Disorders of haem synthesis
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Transcript of Disorders of haem synthesis
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DISORDERS OF HAEM SYNTHESIS
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Porphyrias
Lead Poisoning
Sideroblastic Anaemia
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Structure of Haem
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• Ferrous iron (Fe++)
• Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges.
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HAEM SYNTHESIS
• 85% haem synthesis occurs in red cell precursors.
• Reticulocytes continue to synthesize haemoglobin for 24-48hrs after release from bone marrow.
• Ceases when RBC’s mature because they lack mitochondria.
• Liver is the main non-RBC source of haem synthesis.
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• 80% transferrin iron normally enters developing red cells for haem synthesis.
• Transferrin-receptor complex taken up into mitochondria by endocytosis.
• Iron released at low pH of endosome via DMT1 & reduced from Fe+++ to Fe++ by STEAP3, a ferrireductase.
• Transported into mitochondria by mitoferrin or enters ferritin.
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Iron uptake by developing red cell
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HAEM SYNTHESISMitochondrion Cytoplasm
Succinyl-CoA
Glycine
δ-Aminolaevulinic acid
Porphobilinogen
Hydroxymethylbilane
Uroporphyrinogen III
Coproporphyrinogen IIIProtoporphyrinogen III
Haem
Protoporphyrin IX
PBG-deaminase
Uro’gen III synthase
Uro’gen III decarboxylase
Copro’gen III oxidase
Proto’gen III oxidase
Ferrochelatase
δ ALA-synthasePyridoxal phosphate
ALA-dehydrogenase
+
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Coordination of haem synthesis, globin synthesis & iron regulation.
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• Reduced levels of haem rapidly trigger formation of haem-regulated inhibitor(HRI).
• HRI interacts with translation initiating factor eIF-2α & prevents translation of α & β chains.
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PORPHYRIAS
• Group of inherited or acquired diseases.
• Each characterized by a partial defect in one of the enzymes of haem synthesis.
• Classified into two groups: Hepatic & Erythropoietic.
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Hepatic Porphyrias
FORM
• Acute intermittent porphyria
• Hereditary coproporphyria
• Porphyria variegate
• Porphyria cutanea tarda (PCT)
ENZYME DEFECT
• Porphobilinogen deaminase (PBG)
• Coproporphyrinogen oxidase
• Protoporphyrinogen oxidase
• Uroporphyrinogen decarboxylase
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Erythropoietic Porphyrias
FORM
• Congenital erythropoietic porphyria
• Erythropoietic protoporphyria
ENZYME DEFECT
• Uroporphyrinogen oxidase
• Ferrochelatase
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Congenital Erythropoietic Porphyria
• Rare autosomal recessive disorder.
• Reduced uroporphyrinogen III synthase activity d/t mutations in the encoding gene.
• Males/females equally effected.
• Age of onset is variable but typically seen in infants & children.
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Clinical presentation:
• Highly variable.
• Characterized by cutaneous photosensitivity & dermatitis (ranging from mild to severe).
• Spontaneous oxidation of accumulated porphyrinogens to photoactive porphyrins.
• Hemolytic anaemia, may be mild to severe with resultant splenomegaly & osseous fragility.
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• Hypertrichosis
• Port-wine coloured urine
• Hydrops fetalis
• Blepharitis, conjunctivitis, corneal scarring & blindness.
• Inc. amounts of uroporphyrin & coproporphyrin in bone marrow, red cells, plasma, urine & faeces.
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Management:
• Avoidance of sunlight
• Splenectomy (to improve red cell survival) is only partially effective.
• High level blood transfusions & iron chelation therapy (to suppress erythropoiesis) sufficiently improve symptoms.
• Allogeneic bone marrow transplantation has been successful.
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Erythropoietic Protoporphyria
• Autosomal dominant disorder.
• Deficiency of ferrochelatase enzyme d/t mutations in the encoding gene.
• Males/females equally effected.
• Onset is usually in childhood.
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• Inc. protoporphyrin concentrations in bone marrow, red cells, plasma & bile.
• Bone marrow reticulocytes are primary source of excess protoporphyrin.
• Photosensitivity & dermatitis range from mild or absent to severe.
• Little haemolysis but mild hypochromic anaemia may occur.
• Occasionally severe liver disease may occur.
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• Urinary porphyrin levels are normal in patients without liver dysfunction.
• Management:
• Avoid sunlight.
• Beta-carotene may also diminish photosensitivity.
• Iron deficiency should be avoided as this may inc. amount of free protoporphyrin.
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Porphyria Cutanea Tarda (PCT)
• Most common hepatic porphyria.
• Type I (acquired) - 80%• Type II (autosomal dominant)
• Dec. activity of uroporphyrinogen decarboxylase (UROD)
• More common in men.
• Precipitated in middle or later life by factors like alcohol, liver disease or estrogen therapy.
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• Inc. amounts of uroporphyrins & carboxyl-porphyrins excreted in urine.
