Macrocytic anaemia (Macrocytosis) is described as an increase in the mean cell volume of red cells above the normal range (80-95 fl (femtolitres) in adults). It is detected with a blood count, which measures the mean cell volume as well as other red cell indices. The mean cell volume in children is smaller than in adults, with a typical mean of 70 fl at one year of age, increasing by about 1 fl each year before it reaches adult volumes at puberty.
Causes of Macrocytic anaemia
The causes of Macrocytic anaemia are divided into two categories:
- Vitamin B12 (cobalamin) or folate deficiency (or, in extreme cases, defects in their metabolism), in which the bone marrow is megaloblastic,
- Other causes, in which the bone marrow is normally normoblastic.
Vitamin B12 or folate deficiency
Vitamin B12 Deficiency
The body needs approximately 1g of vitamin B12 per day. Vitamin B12 is absorbed by the ileum, which is aided by intrinsic factor, which is secreted by the parietal cells of the stomach. Absorption is limited to 2-3g per day.
Causes of Vitamin B12 Deficiency
- Vitamin B12 deficiency is normally caused by pernicious anaemia, which now accounts for up to 80% of all cases of megaloblastic anaemia. The disease affects all races.
- The underlying mechanism is an autoimmune gastritis, which causes achlorhydria and the absence of intrinsic factor. The disorder has a female: male incidence of 1.6:1.0 and is more prevalent in those with early greying, blue eyes, and blood group A, as well as those with a family history of the disease or disorders that may be associated with it, such as vitiligo, myxoedema, Hashimoto’s disease, Addison’s disease of the adrenal gland, and hypoparathyroidism.
- Veganism is a rare cause of extreme deficiency since most vegetarians and vegans consume some vitamin B12. Furthermore, unlike in pernicious anaemia, the enterohepatic circulation for vitamin B12 is intact in vegans, preserving vitamin B12 stores. Gastric resection and intestinal causes of vitamin B12 malabsorption, such as ileal resection or the intestinal stagnant loop syndrome, are less common now that abdominal tuberculosis is uncommon and H2-antagonists for treating peptic ulceration have been introduced, eliminating the need for gastrectomy.
The daily requirement for folate is 100-200g, and a typical mixed diet provides 200-300g. Natural folates are often of the polyglutamate type, which is absorbed via the upper small intestine after being deconjugated and converted to the monoglutamate 5-methyl tetrahydrofolate.
Just about four months’ worth of body stores are available.
- Folate deficiency may occur as a result of insufficient dietary intake, malabsorption (particularly gluten-induced enteropathy), or excessive use as proliferating cells degrade folate.
- Deficiency during pregnancy can be due to a combination of factors, including an insufficient diet, folate transfer to the fetus, and increased folate degradation.
Other causes of Macrocytic anaemia
- Alcohol is the most common cause of Macrocytic anaemia in the United Kingdom. Small amounts of alcohol, such as two gin and tonics or half a bottle of wine per day, will cause an increase in mean cell volume to 100 fl, usually without anaemia or any discernible improvement in liver function. The mechanism underlying the increase in mean cell volume is unknown. The volume of the liver can increase in disease due to excessive lipid deposition on red cell membranes, and this increase is especially pronounced in alcohol-induced liver disease. In extreme thyroid deficiency, there is a slight increase in mean cell volume.
- Some haematological anomalies are commonly present in other causes of macrocytosis. In myelodysplasia (a common cause of macrocytosis in the elderly), there are usually quantitative or qualitative differences in the white cells and platelets in the blood.
- Pancytopenia is present in aplastic anaemia; pure red cell aplasia can also cause macrocytosis.
- Changes in plasma proteins, such as the presence of a paraprotein (as in myeloma), may cause an increase in mean cell volume without the presence of macrocytes in the blood film.
- Pregnancy and the neonatal cycle are the physiological causes of macrocytosis.
