Blockage of a key metabolic enzyme could explain the profound lack of energy and other symptoms experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), new research suggests.

The findings were published December 22, 2016, in the Journal of Clinical Investigation Insight by Øystein Fluge, MD, from the Department of Oncology and Medical Physics at Haukeland University Hospital, Bergen, Norway, and colleagues.

The study included 200 patients with ME/CFS, as defined by the 2003 Canadian Consensus Criteria, which requires the hallmark symptom of postexertional malaise, among others, to make the diagnosis of ME/CFS. The authors compared serum concentrations of 20 standard amino acids from the 200 patients with ME/CFS and 102 healthy control patients.

In the patients with ME/CFS, there was a specific reduction of amino acids that fuel oxidative metabolism, pointing to functional impairment of pyruvate dehydrogenase (PDH), a key enzyme for the conversion of carbohydrates to energy. Impairment of PDH could result in the cells switching to consumption of alternative fuels, causing a sudden shortage of energy in the muscles and a buildup of lactate, experienced by patients as a burning sensation in their muscles after even minor exertion.

"I think that at present our data are primarily telling us something about the ME/CFS disease. Our findings indicate an impaired function of the PDH enzyme complex, resulting in reduced flux of pyruvate to the [tricarboxylic acid (TCA)] cycle. Increased lactic acid accumulates upon limited exertion, and there is a compensatory use of alternative substrates to fuel the TCA cycle. So, the results indicate an impaired mitochondrial PDH complex function, we believe induced by the immune system," Dr Fluge told Medscape Medical News.

The model, if correct, has implications for prescribing exercise for patients with ME/CFS. "Based on the findings in the study, we can understand why patients need to stay at rest, minimizing the energy deficiency and reducing the symptoms caused by lactic acid accumulation.... The value of doing exercise should, however, not be underestimated, and the level of activity tolerated will depend on the severity of the disease," Dr Fluge said.

He added, "An ME/CFS patient's ability to handle exercise is very individual. Generally, I think the physicians should listen carefully to the patients, and find the optimal activity level through pacing, to avoid 'crashing' with the resulting major symptom increase that can last for weeks and months."

Asked to comment, Anthony L. Komaroff, MD, professor of medicine at Harvard University, Boston, Massachusetts, and editor-in-chief of the Harvard Health Letter, told Medscape Medical News, "This is the latest of many research studies that are pursuing a simple idea: That the human being who says 'I don't have enough energy' could have a problem with their cells producing enough energy.... It adds to a large literature indicating that cellular energy metabolism is abnormal in patients with ME/CFS."

However, he cautioned that the investigators inferred the abnormality in PDH, rather than directly measuring it, and that although "[t]heir argument seems plausible...I wouldn't be convinced until a second study by other investigators, studying other patients with ME/CFS, confirmed this."

Dr Komaroff also said, "What is urgently needed are some testable hypotheses that would explain the several different reported abnormalities in energy metabolism [in ME/CFS]."

Effect Seen Primarily in Women

Dr Fluge and colleagues found different results between women and men. Compared with control patients, the 162 women with ME/CFS in the sample had significantly reduced levels of six specific amino acids (isoleucine, leucine, lysine, phenylalanine, tryptophan, and tyrosine) that enter the oxidation pathway as acetyl-CoA, which fuels the TCA cycle directly and independently of PDH (P < .001 for isoleucine, leucine, phenylalanine, and tyrosine, and P = .001 and .009 for lysine and tryptophan, respectively). This finding suggests that the PDH enzyme is not functioning as it should, the authors suggest.

In contrast, the 38 men with ME/CFS had slight but insignificant reductions in serum tyrosine and phenylalanine compared with control patients, but also had significantly elevated concentrations of 3-methylhistidine, a marker of endogenous protein catabolism (P = .003 compared with healthy men). That difference was not seen in the women.

An explanation for this, Dr Fluge said, is that males use muscle tissue as a source of amino acids, whereas females, who have less muscle mass, preferentially use serum free amino acids as fuel.

Nevertheless, he added, "the PDH impairment seems to be the same in both sexes, with no gender difference in up-regulation of mRNA for the PDH inhibitors PDK1, PDK2, PDK4, and SIRT4 in peripheral blood mononuclear cells of the ME/CFS patients."

Accounting for Deconditioning

There are several reasons why the authors believe their findings are not a result of deconditioning resulting from inactivity, a factor that potentially confounds all ME/CFS studies. For one, the amino acid levels did not correspond to the number of steps the patients took in the 7 days or 24 hours before the study, as measured by activity monitors, nor to their overall illness severity.

Moreover, Dr Fluge said, the female/male differences argue against the deconditioning explanation, as their physical activity levels were similar. In addition, the specific amino acid changes found in the patients with ME/CFS "do not resemble data from other articles analyzing metabolism of inactivity."

Therefore, he told Medscape Medical News, "our conclusion is that the specific pattern observed is not primarily due to inactivity or deconditioning, but rather reflects an altered energy metabolism with alternative use of substrates to fuel the TCA cycle, due to the impaired oxidation of carbohydrates."

Dr Komaroff commented, "They did not find that the level of physical activity of their ME/CFS patients affected their results, which suggests that deconditioning was not a factor. However, it does not appear that their healthy control subjects were matched to the cases by their level of physical activity. So it seems possible that deconditioning might confound the results."

Implications for Treatment?

Most of the 200 patients in this study are participants in one of two ongoing trials, RituxME and CycloME, that Dr Fluge, his colleague Olav Mella, MD, and their team are conducting to see whether the B-cell-depleting cancer drugs rituximab and cyclophosphamide can alleviate the symptoms of ME/CFS.

They came to this by accident: Both Dr Fluge and Dr Mella are oncologists, and they happened to notice that when they gave rituximab to patients with lymphoma with ME/CFS, their patients' fatigue symptoms diminished. They subsequently conducted a small, randomized, placebo-controlled trial that appeared to confirm the observation.

Dr Fluge told Medscape Medical News, "An important scientific question, if the RituxME trial shows a positive result, is to understand the link between the disturbed immune response and the impaired energy metabolism. We presently hypothesize that in a subgroup of patients, a signaling pathway is disturbed by an autoantibody."

Dr Komaroff adds, "If we understand the biochemistry of making energy molecules, then possibly supplements that restore levels of energy molecules that are measurably low are a theoretical way this research could point to treatments."

This work has received financial support from the Kavli Trust. The clinical trials recruiting patients for the biobank and the laboratory analysis in this study received financial support from the Research Council of Norway, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid. Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for ME/CFS. Dr Fluge and Dr Mella are named as inventors. The other authors and Dr Komaroff have disclosed no relevant financial relationships.

J Clin Investig Insight. Published December 22, 2016. Abstract

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