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Iron overload

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iron over load disease
clinical syptoms

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Iron overload

  1. 1. Iron overload<br />Dr. Niveen M. Daoud<br />Ass. Prof. clinical pathology and molecular biology<br />Faculty of Medicine , Taif University<br />
  2. 2. Hepcidin<br />Hepcidinisthe key hormone of ironregulation<br />
  3. 3. Body Iron Regulation by Hepcidin<br />Body iron decrease lowers hepcidin synthesis in the liver<br />1<br />Hepcidin deficiency targets the duodenum and spleen<br />2<br />Duodenal absorption of iron increases<br />3<br />Splenic iron is released into the circulation<br />4<br />Iron concentration in plasma increases, leading to restoration of iron balance<br />5<br />Iron Deficiency<br />1<br />Hepcidin<br />2<br />Iron<br />4<br />5<br />3<br />Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.<br />
  4. 4. What Is iron overload ?<br />Iron overload, is a disease more clinically known as hereditary hemochromatosis (HH) in which the body absorbs more iron from the gut than it loses, causing the mineral to accumulate in specific areas of the body cause damage to various organs. <br />caused commonly by genetic disorder (HH) or <br />Acquired hemochromatosis which caused by numerous blood transfusions, iron injections, high levels of iron supplements.<br />
  5. 5. Genetics of Iron Overload (HH)<br /><ul><li>Iron overload is a genetic disorder that can only be transmitted via inheritance of abnormal genes from both parents. If the child inherits abnormal genes from both sets of parents there is a chance to the develop of the disease. It cannot develop of the child receives the abnormal gene from only one parent.</li></li></ul><li>Autosomal Recessive Inheritance<br />Legend<br />B:Normal HFE gene<br />b: HFE gene with mutation<br />Unaffectedcarrier<br />Unaffected Carrier<br />Bb<br />Bb<br />BB<br />Bb<br />Bb<br />bb<br />Unaffected<br />Susceptible genotype for <br />Hemochromatosis<br />Unaffected<br />carrier<br />Unaffected<br />carrier<br />
  6. 6. HFE or non HFE mutations decrease hepcidin synthesis in the liver<br />1<br />Hepcidin deficiency targets the duodenum and spleen<br />2<br />Duodenal absorption of iron increases<br />3<br />Splenic iron is released into the circulation<br />4<br />Iron concentration in plasma strongly increases<br />5<br />Increased plasma iron produces parenchymal iron deposition<br />6<br />Haemochromatosis—Quantitative Hepcidin Defect<br />1<br />HFE 0r non HFE(mutations<br />Hepcidin<br />6<br />2<br />Iron<br />4<br />5<br />3<br />Brissot P, et al. Blood Rev. 2008;22:195-210.<br />
  7. 7. Other causes of the disease<br />Other factors may influence the progression of hemochromatosis. These factors include: <br />Excess iron in the diet <br />Alcohol consumption <br />Vitamin C intake <br />Infections (virus C)<br />blood donations <br />Environmental factors<br />
  8. 8. II. Hemosiderosis<br />It include all cases of excessive iron deposition except idiopathic hemochromatosis<br />CAUSES<br />Blood transfusion<br />Excessive iron medication <br />Thalassemias<br />Liver disease <br />Idiopathic pulmonary hemosiderosis (local)<br />Treated by iron chelating agents.<br />
  9. 9. Iron Overload Diseases<br />Anaemia<br />Sideroblasticanaemias<br />Thalassaemias<br />Sicklecelldisease<br />Rare anaemias<br />Iron Overload<br />
  10. 10. Iron Overload Diseases<br />Dyserythropoiesis<br />Hepcidin<br />Sideroblasticanaemias<br />Thalassaemias<br />Sicklecelldisease<br />Rare anaemias<br />Anaemia<br />Iron Overload<br />Graphic courtesy of Dr. P. Brissot.<br />
