Sunday, August 27, 2006

Fatigue in CLL

Many patients with CLL complain about fatigue.

It is also true that many patients without CLL complain about fatigue.

The commonest reason for a general practitioner requesting a CBC is "tired all the time". I suspect that they suspect anemia, which is certainly a cause of fatigue. Hardly any of those patients have anemia.

There are many possible causes of fatigue. People feel fatigued when they have been working hard - either physically or mentally. If you play a hard game of rugby or soccer you certainly feel fatigued at the end of it. If you drive 200 miles, if you go for a job interview, if you watch you children perform in the school play, the emotional tension makes you feel tired afterwards.

Tiredness is the natural consequence of being awake for a while, an indication that we need to sleep. Clearly this is not what patients are complaining about.

There are medical conditions which manifest as tiredness. I'm not sure that tiredness is a good word to describe it, though it is certainly part of it. Fatigue is a word often used, though this is a technical word in medicine, which has a specific meaning. It refers to what happens when a muscles is stimulated repeatedly by electricity. After each stimulation there is a period when it cannot be stimulated again - the muscle is said to be fatigued and requires the regeneration of certain chemicals before it can be restimulated.

Asthenia was a word that was formerly used. It describes that feeling of exhaustion, lack of energy or indeed the will to do anything; being washed out and weak and watery. It was often associated with anemia or chronic infection, especially with TB.

Anemia induces this feeling because insufficient oxygen is reaching the muscles. In France and Germany doctors are prone to diagnose asthenic patients as having low blood pressure, and the German Health Service has quite a large budget to spend on drugs to raise the blood pressure, something that is unknown in the UK.

Some years ago I began to be referred patients who claimed that they had myalgic encephalitis or ME. There is an ME society. What these patients had in common was severe fatigue. Commonly they would sleep for 12-16 hours at night. Often they had muscle pains (hence the myalgia) and they would often complain of a muzzy head, being unable to concentrate or focus on anything (hence the encephalitis). They were unable to hold down a job. Many of them dated their symptoms from a viral infection, often glandular fever, that never seemed to have got better, although often the glandular fever had not been diagnosed virologically, but simply labelled as that from a GP without investigation. One woman dated her illness to when she was biten by a squirrel.

At the time I was interested in infectious mononucleosis. However, I could find no really convincing evidence of EBV having anything to do with it. A clinical trial of levamisole as an immune booster had no effect.

Nowadays this condition is called chronic fatigue syndrome and it is treated by cognitive behavioural therapy, though sometimes older doctors and rheumatologists label it as fibromyalgia (which being translated means, "I know you have aches and pains but I can't find anything wrong").

The problem about making the diagnosis of pathological fatigue is that it is a diagnosis of exclusion. That means that as it has no spcific symptoms and no clinical signs or characteristic blood tests, the doctor must first exclude all the conditions that can be tested for

Simply getting older is the commonest cause of fatigue. It affects some more than others.

Fatigue often has a psychological cause. It doesn't mean that you are psychologically ill, but things like children leaving home, retiring or nearing retirement, downsizing your house, divorce, bereavement, disappointments, fears, even the war in Iraq can leave us feeling fatigued.

Then there is actual depression. Subclinical depression is much commoner that is recognized. And so is anxiety neurosis.

Medications cause fatigue. Any sort of sleeping tablet, any type of blood pressure tablet, any type of anxiolytic, many antihistamines.

Sleep apnoea is a possibility, especially in anyone who is overweight, then there is any degree of heart failure, certain types of neurological disease, any type of cancer, diabetes, hypothyroidism, Addison's disease and I expect there are other conditions that I haven't thought of.

When a blood test for 'tired all the time' is done, some people will be found to have undiagnosed CLL. But perfectly well people having a blood test prior to, say, hernia repair, will also be found to have CLL. We can't just say, "Aha! We have found the cause of the fatigue." Lots of people, perhaps the majority, who have CLL do not have fatigue.

