IRON OVERLOADIRON OVERLOAD

Prepared by:Prepared by:Najla AbdulAziz Al-SweelNajla AbdulAziz Al-Sweel

Supervised by:Supervised by:Dr.Sadia AjumandDr.Sadia Ajumand

Iron Homeostasis:Iron Homeostasis:

Iron absorption is regulated by three Iron absorption is regulated by three mechanisms:mechanisms:

1-dietary regulator1-dietary regulator

2-stores regulator2-stores regulator

3-erythropoietic regulator3-erythropoietic regulator

Definition of iron overload:Definition of iron overload:

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

Classification:Classification:

1-Primary iron overload1-Primary iron overload A) Hereditary hemochromchromatosis:A) Hereditary hemochromchromatosis: B) Aceruloplasminaemia B) Aceruloplasminaemia C) Congenital atransferrinaemia C) Congenital atransferrinaemia D) Neonatal hemochromatosisD) Neonatal hemochromatosis2-Secondary iron overload2-Secondary iron overload

A) Dietary iron overloadA) Dietary iron overloadB) Parenteral iron overload B) Parenteral iron overload C) Iron loading anaemiasC) Iron loading anaemiasD) Long term haemodialysisD) Long term haemodialysisE)Chronic liver disease:E)Chronic liver disease:F) Porphyria cutanea tardaF) Porphyria cutanea tardaG) Post-portacaval shuntingG) Post-portacaval shuntingH)Dysmetabolic iron overload syndromeH)Dysmetabolic iron overload syndrome

3-Miscellaneous3-MiscellaneousIron overload in sub-Sahara AfricaIron overload in sub-Sahara Africa

PRIMARY IRON OVERLOADPRIMARY IRON OVERLOAD

Hereditary Hemochromatosis (HH) Type 1Hereditary Hemochromatosis (HH) Type 1Haemochromatosis is a hereditary disease characterized by Haemochromatosis is a hereditary disease characterized by improper processing by the body of dietary iron which causes iron to improper processing by the body of dietary iron which causes iron to accumulate in a number of body tissues, eventually causing organ accumulate in a number of body tissues, eventually causing organ dysfunction. It is the main iron overload disorder.dysfunction. It is the main iron overload disorder.

Epidemiology:Epidemiology:Worldwide frequency of the C282Y and H63D mutations was found Worldwide frequency of the C282Y and H63D mutations was found to be 1.9% and 8.1%, respectively.to be 1.9% and 8.1%, respectively.HH is the most commonly inherited disorder in white patients, HH is the most commonly inherited disorder in white patients, especially in Caucasians of northern European descent.especially in Caucasians of northern European descent.Symptoms of HH occur more frequently in males than in females, Symptoms of HH occur more frequently in males than in females, with a male-to-female ratio of 3:1.with a male-to-female ratio of 3:1.Symptoms of HH develop in persons older than 40 years.Symptoms of HH develop in persons older than 40 years.

Genetics of HH Type 1:Genetics of HH Type 1:

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

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

Mutations in the HFE gene are Mutations in the HFE gene are responsible for 90% of responsible for 90% of HHHH Type 1 cases. Type 1 cases.

These mutations include:These mutations include:

1. C282Y (major mutation):1. C282Y (major mutation): This missense mutation, caused by a guanine to adenine This missense mutation, caused by a guanine to adenine

transition at nucleotide 845 (TGC TAC), results in the transition at nucleotide 845 (TGC TAC), results in the substitution of cysteine (C) by tyrosine (Y) at amino acid substitution of cysteine (C) by tyrosine (Y) at amino acid position 282 in the HFE protein product.position 282 in the HFE protein product.

2. H63D (minor mutation):2. H63D (minor mutation): This missense mutation caused by a guanine to cytosine This missense mutation caused by a guanine to cytosine

transition at the187th nucleotide, results in the transition at the187th nucleotide, results in the substitution of histidine (H) by aspartate (D) at amino substitution of histidine (H) by aspartate (D) at amino acid position 63 in the HFE protein.acid position 63 in the HFE protein.

