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 overloadDr. Niveen M. DaoudAss. Prof. clinical pathology and molecular biologyFaculty of Medicine , Taif University

2. HepcidinHepcidinisthe key hormone of ironregulation

3. Body Iron Regulation by HepcidinBody iron decrease lowers hepcidin synthesis in the liver1Hepcidin deficiency targets the duodenum and spleen2Duodenal absorption of iron increases3Splenic iron is released into the circulation4Iron concentration in plasma increases, leading to restoration of iron balance5Iron Deficiency1Hepcidin2Iron453Ganz 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.

5. Genetics of Iron Overload (HH)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.Autosomal Recessive InheritanceLegendB:Normal HFE geneb: HFE gene with mutationUnaffectedcarrierUnaffected CarrierBbBbBBBbBbbbUnaffectedSusceptible genotype for HemochromatosisUnaffectedcarrierUnaffectedcarrier

6. HFE or non HFE mutations decrease hepcidin synthesis in the liver1Hepcidin deficiency targets the duodenum and spleen2Duodenal absorption of iron increases3Splenic iron is released into the circulation4Iron concentration in plasma strongly increases5Increased plasma iron produces parenchymal iron deposition6Haemochromatosis—Quantitative Hepcidin Defect1HFE 0r non HFE(mutationsHepcidin62Iron453Brissot P, et al. Blood Rev. 2008;22:195-210.

7. Other causes of the diseaseOther 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. HemosiderosisIt include all cases of excessive iron deposition except idiopathic hemochromatosisCAUSESBlood transfusionExcessive iron medication ThalassemiasLiver disease Idiopathic pulmonary hemosiderosis (local)Treated by iron chelating agents.

9. Iron Overload DiseasesAnaemiaSideroblasticanaemiasThalassaemiasSicklecelldiseaseRare anaemiasIron Overload

10. Iron Overload DiseasesDyserythropoiesisHepcidinSideroblasticanaemiasThalassaemiasSicklecelldiseaseRare anaemiasAnaemiaIron OverloadGraphic courtesy of Dr. P. Brissot.

11. GDF15Effect of Dyserythropoiesison Body Iron RegulationDyserythropoiesisHepcidinIronAbbreviation: GDF, growth differentiation factor.Tanno T, et al. Nat Med. 2007;13:1096-1101.

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

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

14. ROSEffect of Hepatitis C Virus Infection on Body Iron RegulationHepcidinHepatitis C VirusIronNishina S, et al. Gastroenterology. 2008;134:226-238.

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

16. PathophysiologyInborn error in iron metabolismIncreased iron absorption from the dietIron overloadEventual fibrosis and organ failureCirrhosisCardiomyopathyDiabetesHypogonadism

17. Clinical ManifestationsInfluenced byAgeSexDietary ironAlcoholBlood loss in menstruation and pregnancyAlcohol 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 ConceptCirrhosis (hepatic damage)Diabetes (type II) (pancreatic damage)Bronzing of skin (hyperpigmentation)Traditional triad means diagnosed too late!Damage may be only partially reversibleGoal is to detect the disease BEFORE organ damage occurs

20. Reversible ManifestationsHeart: cardiomyopathy, conduction disturbancesLiver: abdominal pain,, hepatomegalySkin: bronzing (melanin deposition), gray pigmentation (iron deposition)Infection (Vibriovulnificus, Listeriamonocytogenes, Pasteurellapseudotuberculosis)

21. Irreversible ManisfestationsLiver: cirrhosis, hepatocellular carcinoma (most common cause of death)Pituitary gland: gonadotropin insufficiency leading to secondary hypogonadismadrenal function disordersPancreas: diabetes mellitus (30-60%)Thyroid: hypothyroidismGenitalia: primary hypogonadismJoints: arthropathy(20-70%), pseudogout

22. Iron Overload DiagnosisLuckily, 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.DiagnosisCombination of criteriaClinical manifstationLaboratoryElevated serum transferrin saturation >45%(earliest abnormality) and an elevated serum ferritinCaution serum ferritin = acute phase reactantN.B. Transferrin saturation represent the amount of iron binding sites that are occupied(33%).Ferritin is the chief iron storage protein in the body.

23. Laboratory finding cont. Raised serum iron levelAbnormal liver functionEndocrine abnormalities ( increase blood glucose)PATHOLOGIC Liver biobsy is gold indicator test

24. Men versus womenSymptoms 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

25. iron overload ComplicationAs 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.Iron Overload or Hemochromatosis treatment 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).

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

27. HFE-HaemochromatosisResults of PhlebotomiesTwo important notionsIf 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. If cirrhosis or insulin-dependent diabetes was not present prior to phlebotomies, life expectancy returns to normal2Principle of PhlebotomyFeFeFeFeFeFeRBCRBCRBC PhlebotomyHepatocyteBone marrow32BLOOD1Courtesy of P. Brissot

29. PhlebotomyRemoval of 500 ml of bloodRemoves 250 mg ironDo weekly until iron depletionHgb < 120Ferritin < 50Transferritin saturation < 50%2-3 years may be required to remove >20gLong term maintenance about once every 3 months

30. Treatment PerspectivesShort-term perspective Once daily oral chelatorLonger-termperspective Hepcidinsupplementation

31. Prevention/SolutionEven 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