Iron and Hemochromatosis

 

Iron and Hemochromatosis

     PKGhatak,MD

Iron is an essential element for Humans. Iron acts as an electron receptor and donor (redox). In every living cell, in both plants and animals, the vast majority of iron is present in the enzyme system in which reduction and oxidation take place. Iron, when reacts with hydrogen peroxide (H2O2), releases an oxygen radical that is a poison for the cell and ultimately the cell dies. During iron transport and storage, the iron molecule is combined with proteins and the iron protein compound is stable and less reactive. In the blood hemoglobin is the main form of iron. Hemoglobin transports oxygen(O2) from the lungs to every cell of the body. After receiving oxygen, the mitochondria of the cell utilize O2 for oxidative phosphorylation and the released energy is utilized for cellar functions.

Knowledge in Iron absorption, transport, utilization, and storage mechanisms has greatly evolved in the last 10 years, a brief summary will be presented here.

Iron is present as ferrous and ferric forms. In the duodenum, the enterocytes use separate transfer proteins for inorganic ferrous iron and organic ferric iron absorption. Duodenal cytochrome b (Dcytb) converts ferric to ferrous form and DMT1 (divalent metal transporter 1) ferries ferrous iron across the cell membrane into the cell. The HCP1 (heme carrier protein 1) transfers Heme, organic iron, across the apical membrane.

After entry into the cell iron is again converted to ferric form and binds with a protein called apoferritin. When iron needs to be exported to other cells the ferric iron is converted back to ferrous form and once out of the cell, iron is converted back to ferric form and carried in the blood combined with the protein transferrin.

The amount of iron absorbed varies according to the iron storage status. When the store is full the absorption may be only 5 %, whereas, in iron deficiency, 35 % of iron is absorbed. A polypeptide hormone, Hepcidin, secreted by hepatocytes of the liver is the master regular of iron metabolism in response to the total iron concentration of the body - an increase in iron results, in an increase in Hepcidin. Hepcidin by its action on iron binding receptors of duodenal enterocytes and macrophages prevents absorption of dietary iron and prevents release from macrophages. Chronic inflammation, chronic renal failure, acute infection, and cancer stimulate increased hepcidin production and lower the body's iron stores.

Iron in the body.

The adult male has 4.5 gm of iron and an adult female has 3.5 gm of iron in the body. Iron is lost on a regular basis in the female on account of menstrual blood loss and transfer of iron to the developing child during pregnancy.

In premenopausal women, iron storage may be as low as 500 mg. Iron is stored in bone marrow, liver, spleen and in muscles as myoglobin, in tissues in the megakaryocytes. Organic iron ferritin in mitochondria and cytochrome enzyme system acts as a coenzyme. In the blood, in addition to hemoglobin, a small amount of about 4 mg is present as transferrin. Muscles retain iron as myoglobin.

The daily requirement of iron.

Adult female of reproductive age requires 18 mg of iron daily. Whereas, adult males need only 8 mg and children need 15 mg daily.

An individual with normal dietary habits gets about 15 mg of iron in the food. Plant based food containing a good amount of iron are mulberries, fruit, lentils, tofu, potatoes, and spinach. Of the animal source, a high amount of iron is present in red meat, liver, giblets and egg yolk.

Gastric acid is needed for releasing iron from food. Vitamin C helps iron absorption. Alcohol increases iron abortion. High calcium in the food, zinc, manganese, and excessive amount of tea and coffee decrease iron absorption.

Daily loss of iron from the body is about 1 mg /day in adult males, and about 2 mg daily in females of reproductive age. Loss of iron is due to the shedding of cells in the GI tract and from the skin.

Hemochromatosis.

Hemochromatosis is due to the overload of the body with iron. Iron overload kills the cells and produces varieties of symptoms depending on the organ damage. In general, the liver is commonly affected, iron is stored in the liver as hemosiderin. Other organs damaged are the pancreas, heart, skin, gonads, adrenals, pituitary and joints.

There are two distinct groups of hemochromatosis. One due to hereditary causes, the other due to repeated blood transfusions required in refractory anemia leading to iron overload.

Hereditary Hemochromatosis.

The gene encodes Hepcidin, the HFE gene, and maintains a steady level of Hepcidin production, even though it is readily excreted by kidneys. Mutation of the HFE gene results in the majority of Hereditary hemochromatosis. It is inherited by an Autosomal recessive pattern. Two important HFE gene mutations are C282Y (C stands for amino acid cysteine 282 is band location is replaced by amino acid tyrosine Y), and H63D (histidine is replaced by amino acid asperate )

Hereditary hemochromatosis is clinically classified as type I, type II, type III and type IV. Types I, II, III are inherited as autosomal recessive mode, and type IV is the autosomal dominant mode. Even when a person has one pair of mutated genes the disease manifestation requires some form of liver injury like alcohol consumption or viral hepatitis. 

Type Ia Hereditary hemochromatosis.

