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Macrocytic Anemia

Causes of macrocytic anaemia
  1. Macrocytic megaloblastic anaemia
    1. BM abnormal, all precursors of RHC, WBC & platelet are megaloblastic along with peripheral blood macrocytosis.
    2. Responsive to Vit B12 / folate therapy
    3. Causes includes:
      1. Vit B12 Deficiency
      2. Folate Deficiency
      3. Therapy with antifolate drug
      • DH reductase inhibitors – Methotrexate, trimethoprim, pyrimethamine, cotrimoxazole, pentamidine
      • Other – Anticonvulsant (Phenytoin, Primidone, Phenobarbitone, NO), OCP
      1. Drugs that inhibit DNA synthesis
      • Purine antagonist – 6 mercaptopurine, azathioprine
      • Pyrimidine antagonist – 5FU, cytosine arabinoside
      • Others – Hydroxyurea, Zidovudine, acyclovir, Procarbazine
  2. Macrocytic normoblastic anaemia
    1. BM percussors are normoblastic, either reticulocyte or mature RBC show increase size (Macrocyte)
    2. Unresponsive to Vit B12 / folate therapy
    3. Causes:
      1. Orotic aciduria
      2. Liver disease
      3. Hypothyroidism
      4. Thiamine deficiency
      5. Alcoholism
      6. No inhalation
      7. Myelodysplastic anaemia
      8. Anaemia of marrow infiltration
      9. Scurvy
Normal values of vitamin B12 is >250 pg/ml
Causes of Vitamin B12 Deficiency
  1. Deficient diet (pure plant diet)
  2. Malabsorption
  3. Pernicious anemia (Intrinsic factor deficiency), Partial/total gastrectomy, Crohn’s disease, Tropical sprue, Ileal resection, ileo cecal disease. (AIIMS Nov 09)
  4. Blind loop syndrome (Bacterial overgrowth causes B12 deficiency)
  5. Chronic pancreatitis
  6. Fish tapeworm (Diphyllobothrium latum).

Vit B12



Vegetable – Poor

Animal food – Rich

Vegetable – Rich

Animal food - Poor

Daily requirement

2-4 μg/day

100 μg /day

Main site of absorption


Duodenum & jejunum

Body store

2-5 mg

5-20 mg

Body store exhaust in

App. 4 years

App 4 Month


Clinical Features

  1. Pallor (lemon Colour), smooth tongue, cardiac “hemic” systolic murmur, hepatomegaly, rarely splenomegaly.
  2. Neurologic picture in vitamin B12 deficiency ranges from mental inattentiveness to severe mental confusion with or without dorsal and lateral column signs (subacute combined degeneration).
  3. These signs are reversible with cobalamin therapy.


Tongue in Vit B12 deficiency
  1. Macroglossia
  2. Atrophic glossitis (smooth tongue due to Loss of papillae)
  3. Moeller’s glossitis (A superficial form of glossitis marked by irregular red patches on the tongue and sensitivity to hot or spicy food)
  4. Sore Tongue (Red and inflamed)
  5. Beefy tongue
Neurological Findings in B12 Deficiency
  1. Peripheral nerves
    1. Glove and stocking paraesthesia
  2. Spinal cord
    1. Subacute combined degeneration
    2. Posterior columns – diminished vibration and proprioception
    3. Corticospinal tracts – upper motor neuron signs
  3. Cerebrum - Dementia (reversible dementia) AIPG 2007
  4. Cranial nerve- Optic atrophy
  5. Autonomic neuropathy
Extra Edge: In B12 deficiency, despite involvement of corticospinal tract, DTR are not brisk but planter is up going. (PGI Dec 2008) (Normal DTR with positive Babinski sign)

  1. Blood film shows hypersegmented (> 5 lobes) polymorphs are present in B12 deficiency and folate deficiency

Absolute values in megaloblastic anemia

1. Red cell count -- LOW
2. Hb -- LOW
3. PCV -- LOW
4. MCV -- High, e.g. (average cell is larger than normal)
5. MCH -- High (average cell contains more Hb than normal)
6. MCH -- Normal (Average cell contains normal Hb concentration)

  1. Bone marrow biopsy
    1. Megaloblastic – B12 or folate deficiency
    2. Normoblastic – liver damage, myxoedema
    3. Increased erythropoiesis – bleeding or hemolysis
    4. Abnormal erythropoiesis – sideroblastic anemia, leukemia, aplastic Anaemica.

Note: Pancytopenia can occur in pernicious anemia.

