Hemochromatosis

Group 5
Members: Roy Permual Leeanna Humphrey Anupana Himendranauth Joanne Beejaimal Nikita Shaw Rajshrie Ramlochan

Hemochromatosis
Hemochromatosis (also known as primary or hereditary hemochromatosis) is a genetic disorder in which there is abnormal accumulation of iron in the body. The body absorbs an excessive amount of iron from the diet which is deposited mainly in parenchymal organs such as the liver, heart and pancreas.[1] It is the most common inherited liver disease in Caucasians and the most common autosomal recessive genetic disorder. Accumulation of iron in tissues resulting from blood transfusions and blood disorders is known as secondary/acquired hemochromatosis or hemosiderosis.[2]

Pathology
Because there is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. In hemochromatosis, this regulation is abnormal, and leads to a net iron accumulation of 0.5 to 1.0 g/year, mainly in the liver. The disease typically manifests itself after 20g of stored iron would have accumulated.[2] The main regulator of iron absorption is the protein hepcidin, produced by hepatocytes. It prevents the release of iron from intestinal cells and macrophages thus helping to lower plasma iron levels. Conversely, a deficiency in hepcidin causes iron overload. Other proteins involved in iron metabolism, do so by regulating hepcidin levels. These include hemojuvelin (HJV), which is expressed in the liver, heart, and skeletal muscle; transferrin receptor 2 (TfR2), which is highly expressed in hepatocytes, where it mediates the uptake of transferrin-bound iron; and HFE, the product of the hemochromatosis gene.[2] Hemochromatosis is caused when there us a lack of hepcidin expression caused by mutations in either hepcidin, HJV, TfR2, or HFE. Of these mutations, those of HFE are the most common. Mutations of HJV cause a severe form of hereditary hemochromatosis, known as juvenile hemochromatosis.

Aetiology
Hereditary hemochromatosis is an autosomal recessive disease with an estimated prevalence of 1 in 500 among Europeans and Americans. The gene responsible for this condition is known as the HFE gene which is located on chromosome 6. HFE basically regulates the amount of iron absorbed from food and mutations in this gene are the cause of hereditary hemochromatosis. The two known mutations of HFE are C282Y and H63D.[3] The first mutation, C282Y, involves the substitution of tyrosine for cysteine at amino acid position 282 on the HFE gene. In the second mutation, H63D, aspartic acid is substituted for histidine at position 63 on the HFE gene. C282Y homozygosity or compound heterozygosity [C282Y/H63D] is found in most patients with hereditary hemochromatosis.[4] ~1~

C282Y is the more important of the two mutations. In persons who inherit C282Y from both parents, the body absorbs too much iron and hemochromatosis can result. However, hemochromatosis shows reduced penetrance and not everyone with two abnormal genes develops signs and symptoms of the disease. Those who inherit the defective gene from only one parent are carriers for the disease and usually do not develop it. However, they tend to have higher than average iron absorption.[4] Secondary hemochromatosis is caused by disorders of erythropoiesis and treatment with blood transfusions. Transfused erythrocytes are damaged by macrophages leading to the release of iron from haeme which then accumulates in the body in the liver, heart and skin etc. It is mainly induced by diseases of erythropoiesis, including thalassemias, sickle cell anaemia and pyruvate kinase deficiency.[2]

Signs and Symptoms

Early Stage: These symptoms are easily missed because they are similar to other diseases. They include fatigue, weakness, weight loss, unexplained abdominal pain, joint pain and/or a fluttering in chest and loss of body hair.[5] Advanced Stage: If not diagnosed and treated ,iron builds up and can lead to; Liver disease, including an enlarged liver, liver failure, liver cancer, or cirrhosis Heart problems, such as, arrhythmias (irregular heartbeats) and heart failure Joint damage and pain, including arthritis Changes in skin colour that make the skin look grey or bronze Reproductive organ failure, such as erectile dysfunction (impotence), shrinkage of the testicles, loss of sex drive in men and absence of the menstrual cycle and early menopause in women Other complications include underactive pituitary and thyroid glands, damage to the adrenal glands and diabetes.[6]

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Diagnosis of Hemochromatosis
Hereditary hemochromatosis can be difficult to diagnose. Early symptoms such as stiff joints and fatigue can result from a number of conditions that are more common than hemochromatosis. A physical examination shows liver and spleen swelling, and skin colour changes.[7] Blood Tests Serum transferrin saturation: This test measures the amount of iron bound to the transferrin protein that carries iron in the blood. Transferrin saturation values greater than 45% are considered too high.[8] Serum ferritin: This test measures the amount of iron stored in the liver. If the results of the serum transferrin saturation test are higher than normal, a serum ferritin test is usually ordered. (Normal values: >200 g/L in females and >300 g/L in males).[8] Additional Testing To confirm a diagnosis of hereditary hemochromatosis, doctors may suggest other tests, including: Testing for gene mutations: A test is carried out on a sample of DNA for mutations in the HFE gene. This test can help confirm a diagnosis of hereditary hemochromatosis.[8] Removing a sample of liver tissue for testing: During a liver biopsy, doctors remove a sample of tissue from the liver via fine needle biopsy. The sample is sent to a laboratory where it is checked for the presence of iron as well as for evidence of liver damage, especially scarring or cirrhosis. Risks of biopsy include bruising, bleeding and infection.[8] Screening healthy people for hemochromatosis: People considered to have a high risk of hemochromatosis may undergo screening tests to determine whether they have the condition before complications can occur, Doctors may recommend a blood test to determine if someone has hemochromatosis even if it is asymptomatic, .[8]

