Large Red Blood Cells (Megaloblastic Anemia)

Red blood cells (RBCs) or erythrocytes are small round cells that circulate in the blood stream and carry oxygen throughout the body. These cells measure about 6 to 8 micrometers (um) in diameter which is equivalent to 0.006 to 0.008 millimeters – too small to be seen by the naked eye. The cells are disc shaped with a central depression – the thickness in the middle is about 1um while at outer edges it is about 2.5um. On average, a red blood cell is about 7.8um in diameter and 2um thick. Its size and flexibility allows it to pass or squeeze through even the smallest of blood vessels. Different diseases can change many physical features of these red blood cells, thereby distorting its shape and size.

What is megaloblastic anemia?

Megaloblastic anemia is a group of  disorders characterized by abnormally large red blood cells. In a person with megablastosis, the red blood cells vary significantly in size (anisocytosis) and in shape (poikilocytosis) compared to the constant and regular shape and size of normal red blood cells. The abnormally large shape is evident from the early stages of development while the cell is still an immature precursor. Neutrophils, a type of leukocyte (white blood cell), is also enlarged with more than the three to four nuclear lobules it normally has. This enlargement of the neutrophils is an important diagnostic indicator of megaloblastic anemia.

Red blood cells are manufactured in the bone marrow from hematopoietic stem cells. Over a period of 7 days these cells undergo various stages of development until the mature red blood cell is released into circulation. In the final stages of maturation, vitamin B12 (cobalamin) and folate (folic acid) is required and a deficiency of these nutrients gives rise to megaloblastic anemia. However it is important to realise that the abnormality in shape and size is evident throughout the stages of development from a hematopoietic stem cell to a mature red blood cell.

Effect of Abnormally Enlarged Red Blood Cells

These oversized cells known as megaloblasts may undergo apoptosis (a self-orchestrated death) before it even leaves the bone marrow. Megaloblastic cells also have a fragile cell membrane and rupture easily due to various stresses a red blood cell experiences in its life cycle. Hemolysis (red blood cell rupture and destruction) also occurs for no known reason in megalobalstosis. All of these effects lead to a deficiency in red blood cells, hence the term megaloblastic anemia.

Causes of Megaloblastic Anemia

Vitamin B12 and folate occur naturally in foods. Folic acid is the synthetic form of folate and these compounds are collectively known as vitamin B9. Vitamin B12 and folate is necessary for normal DNA synthesis which occurs when red blood cells are developing. Once this DNA synthesis is disrupted, the deformities in shape and size occur. Deficiencies in vitamin B12 and folate occur for various reasons and megaloblastic anemia may also occur in other conditions where DNA synthesis is disrupted despite sufficient nutrients.

Both vitamins are abundant in meat, dairy and eggs. In addition, folate is also found in leafy green vegetables, fruits like oranges, tomatoes and mushrooms. Inadequate nutrition, especially a low intake of these foods, may lead to megaloblastic anemia.  Vitamin B12 need to bond with intrinsic factor produced in the stomach so that the vitamin-intrinsic factor complex can be absorbed in the small intestine. Failure to absorb vitamin B12 due to intrinsic factor deficiency leads to pernicious anemia. While folate does not need to form this complex to be absorbed into the blood stream, any intestinal disease can affect the absorption.

  • Diet. Deficiency of vitamin B12 and folate may be due to starvation, poor dietary habits and vegetarianism (vitamin B12). Folate deficiency is also seen with alcoholism and in infancy.
  • Surgery. Gastric (stomach) resection affects vitamin B12 absorption specifically and intestinal resection (particularly the ileum) may lead to both vitamin B12 and folate deficiency.
  • Intrinsic factor (IF) deficiency. This may be seen with a functional deficiency of IF as is seen with pernicious anemia or alterations in gastric acidity – hypochlorhydria (anacidity) or hyperchlorhydria (Zollinger-Ellison syndrome).
  • Malabsorption states may be associated with physiological and pathological factors including congenital and acquired intestinal disease, inflammation and cancer. This includes conditions like tropical sprue, chronic enteritis, intestinal lymphoma, Whipple disease and scleroderma.  Certain drugs like oral contraceptives and anticonvulsants may also affect absorption.
  • Increased utilization may be seen in pregnancy due to the demands of the fetus for development.
  • Vitamin loss may be seen with hemodialysis.
  • Bacteria. Bacterial overgrowth results in competitive intake as the bacteria may consume the nutrients. This is more likely to occur with blind loop syndrome.
  • Parasitic worms like in a fish tapeworm infestation results in competition for the uptake of vitamin B12.
  • Medication that blocks or inhibits the action of vitamin B12 and/or folate includes drugs like :
    • Methotrexate
    • Metformin (diabetes mellitus)
    • Anti-gout medication
    • Certain antibiotics

Signs and symptoms

Megaloblastic anemia develops gradually so patients may be asymptomatic for long periods of time. The three most common symptoms are :

  • Malaise – general feeling of being unwell
  • Parasthesia – abnormal sensations like tingling or pricking of the skin
  • Breathlessness – initially short of breath upon moderate activity, later constant breathlessness

Later symptoms like weight loss and fever may develop. Other signs and symptoms include :

Skin and hair

  • Abnormal skin pigmentation – a pale yellow (lemon yellow)
  • Gray hair – excessive, early graying


  • Sore mouth
  • Smooth tongue
  • Angular cheilosis – cracking at the corner of the mouth
  • Vitiligo – whitish patches of skin due to loss of pigmentation (no rash)

Central nervous system

  • Depression
  • Poor memory
  • Personality changes
  • Hallucinations
  • Visual disturbances


  • Erectile dysfunction
  • Heart failure

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