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Biochemistry
Iron is one of the most abundant earth elements, yet only traces are essential for living cells of plants and animals. In humans, most of the iron is contained within the porphyrin ring of heme in proteins such as hemoglobin, myoglobin, catalase, peroxidases, and cytochromes. as well as iron-sulfur proteins such as NADH dehydrogenase and succinate dehydrogenase, in which iron is present in clusters with inorganic sulfur. In all these systems, iron has the ability to interact reversibly with oxygen and to function in election transfer reactions that makes it biologically indispensable.

Pathophysiology
The average adult male contains approximately 4 grams of body iron. About 65% to 70% is found in hemoglobin, 4% in myoglobin, and less than 1% in other iron-containing enzymes and proteins. The remaining 25% to 30% represent the storage pool of iron. By contrast, women have a much smaller iron reserve, with the adult female body containing about 3 grams of iron. Women also have a slightly lower hemoglobin concentration in blood than males. Patients with iron overload diseases may store as much as 20 g of iron.

Excess iron can result in cell injury. Menstruation, bleeding due to injury, or bloodletting help to excrete excess iron. Other than that, humans do not excrete excess iron effectively.

Iron overload can result from an increased absorption of dietary iron or from parenteral administration of iron. When the iron burden exceeds the body's capacity for safe storage, the result is widespread damage to the liver, heart, joints, pancreas, and other endocrine organs.¹ It must be noted that low serum iron alone is not an indicator of iron deficiency. Serum ferritin, transferrin levels and total iron binding capacity must confirm the diagnosis before iron is supplemented. To improve iron absorption and utilization, adequate amounts of vitamins C and B, especially folic acid, B6, and B12, must be provided.

Diseases of Iron Overload
There are several inherited and acquired disorders such as hemochromatosis that can result in chronic iron overload in humans. The major clinical consequences are hepatic fibrosis, cirrhosis, hepatocellular cancer, cardiac disease, and diabetes. Lipid peroxidation is a result of iron overload.

Researchers from the Department of Internal Medicine, St. Louis University Health Sciences Center, Missouri, write: "In the liver, this lipid peroxidation is associated with impairment of membrane-dependent functions of mitochondria and lysosomes. Iron overload impairs hepatic mitochondrial respiration primarily through a decrease in cytochrome C oxidase activity, and hepatocellular calcium homeostasis may be compromised through damage to mitochondrial and microsomal calcium sequestration. DNA has also been reported to be a target of iron-induced damage, and this may have consequences in regard to malignant transformation."^2,3

Iron overload or acquired hemochromatosis may be a complication of chronic anemias such as thalassemia and sideroblastic anemia. In the initial stage of iron overload, referred to as hemosiderosis, tissues remain anatomically and functionally normal. As the iron load increases, the clinical pattern resembles that of hemochromatosis. Acquired hemochromatosis can result from frequent blood transfusions or excess iron ingestion. The Bantu of South Africa drink home-brewed alcoholic beverages with a very high iron content and therefore have a high incidence of the disease. Alcoholics with chronic liver disease such as cirrhosis are also susceptible to developing an increase in iron storage. Genetic predisposition increases the onset of the disease.

Signs and symptoms of hemochromatosis are related to the organs involved, such as:
· liver enlargement and cirrhosis;
· hepatocellular carcinoma;
· diabetes mellitus (in about two-thirds of the patients);
· increase in skin pigmentation, caused by increased melanin production, found in 90% of patients;
· cardiac involvement, which may lead to congestive heart failure or arrhythmia;
· testicular atrophy;
· loss of libido, caused by drop in production of gonadotropins by the impaired hypothalamus-pituitary axis.

Sources of excess iron:
· iron-rich drinking water;
· cooking acidic food in iron cookware;
· excessive iron supplementation or prolonged iron therapy;
· repeated blood transfusions;
· protein malnutrition.

Therapeutic considerations:
· Phlebotomy therapy is treatment of choice.
· Iron-chelation with Deferoxamine or other iron-specific chelating agents
· Vegetarian diet
· Check blood for manganese, copper, and zinc levels, and balance blood chemistry.
· Vitamin C must be restricted. Doses should be not higher than 250–500mg/day and should be used only on those days when Desferal infusion or other iron chelation is performed.⁶

Diagnosing Hemochromatosis
To diagnose the disease is not difficult. There are basically three tests that confirm an iron overload.

Test 1. Transferrin Saturation (TS) or, as it is called in some labs, percentage of saturation: After a 12-hour fast, measure total iron binding capacity (TIBC) and the serum iron (SI). To achieve the percentage of saturation you divide the TIBC into SI.

Serum Iron SI
------- = Yields Transferrin Saturation (TS)
Total Iron Binding TIBC or in some labs percentage of saturation
Capacity
Safe range = 12–44%
Any values above this range must be considered diagnostic for hemochromatosis and should cause immediate treatment. Any values far below this range may be a sign of bleeding ulcers, chronic infection, or cancer. Physicians should look for the cause of anemia.

Test 2. Serum Ferritin (SF): Using the blood from the first draw, next check the amount of storage iron.
Safe range = 5–150
A hemochromatosis patient needs to be at the lowest end of this range. Below 10 is the treatment goal.

Test 3. Unbound iron binding capacity (UIBC), used less frequently.
Safe range is above 146
If a patient checks below this test value, then he or she needs to be treated for hemochromatosis or other iron overload conditions.

