|UK ME Biobank Research: “We found that people with ME (PWME) had lower creatine kinase (CK) levels than healthy controls, and that CK was significantly lower in people with severe ME/CFS compared to those who were mild/moderately affected.”|
In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity.
We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB).
After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L).
The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases).
|“This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.”|
In this study we compared baseline laboratory tests results from UKMEB participants with ME/CFS, including mildly/moderately and severely affected (i.e., house-bound or bed-bound) individuals, and healthy controls, which were collected as part of the routine workup of participants.
This study included a sample of 272 confirmed ME/CFS cases and 136 healthy controls. ME/CFS cases were further classified as mild/moderate (n = 216) or severe (n = 56). The definition of severity was made at recruitment based on whether the patient was mainly house-bound or bed-bound (severe) or was ambulatory (mild/moderate cases).
Routine laboratory tests are usually reported as normal in PWME, when they are used to exclude other illnesses causing chronic fatigue. Among the routine laboratory tests for ME/CFS is serum CK, with studies typically reporting CK results within normal ranges if, indeed, they are reported.
|“We found that PWME had lower CK levels than healthy controls, and that CK was significantly lower in people with severe ME/CFS compared to those who were mild/moderately affected.”|
The associations persisted after adjusting for sex, age-group, BMI, muscle mass, or recent physical activity levels (all of which potentially affect CK concentrations in serum [13,14]), as well as disease duration where appropriate (i.e., when comparing cases of differing severity levels).
Creatinine and bilirubin were also found to be significantly lower in severely-affected patients compared to mild/moderate cases, while albumin was higher in severe cases. There was a trend towards higher levels of CRP and ESR in ME/CFS, and particularly in those with mild/moderate disease.
CK levels were found to be good predictors of severe ME/CFS cases as compared to those who were less severely-affected or healthy controls; this was enhanced by the inclusion of other laboratory tests results in the model.
|“Creatine kinase (CK) is a key enzyme involved in energy production and homeostasis processes, particularly in tissues with highly dynamic and fluctuating energy demands which must be quickly satisfied, such as the brain, skeletal muscle, and heart. It is also present in many other cells, such as immune and epithelial cells, where it also plays a crucial role in energy production.”|
Cellular energy is mainly generated from the breakdown of the high-energy molecule, adenosine triphosphate (ATP). Although the complex mechanisms of cellular energy balance are not fully understood, there is evidence that muscle cells depend on several processes to increase energy availability and to avoid complete energy depletion by drawing on stores of ATP.
Creatine kinase (CK) plays a crucial role in these processes: firstly, by establishing an efficient cytosolic storage of high-energy phosphates for rapid ATP replenishment, it catalyses the relocation of γ-phosphate from ATP to creatine to generate phosphocreatine and adenosine diphosphate (ADP), in a reversible process; and secondly, it is involved in the transfer of high-energy phosphate from the mitochondria to the muscle cell cytoplasm, where it is used during muscle contraction.
Thus, measures of CK in serum may indicate the availability of cellular energy.
Low serum CK concentrations have been reported less frequently, but they may be of clinical significance in some rheumatological and connective tissue diseases.
The causes and significance of these findings are unclear, but it has been suggested that serum CK may be inversely related to inflammatory processes, and low CK levels have been associated with muscle weakness, independently of muscle atrophy.
|“The low concentrations of serum CK found in people with ME/CFS suggests an abnormality in energy metabolism, which have been reported by distinct authors and could explain the intolerance to exertion commonly reported by patients, and consequent reduction in activity levels.”|
An alternative or additional explanation is that the lower serum CK resulted, at least partially, from physical inactivity. Nevertheless, the persistent significant association between lower serum CK and disease severity in the multivariate model that controls for activity suggests that these results cannot be fully explained by reduced physical activity, but that there are other factors involved.
|“In addition to intolerance to physical exercise, patients with ME/CFS usually also report mental fatigue and “brain fog”, as well as subjective muscle weakness. Considering the importance of CK in both muscle and brain metabolism, the low concentrations of this enzyme could, at least partially, explain those symptoms.”|
Further investigations with a larger sample size and more detailed explorations of metabolic pathways will be needed to confirm whether low CK activity is a primary or secondary event in ME/CFS or, indeed, whether it reflects some other metabolic dysfunction.
This could benefit from the use of “diseased” controls groups, such as selected orthopaedic patients with prolonged immobility. Meanwhile, we suggest that CK could be used as a potential marker of severe ME/CFS.
It is important to consider the clinical history and physical examination findings, as well as measures of activity (e.g., outputs from accelerometers) at the time of the blood draws for serum CK. Moreover, a “high-normal” result in people who are often sedentary or bedbound, particularly those with severe ME/CFS, should be interpreted with caution, as it could indicate the presence of muscle injury.
|“Our findings give significant support to the growing body of evidence on metabolic abnormalities in ME/CFS, and we suggest further adequately-powered studies that include a fuller investigation of specific metabolic pathways to elucidate whether CK is a primary or secondary abnormality in all or in a sub-group of ME/CFS cases.”|
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