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Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities

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A Correction to this article was published on 08 June 2020

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Abstract

Background

Factors underlying gastroparesis are not well defined.

Aims

We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study.

Methods

We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations.

Results

Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities.

Conclusions

We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status.

Trail Registry

This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370.

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Change history

Abbreviations

GES:

Gastric electrical stimulation

Gp:

Gastroparesis

CUN:

Chronic unexplained nausea and vomiting

GLS:

Gastroparesis-like syndrome

GCSI:

Gastroparesis cardinal symptom index

PAR:

Postural adjustment ratio

% RRI:

Percentage variation with RRI

%VC:

Percentage of vasoconstriction

EGG:

Electrogastrography

EG:

Electrogram

ANS:

Autonomic nervous system

GERD:

Gastroesophageal reflux disease

NPO:

Nothing by mouth

MAC:

Monitored anesthesia care

DiaComp:

Diabetes complication consortium

CPM:

Cycles per minute

mV:

Millivolts

References

  1. Camilleri M. Functional dyspepsia and gastroparesis. Dig Dis. 2016;34:491–499.

    PubMed  Google Scholar 

  2. Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18–37. quiz 38.

    CAS  PubMed  Google Scholar 

  3. Talley NJ. Functional dyspepsia: advances in diagnosis and therapy. Gut Liver. 2017;11:349–357.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Park SY, Acosta A, Camilleri M, et al. Gastric motor dysfunction in patients with functional gastroduodenal symptoms. Am J Gastroenterol. 2017;112:1689–1699.

    PubMed  Google Scholar 

  5. Parkman HP, Yates K, Hasler WL, et al. Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity. Gastroenterology. 2011;140:101–115.

    PubMed  Google Scholar 

  6. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011;9:1056–1064.

    PubMed  Google Scholar 

  7. Pasricha PJ, Colvin R, Yates K, et al. Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying. Clin Gastroenterol Hepatol. 2011;9:567–576. e561–564.

    PubMed  PubMed Central  Google Scholar 

  8. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40:136–154.

    CAS  PubMed  Google Scholar 

  9. Kalkan C, Soydal C, Ozkan E, et al. Relationships between autonomic nerve function and gastric emptying in patients with autoimmune gastritis. Clin Auton Res. 2016;26:189–196.

    PubMed  Google Scholar 

  10. Abell TL, Familoni B, Voeller G, et al. Electrophysiologic, morphologic, and serologic features of chronic unexplained nausea and vomiting: lessons learned from 121 consecutive patients. Surgery. 2009;145:476–485.

    PubMed  Google Scholar 

  11. Grover M, Farrugia G, Lurken MS, et al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology. 2011;140:1575–1585. e1578.

    CAS  PubMed  Google Scholar 

  12. Angeli TR, Cheng LK, Du P, et al. Loss of interstitial cells of cajal and patterns of gastric dysrhythmia in patients with chronic unexplained nausea and vomiting. Gastroenterology. 2015;149:56–66. e55.

    PubMed  Google Scholar 

  13. O’Grady G, Angeli TR, Du P, et al. Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping. Gastroenterology. 2012;143:589–598. e581–583.

    PubMed  Google Scholar 

  14. Meleine M, Melchior C, Prinz P, et al. Gastrointestinal peptides during chronic gastric electrical stimulation in patients with intractable vomiting. Neuromodulation. 2017;20:774–782.

    PubMed  Google Scholar 

  15. Moon TC, Befus AD, Kulka M. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol. 2014;5:569.

    PubMed  PubMed Central  Google Scholar 

  16. Abell TL, Malagelada JR, Lucas AR, et al. Gastric electromechanical and neurohormonal function in anorexia nervosa. Gastroenterology. 1987;93:958–965.

    CAS  PubMed  Google Scholar 

  17. Cutts T, Holmes S, Kedar A, et al. Twenty-five years of advocacy for patients with gastroparesis: support group therapy and patient reported outcome tool development. BMC Gastroenterol. 2016;16:107.

    PubMed  PubMed Central  Google Scholar 

  18. Food and Drug Administration (FDA). Gastroparesis: clinical evaluation of drugs for treatment. Guidance for Industry. 2015. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/gastroparesis-clinical-evaluation-drugs-treatment.

  19. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol. 2000;95:1456–1462.

    CAS  PubMed  Google Scholar 

  20. Taubes G. Cardiovascular disease. Does inflammation cut to the heart of the matter? Science. 2002;296:242–245.

    CAS  PubMed  Google Scholar 

  21. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001;32:133–138.

    PubMed  Google Scholar 

  22. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol. 2012;34:43–62.

