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Macrocytosis –An increase in the mean cell volume ( MCV) above the normal range 

 Upper range may be quoted as 95-100 fl. Prevalence ranges from 1.7 % to 5 % Up to 60-80 % with macrocytosis may not have anaemia

Main causes- Alcohol B12 and or folate deficiency Medications Hypothyroidism ( rarely ) Bone marrow dysplasias Liver disease ( non-alcoholic ) Reticulocytosis Physiological ( neonates , pregnancy ) Unexplained

Macrocytosis with anaemia – Alcoholism Liver disease Hemolysis with bleeding Hypothyroidism Folate or B12 deficiency Exposure to chemotherapy and other drugs Myelodysplasias Hereditary haemochromatosis Plasma cell dyscrasias

Macrocytosis without anaemia – Take detailed history Alcohol Drugs Tests ( particularly reticulocyte count and peripheral smear ) About 10 % cases may remain unexplained even after evaluation

Drug induced megaloblastic anaemia- Modulate purine metabolism -
○ azathioprine
○ mycophenolate mofetil
○ mercaptopurine
○ methotrexate
○ allopurinol
 Interfere with pyrimidine synthesis
○ antineoplastic agents ( e. g . hydroxyurea , methotrexate )
○ trimethoprim
○ leflunomide
 Decreased folic acid absorption
○ alcohol
○ aminosalicylic acid
○ contraceptive pills
○ estrogens
○ tetracyclines
○ penicillins 
○ chloramphenicol
○ nitrofurantoin
○ erythromycin
○ phenobarbital
○ phenytoin
○ malaria drugs as quinine , chloroquine , primaquine
 Folate analogue activity
○ methotrexate
○ proguanil
○ trimethoprim
 Vit B12 – decreased absorption
○ isoniazid
○ metformin
○ proton pump inhibitors , H2 blockers
○ neomycin
 Unknown – sulfasalazine

Investigations – B12 and folate
If available metabolites methylmalonic acid and homocysteine can be checked to determine true B12 deficiency If B12 deficient – check intrinsic factor antibody and gastric parietal cell antibody Blood film Reticulocyte count Liver function test Thyroid function test Lipids/ cholesterol Immunoglobulins and protein electrophoresis Urine for BJP Bone marrow biopsy

Referral –Suspected myelodysplasia syndrome 
( based on blood film , myelodysplasia may progress to leukaemia ) Other primary haemotological cause suspected MCV > 100 fl with accompanying cytopenia 
( excluding b12/ fol deficiency ) Peristent unexplained MCV > 105 fl ( this may vary some guidelines mention from 104 ) B12 deficiency of uncertain cause requiring further investigation

Elderly frail patients with isolated macrocytosis ( ie no cytopenias , haemolysis or myeloma ) consider monitoring in the community or advice from haematology Mild isolated macrocytosis ( < 105 fl ) in an otherwise fit patient – can be monitored in community


  1. Evaluation of Macrocytosis Am Fam Physician , 2009 feb 1;79(3):203-208
  2. Macrocytosis An Australian general practice perspective   Australian Family Physician Vol. 36, No. 7, July 2007 571
  3. How do you evaluate macrocytosis without anaemia ? The Journal of Family Medicine Vol 57, No 8 / august 2008
  4. Drug-Induced Megaloblastic Anemia N Engl J Med 373;17 Oct 2015
  5. The Significance of Unexplained Macrocytosis Blood 2008 112:3449
  6. UH Bristol Haematology Referral Guidelines for Primary Care C Bradbury May 2016
  7. Macrocytosis GPOnline by Dr Cecil Reid November 2017


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