Sunday, 8 April 2012

Is stomach acid low in CFS?

Anecdotal reports from patients and practitioners suggest stomach acid (Hydrochloric acid or HCl) levels are often low in CFS. This situation may relate to the slowed gastric emptying reported in CFS 1, since a positive relationship between gastric acidity and gastric emptying exists 2,3. Low HCl levels also likely accompany many other chronic illnesses and the ageing process itself 4. However there is almost no science examining the prevalence and pathogenesis of low HCl conditions. Low HCl could conceivably arise due to many reasons such as stress, infections (e.g. H. pylori), autoimmunity (e.g. pernicious anaemia), low ATP or altered signal-stimulated production. Low stomach acid potentially sets the stage for numerous digestive and dysbiotic issues, and many CFS specialists consider correcting HCl levels as fundamental to any CFS treatment protocol. I have compiled some of the key components and factors that I think may be involved in low HCl secretion below. However if anyone has any other ideas related to lowered HCl secretion and digestion please mention them in the comments section. I would love to research this topic more in the future, so more ideas are extremely welcome.

HCl function
Stomach acid has various crucial functions. The highly acidic (pH 1-2) environment in the stomach created by HCl denatures proteins, which exposes their peptide bonds and initiates protein digestion. HCl also sets up the right pH to trigger the secretion and activity of various digestive enzymes in the small intestine, and therefore promotes the digestive process through the gut. Micronutrients such as minerals and protein-bound vitamins (especially B12) 5 also require HCl for efficient absorption. HCl is further required to sterilise food and discourage the passage and growth of bad bacteria/yeast in the small intestine 6. Given the major physiological roles of HCl, low levels may disrupt digestion and absorption of proteins and micronutrients, and may also facilitate dysbiosis (bad bacteria/yeast overgrowth). Indeed use of acid suppressing drugs such as proton pump inhibitors has been associated with such changes 7–9. A low stomach acid condition also likely perpetuates itself by promoting deficiency of various nutrients required to make and secrete HCl (e.g. histidine).

HCl production
HCl is secreted by the parietal cells in the stomach, along with intrinsic factor which is required for B12 absorption. Acid secretion into the gastric lumen requires the movement of hydrogen (H+), chloride (Cl-) and potassium (K+) ions, which may be achieved via several pumps and channels 10,11. In particular these cells largely depend upon the H+/K+-ATPase, an MgATP-dependent ion pump, to create a massive hydrogen gradient and ultimately HCl 12. While the H+/K+-ATPase shares homology with other widely expressed ion pumps such as the Ca2+-ATPase and Na+/K+-ATPase it is almost exclusive to the gastric parietal cells (with an additional small presence in renal medulla), and represents the major target of proton pump inhibitors 13. The dependence upon large ion gradients for the secretion of HCl parallels a huge dependence upon energy (ATP) generation. In fact parietal cells have one of the largest density of mitochondria in the body, filling up to 40% of the total cell volume 10. Accordingly a recent study reported that parietal oxidative stress induced by SOD2 (mitochondrial SODase) deficiency impaired mitochondrial metabolism and markedly decreased basal and stimulated-HCl secretion while increasing cell sensitivity to injury 14. Interestingly stress-induced inhibition of HCl secretion may also involve parietal oxidative stress 15. Further illustrating the dependence upon ATP for adequate HCl secretion is the finding that activation of AMP-kinase, a ubiquitous cellular energy sensor activated with a falling ATP:AMP ratio, switches off parietal HCl secretion 16; via this mechanism ethanol also suppresses acid secretion 17. These studies emphasise a potential metabolic cause of low HCl in chronic illnesses featuring oxidative stress and mitochondrial dysfunction, as suggested by a current CFS hypothesis 18. Immune activation and oxidative stress are also recognised early events in inflammatory bowel disease which likely mediate damage to the enteric nervous system and will therefore affect wider signal-regulated aspects of overall gut function 19.

HCl regulation
Under physiological conditions HCl secretion is regulated by various neural fibers (i.e. enteric nervous system and vagus nerve), neurotransmitters, hormones and local feedback mechanisms. These systems maintain basal acid levels and the secretion dynamics produced in response to the smell and taste of food (cephalic phase) and direct contact with food (gastric phase). Once in the gastric lumen HCl secretion is stimulated by food components such as peptides, individual amino acids and divalent metals (i.e. Ca2+ and Mg2+) 20–22. Endogenous signaling systems involved in promoting secretion include acetylcholine (i.e. parasympathetic activity), gastrin and histamine. While acetylcholine stimulates acid secretion via the vagus nerve, histamine is involved at a paracrine level. Local histamine receptor type-2 (H2) activation on parietal cells stimulates acid production via an intracellular cAMP-PKA pathway which promotes translocation of the H+/K+-ATPase to the secretory surface of the cell 10. Accordingly antagonism of the H2 receptor represents another pharmacological approach used clinically to inhibit acid secretion. Physiological inhibitors of HCl secretion include messengers such as noradrenaline (i.e. sympathetic activity) and somatostatin 6,13,23. In particular, and in contrast to H2 receptor activation, somatostatin activates an inhibitory G-protein signaling pathway on parietal cells which lowers intracellular cAMP concentrations 10. HCl secretion is also regulated locally by luminal pH sensors which trigger acid secretion in response to a high pH, which may particularly involve pH-dependent modulation of the calcium-sensing receptor 20. Negative feedback regulation of acid secretion is mediated by local somatostatin release and down-regulation of gastrin 20. Additionally the immediate mucosal defence against acid may involve COX-1-derived prostaglandin E2 (PGE2); PGE2 signaling inhibits HCl secretion 24 and promotes neutralisation via enhanced bicarbonate (HCO3-) secretion 25,26. Indeed it is inhibition of COX by NSAIDs (e.g. aspirin) which leads to increased HCl secretion and the resulting potential for gastric ulceration 27–29.

