Transcript Folate Deficiency

Megaloblastic Anemias
DEFINITION:
 Megaloblastic
anemias are caused
by defects in DNA synthesis that
lead to abnormalities of bone
marrow and peripheral blood cells.
 The term megaloblastic refers to a
morphologic abnormality (mainly
affecting the size and morphology)
of the cell and it's nucleus
Causes of Megaloblastic Anemia
I. Cobalamin(vit B12) deficiency
A. Decreased ingestion: vegetarians.
B. Impaired absorption: small intestinal disease.
C.Impaired utilization.
II. Folate deficiency
A. Decreased ingestion:prolonged parenteral
feeding,alcoholism.
B. Impaired absorption:small intestinal disease.
C. Impaired utilization:drug induced eg; sulfa
drugs,methotrexate,phenytoin…
D. Increased requirement:pregnancy,hemolysis.
E. Increased loss:through urine.
III. Drugs — metabolic inhibitors
IV. Miscellaneous
A. Inborn errors
B. Unexplained disorders
Cobalamine Metabolism
Cobalamine is an animal product.
 Daily need=1microgram.
 Dietary cobalamin enters the duodenum bound
to R protein.
 Pancreatic
proteases degrade R protein–
cobalamin complexes in the jejunum; cobalamin
is bound to intrinsic factor only after this process
occurs.
 The intrinsic factor–cobalamin complex binds
with receptors on ileal mucosal cells. Cobalamin
then enters these cells and reaches the portal
plasma, which contains three cobalamin binding
proteins known as transcobalamin I, II, and III.
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Vitamin B12 Absorption
Folate Metabolism
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Folate is widely distributed in plants and and animal
products.Daily need=50microgram.
Enzymes in the small intestine convert the
polyglutamate forms of folate to the monoglutamate
and diglutamate forms, which are absorbed in the
proximal jejunum.
Folate
in
plasma
is
present
as
5methyltetrahydrofolate in the monoglutamate form.
it is taken up by receptors present on cells
throughout the body.
The 5-methyltetrahydrofolate is converted to
tetrahydrofolate by the cobalamin-dependent
enzyme methionine synthase before it can be
converted to the polyglutamate form and take part
in the other folate-dependent enzymatic reactions
Folate and Cobalamine metabolism
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Clinical Manifestations of Megaloblastic Anemia
Symptoms of slowly progressive anaemia
Jaundice(Cobalamine deficiency).
Glossitis
Stomatitis
Gastrointestinal symptoms
Orthostatic hypotension
Weight loss
Neuropsychiatric :in Cobalamine deficiency
Paresthesia , Abnormal gait , Memory loss.
Disorientation, Decreased or Increased
reflexes,Romberg's sign.
Spasticity, Babinski's sign, Psychosis, Slow Mentation.
Laboratory Investigations
1- Complete Blood Count &Blood Film:
Macrocytosis (increased MCV),Neutropenia,Thrombocytopenia,
Neutrophil hypersegmentation, Reticulocytopaenia
2- Bone Marrow Aspirate &Biopsy:
Hypercellular, Megaloblastic morphology ,Giant bands
&metamyelocytes.
3- Indirect Hyperbilirubinemia, elevated s.LDH.
4- Serum cobalamin: in cobalamine deficiency(normal, 200–900
pg/mL).
5- Serum folate: in folate deficiency(normal, 2.5–20 ng/mL).
6- Schilling Test for diagnosing the cause of Cobalamine
malabsorption.
7- Gastric biopsy for pernicious anemia(cobalamine deficiency)
and/or Small Intestinal Biopsy for malabsorption .
8- Anti-Intrinsic factor Ab& Anti-Parietal cell Ab in Pernicious
anemia(Cobalamine deficiency).
9- Elevated serum Methylmalonic acid in Cobalamine deficiency.
Macrocytes and Hypersegmented
Neutrophil
Megaloblastic Bone Marrow
PERNICIOUS ANEMIA
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The most common cause of cobalamin malabsorption is
pernicious anemia.