The mutations are on chromosome 6 and in the C282Y gene known as the HFE gene. Type 1a, patients are homozygous for the C282Y gene on chromosome 6. This type constitutes 85 % of all hereditary hemochromatosis. Iron accumulation begins in the 20s in male, and become symptomatic when reaching 40 -50 yrs. of age. In females, the onset of symptoms is after menopause. The mode of inheritance is autosomal recessive.

Type Ib. The patients have one copy of chromosome containing mutated gene C282Y from one parent and another copy of chromosome containing the mutation of gene H63D from the other parent. This group constitutes about 2 % of all hemochromatosis patients. Diabetes and fatty liver are common presentations.

Type II. This disorder results in the early development of symptoms. Mutation of the juvenile gene that encodes iron regulator protein hemojuvelin results in cardiac iron deposit and results in cardiac fibrosis and heart failure.

Type III is a disorder of the Transferrin receptor protein due to a mutation of the TFR 2 gene. The severity of symptoms is between type II and type I.

Type IV. In this type one copy of the mutated SLC40A1 gene that encodes Ferroprotein produces hemochromatosis.

The clinical picture of common in all types of hemochromatosis.

Initial symptoms are nonspecific like fatigue and pain in joints. Later in the course of the disease dark discoloration of the skin, abdominal discomfort, hepatomegaly, and the onset of diabetes mellitus develop. If left untreated congestive heart failure, cardiac arrhythmias, cardiomegaly and various symptoms due to hypogonadism manifest in young men and in women after menopause. Patients are susceptible to infection by iron loving bacteria like Vibrio, Listeria and Yersinia.

Diagnosis of hemochromatosis.

Serum ferritin levels over the normal limit of 200 nanogram/ml in adult males and over 300 nanogram/ml in postmenopausal women and ferritin saturation over   45 % in patients with clinical suspicion of hemochromatosis should be confirmed by finding gene mutation by chromosome study. MRI of the liver is not essential for diagnosis but MRI R2/T2 images show the degree of the iron store. The liver biopsy tissue when stained with Prussian-blue, iron loaded hepatocytes and bile duct becomes evident.

 

 Secondary Hemochromatosis.

Secondary hemochromatosis develops when repeated blood transfusions are required for a prolonged period of time. Each unit of blood has 200 to 250 mg of iron. In children, 10 units of blood transfusion can overload the body with iron and in adults, 20 units will do the same. In iron overload conditions, the blood levels of ferritin reach over 1000 micrograms/ L.

Type of anemia where repeated transfusion is necessary.

Thalassemia, Myelodysplasia, Chronic hemolytic anemia, Acquired bone marrow aplasia, Multiple myeloma, Acute leukemia, Lymphoma, and Chemotherapy induced bone marrow depression.

To prevent iron overload, a Chelator Agents is used. At present three agents are approved for use in secondary hemochromatosis.

Deferoxamine. Deferoxamine is given IV, and the dose is 25 -50 mg/ Kg body weight. It used to be commonly used but now it is not. IV infusion site pain and infection are the main reason the compliance is poor.

Deferiprone. Deferiprone is given by mouth, the dose is 75 mg/ Kg body weight, and the drug must be given in 3 divided doses. The main adverse effect is agranulocytosis. The patient's compliance is good with deferiprone.

Deferasirox. Deferasirox is also an oral drug, given only once a day, the dose is 10-30 mg /Kg body weight. GI symptoms are a major side effect, and compliance is also good. At present, it is frequently prescribed chelating drug.

The goal of Chelating agent therapy is to bring down Ferritin levels to the normal range.

Complications:

In hereditary hemochromatosis, the liver is the first to be involved. The following complications are known to occur in hereditary cases.

Enlarged liver, enlarged spleen, cirrhosis of the liver. hepatocellular carcinoma, arthritis, impotency in males, early menopause in females, enlarged heart, cardiac arrhythmias, congestive heart failure, hypothyroidism and dark skin.

Prevention of Hereditary Hemochromatosis.

Hereditary hemochromatosis is an autosomal recessive inherited disease. In first degree relatives, of a hemochromatosis patient, there is a 25 % chance of having a carrier with one copy of the defective gene. The genetic tests of first-degree relatives are the main focus in preventing future generations of new hemochromatosis cases. Genetic counseling must follow all genetic tests.

Diet.

If the disease is diagnosed before the patient is symptomatic a balanced diet is advised with the exception of iron fortified cereals, vitamin C, and alcohol. The patients should avoid oysters and clams in order to avoid infection by iron loving bacteria.

Treatment of Hereditary Hemochromatosis.

Phlebotomy. Patients are required to undergo phlebotomy once a week until the blood ferritin reaches near normal levels. At each phlebotomy session, about 500 ml of blood is removed. Maintenance phlebotomy is generally required, on average, 2 to 3 times a year to keep the ferritin levels in the normal range.

In hereditary hemochromatosis chelating therapy usually is not required.

Prognosis.

In early detected cases the life expectancy should be normal. In late detected cases the prognosis varies according to the degree of damage to organs and the organs involved.

written in memoriam of classmate Rama Mukherjee. 

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