Review A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 2023, Taccori et al

[Andy]

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls.

Methods
Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17.

Results
Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult.

Conclusions
There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.

Open access, https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04295-0

 

[Hutan]

Looks like a solid study from what I have read so far. From NCNED

21 studies on urine in ME/CFS were found.
14 properly matched ME/CFS participants with controls.
16 noted the ME/CFS criteria used.
11 are reported as using appropriate statistical analysis


8 studies investigated cortisol, with 4 finding reduced levels, 3 finding no significant difference and 1 reportedly not being clear what they found. The high number of studies on urinary cortisol relative to anything else reflects the fixation on HPA axis and stress responses as being the key to ME/CFS. I've commented elsewhere about the reasons we might expect to find slighter lower but still normal levels of cortisol in people with ME/CFS (delayed morning waking peak; reduced physical activity). So, there's nothing to see there. But still, people keep measuring cortisol, in blood, in saliva, in hair and in urine, expecting to find something game-changing.
Researchers have looked at cortisol metabolites too:

Urinary cortisol metabolites were measured in three studies [20,21,22]. There were no significant differences found in urinary cortisol metabolite levels between ME/CFS patients and HC in any of the studies [19,20,21].

It sounds as though little attention has been paid to the presence or absence of PEM. The only comment about PEM in this paper was:

McGregor et al. investigated metabolite levels in urine in ME/CFS patients who experienced or did not experience PEM seven days prior to urine collection [27]. A significant association with PEM was a lower serum level of the purine metabolite, hypoxanthine. Therefore, parameters measured may also be influenced by illness presentation and progression [27].

I'm not sure if there is a typo in there, but nothing is reported about investigations of levels in urine during PEM. We really need to get samples taken when people are in florid PEM. The finding of the hypoxanthine is interesting given it is an ATP degradation product, with higher levels being observed in hypoxic clinical conditions, but it's hard to make a hypothesis when we don't know how the levels are changing with symptoms. 'Whether PEM was experienced in the seven days prior to urine collection' surely is nowhere near specific enough.

There's more of note in this study.

 

[Hutan]

The most frequent case criteria used to define ME/CFS patients across the studies included in this systematic review was the FC [12, 16, 19,20,21,22,23,24,25, 28,29,30,31,32]. The FC is limited due to its broad and non-specific criteria and overlap with other clinical conditions [4, 5]. There is also significant heterogeneity shown between patients diagnosed using this definition that may reflect in the study findings making comparisons difficult [3]. Therefore, considerations for future experiments should involve use of more stringent case criteria used to select patients for recruitment, in particular the CCC and ICC case definition [4, 5].

Nice to see this highlighting of the issues with Fukuda.

 

[Creekside]

We really need to get samples taken when people are in florid PEM.

Before, during and after. PEM is easy enough to plan in advance, so you can get a reliable baseline, then observe while it rises, then falls (hopefully back to the baseline). That might be more useful than comparing with "healthy controls".

 

[Hutan]

PEM is easy enough to plan in advance,

Somewhat easy, but can't be timetabled. It can be hard to know when florid PEM will strike and how long it will last for. I think you'd either have to have people come into a residential clinic for a few days to do triggering activities and then wait for the full-on PEM, or have systems for collection of samples at home. I believe Chris Armstrong is doing good day, bad day testing. I don't think we've heard much from him for a while.

 

[dreampop]

Unless I am mistaken they don't include the recent Hanson study in this review. That was a pre/post CPET study that found me/cfs patients changes were unexpectedly lower suggesting a blunted response to stressors . It may just have been too recent. They don't mention hypoxanthine outside of a discussion of female controls (it wasn't raised in any case).

https://www.mdpi.com/1422-0067/24/4/3685

It certainly seems worth of repeating a similar study. I do wonder if patients (perhaps NIH study did this) are only really providing results mid-day/morning and if night time, later afternoon and further CPET studies would be a of value.

 

[Creekside]

It can be hard to know when florid PEM will strike and how long it will last for.

I'm pretty sure my journal never used the term "florid PEM". My PEM was pretty consistent for known triggers, and I don't think it ever lasted more than a day, so in my experience, PEM was easy to plan in advance. I certainly couldn't plan for a major crash, since I never had one. Surely there are more people with consistent PEM triggers and responses.