*Other mutations have been described in HFE*Other mutations have been described in HFE but most are but most are very low frequency.very low frequency.

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

Factors which influence the phenotypic Factors which influence the phenotypic expression of HH Type 1:expression of HH Type 1:

Environmental factors which affect iron storesEnvironmental factors which affect iron stores

Factors which affect iron absorptionFactors which affect iron absorption

Inheritance of HH Type 1:Inheritance of HH Type 1:

The pattern of inheritance in families of HH is The pattern of inheritance in families of HH is described as autosomal recessive, meaning that described as autosomal recessive, meaning that a child must inherit two mutated copies of the a child must inherit two mutated copies of the gene, one from each parent, in order to develop gene, one from each parent, in order to develop HH.HH.

Pathophysiology:Pathophysiology:

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

Consequences

1. Damage to the liver:1. Damage to the liver:

2. Damage to the heart:2. Damage to the heart:

3. Damage to the endocrine 3. Damage to the endocrine system:system:

4. Damage to the skeletomuscular 4. Damage to the skeletomuscular system:system:

5. Effects on skin5. Effects on skin::

6. Compromise of the immune 6. Compromise of the immune system:system:

Withholding iron from potential pathogens Withholding iron from potential pathogens is a strategy used in host defense.is a strategy used in host defense.

Very high transferrin saturations Very high transferrin saturations compromise the bacteriostatic properties compromise the bacteriostatic properties of transferrin.of transferrin.

The natural history of HH The natural history of HH includes three phases:includes three phases:

A phase of latency. A phase of latency. A phase of biochemical A phase of biochemical expression, asymptomatic, expression, asymptomatic, which appears around the which appears around the age of 20.age of 20.A phase of clinical A phase of clinical expression, symptomatic, expression, symptomatic, which appears later during which appears later during adulthood.adulthood.

Signs and Symptoms:Signs and Symptoms:Hemochromatosis is Hemochromatosis is notoriously protean.notoriously protean.

Diagnosis:Diagnosis:1. Transferrin saturation test:1. Transferrin saturation test:

Normal TS values range from 16% to 45%, if the TS test result Normal TS values range from 16% to 45%, if the TS test result is >45% it is considered elevated and is suggestive of HH.is >45% it is considered elevated and is suggestive of HH.

2. Serum ferritin test:2. Serum ferritin test:Normal SF levels are <200ng/ml in premenopausal females Normal SF levels are <200ng/ml in premenopausal females and <300ng/ml in males, SF levels >200ng/ml in and <300ng/ml in males, SF levels >200ng/ml in premenopausal females or >300ng/ml in males or premenopausal females or >300ng/ml in males or postmenopausal females is considered elevated.postmenopausal females is considered elevated.

3. Confirming the HH diagnosis:3. Confirming the HH diagnosis:A. Quantitative phlebotomyA. Quantitative phlebotomyB. Molecular genetic testingB. Molecular genetic testingC. Liver biopsyC. Liver biopsy

A hemochromatosis diagnosis identifies a patient who needs A hemochromatosis diagnosis identifies a patient who needs treatment and a family potentially at risk. Family-based treatment and a family potentially at risk. Family-based detection is an efficient way to identify those who have an detection is an efficient way to identify those who have an increased risk of developing hemochromatosis, and an increased risk of developing hemochromatosis, and an important disease prevention opportunity.important disease prevention opportunity.

Treatment and Management:Treatment and Management:

Periodic phlebotomy is a simple, inexpensive, safe, and Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment.effective treatment.

Therapeutic phlebotomy includes an induction phase to Therapeutic phlebotomy includes an induction phase to induce iron depletion and a maintenance phase to induce iron depletion and a maintenance phase to prevent excess iron reaccumulation.prevent excess iron reaccumulation.

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

Current Research in Current Research in Hemochromatosis is Hemochromatosis is

Concentrated in Four Areas:Concentrated in Four Areas:

GeneticsGenetics

PathogenesisPathogenesis

EpidemiologyEpidemiology

Screening and testingScreening and testing

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