Sideroblastic anemia pathophysiology: Difference between revisions
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=== Pathogenesis === | === Pathogenesis === | ||
* It is understood that sideroblastic anemia is the result of defects in the steps of heme biosynthesis that occur within the mitochondrion. | * It is understood that sideroblastic anemia is the result of defects in the steps of heme biosynthesis that occur within the mitochondrion. | ||
* The pathophysiology of sideroblastic anemia depends on the underlying cause. | * The pathophysiology of sideroblastic anemia depends on the underlying cause. | ||
* The X-linked hereditary sideroblastic anemias result from mutations in the gene encoding | |||
* Isoniazide, produces sideroblastic anemia in people who dont use pyridoxine prophylaxis, | * The X-linked hereditary sideroblastic anemias result from mutations in the gene encoding ALAS2. | ||
* Isoniazide, produces sideroblastic anemia in people who dont use pyridoxine prophylaxis, | |||
* Pyridoxine is a cofactor for ALAS2 enzyme. | |||
* Its deficiency directly impairs ALAS function | * Its deficiency directly impairs ALAS function | ||
* Mitochondrial cytopathies result from deletions of portions of the mitochondrial genome . | * Mitochondrial cytopathies result from deletions of portions of the mitochondrial genome . | ||
* The consequent marked mitochondrial dysfunction | |||
* Ethanol is the most common cause of toxin-induced sideroblastic anemia. | * The consequent marked mitochondrial dysfunction causes sideroblastic anemia in these disorders. | ||
* Ethanol is the most common cause of toxin-induced sideroblastic anemia. | |||
* Ethanol causes sideroblastic anemia by two mechanisms | * Ethanol causes sideroblastic anemia by two mechanisms | ||
** Direct antagonism to pyridoxal phosphate | ** Direct antagonism to pyridoxal phosphate | ||
** Dietary deficiency of this compound. | ** Dietary deficiency of this compound. | ||
* The bone marrow shows sideroblasts and vacuoles in the normoblasts in ethanol toxicity. | * The bone marrow shows sideroblasts and vacuoles in the normoblasts in ethanol toxicity. | ||
* Lead intoxication causes sideroblastic anemia by inhibiting two enzymes in heme pathway: | * Lead intoxication causes sideroblastic anemia by inhibiting two enzymes in heme pathway: |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.
Overview
Sideroblastic anemia pathophysiology | |
Sideroblastic (microcytic) anemia |
Pathophysiology[1][2]
Physiology
Heme is porphyrin containing compound, with an Fe iron ion in the centre,surrounded by heterocyclic organic ring of porphyrin.
The normal physiology of heme synthesis can be understood as follows:
- Mitochondria in the developing erythroid cells are the cellular site of heme production and iron utilization.
- Glycine combines with succinylcoA to form aminolenolinic acid(ALA)
- This reaction is catalyzed by ALA sunthetase enzyme (ALAS2) in mitochondria
- ALA synthetase requires vit B-6 as a cofactor
- Two molecules of aminolenolinic acid condense in cytosol to form porphobilinogen(PBG)
- This reaction is catalyzed by zinc containing enzyme called ALA dehydratase.
- Multiple enzymatic transformations in cytoplasm produce coproporphyrinogen III (CPG).
- Coproporphyrinogen III (CPG) enters the mitochondrion.
- Additional modifications of CPG in mitochondrion produces protoporphyrin IX.
- The final step is the insertion of iron into the protoporphyrin IX ring producing HEME.
- This final reaction is catalyzed by enzyme ferrochelatase.
Pathogenesis
- It is understood that sideroblastic anemia is the result of defects in the steps of heme biosynthesis that occur within the mitochondrion.
- The pathophysiology of sideroblastic anemia depends on the underlying cause.
- The X-linked hereditary sideroblastic anemias result from mutations in the gene encoding ALAS2.
- Isoniazide, produces sideroblastic anemia in people who dont use pyridoxine prophylaxis,
- Pyridoxine is a cofactor for ALAS2 enzyme.
- Its deficiency directly impairs ALAS function
- Mitochondrial cytopathies result from deletions of portions of the mitochondrial genome .
- The consequent marked mitochondrial dysfunction causes sideroblastic anemia in these disorders.
- Ethanol is the most common cause of toxin-induced sideroblastic anemia.
- Ethanol causes sideroblastic anemia by two mechanisms
- Direct antagonism to pyridoxal phosphate
- Dietary deficiency of this compound.
- The bone marrow shows sideroblasts and vacuoles in the normoblasts in ethanol toxicity.
- Lead intoxication causes sideroblastic anemia by inhibiting two enzymes in heme pathway:
- ALA dehaydratase
- Ferrochelatase
- Penicillamine or triethylene tetramine dihydrochloride (Trientene or TTH) used in treatment of Wilsonís disease can produce sideroblastic anemia.
- Excessive chelation produces copper deficiency.
- Copper catalyzes the last step in heme biosynthesis, insertion of iron into protoporphyrin IX.
- Zinc intoxication causes sideroblastic anemia in patients using large amount of zinc supplements.
- Excessive zinc reduces serum copper levels..
Genetics[edit | edit source]
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
- [Gene1]
- [Gene2]
- [Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
References
- ↑ Fujiwara T, Harigae H (December 2013). "Pathophysiology and genetic mutations in congenital sideroblastic anemia". Pediatr Int. 55 (6): 675–9. doi:10.1111/ped.12217. PMID 24003969.
- ↑ Fleming MD (2011). "Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation". Hematology Am Soc Hematol Educ Program. 2011: 525–31. doi:10.1182/asheducation-2011.1.525. PMID 22160084.