1. Prepared by: Najla AbdulAziz Al-Sweel Supervised by: Dr.Sadia Ajumand
IRON OVERLOAD
Prepared by: Najla AbdulAziz Al-Sweel Supervised by: Dr.Sadia Ajumand

2. Iron Homeostasis:

3. Iron absorption is regulated by three mechanisms:
1-dietary regulator
2-stores regulator
3-erythropoietic regulator

4. Definition of iron overload:
A polyetiologic condition characterized by a moderate or severe increase in body iron levels that has or will have negative effects on health.

5. Classification: 1-Primary iron overload
A) Hereditary hemochromchromatosis:
B) Aceruloplasminaemia
C) Congenital atransferrinaemia
D) Neonatal hemochromatosis
2-Secondary iron overload A) Dietary iron overload B) Parenteral iron overload C) Iron loading anaemias D) Long term haemodialysis E)Chronic liver disease: F) Porphyria cutanea tarda G) Post-portacaval shunting H)Dysmetabolic iron overload syndrome
3-Miscellaneous Iron overload in sub-Sahara Africa

6. PRIMARY IRON OVERLOAD
Hereditary Hemochromatosis (HH) Type 1
Haemochromatosis is a hereditary disease characterized by improper processing by the body of dietary iron which causes iron to accumulate in a number of body tissues, eventually causing organ dysfunction. It is the main iron overload disorder.
Epidemiology:
Worldwide frequency of the C282Y and H63D mutations was found to be 1.9% and 8.1%, respectively.
HH is the most commonly inherited disorder in white patients, especially in Caucasians of northern European descent.
Symptoms of HH occur more frequently in males than in females, with a male-to-female ratio of 3:1.
Symptoms of HH develop in persons older than 40 years.

7. Genetics of HH Type 1:
The HFE gene resides on chromosome 6, is located at band 6p22 and encodes a protein containing 343 amino acids. This HFE protein spans the cell membrane.
Its external portion includes a nonfunctional peptide-binding domain, it has an alpha3 loop, the site where HFE associates with an accessory protein called beta2-microglobulin. This interaction is necessary for normal presentation on the cell surface.

8. The role of HFE in the regulation of cellular iron uptake:

9. Mutations in the HFE gene are responsible for 90% of HH Type 1 cases
Mutations in the HFE gene are responsible for 90% of HH Type 1 cases. These mutations include:
1. C282Y (major mutation):
This missense mutation, caused by a guanine to adenine transition at nucleotide 845 (TGC TAC), results in the substitution of cysteine (C) by tyrosine (Y) at amino acid position 282 in the HFE protein product.
2. H63D (minor mutation):
This missense mutation caused by a guanine to cytosine transition at the187th nucleotide, results in the substitution of histidine (H) by aspartate (D) at amino acid position 63 in the HFE protein.
*Other mutations have been described in HFE but most are very low frequency.

10. The effect of major and minor HFE mutations on cellular iron uptake:

11. Factors which influence the phenotypic expression of HH Type 1:
Environmental factors which affect iron stores
Factors which affect iron absorption
Inheritance of HH Type 1:
The pattern of inheritance in families of HH is described as autosomal recessive, meaning that a child must inherit two mutated copies of the gene, one from each parent, in order to develop HH.

12. Pathophysiology:
The causative defect--the one permitting excessive iron absorption--is most likely to be within the intestinal lining. The sensor pathway inside the enterocyte is disrupted due to the genetic errors.
Persons affected with HH absorb 3 to 4 mg/day of iron. Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin starts to get stored as a breakdown product of ferritin called haemosiderin which is toxic to tissue.
As ferrous iron accumulates in the parenchymal tissues, the intracellular iron-binding sites are overwhelmed. Labile iron can promote damage of cellular organelles by radical formation which results in lipid peroxidation, cellular injury, and fibrosis.

13. Consequences

14. 1. Damage to the liver:

15. 2. Damage to the heart:

16. 3. Damage to the endocrine system:

17. 4. Damage to the skeletomuscular system:

18. 5. Effects on skin:

19. 6. Compromise of the immune system:
Withholding iron from potential pathogens is a strategy used in host defense.
Very high transferrin saturations compromise the bacteriostatic properties of transferrin.

20. The natural history of HH includes three phases:
A phase of latency.
A phase of biochemical expression, asymptomatic, which appears around the age of 20.
A phase of clinical expression, symptomatic, which appears later during adulthood.
Signs and Symptoms:
Hemochromatosis is notoriously protean.

21. Diagnosis: 1. Transferrin saturation test:
Normal TS values range from 16% to 45%, if the TS test result is >45% it is considered elevated and is suggestive of HH.
2. Serum ferritin test:
Normal SF levels are <200ng/ml in premenopausal females and <300ng/ml in males, SF levels >200ng/ml in premenopausal females or >300ng/ml in males or postmenopausal females is considered elevated.
3. Confirming the HH diagnosis:
A. Quantitative phlebotomy
B. Molecular genetic testing
C. Liver biopsy
A hemochromatosis diagnosis identifies a patient who needs treatment and a family potentially at risk. Family-based detection is an efficient way to identify those who have an increased risk of developing hemochromatosis, and an important disease prevention opportunity.

22. Treatment and Management:
Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment.
Therapeutic phlebotomy includes an induction phase to induce iron depletion and a maintenance phase to prevent excess iron reaccumulation.

23. Prognosis:
The degree of iron overload at the time of diagnosis, as well as organ dysfunction, have prognostic implications.
The causes of death in untreated patients include cardiac failure (30%), liver failure or portal hypertension (25%), and hepatocellular carcinoma (30%).
When HH is found early and properly managed, long-term prognosis, including life expectancy, should not differ from that of persons without the disorder.

24. Current Research in Hemochromatosis is Concentrated in Four Areas:
Genetics
Pathogenesis
Epidemiology
Screening and testing

25. THANK
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