• Major morbidity is d/t photosensitivity & skin fragility & blistering, hampering daily activities.
• Iron is known to inhibit UROD.
• Removal of iron by repeated phlebotomy is standard treatment, usually leading to remission.
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SIDEROBLASTICANAEMIA
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• Group of refractory anaemias characterized by:
• Variable numbers of hypochromic cells in peripheral blood.
• Ring sideroblasts comprising 15% or more of marrow ertyhroblasts.
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• Siderocyte
• Normal sideroblast
• Mature red cell containing 1 or more siderotic granules.
• Nucleated red cell containing 1 or more siderotic granules:
› Few & difficult to see.
› randomly distributed in cytoplasm.
› reduced proportion of sideroblasts in iron deficiency & anaemia of chronic disorders
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Abnormal sideroblastsCytoplasmic iron deposits• Ferritin aggregates
• Numerous & larger granules
• Easily visible & randomly distributed
• Proportion of sideroblasts usually parallels % saturation of transferrin.
• E.g: haemolytic & megaloblastic anaemia, iron overload, thalassaemia disorders.
Mitochondrial iron deposit• Non-ferritin iron
• More than 4 perinuclear granules, covering 1/3rd or more of the nuclear circumference. (Ring sideroblasts)
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CLASSIFICATION
ACQUIRED PRIMARY SECONDARY
MYELODYSPLASIA(RARS)
DRUGSTOXINS
HAEMATOLOGIC MALIGNANCIES
OTHER BENIGN CONDITIONS
HEREDITARY
X-LINKED
AUTOSOMAL
MITOCHONDRIAL
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HEREDITARY SIDEROBLASTIC ANAEMIAS:
• Rare disorders
• Manifesting mainly in males
• Onset usually in childhood or adolescence
• Occasional late presentation
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X-LINKED MUTATIONS
ABCB7 MUTATIONS
ALAS2 MUTATIONS
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ALAS2 MUTATIONS:
• More than 25 mutations of the gene for erythroid specific ALAS2 on X chromosome.
• Most lead to changes in protein structure, causing instability or loss of function.
• Function may be rescued to a variable degree by administration of pyridoxal phosphate (B6).
• Response is better if iron overload is removed by phlebotomy or chelation.
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• Hypochromic, often microcytic anaemia.
• Bone marrow shows; › erythroid hyperplasia › microcytic erythroblasts with vacuolated cytoplasm › more than 15% ringed sideroblasts
• Few circulating siderocytes, normoblasts & cells with punctate basophilia. ( pronounced only if spleen has been removed)
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• Erythroid expansion may result in bossing of skull & enlargement of facial bones.
• Spleen may be enlarged.
• Severe iron overload may occur.
• Female carriers may show partial haematological expression, depending on the severity of defect in the enzyme & degree of lyonization of effected X-chromosome.
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ABCB7 MUTATIONS
• Rare form of X-linked sideroblastic anaemia
• ABCB7, a transmembrane protein that binds & hydrolyses ATP, transfers iron-sulphur clusters from mitochondria to cytosol.
• Iron-sulphur clusters are part of IRP1, which controls ALAS2, & ferrochelatase enzyme.
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• Early onset.
• Anaemia is mild to moderately severe.
• Non-progressive cerebellar ataxia. (may be due to iron damage to mitochondria in neural cells)
• Inc. red cells zinc protoporphyrin level.
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THIAMINE TRANSPORTER
GENE MUTATION
SLC25A38
MUTATIONS
GLUTAREDOXIN-5 MUTATIONS
MITOCHONDRIAL MYOPATHY
AUTOSOMAL
MUTATIONS
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THTR-1 MUTATIONS
• SLC19A2 gene mutations encoding for THTR-1
• Causes Roger syndrome, an autosomal recessive disorder.
• Responsible for thiamine responsive megaloblastic anaemia & DIDMOAD. (diabetes insipidus, diabetes mellitus, optic atrophy & deafness)
• Ring sideroblasts are typically seen.
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• Onset is usually in childhood.
• SLC25A38 MUTATIONS:
• Transporter protein which transfers glycine to mitochondria.
• An essential step in synthesis of ALA.
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GLUTAREDOXIN-5 (GLRX5) MUTATIONS
• Autosomal recessive disorder.
• This enzyme participates in iron-sulphur cluster formation.
• Hypochromic microcytic anaemia with ring sideroblasts.
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MITOCHONDRIAL DNA M
•
MITOCHONDRIAL MUTATIONS
Pearson (marrow-pancreas) syndrome
Kearns-Syre syndrome
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PEARSON SYNDROME
• Rare multisystemic cytopathy d/t mitochondrial gene deletions.
• Marrow failure is the 1st defining feature & all cell lineages may be effected.
• Macrocytic sideroblastic anaemia typically seen.
• Prominent vacuoles in cells of both myeloid & erythroid lineages.
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• Exocrine dysfunction d/t fibrosis & acinar atrophy, resulting in chronic diarrhoea & malabsorption.
