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.

biomarker image

Has a biomarker for fibromyalgia finally been found?

A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders. Hackshaw KV, Rodriguez-Saona L, Plans M, Bell LN, Buffington CA Analyst. 2013 Aug 21;138(16):4453-62. doi: 10.1039/c3an36615d. Epub 2013 Apr 17.

In this small study blood samples from fibromyalgia, rheumatoid and osteoarthritis patients were analysed 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 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 study was small but the researchers were able to correctly identify 100 percent of the fibromyalgia paitents

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 missclassifications. 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.

Compounds That May Spell Trouble in Fibromyalgia

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.)


The increased kynurenine levels in the blood of FM patients suggested rapid tryptophan breakdown might be releasing toxic byproducts in that disorder

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 SSNRI’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), hynurenine (KNN )can be converted to either a neurotoxic compound (quinolinic acid) or a neuroprotective one.


Dr. Maes believes kynurenine and other tryptophan byproducts may be causing depression and anxiety, increased oxidative stress, damaged mitochondria, neuroexciticity and potentially neurodegeneration.

Researchers believe disturbances in the KNN pathway in the brain may play a role 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 affects 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.

interferon in lab

IFN growing in a lab. IFN”s ability to cause fatigue and other flu-like symptoms in hepatitis patients highlighted the role the immune system can play in producing these symptoms

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.

histamine molecule

Theoharides believes histamine released by mast cell degranulation may be causing pain, sensory issues and orthostatic intolerance in ME/CFS

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.

Given  Sjogren’s syndrome 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.” Buffington

A diagnostic test for fibromyalgia would further legitimize the disease and highlight fundamental biological factors. While more work is needed, this small studies 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 as 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.

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