Macrocytic Anemia - Megaloblastic Anemia
What is megaloblast?
• It is an abnormal erythroid precursor seen only in the bone marrow.
• characterized by delayed maturation of the nucleus relative to that of the cytoplasm.
Megaloblastic Anemia
Definition: A result of impaired DNA synthesis due to def. in Folate and/or vitamin B12 (cobalamin).
- Anemia with macrocytic red cells (MCV>100 fL).
- Features are due to impaired DNA synthesis.
- Maturation of the nucleus being delayed relative to that of the cytoplasm (this is called megaloblastosis).
- This condition affects not only the production of red cells but also, granulocytes and platelets.
Reminder
- Vitamins are organic molecules, required in small quantities for a variety of biochemical functions.
- They function as cofactors for enzymatic reactions.
-Can not be synthesized by mammalian cells and, therefore, must be supplied in the diet.
Causes of Megaloblastic Anemia:
The most common causes of megaloblastosis are:
- Cobalamin (vitamin B-12) and Folate (folic acid) deficiencies.
● Folate functions as a coenzyme in purine and pyrimidine synthesis.
● Vitamin B-12 is required for the demethylation of folate.
Daily folate requirement:100µg
Daily B-12 requirement:1µg
Cobalamin B12
- Is composed of a complex tetrapyrrole ring structure (corrin ring) and a cobalt ion in the center.
- It is synthesized exclusively by microorganisms, so it is absent from plants
- Is found in the liver of animals bound to protein as methylcobalamin.
- Must be hydrolyzed from protein to be active.
- Hydrolysis occurs in the stomach by gastric acids or the intestines by trypsin digestion following the consumption of animal meat.
- The vitamin is then bound by an intrinsic factor (IF)
A protein secreted by parietal cells of the stomach
and transported to the ileum where it is absorbed.
- After absorption, the vitamin is transported to the liver in the blood bound to transcobalamin II.
- Stored in the liver bound to transcobalamin 
Vitamin B12 Dietary sources and recommended intake:
- Vitamin B12 (cobalamin) is only synthesized by micro-organisms.
- Animals obtain vitamins from their natural bacterial flora or eat other animals with vitamin reserves.
- Milk is a good source.
- Vegans are at risk of deficiency.
- Daily requirement = 1-1.5µg/day.
Vitamin B-12 Physiology
● Normal B-12 absorption:
- Dietary B-12 binds to the R factor in saliva and gastric juices.
- In the duodenum, pancreatic enzymes promote dissociation from the R factor and binding to Intrinsic Factor (IF)
- IF-B12 complex is taken up by ileal receptor cubilin.
- Released into plasma bound to transcobalamin (Binding proteins) TC I, II, or III.
- Enters cells through receptor-mediated endocytosis and metabolized into two coenzymes:
- Adenosyl-Cbl and methyl-Cbl
It is stored mainly in the liver in amounts (3-5mg) sufficient to last a couple of years.
The function of vitamin B12
1. Vitamin B12 (as deoxyadenosylcobalamin) is a co-enzyme for the enzyme: methylmalonyl CoA mutase.
2. Vitamin B12 is also a coenzyme in a reaction required in methionine.
H4folate is converted to N5-methyl-H4folate in several different reactions as it accepts methyl groups.
Through the above reaction, only the methyl group can be removed and H 4 folic acid can be regenerated.
Causes of Cobalamin (Vitamin B-12) deficiency
- Nutritional deficiency: rare, deficiency is most commonly due to absorption defect as in:
- Malabsorption
- Pernicious anemia: common
- Gastrectomy
- Severe abnormalities in the terminal ileum due to ileal resection, regional ileitis, tuberculosis, or lymphoma.
- Blind loop syndrome: Bacteria compete with the host for cobalamin.
- Diphyllobothrium latum (i.e., fish tapeworm)
Effects of B12 Deficiency
- Impaired methylmalonyl CoA mutase causes the accumulation of an unusual, odd number of carbon fatty acids.
- These accumulate in nerve cell membranes causing irreversible neurological disorders.
- paired methionine synthase traps H4folate as N5-methyl-H4folate ("folate trap").
- This may lead to a secondary or artificial deficiency of folic acid.
- Anemia due to a true folic acid deficiency is Megaloblastic anemia.
- Anemia due to a true folic secondary folic acid deficiency caused by primary B12 deficiency is pernicious anemia.
Folic acid (Folate)
Dietary Folate and Its Absorption:
- Vegetable, Liver, and meat.
- Degraded by prolonged boiling.
- Daily requirement roughly 100 mcg.
- Folate-free diet causes a deficiency in a few weeks.
- absorption is largely through the jejunum.
Synthesis of Deoxythymidylate (dTMP)
N5, N10-methylene tetrahydrofolate transmit a methyl group to deoxyyuridylate (dUMP) to make dTMP: Essential for DNA synthesis.
Causes of folate deficiency
1. Inadequate intake or/dietary insufficiency:
the destruction of folate by excessive heating of foods, or consuming alternative diets that are low in folate.
