Chronic fatigue syndrome seems to be caused by changes in the body’s metabolism plainpicture/Caiaimages/Paul Bradbury

It’s as if a switch has been flicked. Evidence is mounting that chronic fatigue syndrome (CFS) is caused by the body swapping to less efficient ways of generating energy.

Also known as ME or myalgic encephalomyelitis, CFS affects some 250,000 people in the UK. The main symptom is persistent physical and mental exhaustion that doesn’t improve with sleep or rest. It often begins after a mild infection, but its causes are unknown. Some have argued that CFS is a psychological condition, and that it is best treated through strategies like cognitive behavioural therapy.

But several lines of investigation are now suggesting that the profound and painful lack of energy seen in the condition could in many cases be due to people losing their ability to burn carbohydrate sugars in the normal way to generate cellular energy.


Instead, the cells of people with CFS stop making as much energy from sugar as usual, and start relying more on lower-yielding fuels, such as amino acids and fats. This kind of metabolic switch produces lactate, which can cause pain when it accumulates in muscles.

Together, this would explain both the shortness of energy, and why even mild exercise can be exhausting and painful.

Sex differences

Øystein Fluge of Haukeland University Hospital in Bergen, Norway, and his colleagues studied amino acids in 200 people with CFS, and 102 people without it. The levels of some amino acids in the blood of women with CFS was abnormally low – specifically for the types of amino acid that can be used by the body as an alternative fuel source.

These shortfalls were not seen in men with CFS, but that could be because men tend to extract amino acids for energy from their muscles, instead of their blood. And the team saw higher levels of an amino acid that’s a sign of such a process.

“It seems that both male and female CFS patients may have the same obstruction in carbohydrate metabolism to energy, but they may try to compensate differently,” says Fluge.

Both sexes had high levels of several enzymes known to suppress pyruvate dehydrogenase (PDH), an enzyme vital for moving carbohydrates and sugars into a cell’s mitochondria – a key step for fully exploiting sugar for energy.

Fluge thinks PDH is prevented from working in people with CFS, but that it can spontaneously recover.

Starvation effect

Several studies have now hinted that defects in sugar burning can cause CFS, but there is still uncertainty over how exactly this is disrupted. However, a picture is emerging. Something makes the body switch from burning sugar to a far less efficient way of making energy.

“We don’t think it’s just PDH,” says Chris Armstrong at the University of Melbourne in Australia, whose research has also uncovered anomalies in amino acid levels in patients. “Broadly, we think it’s an issue with sugar metabolism in general.”

The result is not unlike starvation, says Armstrong. “When people are facing starvation, the body uses amino acids and fatty acids to fuel energy for most cells in the body, to keep glucose levels vital for the brain and muscles as high as possible.”

“We think that no single enzyme in metabolism will be the answer to CFS, just as no single enzyme is the ‘cause’ of something like hibernation,” says Robert Naviaux of the University of California at San Diego, who has found depletion of fatty acids in patients suggesting they were diverted as fuel.

Not psychosomatic

So what could flick the switch to a different method of metabolism? Fluge’s team thinks that a person’s own immune system may stop PDH from working, possibly triggered by a mild infection.

His team has previously shown that wiping out a type of white blood cell called B-cells in CFS patients seems to relieve the condition. These white blood cells make antibodies, and Fluge suspects that some antibodies made to combat infections may also recognise something in PDH and disable it.

The team is now conducting a large trial in Norway of the cancer drug rituximab, which destroys the cells that make antibodies, in people with CFS. Results are expected next year.

Together, these metabolic approaches are suggesting that CFS has a chemical cause. “It’s definitely a physiological effect that we’re observing, and not psychosomatic, and I’ll put my head on the block on that,” says Armstrong. However, he adds that psychological and brain chemistry factors might be involved in some cases.

Journal reference: Journal of Clinical Investigation, DOI: 10.1172/jci.insight.89376