Anemia with large red cells: 3 Non-megaloblastic causes

This will be final essay on anemias with large red cells. To complete the two previous essays, I should add that it is dangerous to treat B12 deficiency with folic acid, since although the anemia will improve, the neurological problems will not.

But today I want to deal with macrocytosis that is not due to megaloblastic anemia since megaloblastic anemia accounts for less than 10% of all cases of macrocytosis seen in a hematology lab.

Large red cells are not necessarily associated with anemia and the best example of this is in the newborn where the cells are large and the hemoglobin is high. Why this is so is not clear, but in view of what I shall say later, it should be noted that baby red cells have fetal (HbF) rather than adult (HbA) hemoglobin in them.

When I say baby red cells I mean the red cells of babies rather than freshly produced red cells, although these too are larger than normal. Freshly produced red cells (or reticulocytes) are larger than normal too, probably because they contain extra things like strands of RNA and some nuclear remnants. These are removed as the red cell goes through the spleen so patients who have had a splenectomy also have large red cells. The commonest cause for an increase in reticulocytes is hemolytic anemia, but that is a subject for another day. Response to hematinics or hemorrhage can also cause a reticulocytosis.

In many populations the commonest cause of a raised MCV is alcohol (in Finland it is the cause in 65% of cases!). Alcohol causes a macrocytosis in a number of ways. It can be malnutrition and therefore folate deficiency, but this is relatively rare. Also rare is a severe hemolytic anemia. Most cases are believed to be caused by a direct toxic effect on the bone marrow. In acute alcoholic poisoning the bone marrow shows a characteristic pattern of abnormalities. In terminal alcoholic abuse the red cells are large because of liver failure. A confirmatory test of alcoholism is the serum gamma-GT.

Smokers as well as drinkers may also have a macrocytosis. I used to think that this was because most smokers are also drinkers or perhaps a toxic effect of cigarette smoke, but I now know that it is because smokers frequently have chronic obstructive pulmonary disease (COPD). As many as 50% of patients with COPD have a raised MCV. It has been suggested that this is related to the frequent finding that such patients also have numbers of HbF cells.

Liver disease per se causes a raised MCV, again, often with a normal hemoglobin. It is thought to be caused by increased cholesterol in the cell membrane, a feature of a disordered fat metabolism. The same cause has been attributed to the macrocytosis of hypothyroidism. Hypercholesterolemia is a feature of this and the red cells on the blood film have characteristically wavy edges.

In my practice one of the commonest causes of macrocytosis was myelodysplastic syndrome (MDS). All types of MDS are associated with macrocytosis including sideroblastic anemia, which in the older text-books was said to be a cause of small red cells. This is not completely untrue, since the very rare sex-linked congenital sideroblastic anemia does have small cells, and the MDS-type of sideroblastic anemia does have some small red cells on the blood film, even though the MCV is usually raised.

Anything that is in the bone marrow that shouldn't be there can cause a macrocytosis, be it lymphoma, myeloma, myelofibrosis or secondary cancer. We should not forget drugs as a cause. We have mentioned cytotoxic drugs like hydroxyurea (hydroxycarbamide), 6-mercaptopurine and azathiaprine that produce a pseudo-megaloblastic picture or interfere with folate metabolism like methotrexate, 5-fluorouracil and phenytoin, or its absorption, like metformin and cholestyramine, but we should also mention the anti-AIDS medications, stavudine, lamivudine and zidovudine.

Megaloblastic anemia is one of the less common causes of macrocytosis, so a full history needs to be taken to exclude the other causes. Paradoxically, a history of hypothyroidism should alert the physician to pernicious anemia, since both are autoimmune diseases and there is a considerable overlap between the two.

The order of investigation should be blood film first, followed by a reticulocyte count. The blood film should pick up most cases of megaloblastic anemia and a serum B12 should follow if they are there. A low B12 should send you on a hunt for the cause, but PA is the most likely. Borderline B12 levels are best incestigated by methylmalonic acid and homocysteine levels if the lab does them, as well as a red cell folate level. Serum folates should no longer be done. The main purpose of a bone marrow is to diagnose primary or secondary malignancy (including MDS).