2) Megaloblastic Anemia

8/3/2019 2) Megaloblastic Anemia

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Department of MedicalSciences Faculty of Medicine

University of Brawijaya

MEGALOBLASTIC ANEMIA

RED CELL DISORDERS



Faculty of Medicine University of Brawijaya

Clinical Competencies

Be able to describe:- the etiology of megaloblastic anemia caused byvitamin B12 and folate deficiency

- the pathophysiology of megaloblastic anemia

- the principal management of megaloblastic anemiacaused by vitamin B12 and folate deficiency

Be able to diagnose megaloblastic anemia based onclinical features and laboratory findings




Introduction

Megaloblastic anemiaA heterogeneous group of anemia characteristics:

- RBC are larger: nuclear-to-cytoplasmic ratio >normoblast

- The maturation of nuclei is delayed, cytoplasmicdevelopment is normal

Based on the appearance of developing erythroblasts inthe bone marrow: megaloblastic & non-megaloblastic

There are several causes, but megaloblastic anemia isusually caused by vitamin B12 or folate deficiency.




Etiology

In clinical practice, this is usually caused by vitamin B12 (cobalamine) or folate deficiency .

Causes of vitamin B12 deficiencyNutritional

Malabsorption: gastric and intestinal causesCauses of folate deficiency

NutritionalMalabsorptionExcess urinary folate lossDrugsExcess utilizationMixed



Table 1. The causes of vitamin B12 deficiency

Nutritional Especially vegans/veganism (vegetarian) less commonly

MalabsorptionGastric causes

Pernicious anemiaCongenital lack or abnormality of intrinsic factor

Total or partial gastrectomyIntestinal causes

Intestinal stagnant loop syndrome – jejunal diverticulosis,blind loop, stricture, etc

Chronic tropical sprueIleal resection and Crohn’s disease

Congenital selective malabsorption with proteinuria(autosomal recessive megaloblastic anemia)

Fish tapeworm




Table 2. The causes of folate deficiency

Nutritional

Especially old age, institutions, poverty, famine, special diets, goat’smilk anemia, etc

MalabsorptionTropical sprue, gluten-induced enteropathy (adult or child)Possible contributory factor to folate deficiency in some patients with partialgastrectomy, extensive jejunal resectionor Crohn’s disease

Excess urinary folate loss: active liver disease, congestive heart failureDrugs: anticonvulsants, sulfasalazine

Excess utilization Physiological : pregnancy and lactation, prematurity Pathological

- Hematological diseases: hemolytic anemia, myelofibrosis

- Malignant diseases: carcinoma, lymphoma, myeloma- Inflammatory diseases: Crohn’s disease, tuberculosis,rheumatoid arthritis, psoriasis, exfoliative dermatitis, malaria

Mixed: liver disease, alcoholism, intensive care





Pathophysiology

The molecular basis: a failure in the synthesis andassembly of DNA.

Cobalamin & folate metabolism are intricately related, andabnormalities 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 inpersons with megaloblastosis.




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.




A hallmark of megaloblastic anemia is ineffectiveerythropoiesis, as evidenced by :

- erythroid hyperplasia in the bone marrow- a decreased peripheral reticulocyte count

- an elevation in lactate dehydrogenase (LDH) andindirect bilirubin levels.

The pathogenesis of these findings is the intramedullarydestruction of fragile and abnormal megaloblastic

erythroid precursors.




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 andwidespread melanin pigmentation




Vitamin B12 neuropathyNeural tube defect (anencephaly, spina bifida or

encephalocele) in the fetus

Cardiovascular disease: myocardial infarct, peripheral

& cerebral vascular disease & venous thrombosisOther tissues abnormalities

- Sterility is frequent in either sex with severe B12 or

folate deficiency

- Morphological abnormalities of cervical, buccal,bladder and other epithelia



Figure 1. Megaloblastic anemia: glossitis, and angular cheilosis (stomatitis)



Figure 2. A baby with neural tube defect (spina bifida)




Laboratory Findings

PancytopeniaIncreased MCV and MCHC

Hypersegmented neutrophils (five lobes or more in

segmented neutrophils)

Increased bilirubinIncreased LDH

Hyperplasia in the bone marrow

Decreased M:E ratio

Reticulocytopenia




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




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




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2) Megaloblastic Anemia