4. ā¢ Ferrous iron (Fe++)
ā¢ Protoporphyrin IX:
contains 4 pyrrole
rings linked together
by methenyl bridges.
5. HAEM SYNTHESIS
ā¢ 85% haem synthesis occurs in red cell
precursors.
ā¢ Reticulocytes continue to synthesize
haemoglobin for 24-48hrs after release
from bone marrow.
ā¢ Ceases when RBCās mature because they
lack mitochondria.
ā¢ Liver is the main non-RBC source of
haem synthesis.
6. ā¢ 80% transferrin iron normally enters developing red
cells for haem synthesis.
ā¢ Transferrin-receptor complex taken up into
mitochondria by endocytosis.
ā¢ Iron released at low pH of endosome via DMT1 &
reduced from Fe+++ to Fe++ by STEAP3, a
ferrireductase.
ā¢ Transported into mitochondria by mitoferrin or
enters ferritin.
11. ā¢ Reduced levels of haem rapidly trigger
formation of haem-regulated
inhibitor(HRI).
ā¢ HRI interacts with translation initiating
factor eIF-2Ī± & prevents translation of
Ī± & Ī² chains.
12. PORPHYRIAS
ā¢ Group of inherited or acquired diseases.
ā¢ Each characterized by a partial defect
in one of the enzymes of haem
synthesis.
ā¢ Classified into two groups: Hepatic &
Erythropoietic.
15. Congenital Erythropoietic Porphyria
ā¢ Rare autosomal recessive disorder.
ā¢ Reduced uroporphyrinogen III synthase activity d/t
mutations in the encoding gene.
ā¢ Males/females equally effected.
ā¢ Age of onset is variable but typically seen in infants &
children.
16. Clinical presentation:
ā¢ Highly variable.
ā¢ Characterized by cutaneous photosensitivity &
dermatitis (ranging from mild to severe).
ā¢ Spontaneous oxidation of accumulated porphyrinogens
to photoactive porphyrins.
ā¢ Hemolytic anaemia, may be mild to severe with
resultant splenomegaly & osseous fragility.
17. ā¢ Hypertrichosis
ā¢ Port-wine coloured urine
ā¢ Hydrops fetalis
ā¢ Blepharitis, conjunctivitis, corneal scarring &
blindness.
ā¢ Inc. amounts of uroporphyrin &
coproporphyrin in bone marrow, red
cells, plasma, urine & faeces.
18. Management:
ā¢ Avoidance of sunlight
ā¢ Splenectomy (to improve red cell survival) is only
partially effective.
ā¢ High level blood transfusions & iron chelation therapy
(to suppress erythropoiesis) sufficiently improve
symptoms.
ā¢ Allogeneic bone marrow transplantation has been
successful.
19. Erythropoietic Protoporphyria
ā¢ Autosomal dominant disorder.
ā¢ Deficiency of ferrochelatase enzyme d/t mutations in
the encoding gene.
ā¢ Males/females equally effected.
ā¢ Onset is usually in childhood.
20. ā¢ Inc. protoporphyrin concentrations in bone
marrow, red cells, plasma & bile.
ā¢ Bone marrow reticulocytes are primary source of
excess protoporphyrin.
ā¢ Photosensitivity & dermatitis range from mild or
absent to severe.
ā¢ Little haemolysis but mild hypochromic anaemia may
occur.
ā¢ Occasionally severe liver disease may occur.
21. ā¢ Urinary porphyrin levels are normal in patients
without liver dysfunction.
ā¢ Management:
ā¢ Avoid sunlight.
ā¢ Beta-carotene may also diminish photosensitivity.
ā¢ Iron deficiency should be avoided as this may inc.
amount of free protoporphyrin.
22. Porphyria Cutanea Tarda (PCT)
ā¢ Most common hepatic porphyria.
ā¢ Type I (acquired) - 80%
ā¢ Type II (autosomal dominant)
ā¢ Dec. activity of uroporphyrinogen decarboxylase
(UROD)
ā¢ More common in men.
ā¢ Precipitated in middle or later life by factors like
alcohol, liver disease or estrogen therapy.
23. ā¢ Inc. amounts of uroporphyrins & carboxyl-porphyrins
excreted in urine.
ā¢ Major morbidity is d/t photosensitivity & skin
fragility & blistering, hampering daily activities.
ā¢ Iron is known to inhibit UROD.
ā¢ Removal of iron by repeated phlebotomy is standard
treatment, usually leading to remission.
