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.
10 comments:
My counts began dropping in 2008, and I feared I was relapsing. But a test showed that I was B-12 deficient. My family doc gave me a prescription for a B-12 nasal spray that worked great and makde my counts shoot up. But the spray was so expensive that I changed to sublingual pills that are also working well.
I can't see why anyone would want to pay 15 times as much for the spray.
My oncologist says he prefers injections because they can be better controlled, but the pills are working fine.
I found this a very helpful article, however, I am dismayed at the reference to the placebo effect. Why is it that doctors decide that reported symptoms aren't real and that the patient is only feeling better because they think they are being treated?
I had a serum level in the normal range yet have continued to need three injections a week for the last year. I have substantial nerve damage in one leg and have lost bowel and bladder function due to the nerve damage affecting the sacral nerve. I get a return of symptoms within five days from my last injection which includes loss of balance, bouts of severe fatigue, leg cramps and gastric upset. Fortunately, my GP believes me and has allowed me the level of treatment required, which includes a permanent folic acid supplement and regular iron supplement. I am now about to be seen by a biochemist to investigate whether it is an intracellular or Methylation Cycle defect.
Please give patients credit for knowing when they have symptoms and allow them whatever level of treatment deals with these symptoms. Very few people would happily subject themselves to regular injections without a good cause.
Anon
Notice that I said that it was the favorite placebo of some doctors, not some patients. Placebos are quite effective and trials have shown that injections are more effective than pills and that color is important. I have not suggested that your use of B12 is a placebo, merely that some doctors use it as a placebo. Physiological effects of B12 should be available when it is taken orally. For those who don't have a problem with absorption, like pernicious anemia, then far more than the 1-2% of the dose is absorbed.
Terry,
Can you tell me on what occasions a doctor would give B12 as a placebo? Would it be for the reported symptoms of B12 deficiency without haematological signs or for any complaint which the doctor can find no reason for and gives a placebo to address what he feels is a psychological problem rather than a physical one?
I suppose patients don't really know about the use of placebos so do doctors have a list of official looking pills or injections to give in cases where they feel nothing physical is wrong but want to give the impression to the patient that they have been treated? Also, what do they tell the patient they are being given and why?
Sorry to ask so many questions but I'm intrigued to know whether I've ever been on the receiving end of a placebo and been totally unaware!
Placebos are sometimes given when a patient's complaints do not fit into any pattern of disease, or if the pattern of disease that they do fit has been excluded by other tests. Such symptoms are often a feature of anxiety. They can be dealt with by reassurance and education, but sometimes a patient insists that something should be done.
In these circumstances a physician might refer to an alternative practitioner or an acupuncturist, or might try a placebo.
Mmm, I don't think I've ever had a placebo then. I can accept that it may be necessary in a few instances to give something to satisfy a patient's insistence on treatment despite no diagnosis having been made.
It seems rather ironic though that those without a B12 deficiency may end up being given a B12 injection when others with all the signs of a deficiency are refused the opportunity to try the injections.
It's not a question of refusing patients injections, but of offering to spare them injections. I had a time of injecting myself with clexane; I was glad to change to oral warfarin.
Terry,
A few comments and questions on a lovely review.
As a strict vegan for only a few years, I was surprised to find my B12 level in that borderline range with MMA and homocysteine levels confirming a deficit. The often quoted 20 years to reach a deficiency seems wrong to me based on my clinical experience. Could my CLL/ITP be goggling up my B12 much faster?
I am back in the normal range with sub-lingual B12. What do you think of that delivery method?
Finally, I am sure the bright red color of the B12 shot is part of its placebo magic.
Be well
Brian
That's intersting, Brian. I think the 20 years probably refers to clinical anemia rather than a borderline B12 level.
Sublingual works, but just taking an oral preparation is apparently good enough.
It's interesting how our B12 practice is stuck in the past.
B12 injections are refused on many occasions. I am part of the Pernicious Anaemia Society and it is a sadly common story to find that many patients are refused injections despite a deficient B12 level and serious neurological symptoms.
I don't know of anyone who takes B12 for a placebo effect. Very few people willingly subject themselves to repeated injections, myself included, and I only know that if I don't get three injections a week I become most unwell. I also know others who have had no choice but to pay privately for Methyl SC injections at considerable cost to themselves.
It is very clear to us in the PA Society that PA is completely misunderstood, misdiagnosed and mistreated. Unfortunately, if you don't fit their one-size-fits-all policy, you are thrown off the conveyor belt and left to fend for yourself.
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