It must be galling for a patient to keep telling the doctor that the CLL is the cause of the fatigue and yet not have the doctor believe him or her. What more evidence do they want? I used to be well, then I got CLL, now I am fatigued. Why won't you believe me?

So what is the evidence that CLL is the cause of a particular patient's fatigue?

If you search for 'Fatigue' and 'CLL' on PubMed you find a couple of pages of papers most of which refer to fatigue as a complication of treatment or anemia. There is a paper which reviews studies of qualitiy of life in CLL.

This paper by Stephens et al Am J Ther 2005; 12:460-466. has the following quote: "We identified only 8 articles, and none of them analyzed the QOL in untreated CLL patients".

There has been no systematic study of the symptoms suffered by asymptomatic patients.

Some doctors are convinced that CLL causes fatigue. They believe this because a lot of CLL patients have told them that they suffer from fatigue. On the other hand doctors in some countries get paid a lot more if they give patients chemotherapy than if they simply offer watch and weight. Far be it for me to suggest that any doctor would be swayed by this, but some might opine that such a doctor might not be entirely objective.

There is a rationale for fatigue in CLL. We know that CLL cells in the test tube can be shown to secrete a number of cytokines including IL-1, IL-6, IL-8. IL-10, TNF-alpha, TGF-beta. It is also known that when certain cytokines are used therapeutically (IL-2 and interferon) the side effects include prostrating fatigue. In addition several conditions in which fatigue is prominent such as terminal cancer are associated with high levels of certain cytokine such as TNF alpha and IL-6.

If this is the mechanism then one would expect fatigue to be greatest in patients with the greatest bulk of disease. This is sometimes true, and it is behind the NCI guidelines that say that severe fatigue is an indication for treatment. On the other hand some patients who complain about fatigue have only small amounts of indolent disease. One then has to postulate that the tumor is an industrious cytokine secretor. Un fortunately there have been no studies done to measure cytokine levels in patients with fatigue, comparing them with levels in patients without fatigue.

Another possible cause for fatigue in patients with CLL is a chronic infection caused by the immunodefficiency. This might be a low grade bacterial infection; perhaps of the sinuses, or perhaps even TB. It could be the reactivation of a virus infection like EBV or CMV.

I am sure readers will see the theraputic conundrum here. If the fatigue is caused by cytokine secretion from the tumor, then chemotherapy will make it better. If, on the other hand, it is caused by chronic infection, chemotherapy will make the immunodeficiency worse and the infection will progress.

I am sbsolutely convinced that CLL patients get fatigue as a symptom. Trying to find out why is very difficult. Jumping into treatment may not be the correct path to follow. More research into this difficult problem is clearly needed.

If a trial of therapy is to be undertaken in a patient with low bulk disease, then I favor a trial of green tea extract. This will likely cause no harm, and it seems that some patients respond. Next in line would be rituximab alone.

20 comments:

Anonymous said...

Dr. Hamblin,
Very interesting post, thanks for sharing!
When you wrote "trial of green tea extract ", how is the best way to use the extract? I know this sounds stupid
but green tea comes in several forms. What type would you use and should it be mixed with something? Or is it best to have as a tea? Are some brands better than others?
Thanks fo your time,
Carlin C.

Sherry Gardner, Psy. D. said...

I call this type of fatigue "dead tennis ball syndrome." If my old carcass fell over, I'm sure it would make that characteristic dull thud and not rebound a bit. Thanks for your elucidation, Dr. Hamblin.
Sherry Gardner

Jim McVey said...

Thank you for your enumeration of all the conditions that can cause fatigue. I also have Hypothyroidism and I take Levoxyl daily I know that one of the side effects of that is
fatigue. My PCP at one time increased the dose to see if that combated my fatigue but it gave no measurable change.

