Hematology & Internal Medicine & Medical Biology & Family Medicine
Macrocytosis (high VGM)
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Macrocytosis is defined as an increase in the mean corpuscular volume (MCV) of erythrocytes above 100 femtolitres (fL) in adults - the upper limit of normal varying slightly from laboratory to laboratory (96-100 fL). It represents a frequent biological anomaly, often discovered incidentally on a CBC (blood count), which may be isolated (without associated anemia) or associated with macrocytic anemia. Macrocytosis may be megaloblastic (abnormal DNA synthesis in erythroid precursors, leading to asynchronous nucleocytoplasmic maturation, with large + cells with immature nuclei = megaloblasts in the marrow) or non-megaloblastic (various mechanisms not directly affecting DNA synthesis). The distinction between these two forms is clinically important, as the causes, investigations and treatments differ. The most frequent causes in clinical practice are: vitamin B12 deficiency (cobalamin - 1st cause of megaloblastic macrocytosis apart from alcoholism) + folate deficiency (folic acid - 2nd cause) + chronic alcohol consumption (most frequent cause of non-megaloblastic macrocytosis in Western countries) + hypothyroidism + drugs interfering with DNA synthesis (methotrexate + hydroxyurea + azathioprine + 5-FU + zidovudine). Severe megaloblastic macrocytosis due to B12 deficiency can cause irreversible neurological complications (combined sclerosis of the bone marrow) - even in the absence of anemia - which justifies rapid screening and correction.
Pathophysiology, classification and main causes
- Pathophysiological mechanisms of macrocytosis and classification : mechanisms of megaloblastic macrocytosis: vitamin B12 or folate deficiency → disruption of thymidylate monophosphate (TMP) synthesis → reduced DNA synthesis → nucleocytoplasmic asynchronism → immature nuclei in cells with mature cytoplasm → megaloblasts in marrow → macrocytic erythrocytes in blood + Howell- bodies.Jolly bodies (chromatin fragments) + segmented nuclei in neutrophils (hypersegmented PNN - one PNN with ≥5 lobes or >5 % of PNN with ≥4 lobes) → pancytopenia if severe deficiency → mechanisms of non-megaloblastic macrocytosis : alcohol: direct ethanol toxicity on erythroid precursors + disruption of hepatic folate metabolism + dietary folate deficiency → macrocytosis by several mechanisms + hypothyroidism: mechanism poorly elucidated - reduced precursor proliferation + increased erythrocyte membrane cholesterol → moderate macrocytosis (GMV 100-110 fL) + chronic renal failure: variable mechanism → normocytic or sometimes macrocytic anemia + chronic liver disease: abnormal membrane lipids → macrocytosis by increased erythrocyte membrane surface area + reticulocytosis: reticulocytes (erythrocyte precursors) are larger than mature erythrocytes → if significant reticulocytosis → increased mean GMV → myelodysplasia: abnormal maturation of precursors → macrocytosis + cytopenias → blast possible; main causes of macrocytosis to be aware of in order of clinical frequency in developed countries: chronic alcohol (most common) → moderate macrocytosis GMV 100-115 fL + drugs (methotrexate + hydroxyurea + azathioprine + 5-FU + zidovudine + stavudine + lamivudine + antiretroviral treatments + valproate + barbiturates + phenytoin + some diuretics) → vitamin B12 deficiency → folate deficiency → hypothyroidism → chronic liver disease + cirrhosis → myelodysplasia → reticulocytosis (hemolytic anemia + acute bleeding) → pregnancy → advanced age (moderate physiological macrocytosis)
- Vitamin B12 and folate deficiency - physiology and symptoms : vitamin B12 (cobalamin) - physiology and absorption: dietary intakes: meat + fish + dairy products + eggs → vegans: inadequate intakes + gastric absorption: intrinsic factor (IF) produced by gastric parietal cells binds to ingested B12 → IF-B12 complex absorbed in terminal ileum → pernicious anemia (Biermer's disease) : most common autoimmune cause of B12 deficiency → anti-parietal cell + anti-FI antibodies → atrophic gastritis → reduced FI → B12 malabsorption → causes of B12 deficiency: Biermer disease (pernicious anemia) + gastrectomy (total or subtotal) + ileal resection + ileal Crohn's disease + bacterial overgrowth (consume B12) + strict veganism (insufficient intakes) + metformin (reduced B12 absorption in 10-20 % of patients - mechanism: reduction of calcium-dependent transport) + high hepatic reserves (2-4 mg = 3-5 years of autonomy) → deficiency sets in slowly → symptoms delayed after years of vegan diet without supplementation → clinical manifestations of B12 deficiency: hematological (macrocytosis + megaloblastic anemia + pancytopenia if severe) + neurological: subacute combined degeneration of the spinal cord → demyelination of the posterior + lateral cords → bilateral distal paresthesias + proprioceptive ataxia (Romberg test) + Lhermitte's sign (electrical discharge on neck flexion) + pyramidal syndrome + dementia + psychiatric + CAUTION: neurological signs may precede and exist without anemia + even «normal low» B12 may cause neuropathy → VGM may be normal if discreet deficiency → folates - physiology and absorption: dietary intake: green vegetables + legumes + fruit + liver → absorption: proximal jejunum (fast) → liver reserves: 3-6 months (much less than B12) → causes of folate deficiency: alcoholism + malnutrition + malabsorption (celiac disease + Crohn's enteritis + tropical sprue) + drugs (methotrexate ++ + phenytoin + barbiturates + oral contraceptives + trimethoprim) + pregnancy + prematurity (increased needs) + chronic hemolysis (increased needs) + manifestations: hematological (identical to B12) + CAUTION: NO direct neurological manifestations in folate deficiency - fundamental difference with B12
Diagnosis and treatment of macrocytosis
| Appearance / cause | Assessment, diagnosis and treatment | References and recommendations |
|---|---|---|
| Diagnostic workup for macrocytosis CBC smear - hypersegmented PNN - reticulocytes - B12 serum folate - methylmalonic acid - homocysteine - TSH - liver workup - GGT alcohol - myelogram - LDH bilirubin - Schilling test - anti-FI antibodies |
Diagnostic workup for macrocytosis - systematic approach: Step 1 - Complete CBC + expert blood smear: high GMV (≥100 fL) + erythrocyte morphology (macro-ovalocytes = characteristic of megaloblastosis) + hypersegmented PNN (≥5 lobes in >5 % of PNN = early and sensitive sign of megaloblastosis) + reticulocytes (if elevated → hemolysis or hemorrhage) + thrombocytopenia + leukopenia if severe deficiency + elevated LDH + indirect bilirubin (intramedullary hemolysis in megaloblastosis) → 2nd step - 1st-line etiological workup: serum vitamin B12: normal: 160-950 pg/mL → value between 150-300 pg/mL = gray area (may be deficient) → value <150 pg/mL = deficiency → CAUTION: serum B12 is not very sensitive - a «low normal» B12 (150-300 pg/mL) does not exclude functional deficiency + serum or erythrocyte folates: serum folates <3-4 ng/mL = deficiency → erythrocyte folates (more stable - reflects chronic deficiency - less influenced by recent meals) → TSH: hypothyroidism → liver workup: liver workup + GGT (very sensitive to alcohol) → 3rd step - functional markers (if doubt about B12 deficiency despite «low normal» B12): homocysteine (Hcy): increased if B12 + or folate deficiency → sensitive (increases early) → but not very specific (also elevated in CKD + hypothyroidism + smoking) + methylmalonic acid (AMM): increased ONLY if B12 deficiency (specific marker of functional B12 deficiency) → N <0.4 µmol/L → if GMV high + normal B12 low + AMM high → functional B12 deficiency → treat + 4th stage - if etiology not identified or suspicion of myelodysplasia: myelogram → megaloblasts + maturation abnormalities in nutritional deficiency vs. trilineage dysplasia + blasts in MDS → anti-parietal cell + antiintrinsic factor antibodies: if pernicious anemia suspected (vegan + history of atrophic gastritis + neurology) + search for alcoholism: questioning + GGT ++ + CDT (carbohydrate-deficient transferrin) → marker of chronic alcohol consumption. | Stabler 2013 - NEJM: B12 deficiency → markers + diagnosis + treatment → reference + Carmel 2008 - Hematology ASH: megaloblastic anemia → B12 folates → diagnosis + Oh 2011 - American Family Physician: macrocytosis → diagnostic approach + causes + Andrès 2004 - Quarterly Journal of Medicine: B12 deficiency + pernicious anemia → diagnosis + Langan 2017 - American Family Physician: anemia due to B12 + folate deficiency → + INSPQ Quebec: macrocytosis + workup + INESSS Quebec + RAMQ: B12 + folates + TSH + homocysteine + AMM → reimbursed if indicated |