• Lactic acidemia d/t defect in oxidative phosphorylation.
• Death often occurs in infancy or early childhood d/t infection, metabolic crisis &/or multi-organ failure.
• Older survivals develop KSS.
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KEARSON-SYRE SYNDROME (KSS)
• Rare neuromuscular disorder d/t mitochondrial gene mutations.
• Onset usually before the age of 20yrs.
• Skeletal muscle weakness.
• Short stature
• Hearing loss
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• Heart block ( conduction defect)
• Ataxia
• Endocrine dysfunctions
• Impaired cognitive function
• Treatment is generally symptomatic & supportive.
• Prognosis is usually poor.
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ACQUIRED
SECONDARY
DRUGSTOXINS
DEFICIENCIESSYSTEMIC DISEASE
PRIMARY
RARS
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REFRACTORY ANAEMIA WITH RING SIDEROBLASTS (RARS)
• A myelodysplastic syndrome characterized by:
• Anaemia• Morphologic dysplasia in erythroid lineage• Ring sideroblasts comprising ≥15% of BM
erythroid precursors.
• No significant dysplasia in non-erythroid lineages.• Myeloblasts comprise ‹ 5% of nucleated BM cells
& are not present in PB.
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Epidemiology
• Accounts for 3-11% of MDS cases.
• Occurs primarily in older individuals with a median age of 60-73yrs.
• Similar frequency in males & females.
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• Etiology
• A clonal stem cell defect manifesting as abnormal iron metabolism in erythroid lineage.
• Acquired defects of mitochondrial DNA may underlie.
• In contrast to congenital X-linked defects, red cell protoporphyrin levels are raised.
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Morphology
• Anaemia is often normochromic macrocytic.
• PB smear may manifest a dimorphic picture with a major population of normochromic RBC’s & minor population of hypochromic cells.
• BM aspirate shows erythroid hyperplasia & dysplasia, including nuclear lobation & megaloblastoid features.
• Haemosiderin laden macrophages are often abundant.
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RING SIDEROBLASTS
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Bone marrow aspirate
Erythroid precursors vary from mildly dyspoietic to large, bizarre multinucleated cells.
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Bone marrow aspirate
Mild megaloblastoid changes but granulocytes have no dysplastic features.
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Bone marrow biopsy
Mildly hypercellular with erythroid proliferation. Megakaryocytes are normal in number & morphology.
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PB smear
Macrocytic RBC’s (MCV=104).Mild aniso & poikilocytosis
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Ring sideroblasts & iron laden macrophages
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• Granulocytes & megakaryocytes show no significant dysplasia.( ‹ 10% dysplastic forms)
• BM biopsy is normocellular to markedly hypercellular.
• 1-2% cases evolve into AML. (less than in other MDS forms)
• Median survival is 108 months.
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DRUGS
• Anti-tuberculous chemotherapy, specially isoniazid & cycloserine
• (pyridoxine antagonists)
• Chloramphenicol inhibits mitochondrial protein synthesis.
• Penicillamine (copper chelating agent)
• Hormones (progesterone)
• Copper deficiency ( zinc suppliments)
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MITOCHONDRIAL TOXINS
• Alcohol
• Lead poisoning
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• LEAD TOXICITY
• Exposure to high levels of lead typically associated with severe health effects.
• Minimum Blood Lead Level (BLL) to cause lead poisoning is 10µg/dL. (WHO guidelines)
• Potential sources: toys, old lead pipes, cement, paint, lead fuel, canned food etc.
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Mechanisms of action:
• Binds to sulfhydryl group of proteins causing denaturation of structural proteins.
• Binds Ca++ activated proteins & effects various transport systems & enzyme systems.
• Interferes with δ-ALAS & ferrochelatase enzymes.
• Interferes with release of neurotransmitters specially glutamate by blocking NMDA receptors.
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• Anaemia is usually normochromic or slightly hypochromic.
• Haemolysis is often, with a mild rise in reticulocytes, but jaundice is rare.
• Basophilic stippling on the ordinary (Romanowsky) stain is characteristic finding. (precipitation of denatured RNA d/t inhibition of the enzyme pyrimidine 5’-nucleotidase)
• Siderotic granules, & ocacasionally Cabot rings are found in circulating red cells.
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Basophilic Stippling
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Pappenheimer bodies ( Siderotic granules)
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Siderotic granules
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Management:
• Supportive care
• Reduce exposure
• Chelation therapy in extreme cases.
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Treatment of Sideroblastic Anaemia
• Some patients with X-linked sideroblastic anaemia respond to pyridoxine.
• Some secondary sideroblastic anaemias may be completely reversed by pyridoxine therapy.
• Pyridoxine therapy almost always ineffective in refractory anaemia with ring sideroblasts.
• Folic acid may benefit patients with secondary anaemias.
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• In cases of iron overload, anaemia may improve after phlebotomy or iron chelation therapy.
• Splenectomy usually does not benefit anaemia & leads to post-operative high platelet counts.