance therapy, which involves giving a pint of blood every 2 to 4 months for life, begins. Some people may need it more often. An annual blood ferritin test will help determine how often blood should be removed.
The earlier hemochromatosis is diagnosed and treated in appropriate cases, the better. If treatment begins before any organs are damaged, associated conditions-such as liver disease, heart disease, arthritis, and diabetes-can be prevented. The outlook for people who already have these conditions at diagnosis depends on the degree of organ damage. For example, treating hemochromatosis can stop the progression of liver disease in its early stages, which means a normal life expectancy. However, if cirrhosis has developed, the person’s risk of developing liver cancer increases, even if iron stores are reduced to normal levels. Appropriate regular follow-up with a specialist is necessary.
People who have complications of hemochromatosis may want to consider getting treatment from a specialized hemochromatosis center. These centers are located throughout the country. Information is available from the organizations listed under For More Information http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm .
People with hemochromatosis should not take iron supplements. Those who have liver damage should not drink alcoholic beverages because they may further damage the liver.
Although treatment cannot cure the conditions associated with established hemochromatosis, it will help most of them. The main exception is arthritis, which does not improve even after excess iron is removed.
# Tests for Hemochromatosis
Screening for hemochromatosis (testing people who have no symptoms) is not a routine part of medical care or checkups. However, researchers and public health officials do have some suggestions:
· Brothers and sisters of people who have hemochromatosis should have their blood tested to see if they have the disease or are carriers.
· Parents, children, and other close relatives of people who have the disease should consider testing.
· Doctors should consider testing people who have joint disease, severe and continuing fatigue, heart disease, elevated liver enzymes, impotence, and diabetes, because these conditions may result from hemochromatosis.
Since the genetic defect is common and early detection and treatment are so effective, some researchers and education and advocacy groups have suggested that widespread screening for hemochromatosis would be cost-effective and should be conducted. However, a simple, inexpensive, and accurate test for routine screening does not yet exist, and the available options have limitations. For example, the genetic test provides a definitive diagnosis, but it is expensive. The blood test for transferrin saturation is widely available and relatively inexpensive, but it may have to be done twice with careful handling to confirm a diagnosis and to show that it is the consequence of iron overload.
# Hope Through Research
Current research in hemochromatosis is concentrated in four areas:
– Genetics. Scientists are working to understand more about how the HFE gene normally regulates iron levels and why not everyone with an abnormal pair of genes develops the disease.
– Pathogenesis. Scientists are studying how iron injures body cells. Iron is an essential nutrient, but above a certain level it can damage or even kill the cell.
– Epidemiology. Research is under way to explain why the amounts of iron people normally store in their bodies differ. Research is also being conducted to determine how many people with the defective HFE gene go on to develop symptoms, as well as why some people develop symptoms and others do not.
– Screening and testing. Scientists are working to determine at what age testing is most effective, which groups should be tested, and what the best tests for widespread screening are.
For More Information
American Hemochromatosis Society Inc., 4044 West Lake Mary Boulevard, Unit #104, PMB 416, Lake Mary, FL 32746-2012
Phone: 1-888-655-IRON (4766) or 407-829-4488, Fax: 407-333-1284
Email: email@example.com, Internet: http://www.americanhs.org/
American Liver Foundation (ALF), 75 Maiden Lane, Suite 603, New York, NY 10038-4810
Phone: 1-800-465-4837,1-888-443-7872, or 212-668-1000 Fax: 212-483-8179
Email: firstname.lastname@example.org, Internet: http://www.liverfoundation.org/
Iron Disorders Institute Inc., P.O. Box 2031, Greenville, SC 29602
Phone: 1-888-565-IRON (4766) or 864-292-1175, Fax: 864-292-1878
Email: email@example.com, Internet: http://www.irondisorders.org/
National Organization for Rare Disorders Inc., 55 Kenosia Avenue, P.O. Box 1968, Danbury, CT 06813-1968
Phone: 1-800-999-6673 or 203-744-0100, Fax: 203-798-2291
Email: firstname.lastname@example.org, Internet: http://www.rarediseases.org/
National Digestive Diseases Information Clearinghouse, 2 Information Way, Bethesda, MD 20892-3570
The National Digestive Diseases Information Clearinghouse (NDDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health under the U.S. Department of Health and Human Services. Established in 1980, the Clearinghouse provides information about digestive diseases to people with digestive disorders and to their families, health care professionals, and the public. The NDDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about digestive diseases.
Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts. This fact sheet was reviewed by Bruce R. Bacon, M.D., Saint Louis University School of Medicine; and Anthony Tavill, M.D., Case Western Reserve University School of Medicine.
