Sideroblastic anemia - Etiopathogenesis, Clinical features, Advances in Management

1. SIDEROBLASTIC ANEMIA
CHAIR PERSON: Dr.RAM KAULGUD
STUDENT: Dr.MOHITH H N

2. Anemia
• DEFINITION: Anemia is a condition in which the
number of red blood cells,hemoglobin or their
oxygen-carrying capacity is insufficient to meet
physiologic needs, which vary by age, sex, altitude,
smoking, and pregnancy status.

6. Example: when reticulocyte % is 4% wit hb of 7
(hematocrit=21)g/dl, calculate RPI ?
Corrected retic count = 4*7/14=2
RPI=2/2=1

7. SIDEROBLASTIC ANEMIA
• DEFINITION
• CLASSIFICATION
• CAUSES
• SYMPTOMS
• DIAGNOSIS
• TREATMENT

8. DEFINITION
• Sideroblastic anemia are a heterogeneous group of disorders
uniquely characterized by pathologic iron deposits in
• erythroblast mitochondria , in which the bone marrow
produces ringed sideroblasts rather than healthy red blood
cells (erythrocytes).
• The body has iron available but cannot incorporate it
into hemoglobin, which red blood cells need in order to
transport oxygen efficiently.
• INCIDENCE is very low , 1 in 200000.

9. • The disorder may be caused either by a genetic disorder or
indirectly as part of myelodysplastic syndrome,which can
develop into hematological malignancies(AML).
• Sideroblasts (sidero + blast)
are nucleated erythroblasts (precursors to mature red blood
cells) with granules of iron accumulated in
the mitochondria surrounding the nucleus

10. • Normally, sideroblasts are present in the bone marrow, and
enter the circulation after maturing into a normal erythrocyte.
The presence of sideroblasts per se does not define
sideroblastic anemia.
• Only the finding of ring (or ringed) sideroblasts characterizes
sideroblastic anemia.

11. • Ring sideroblasts are named so because iron-laden
mitochondria form a ring around the nucleus. It is a subtype
of basophilic granules of the erythrocyte, but which can only
be seen in bone marrow.

12. Causes
• Dysfunctional heme synthesis or processing. This leads to
granular deposition of iron in the mitochondria that form a
ring around the nucleus of the developing RBC.
• Congenital forms often present with normocytic or microcytic
anemia while acquired forms of sideroblastic anemia are
often normocytic or macrocytic.

15. Classification
• Sideroblastic anemia is typically divided into subtypes based
on its cause,
1. Hereditary or congenital sideroblastic anemia
2. Acquired, or secondary sideroblastic anemia.

16. Hereditary sideroblastic anemia
1. X-linked sideroblastic anemia (XLSA)
2. Autosomal recessive sideroblastic anemia
3. Sideroblastic anemia with spinocerebellar ataxia (ASAT)
4. Pyridoxine-refractory autosomal recessive sideroblastic anemia
5. Glutaredoxin 5 deficiency
6. Pearson syndrome

18. X-linked sideroblastic anemia
• This is the most common congenital cause of sideroblastic
anemia and involves a defect in ALAS2, which is involved in
the first step of heme synthesis.
• Most Common among males , Although X-linked,
approximately one third of patients are women due to
skewed X-inactivation (lyonizations).

19. Autosomal recessive sideroblastic
anemia
• Involves mutations in the SLC25A38 gene. The function of this
protein is not fully understood, but it is involved in
mitochondrial transport of glycine. Glycine is a substrate
for ALAS2 and necessary for heme synthesis. The autosomal
recessive form is typically severe in presentation..

21. Glutaredoxin 5 deficiency
• Deficient in glutaredoxin 5, which is essential for the
synthesis of Fe-S clusters such as for IRP1 and thus ALAS2
translation.
• A homozygous mutation in the GLRX5 gene that affects intron
1 splicing and markedly reduces GLRX5 RNA production was
associated with microcytic sideroblastic anemia.
• The anemia was detected in the fifth decade.
• Severe impairment of Fe-S cluster biogenesis and also
revealed markedly reduced levels of ferrochelatase.

22. Pearson syndrome

23. • Genetic syndromes: Rarely, sideroblastic anemia may
be part of a congenital syndrome and present with associated
findings, such as ataxia, myopathy, and pancreatic
insufficiency.

