Rhyothemis Princeps* 1
1 Independent Patient-Researcher
Email: citrine.dreams@gmail.com
Cite as: Princeps, R. (2024). Hypothesis: Carbonic anhydrase activity is increased in myalgic encephalomyelitis/chronic fatigue syndrome. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 2, 17-22
Abstract
Recent research has shown reduced levels of carbon dioxide in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. This may be explained by an increase in the activity of carbonic anhydrase, which is one of the enzymes responsible for the conversion and transport of carbon dioxide and for pH regulation. An increase in carbonic anhydrase activity could alter the redox metabolism, increase mast cell- mediated inflammation, and produce neurological symptoms by triggering vasoconstriction in the brain. If proven right, testing for increased carbonic anhydrase activity may be used as a diagnostic and/or surrogate outcome biomarker, while carbonic anhydrase inhibitors may be of benefit in the treatment of ME/CFS and Long COVID.
Hypothesis
There are many anecdotal reports on social media of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) presenting with hypocapnia/low blood carbon dioxide (CO2). It is assumed that in the absence of cardiac or pulmonary pathology, hypocapnia is due to hyperventilation.1 Recently, Natelson et al. utilized capnography to measure end tidal CO2 in 32 ME/CFS patients and found the majority to be hypocapnic.2 Tachypnea (rapid breathing) was not present and the authors concluded that hypercapnia was the result of hyperpnea (deep breathing), but the volume of breath was not measured.
It seems possible there could be other explanations for hypocapnia could be possible, such as impaired cellular respiration leading to lowered CO2 production, as in the itaconate shunt hypothesis of ME/CFS proposed by Phair,3 or increased carbonic anhydrase activity.
Carbonic anhydrase (CA) is a metalloenzyme that catalyzes the interconversion of CO2 and bicarbonate; the direction of the reaction depends on pH.4 Humans possess 15 isoforms of CA found in a variety of tissues.5,6 CA II, present in erythrocytes and responsible for CO2 transport, is notable for having an extraordinarily high turnover number.7 CA II associates with the CO2 metabolon, which facilitates rapid gas exchange across the red blood cell membrane.8 If CA II activity is increased, then hypocapnia may be present, as CO2 may be more readily taken up by erythrocytes, where it is held as bicarbonate, carbaminohemoglobin, and other carbamino compounds.9,10
In addition to its roles in CO2 transport and pH regulation,9,10 CA is involved in diverse processes including bone resorption,11 hepatic gluconeogenesis,7,12 mast cell- mediated inflammation,13 olfaction and gustation,14 and diet preferences.15,16
CA impacts neurological function directly by altering the pH of the brain.17 Another mechanism by which CA produces neurological symptoms is through a reduction in cerebral perfusion, as hypocapnia decreases the cerebral blood flow by decreasing the diameter of cerebral arterioles.18 Acetazolamide, a non-specific carbonic anhydrase inhibitor, has been used in the treatment of intracranial hypertension in Ehlers-Danlos Syndrome;19 hypermobility and intracranial hypertension are common in ME/CFS.20 Lubell has proposed that high- dose thiamine may act as a CA inhibitor and suggested clinical trials for its efficacy in treating symptoms of ME/CFS, which include profound fatigue and reduced mental acuity or ‘brain fog’.21
Increased CA activity may have links to other signs, symptoms, and comorbidities of ME/CFS besides hypocapnia. Increased CA activity can cause bone resorption which is inhibited by acetazolamide;10 ME/CFS patients are at increased risk of fracture, but it is unclear if this is due to osteoporosis.22 CA inhibition was found to limit mast cell- mediated inflammation;12 individuals diagnosed with moderate and severe ME/CFS have increased levels of circulating naive mast cells, as well as aberrant expression of mast cell surface markers in severe cases.23 Low dose acetazolamide has been used to treat premenstrual dysphoric disorder;24 premenstrual mood lability and premenstrual syndrome are common in ME/CFS.25,26
ME/CFS is characterized by increased markers of oxidative and nitrosative stress.27 CO2 is not merely a by-product of metabolism, but an important signaling molecule and modulator of redox reactions.28 It is conceivable that increased CA activity could alter redox metabolism and signaling, leading to redox imbalance and increased oxidative stress.
While unfortunately it is not possible to test activities of all CA isoforms in all tissues, it is feasible to test CA activity in the blood and saliva of ME/CFS patients against that of healthy controls. If a difference is found, it could explain symptoms and signs as discussed above, and perhaps CA activity could be used as a diagnostic or surrogate outcome biomarker. A finding of no difference in CA activity between ME/CFS and healthy controls could indicate decreased CO2 production due to impaired cellular respiration, or possibly a difference in CO2 metabolon function in the ME/CFS cohort. The CO2 metabolon includes band 3; band 3 phosphorylation is known to affect erythrocyte deformability,29 which is diminished in ME/CFS.30
Another feasible test is to In addition to healthy controls, it might be interesting to measure blood and salivary CA activity in Long COVID (LC) patients, since LC has been compared with ME/CFS in terms of similarities of symptoms and possible underlying disease mechanisms.27,31 Mancini et al. found that 46% of people with LC met diagnostic criteria for ME/CFS.32 Mancini et al. also reported hypocapnia at rest as measured by end tidal CO2 in both LC and ME/CFS cohorts, and that the pooled average resting respiration rate was 15.6 (n=41, SD=5), which is within normal range.32 Acute infection with some COVID-19 variants is associated with anosmia and dysgeusia.33 Repetitive transcranial magnetic stimulation was found to improve the sense of smell and taste in a clinical study of 93 patients with non-COVID related phantogeusia and/or phantosmia, hyposmia, and hypogeusia. The improvement was accompanied by an increase in blood and salivary CA activity.34 Anosmia in LC suggests reduced CA VI activity, but hypocapnia with normal respiratory rate at rest might suggest increased CA II activity. Anosmia in LC tends to resolve over time;35 a longitudinal study of blood and salivary CA activity and LC symptoms could reveal if there are time-dependent changes in either marker and whether they correlate with specific symptoms.
*Author chose to use a pseudonym to protect themselves from possible discrimination at work and school. PLRC verified the author’s identity, and the author is available for communication via their email. PLRC feels it is important to allow for the voices of patients and caregivers, to be elevated who would otherwise be silenced due to society’s unfair treatment of people with chronic illnesses, must be elevated.
References
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