The word fatigue may be a contributory reason why it is not
investigated. I associate that with Comet Wings and metal fatigue. I would opt for the old descriptive word Asthenia and especially the phrases, “feeling of exhaustion, or “indeed the will to do anything”. I feel it is in my head, if I am asleep in my recliner(they should be banned) I may come semi awake but I cannot climb out of the pit of sleep I am in.

My purpose in posting about Fatigue the way I did, was to generate an interest in examining the various chemical reactions that CLL has in ones body. Perhaps if they were examined in some depths they would lead to new treatment options.
The thrust at the moment is to find a CLL treatment, so other side effects do not have the same appeal to researchers. I fear that most research is $$$ driven in this material world so perhaps if QOL was the aim, new fields would be realized.

I have taken Melatonin to fall asleep and believe it acts on the
brain for it’s sleep action. So there could be a similar chemical which causes Asthenia. Perhaps some bright researcher not $$$ driven
would be triggered by this thought, I have also read that other blood cancers cause similar fatigue.

Andrew Gach’s, Digest post on Chronic Fatigue Syndrome
He says [While unconnected to CLL and SLL, it's interesting that
CFS/ME also involves the immune system and the lymph glands. - AG]
If we could somehow piggy back on this research for CLL Asthenia,
it may produce results we can live with. They are examining genes
which act strangely in CFS patients. Perhaps our CLL genes are
there as well.

I feel better now that I have commented, thanks for the opportunity.

Wayne McPherson said...

Dr. Hamblin,
Thanks for sharing this information;
thanks for sharing your opinions;
and a special thank-you for
sharing your Christian faith.
Sincerely,
Wayne McPherson

Steve Madden said...

Terry

Thanks for the good summary of this phenomena.

For me it was as you stated a blood test for "some virus" that was making me feel like crud.

Since then I have been inspected, detected, irradiated, biopsied, contrasted, given miltiple arms full of blood for examination and everything else is working just fine. (That goodness)

No sleep apnoea, no heart problems (although the treadmill nearly killed me :) ) no thyroid issues, no lung issues, kidneys working well, liver function fine.

No drugs have had any effect.

Depression, well CLL is pretty depressing but I had these symptoms before I had ever heard of CLL.

Just as some CLL clones make a para-protein others do not, do we even know everything that the clone can make?

Anonymous said...

I think you are on the right track. This was just posted on the CLL Research web page:

High Cytokine Levels Linked to Fatigue and Cognitive Impairment

Allison Gandey
Medscape Medical News 2006. © 2006 Medscape

August 24, 2006 –- Studying patients with colorectal cancer,
researchers confirm the link between cytokine levels and some of the
bothersome cognitive effects of disease. "Cytokine levels were
elevated in most patients," lead author Janette Vardy, MD, from the
Princess Margaret Hospital in Toronto, Ontario, said. Her work
appeared in a poster session at the recent 42nd annual meeting of the
American Society of Clinical Oncology.

As part of the group's longitudinal study evaluating cognitive
symptoms, the researchers looked at colorectal cancer patients after
surgery or before neoadjuvant therapy. They measured serum levels of
12 cytokines on patients at baseline and at 6 and 12 months.

Participants were divided into 2 groups. Group A consisted of stage 3
high-risk patients who received chemotherapy. Group B included stage
1 and 2 patients who received no chemo. Baseline data are available
for 82 patients — 65 in Group A and 17 in Group B. The mean age of
the cohort was 58 years, and 68% were male.

All patients completed questionnaires on quality of life, fatigue,
anxiety and depression, and perception of cognitive function. They
underwent neuropsychological assessment with traditional as well as
computerized tests. The researchers looked for associations between
cytokine levels, test results, and demographic and disease-related
factors.

The investigators found that cytokine levels were elevated in all
groups with larger ranges after surgery. "There was cognitive
impairment at baseline in 28% on traditional neuropsychological
tests," Dr. Vardy reported. "At 6 months, chemotherapy patients had
more fatigue, perceived more cognitive impairment, and had more
cognitive impairment on computerized testing (42% vs 17%)." But the
researchers did not observe these changes on traditional
neuropsychological tests (32% vs 33%).