24. ACQUIRED SIDEROBLASTIC ANEMIA
1.Acquired clonal sideroblastic anemia
2.Acquired reversible sideroblastic anemia

25. Acquired clonal sideroblastic anemia
• Clonal sideroblastic anemias fall under the broader category
of myelodysplastic syndromes (MDS). Three forms exist and
include
1.Refractory anemia with ringed sideroblasts (RARS).
2.Refractory anemia with ringed sideroblasts
and thrombocytosis (RARS-T), and
3.Refractory cytopenia with multilineage dysplasia and ringed
sideroblasts (RCMD-RS).

26. RARS
• 3-11 %
• Ps –Anemia and No blasts
• Bone marrow- Unilineage erythroid dysplasia
≥15% of erythroid precursors are ringed
sideroblasts

27. RARS-T
• Ps –Anemia and No blasts with thromocytosis
• Bone marrow- Unilineage erythroid dysplasia
≥15% of erythroid precursors are ringed
sideroblasts

28. RCMD
• PS- Cytopenia(s) <1% blasts
• Bone marrow- Multilineage dysplasia ―
ringed sideroblasts
<5% blasts
No Auer rods

29. Acquired reversible sideroblastic
anemia
• Excessive alcohol use (the most common reversible cause of
sideroblastic anemia),
• Pyridoxine deficiency (vitamin B6 is the cofactor in the first
step of heme synthesis)
• Lead poisoning

30. • Copper deficiency.
• Excess zinc can indirectly cause sideroblastic anemia by
decreasing absorption and increasing excretion of copper.
• Hypothermia.

31. Alcohol
• Anemia associated with alcoholism usually has numerous
causes
• A ring sideroblast abnormality is never the sole cause ,but
occurs in 25% to 30% of anemic alcoholic patients and
probably only in the presence of malnutrition and folate
deficiency.
• Production of heme is impaired by ethanol.

32. • Reduced activity of
1.Erythrocyte ALA dehydratase,
2.Erythrocyte uroporphyrinogen decarboxylase
3.Leukocyte coproporphyrinogen oxidase, and
4.Ferrochelatase
• The colony formation of early (burst-forming unit–erythroid)
and late colony-forming unit–erythroid) human erythroid
progenitor cells is preferentially suppressed by ethanol
• Mitochondrial protein synthesis inhibition.

33. Lab findings
• Blood hemoglobin values range from 6 to 10 g/dl, and the
MCV is normal or increased.
• The transient sideroblastic change is commonly evident in
dimorphic circulating erythrocytes.
• Siderocytes, present in approximately one third of patients,
are a specific finding and provide the most persistent clue for
the ethanol associated ring sideroblast defect.

34. • Megaloblastic hematopoiesis resulting from folate
deficiency is frequent but is not always present. A striking
finding is vacuolization of pronormoblasts.
• The percentage of marrow ring sideroblasts ranges up to
70%, and they typically represent later stage
normoblasts.
• Marrow iron stores usually are increased, as are the
serum transferrin saturation and the serum ferritin level.

35. Drug induced
• ISONIAZID-interfere with vitamin B6 metabolism, and
deprivation of PLP reduces ALA synthesis and, thus, heme
production. Bone marrow ALA synthase activity is also
inhibited.
• CYCLOSERINE inhibits PLP-requiring enzyme reactions and
directly inactivates pyridoxal.
• PYRAZINAMIDE appears to have anti–vitamin B6 properties,
but a specific mechanism has not been determined.

36. Chloramphenicol and Linezolid
• Sporadic or idiosyncratic
• fatal aplastic anemia
• reversible hematologic toxicity of the drug is predictable and
is characterized by suppression of erythropoiesis and by the
ring sideroblast abnormality.
• Inhibit the synthesis of mitochondrial membrane proteins,
such as cytochrome a3 and b, and, thus, mitochondrial
respiration.
• Impaired heme synthesis is evident in reduced activities of
ferrochelatase and ALA synthase,

37. Lead poisoning
• ETIOLOGY:
1. Lodged bullets, inhaled fumes or
2. Fire arms, ingested contaminated herbs and
food supplements,
3. In children, the lead-based paint chips.
4. Organic lead is acquired by absorption
through the skin or by gasoline sniffing.
5. Heterozygotes of hereditary ALA
dehydratase deficiency are said to be more
susceptible to lower levels of lead exposure,

38. Enzymes inhibited
• ALA dehydratase- is most sensitive
• Ferrochelatase
• Coproporphyrinogen oxidase, and
• PBG deaminase

39. MOA
• Lead impedes the intracellular delivery of iron to waiting
ferrochelatase, and the surrogate metal zinc is inserted into
protoporphyrin b ferrochelatase as in iron deficiency so that
zinc protoporphyrin accumulates.
• Absence of the ring sideroblast abnormality in persons with
lead intoxication.
• Ferrochelatase may be directly inhibited in acute poisoning
• Impairs globin synthesis.
• Prolonged lead exposure, erythroid hypoplasia may occur.