This publication is not copyrighted. The Clearinghouse encourages users of this fact sheet to duplicate and distribute as many copies as desired.
NIH Publication No. 05-4621, December 2004
## ANTIOXIDANTS FOR HAEMOCHROMATOSIS, http://users.mrbean.net.au/~wlast/haemochromatosis1.html
This article was published in the International Clinical Nutrition Review (Volume 11, No.2, pages 71-74, 1991)
ANTIOXIDANTS FOR HAEMOCHROMATOSIS, Walter Last
Hemochromatosis is a potentially fatal iron storage disease with excessive iron deposits especially in the liver. The idiopathic form occurs usually in males and manifests from the age of 30 to 50. It is thought to result from a lifetime of excessive iron absorption, the cause of which is not known. Prominent long-term effects are liver cirrhosis, diabetes mellitus, cardiac failure and strong skin pigmentation.
Iron is deposited in the 3-valence form as ferritin and hemosiderin. Serum ferritin levels closely reflect tissue levels and are greatly increased. The diagnosis is confirmed by a liver biopsy. The conventional treatment consists of phlebotomy with weekly to monthly bleedings until plasma iron or ferritin levels reach the lower normal range.
Chelation of iron as with desferrioxamine to increase urinary excretion is not very effective and usually confined to anaemic patients.
# CASE HISTORY
A 48-year-old male collapsed at work in December 1987. The main symptoms were dizziness, tachycardia, heavy sweating, difficulty breathing and extreme’ weakness. Treatment in an Intensive Care Unit with numerous tests produced no definite diagnosis. Loss of weight and weakness continued after discharge. The diagnosis of hemochromatosis was established in March 1989 by liver biopsy and a serum ferritin level of 1585 ng/ml (normal for males: 30-4OOng/ml).
Phlebotomy was performed initially fortnightly and later monthly of one litre of blood. Serum ferritin levels fell initially steeply but very slowly in the last 6 months to a low of 440 ng/ml at the end of October 1990. During all this time the patient was very weak. In early December 1990 a specialist diagnosed Meniere’s disease as an additional complication.
Phlebotomy was stopped and nutritional therapy started in December 1990. It consisted predominantly of a vegetarian raw food diet with supplements of B complex, sublingual vitamin B 12, Kyolic garlic, lecithin, freeze-dried acidophilus culture, zinc, copper, manganese, and high levels of antioxidant vitamins, in particular 20g of ascorbate, 1000 iu of natural vitamin E and 10,000 iu of vitamin A, all in divided doses. Ascorbic acid was not well tolerated and sodium ascorbate used instead. In order to minimise any increased iron absorption due to ascorbate this was initially taken with water or fruit well before meals.
After about 3 days on this program, on December 11 the serum ferritin level was 458 ng/ml. However, on December 28 the ferritin level was 393 ng/ml, within the normal range for the first time since diagnosis. After this the diet was relaxed to include cooked and flesh foods. In order to assess the effectiveness of a lower ascorbate level, the daily intake was reduced to 5 g and (to preclude any direct influence of high ascorbate levels on tests) no supplementation was used in the 24 hours before the next test on January 10,1991, which showed a further drop of the ferritin level to 380 ng/ml.
With the start of the nutritional therapy the patient began to feel well for the first time in 3 years with rapidly increasing strength and disappearance of all signs of Meniere’s disease. The red blood cell count which was below the normal range in December, moved into the normal range and haemoglobin, which had been near the lower limit, moved towards the middle of the normal range. Preliminary maintenance supplementation consists of about 5 g of ascorbate, 500 iu of vitamin E, 10,000 iu of vitamin A, B complex and lecithin.
Vitamin C therapy is generally regarded as potentially harmful in cases of iron overload. Ascorbic acid may increase the absorption of iron and it is perceived that toxic products may form from the combination of ascorbate with iron salts liberated from ferritin tissue stores (1). In this way, cardiac damage, often transient, has been detected in thalassemia patients taking 500 mg/day of ascorbic acid (2). Such tissue damage may result from the peroxidation of membrane lipids and is really not surprising in tissues severely deficient in antioxidants. To avoid or limit toxic effects from iron liberated by ascorbic acid it has been proposed to use vitamin C supplementation only in combination with desferrioxamine in the treatment of iron overload (2).
However, it would appear much more effective to protect cell membranes from iron-induced peroxidation damage during therapy with a high level of antioxidant supplementation. Also sufficient vitamin B6 is required to prevent iron overload.
It is well known that high concentrations of ferric ions oxidise the protective antioxidants, notably the vitamins C and E. This means that on an unsupplemented diet we can expect pronounced tissue deficiencies of these antioxidants in iron overload diseases.