Testing and treatment
There is a simple home test that can be done to give a good basic indicator of HCl levels known as the bicarb test, instructions for which can be found on the net. This test uses bicarbonate of soda as an alkaline challenge to test the body’s capacity to buffer it with acid secretion. Further testing can be achieved by looking at salivary VEGF levels, or by swallowing a capsule which directly measures stomach pH. A salivary VEGF test is available at acumen; capsule testing is available at gastro-test.

Permanent resolution of a low stomach acid condition likely requires removal of the various pathogenic mechanisms responsible for its aetiology. One approach might be to improve parietal cell function via micronutrient and antioxidant supplementation, while removing potentially disruptive drug therapies. Other approaches might correct low HCl at a signaling level by restoring proper enteric control, such as via modulation of microflora or hormonal balance. Healing gastric ulcers and leaky gut may also convey benefit, perhaps via favourable modulation of inflammation, autoimmunity or parietal cell function. HCl can also currently be supported directly by a couple of basic means. Acidic solutions can be drunk through a straw with each meal, such as the juice of a slice of lemon (pH 2-3), cider vinegar, or diluted pure HCl (available from allergy research group). Alternately Betaine HCl supplements can be taken.

References
1.         Burnet, R.B. & Chatterton, B.E. Gastric emptying is slow in chronic fatigue syndrome. BMC gastroenterology 4, 32 (2004).
2.         Emerenziani, S. & Sifrim, D. Gastroesophageal reflux and gastric emptying, revisited. Current gastroenterology reports 7, 190-5 (2005).
3.         Sanaka, M., Yamamoto, T. & Kuyama, Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Digestive diseases and sciences 55, 2431-40 (2010).
4.         Grassi, M. et al. Changes, functional disorders, and diseases in the gastrointestinal tract of elderly. Nutrición hospitalaria : organo oficial de la Sociedad Española de Nutrición Parenteral y Enteral 26, 659-68 (2011).
5.         Andrès, E. et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne 171, 251-9 (2004).
6.         Schubert, M.L. Gastric exocrine and endocrine secretion. Current opinion in gastroenterology 25, 529-36 (2009).
7.         Lombardo, L., Foti, M., Ruggia, O. & Chiecchio, A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 8, 504-8 (2010).
8.         Compare, D. et al. Effects of long-term PPI treatment on producing bowel symptoms and SIBO. European journal of clinical investigation 41, 380-6 (2011).
9.         Ito, T. & Jensen, R.T. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Current gastroenterology reports 12, 448-57 (2010).
10.       Kopic, S., Murek, M. & Geibel, J.P. Revisiting the parietal cell. American journal of physiology. Cell physiology 298, C1-C10 (2010).
11.       Heitzmann, D. & Warth, R. No potassium, no acid: K+ channels and gastric acid secretion. Physiology (Bethesda, Md.) 22, 335-41 (2007).
12.       Shin, J.M., Munson, K., Vagin, O. & Sachs, G. The gastric HK-ATPase: structure, function, and inhibition. Pflügers Archiv : European journal of physiology 457, 609-22 (2009).
13.       Schubert, M.L. Gastric secretion. Current opinion in gastroenterology 27, 536-42 (2011).
14.       Jones, M.K. et al. Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice. American journal of physiology. Gastrointestinal and liver physiology 301, G537-46 (2011).
15.       Azlina, M.F., Nafeeza, M.I. & Khalid, B.A.K. A comparison between tocopherol and tocotrienol effects on gastric parameters in rats exposed to stress. Asia Pacific journal of clinical nutrition 14, 358-65 (2005).
16.       Sidani, S. et al. AMP-activated protein kinase: a physiological off switch for murine gastric acid secretion. Pflügers Archiv : European journal of physiology 459, 39-46 (2009).
17.       Kopic, S. et al. Ethanol inhibits gastric acid secretion in rats through increased AMP-kinase activity. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25, 195-202 (2010).
18.       Van Konynenburg, R.A. Glutathione depletion-methylation cycle block: a hypothesis for the pathogenesis of chronic fatigue syndrome. 8th International IACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and other Related Illnesses (2007).
19.       Lakhan, S.E. & Kirchgessner, A. Neuroinflammation in inflammatory bowel disease. Journal of neuroinflammation 7, 37 (2010).
20.       Goo, T., Akiba, Y. & Kaunitz, J.D. Mechanisms of intragastric pH sensing. Current gastroenterology reports 12, 465-70 (2010).
21.       Ceglia, L., Harris, S.S., Rasmussen, H.M. & Dawson-Hughes, B. Activation of the calcium sensing receptor stimulates gastrin and gastric acid secretion in healthy participants. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20, 71-8 (2009).
22.       Khropycheva, R., Uneyama, H., Torii, K. & Zolotarev, V. Dietary monosodium glutamate enhances gastric secretion. The journal of medical investigation : JMI 56 Suppl, 218-23 (2009).
23.       Osumi, Y. Central neurotransmitters and regulation of gastric acid secretion. Nihon yakurigaku zasshi. Folia pharmacologica Japonica 96, 205-16 (1990).
24.       Befrits, R. & Johansson, C. Oral PGE2 inhibits gastric acid secretion in man. Prostaglandins 29, 143-52 (1985).
25.       Takeuchi, K., Aihara, E., Sasaki, Y., Nomura, Y. & Ise, F. Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid-induced HCO3- secretion in stomach. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 57, 661-76 (2006).
26.       Baumgartner, H.K., Starodub, O.T., Joehl, J.S., Tackett, L. & Montrose, M.H. Cyclooxygenase 1 is required for pH control at the mouse gastric surface. Gut 53, 1751-7 (2004).
27.       Nandi, J., Das, P.K., Zinkievich, J.M., Baltodano, J.D. & Levine, R.A. Cyclo-oxygenase-1 inhibition increases acid secretion by modulating H+,K+-ATPase expression and activation in rabbit parietal cells. Clinical and experimental pharmacology & physiology 36, 127-34 (2009).
28.       Zinkievich, J.M., George, S., Jha, S., Nandi, J. & Levine, R.A. Gastric acid is the key modulator in the pathogenesis of non-steroidal anti-inflammatory drug-induced ulceration in rats. Clinical and experimental pharmacology & physiology 37, 654-61 (2010).
29.       Wang, G.-Z. et al. Aspirin can elicit the recurrence of gastric ulcer induced with acetic acid in rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20, 205-12 (2007).