Treatment
The goals of treating hemochromatosis are aimed at; Reducing the amount of iron in the body to normal levels Preventing or delaying organ damage from iron overload Treating complications of the disease Maintaining a normal amount of iron in your body for the rest of your life

Treatment options include therapeutic phlebotomy, iron chelation therapy, dietary changes, and treatment for complications. ~3~

Therapeutic Phlebotomy This is a procedure that removes blood (and iron) from your body. A needle is inserted into a vein, and blood flows through an airtight tube into a sterile container/bag.[9] In the first stage of treatment, about one pint of blood is removed once or twice a week. After iron levels return to normal, the person may continue phlebotomy treatments, although less frequentlytypically every 24 months.[9] Iron Chelation Therapy Iron chelation therapy uses medicine to remove excess iron from your body. This treatment is a good option for people who cannot have routine blood removal. The medicine used in iron chelation therapy is either injected or taken orally. Injected iron chelation therapy is done at a doctor's office. Oral iron chelation therapy can be done at home.[9] Dietary Changes Avoid taking iron; including iron pills, iron injections, or multivitamins that contain iron. Limit intake of vitamin C; this helps your body absorb iron from food. Avoid uncooked fish and shellfish as some contain bacteria that can cause infections in people who have chronic diseases such as hemochromatosis. Limit alcohol intake; drinking alcohol increases the risk of liver disease and can also make existing liver disease worse.[10]

Prognosis
Sharpened diagnostic awareness has improved the early diagnosis of hereditary hemochromatosis and as such, increased its diagnostic frequency. Early detection and treatment of this common iron overload disorder can guarantee a normal lifespan in patients with hemochromatosis. The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. Patients without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy. If untreated, hemochromatosis may lead to death from cirrhosis, diabetes, malignant hepatoma, or cardiac disease.[11] Potential complications of hemochromatosis include liver cirrhosis, hepatocellular carcinoma, congestive heart failure, cardiac arrhythmias, diabetes mellitus, hypogonadism, impotence, arthropathy, thyroid dysfunction and sepsis.[12]

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Bibliography
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Kumar, Abbas, Fausto, & Mitchell. (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders Elsevier. Kumar, Abbas, Fausto, & Aster. (2010). Robbins and Cotran Pathologic Basis of Disease (8th ed.). Philadelphia: Saunders Elsevier. Mayo Clinic. (2011, August 2). Hemochromatosis: Causes. Retrieved May 10, 2012, from http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=causes Duchini, A., Sfeir, H. E., Klachko, D. M., & Katz, J. (2011, December 1). Hemochromatosis: Background. Retrieved May 10, 2012, from Medscape: http://emedicine.medscape.com/article/177216-overview ThirdAge. (2010, May 6). Hemochromatosis: Signs & Symptoms. Retrieved May 10, 2012, from http://www.thirdage.com/blood-disorders/hemochromatosis-signs-symptoms Adam & Yahoo Health. (2012). Hemochromatosis. Retrieved May 10, 2012, from http://health.yahoo.net/channel/hemochromatosis.html The National Digestive Diseases Information Clearinghouse (NDDIC). (2007, April). Hemochromatosis. Retrieved May 10, 2012, from http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/#tests Mayo Clinic. (2010, September 11). Hemochromatosis: Tests and Diagnosis. Retrieved May 10, 2012, from http://www.mayoclinic.com/health/hemochromatosis/ds00455/dsection=tests-anddiagnosis National Heart, Lung, and Blood Institute (NHLBI). (2011). Hemochromatosis:Treatment. Retrieved May 10, 2012, from http://www.nhlbi.nih.gov/health/healthtopics/topics/hemo/treatment.html Dugdale, D. C., Mason, J. R., & Zieve, D. (2010, April 12). Hemochromatosis: Treatment. Retrieved May 10, 2012, from MedlinePlus: http://www.nlm.nih.gov/medlineplus/ency/article/000327.htm Niederau, C., & Strohmeyer, G. S. (1994). Epidemiology, clinical spectrum and prognosis of hemochromatosis. Advances in Experimental Medicine and Biology, 356;293-302. Milman, N., Pedersen, P., Steig, T., Byg, K., Graudal, N., & Fenger, K. (2001). Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients, Annals of Hematology, 80 (12);737-44.

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