Hoopoe
Senior Member (Voting Rights)
Google translation of the response by Karl Johan Tronstad, Øystein Fluge, Olav Mella
We thank you for your input. At the same time, we wonder why this type of debate is addressed in the journal and not in the journal that published the study.
Bliksrud gives an incorrect representation of the findings with partially uncritical use of sources, and an insufficient picture of a complex research field.
We have promoted the hypothesis that impaired pyruvate dehydrogenase function can be linked to chronic fatigue syndrome without having been stuck "without reservation". It is a scientifically based hypothesis that will be thoroughly tested through further research. We have emphasized that patients with chronic fatigue syndrome do not have a structural defect in, or lack of, the pyruvate dehydrogenase enzyme itself. We claim that the enzyme function may be misregulated. We have repeatedly stressed that these findings currently do not legitimize new methods of treatment or diagnostics. How the results are reproduced in the media is of course difficult to control.
We strive to be clear and conceptual when reviewing the results of the study to avoid misunderstandings. Concepts like "pyruvate dehydrogenase deficiency" give a wrong picture, and it is unfortunate that Bliksrud chooses to use this in his comment, also in the title. There is no indication that the enzyme is missing. On the other hand, we have explained why we believe the results may match a partially inhibited enzyme function as a result of changes in the underlying regulatory mechanisms.
Pyruvate dehydrogenase is a very central enzyme in the energy metabolism, and is carefully regulated both allosterically, posttranslationally and by gene transcripts, including via energy sensitive signal pathways (1, 2). When Bliksrud is on its way, the enzyme isolates its role in disease mechanisms to what it sees in genetic primary pyruvate dehyrogen deficiency, the comparative basis becomes too narrow. It is not obvious that one should be able to compare such a systemic and permanent condition with a more varying, perhaps local, situational inhibition of enzyme function. There are a variety of conditions in which pyruvate dehydrogenase is associated with other potentially disease-causing mechanisms. An example is primary biliary cirrhosis, where patients have autoantibodies to components of the pyruvate dehydrogenase complex, and fatigue is a characteristic symptom (3). It is also relevant to look at conditions involving glucose metabolism and regulation of pyruvate dehydrogenase, such as diabetes and cancer (2), as well as normal adaptation to varying metabolic and physiological conditions (4). We have in the article outlined how we believe this type of mechanism can play a role in chronic fatigue syndrome.
No systematic studies have been published that show plasma lactation in resting on chronic fatigue syndrome, but many patients describe the sense of rapid lactic acid accumulation (lactate) in activity. Lactate accumulation appears to occur at significantly lower muscle load than normal. Alanin will normally increase in plasma by muscle work, in parallel with lactate (1), but this is believed to be significantly more permanent in genetic primary pyruvate dehydrogenase deficiency than in chronic fatigue syndrome where the effects are situation-related and activity-triggered. Since alanine plays a very important role in transporting amino groups from amino acid degradation in muscle to liver, levels are expected to vary more independently of changes in glucose degradation. Therefore, in order to limit possible misinterpretation, we chose to keep alanine out of the statistical analyzes of the amino acid residues. Studies of both lactate and alanine in chronic fatigue syndrome will be best done according to standardized physical load protocols. We would also point out that consumption of citric acid cycle substrates is used for mapping of myocondrial pyruvic oxidation errors (5).
A direct measurement of pyruvate dehydrogenase activity is of course relevant but not uncomplicated to perform. A method developed for the measurement of genetic primary pyruvate dehydrogenase deficiency will not necessarily capture a reversible and situational enzyme inhibition, for example. due to variable phosphorylation status. Therefore, as shown in the article, we also work with live cell cultures that add serum from either patients with chronic fatigue syndrome or healthy, with analysis of key parameters for energy metabolism.
Although single patients say they avoid certain food types, there are no systematic studies showing that patients with chronic fatigue syndrome, with body mass index as the population in general, have a significantly changed diet compared to healthy ones. Bliksrud surprisingly refers to a casualty series of four patients who had known eating disorders and also developed chronic fatigue syndrome. This article is of course not relevant documentation for the diet of the patient group, neither in general nor in our study. Nevertheless, as long as we do not have accurate dietary records available, we can not categorically exclude impact from the diet. As there are no known systematic differences in diet at the group level, the included number of patients (153) and healthy (102) will counteract significant bias in the assays. We observed that fasting overnight led to reduced levels of several amino acids, and therefore not compared fasting groups (see additional tables for the article). The relevant amino acid changes were primarily detected in non-fasting women with chronic fatigue syndrome, with differences in moderate effect size, and with a mean average mean of approximately 15%, but with values significantly in the normal range. There are thus no shortcomings, but more likely a reflection of compensation mechanisms for a somewhat altered metabolism. In the same samples, there was no difference in level of triglycerides, which increase after meal, or free fatty acids that increase by fasting (1). It is therefore unlikely that differences in fixed status explain the changes. Our findings are consistent with other minor reports, including where only fasting patients were included (see references in the article). Our study included a larger patient group than previous metabolic studies. The changes in amino acid profiles could not be explained either by disease severity, duration of illness, age, BMI or physical activity level (see supplementary tables in the article). Bliksrud mentions without further specification that immobilization provides extensive metabolic changes and refers to a study of one-legged fixation and subsequent mRNA assays in muscle biopsies. There are more relevant and comparable studies of serum metabolites by immobilization, where the findings do not coincide with what we found in patients with chronic fatigue syndrome (6, 7). We have not found reports showing an amino acid pattern similar to that found in patients with chronic fatigue in healthy subjects, for example, exercise, inactivity or dietary changes, or in other patient groups. This does not mean that the changes we see only apply to patients with chronic fatigue syndrome. We have not claimed that the changes are specific to chronic fatigue syndrome and we totally agree with Bliksrud that it will be interesting to investigate if something similar may apply in other patient groups with pronounced exhaustion. We hope that we have been disseminated more sophisticated picture than Bliksrud manufactures, confirming that the hypothesis stands by law.