  11. 11. GDF15<br />Effect of Dyserythropoiesison Body Iron Regulation<br />Dyserythropoiesis<br />Hepcidin<br />Iron<br />Abbreviation: GDF, growth differentiation factor.<br />Tanno T, et al. Nat Med. 2007;13:1096-1101.<br />
  12. 12. HIF<br />Effect of Hypoxia on Body Iron Regulation<br />Hypoxia<br />Hepcidin<br />Iron<br />Abbreviation: HIF, hypoxia inducible factor.<br />Peyssonnaux C, et al. J Clin Invest. 2007;117:1926-1932.<br />
  13. 13. ROS<br />Effect of Alcohol on Body Iron Regulation<br />Hepcidin<br />Iron<br />Abbreviation: ROS, reactive oxygen species.<br />Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930.<br />
  14. 14. ROS<br />Effect of Hepatitis C Virus Infection on Body Iron Regulation<br />Hepcidin<br />Hepatitis C Virus<br />Iron<br />Nishina S, et al. Gastroenterology. 2008;134:226-238.<br />
  15. 15. Iron Overload<br />Net absorption of 3-4 mg/day <br />Accumulation of 500 to 1000 mg iron/yr<br />Clinical manifestations often occur after age 40 OR when stores are 15-40 g<br />
  16. 16. Pathophysiology<br />Inborn error in iron metabolism<br />Increased iron absorption from the diet<br />Iron overload<br />Eventual fibrosis and organ failure<br />Cirrhosis<br />Cardiomyopathy<br />Diabetes<br />Hypogonadism<br />
  17. 17. Clinical Manifestations<br />Influenced by<br />Age<br />Sex<br />Dietary iron<br />Alcohol<br />Blood loss in menstruation and pregnancy<br />Alcohol abuse and Hepatitis C accelerate <br />Classic description: cutaneoushyperpigmentation and diabetes in a patient with cirrhosis<br />
  18. 18. What Are the Symptoms of Iron Overload or Hemochromatosis?<br />While there is no distinct set of symptoms that indicate iron overload, early symptoms of iron overload or hemochromatosis include: <br />Fatigue <br />Weakness <br />Weight loss <br />Joint pain <br />Abdominal pain<br />
  19. 19. Symptoms – Traditional Concept<br />Cirrhosis (hepatic damage)<br />Diabetes (type II) (pancreatic damage)<br />Bronzing of skin (hyperpigmentation)<br />Traditional triad means diagnosed too late!<br />Damage may be only partially reversible<br />Goal is to detect the disease BEFORE organ damage occurs<br />
  20. 20. Reversible Manifestations<br />Heart: cardiomyopathy, conduction disturbances<br />Liver: abdominal pain,, hepatomegaly<br />Skin: bronzing (melanin deposition), gray pigmentation (iron deposition)<br />Infection (Vibriovulnificus, Listeriamonocytogenes, Pasteurellapseudotuberculosis)<br />
  21. 21. Irreversible Manisfestations<br />Liver: cirrhosis, hepatocellular carcinoma (most common cause of death)<br />Pituitary gland: gonadotropin insufficiency leading to secondary hypogonadism<br />adrenal function disorders<br />Pancreas: diabetes mellitus (30-60%)<br />Thyroid: hypothyroidism<br />Genitalia: primary hypogonadism<br />Joints: arthropathy(20-70%), pseudogout<br />
  22. 22. Iron Overload Diagnosis<br /><ul><li>Luckily, iron overload is usually diagnosed early as part of a routine test of the iron levels in the blood. The test will return with abnormally high levels of the mineral. It can also be discovered through routine screening of children of parents with the abnormal gene. Symptoms of hereditary hemochromatosis do not usually appear until much later in life.</li></li></ul><li>Diagnosis<br />Combination of criteria<br />Clinical manifstation<br />Laboratory<br />Elevated serum transferrin saturation >45%(earliest abnormality) and an elevated serum ferritin<br />Caution serum ferritin = acute phase reactant<br />N.B. Transferrin saturation represent the amount of iron binding sites that are occupied(33%).<br />Ferritin is the chief iron storage protein in the body.<br />
  23. 23. Laboratory finding cont. <br />Raised serum iron level<br />Abnormal liver function<br />Endocrine abnormalities ( increase blood glucose)<br />PATHOLOGIC <br />Liver biobsy is gold indicator test <br />
