Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency

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    Researchers studying the energy metabolism of patients with chronic fatigue syndrome have reached the conclusion that these patients have impaired pyruvate dehydrogenase function, but their measurements are not consistent with the changes we see in patients with primary genetic pyruvate dehydrogenase deficiency.

    A cross-sectional study published in December 2016 found a change in the pattern of amino acids in the plasma of patients with chronic fatigue syndrome. Gene expression in white blood cells and energy metabolism in muscle cells was also found to have changed (1). The authors interpret the results as an expression of functional inhibition of the enzyme pyruvate dehydrogenase, and they postulate dysregulation of the enzyme complex as a possible key factor in the pathogenesis associated with chronic fatigue syndrome.

    The study received extensive media coverage (2, 3), and the link to pyruvate dehydrogenase is published without reservations as an established fact (4, 5). At our laboratory we are now receiving samples for metabolic screening from patients with suspected fatigue syndrome. On the basis of my own experience with biochemical diagnostic workup for pyruvate dehydrogenase deficiency, I would like to point out weaknesses in the study that should have prompted much greater caution in the conclusions.

    Criticism of method and interpretation

    Criticism of method and interpretation

    The plasma amino acid concentrations of 200 patients and 102 healthy control persons were examined in the study. The researchers found significant differences between the two groups, but the implications of this are uncertain because they did not adhere to established diagnostic workup for pyruvate dehydrogenase deficiency, and because the samples were not taken in a standardised manner.

    The amino acid pattern is not consistent with what we see in patients with primary pyruvate dehydrogenase deficiency

    The amino acid pattern is not consistent with what we see in patients with primary pyruvate dehydrogenase deficiency

    Pyruvate dehydrogenase deficiency results in an increased concentration of pyruvate, in muscle and nerve cells, for example. Pyruvate is converted into lactate and the amino acid alanine. Alanine is the only amino acid that is expected to be outside the reference range in plasma and cerebrospinal fluid in cases of primary pyruvate dehydrogenase deficiency (one and a half times to twice the upper reference limit) (6). However, the study reports a tendency to a lower alanine level in these patients. It is surprising that this striking discrepancy is not mentioned in the article.

    Failure to standardise sampling may explain the difference between the groups

    Failure to standardise sampling may explain the difference between the groups

    A fasting sample is strongly recommended for assaying plasma amino acid concentrations, because levels vary substantially with diet, and also naturally over a 24-hour period, by up to 10–15 % (6). In the study, non-fasting amino acid patterns with small differences are compared; significance is attached to differences down to 3 %.

    It is very strange that the authors do not make greater reservations about diet as a confounding factor, when they themselves have shown that diet affects precisely the group of amino acids that they use in their argument for pyruvate dehydrogenase deficiency.

    The study found significant differences between fasting and non-fasting patients. The fasting patients were therefore excluded in subsequent statistical work. The authors should then also have made clearer reservations to the effect that a possible concealed discrepancy between patient group and control group with respect to diet and sampling might be an alternative explanation for several of the differences they found. Systematic dietary differences between the groups are not inconceivable.

    Gastrointestinal symptoms (abdominal pain, nausea, irritable bowel etc.) are some of the consensus criteria for the diagnosis (7). There have been earlier reports of special dietary habits among patients with chronic fatigue syndrome (8).

    What about the pyruvate/lactate ratio and direct measurement of pyruvate dehydrogenase activity?

    What about the pyruvate/lactate ratio and direct measurement of pyruvate dehydrogenase activity?

    The pyruvate/lactate ratio in plasma may distinguish patients with pyruvate dehydrogenase deficiency from other patients with hyperlactacidaemia. The ratio therefore plays a central part in the biochemical workup of pyruvate dehydrogenase deficiency (9).

    The pyruvate/lactate ratio was not determined in the study. This is unfortunate, because the ratio could have provided important evidence for, or against, pyruvate dehydrogenase deficiency. Direct determination of enzyme activity in cells is also a key factor in routine diagnosis of pyruvate dehydrogenase deficiency. It is strange that this was not performed in the study of muscle cells cultured in the presence of patient serum.

    Chronic fatigue syndrome is not typical of primary genetic pyruvate dehydrogenase deficiency

    Chronic fatigue syndrome is not typical of primary genetic pyruvate dehydrogenase deficiency

    The authors suggest that pyruvate dehydrogenase deficiency is a key to the pathophysiology of chronic fatigue syndrome. Chronic fatigue is not a typical symptom of patients with primary genetic pyruvate dehydrogenase deficiency, either the severe or the mild form (9). This requires a comment, but is not mentioned at all.

    Objective assessments called for

    Objective assessments called for

    Research on metabolic mechanisms associated with chronic fatigue syndrome is interesting, and the major work of Fluge et al. may generate hypotheses that are well worth investigating further. But the authors have been too quick to state almost categorically that pyruvate dehydrogenase deficiency is a part of the pathophysiology underlying chronic fatigue syndrome. At present, the link between detected amino acid changes and pyruvate dehydrogenase deficiency is too tenuous, and the change in gene expression and energy metabolism too non-specific for so categorical a conclusion.

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