High MCV (Macrocytosis): Causes Beyond Vitamin B12 Deficiency

MCV (mean corpuscular volume) is the average volume of a single red blood cell, expressed in femtolitres (fL). The haematology analyser calculates it from the size distribution of all the red cells counted. The normal range is usually about 80–100 fL (limits differ slightly between laboratories), and macrocytosis is diagnosed when the MCV exceeds 100 fL. Below 80 fL we speak of microcytosis, which we cover in the articles on low MCV.

Because MCV is an average, its value depends on the proportion of large and small cells. It is therefore worth looking at it together with the RDW, the index of variation in red cell size. A high MCV with a high RDW suggests a mixture of cells of different sizes, typical of vitamin deficiencies, and a high MCV with a normal RDW is more common with alcohol, liver disease or an underactive thyroid. These are only clues, not rules. A mixed picture is especially important: iron deficiency (which lowers MCV) can coexist with B12 deficiency (which raises it), and then the average comes out normal even though the smear shows cells of very different sizes and the RDW is high.

Another important distinction: macrocytosis is not the same as anaemia. You can have a high MCV with normal haemoglobin (isolated macrocytosis) or with low haemoglobin (macrocytic anaemia). Whether or not there is anaemia, a value above 100 fL is a reason to establish the cause. As a rough guide, the higher the MCV, the greater the likelihood of a megaloblastic cause (B12, folate) or marrow disease, whereas values only slightly above 100 fL, for example 100–105, more often accompany alcohol, liver disease and some drugs. This is only a tendency, and further investigation is always needed.

Macrocytosis is divided into two groups according to mechanism. The first is megaloblastic macrocytosis, caused by impaired DNA synthesis in marrow cells. When vitamin B12 or folate is lacking (or a drug that inhibits their metabolism acts), the precursors of blood cells grow but cannot divide properly, so large, immature cells called megaloblasts form, and from them giant red cells, seen on the smear as macro-ovalocytes. Other cell lines are affected too, which is why hypersegmented neutrophils are typical and white cells and platelets are sometimes reduced. B12 deficiency is the most common cause of megaloblastic anaemia, with folate deficiency next.

The second group is non-megaloblastic macrocytosis, in which DNA synthesis is normal and the cells are larger for other reasons. A review for family doctors lists here chronic liver disease, an underactive thyroid, alcohol use disorder and myelodysplastic disorders. A physiological situation also belongs to this group: the release of reticulocytes, that is, young, larger red cells, in response to acute anaemia (after bleeding or haemolysis). In that case the MCV rises not because the marrow is diseased but because it is releasing young cells, and after recovery the value returns to normal.

The distinction between megaloblastic and non-megaloblastic is very useful in practice because it shortens the work-up. A blood smear with macro-ovalocytes and hypersegmented neutrophils strongly points to B12 or folate deficiency. A smear without such features, together with a reticulocyte count, points instead to a toxic effect of alcohol or drugs, or to haemolysis or bleeding. This is exactly the logic of the diagnostic guidance to which we return in the section on tests.

What follows? First, three items (alcohol, B12 and drugs) explain most cases, which makes the first stage of reasoning easier. Second, almost one fifth of patients with B12 deficiency had macrocytosis without anaemia, so normal haemoglobin does not close the subject. Third, about a quarter of patients remained unexplained despite testing, which shows that the absence of a clear cause is not rare and calls for follow-up.

The limitations must be remembered, however: this is a single-centre study in India, in a selected group of patients admitted or referred for tests, in a population with a different pattern of alcohol consumption and diet than in Poland. The proportions may differ, and in a Polish clinic deficiencies resulting from drugs (metformin, proton pump inhibitors) and plant-based diets may have a larger share. We therefore treat the conclusions as an illustration of orders of magnitude, not exact probabilities.

Vitamin B12 deficiency may result from diet (vegetarianism and veganism without supplementation), from absorption disorders (atrophic gastritis and pernicious anaemia, diseases of the ileum, bariatric surgery), from ageing and from drugs. The latter include metformin, whose long-term use lowers B12 levels: a randomised Dutch trial showed an average fall of 19% compared with placebo, which we discuss at greater length in the article on metformin and vitamin B12 deficiency. Proton pump inhibitors and other drugs that reduce stomach acidity act similarly, hindering the release of B12 from food.

Folate deficiency most often results from inadequate intake (a diet low in leafy vegetables and legumes), alcohol, increased demand (pregnancy) and some antifolate drugs. The interpretation of B12 and folate tests is described in our knowledge base entries; it is worth remembering that serum B12 has limited sensitivity and at borderline values methylmalonic acid or holotranscobalamin can help, while measuring homocysteine may help in differentiation.

Why does identifying a deficiency matter so much? Because B12 deficiency, unlike folate deficiency, can lead to nervous system damage (tingling, balance problems, worsening memory) that with long duration does not always fully reverse. Treatment with folic acid alone without excluding B12 deficiency may improve the blood count while masking worsening neurological changes. That is why, when megaloblastosis is suspected, both parameters are checked and not just one.