2. Impaired absorption:
- Tropical sprue: tropical sprue can lead to cobalamin deficiency and folate deficiencies.
- Other intestinal disorders: regional enteritis, intestinal lymphoma, surgical intestinal resection, amyloidosis.
3. Increased turnover or requirements:
- pregnancy and lactation.
- Psoriasis and exfoliative dermatitis.
- Hemolytic anemias.
- Infants: premature infants with infection or diarrhea, and infants on synthetic diets for congenital disorders.
- Miscellaneous: hemodialysis, alcoholism, drugs.
Megaloblastic anemia
Signs & symptoms:
-Most patients are relatively asymptomatic.
-Dyspnea, light-headedness, palpitations, and heart failure. Jaundice, weakness.
- Smooth tongue due to loss of papillae
- Dermatological signs include hyperpigmentation of the skin and depigmentation of the hair.
- Other autoimmune disorders.
- Neurological symptoms include:
paresthesia in the feet and fingers, poor gait, and memory loss. In the later stages, the patient's gait may be severely disturbed, loss of position sense, blindness, and mental illness caused by optic atrophy.
- Neuropsychiatric signs are usually found only in patients with cobalamin deficiencies: subacute combined degeneration of the spinal cord; which results in progressive neuropathy that affects peripheral sensory nerves and posterior and lateral columns. This condition presents clinically as neuropathy of the lower limbs causing tingling in the feet, abnormal gait, and loss of proprioception, which causes the patient to fall in the dark.
- Folate or B12 deficiency in the mother predisposes to NTD: neural tube defect such as (anencephaly, spina bifida, encephalocele).
Diagnosis of megaloblastic Anemia
- CBC (complete blood count), RBC indices, platelet count, differential count, reticulocyte count, and microscopic examination of the peripheral blood smear should be performed.
- macrocytic anemia, thrombocytopenia, and reduced reticulocyte count. The mean cell volume (MCV) can range from 100-150 fL or greater.
- Hypersegmented neutrophils.
- Macroovalocytes.
- Increase LDH and indirect bilirubin.
- BM Aspirate: showed hypercellular BM & the erythroblasts are large, there are giant metamyelocytes.
- Tests for the diagnosis of cobalamin deficiency are described as follows:
- Low serum cobalamin level.
- Serum folate levels
- Tests for folate deficiency
▪Serum folate
▪The RBC folate level is usually low
Pernicious Anemia
- This is a special type of Megaloblastic anemia.
- Caused by absorption defect in vitamin B-12 due to autoimmune disease.
Clinical Features:
- Megaloblastic anemia
- Serum B-12 deficiency.
- Chronic atrophic gastritis
- Nervous system manifestations (paresthesias, numbness, weakness, memory loss, personality changes, ataxia, loss of vibration and sense of position, psychosis “megaloblastic madness”)
- Atrophic glossitis
- Achlorhydria (lack of HCl in gastric juice).
- Elevated serum bilirubin and LDH reflective of increased RBC breakdown due to ineffective erythropoiesis.
Pathophysiology
- Autoantibody to IF
Two types:
▪Type I blocks the attachment of B-12 to IF.
▪Type II blocks B-12-IF complex to the ileal receptor.
Present in up to 70% of patients with P.A. and Sn approaches 100%.
- Autoantibody to gastric parietal cells
▪Directed against the H/K-ATPase on the cell membrane
▪This leads to a decline in the number of parietal cells and IF production.
▪Leads to chronic atrophic gastritis and gastric atrophy.
▪Found in 90% of patients with pernicious anemia.
Schilling test
- Is a radiometric test of cobalamin absorption. The test is given in 3 parts, as follows:
▪In the first part of the test, radioactive cyanocobalamin is given orally. Unlabeled cyanocobalamin is given intramuscularly to inhibit the uptake of radioactive cobalamin by the liver. Next, the urinary secretion of radioactive cobalamin is measured to estimate whether the orally administered cobalamin has been taken up. Low secretion suggests either pernicious anemia or an abnormality in the terminal ileum that prevented the uptake of IF-cobalamin complexes.
▪The second part of the test is performed in the same manner, except that IF is given orally along with radioactive cyanocobalamin. If the intake of radioactive cyanocobalamin is resumed, the patient is likely to have pernicious anemia. However, if IF does not restore uptake, then an abnormality in the terminal ileum is most likely present.
▪A third phase can be performed in which the patient is treated with antibiotics (Ab) before administering radioactive cyanocobalamin. If the antibiotic restores the absorption of cobalamin from the gastrointestinal tract, the patient is most likely to have blind ring syndrome.
Schilling test
|
Causes of
Cobalamin Deficiency |
Part I
without IF |
Part II
with IF |
Part III
with Ab |
|
Pernicious
Anemia |
Low |
Normal |
Not Needed |
|
Bacterial
Overgrowth |
Low |
Low |
Normal |
|
Ileal
Dysfunction |
Low |
Low |
Low |
Treatment:
- Cobalamin and folic acid therapy can treat these deficiencies.
- Treatment of the underlying cause if possible
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