Megaloblastic anemias

Lack of vitamin B12 or folic acid leads to the production in the bone marrow of abnormal nucleated red cells known as megaloblasts. Such cells can be identified by their characteristic appearance. When such a vitamin deficiency occurs, bone marrow activity is seriously impaired; marrow cells proliferate but do not mature properly, and erythropoiesis becomes largely ineffective. Anemia develops, the number of reticulocytes is reduced, and even the numbers of granulocytes (leukocytes that contain granules in the cell substance outside the nucleus) and platelets are decreased. The adult red cells that are formed from megaloblasts are larger than normal, resulting in a macrocytic anemia. The impaired and ineffective erythropoiesis is associated with accelerated destruction of the red cells, therebyproviding the features of a hemolytic anemia.

Vitamin B12 is a red, cobalt-containing vitamin that is found in animal but not in vegetable foods. Unlike other vitamins, it is not formed by higher plants but only by certain bacteria andmolds and in the rumina of sheep and cattle, provided that traces of cobalt are present in their fodder. In other species, including humans, vitamin B12 must be obtained passively, by eating food of animal source. Furthermore, this vitamin is not absorbed efficiently from the human intestinal tract unless a certain secretion of the stomach, the so-called intrinsic factor (IF), is available to concentrate the vitamin on the intestinal wall.

The most common cause of vitamin B12 deficiency is pernicious anemia, a condition usually affecting patients past middle age. In this disorder all stomach secretion of IF fails, perhaps as the result of an immune process consisting of the production of antibodies directed against the stomach lining. The tendency to form such antibodies may be hereditary.

The English physician Thomas Addison first described this condition in 1849. The discovery ofvitamin B12 came about because of the investigations of the American physician George H. Whipple, who studied the value of various foods in promoting the formation of hemoglobin in dogs made anemic by bleeding. Whipple found liver to be most effective in the treatment of pernicious anemia. The American physicians George R. Minot and William P. Murphy further tested the value of liver. The activity of the foods tested by Whipple was due mainly to their iron content rather than to the presence of vitamin B12. Investigations by William B. Castle, also an American physician and medical scientist, later revealed the defect in pernicious anemia to be a deficiency of a factor secreted by the stomach, which is necessary for the absorption of vitamin B12 across the wall of the intestine into the circulation.

The first treatment for pernicious anemia was to prescribe that the patient eat liver each day;later regular amounts of liver extract were given orally or by injection. Today patients are given injections of the equivalent of a millionth of a gram of vitamin B12 per day. In practice, the necessary amount of this vitamin can be given once a month or even once in three months. Oral treatment with vitamin B12 is possible but inefficient because absorption is poor.

Other forms of vitamin B12 deficiency are rare. They are seen in complete vegetarians whose diets lack vitamin B12, in persons whose stomachs have been completely removed and so lack a source of IF, in those who are heavily infested with the fish tapeworm Diphyllobothriumlatum or have intestinal cul-de-sacs or partial obstructions where competition by the tapeworms or by bacteria for vitamin B12 deprives the host, and in persons with primary intestinal diseases that affect the absorptive capacity of the small intestine (ileum). In these conditions, additional nutritional deficiencies, as of folic acid and iron, are also likely todevelop.

Blood changes similar to those occurring in vitamin B12 deficiency result from deficiency of folic acid. Folic acid is a vitamin found in leafy vegetables, but it is also synthesized by certain intestinal bacteria. In humans deficiency usually is the result of a highly defective diet or of chronic intestinal malabsorption as mentioned above. Pregnancy greatly increases the need for this vitamin. There is also an increased demand in cases of long-continued accelerated production of red cells. This type of deficiency also has been observed in some patients receiving anticonvulsants, and there is some evidence that absorption of the vitaminmay be impaired in these cases. Often several factors affecting supply and demand of the vitamin play a role in producing folic acid deficiency.

Unless folic acid deficiency is complicated by the presence of intestinal or liver disease, its treatment rarely requires more than the institution of a normal diet. In any event the oral administration of folic acid relieves the megaloblastic anemia. Some effect can be demonstrated even in pernicious anemia, but this treatment is not safe because the nervous system is not protected against the effects of vitamin B12 deficiency, and serious damage to the nervous system may occur unless vitamin B12 is given.

In the above conditions, megaloblastic anemia develops as the result of dietary deficiency of, faulty absorption of, or increased demands for vitamin B12 and/or folic acid. In addition to these circumstances, megaloblastic anemia may arise in still other situations. Selective vitamin B12 malabsorption may be the consequence of a hereditary defect. Deranged metabolism may play a role in some instances of megaloblastic anemia that accompany pregnancy. Metabolic antagonism is thought to be the mechanism underlying the megaloblastic anemia associated with the therapeutic use of certain anticonvulsant drugs and some drugs employed in the treatment of leukemia and other forms of cancer. In fact, oneof the earliest drugs used to treat leukemia was a folic acid antagonist.