How Common Are Iron Overload Diseases?
One in three Irish natives is predisposed genetically. In the US, a carrier rate of 20% is reported for Irish Americans. African Americans too have a 20% carrier rate in the US. Typical for this population is that the main screening lab value – transferrin saturation (TS) – sometimes seems normal. To evaluate this group, more attention must be paid to family history, symptoms, and a complete diagnostic schedule as outlined above.
People with hemochromatosis should not take iron or vitamin C supplements, which increase iron availability. Those who have liver damage should not consume alcoholic beverages or eat raw seafood.

Treating Iron Overload
The object is to induce a mild anemia and maintain it until the storage iron is greatly reduced. Serum ferritin is the measure of storage iron, and it needs to come down below 10. This is accomplished by therapeutic phlebotomies, which must be done regularly in a medical setting. The treatment schedule may continue for 6 months to 3 years, depending on the iron burden. Age is never a reason to disqualify someone from treatment. Frailty, small stature, and extreme youth/age may require adjustments in the amount of blood removed, but never the frequency. The process of bloodletting can arrest or reverse most symptoms and return the patient to a normal life span. Some patients might experience a complete reversal of all symptoms. Unfortunately, treatment cannot cure the conditions associated with established hemochromatosis, but it will bring relief to most. The main exception is arthritis, which is said not to improve even after excess iron is removed. To exclude any hemochromatosis patient from treatment for any reason is a death sentence.

Chelation
Chelation can be an alternative when bloodletting is contraindicated. There are three agents used for iron chelation in the US: Exjade, Desferal (also called Deferoxamin or desferrioxamine), and Deferiprone, usually limited to thalassemia major.

Desferal can be given intravenously or subcutaneously. It is rapidly absorbed after administration, but only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa. Recommended are infusions of 2 or 2.5 grams; 100 mg is capable of binding approximately 8.5 mg of trivalent (ferric) iron.

To evaluate the efficacy of Desferal therapy, a 24-hour urine collection should be performed on the third day for iron determination. This value should be compared with a preinfusion 24-hour urine iron determination. In order to gain benefit from the use of Desferal, a 24-hour excretion of 30 mg or more of iron is generally required, particularly for patients with significant ongoing transfusion requirements. Patients should be warned that their urine will become orange. This is the iron-Desferal complex (ferrioxamine), which is being excreted.

For some hemochromatosis patients, Desferal is infused overnight with a portable pump at home during sleep over a 12-hour period. In some cases, the infusion pump is installed in the body of the patient.⁴ Monthly Desferal treatments may cost $6000 to $8000.

Exjade and Deferiprone are similar in action to Desferal, are used orally, have fewer side effects, and are less expensive.⁵

Ethylenediamine Tetraacetic Acid (EDTA)
EDTA has a good iron binding capacity, and while intravenous EDTA chelation is not mentioned in any conventional medical textbook, it does provide options for mild cases of iron overload or as a maintenance schedule for hemochromatosis. The treatment costs would be comparatively inexpensive. A treatment plan, consisting of one infusion per week, would cost $600 to $1,000 per month. Interestingly, alternative medicine has not yet recognized nor studied the beneficial effects of EDTA's iron-binding ability. Controlled studies are needed.

The following chart reflects EDTA's iron-binding capacity in comparison to DMPS (2,3-Dimercapto-1-propanesulfonic acid) and DMSA (meso-2,3-Dimercaptosuccinic acid). Test values represent a 95th percentile and have been obtained from people with normal iron status. It can be assumed that EDTA chelation performed on a hemochromatosis patient would result in a greater iron binding than seen in Table 1. The 95th-percentile level of about 800 mcg/g creatinine (= approx 0.8mg/L) obtained from a pool of people who do not have an iron-overload problem. It explains the anti-inflammatory benefit of EDTA chelation treatment.

Table 1

Maintenance
After the patient has had his ferritin reduced below 10, he is declared deironed. Now it is time to change the phlebotomy schedule, and this is often a matter of trial and error by the physician and patient. Serum ferritin should be checked regularly, at least yearly. Maintenance will have to be a lifetime affair. To permit iron to reaccumulate is to invite premature death.

Dr. E. Blaurock-Busch is laboratory and research director at Micro Trace Minerals Clinical Laboratory of Germany and Boulder, Colorado. She is scientific advisor to the IBCMT (International Board of Clinical Metal Toxicology) and the German Medical Association for Clinical Metal Toxicology. She has written books on laboratory diagnostics and chelation.

For more information, contact the author at info@microtraceminerals.com.

1. Britton RS, Bacon BR, Recknagel RO. Lipid peroxidation and associated hepatic organelle dysfunction in iron overload. Chem Phys Lipids. 1987 Nov-Dec;45(2-4):207-239.
2. Britton RS, Ramm GA, Olynyk J, Singh R, O'Neill R, Bacon BR. Pathophysiology of iron toxicity. Adv Exp Med Biol. 1994;356:239-253.
3. Britton RS, Leicester KL, Bacon BR. Iron toxicity and chelation therapy. Int J Hematol. 2002 Oct;76(3):219-228.
4. Porter JB. A risk-benefit assessment of iron-chelation therapy. Drug Saf. 1997 Dec;17(6):407-421.
5. Maggio A, D'Amico G, Morabito A, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis. 2002 Mar-Apr;28(2):196-208.
6. Information Center for Sickle Cell and Thalassemic Disorders. Subcutaneous Desferal® for transfusional iron overload. Available at: http://sickle.bwh.harvard.edu/dfsc.html.