    CAS  PubMed  Google Scholar 

  23. Kamphuisen PW, Eikenboom JC, Vos HL, et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost. 1999;81:680–683.

    CAS  PubMed  Google Scholar 

  24. O’Donnell J, Tuddenham EG, Manning R, et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost. 1997;77:825–828.

    PubMed  Google Scholar 

  25. Albert MA, Staggers J, Chew P, et al. The pravastatin inflammation CRP evaluation (PRINCE): rationale and design. Am Heart J. 2001;141:893–898.

    CAS  PubMed  Google Scholar 

  26. Rashed H, Abell TL, Familoni BO, et al. Autonomic function in cyclic vomiting syndrome and classic migraine. Dig Dis Sci. 1999;44:74S–78S.

    CAS  PubMed  Google Scholar 

  27. Aslam N, Kedar A, Nagarajarao HS, et al. Serum catecholamines and dysautonomia in diabetic gastroparesis and liver cirrhosis. Am J Med Sci. 2015;350:81–86.

    PubMed  PubMed Central  Google Scholar 

  28. Stocker A, Abell TL, Rashed H, et al. Autonomic evaluation of patients with gastroparesis and neurostimulation: comparisons of direct/systemic and indirect/cardiac measures. Gastroenterol Res. 2015;9:10.

    Google Scholar 

  29. Lahr CJ, Griffith J, Subramony C, et al. Gastric electrical stimulation for abdominal pain in patients with symptoms of gastroparesis. Am Surg. 2013;79:457–464.

    PubMed  PubMed Central  Google Scholar 

  30. Abell TL, Cardoso S, Schwartzbaum J, et al. Diabetic gastroparesis is associated with an abnormality in sympathetic innervation. Eur J Gastroenterol Hepatol. 1994;6:241–247.

    Google Scholar 

  31. Colombo J, Arora RR, DePace NL, et al. Clinical Autonomic Function. Berlin: Springer; 2015.

    Google Scholar 

  32. Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, et al. Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities. J Diabetes Sci Technol. 2008;2:645–657.

    PubMed  PubMed Central  Google Scholar 

  33. Grover M, Bernard CE, Pasricha PJ, et al. Clinical-histological associations in gastroparesis: results from the gastroparesis clinical research consortium. Neurogastroenterol Motil. 2012;24:531–539. e249.

    CAS  PubMed  Google Scholar 

  34. O’Grady GO, Abell TL. Low- and high-resolution mapping of gastric electrical activity. Gastroenterol Clin N Am. 2015;44:169–184.

    Google Scholar 

  35. Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47:1042–1048.

    CAS  PubMed  Google Scholar 

  36. Selim MM, Wendelschafer-Crabb G, Redmon JB, et al. Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy? Neurology. 2010;75:973–981.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17:903–912. e944–909.

    CAS  PubMed  Google Scholar 

  38. Kim CH, Hanson RB, Abell TL, et al. Effect of inhibition of prostaglandin synthesis on epinephrine-induced gastroduodenal electromechanical changes in humans. Mayo Clin Proc. 1989;64:149–157.

    CAS  PubMed  Google Scholar 

  39. Paskaranandavadivel N, Bull SH, Parsell D, et al. A system for automated quantification of cutaneous electrogastrograms. Conf Proc IEEE Eng Med Biol Soc. 2015;2015:6098–6101.

    Google Scholar 

  40. Abell TL, Malagelada JR. Glucagon-evoked gastric dysrhythmias in humans shown by an improved electrogastrographic technique. Gastroenterology. 1985;88:1932–1940.

    CAS  PubMed  Google Scholar 

  41. Du L, Chen B, Kim JJ, et al. Micro-inflammation in functional dyspepsia: a systematic review and meta-analysis. Neurogastroenterol Motil. 2018;30:e13304.

    CAS  PubMed  Google Scholar 

  42. Hasler W, Wilson L, Nguyen LAB, et al. Relation of opiate use to clinical manifestations, quality of life, and resource use in gastroparesis: impact of μ-opioid agonist potency. Gastroenterology. 2017;152:S518–S519.

    Google Scholar 

  43. Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127:355–360.

    PubMed  Google Scholar 

  44. Koduru P, Irani M, Quigley EMM. Definition, pathogenesis, and management of that cursed dyspepsia. Clin Gastroenterol Hepatol. 2018;16:467–479.

    PubMed  Google Scholar 

  45. Alcalá HE, Chen J, Langellier BA, et al. Impact of the Affordable Care Act on health care access and utilization among Latinos. J Am Board Fam Med. 2017;30:52–62.

    PubMed  Google Scholar 

  46. Abell TL, McCallum RW, May KP, et al. Effectiveness of gastric electrical stimulation in gastroparesis: results from a large prospectively collected database of a national gastroparesis registry (abstract). Gastroenterology. 2015;148:S65.

    Google Scholar 

  47. Xue HB, Fan HZ, Meng XM, et al. Fluoroscopy-guided gastric peroral endoscopic pyloromyotomy (G-POEM): a more reliable and efficient method for treatment of refractory gastroparesis. Surg Endosc. 2017;31:4617–4624.

