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Adelaide University, Lactic Acid Research
The following information was supplied as a handout at the 7 November talk given by Professor Gary Scroop, at the AGM of the ME/Chronic Fatigue Syndrome Society of Victoria Inc.
Chronic Fatigue Syndrome — Quo Vadimus
Garry C. Scroop
The Adelaide Chronic Fatigue Syndrome Research Group
My interest in Chronic Fatigue Syndrome began about 3 years ago from a purely chance observation. My laboratory in the Department of Physiology at the University of Adelaide is an Exercise Research Unit. We see a lot of athletes and one of the things we’ve long been interested in is lactic acid metabolism during exercise. Lactic acid is a by-product from exercise. Therefore, it is of vital concern to athletes, who want to reduce lactic acid production and increase their exercise endurance.
In late 1995 Richard Burnet of the Endocrine and Metabolic Unit at the Royal Adelaide Hospital approached me to look at potassium release from the exercising muscles of a group of CFS patients in his care. He had evidence of a deficiency in total body potassium and clinical improvement when patients were treated with the potassium retaining drug, Spironolactone. We decided to compare the potassium responses in CFS patients with those in a closely matched group of healthy people with the same level of fitness. Both groups did exactly the same amount of exercise on an exercise bike and we took a lot of blood samples throughout for potassium assay. Because of my interest in lactic acid metabolism in exercise we took a few extra blood samples for lactate assay, but as they were not out main interest they lay in the freezer for 6 months until we had the funds and personnel to assay them. When we did so, we were astonished to see that the CFS patients released more lactic acid into the blood than the healthy control subjects, sometimes twice as much. Given the well-established role of lactic acid as a cause of fatigue in healthy people you can see that to find abnormal amounts being released in patients with CFS was really quite exciting. If consistent, this abnormality has the potential to provide a real window of opportunity into understanding CFS, but it is a window into a very dark room.
At this stage we are concentrating on several new research projects which we hope will give us the most information in the shortest possible time. Firstly, provided the lactic acid response remains a consistent finding in all patients with CFS then it could form the basis of a the first definitive laboratory diagnostic test for CFS. At this point in time, the diagnosis of CFS is based only on the clinical history and this is often only made after months or years of frustration for the patient. If we can develop a diagnostic test which is reliable, reproducible and accurate, then it would have tremendous impact in speeding up the whole process of diagnosis, treatment and community acceptance.
Peter Memeth in my laboratory is running this study and preliminary results are encouraging. To avoid patient discomfort we chose forearm exercises by the abnormality in lactic acid production has not been consistent as with cycle exercise- we believe this is due to the exercise protocol and are making adjustments. With the cycle exercise test, which involves whole body exercise, we had a 100% strike rate in finding lactic acid abnormality, whereas with the forearm test it is just under 50% but equally as effective for men and women. We need to establish reproducibility of the test and look at doing the cycle test in as many of these patients as we can. Secondly, if the lactic acid response is widespread in patients with CFS then it may provide a means of alleviating the fatigue in CFS. However, the important issue to address for long term benefits is to find out why the abnormal lactate response occurs and what it means in the broad context of CFS.
Charlie Sargent is a Doctoral student in the Exercise Physiology Research Unit at the Department of Physiology in the Adelaide University and has begun work with Richard and I and Jon Buckley from the University of SA looking at this third research area. We believe that the lactic acid abnormality which we see in exercising muscle is a small part of a much more substantial problem in systemic energy production due to some deleterious change in the energy generating metabolic processes. IN this regard we have just been funded to look at the impact of varying the availability of pyruvate for conversion to lactic acid, but this study will involve intravenous administration of the drug and is directed at the mechanism of CFS rather than offering a potential treatment. We have three different treatment trials either in progress of about to begin but these are best regarded as intelligent guesses rather than specific treatments to correct a defined abnormality, which is the ultimate goal. As a further extension of the research into the mechanisms of CFS, we are about to undertake a study looking at both the blood metabolic responses and the skeletal muscle histochemical changes to repeat exercise in CFS patients — if we can convince the patients!!!
I can honestly say that after 35 years of basic scientific research the lactic acid finding is without question the most exciting and potentially beneficial piece of research I’ve been involved with. However, our results are very preliminary and need to be treated with caution. There has been a lot of poorly controlled research in CFS and many false dawns, and this has led to much frustration in patients who have been coerced into expensive and fruitless treatment programmes. We need to do a lot more studies into CFS patients to determine the consistency and reproducibility of the lactic acid abnormality and find out what it means in the broad context of such a multi-system disease as CFS.
The experiments require blood samples to be taken during exercise which in itself is a problem for CFS patients who find exercise so damaging to their illness and have provided so many blood samples in the past with little progress. As the experiments are on human subjects they require a high degree of sterility and the use of expensive, disposable consumables. With this cost and that of the blood assays, all up each experiment can cost as much as $300. Up until now, because the work is new, Richard and I have worked on a shoe string budget and this has been a real impediment and is tremendously frustrating when we have so many ideas we wish to pursue. The amount of money available for medical research in Australia is quite small. Taken together with the common perception by large sections of the scientific and medical community that CFS is an illness with a primarily psychogenic basis, funding is proving quite difficult to obtain. The Adelaide Chronic Fatigue Syndrome Research Group is therefore particularly grateful to members of the ME/CFS Society in South Australia for putting in such a tremendous effort in establishing and supporting the development of a new research fund specifically for ME/CFS research. It is always very dangerous in research to make predictions, but we believe that our finding has a real chance for making substantial progress with this awful illness. But research funding and collegiate support are thin on the ground and our progress, like that of our patients, is frustratingly slow.