It has recently been reported that vitamin A supplementation improved the iron status (serum iron, haemoglobin as well as transferrin saturation) without at the same time increasing ferritin levels, while iron supplements without additional vitamin A increased ferritin levels. Also vitamin A deficient subjects developed anaemia despite sufficient dietary iron (3,4). This may be interpreted as a normalising function of vitamin A in the transport and usage of iron, while iron alone may mainly increase iron stores in case of vitamin A deficiency.
A similar normalising role in iron metabolism may be exhibited by the other antioxidants. Vitamin C not only improves the absorption of iron, it is also required to move iron in and out of ferritin tissue stores. Without adequate antioxidants, ferric iron stores may build up because iron cannot be liberated from tissue ferritin and transferred onto plasma transferrin, a step that requires a temporary reduction of ferric to ferrous iron.
However, recent studies show that excess tissue ferritin is catabolized by lysozyme activity, which is inhibited by ascorbate. The mechanism for this inhibition is not known (1). I suggest that in the case of iron overload, physiological levels of ascorbate are actually present to a high percentage in oxidised form as reversible dehydroascorbate or as irreversible oxidation products.
The observed lysozyme inhibition would then actually be due to oxidised ascorbate. Similarly, any liberated iron would be in the form of ferric dehydroascorbate and other oxidised products and it is these, which cause the peroxidative membrane damage. With sufficiently high antioxidant levels, on the other hand, ascorbate may well stimulate lysozyme activity and liberated iron would be present as harmless or even beneficial ferro ascorbate.
Stevens et al (5) reported an increased risk of cancer in men with excess stored iron who also had lower total iron binding capacity and higher transferrin saturation. Generally no correlation was found between iron status and dietary iron intake. Again, I suggest that there may be an association between iron overload as well as cancer with the antioxidant status. High antioxidant levels can be expected to lower not only excess iron stores but also independently of the iron metabolism reduce the risk of cancer.
Judging by the health of the Bantu people it has been speculated that scurvy may be beneficial with iron overload (2). I suggest that on the contrary, the loss of vitamin C due to cooking in iron pots was the primary reason for their iron overload.
There are two sites or steps at which antioxidant deficiency might cause or contribute to hemochromatosis. The synthesis of haem requires the reduction of ferric to ferrous ions. While this reduction proceeds enzymatically through ferrochelatase, there may be either a deficiency of this enzyme or an impeded function if the cell is deficient in antioxidants. In addition, ferrochelatase is inhibited by lead ions. This would lead to low haemoglobin levels, possibly raised methaemoglobin and increased ferritin stores as a cellular deficiency of ferrous ions for the haem synthesis could stimulate increased absorption of iron.
The second possibility appears to be more important in hemochromatosis and could arise from a difficulty in recycling iron from the continual breakdown of haemoglobin in the spleen. About 25 mg of iron are recycled daily in this way, but this requires a reduction-oxidation step to transfer ferritin iron in the tissue onto plasma transferrin. With antioxidant deficiency there would be only a partial recycling. Most of the iron stores would build up in the liver where the decomposed haemoglobin arrives through the portal vein after its liberation from old erythrocytes in the spleen.
However, very high ferric iron stores in the liver would also make this organ more antioxidant deficient than other tissue. The highest antioxidant activity may well be in the intestinal mucosa as these have first call on the antioxidants absorbed from food. Therefore, transferrin will preferentially pick up iron from the intestinal mucosa and avoid the liver stores as too difficult to convert. Another piece of evidence for this proposed mechanism may be seen in the rapid normalisation of ferritin levels in the reported case without any abnormal loss of iron with the urine.
In summary, it is postulated that the basic biochemical defect which leads to the development of hemochromatosis is a tissue deficiency of antioxidants which inhibits the recycling of iron from old erythrocytes and this in turn induces increased intestinal absorption for the necessary synthesis of haem. The obvious advantages of antioxidant therapy as compared to the traditional management of hemochromatosis will hopefully stimulate more research in this area.
1. Editorial: Ascorbic acid and ferritin catabolism. Nutr Rev 47 (7), 218-219 (1989)
2. Editorial: Iron overload and vitamin C. N EngI J Med 304 (3), 170-171 (1981)
3. Editorial: Vitamin A and iron deficiency. Nutr Rev 47 (4), 119-121 (1989)
4 . Bloem MW, Wedel M, Agtmaal EJ, et al. Vitamin A intervention: short-term effects of a single, oral, massive dose on iron metabolism. Am J Clin Nutr 51, 76-79 (1990)
5. Stevens RG, Jones DY, Micozzi MS, et al.: Body iron stores and the risk of cancer. N EngI J Med 319 (16), 1047-1052 (1988)