Friday, June 26, 2009

Anemia in cancer patients

Why have a blood transfusion? Is it a] to raise your hemoglobin? b] to improve your color? c] to improve the oxygen carrying capacity of your blood?

The answer, of course, is c] but while it will do both a] and b] it won't do c] immediately. Oxygen is carried by hemoglobin and is released to the tissues where it is needed. It is helped to do this by a chemical called 2,3,DPG. In order to release oxygen, its place on the hemoglobin molecule must be taken by this chemical. 2,3,DPG is manufactured by all cells from the burning of glucose (the process is known as glycolysis and the biochemical pathway is known as the Emden-Myerhoff pathway. The particular trick of producing 2,3,DPG is known as the Rapaport-Leubering Shuttle). If a cell is not metabolising glucose then it won't make any 2,3,DPG, and this is what happens when blood is stored in a fridge. So when you receive blood from the blood bank it has very little 2,3,DPG and therefore the hemoglobin molecules cling on to their oxygen. That's why someone who has been transfused gets no immediate benefit from it; it can't release its oxygen to the tissues until it regenerates 2,3,DPG, which takes a couple of days.

This is one of the reasons that patients are dissatisfied with blood transfusion. That and the risk of transmitting viruses, or prions, or making their cancer worse by suppressing their immunity. In fact blood transfusion is very safe. Blood is screened for HIV, hepatitis B and C and a host of other possible infections. It cannot be screened for prions, but the risk of developing new variant CJD from transfusion is vanishingly small. The greatest risk of a transfusion is that some idiot will give you the wrong blood.

The alternative is EPO. Lots of cancer patients have been given it, but the unfortunate fact is that it shortens life. A recent meta-analysis published in the Lancet looked at 53 separate trials involving 13,933 patients. Although the effect was not great (a hazard ration of 1.06) it was statistically significant. Partly this effect is because EPO may raise the hemoglobin too much and the thrombotic complications of polycythemia come into play, but also there is the worrying fact that EPO is a growth factor for some tumors.

With so much to worry about we need to look at anemia again. In some cases the problem can be sorted with iron therapy. (Oral iron is best; there is no evidence that intravenous or intramuscular iron is more likely have a response or have a quicker response.) But we need to be able to recognise iron deficiency (which is almost always caused by bleeding). The easiest way is to look at the mean cell volume on the blood count. If this is below 80 fl then iron deficiency is the most likely diagnosis. Thalassemia trait can cause a low MCV and this is an important catch for people of Mediterranean background, but the only other cause of a low MCV is the anemia of chronic disorders (ACD).

I have bee surprised recently by how little even hematologists know about ACD. They seem to be unaware that it can cause a low MCV. I can only think that they have never looked at the blood counts of patients with rheumatoid arthritis, ulcerative colitis and Crohn's disease, let alone people with chronic infections or disseminated cancer. The serum iron in ACD can be as low as it is in iron deficiency, as can the MCV. The difference is that the iron binding capacity or the blood (or the serum transferrin) is raised in iron deficiency and lowered in ACD. Serum ferritin is low in iron deficiency and raised in ACD.

What happens in ACD is that the macrophages are over active and snaffle all the iron in the body and won't release it to the newly formed red blood cells. We now know that a chemical called hepcidin, a small peptide produced by the liver that inhibits both iron absorption and release of iron from the macrophages. Patients with excess hepcidin will not respond to more iron, whether oral or intravenous, nor to EPO. Only blood transfusion will raise the hemoglobin.

High hepcidin levels are found in association with high sed rates, high CRPs, high IL-6 levels and other indicators of inflammation.


bob larkin said...

I've been on a transfusion run (reds & platlets)these past couple months of my Campath regimen. This information is quite timely and very helpful for me.

Thanks Terry.

Anonymous said...

Over the years I have seen many patients in consultation for presumed gastrointestinal bleeding as a cause of anemia erroneously felt to be due to iron deficiency when they, in fact, had ACD.

The role of hepcidin is becoming established and may help to sort this out. In the US many PCPs want thrit anemic patients to undergo panendoscopy to exclude sources of gastrointestinal bleeding (the most common cause of iron deficiency anemia in the US) when the patients really have no evidence of iron deficiency or of bleeding.

Many years ago while a resident I located a paper (don't ask me where) describing a series of patients with elevated ESR anf apparent ACD. These patients were asymptomatic apart from the symptoms related to their anemia and all responded well to modest doses of prednisone with correction of the elevated ESR and rise on their hemoglobin.

The authors positied that they had "polymyalgia rheumatica without the rheumatic symptoms".

Whether this was true or not I cannot say, but I have repaired ACD more than once with cautious trials of low dose prednisone.

The other side of the coin is that I have had to treat so many patients with active gastrointestinal bleeding that I'm certain that I'd be shocked to know just how many gallons of blood I've transfused over the years.

I am aware of a few cases of transmitted hepatitis and one fatal case of HIV transmission in these patients, but agree that overall the transfusion of blood products (when appropriate) is fairly safe and often may be lifesaving.

Giving a transfusion just to elevate the hemoglobin in patients who aren't in danger and who aren't especially symptomatic is not a good practice. Nor is the transfusion of any other blood product unless the benefit is clear cut and outweighs even small risks that may be accrued.

I still reflect on the patient who contracted AIDS and died as he received 2 units of pRBCs after he was stabilized...were these the units which transmitted the HIV or was the virus in one of the earlier units whose use was clearly necessary?...I will never know.


Burke said...

I wonder if EPO isn't dangerous in another way too: masking underlying problems.

I took EPO when I was on W&W back in 2006. They watched my hemoglobin very closely, and I responded well. But my platelets were low, so they decided to do a splenectomy and were planning to leave me on EPO "indefinitely" afterward.

Shortly before the splenectomy, a BMBx (that I had pushed them to give me) showed me with 70% marrow involvement, so they cancelled the procedure and rushed me into FCR instead (which worked out great).

Afterward, I asked my doc if she thought the EPO had been masking the effects of my extensive marrow involvement by hiding my anemia.

She said no, but I'm not so sure.

After reading more about EPO, I don't think I would have ever agreed to use it. And I'm a little irritated that they didn't tell me about its dangers.

Terry Hamblin said...

'Polymyalgia sine polymyalgia' is what I used to call it at least a decade before the paper you are referring to. Many of my patients responded to steroids but occasionally you can be fooled by an occult cancer, as I was by a colleague's father who turned out to have prostate cancer (in the days before PSA). Still, it is a good tip.

One quite well known international doctor actually advocated down-staging in CLL with EPO, turning stage 3 patients into stage 1 patients and therefore denying them treatment. I refereed his paper several times for different journals, each time turning it down for crass stupidity, but it was eventually published somewhere.