Alcohol is one of the most common causes of macrocytosis, and in the study described above it accounted for the highest share of patients. It raises MCV both through a direct toxic effect on blood cell precursors and through coexisting folate deficiency and liver damage. A characteristic feature is usually macrocytosis without megaloblastic features on the smear, often with normal haemoglobin. After drinking stops, MCV usually normalises within a few months, because the lifespan of a red cell is about 120 days, which is also practical proof of alcohol's role. An important caveat: a high MCV is not a specific marker of alcohol and it must not be used to conclude that someone drinks. It is only one clue, together with the history and other tests.

Chronic liver diseases (cirrhosis, fatty liver disease, hepatitis) raise MCV through changes in the lipid composition of the red cell membrane, which produces target cells and larger cells. They are usually accompanied by abnormal liver tests and sometimes low platelets and an enlarged spleen. That is why, with macrocytosis, assessing ALT, AST, bilirubin and, if needed, a liver ultrasound is standard.

An underactive thyroid raises MCV by a non-megaloblastic mechanism; it is usually a mild macrocytosis, often with accompanying anaemia, that resolves once hormones are corrected. Because hypothyroidism is common and its symptoms are non-specific (tiredness, feeling cold, dry skin), TSH is a routine part of the work-up of macrocytosis. We describe the interpretation of TSH in our entry on TSH and thyroid hormones, and the symptoms of hypothyroidism that are easily mistaken for other conditions in a separate article. Interestingly, hypothyroidism is also sometimes associated with B12 deficiency (through the autoimmune background of both diseases), so it is worth checking both at once.

Drugs are the third major pillar of macrocytosis. Those that most often raise MCV include cytostatic and immunosuppressive drugs (methotrexate, hydroxyurea, azathioprine, mercaptopurine), some antiretroviral drugs (zidovudine), anticonvulsants (phenytoin, valproate), trimethoprim (a folate antagonist) and metformin (through B12 deficiency). Hydroxyurea and methotrexate are among the drugs that cause macrocytosis often and predictably, and its appearance is even used as an indirect indicator that the drug is being taken.

For the patient this means that when macrocytosis is found, the full list of medicines and supplements must be reviewed with the doctor. A high MCV in a person treated with these preparations often needs no additional work-up and is not a reason to stop the drug, but the decision belongs to the treating doctor. Sometimes it is enough to replace folate or B12, and sometimes to adjust the dose. If there is no explanation, a drug is stopped or replaced only on a doctor's advice.

Myelodysplastic syndromes (MDS) are a group of chronic marrow neoplasms in which blood cell production is ineffective. Macrocytosis can be one of the first signs, sometimes with cytopenia (low haemoglobin, platelets, white cells). They affect mainly older people. Signals that raise suspicion of MDS are macrocytosis persisting despite exclusion of vitamin deficiencies, alcohol, drugs, liver disease and thyroid disease, especially with anaemia or other cytopenias, dysplastic features on the smear or a progressive fall in haemoglobin. In such a situation a haematologist's assessment is needed, and often a marrow examination. Diagnostic reviews list marrow dysplasias and myeloproliferative disorders among the more common causes of macrocytosis once simpler explanations are excluded.

Reticulocytosis, that is, a raised number of young red cells after bleeding, haemolysis or during treatment of anaemia (for example after starting treatment for B12 deficiency), raises MCV transiently. That is why a reticulocyte count is an important part of the work-up, and with haemolysis bilirubin, LDH and haptoglobin are also measured.

Finally, MCV can be falsely high for laboratory reasons: clumps of red cells (cold agglutinins) may be counted as single large cells, very high blood glucose causes cells to swell in the sample, and long storage of the sample before testing can increase their volume. Repeating the test on a fresh sample and reviewing the smear help. A small rise in MCV also occurs physiologically in pregnancy and in older people, and with a borderline result (100–102 fL) in the absence of anaemia and symptoms it is quite sensible simply to observe and repeat the test after a few weeks.

This order corresponds directly to the algorithm described in the review for family doctors: history and physical examination, a B12 level, a reticulocyte count and a peripheral blood smear help narrow the cause. When the smear shows megaloblastic anaemia, B12 or folate deficiency is the most likely cause, and when it is non-megaloblastic, the reticulocyte count helps distinguish the toxic effect of drugs and alcohol from haemolysis or bleeding. Only later are an underactive thyroid, liver disease and primary marrow dysplasias considered.

On the other hand, an MCV only slightly above normal (100–102 fL), without anaemia, without symptoms and without obvious risk factors, rarely needs urgent action. It is worth repeating after a few weeks, checking B12, folate and TSH and agreeing a plan of observation with the doctor.

Also misleading is the belief that a high MCV always means alcohol misuse. MCV is a non-specific index and can be raised for many reasons, so it is not used to make accusations or to diagnose dependence. If in doubt, other, more specific tests and a conversation with the doctor are used.

A high MCV is best treated as a well-posed diagnostic question rather than a ready answer. Most often three factors stand behind it: alcohol, B12 or folate deficiency and drugs, and a blood smear, reticulocytes and a few simple tests usually settle which one. Do not reach for a B12 supplement just because the MCV is high, because you may miss liver, thyroid or marrow disease. On the other hand, do not ignore the result, even with normal haemoglobin. In our series on unusual blood count results we also cover high and low platelets, high eosinophils and low white cells.