megaloblastic anemias
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MEGALOBLASTIC ANEMIASANNA GOYENECHEA-CINIO MD
INTRODUCTION
Impaired DNA synthesis Cells affected have relatively rapid
turnover Hematopoietic precursors Gastrointestinal epithelial cells
Cell division is slow but cytoplasmic development progresses normally
Cells tend to be large Increased ratio of RNA to DNA
INTRODUCTION
Megaloblastic eythroid progenitors destroyed in the marrow
Marrow cellularity often increased RBC production decreased ineffective
erythropoiesis Most cases due to deficiency of:
Cobalamin Folic acid
DIAGNOSIS
Significant macrocytosis (MCV > 100 fl) If MCV > 110 fl, megaloblastic anemia
is more likely Low reticulocyte count, decreased
leukocyte and platelet count especially in severely anemic patients
PBS: marked anisocytosis, poikilocytosis with macroovalocytes
DIAGNOSIS
Nucleated RBC’s, hypersegmented nucleus of the neutrophils
Hypercellular bone marrow with decreased myeloid/erythroid ratio and abundant stainable iron
RBC precursors abnormally large, nuclei appear much less mature
Nuclear chromatin condenses in a fenestrated pattern
Ineffective erythropoiesis RBC folate level better than serum folate level as
an index of folate stores
DIAGNOSIS
Cobalamin increased methylmalonic acid and homocysteine levels
Folate: increased homocysteine
FOLIC ACID DEFICIENCY
Sources: fruits and vegetables Destroyed by cooking Requirement: 50 ug/day
Increased during pregnancy Absorbed in proximal jejunum Plasma folate: N5 –
methyltetrahydrofolate Normal: 5-20mg in various body stores,
half in the liver
FOLIC ACID DEFICIENCY
Transfer methyl and formyl groups to organic compounds to form metabolic intermediates used in the synthesis of: Purines Deoxythymidylate monophosphate (dTMP) methionine
FOLIC ACID DEFICIENCY
Some drugs inhibit dihydrofolate reductase- producing folate deficiency despite normal tissue folate concentrations
Patients more malnourished GIT manifestations more severe Diarrhea often present May have cheilosis and glossitis but
neurologic abnormalities do not occur Due to inadequate intake, increased
demand or malabsorption
FOLIC ACID DEFICIENCY
INADEQUATE INTAKE Alcoholics Narcotic addicts malnutrition Indigent or elderly individuals on canned
foods or “tea or toast” Teenagers junk food Food supplementation
FOLIC ACID DEFICIENCY
INCREASED DEMAND Pregnant women neural tube
defects in the fetus Folate food supplementation has
decreased neural tube defects by 50%
Infancy Adolescence Chronic dialysis
FOLIC ACID DEFICIENCY
MALABSORPTION Tropical sprue Improved symptoms upon taking
folic acid or antibiotics Also in non-tropical sprue and
alcoholics Primary small bowel disorders
FOLIC ACID DEFICIENCY
TREATMENT Folate 1 mg/day PO Up to 5 mg/day in malabsorption Reticulocytosis after 4 days Correction of anemia at 1-2 months In hemolytic anemia and malabsorption or
chronic malnutrition: oral folic acid indefinitely
FOLIC ACID DEFICIENCY
DRUGS Interferes with DNA synthesis
Direct inhibitors of DNA synthesis Purine analogues (6-mercaptopurine)
Pyrimidine analogues (5-FU) Others (hydroxyurea) Zidovudine (AZT)
FOLIC ACID DEFICIENCY
DRUGS Interferes with DNA synthesis
Folate antagonists Methotrexate- inhibits dihydrofolate reductase
Pentamidine Trimethoprim Triamterene pyrimethamine
FOLIC ACID DEFICIENCY
DRUGS Interferes with DNA synthesis
OTHERS: Mild megaloblastic anemia May affect intestinal absorption of folate:
Phenytoin Primidone phenobarbital
COBALAMIN DEFICIENCY
Cannot be synthesized in the human body Must be supplied in the diet Animal products: meat and dairy foods Minimum daily requirement: 2.5ug/day Absorbed in distal ileum Requires binding to intrinsic factor from
parietal cells of the stomach Transport is via the transcobalamin II
