Anemia with large red cells. 1 Vitamin B12

I learned my hematology 40 years ago. I have just started teaching some new trainees, and rather than rely on what I remembered, I have perused the journals to ensure that I am up-to-date in what I am teaching them. Having done microcytic anemias last week, my subject for today is macrocytic anemias. Macrocytosis for the purpose of this essay is an MCV of more than 100 fl.

Macrocytes, or large red cells, occur quite commonly in a hematologist's experience and he/she must have a plan of how to cope with them. The first thing that one has to decide is whether this is a megaloblastic process or not and this is done by looking at the blood film.

For the megaloblastic anemias you expect to find oval macrocytes rather than round ones and neutrophil polymorphs with 5 or more lobes. Finding those immediately sends you down the road of investigating for a megaloblastic process. In any case probably everyone who doesn't have an explanation for his large red cells should have a serum B12 measured.

The method for measuring vitamin B12 has changed over the years that I have been practising hematology. originally the patient's serum was used as a source of B12 to make a bacterium grow, then there was a radio-assay, but more recently radioactive isotopes have been banned from routine laboratories, but the method we use now has a large grey area where we are not sure whether the result is low or normal. Levels less than 100 pg per ml (74 pmol/L) mean definite B12 deficiency, but levels between 100-400 pg per ml (75-295 pmol/L) are borderline. It is clear what to do with definite low levels, but if the level is borderline then clinical judgement is required. If available (but usually they are not) measurements of methylmalonic acid and homocysteine may be helpful. Sometimes it is wise to exclude deficiency of folic acid (about which more next time).

Most people who have a low B12 level have pernicious anemia, but there are other causes. Pernicious anemia is an autoimmune disease where the immune system attacks the stomach, preventing the secretion of intrinsic factor (IF). We used to diagnose with with a Schilling test which measure the absorption of B12 with and without IF, but the inordinate fear of radioactivity has also driven this test from the menu. Instead we look for evidence of autoimmunity, looking for antibodies to gastric parietal cells (GPC) and IF. These tests are very poor with 40% false positives for GPC and 50% false negatives for IF. Even doing both tests mistakes are easily made.

It is therefore important to check for other causes of B12 deficiency such as carcinoma of the stomach, Crohn's disease affecting the terminal ileum, previous operations on either the stomach or the terminal ileum, chronic infection with H. pylori and if you have been eating raw fish in Finland, infestation with the fish tapeworm, Diphillobothrium latum, which actually eats B12 as it passes and any form of blind loop in the intestines (incuding jejunal diverticulae) that can become infected with B12-eating bacteria. Rare causes include some very uncommon congenital conditions like Immerslund syndrome and transcobalamin II defeiciency, Zollinger Ellison syndrome, nitrous oxide abuse, and some sorts of medicines including PPI drugs like omeprazole (because IF production in the stomach is linked to acid production), and the anti-diabetic drug, metformin.

This is new. You can treat B12 deficiency with oral vitamin B12.

The absorption of B12 is complex. We get all our vitamin B12 from meat of one sort or another - we can't manufacture it from a substrate. Absorption takes place in the last 18 inches of the small bowel, and nowhere else. To get into this bit of small bowel (known as the terminal ileum) you need intrinsic factor which is made in the stomach. B12 is excreted in the bile, but on re-entering the small bowel it binds to IF and gets re-absorbed. If your diet is deficient in B12 it can take 20 years before it shows, but if you lack IF or a terminal ileum you become anemic within a year or five at the most. Even so, most people who are B12 deficient are not yet anemic.

Some people find it hard to believe that you can't survive on a diet without meat and they point to the Hindus of India who are Vegans. What they don't realize is that you can also get B12 from bacteria. That's why cows have 4 stomachs and chew the cud, and rabbits eat their own feces (called coprophagia). Vegans in India get their B12 from bacterially contaminated food. B12 is stable even when cooked to destroy the bacteria.

However, contrary to what I was taught, it appears that 1-2% of B12 can be absorbed by simple diffusion, so that if a large enough dose is given orally, enough will be absorbed to treat pernicious anemia. This is not just a whim; it has been the subject of a Cochrane review, and that is about as Kosher as you can get. The dose is 1-2mg daily for a week then 1-2mg weekly for a month and thereafter 2mg monthly. From the randomized controlled trials that have been performed it seems that B12 deficiency from any cause will respond to oral B12. In Sweden three-quarters of all B12 prescriptions are for the oral medication and it is becoming popular in Canada. It is estimated that switching to oral B12 would save millions of dollars every year. Of course, the placebo effect is less, and B12 intramuscularly is the favorite placebo of some doctors.

What does vitamin B12 do? Several things. It is heavily involved in the metabolism of folic acid which is necessary for the manufacture of DNA, and which I shall write about next time. But it is also involved in some complex biochemical reactions such as those involved with homocysteine and methylmalonic acid. It is also necessary for the correct functioning of the nervous system. How it affects the nervous system is not known, though it has been suggested that homocysteine metabolism may be involved. However, it is important to recognize that the neurological problems are those of B12 deficiency alone and do not involve folic acid. There is a peripheral neuropathy caused by degeneration of the posterior and lateral columns of the spinal cord. This shows itself as numbness, loss of positional sense, absent ankle jerks and brisk knee jerks. In severe cases there may be atrophy of the optic nerves and dementia.