Megaloblastic anemias

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


Transfer methyl and formyl groups to organic compounds to form metabolic intermediates used in the synthesis of: Purines Deoxythymidylate monophosphate (dTMP) methionine


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


INADEQUATE INTAKE Alcoholics Narcotic addicts malnutrition Indigent or elderly individuals on canned

foods or “tea or toast” Teenagers junk food Food supplementation


INCREASED DEMAND Pregnant women neural tube

defects in the fetus Folate food supplementation has

decreased neural tube defects by 50%

Infancy Adolescence Chronic dialysis


MALABSORPTION Tropical sprue Improved symptoms upon taking

folic acid or antibiotics Also in non-tropical sprue and

alcoholics Primary small bowel disorders


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


DRUGS Interferes with DNA synthesis

Direct inhibitors of DNA synthesis Purine analogues (6-mercaptopurine)

Pyrimidine analogues (5-FU) Others (hydroxyurea) Zidovudine (AZT)



Folate antagonists Methotrexate- inhibits dihydrofolate reductase

Pentamidine Trimethoprim Triamterene pyrimethamine



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


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


Exists in 2 forms: Methylcobalamin

required for methionine synthase Conversion of homocysteine to methionine

Synthesis of choline from methionine

Neurologic deficits


Exists in 2 forms: Adenosylcobalamin

Conversion of methymalonyl CoA to succinyl CoA


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


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


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


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


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


PERNICIOUS ANEMIA Insidious onset hypergastrinemia, hematologic

abnormalities Nervous system changes may be

irreversible Subject to gastric polyps and 2x the

normal incidence of cancer


Postgastrectomy/ extensive damage to gastric mucosa

Intestinal organisms Bacterial overgrowth consume cobalamin Tetracycline, ampicillin D. latum competes for cobalamin


Ileal abnormalities Common in tropical sprue Regional enteritis, Whipple’s disease,

tuberculosis Segmental lesions of distal ileum Leal resection Sollinger-Ellison syndrome Chronic pancreatitis


Nitrous Oxide Destroys endogenous cobalamin Repeated or protracted use (>6 hours) Especially in the elderly


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


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

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Megaloblastic anemias