| Treatment - B12, folate deficiency and non-nutritional causes B12 IM cyanocobalamin hydroxycobalamin - B12 PO high dose - folic acid folate correction - DO NOT correct folate without B12 - reticulocyte response - alcohol withdrawal - folic acid methotrexate - levothyroxine hypothyroidism - myelodysplasia |
Treatment of vitamin B12 deficiency: parenteral (IM) route - gold standard if malabsorption: cyanocobalamin 1,000 µg IM × 1/d × 7 days → then 1,000 µg IM × 1/week × 4 weeks → then 1,000 µg IM × 1/month for life (if uncorrectable cause of malabsorption - pernicious anemia + gastrectomy + ileal resection) → hydroxycobalamin : preferred form in Europe (longer half-life) → high-dose oral route - effective alternative even in case of malabsorption: oral B12 1,000-2,000 µg/d → mechanism: passive absorption (without IF) allows 1-2 % absorption of very high oral doses → Vidal 2016: High-dose oral B12 vs. IM → comparable efficacy → less invasive → preferred in absence of severe neurological symptoms + therapeutic response: reticulocytosis expected within 5-7 days after start of treatment (peak D7-J10) = good sign of response → hemoglobin improvement in 4-8 weeks → normalization of GMV in 2-4 months → neurological improvement: slow + incomplete if established lesions → early correction = better prognosis + CLASSIC TRICK: NEVER correct folates alone without correcting B12 first → risk of masking B12 deficiency + precipitating or worsening neurological complications → folate supplementation will correct anemia but does not treat B12 deficiency → neurological damage progresses even if anemia is corrected → treatment of folate deficiency: folic acid 1-5 mg/d PO × 4 months (or until cause is corrected) → prevention of recurrence: treat cause + remove alcohol + correct malnutrition → supplementation in pregnant women: 0.4 mg/d (5 mg/d if ATCD of neural tube closure defect) → reduce risk of spina bifida + other neural tube defects → folate-interfering drugs: methotrexate → folic acid 1 mg/d the day after methotrexate or every day except MTX day → reduces toxicity without reducing efficacy; non-nutritional causes of macrocytosis: alcohol: withdrawal + balanced diet → progressive normalization of VGM in 2-4 months + hypothyroidism: levothyroxine + normalization of VGM after treatment + drugs: stop if possible + or folate supplementation if MTX → myelodysplasia: if very high VGM (VGM >115-120 fL) without nutritional cause + cytopenias + or blasts → myelogram + cytogenetics → treatment according to stage (iron chelation + erythropoietin + azacitidine + transplant if eligible) | Stabler 2013 - NEJM: B12 + treatment + oral vs IM → reference + Andrès 2004 - QJM: pernicious anemia + B12 oral → efficacy + Vidal 2016 : B12 oral high dose + malabsorption → comparable efficacy IM + Carmel 2008 - Hematology ASH: megaloblastosis → treatment → folates + B12 → TRICK: DO NOT correct folates without B12 → Langan 2017 - American Family Physician: B12 deficiency + folates + treatment + Reynolds 2006 - Lancet: methotrexate + folates → supplementation reduces toxicity + Greenberg 2012 - Blood (IPSS-R): myelodysplasia + classification + INESSS Québec + RAMQ: B12 IM + B12 PO + folic acid → reimbursed + levothyroxine → reimbursed + cyanocobalamin hydroxycobalamin available |
| Pernicious anemia, neurological B12 deficiency and special situations Biermer disease - anti-parietal cells - anti-FI - atrophic gastritis - veganism - metformin - combined marrow sclerosis - paresthesias - ataxia - Romberg - Lhermitte - normal low B12 neuropathy - B12 pregnancy - NFS monitoring |
Pernicious anemia (Biermer disease) - clinical features: autoimmune disease → anti-parietal cell antibodies (ACPA - present in 90 % of patients with Biermer + but not very specific as present in 10 % of the general population from age 60) + antiintrinsic factor (AFI - present in 50-70 % - highly specific) → atrophic gastritis → reduced IF production → B12 malabsorption → progressive deficiency over several years → frequent association with other autoimmune diseases (Hashimoto's thyroiditis + Addison's disease + vitiligo + T1DM) → screening for gastric dysplasia and gastric cancer : atrophic gastritis increases the risk of gastric cancer → high endoscopy + biopsies recommended at diagnosis → gastroenterological follow-up → combined cord sclerosis (subacute combined degeneration) - neurological emergency: demyelination of posterior cords (deep sensitivity) + lateral cords (pyramidal pathway) → symptoms: bilateral distal paresthesias (hands + feet - «gloves and socks») + ataxia (positive Romberg test) + Lhermitte sign (electric shock on neck flexion) + pyramidal syndrome (hyperreflexia + Babinski) + dementia + psychiatric disorders → CAPITAL: neurological signs may be present WITHOUT anemia or macrocytosis → do not rely on absence of anemia to exclude diagnosis + «normal low» B12 (150-300 pg/mL) may be sufficient to cause neuropathy → if strong clinical suspicion → assay for methylmalonic acid (MA) and homocysteine → urgent neurological treatment with B12 IM → partial improvement if lesions already established → B12 deficiency in vegans: zero animal B12 intake → mandatory supplementation (B12 PO 250 µg/d or 2,000 µg/week) → without supplementation → deficiency in 3-5 years + B12 deficiency on metformin: metformin → reduces intestinal absorption of B12 (calcium-dependent mechanism) → monitor B12 every 1-2 years in patients on metformin → supplement if B12 low + pregnancy: risk of folate deficiency (requirements × 2) + B12 deficiency if vegan → folates 0.4-5 mg/d + B12 if vegan | Stabler 2013 - NEJM: pernicious anemia + Biermer + neurology + treatment → reference + Andrès 2004 - QJM: pernicious anemia + antibodies + atrophic gastritis + oncological monitoring + Green 2017 - NEJM: B12 deficiency + neurology + diagnosis → review + Langan 2017 - AFP: B12 + folates + treatment + Carmel 2008 - Hematology ASH: B12 + dosage + interpretation + Reinstatler 2012 - Diabetes Care: metformin + B12 → deficit + monitoring → Oh 2011 - AFP: macrocytosis + diagnostic approach + INESSS Quebec + RAMQ: B12 IM + folic acid reimbursed + high endoscopy reimbursed if Biermer + CMQ: veganism + supplementation + biological monitoring |
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Never correct folates alone without first ruling out and treating a vitamin B12 deficiency - folate supplementation can mask anemia but allows the irreversible neurological complications of B12 deficiency to progress: neurological signs (paresthesias + ataxia + pyramidal syndrome) may precede anemia and be present with normal VGM. Low-normal« vitamin B12 (150-300 pg/mL) may cause neuropathy - assay for methylmalonic acid if suspected. Patients on metformin should have their B12 levels monitored every 1-2 years.
Situations requiring urgent or priority care
Very high GMV + severe anemia (Hb <70-80 g/L) + pancytopenia (leukopenia + thrombocytopenia) + very high LDH + smear showing macro-ovalocytes + hypersegmented PNNs → severe megaloblastosis → B12 + folates urgent + myelogram if doubt (rule out myelodysplasia or leukemia) → B12 IM immediately if likely deficiency → transfusion if very severe anemia + hemodynamic instability.
Patient with progressive distal bilateral paresthesias + ataxia + positive Romberg + Lhermitte's sign ± absence of anemia on CBC → combined marrow sclerosis due to probable B12 deficiency → serum B12 + methylmalonic acid + homocysteine urgent → B12 IM 1,000 µg/d × 7 days without waiting if strong suspicion → spinal cord MRI → neurological consultation → early treatment = better neurological prognosis.
VGM >115-120 fL + cytopenias (anemia + thrombocytopenia + neutropenia) + with no obvious nutritional cause (normal B12 + normal folates + normal TSH + no alcohol + no medication) → myelodysplasia to be excluded → myelogram + karyotype + FISH → haematological consultation → DO NOT treat empirically without a confirmed diagnosis.
Consult at Clinique Omicron
Les médecins de Clinique Omicron prescrivent et interprètent le bilan de la macrocytose (NFS + frottis + B12 + folates + TSH + bilan hépatique + GGT), initient le traitement par B12 IM ou PO haute dose et par acide folique selon la cause, recherchent l'anémie pernicieuse (anticorps anti-FI), surveillent la B12 chez les patients sous metformine et les végétaliens, orientent vers le neurologue si signes de sclérose combinée de la moelle, et vers l'hématologue si myélodysplasie suspectée. Des consultations sont disponibles dans plusieurs points de service au Québec et en télémédecine. Pour prendre rendez-vous, choisissez votre service en ligne.
The contents of this page are provided for information purposes only and do not replace the advice of a physician or hematologist. Never supplement with folates without first ruling out and treating vitamin B12 deficiency. The neurological complications of B12 deficiency can be irreversible if treatment is delayed.
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