Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a comprehensive review, by
Mateo Cortes Rivera, Claudio Mastronardi, Claudia T Silva-Aldana, Mauricio Arcos-Burgos and Brett A Lidbury in Diagnostics 2019, 9(3), 91; 7 August 2019[https://doi.org/10.3390/diagnostics9030091]

Review abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1.

Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease.

At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.

Excerpt from the Discussion:

The first clinicians to describe the syndrome, as reviewed earlier, immediately associated the disease with an ongoing infection. Nowadays, with a significant core of research, it is known that the disease has its pathophysiological sustenance in “three pillars” that continuously interact with each other: the immune system, the nervous system, and the neuroendocrine network. Table 1 offers a brief summary of the main features of the tissues involved in the “three pillars” hypothesis.

As can be seen in Table 3, current therapeutic strategies target several elements of the proposed neuro-immunoendocrine network, which also supports the “three pillars” hypothesis that we are discussing in this review. The immune system is involved in modulating neural plasticity, learning, and memory, although the precise link between these two seemingly distinct systems was, until recently, unclear [54]. The connection may be explained by the coevolution of the nervous and immune systems, as the two systems share mechanisms of stimulation, cell communication and signaling, gene regulation, and supracellular organization. The immune system supports the central nervous system (CNS) and aids functional recovery by facilitating the renewal, migration and cell lineage specification of neural progenitor cells [221].

The immune system is involved in the stress response, since stress activates the immune system, leading to peripheral inflammation that may ultimately contribute to the onset of a part of the symptomatology of the disease [222]. Indeed, stress has been shown to be an essential predisposing factor in the development of several neurodegenerative and psychiatric disorders [223]. The hypothalamic–pituitary–adrenal (HPA) axis and the systemic sympatho-adrenomedullary (SAM) system are essential modulators of stress response systems [224]. The HPA axis is an endocrine pathway that regulates standard stress response and merges with the immune system to maintain homeostasis [138,139].

Therefore, stress stimulates the release of glucocorticoids, particularly cortisol, which is able to cross the BBB and alter the transcription of proteins in the brain [225]. Glucocorticoids bind to the glucocorticoid receptor (GR), resulting in disassociation from the heat-shock protein, and promoting a structural change of the receptor that enables the glucocorticoid-GR complex to enter the nucleus. The glucocorticoid-GR complex binds to the glucocorticoid response element on the DNA, resulting in the activation of transcription of immune-mediator genes, among others [223,226]. Therefore, stress hormones, such as cortisol, have the ability to regulate the immune system.

However, HPA is not the only neuroendocrinological network that can interact with the immune system. The SAM is also activated by stress, leading to the release of catecholamines (e.g., epinephrine and norepinephrine) in the adrenal medulla in response to stress [134,227]. Catecholamines have been found to regulate the synthesis of immune system mediators through β-adrenergic receptor stimulation [226], suggesting an alternative pathway that links the neuroendocrine and immunological systems.
ME/CFS patients show heightened negative feedback inhibition of the HPA axis, which is associated with hypocortisolism and heightened GR sensitivity [224].

As a result, patients with ME/CFS often show heightened immune responses owing to the combined effects of chronic stress with activated microglia [130,223] and increased HPA-axis sensitivity [224]. The HPA axis has been of great importance for the understanding of the pathophysiology of the disease, since the consequences of its alteration, such as hypocortisolism, have allowed us to understand the persistence of an altered immune status, the high risk of infections and the generation of humoral autoreactivity.
Although the metabolic sphere is not part of the aetiopathological pillars of the disease, it is clear that it is a physiological aspect compromised in patients with ME/CSF.

The dysregulation of the energetic metabolism can be understood as the tip of the iceberg, which will trigger the symptomatology experienced by the patient. However, the etiology of this metabolic imbalance in ME/CSF has not yet been understood, which is most likely because it is a pathological process that is the product of complex multisystemic interactions. Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism [228,229].

The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production, leading to thoughts of some type of etiology in this organelle, but as we have seen previously, apparently the mitochondria are affected with the course of the disease [230]. As well as throughout the review, more studies are needed to understand which is the metabolic pathway that is first affected or which is the most altered in order to understand where to direct the etiological search in this complicated disease.