3 comments:

  1. I have an idea that the deficiency of stomach acid secretion often found in ME/CFS may be due to malfunction of the vagus nerve (which is part of the parasympathetic nervous system) that is responsible for stimulating the parietal cells to produce gastric acid, and stimulating the pancreas to secrete digestive enzymes.

    In ME/CFS and its related co-morbid conditions (such as orthostatic hypotension, Sjögren's syndrome, interstitial cystitis) you often find patients produce autoantibodies to the muscarinic acetylcholine receptors found on the parasympathetic nerves, thus interfering with nerve signal transmission.

    In some of these disease conditions, these muscarinic receptor autoantibodies are found to block muscarinic receptor function (thus presumably tending to block parasympathetic nerve signal transmission); other times the autoantibodies are found to activate the muscarinic receptors (thus presumably tending to tending to activate the parasympathetic nerve).

    Since both the parietal cells that secrete stomach acid and the pancreas that secretes digestive enzymes are controlled by the parasympathetic nerves, if these muscarinic receptor autoantibodies are blocking parasympathetic nerve function, and preventing nerve signals getting through to the parietal cells and the pancreas, this might explain why stomach acid and digestive enzyme secretion is often feeble in ME/CFS.

    In summary: the weak digestion may conceivably be due to the autoimmune processes (that are known to exist in ME/CFS) affecting the nerves that control the secretion of stomach acids and digestive enzymes.

    References:

    The following pages have links to studies detailing the anti-muscarinic receptor autoantibodies found in ME/CFS, orthostatic hypotension, Sjögren's syndrome and interstitial cystitis:

    http://forums.phoenixrising.me/showthread.php?11130-New-video-Is-acetylcholine-toxicity-the-cause-of-CFS&p=229549&viewfull=1#post229549

    http://forums.phoenixrising.me/showthread.php?11130-New-video-Is-acetylcholine-toxicity-the-cause-of-CFS&p=229706&viewfull=1#post229706

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  2. Thank you very much for your thoughts! I have read the posts you link to and saved references. I'm certainly very interested in the autoimmune component of CFS. I also intend to look further into the autonomic regulation of HCl and digestive secretion, and I will update the post above in the future.

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  3. I only relatively recently learnt that that there are these receptor autoantibodies in ME/CFS.

    Apparently viral or bacterial infection tends to precipitate autoimmunity and autoantibodies. What is amazing is that this autoimmune attack may go on to cause a whole array of symptoms/pathophysiologies over and above the symptoms caused by the infection.

    I have read some suggestions that the sympathetic/parasympathetic balance has an impact on the Th1/Th2 immune system balance (although I cannot find any solid studies that have demonstrated this). This makes me wonder whether a parasympathetic nervous system that is inhibited by muscarinic receptor antibodies may act to shift the immune response away from Th1, so preventing viral clearance. If this is the case, it also makes you wonder if this autoimmune attack on the parasympathetic nerves might be deliberately staged and directed by the virus itself somehow, in order to prevent the immune system from eliminating the virus.

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