There is atrophy of the gastric parietal cells leading to the
absence of IF and HCl secretion.
There is association of pernicious anemia with other
autoimmune diseases. There is a positive family history for
about 30% of patients
The histologic appearance of the gastric mucosa (infiltration
with plasma cells and lymphocytes) is suggestive of
autoimmune-type lesions.
There is also a high incidence of anti-parietal cell IgG
antibodies in the serum of 90% of patients with pernicious
anemia.
Treatment of Megaloblastic Anemia
Cobalamine Deficiency:
Hydroxycobalamine 1 mg i.m. daily for 10 days
,then once every one month for life.Iron is added
for slow response. Hypokalemia may develop
during therapy. Reticulocytosis at day 7 will indicate
response.
Blood is given for severly symptomatic patients.
Folate Deficiency:
Oral Folic acid 5 mg/day for 3 weeks then weekly
as maintenance.
Summary
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Iron deficiency anemia is the most common cause of anemia.
Chronic blood loss is the most common cause of iron
deficiency in adults and physiological increased demand in
pregnants and children.
A hpochromic microcytic anemia with low serum ferritin, low
serum iron and increased TIBC are diagnostic of iron
deficiency anemia.
Oral iron therapy is the standard of care. Injectable iron is
needed in special circumstances.
Megaloblastic anemia is caused by vit B12 or folate deficiency.
Neuropsychiatric manifestations are seen in vit B12 deficiency.
A macrocytic anemia with megaloblastic changes in bone
marrow are the criteria to diagnose megaloblastic anemia.
Vitamin B12 replacement in pernicious anemia is continued
indefinitely.
Oral folate is the standard of care for folate deficiency.
Anemia of Chronic Disease
Etiology
 Infections, cancer, endocrine disorders (e.g. thyroid).
 Inflammatory and rheumatologic disease.
 Renal disease.
Pathophysiology
 A mild hemolytic component is often present, red blood
cell survival is moderately decreased.
 Erythropoietin levels are normal or slightly elevated but
are inappropriately low for the degree of anemia,
erythropoietin level is low in renal failure
 Iron cannot be removed from its storage pool in
hepatocytes and RES cells.
Anemia of Chronic Disease
Diagnosis
RBC are usually normocytic normochromic if the
anemia is mild, but may be microcytic
normochromic, or even microcytic hypochromic,Hb
rarely < 9 g/dL except in renal failure.
 Serum iron, TIBC, and % saturation all normal or
slightly reduced, serum ferritin is normal or
increased.
 Normal or increased iron stores in bone marrow,
decreased “normal” sideroblasts.
Management
 Resolves if underlying disease is treated.
 Erythropoietin may normalize the hemoglobin value
especially in chronic renal failure. Dose of
erythropoietin required is lower for patients with
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Case Presentation
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A 50 year old female presented with one month
history of progressive pallor, multiple ecchymoses
,epistaxis and attacks of fever and sore throat.
Her clinical examination revealed severe pallor,
multiple bleeding spots on her legs .
Blood counts revealed pancytopenia
What is your differential diagnosis?
1-Aplastic Anemia.
2-Acute leukemia.
3-Myelodysplasia.
Aplastic Anemia
Etiology
Radiation
 Drugs
• anticipated (chemotherapy)
• idiosyncratic (chloramphenicol, phenylbutazone)
 Chemicals
• benzene and other organic solvents
• DDT and insecticides
 Post viral e.g. hepatitis B, parvovirus,HIV.
 Idiopathic
• often immune (cell mediated)
 Paroxysmal nocturnal hemoglobinuria
 Marrow replacement
 Congenital: Fanconi anemia, associated with dysmorphic
features.
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Abnormal Thumbs in Fanconi Anemia
Clinical Presentation of Aplastic Anemia
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Occurs at any age
Slightly more common in males.
Can present acutely or insidiously.
Features of anemia or neutropenia or
thrombocytopenia (any combination).
Thrombocytopenia as bruising, bleeding
gums, epistaxis.