transporter
COBALAMIN DEFICIENCY
Liver: 2mg Another 2 mg elsewhere in the body 3-6 years for a normal person to
develop deficiency if absorption stops Cofactor for: methionine synthase and
methylmalonyl-CoA synthase
COBALAMIN DEFICIENCY
Exists in 2 forms: Methylcobalamin
required for methionine synthase Conversion of homocysteine to methionine
Synthesis of choline from methionine
Neurologic deficits
COBALAMIN DEFICIENCY
Exists in 2 forms: Adenosylcobalamin
Conversion of methymalonyl CoA to succinyl CoA
COBALAMIN DEFICIENCY
CLINICAL DISORDERS Alcoholics Pernicious anemia Tropical sprue Diphyllobothrium latum Cobalamin almost always due to malabsorption Folic acid- decreased dietary intake, increased
metabolic demand, malabsorption Severe deficiency of one can lead to
malabsorption of the other
COBALAMIN DEFICIENCY
Blood, GIT, nervous system Anemia Rarely purpura Pale, slightly icteric skin and eyes,
jaundice Heart may be enlarged Systolic flow murmur Sore, smooth and beefy tongue Anorexia, weight loss, diarrhea
COBALAMIN DEFICIENCY
Folate supplementation may increase the likelihood of neurologic symptoms
Anemia may be very severe but well-tolerated because it develops slowly
People > 70 years cannot absorb from food but can absorb form crystalline form
PPI’s inhibit release of cobalamin from food
COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA Most common cause Absence of intrinsic factor due to atrophy of
gastric mucosa or autoimmune destruction of parietal cells
Less common in Europeans and Asians Males=females Presents near age 60, rare under age 30, can be
seen in children under age 10 Increased in immunologic diseases
Graves’ disease, myxedema, thyroiditis, vitiligo, hypoparathyroidism, idiopathic adrenocortical insufficiency
COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA Abnormal circulating antibodies 90% anti-parietal cell antibody against HK-
ATPase 60% anti-IF antibody, absent in patients with
gastric atrophy but no pernicious anemia Relatives have increased incidence Common in agammaglobulinemia Glucocorticoids may reverse the disease Gastric atrophy with antral sparing Cellular atypia in gastric cytology specimens
COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA Insidious onset hypergastrinemia, hematologic
abnormalities Nervous system changes may be
irreversible Subject to gastric polyps and 2x the
normal incidence of cancer
COBALAMIN DEFICIENCY
Postgastrectomy/ extensive damage to gastric mucosa
Intestinal organisms Bacterial overgrowth consume cobalamin Tetracycline, ampicillin D. latum competes for cobalamin
COBALAMIN DEFICIENCY
Ileal abnormalities Common in tropical sprue Regional enteritis, Whipple’s disease,
tuberculosis Segmental lesions of distal ileum Leal resection Sollinger-Ellison syndrome Chronic pancreatitis
COBALAMIN DEFICIENCY
Nitrous Oxide Destroys endogenous cobalamin Repeated or protracted use (>6 hours) Especially in the elderly
COBALAMIN DEFICIENCY
TREATMENT Generally given parenteral (IM cyanocobalamin) 1000 ug cobalamin/ week for 8 weeks followed by
1000 ug IM every month for the rest of the patient’s life or 2 mg crystalline B12/day
Increase in strength, improved sense of well-being Marrow morphology reverts to normal within a few
hours Reticulocytosis after 4-5 days, peaks at day 7 Anemia resolves over the next several weeks Hypokalemia, salt retention, thrombocytosis may be
seen
COBALAMIN DEFICIENCY
TREATMENT Severe anemia- emergency transfusion Neurologic symptoms may not be fully
corrected Folate may improve anemia without
improving or even worsening of neurologic symptoms
0.1 mg oral crystalline cobalamin prophylaxis daily in people over 65 years old
THANK YOU!!!
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