The patient's full blood count was as follows (normal ranges are in brackets):
- White Cell Count: 1.2 x 109/l (4-11)
- Haemoglobin: 2.4 g/dl (11.5-16.5)
- MCV [mean corpuscular volume]: 112 fl (80-95)
- Platelets: 23 x 109/l (150-450)
Question 4: How does the blood count reconcile the patient's haematemesis with her normal gastroscopy findings?
The patient has a severe pancytopenia, including a severe thrombocytopenia. The latter causes a bleeding tendency, which may occassionally present as an upper GIT bleed in the absence of significant ulcers or erosions.
Question 5: Are there any clues as to the aetiology of the pancytopenia from the blood count?
Yes - the anaemia is macrocytic (the MCV is markedly raised). This raises the possibility that we are dealing with a megaloblastic anaemia, which is caused by a deficiency or folate and/or vitamin B12. A severe enough deficiency of one of these vitamins can cause a pancytopenia.
Sure enough, the peripheral blood smear showed oval (as opposed to round) macrocytes and hypersegmented neutrophils. Together with the raised MCV, this is virtually diagnostic of a megaloblastic anaemia, and hence possibly the pancytopenia by extension. As further blood results poured in, the folate level was found to be normal, but the B12 level was only about a third of the lower limits of normality. We had our presumptive diagnosis: pancytopenia secondary to a severe vitamin B12 deficiency.
Question 6: What are the causes of B12 deficiency?
We've answered that, in passing, here.
The rest of the patient's presenting pathologies then fell into place:
- Her weight loss turned out to be from a long-standing combination of gastrointestinal symptoms including nausea and diarrhoea. There was probably an element of malabsorption too. These aren't infrequent symptoms in megalobastic anaemias, since like the haematological cells, the mucosa's turnover rate is extremely rapid and thus very sensitive to a nutrients.
- Careful examination revealed a glossitis (in which the normal tongue papillae are absent), which is an extension of the GIT involvement in general.
- The ejection systolic murmur, by the way, was due to the patient's high cardiac output state, which was secondary to her severe anaemia in turn. The increased rate of ejection of an increased volume of blood causes turbulence around the aortic outlet, even though the actual valve is anatomically normal. Why do you get a high cardiac output state in anaemia? See here.
Fortunately, the patient hadn't developed any neurological symptoms (such as paraesthesias, numbness or defects of proprioception), since these are often permanent.
Question 7: Why does a vitamin B12 deficiency affect the blood and gastrointestinal mucosal cells most?
A deficiency of vitamin B12 affects all cells that divide, since it leads to an inability to synthesize adequate amounts of DNA. (Cells that divide each have to take a copy of the body's DNA with them, and so must replicate it before dividing.) It turns out that vitamin B12 is a vital cofactor in the synthesis of thymidine (T) from uridine (U). Therefore, without it cells can't make DNA (thymidine is one of the nucleosides, remember?), and therefore can't divide at the appropriate rate. The commonest symptoms (haematological and gastrointestinal) simply reflect the fact that these cells divide the quickest, and so any slowing of cellular division is likely to be noticed there first.
Question 8: Why does vitamin B12 deficiency cause neurological dysfunction? Those cells either don't divide quickly or at all!
Indeed, neurological dysfunction in B12 deficiency is by another mechanism (or two). In addition to being a cofactor in normal thymidine synthesis, B12 is also a cofactor in the synthesis of an amino acid called methionine. Although the exact pathogenetic chain is yet to be worked out, it seems as if the deficiency of methionine causes demyelination (loss of the normal myelin sheaths around the nerves). Furthermore, succinyl-CoA production is also slowed in B12 deficiency. The fact that this compound is involved in fatty acid synthesis may also partly account for the demyelination.
The patient was supplemented with B12 by means of a series of intramuscular injections. She responded beautifully, with a rapid response in all three cell lines. Within days, both her platelets and her white cells were at normal levels, and her anaemia was well on the road to oblivion.
Currently, she is being worked up as to the cause of her B12 deficiency. Could it be pernicious anaemia? None of the other likely causes of B12 deficiency seemed to fit. The gastroscopy findings didn't mention gastric atrophy, but I doubt if this was specifically looked for at 2 o'clock in the morning when we thought we were dealing with a severe upper gastrointestinal bleed alone. Two antibodies associated with pernicious anaemia might shed some light on the matter - anti-parietal cell antibody, and anti-intrinsic factor antibody. These results are currently pending.
Question 9: How does pernicious anaemia cause B12 deficiency?
'Pernicious anaemia' is the result of an autoimmune attack on the stomach's parietal cells. As a result of the loss of parietal cell mass, stomach acid production falls to virtually nothing (achlorhydria) and insufficient intrinsic factor is produced. Both of these facts cause a decrease in vitamin B12 absorption. A low pH is necessary to release B12 from any ingested food, and intrinsic factor's job is to bind B12, thereby preventing its degradation, and enhancing its absorption in the terminal ileum.
That about does it for the first case. Comments on the format, anyone? Good, bad, indifferent?