  24. 24. Men versus women<br />Symptoms of iron overload do not typically show up until the 40s or 50s in most men and 15-20 years later in women. Men have a tendency to eat more foods high in iron and women lose more iron than men through both menstruation and breast feeding<br />
  25. 25. iron overload Complication<br /><ul><li>As the iron accumulates in the body, it settles in areas like the testes, heart, liver, and pancreas. Once the iron has settled into these organs and increases in amount through the years, it can begin damaging the organs and causing severe complication. Iron in the testes can result in impotence and testicular shrinkage. Iron in the heart can develop cause heart attacks and deposits in the liver can cause cirrhosis and liver cancer. If the iron deposits in the pancreas, it can cause diabetes. If gone untreated, the complications from iron overload could lead to death.</li></li></ul><li>Iron Overload or Hemochromatosis treatment <br />The most common way to treat iron overload is to reduce the amount of iron in the body. This can be done through diet by eating foodslow in iron or through the withdrawal of blood. The preferred treatment for reducing iron levels in hemochromatosis patients is called therapeutic phlebotomy ( repeated venesection). <br />
  26. 26. Iron Overload or Hemochromatosis treatment <br />Phlebotomy is simply the removing of blood from the body. Begun early, phlebotomy prevents much of the damage that is caused by iron overload. Patients who have no evidence of tissue or organ damage when diagnosed can often expect a full and normal life. Patients who already have organ or tissue damage can stop the progression of hemochromatosis and expect no further damage, a reduction in symptoms, and improved life expectancy once phlebotomy begins.<br />The usual course of treatment involves the removal of one unit of whole blood once or twice weekly. Phlebotomy continues until all excess iron is removed. Iron levels in the blood are monitored continuously throughout treatment. The length and frequency of treatment is determined by patient age, gender, reason for diagnosis, and severity of symptoms. <br />Once normal iron levels are achieved, the frequency of phlebotomy may be reduced to three or four times a year according to individual patient symptoms and levels of hemoglobin and serum ferritin<br />
  27. 27. HFE-HaemochromatosisResults of Phlebotomies<br />Two important notions<br /><ul><li>If cirrhosis was present prior to phlebotomies, the risk for hepatocellular carcinoma remains (requiring plasma alpha-feto-protein dosage and liver ultrasound every 6 months)1
  28. 28. If cirrhosis or insulin-dependent diabetes was not present prior to phlebotomies, life expectancy returns to normal2</li></li></ul><li>Principle of Phlebotomy<br />Fe<br />Fe<br />Fe<br />Fe<br />Fe<br />Fe<br />RBC<br />RBC<br />RBC<br /> Phlebotomy<br />Hepatocyte<br />Bone marrow<br />3<br />2<br />BLOOD<br />1<br />Courtesy of P. Brissot<br />
  29. 29. Phlebotomy<br />Removal of 500 ml of blood<br />Removes 250 mg iron<br />Do weekly until iron depletion<br />Hgb < 120<br />Ferritin < 50<br />Transferritin saturation < 50%<br />2-3 years may be required to remove >20g<br />Long term maintenance about once every 3 months<br />
  30. 30. Treatment Perspectives<br /><ul><li>Short-term perspective </li></ul>Once daily oral chelator<br /><ul><li>Longer-termperspective </li></ul>Hepcidinsupplementation<br />
  31. 31. Prevention/Solution<br />Even in cases where blood transfusions can't be avoided as in ….., exercising caution in the amount of iron supplements and iron injections a patient takes may help decrease the chances of iron overload<br />