1. Iron overload, also known as hemochromatosis, occurs when the body absorbs more iron than it loses, causing excess iron to accumulate and damage organs. It is commonly caused by a genetic disorder or frequent blood transfusions. 2. Hepcidin regulates iron levels in the body. Iron overload results from low hepcidin leading to increased iron absorption in the gut and spleen. 3. Treatment involves regular phlebotomy to remove excess iron from the body. Phlebotomy can prevent organ damage if started early and allows patients to live normally once iron levels are normalized.

1. Iron overload Dr. Niveen M. Daoud Ass. Prof. clinical pathology and molecular biology Faculty of Medicine , Taif University

2. Hepcidin Hepcidinisthe key hormone of ironregulation

3. Body Iron Regulation by Hepcidin Body iron decrease lowers hepcidin synthesis in the liver 1 Hepcidin deficiency targets the duodenum and spleen 2 Duodenal absorption of iron increases 3 Splenic iron is released into the circulation 4 Iron concentration in plasma increases, leading to restoration of iron balance 5 Iron Deficiency 1 Hepcidin 2 Iron 4 5 3 Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.

4. What Is iron overload ? 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. caused commonly by genetic disorder (HH) or Acquired hemochromatosis which caused by numerous blood transfusions, iron injections, high levels of iron supplements.

6. HFE or non HFE mutations decrease hepcidin synthesis in the liver 1 Hepcidin deficiency targets the duodenum and spleen 2 Duodenal absorption of iron increases 3 Splenic iron is released into the circulation 4 Iron concentration in plasma strongly increases 5 Increased plasma iron produces parenchymal iron deposition 6 Haemochromatosis—Quantitative Hepcidin Defect 1 HFE 0r non HFE(mutations Hepcidin 6 2 Iron 4 5 3 Brissot P, et al. Blood Rev. 2008;22:195-210.

7. Other causes of the disease Other factors may influence the progression of hemochromatosis. These factors include: Excess iron in the diet Alcohol consumption Vitamin C intake Infections (virus C) blood donations Environmental factors

8. II. Hemosiderosis It include all cases of excessive iron deposition except idiopathic hemochromatosis CAUSES Blood transfusion Excessive iron medication Thalassemias Liver disease Idiopathic pulmonary hemosiderosis (local) Treated by iron chelating agents.

9. Iron Overload Diseases Anaemia Sideroblasticanaemias Thalassaemias Sicklecelldisease Rare anaemias Iron Overload

10. Iron Overload Diseases Dyserythropoiesis Hepcidin Sideroblasticanaemias Thalassaemias Sicklecelldisease Rare anaemias Anaemia Iron Overload Graphic courtesy of Dr. P. Brissot.

11. GDF15 Effect of Dyserythropoiesison Body Iron Regulation Dyserythropoiesis Hepcidin Iron Abbreviation: GDF, growth differentiation factor. Tanno T, et al. Nat Med. 2007;13:1096-1101.

12. HIF Effect of Hypoxia on Body Iron Regulation Hypoxia Hepcidin Iron Abbreviation: HIF, hypoxia inducible factor. Peyssonnaux C, et al. J Clin Invest. 2007;117:1926-1932.

13. ROS Effect of Alcohol on Body Iron Regulation Hepcidin Iron Abbreviation: ROS, reactive oxygen species. Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930.

14. ROS Effect of Hepatitis C Virus Infection on Body Iron Regulation Hepcidin Hepatitis C Virus Iron Nishina S, et al. Gastroenterology. 2008;134:226-238.

15. Iron Overload Net absorption of 3-4 mg/day Accumulation of 500 to 1000 mg iron/yr Clinical manifestations often occur after age 40 OR when stores are 15-40 g

16. Pathophysiology Inborn error in iron metabolism Increased iron absorption from the diet Iron overload Eventual fibrosis and organ failure Cirrhosis Cardiomyopathy Diabetes Hypogonadism

17. Clinical Manifestations Influenced by Age Sex Dietary iron Alcohol Blood loss in menstruation and pregnancy Alcohol abuse and Hepatitis C accelerate Classic description: cutaneoushyperpigmentation and diabetes in a patient with cirrhosis

18. What Are the Symptoms of Iron Overload or Hemochromatosis? While there is no distinct set of symptoms that indicate iron overload, early symptoms of iron overload or hemochromatosis include: Fatigue Weakness Weight loss Joint pain Abdominal pain

19. Symptoms – Traditional Concept Cirrhosis (hepatic damage) Diabetes (type II) (pancreatic damage) Bronzing of skin (hyperpigmentation) Traditional triad means diagnosed too late! Damage may be only partially reversible Goal is to detect the disease BEFORE organ damage occurs

20. Reversible Manifestations Heart: cardiomyopathy, conduction disturbances Liver: abdominal pain,, hepatomegaly Skin: bronzing (melanin deposition), gray pigmentation (iron deposition) Infection (Vibriovulnificus, Listeriamonocytogenes, Pasteurellapseudotuberculosis)

21. Irreversible Manisfestations Liver: cirrhosis, hepatocellular carcinoma (most common cause of death) Pituitary gland: gonadotropin insufficiency leading to secondary hypogonadism adrenal function disorders Pancreas: diabetes mellitus (30-60%) Thyroid: hypothyroidism Genitalia: primary hypogonadism Joints: arthropathy(20-70%), pseudogout

23. Laboratory finding cont. Raised serum iron level Abnormal liver function Endocrine abnormalities ( increase blood glucose) PATHOLOGIC Liver biobsy is gold indicator test

24. Men versus women 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

26. Iron Overload or Hemochromatosis treatment 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. 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. 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

29. Phlebotomy Removal of 500 ml of blood Removes 250 mg iron Do weekly until iron depletion Hgb < 120 Ferritin < 50 Transferritin saturation < 50% 2-3 years may be required to remove >20g Long term maintenance about once every 3 months

31. Prevention/Solution 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