Steve Madden said...

anon e mouse

The problem is that cytokine levels are not elevated in CLL, if I have kept up with my reading.

Anonymous said...

I have CLL and the only thing that makes me tired is thinking about it. If I don't think about it I am not tired at all and feel like a spring chicken.

Willie H said...

My GP tells me that fatigue in CLL is caused by the elevated levels of white blood cells. He says that white blood cells demand a disproportionate amount of energy which is why one gets tired when dealing with an infection. A reasonable explanation if true.
Has there been research on this?

Anonymous said...

I have read your article on fatigue in CLL with very great interest. I have CLL which was discovered during routine blood tests following a diagnosis of CFS.
Years ago I was diagnosed with ME following a bout of glandular fever. For years I was unable to recover normally from viral infections. Four years ago my longterm partner collapsed and died in the place where we both worked. Following this trauma I started to suffer once again from recurrent viral illnesses. I have now been unable to work for a year.

The diagnosis of CLL made sense to me as it seemed to explain everything, but it is the CFS which my doctors are trying to treat and I find this worrying. Nobody is really able to answer my questions. There surely has to be a link between the two. Does anybody want to use me as evidence?

Alison

Terry Hamblin said...

It is not possible to assess whether fatigue is due to CLL or to other causes. It has to be trial and error.

Anonymous said...

Interesting reading about the fatigue.
I have suffered from Crohn's disease for 25 odd years & was diagnosed with CLL a month agao from my routine bloodtest i have to check how my Azathioprine drug is affecting my bloods.
I have suffered fatigue this last 18 months 2 years & just put it down to the Crohn's.
GP thinks ive had CLL for at least a year, whereas Haematologist thinks i may have had CLL longer.
Any comments on the interaction between CLL & Crohn's ??

Terry Hamblin said...

I don't really have any information on Crohn's and CLL.

madeline boyle said...

Very good article. Thanks. Isn't it "watch and wait"? - not "watch and weight"?

Terry Hamblin said...

It's been up nearly 4 years and you are first to spot the deliberate mistake.

Vicky said...

I have used porcine thyroid for more than a year and I have had nothing but great results. I have hypothyroidism and this makes me feel so alert and has helped me lose weight. I also exercise but porcine thyroid have helped me drop weight. I tried a different pill but ended up going back to this due to my positive results. I highly recommend porcine thyroid!

Nick said...

Thank you for your article,

During my current reading am I ubderstanding correctly that TNF-α levels are higher in the blood of CLL patients? My reading did bring up a question about fatigue, that was thrown up in the paper below. Does TNF-α over expression also play a role in CLL fatigue?

“Our findings also extend previous observations on the effects of TNF-α in the CNS (i.e., the regulation of expression of clock genes), which may explain the high prevalence of fatigue in inflammatory diseases (22).”

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system
http://www.pnas.org/content/early/2011/01/13/1011774108.full.pdf

Regards

Nick

Terry Hamblin said...

am I ubderstanding correctly that TNF-α levels are higher in the blood of CLL patients?

I believe its still true.

Nick said...

Thank you

( :, Yes of course, I guess in CLL it gets everywhere. It was intriguing to learn that it's normal low level expression by my brain during a TIA prior to a full blown ischemic event. Had a protective effect and probably reduced damage. Whether high levels in the blood in the first place were part of the trigger I don't know.

I guess this is a very clever molecule, it was its positive effect on brain as well as it's negative that I found interesting. We experience fatigue because our brain tells us it is so, I guess TNF-a meddling with the CNS and clock genes as a possible part of cancer fatigue is not that hard to believe? Could you impart any knowledge?

Terry Hamblin said...

No, I think that's my limit.