Donations may be made either directly to the Department of Physiology, University of Adelaide, or via the ME/CFS Society of Victoria. Cheques made payable to the Adelaide Chronic Fatigue Syndrome Research Group.
Normal Aerobic Capacity and Lactate Threshold during Incremental Exercise in Patients with Chronic Fatigue Syndrome
G C Scroop, R B Burnet, B Yeap, J D Buckley, S S Lim and T Ho
Exercise Physiology Research Unit, Department of Physiology, Unversity of Adelaide, SA 5005.
The metabolic responses during incremental exercise to exhaustion in 5 patients with Chronic Fatigue Syndrome (CFS) were compared with 5 healthy sedentary controls matched for gender (3 female, 2 male), age (CFS 34.80 +/- 4.73; controls, 35.20 +/- 4.59, yr), height (CFS, 170.40 +/- 4.39; controls 171.70 +/- 5.00, cm) and mass (CFS, 72.12 +/- 9.58; controls, 76.58 +/- 9.80, kg). Control subjects exercised for longer (CFS, 18.80 +/- 0.58; controls, 23.66 +/- 1.01,min p<0.006), reached a higher peak workload (CFS, 125.00 +/- 7.91; controls 165.00 12.75, watts, p<0.04), and consequently did more work (CFS, 67.20 +/- 8.78; controls, 114.45 +/- 16.58, kJ, p<0.05). Peak VO2 (VO2peak) at exhaustion was not significantly different between these 2 subject groups (CFS, 28.01 +/- 1.93; controls, 35.23 +/- 3.54; ml.kg-1.min-1, NS) or from their predicted VO2max determined during an earlier submaximal cycling test (CFS, 29.87 +/- 1.36; controls, 33.34 +/- 3.76; ml.kg-1.min-1; NS). VO2peak achieved at peak heart rates (Hrpeak) which were not significantly different from each other (CFS, 177+/- 5; controls, 180 +/- 6; beats.min-1) or from their age-predicted maximum heart rates (Hrmax; CFS, 185 +/- 5; controls, 185 +/- 5; beats.min-1; NS). The lactate threshold (LT, determined from a log-log plot of absolute VO2 versus blood lactate concentration) occurred at VO2 levels which were not significantly different between the 2 groups whether expressed in relative (CFS, 14.53 +/- 1.26 ml.kg-1.min-1; controls 14.16 +/- 2.05 ml.kg-1.min-1) or percentage (CFS, 52.2 +/- 3.4; controls, 41.9 +/- 7.8; % VO2peak) terms. Despite doing less work the blood lactate concentration (CFS, 4.54 +/- 0.84; controls, 6.38 +/- 0.36; mmol.l-1) and VO2 at exhaustion in patients with CFS were not different from controls. It is concluded that while the work capacity of patients with CFS is significantly less than sedentary controls, aerobic capacity and the LT are not, suggesting that factors other than so-called "deconditioning" are responsible for the earlier fatigue during exercise.
Total Body Potassium in the Chronic Fatigue Syndrome
Richard B Burnet(1), Barry E Chatterton(2), Robert D Gaffney(2), Garry C Scroop(3).
Endocrine and Metabolic Unit, Royal Adelaide Hospital (R.B.B.)
Department of Nuclear Medicine Royal Adelaide Hospital (B.E.C, R.D.G)
Exercise Physiology Research Unit, Department of Physiology, University of Adelaide (G.C.S)
Normal potassium levels (both intra and extracellular) are essential for initiating a full muscle contraction and neural transmission. Approximately 80% of the body potassium is found in muscle and a further 10% in the brain. The remainder is in the blood stream and other organs. Potassium is primarily an intracellular ion.
A number of medical conditions that cause low potassium are associated with fatigue. Previous studies in Chronic Fatigue Syndrome (CFS) have not demonstrated an abnormality in the level of serum potassium but the present studies have concentrated on intra-cellular potassium and its relationship with CFS.
An initial study of Total Body Potassium (TBK) measured by whole body counting in 20 matched pairs of patients and controls matched for age, weight and sex showed that there was a significant decrease in the values of those persons who had CFS as defined by the British, Australian and American clinical criteria. Eight pairs of subjects in this study had a whole body DEXA scan which showed no significant difference in the amount of lean body mass or total bone mass.
There was overlap in the levels of TBK in patients with CFS and controls so further investigations were undertaken to define the abnormality.
Patients with CFS were divided into two groups, those with fatigue symptoms only and those patients who had a mixed symptomatology of fatigue and myalgia. This was defined by patient assessment of their disability at the medical consultation.
Fifty-one subjects with CFS only (29) or myalgia/fatigue (22) were studied with a TBK a full biochemical profile and the results were analysed for these 2 groups. The CFS group with fatigue only, showed a significant reduction in the level of TBK and in one half of these the reduction in TBK was greater than 10% of the normal estimated for age weight and sex. The serum potassium levels were normal in all subjects.
In the myalgic group there was no reduction in TBK. There was no correlation in the TBK with age, sex, duration of illness, reduction in daily living activities and time for recovery from exercise. Nor was there any correlation with any allergic symptomatology or recurrent chronic infections. There was a strong inverse correlation of the TBK and the total time spent resting (p=0.02).
These investigations show that in approximately 50% of subjects with CFS where fatigue is the primary symptom there is a significant reduction in the level of TBK. This decrease in TBK is not found if there are myalgic symptoms even if there is associated fatigue.
Longer term studies are needed to define this abnormality further, whether it fluctuates with the disease and its progression is unknown.
This finding of a lowered TBK has great significance as a possible marker of CFS with fatigue and also points a way to improving therapy by determining the effects of normalising the intracellular potassium.
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