Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue: Fluge et al Jan 2020

[Sly Saint]

Abstract
Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy.

Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism.
Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation.

Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME.

Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227384

 

[Rain]

Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME.

I know dr Phair has some theories on Trypyophan being a contributor to the IDO metabolic trap. But what are they referring to here?

 

[Hutan]

From the Discussion:
The authors are suggesting fatigue after cancer treatment is different to CFS/ME:

The study was planned to evaluate possible changes in amino acid concentrations in survivors with CF as previously described in patients with CFS/ME [18, 19]. In CFS/ME these changes have been indicative of a defect in the tricarboxylic acid cycle, and have been postulated to play a role in the pathogenesis of this disorder. Importantly, the defects in energy metabolism could be responsible for post exertional malaise, a key clinical finding associated with fatigue in CFS/ME. No similar differences in amino acid concentrations were found when we compared lymphoma survivors after HDT-ASCT that suffer from CF to survivors without CF.

The absence of similar changes of serum amino acid levels in the present study indicates different pathomechanisms in lymphoma survivors with CF and patients with CFS/ME, explaining also the clinical differences between the two conditions, i.e. female preponderance and presence of post exertional malaise, a marked aggravation of symptoms after exercise, in CFS/ME [4]

Re the Trp levels:

Interestingly, the difference in Trp levels observed in lymphoma survivors with or without CF (mean values 73.4 μM and 77.6 μM, respectively), were also seen when comparing patients with CFS/ME (mean concentration 73.4 μM) to healthy age matched individuals (77.8 μM) [19]. For the other amino acids tested, the lymphoma survivors resemble more closely the healthy control subjects of the latter study, irrespective of a diagnosis of CF or not [19].

So lymphoma survivors with fatigue and people with CFS/ME had similar levels of Trp (averages 73.4 and 73.4). And lymphoma survivors without fatigue and healthy controls from the CFS/ME study both had higher levels (77.6 and 77.8).

But here's the graph of Trp levels from this study of cancer survivors (Trp is the graph on the left):


Look at the huge amount of overlap (and note the truncated scale). If there's really a difference in average Trp levels between cancer survivors with and without fatigue, it's certainly not a consistent difference at the patient level.