25. ā¢ Group of refractory anaemias
characterized by:
ā¢ Variable numbers of hypochromic cells
in peripheral blood.
ā¢ Ring sideroblasts comprising 15% or
more of marrow ertyhroblasts.
26. ā¢ Siderocyte ā¢ Mature red cell containing 1 or more
siderotic granules.
ā¢ Normal ā¢ Nucleated red cell containing 1 or
sideroblast more siderotic granules:
āŗ Few & difficult to see.
āŗ randomly distributed in cytoplasm.
āŗ reduced proportion of sideroblasts in
iron deficiency & anaemia of chronic
disorders
27. Abnormal sideroblasts
Cytoplasmic iron deposits Mitochondrial iron deposit
ā¢ Ferritin aggregates ā¢ Non-ferritin iron
ā¢ Numerous & larger granules ā¢ More than 4
ā¢ Easily visible & randomly perinuclear
distributed granules, covering
1/3rd or more of the
ā¢ Proportion of sideroblasts
nuclear
usually parallels %
circumference. (Ring
saturation of transferrin.
sideroblasts)
ā¢ E.g: haemolytic &
megaloblastic anaemia, iron
overload, thalassaemia
disorders.
31. ALAS2 MUTATIONS:
ā¢ More than 25 mutations of the gene for erythroid
specific ALAS2 on X chromosome.
ā¢ Most lead to changes in protein structure, causing
instability or loss of function.
ā¢ Function may be rescued to a variable degree by
administration of pyridoxal phosphate (B6).
ā¢ Response is better if iron overload is removed by
phlebotomy or chelation.
32. ā¢ Hypochromic, often microcytic anaemia.
ā¢ Bone marrow shows;
āŗ erythroid hyperplasia
āŗ microcytic erythroblasts with vacuolated
cytoplasm
āŗ more than 15% ringed sideroblasts
ā¢ Few circulating siderocytes, normoblasts & cells with
punctate basophilia. ( pronounced only if spleen has
been removed)
33. ā¢ Erythroid expansion may result in bossing of skull &
enlargement of facial bones.
ā¢ Spleen may be enlarged.
ā¢ Severe iron overload may occur.
ā¢ Female carriers may show partial haematological
expression, depending on the severity of defect in
the enzyme & degree of lyonization of effected X-
chromosome.
34. ABCB7 MUTATIONS
ā¢ Rare form of X-linked sideroblastic anaemia
ā¢ ABCB7, a transmembrane protein that binds &
hydrolyses ATP, transfers iron-sulphur clusters from
mitochondria to cytosol.
ā¢ Iron-sulphur clusters are part of IRP1, which controls
ALAS2, & ferrochelatase enzyme.
35. ā¢ Early onset.
ā¢ Anaemia is mild to moderately severe.
ā¢ Non-progressive cerebellar ataxia. (may be due to
iron damage to mitochondria in neural cells)
ā¢ Inc. red cells zinc protoporphyrin level.
36.
37. THTR-1 MUTATIONS
ā¢ SLC19A2 gene mutations encoding for THTR-1
ā¢ Causes Roger syndrome, an autosomal recessive
disorder.
ā¢ Responsible for thiamine responsive megaloblastic
anaemia & DIDMOAD. (diabetes insipidus, diabetes
mellitus, optic atrophy & deafness)
ā¢ Ring sideroblasts are typically seen.
38. ā¢ Onset is usually in childhood.
ā¢ SLC25A38 MUTATIONS:
ā¢ Transporter protein which transfers glycine to
mitochondria.
ā¢ An essential step in synthesis of ALA.
39. GLUTAREDOXIN-5 (GLRX5) MUTATIONS
ā¢ Autosomal recessive disorder.
ā¢ This enzyme participates in iron-sulphur cluster
formation.
ā¢ Hypochromic microcytic anaemia with ring
sideroblasts.
40. MITOCHONDRIAL
MUTATIONS
MITOCHONDRIAL DNA M
ā¢
Pearson
(marrow- Kearns-Syre
pancreas) syndrome
syndrome
41. PEARSON SYNDROME
ā¢ Rare multisystemic cytopathy d/t mitochondrial gene
deletions.
ā¢ Marrow failure is the 1st defining feature & all cell
lineages may be effected.
ā¢ Macrocytic sideroblastic anaemia typically seen.
ā¢ Prominent vacuoles in cells of both myeloid &
erythroid lineages.
42.
43. ā¢ Exocrine dysfunction d/t fibrosis & acinar
atrophy, resulting in chronic diarrhoea &
malabsorption.
ā¢ Lactic acidemia d/t defect in oxidative
phosphorylation.
ā¢ Death often occurs in infancy or early childhood d/t
infection, metabolic crisis &/or multi-organ failure.
ā¢ Older survivals develop KSS.
44. KEARSON-SYRE SYNDROME (KSS)
ā¢ Rare neuromuscular disorder d/t mitochondrial gene
mutations.
ā¢ Onset usually before the age of 20yrs.
ā¢ Skeletal muscle weakness.
ā¢ Short stature
ā¢ Hearing loss
45. ā¢ Heart block ( conduction defect)
ā¢ Ataxia
ā¢ Endocrine dysfunctions
ā¢ Impaired cognitive function
ā¢ Treatment is generally symptomatic &
supportive.
ā¢ Prognosis is usually poor.
47. REFRACTORY ANAEMIA WITH RING
SIDEROBLASTS (RARS)
ā¢ A myelodysplastic syndrome characterized by:
ā¢ Anaemia
ā¢ Morphologic dysplasia in erythroid lineage
ā¢ Ring sideroblasts comprising ā„15% of BM erythroid
precursors.
ā¢ No significant dysplasia in non-erythroid lineages.
ā¢ Myeloblasts comprise ā¹ 5% of nucleated BM cells &
are not present in PB.
48. Epidemiology
ā¢ Accounts for 3-11% of MDS cases.
ā¢ Occurs primarily in older individuals with a median age
of 60-73yrs.
ā¢ Similar frequency in males & females.
49. ā¢ Etiology
ā¢ A clonal stem cell defect manifesting as
abnormal iron metabolism in erythroid
lineage.
ā¢ Acquired defects of mitochondrial DNA
may underlie.
ā¢ In contrast to congenital X-linked
defects, red cell protoporphyrin levels
are raised.
50. Morphology
ā¢ Anaemia is often normochromic macrocytic.
ā¢ PB smear may manifest a dimorphic picture with a
major population of normochromic RBCās & minor
population of hypochromic cells.
ā¢ BM aspirate shows erythroid hyperplasia &
dysplasia, including nuclear lobation & megaloblastoid
features.
ā¢ Haemosiderin laden macrophages are often abundant.
57. ā¢ Granulocytes & megakaryocytes show no significant
dysplasia.( ā¹ 10% dysplastic forms)
ā¢ BM biopsy is normocellular to markedly hypercellular.
ā¢ 1-2% cases evolve into AML. (less than in other MDS
forms)
ā¢ Median survival is 108 months.
60. ā¢ LEAD TOXICITY
ā¢ Exposure to high levels of lead typically associated
with severe health effects.
ā¢ Minimum Blood Lead Level (BLL) to cause lead
poisoning is 10Āµg/dL. (WHO guidelines)
ā¢ Potential sources: toys, old lead
pipes, cement, paint, lead fuel, canned food etc.
61.
62. Mechanisms of action:
ā¢ Binds to sulfhydryl group of proteins causing
denaturation of structural proteins.
ā¢ Binds Ca++ activated proteins & effects various
transport systems & enzyme systems.
ā¢ Interferes with Ī“-ALAS & ferrochelatase enzymes.
ā¢ Interferes with release of neurotransmitters
specially glutamate by blocking NMDA receptors.
63.
64. ā¢ Anaemia is usually normochromic or slightly
hypochromic.
ā¢ Haemolysis is often, with a mild rise in
reticulocytes, but jaundice is rare.
ā¢ Basophilic stippling on the ordinary (Romanowsky)
stain is characteristic finding. (precipitation of
denatured RNA d/t inhibition of the enzyme
pyrimidine 5ā-nucleotidase)
ā¢ Siderotic granules, & ocacasionally Cabot rings are
found in circulating red cells.
69. Treatment of Sideroblastic Anaemia
ā¢ Some patients with X-linked sideroblastic anaemia
respond to pyridoxine.
ā¢ Some secondary sideroblastic anaemias may be
completely reversed by pyridoxine therapy.
ā¢ Pyridoxine therapy almost always ineffective in
refractory anaemia with ring sideroblasts.
ā¢ Folic acid may benefit patients with secondary
anaemias.
70. ā¢ In cases of iron overload, anaemia may
improve after phlebotomy or iron
chelation therapy.
ā¢ Splenectomy usually does not benefit
anaemia & leads to post-operative high
platelet counts.