Produced by the Royal College of Physicians of Edinburgh and Royal College of Physicians and Surgeons of Glasgow

Chronic fatigue syndrome: altered physiology and genetic influences

  • Dr F Nye, Consultant Physician, Chronic Fatigue Syndrome Service, Royal Liverpool University Hospital
  • Dr E Crawley, Consultant Paediatrician, Royal National Hospital for Rheumatic Diseases, Bath

Summary

There has been much debate regarding the cause of CFS/ME. Is CFS/ME caused by poorly understood physical processes or by behavioural responses to everyday life? In this article Dr Fred Nye and Dr Esther Crawley examine some new research which suggests genetic factors may play a significant role in CFS/ME.

Key Points

Declaration of interests: Esther Crawley is Medical Adviser to Action for Young people with ME (AYME).

Key Points

  • The aetiology (cause) of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is controversial. There is a polarity between a search for organic causes and an attempt to provide behavioural explanations for symptom production.

  • There is good evidence of altered physiology in CFS/ME, particularly affecting neuroendocrine and hypothalamic-pituitary-adrenal (HPA) axis function.

  • Classic twin studies have demonstrated a strong heritable component to CFS/ME and other conditions of abnormal fatigue.

  • New genetic information describes associations between patients with fatigue and CFS/ME and genes involved in neuroendocrine and sympathetic nervous system function.

  • One model that may explain this is provided by evidence that vagal nerve activity may modulate the release of fatigue-inducing cytokines.

  • Environmental factors, abnormal physiological pathways and genetic pre-disposition are all likely to contribute to symptom production and response to illness in CFS/ME.

  • An understanding of CFS/ME is best served by taking all the likely aetiological factors into account. The new genetic information helps us to move away from the conflict between medical models of CFS/ME and a bio-psychosocial view of the illness.

Controversies over the ‘cause’ of CFS/ME

Debate about the cause of chronic fatigue syndrome (CFS) has for too long generated more heat than light. Are the symptoms of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME ) largely determined by poorly understood physical processes, or by behavioural and psycho-social responses to life events? There is thus a duality between a conventional medical model of CFS/ME and a bio-psychosocial approach to the disorder. This duality is often reflected in CFS/ME research activity which has taken two main directions, one focusing on patho-physiological abnormalities and the other on psychological and behavioural determinants and interventions. It is sometimes difficult to discern any commonality between these two approaches; however new genetic research starts to cross these artificial boundaries.

Evidence of altered physiology

There is good evidence of altered physiology in patients with CFS/ME compared with healthy controls. Abnormalities include derangement of circadian rhythms: in particular a dissociation between melatonin secretion and hypothalamic control of body temperature.1 Shift workers, who also have disturbed body rhythms, often complain of increased subjective effort for a given workload, mirroring one of the cardinal symptoms of CFS/ME. The hypothalamic-pituitary-adrenal axis (HPA) has been much studied in CFS/ME.2 Evidence points to increased negative feedback and glucocorticoid receptor function, and to diminished adrenocorticotropic hormone (ACTH) and cortisol responses to a number of challenges. In contrast, serotonin status is enhanced. CFS/ME patients have significantly raised serum levels of tryptophan, both in total and relative to its competitors.3 Availability to the brain of this rate-limiting precursor of serotonin is thus augmented. Despite the relevance of these physiological changes it is not always clear to what extent they are cause or effect. For example, abnormalities in skeletal muscle and cardiovascular function probably represent the consequences of inactivity and prolonged physical deconditioning4.

The genetics of CFS: getting us away from the mind-body split

Several adult twin studies have shown consistently higher concordance rates in monozygotic (MZ) twins compared to dizygotic (DZ) twins for CFS/ME (MZ = 0.55, DZ = 0.19) with heritability increasing with increasingly stringent case definition.5 This is consistent with studies of fatigue in children in the UK where carers of 670 twin pairs were questioned about disabling fatigue of more than a week and more than a month. In both cases the concordance was higher in monozygotic twins compared to dizygotic twins (0.81 vs 0.59 for one week, 0.75 vs 0.47 for one month).6 These studies suggest that part of the heritability in fatigue and CFS/ME, such as that described by Dr Bell 15 years ago,7 is due to genetic susceptibility.

Given the heritability demonstrated, the quest has been to find out which genes are involved. Four relatively small studies have described altered gene expression in patients with CFS/ME compared to controls, but the associations identified have not been replicated in any study. The application of gene expression methods to patients with CFS/ME is problematic given that sedentary activity itself, let alone differences in medication or diet, may well contribute to the associations described.