40. Clinical manifestations
• Autonomic neuropathy causing abdominal pain and
ileus (lead colic)
• Motor neuropathy (lead palsy).
• A lead line may be seen on the gums and tonsils
• Renal dysfunction (lead nephropathy)
• Musculoskeletal and neuropsychiatric complaints

41. Diagnosis

42. Continue..
• Urinary ALA is greatly increased,
• Urinary coproporphyrin, uroporphyrin, levels are also
increased
• The zinc protoporphyrin level in erythrocytes increased
• concentrations that exceed 75 mg/ dl. Concentrations in urine
>0.1 mg/24 hours also establish the diagnosis of lead
intoxication.

43. Treatment
• Removal of the lead source and administration of
ethylenediaminetetraacetic acid, 50 mg/kg/day in
two divided doses, by slow intravenous infusion with
ample fluids for 5 days.
• This regimen may be repeated in 3 to 4 weeks,
depending on the response of blood lead levels.
• Renal function should be monitored..
• An oral chelating agent, 2,3-dimercaptosuccinic acid,
is also available.

45. o SIGNS
• Enlarged spleen and liver.
• Heart disease , liver damage, and kidney failure can result
from iron buildup in these organs.s

46. diagnosis

48. MICROCYTIC HYPOCHROMIC ANEMIA
DIFFENTIALS

49. Laboratory findings
• The anemia is moderate to severe and dimorphic.
• Serum Iron: high
• Increased ferritin levels
• Decreased total iron-binding capacity
• High transferrin saturation
• Hematocrit of about 20-30%
• The mean corpuscular volume or MCV is usually
normal or low for congenital causes of sideroblastic
anemia but normal or high for acquired forms.

50. Peripheral blood smear
• On the peripheral blood smear can be found erythrocytes
with basophilic stippling(cytoplasmic granules of RNA
precipitates) and Pappenheimer bodies (cytoplasmic granules
of iron).
• Target cells are common.
• The RDW is increased with the red blood cell histogram
shifted to the left.
• Leukocytes and platelets are normal.

51. Basophilic stippling

52. Bone Marrow
• To count a cell as a ring sideroblast, the ring must encircle a
third or more of the nucleus and contain five or more iron
granules
• Bone marrow shows erythroid hyperplasia with a maturation
arrest.

53. • Specific test: Prussian blue stain of RBC in
marrow shows ringed sideroblasts. Prussian
blue staining involves a non-enzymatic
reaction of ferrous iron with Ferro
cyanide forming ferric-ferrocyanide, which is
blue in color. A counterstain may be used to
provide better visualization

57. The WHO International Working Group on Morphology
of MDS (IWGM-MDS) defined three types of
sideroblasts:
• Type 1 sideroblasts: fewer than 5 siderotic
granules in the cytoplasm
• Type 2 sideroblasts: 5 or more siderotic
granules, but not in a perinuclear distribution
• Type 3 or ring sideroblasts: 5 or more
granules in a perinuclear position, surrounding
the nucleus or encompassing at least one
third of the nuclear circumference.

59. Treatment
• Occasionally, the anemia is so severe that support
with transfusion is required. These patients usually
do not respond to erythropoietin therapy.
• Some cases have been reported that the anemia is
reversed or heme level is improved through use of
moderate to high doses of pyridoxine (vitamin B6).

60. • In severe cases of SBA, bone marrow transplant is
also an option with limited information about the
success rate. In the case of isoniazid-induced
sideroblastic anemia, the addition of B6 is sufficient
to correct the anemia.
• Deferoxamine, a chelating agent, is used to treat iron
overload from transfusions. Therapeutic phlebotomy
can be used to manage iron overload.

61. PROGNOSIS
• Sideroblastic anemias are often described as
responsive or non-responsive in terms of increased
hemoglobin levels to pharmacological doses of
vitamin B6.
• 1- Congenital: 80% are responsive, though the
anemia does not completely resolve.
• 2- Acquired clonal: 40% are responsive, but the
response may be minimal.

62. • 3- Acquired reversible: 60% are responsive, but course
depends on treatment of the underlying cause.
• Severe refractory sideroblastic anemias requiring regular
transfusions and/or that undergo leukemic transformation (5-
10%) significantly reduce life expectancy.

64. References
• Wintrobe’s clinical hematology 13th edition
• Harrisons principles of Internal medicine 20th
edition

65. •THANK YOU