RED CELL DISORDERS

MEGALOBLASTIC ANEMIA

Department of Medical Sciences

Faculty of Medicine University of Brawijaya
 Clinical Competencies

Be able to describe:
- the etiology of megaloblastic anemia caused by
vitamin B12 and folate deficiency
- the pathophysiology of megaloblastic anemia
- the principal management of megaloblastic anemia
caused by vitamin B12 and folate deficiency
Be able to diagnose megaloblastic anemia based on
clinical features and laboratory findings

Faculty of Medicine
University of Brawijaya
 Introduction

Megaloblastic anemia
A heterogeneous group of anemia characteristics:
- RBC are larger: nuclear-to-cytoplasmic ratio >
normoblast
- The maturation of nuclei is delayed, cytoplasmic
development is normal
Based on the appearance of developing erythroblasts in
the bone marrow: megaloblastic & non-megaloblastic
There are several causes, but megaloblastic anemia is
usually caused by vitamin B12 or folate deficiency.

Faculty of Medicine
University of Brawijaya
 Etiology

In clinical practice, this is usually caused by vitamin B12

(cobalamine) or folate deficiency.
Causes of vitamin B12 deficiency
Nutritional
Malabsorption: gastric and intestinal causes
Causes of folate deficiency
Nutritional
Malabsorption
Excess urinary folate loss
Drugs
Excess utilization
Mixed

Faculty of Medicine
University of Brawijaya
 Table 1. The causes of vitamin B12 deficiency
Nutritional
Especially vegans/veganism (vegetarian) less commonly
Malabsorption
Gastric causes
Pernicious anemia
Congenital lack or abnormality of intrinsic factor
Total or partial gastrectomy
Intestinal causes
Intestinal stagnant loop syndrome jejunal diverticulosis,
blind loop, stricture, etc
Chronic tropical sprue
Ileal resection and Crohns disease
Congenital selective malabsorption with proteinuria
(autosomal recessive megaloblastic anemia)
Fish tapeworm

Faculty of Medicine
University of Brawijaya
 Table 2. The causes of folate deficiency
Nutritional
Especially old age, institutions, poverty, famine, special diets, goats
milk anemia, etc
Malabsorption
Tropical sprue, gluten-induced enteropathy (adult or child)
Possible contributory factor to folate deficiency in some patients with partial
gastrectomy, extensive jejunal resectionor Crohns disease
Excess urinary folate loss: active liver disease, congestive heart failure
Drugs: anticonvulsants, sulfasalazine
Excess utilization
Physiological : pregnancy and lactation, prematurity
Pathological
- Hematological diseases: hemolytic anemia, myelofibrosis
- Malignant diseases: carcinoma, lymphoma, myeloma
- Inflammatory diseases: Crohns disease, tuberculosis,
rheumatoid arthritis, psoriasis, exfoliative dermatitis, malaria
Mixed: liver disease, alcoholism, intensive care

Faculty of Medicine
University of Brawijaya
 Pathophysiology

The molecular basis: a failure in the synthesis and

assembly of DNA.
Cobalamin & folate metabolism are intricately related, and
abnormalities in these pathways are believed to lead
to the attenuated production of DNA.
Megaloblastosis is caused by interference of folate
metabolism by the inhibition of methionine synthesis.
Dietary folate deficiency the size of the deoxythymidine
triphosphate (dTTP) pool is normal or increased in
persons with megaloblastosis.

Faculty of Medicine
University of Brawijaya
Impairment in the deoxyuridine monophosphate (dUMP) &
deoxythymidine monophosphate (dTMP) pathway may be
responsible for nutritional megaloblastosis.
The cobalamin-related neuropathy: megaloblastic
changes in hematopoietic cells.
Hypothesis for the cause of cobalamin neuropathy:
a defect exists in the conversion of adenosyl-
cobalamin-dependent conversion of methylmalonyl
coenzyme A to succinyl coenzyme A.

Faculty of Medicine
University of Brawijaya
A hallmark of megaloblastic anemia is ineffective
erythropoiesis, as evidenced by :
- erythroid hyperplasia in the bone marrow
- a decreased peripheral reticulocyte count
- an elevation in lactate dehydrogenase (LDH) and
indirect bilirubin levels.

The pathogenesis of these findings is the intramedullary

destruction of fragile and abnormal megaloblastic
erythroid precursors.

Faculty of Medicine
University of Brawijaya
 Diagnosis

Based on clinical features and laboratory findings

Clinical Features
Mildly jaundice (lemon yellow tint)
Glossitis (a beefy-red, sore tongue)
Angular stomatitis
Mild symptoms of malabsorption with loss of weight
caused by epithelial abnormality
Purpura as a result of thrombocytopenia and
widespread melanin pigmentation

Faculty of Medicine
University of Brawijaya
 Vitamin B12 neuropathy
Neural tube defect (anencephaly, spina bifida or
encephalocele) in the fetus
Cardiovascular disease: myocardial infarct, peripheral
& cerebral vascular disease & venous thrombosis
Other tissues abnormalities
- Sterility is frequent in either sex with severe B12 or
folate deficiency
- Morphological abnormalities of cervical, buccal,
bladder and other epithelia

Faculty of Medicine
University of Brawijaya
Figure 1. Megaloblastic anemia: glossitis, and angular cheilosis (stomatitis)
Figure 2. A baby with neural tube defect (spina bifida)
 Laboratory Findings

Pancytopenia
Increased MCV and MCHC
Hypersegmented neutrophils (five lobes or more in
segmented neutrophils)
Increased bilirubin
Increased LDH
Hyperplasia in the bone marrow
Decreased M:E ratio
Reticulocytopenia

Faculty of Medicine
University of Brawijaya
 Treatment of Megaloblastic Anemia

Vitamin B12 Deficiency

Compound: hydroxocobalamine
Route: intramuscular, oral
Dose: 1000 g
Initial dose: 6x1000 g over 1-3 weeks
Maitenance: 1000 g every 3 months
Prophylactic: total gastrectomy, ileal resection

Faculty of Medicine
University of Brawijaya
Folate Deficiency
Compound: folic acid
Route: oral
Dose: 5 mg
Initial dose: daily for 4 months
Maitenance: depends on underlying disease; life-long
therapy may be needed in chronic inherited hemolytic
anemia, myelofibrosis, renal dialysis
Prophylactic: pregnancy, severe hemolytic anemia,
dialysis, prematurity

Faculty of Medicine
University of Brawijaya
Faculty of Medicine
University of Brawijaya