More recently, further genetic information has emerged from an elaborate investigation involving 227 residents of Wichita, Kansas, US, carried out by the Centers for Disease Control and Prevention (CDC). During a two-day hospital stay, data was collected on the participants’ psychiatric status, sleep characteristics and cognitive function. Biological samples were collected to measure neuroendocrine status, autonomic nervous system function, systemic cytokines and peripheral blood gene expression. Twenty investigators from the disciplines of medicine, mathematics, biology, engineering and computer science were then given the task of analysing and interpreting the data over six months. The results give a clearer understanding of CFS/ME, but perhaps more importantly describe a novel way of analysing large datasets in a complex illness.

In the first part of the study, the CDC used principle components methodology and latent class analysis to divide a group of women with fatigue, chronic fatigue syndrome and controls into separate groups which could be explained by their symptoms, clinical and laboratory findings.8, 9

When they then looked at gene expression profiles to search for discriminatory genes, they found that 32 and 26 genes were capable of discriminating between the five and six class solutions. The use of fatigued controls avoids some of the problems with gene expression studies mentioned above.10

The group then tested whether single nucleotide polymorphisms (SNPs) could distinguish genetically the groups described above. They found that three of the classes described on clinical and laboratory grounds were associated with genes involved in the HPA axis function or mood-related neurotransmitter systems. This is of particular interest, as it examines the more global question of fatigue as well as the specific question of chronic fatigue syndrome (CFS/ME).11

The group then looked at 43 CFS/ME patients compared with 58 controls. They used the SNP profiles to see whether they could predict whether a patient had CFS/ME or not.12 When one combination of five SNPs was tested against clinical criteria for diagnosis it yielded 49 true negatives, 15 false negatives, 28 true positives and nine false positives (OR 8.94, p<0.00001). The most important genes involved coded for neuronal tryptophan hydroxylase (TPH2), catechol-o-methlyltransferase, and a glucocorticoid receptor, NR3C1. (TPH2 is the rate-limiting enzyme in the synthesis of serotonin, itself a precursor of melatonin). Genes for corticotropin releasing hormone receptors were also implicated.

The genes identified in these and other similar studies are, broadly speaking, concerned with neuroendocrine and sympathetic nervous system function. The parasympathetic system may also be involved. The vagus nerve has been shown to attenuate systemic inflammation by reducing tumour necrosis factor (TNF) synthesis in macrophages via the release of acetylcholine. Acetylcholine significantly inhibits the release of TNF and other pro-inflammatory cytokines such as IL-1β, IL-6 and IL-18 but not IL-10 which is an anti-inflammatory cytokine.13 Many of the symptoms experienced in CFS/ME could theoretically be caused by increased production of IL-6 and TNFα including the fatigue itself. Fatigue scores are correlated with basal lipopolysaccharide (LPS) stimulated TNFα and IL-6 production in patients with CFS/ME.14

Some implications for treatment and recovery

In addition to providing some of the clues in the pathogenesis of CFS/ME; increased vagus nerve activity may explain some of the effects of treatment. Individuals with chronic inflammatory conditions who use biofeedback to relax have been shown to have higher vagus nerve activity and correspondingly lower levels of pro-inflammatory cytokine production.13 Meditation has been shown to provoke the same response. Most behavioural programmes in CFS/ME use the concept of deep rest or regular periods of rest and deep breathing to ameliorate symptoms. It may be that the effectiveness of these interventions is a result of increased vagus nerve activity and subsequent inhibition of pro-inflammatory cytokine production.

Until now the only treatments that have been consistently effective in randomised controlled trials have been graded exercise therapy (GET) and cognitive behaviour therapy (CBT). Both techniques encourage an appropriate balance between rest and exercise, sleep management, and a slow progressive increase in activity. Despite their efficacy in clinical trials these treatments are unpopular with CFS/ME patient support groups, partly because the methods used in therapy are seen to imply a behavioural cause for the illness. In reality, the rationale behind these techniques is largely empirical, and the reasons for their effectiveness are still poorly understood. Physical deconditioning alone cannot account for all the features of CFS so these treatments probably do more than merely reverse its effect. One hypothesis is that both GET and CBT, by slowly normalising daily routine, re-set abnormal physiological pathways and thus reduce symptoms.

Chronic Fatigue Syndrome/ME is a complex debilitating illness which is likely to involve multiple genetic associations, several environmental factors, changes to normal homeostasis, and many different biological pathways. We will not have an accurate understanding of CFS/ME unless we take into account the influence of all these aetiological determinants. A broad view of causation may also do something to resolve some of the unproductive conflicts that have in the past bedevilled almost every aspect of this complex and puzzling illness.

References

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