Anemia as SOB, pallor and fatigue.
Presentation of neutropenia ranges from
infection in the mouth to septicemia.
Aplastic Anemia
Diagnosis
1- CBC: Pancytopenia
• normochromic normocytic anemia.
• neutrophil count < 1.5 x 109/L.
• platelet count < 20 x 109/L.
• corrected reticulocyte count < 1%.
2- Bone marrow aspirate and biopsy
• aplasia or hypoplasia of marrow cells
with fat replacement.
Aplastic Bone Marrow Biopsy
Aplastic Anemia
Management
Removal
of offending agents.
Supportive care (red cell and platelet transfusions,
antibiotics).
Antithymocyte globulin (50-60% of patients respond)
for patients who are >45 years of age and those who
have no donor for bone marrow transplant
Cyclosporin A,mainly useful for mild cases.
Allogeneic bone marrow transplantation for
patients<45 y
• minimize blood products on presentation.
• only irradiated, leuko-depleted blood products
should be used to minimize CMV transmission.
• CMV negative blood for CMV negative patients.
MYELODYSPLASTIC SYNDROMES (MDS)
Pathophysiology
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A group of clonal bone marrow stem cell disorders
characterized by one or more cytopenias.
Ineffective hematopoiesis despite presence of adequate
numbers of progenitor cells (bone marrow is usually
hyper-cellular).
Dysplastic changes affect all the hematopoietic cell
lines due to abnormal maturation and differentiation
which include abnormal size , nuclear shape and
cytoplasmic granules
The blood elements are dysfunctional.
There is increased liability for transformation to AML.
Dysplastic nuclear features in circulating cells. Composite image taken from several cases
of
myelodysplastic syndrome showing dysplastic nuclear features seen in circulating
granulocytes and nucleated RBCs. The right lower figure shows numerous Pappenheimer
bodies.
MDS
Types
 Refractory
anemia (RA).
 Refractory anemia with ring sideroblasts
(RARS).
 Refractory anemia with excess blasts
(RAEB).
 Refractory anemia with excess blasts in
transformation (RAEB-T).
 Chronic
myelomonocytic
leukemia
(CMML).
Clinical Presentation
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MDS
Related to bone marrow failure, most common in
elderly, usually > 70 and post-chemotherapy or radiation
Usually insidious in onset: fatigue, weakness, pallor,
infections, bruising and rarely weight loss, and
hepatosplenomegaly
Diagnosis
1- Anemia ± thrombocytopenia ± neutropenia
RBC: variable morphology with decreased reticulocyte
count.
WBC: decrease in granulocytes and abnormal function.
Platelet: either too large or too small and
thrombocytopenia.
2- Bone marrow : dysmyelopoiesis in bone marrow
precursors
3- Chromosomal Abnormalities:5,7,8 ,others
MDS
Management
1- Symptomatic (transfusion, antibiotics)
2- Growth factors: Erythropoietin,G-CSF.
3- Cytotoxics for RAEB & RAEBT&CMML
4- Bone marrow transplant for young
patients with advanced disease.
5- Immune modulating and differentiating
agents .
Summary
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Anemia of chronic disease may be confused with iron
deficiency anemia, but the serum ferritin is normal.
Anemia of chronic disease is usually mild except in chronic
renal failure were it responds well to erythropoietin injections.
Aplastic anemia presents with anemia ,repeated infections
and bleeding tendency due to pancytopenia and hypocelluar
marrow.
Idiopathic aplastic anemia is best treated with allogeneic
bone marrow transplantation for patients younger than 45
years old.
Idiopathic aplastic anemia of older patients is treated with
antithymocye globulin and ciclosporin A.
Supportive treatment is essential for aplastic anemia.
Myelodysplastic syndrome is a group of disorders affecting
bone marrow stem cells that result in dysplastic changes, di or
pancytopenia and tendency to transform into AML.
Patients need supportive treatment. Chemotherapy and bone
marrow transplantation are reserved for fit patients with
transformation into AML.