Diagnosis of Macrocytic anaemia
- The serum vitamin B12 and folate assays are the most commonly used screening tests for deficiencies. A low serum concentration indicates a deficiency, but a subnormal serum concentration may occur in the absence of a pronounced body deficiency, such as during pregnancy (vitamin B12) and with recent poor dietary intake (folate).
- Red cell folate may also be used to test for folate deficiency; a low concentration typically indicates significant loss of body folate, but the concentration also falls in extreme vitamin B12 deficiency, making the significance of a low red cell folate concentration in patients with megaloblastic anaemia more difficult to interpret. Furthermore, if the patient has recently undergone a blood transfusion, the red cell folate concentration will represent the folate concentration of the transfused red cells in part.
Some specialized laboratories use serum homocysteine (raised in vitamin B12 or folate deficiency) or methylmalonic acid (raised in vitamin B12 deficiency) assays. Serum homocysteine levels are also elevated in kidney failure, with some medications, such as corticosteroids, and with age and smoking.
It is important to identify the underlying cause of vitamin B12 or folate deficiency in patients. Intrinsic factor antibodies are present in 50% of patients with pernicious anaemia, and parietal cell antibodies are present in 90%. In gluten-induced enteropathy, antigliadin, anti-endomysial, and antireticulin antibodies are usually positive.
Other investigations of Macrocytic anaemia
To confirm megaloblastic anaemia, a bone marrow test is normally performed. It is also used for the diagnosis of macrocytosis-related myelodysplasia, aplastic anaemia, myeloma, and other bone marrow disorders.
- Radioactive vitamin B12 absorption tests, such as the Schilling test, indicate impaired vitamin absorption in pernicious anaemia; this can be reversed by administering intrinsic factor. However, intrinsic factor cannot be used to correct vitamin B12 absorption in patients who have an intestinal lesion. Because of concerns regarding prion disease transmission, human intrinsic factor is no longer approved for this research.
- Endoscopy should be done to confirm atrophic gastritis and rule out gastric carcinoma or polyps, which are two to three times more common in pernicious anaemia patients than in age and gender matched controls.
- If a deficiency in folate is identified, it is critical to determine dietary folate intake and rule out gluten-induced enteropathy using serum antigliadin and anti-endomysial antibodies, endoscopy, and duodenal biopsy. The deficiency is normal in patients with diseases characterized by increased cell turnover who also eat poorly.
Treatment of Macrocytic anaemia
- Vitamin B12 deficiency is treated initially by administering six injections of hydroxo-cobalamin 1 mg at three to four day intervals, accompanied by four such injections a year for the rest of the patient’s existence.
- It is best to begin maintenance injections immediately after a total gastrectomy or ileal resection in patients who are having a total gastrectomy or ileal resection.
- For vegans, less frequent injections, such as one or two a year, can suffice, and the patient should be advised to eat foods fortified with vitamin B12, such as some fortified breads or other foods.
- Folate deficiency is treated with folic acid, usually 5 mg daily orally for four months, which is only continued if the underlying cause cannot be reversed.
- In patients with serious haemolytic anaemia, such as sickle cell anaemia, 5 mg folic acid once weekly is possibly adequate as prophylaxis against folate deficiency.
- Vitamin B12 deficiency must be ruled out in all patients beginning folic acid treatment at these doses, as this treatment may correct anaemia in vitamin B12 deficiency while allowing neurological disease to develop.
Preventing folate deficiency in pregnancy
- Larger doses are not recommended as they may mask megaloblastic anaemia due to vitamin B12 deficiency and thus allow B12 neuropathy to develop
- Since neural tube defects occur by the 28th day of pregnancy, it is advisable for a woman’s daily folate intake to be increased by 400g/day at the time of conception.
- In 1996, the US Food and Drug Administration declared that some grain products (including most enriched breads, flours, cornmeal, rice, noodles, and macaroni) would be expected to be fortified with folic acid at levels ranging from 0.43 mg to 1.5 mg per pound (453 g).
- For mothers who have already had a child with a neural tube defect, higher folic acid doses (e.g., 5 mg daily) are recommended before and during subsequent pregnancies.