  1. Schilling test. It helps to identify the cause of B12 deficiency.

Extra Edge:


Causes of hypersegmented neutrophils

  1. CRF
  2. Vit B12 / Folate Def
  3. Myeloproliferative disorder


Pernicious anaemia or Addison’s anaemia (Do not get confuse with Addison’s disease)
  1. It is commonly associated with other autoimmune disorder including thyroid disease (thyrotoxicosis, myxedema, Hashimoto disease), vitiligo, hypoparathyroidism, premature graying, blue eye, blood group A & HLA-3.
  2. Life expectancy is normal in female
  3. Decrease in male (because of increased incidence of carcinoma stomach – 3 times more as compared to normal person)
  4. Biochemical analysis
    1. HCI secretion
    2. Pepsin secretion
    3. IF secretion
    4. S. gastrin ↑
  5. Gastric biopsy – shows atrophy of all layers of body and fundus, absence of parietal and chief cells.
  6. Types of serum antibody.
    1. Blocking/type I antibody – Prevent combination of Intrinsic Factor and cobalamin – 55%
    2. Binding type II antibody – prevent attachment of Intrinsic Factor to ileal mucosa – 35%
  7. Parietal cell antibody present in 90% of patients.
Complication of B12 replacement therapy
  1. Hypokalemia
  2. It may precipitate Iron deficiency anemia.

Extra Edge:

  1. Selective Malabsorption of Cobalamin with Proteinuria (Imerslund Syndrome: Congenital Cobalamin Malabsorption; Autosomal Recessive Megaloblastic Anemia, MGA1)
  2. This autosomally recessive disease is the most common cause of megaloblastic anemia due to cobalamin deficiency in infancy in Western countries.

Folic acid deficiency

Causes of Folate Deficiency (Ref. Hari. 18th ed., Pg- 869, table 105.5)

  1. Dietary cause
  2. Malabsorption (alcoholism, celiac (LQ 2012) & tropical sprue, Crohn’s disease, scleredema, hypothyroidism)
  3. Increased demand of folate – pregnancy, cell proliferation as in hemolysis, neoplasia, hyperthyroidism, ineffective erythropoiesis (pernicious anemia, sideroblastic anemia).Q
  4. Drugs (phenytoin, methotrexate, trimethoprim, pyrimethamine, alcohol).Q 
Metabolism of Folate
Total body storage capacity is up to 5 mg (3 – 4 months supply).


Extra Edge:


If folic acid alone is given in macrocytic anemia it can improve blood picture but it will precipitate CNS features which occur due to B12 deficiency. So in macrocytic anemia both folic acid and B12 should be given together. (AIIMS May 2008)


  1. In B12 deficiency, hydroxocobalamin 1000 mg twice during the first week,
  2. In folate deficiency 5 mg of folic acid/day orally is given.
  3. Folate supplements 350 mg daily is given for all pregnant women.
Thiamine deficiency
  1. Thiamine functions in the decarboxylation of α-ketoacid, such as pyruvate α-ketoglutarate, and branched-chain amino acids and thus is a source of energy generation.
  2. In addition, thiamine pyrophosphate acts as a coenzyme for a transketolase reaction that mediates the conversion of hexose and pentose phosphates.
  3. Causes:
    1. Poor dietary intake.
    2. Alcoholism (Alcohol interferes directly with the absorption of thiamine and with the synthesis of thiamine pyrophosphate.)
    3. Chronic illness, such as cancer.
    4. Prolonged hyperemesis gravidarum and anorexia,
    5. Patients on chronic diuretic therapy due to increased urinary thiamine losses.
  4. Prolonged thiamine deficiency causes beriberi (wet or dry), Wernicke's encephalopathy, Korsakoff psychosis.
  1. Beriberi
    1. Wet beriberi
      1. Presents primarily with cardiovascular symptoms, due to impaired myocardial energy metabolism and dysautonomia, and can occur after 3 months of a thiamine-deficient diet.
      2. Patients present with an enlarged heart, tachycardia,
      3. High-output congestive heart failure, peripheral edema, and peripheral neuritis.
    2. Dry beriberi
      1. Present with a symmetric peripheral neuropathy of the motor and sensory systems with diminished reflexes.
      2. The neuropathy affects the legs most markedly, and patients have difficulty rising from a squatting position.
  2. Wernicke's encephalopathy, consisting of horizontal nystagmus, ophthalmoplegia (due to weakness of one or more extraocular muscles), cerebellar ataxia, and mental impairment.
  3. Korsakoff psychosis. When there is an additional loss of memory and a confabulatory psychosis, the syndrome is known as Wernicke-Korsakoff syndrome.

Extra Edge:


Prolonged Thiamin (Vitamin B1) deficiency, Leads to lactic acidosis (AIIMS Nov 10)

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