    CAS  PubMed  Google Scholar 

  48. Dacha S, Mekaroonkamol P, Li L, et al. Outcomes and quality-of-life assessment after gastric per-oral endoscopic pyloromyotomy (with video). Gastrointest Endosc. 2017;86:282–289.

    PubMed  Google Scholar 

  49. Camilleri M, Szarka LA. POEMs for gastroparesis. Gastrointest Endosc. 2017;85:129–131.

    PubMed  Google Scholar 

  50. Szarka LA, Gostout CJ. Expanding submucosal endoscopy with applied knowledge. Gastrointest Endosc. 2017;85:140–142.

    PubMed  Google Scholar 

  51. Al-Bayati I, Sarosiek I, McCallum RW. Gastric electrical stimulation, pyloroplasty, gastrectomy, and acustimulation for the treatment of nausea and vomiting in the setting of gastroparesis. In: Koch KL, Hasler WL, eds. Nausea and Vomiting: Diagnosis and Treatment. Cham: Springer International Publishing; 2017:139–151.

    Google Scholar 

  52. Spiller RC. Inflammation as a basis for functional GI disorders. Best Pract Res Clin Gastroenterol. 2004;18:641–661.

    CAS  PubMed  Google Scholar 

  53. Gonzalez-Clemente JM, Mauricio D, Richart C, et al. Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus. Clin Endocrinol (Oxf). 2005;63:525–529.

    CAS  Google Scholar 

  54. Abell TL, Kedar A, Stocker A, et al. Gastroparesis syndromes: response to electrical stimulation. Neurogastroenterol Motil. 2019;31:e13534.

    PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank the following: Bridget Cannon, Heather Barker, Shirish Barve, Craig McClain, Tad Dryden, Cam Falkner, Marion McClain, Samir Vermani, Chirag Patel, Andy Patel, Shifat Ahmed, Kaartik Soota, Siva Cheetirala, Malathi Perugula, Jpriyanga Jayakumar, Pramod Kumar Savarapu, Sathya Krishnasamy, Hamza Hassan, Warren Starkebaum, and Steve Mahanes. The authors would like to thank the staff of Jewish Hospital including the GI Motility Clinic and the University of Louisville CTR/Liver Research Unit as well as the help of Catherine McBride in manuscript preparation. The authors would also like to thank Greg O’Grady for review of the manuscript.

Funding

Primary funding for this work was received from NIH Diabetes Complication Consortium, U24DK076169. This work was also approved as an ancillary study of the NIH GpCRC (U01DK074007). CTG Number: NCT03178370.

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, 550 S. Jackson, ACB A3L15, Louisville, KY, 40202, USA

    Thomas L. Abell, Archana Kedar, Abigail Stocker, Karen Beatty, Michael Hughes, Xiu Yang, Mostafa Fraig, Leila Gobejishvili, Endashaw Omer, Ed Miller & Christina Pinkston

  2. University of Louisville Physicians, Louisville, KY, USA

    Lindsay McElmurray

  3. Methodist Hospital, Memphis, TN, USA

    Hani Rashed

  4. University of Minnesota, Minneapolis, MN, USA

    William Kennedy & Gwen Wendelschafer-Crabb

  5. University of Mississippi, Jackson, MS, USA

    Michael Griswold

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Contributions

TLA and AK contributed to design, data acquisition, data analysis, and writing and review of manuscript. AS, KB, LM, MH, XY, MF, LG, and EO were involved in data acquisition and review of manuscript. HR and EM contributed to design, data acquisition, data analysis, and review of manuscript. WK and GW-C were involved in design, data acquisition, and review of manuscript. MG contributed to design, data analysis, and review of manuscript. CP acquired and analyzed the data and wrote and reviewed the manuscript.

Corresponding author

Correspondence to Thomas L. Abell.

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Conflict of interest

Dr. Abell has been an investigator for Medtronic, Rhythm, Theravance, Vanda and Allergan, and has been a consultant for Theravance, Censa and Nuvaira. He is the GI Section Editor for Med Study, GI Stimulation editor for Neuromodulation, GES editor for Wikistim, and a reviewer for UpToDate. Dr. Abell is the founder of ADEPT-GI, which holds intellectual property covering some aspects of technology in this manuscript. There are no other disclosures.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Supplemental Table

 1. Normal ranges of patient measures and percentage of abnormal values in all patients and among the diagnostic subgroups (DOCX 31 kb)

Supplemental Table

 2. Baseline values, stratified by delay status (DOCX 49 kb)

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Abell, T.L., Kedar, A., Stocker, A. et al. Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities. Dig Dis Sci 66, 1127–1141 (2021). https://doi.org/10.1007/s10620-020-06259-6

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