Reprinted with the kind permission of Cort Johnson and Health Rising.
This technology is currently being developed for routine clinical use in many areas of medicine. (Hackshaw et al, 2013)
A Biomarker for Fibromyalgia
Has a cheap and readily available biomarker for fibromyalgia been found? Ohio State University researchers assert they’ve done just that using a process called infrared micro-spectroscopy that analyses ‘spectra’ to determine the chemical composition of the tissue or the blood. [See “A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders."]
In this small study blood samples from fibromyalgia, rheumatoid and osteoarthritis patients were analyzed for their chemical composition.
A principal components analysis suggested increased levels of pyridine carboxylic acids differentiated the FM patients from the osteoarthritis and rheumatoid arthritis patients. The molecules associated with this spectra were none other than tryptophan, kynurenine (KNN) and pyridine carboxylate – three compounds some studies suggest may play a role in fibromyalgia and related disorders.
The ability of the infrared analysis to accurately differentiate 100% of the FM from the RA and OA patients suggested these researchers were onto something.
“It separated them completely, with no misclassifications. That’s very important. It never mistook a patient with fibromyalgia for a patient with arthritis. Clearly we need more numbers, but this showed the technique is quite effective,” said Buffington.
A separate non-targeted (i.e., open-ended) test of blood metabolic profiles differentiated FM patients with 75% accuracy. Again the some tryptophan metabolites (kynurenine) showed up as well as heme and compounds associated with increased oxidative stress and energy metabolism.
The Kynurenine Tryptophan Connection
The appearance of kynurenine suggested that rapid tryptophan breakdown is occurring in FM. Since tryptophan is the precursor to serotonin and melatonin, low tryptophan levels could translate into low serotonin and melatonin levels. (The two drugs the CFIDS Association of America’s Biovista drug repurposing project identified reportedly were associated with serotonin.)
Low serotonin levels are associated with symptoms like chronic fatigue, poor sleep, hot flushes, muscle cramps, headaches, stomach issues, reduced interest in sex, poor self-confidence, rushing thoughts, irritability, etc. Low serotonin levels are usually treated with SSRI’s or SNRI’s. (A recent review of SNRI efficacy (duloxetine, milnacipran) in fibromyalgia, however, concluded they were not particularly effective.)
Some people with chronic fatigue syndrome/fibromyalgia do, however, benefit from 5-hydroxytryptophan (5-HTP). (If the theory below is correct, however, why that should be is something of a mystery.)
Does Inflammation Drive the Pain Problems in Fibromyalgia?
The potential issues go far beyond low tryptophan level. A byproduct of tryptophan metabolism (e.g. breakdown), kynurenine (KNN) can be converted to either a neurotoxic compound (quinolinic acid) or a neuroprotective one. Researchers believe disturbances in the KNN pathway in the brain may play a role in depression, post-viral depression (i.e., virus-induced depression), multiple sclerosis, ME/CFS, fibromyalgia and cancer.
Inflammation appears to play a key role in the proposed KNN dyregulation. It turns out that a bevy of inflammatory products [interferon (IFN-γ), interleukin-6, tumor necrosis factor-α, oxidative stress and lipopolysaccharides] upregulate the activity of a tryptophan-shattering enzyme called indoleamine-2,3-dioxygenase (IDO) enzyme. Most of these immune factors have been associated with ME/CFS and/or fibromyalgia at some point.
When IDO is turned on it breaks down tryptophan quickly to form toxic metabolites (called tryptophan catabolites or TRYCAT’s) such as kynurenine, kynurenic acid, and quinolinic acid. Maes believes TRYCAT production triggers depression and anxiety, increases oxidative stress, whacks the mitochondria, and to top it off, fosters neuroexciticity and neurotoxicity and potentially neurodegeneration.
Given that witches brew of bad effects it’s not surprising to find Maes in a series of mostly review papers attempting to link TRYCAT’s to a variety of diseases including depression, Parkinson’s, schizophrenia, somatization and yes, chronic fatigue syndrome. In Fibromyalgia: the Cause and Cure, Annesse Brockley adds decreased GABA, high glutamate, bi-polar disorder, IBS, interstitial cystitis, fibromyalgia, and interestingly enough, inflammation of the fascia to the list. Increased tryptophan breakdown is present in people with chronic Epstein-Barr Virus infection, as well.
