4. • Ferrous iron (Fe++)
• Protoporphyrin IX:
contains 4 pyrrole
rings linked together
by methenyl bridges.
5. 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.
6. • 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.
11. • 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.
12. 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.
15. 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.
16. 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.
17. • 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.
18. 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.
19. 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.
20. • 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.
21. • 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.
22. 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.
23. • 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.
25. • Group of refractory anaemias
characterized by:
• Variable numbers of hypochromic cells
in peripheral blood.
• Ring sideroblasts comprising 15% or
more of marrow ertyhroblasts.
26. • Siderocyte • Mature red cell containing 1 or more
siderotic granules.
• Normal • Nucleated red cell containing 1 or
sideroblast more siderotic granules:
› Few & difficult to see.
› randomly distributed in cytoplasm.
› reduced proportion of sideroblasts in
iron deficiency & anaemia of chronic
disorders
27. Abnormal sideroblasts
Cytoplasmic iron deposits Mitochondrial iron deposit
• Ferritin aggregates • Non-ferritin iron
• Numerous & larger granules • More than 4
• Easily visible & randomly perinuclear
distributed granules, covering
1/3rd or more of the
• Proportion of sideroblasts
nuclear
usually parallels %
circumference. (Ring
saturation of transferrin.
sideroblasts)
• E.g: haemolytic &
megaloblastic anaemia, iron
overload, thalassaemia
disorders.
31. 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.
32. • 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)
33. • 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.
34. 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.
35. • 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.
36.
37. 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.
38. • Onset is usually in childhood.
• SLC25A38 MUTATIONS:
• Transporter protein which transfers glycine to
mitochondria.
• An essential step in synthesis of ALA.
39. GLUTAREDOXIN-5 (GLRX5) MUTATIONS
• Autosomal recessive disorder.
• This enzyme participates in iron-sulphur cluster
formation.
• Hypochromic microcytic anaemia with ring
sideroblasts.
40. MITOCHONDRIAL
MUTATIONS
MITOCHONDRIAL DNA M
•
Pearson
(marrow- Kearns-Syre
pancreas) syndrome
syndrome
41. 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.
42.
43. • 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.
44. 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
45. • Heart block ( conduction defect)
• Ataxia
• Endocrine dysfunctions
• Impaired cognitive function
• Treatment is generally symptomatic &
supportive.
• Prognosis is usually poor.
47. 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.
48. 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.
49. • 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.
50. 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.
57. • 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.
60. • 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.
61.
62. 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.
63.
64. • 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.
69. 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.
70. • 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.