High kynurenine levels have also been associated with depression and fatigue associated with interferon treatment, cognitive problems in schizophrenia, neurological problems in Alzheimer’s and, interestingly, cognitive issues and depression in cardiovascular disease.
The Interferon-Kynurenine Connection
The interferon (IFN) connection is an interesting one given IFN’s ability to produce severe fatigue, depression and other aspects of ‘sickness behavior’ in some patients being treated for hepatitis C. The recognition that an immune factor could have such devastating results helped open up investigations into the immune source of fatigue and other symptoms. The high kynurenine levels in IFN-treated hepatitis patients suggest it could play a role in immune mediated fatigue in fibromyalgia and chronic fatigue syndrome.
In fact, a recent study examining the biopsychosocial aspects of interferon treatment suggested tryptophan depletion and increased kynurenine levels were associated with increased levels of depression during IFN treatment. Other factors that increased the risk of becoming depressed included being female, history of mood disorder, high levels of pain, reduced social activity, low health and vitality and ‘emotional role’ (?).
If kynurenine does play a role in FM/ME/CFS the entire process could start with inflammation triggering IDO to break down tryptophan, releasing KNN and quinolinic acid and other factors which then produce havoc.
The Histidine/Histamine Connection
Produced though the degradation of the amino acid histidine (think histamine), increased trans-urocanate levels best differentiated FM from rheumatoid arthritis. High histidine levels could translate to high levels of its by-product histamine and conceivably mast cell problems. Theoharides believes stress induced mast cell release contributes to both sensory amplification (increased pain) and blood vessel dilation and corresponding problems with orthostatic intolerance in ME/CFS/FM.
Another ME/CFS researcher, Biaggioni, believes mast cells are “strategically positioned to modulate sympathetic nervous system (SNS) activity” – an intriguing idea given the SNS activation in ME/CFS/FM. Biaggioni described how mast cell activation (MCA) caused orthostatic intolerance, particularly in ME/CFS patients who experienced ‘flushing’ in a small 2005 study.
Interestingly, neuropeptide Y, a proposed biomarker for ME/CFS, triggers mast cells to degranulate and reduce blood pressure. If you have POTS and are wondering if you might have mast cell activation disorder (MCAD), Biaggioni found POTS patients with MCAD typically experience periods of flushing, shortness of breath, dizziness, headaches, nausea, vomiting and diarrhea.
Check out more on mast cells, fibromyalgia and ME/CFS in an earlier blog I wrote on Phoenix Rising) – "Fibromyalgia Trial Shows Promise…For Chronic Fatigue Syndrome? Mast Cells and Ketiotifen in FM and ME/CFS"
Theoharides, the ‘Mast Cell Master” believes mast cells disorders are behind autism, ME/CFS and other disorders. He proposes that quercetin and luteolin are effective mast cell blockers.
Given Sjogren’s syndrome's recent entrance into the ME/CFS picture, it’s interesting that people with Sjogren’s Syndrome appear to have a limited ability to control their histamine levels.
“We’ve got really good evidence of a test that could be an important aid in the diagnosis of fibromyalgia patients. We would like this to lead to an objective test for primary care doctors to use, which could produce a diagnosis as much as five years before it usually occurs.” said Buffington.
A diagnostic test for fibromyalgia would further legitimize the disease and highlight fundamental biological factors. While more work is needed, this small study's ability to highlight areas of interest in FM and ME/CFS, and it’s 100% accuracy suggests these researchers may be onto something. It also suggests that immune activation and inflammation are major drivers in FM.
This kind of test requires a few drops of dried blood, is inexpensive and requires little interpretation from a physician. On the other hand, infrared spectroscopy is not often used as a diagnostic tool in the medical field. Hopefully, if their work is validated, these researchers will turn to chronic fatigue syndrome next.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising