Gastroparesis pathophysiology: Difference between revisions

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==Overview==
==Overview==
The exact pathogenesis of [disease name] is not fully understood.
The exact [[pathogenesis]] of gastroparesis is not fully understood. However, [[gastric]] emptying process is the result of interaction of [[smooth muscles]], extrinsic and [[enteric]] [[autonomic nervous system]], and [[Interstitial cell of Cajal|interstitial cells of Cajal]] (ICC). Loss of expression of [[neuronal]] [[nitric oxide synthase]] (n[[Nitric oxide synthase|NOS]]) and loss of [[Interstitial cell of Cajal|interstitial cells of Cajal]] (ICC) play pivotal role in the [[pathogenesis]] of gastroparesis. Recent studies suggest that the loss of antioxidant gene expression (NRF2 gene) can contribute to the development of gastroparesis. NRF2 regulates expression of phase II antioxidant genes such as HO-1, SOD1, SOD2, GCLC, GCLM, CAT, and GPX1. On [[microscopic]] [[histopathological]] analysis of full thickness biopsy of the [[gastric]] body. Decreased number of [[Interstitial cell of Cajal|interstitial cells of Cajal]] (also called fibroblast like cells) in circular muscle layer, [[immune cells]] infiltration of [[gastric]] tissue especially [[myenteric plexus]] predominantly consisting of [[lymphocytes]] and [[macrophages]] showing [[CD45]] and [[CD68]] immunoreactivity, and [[enteric]] [[nerve fiber]] loss within the circular [[Smooth muscle|smooth muscle layer]] are characteristic findings of gastroparesis.  
 
OR
 
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
 
OR
 
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
 
OR
 
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
 
OR
 
 
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
 
OR
 
The progression to [disease name] usually involves the [molecular pathway].
 
OR
 
The pathophysiology of [disease/malignancy] depends on the histological subtype.


==Pathophysiology==
==Pathophysiology==


===Pathogenesis===
===Pathogenesis===
*The exact pathogenesis of gastroparesis is not fully understood. However, it is well known that gastric emptying process is the result of interaction of smooth muscles, extrinsic and enteric autonomic nervous system, and interstitial cells of Cajal.<ref name="pmid23350043">{{cite journal| author=Oh JH, Pasricha PJ| title=Recent advances in the pathophysiology and treatment of gastroparesis. | journal=J Neurogastroenterol Motil | year= 2013 | volume= 19 | issue= 1 | pages= 18-24 | pmid=23350043 | doi=10.5056/jnm.2013.19.1.18 | pmc=3548121 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23350043  }}</ref> The final process for delay of gastric emptying is increased tone of pylorus. Gastric emptying is mediated by the vagus nerve, which involves fundus accommodation, antrum contraction, and pyloric relaxation. Interstitial cells of Cajal are the pacemaker cells in the gut with unique ability to generate and propagate slow waves in gastrointestinal muscles. The electrical slow wave activity is the determinant of the characteristic frequency of phasic contractions of the stomach, intestine and colon as well as the direction and velocity of propagation of peristaltic activity, in coordination with the enteric nervous system.<ref name="pmid12790758">{{cite journal| author=Camborová P, Hubka P, Sulková I, Hulín I| title=The pacemaker activity of interstitial cells of Cajal and gastric electrical activity. | journal=Physiol Res | year= 2003 | volume= 52 | issue= 3 | pages= 275-84 | pmid=12790758 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12790758  }}</ref> Interstitial cells of Cajal regulate both gastric pacemaker activity and enteric neurons, which initiate smooth muscle cell activity.<ref name="pmid25667023">{{cite journal| author=Parkman HP| title=Idiopathic gastroparesis. | journal=Gastroenterol Clin North Am | year= 2015 | volume= 44 | issue= 1 | pages= 59-68 | pmid=25667023 | doi=10.1016/j.gtc.2014.11.015 | pmc=4324534 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25667023  }}</ref> slow wave activity originated from a pacemaker region at the mid/upper corpus on the greater curvature. From this pacemaker region, a band of activity rapidly formed and propagated in an organised fashion towards the distal antrum.<ref name="pmid25313679">{{cite journal| author=Cheng LK| title=Slow wave conduction patterns in the stomach: from Waller's foundations to current challenges. | journal=Acta Physiol (Oxf) | year= 2015 | volume= 213 | issue= 2 | pages= 384-93 | pmid=25313679 | doi=10.1111/apha.12406 | pmc=4405773 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25313679  }}</ref>
*The exact [[pathogenesis]] of gastroparesis is not fully understood. However, it is well known that [[gastric]] emptying process is the result of interaction of [[smooth muscles]], extrinsic and [[enteric]] [[autonomic nervous system]], and interstitial cells of Cajal (ICC).<ref name="pmid23350043">{{cite journal| author=Oh JH, Pasricha PJ| title=Recent advances in the pathophysiology and treatment of gastroparesis. | journal=J Neurogastroenterol Motil | year= 2013 | volume= 19 | issue= 1 | pages= 18-24 | pmid=23350043 | doi=10.5056/jnm.2013.19.1.18 | pmc=3548121 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23350043  }}</ref>  
OR
*The final process for the development of delayed of [[gastric]] emptying is increased tone of [[pylorus]].  
*It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
*[[Gastric]] emptying is mediated by the [[vagus nerve]]. The process of gastric emptying involves the following sequential steps:
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
**[[Fundus (stomach)|Fundal]] accommodation  
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
**[[Antrum|Antral]] [[contraction]]
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
**[[Pylorus|Pyloric]] [[relaxation]]
*The progression to [disease name] usually involves the [molecular pathway].
*[[Interstitial cell of Cajal|Interstitial cells of Cajal]] generate the contractile rhythm within the [[gut]] and possess a unique ability to produce slow waves in [[gastrointestinal]] [[smooth muscles]].  
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
*This electrical slow wave activity is the determinant of the characteristic frequency of phasic [[contractions]] of the [[stomach]], [[intestine]] and [[colon]] as well as the direction and velocity of propagation of [[Peristalsis|peristaltic]] activity, in coordination with the [[enteric nervous system]].<ref name="pmid12790758">{{cite journal| author=Camborová P, Hubka P, Sulková I, Hulín I| title=The pacemaker activity of interstitial cells of Cajal and gastric electrical activity. | journal=Physiol Res | year= 2003 | volume= 52 | issue= 3 | pages= 275-84 | pmid=12790758 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12790758  }}</ref>  
 
*[[Interstitial cell of Cajal|Interstitial cells of Cajal]] regulate both [[gastric]] pacemaker activity and [[enteric]] [[neurons]], which then initiate [[smooth muscle cell]] activity.<ref name="pmid25667023">{{cite journal| author=Parkman HP| title=Idiopathic gastroparesis. | journal=Gastroenterol Clin North Am | year= 2015 | volume= 44 | issue= 1 | pages= 59-68 | pmid=25667023 | doi=10.1016/j.gtc.2014.11.015 | pmc=4324534 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25667023  }}</ref> Slow wave activity in human [[stomach]] originates from a pacemaker region at the mid/upper corpus on the [[Greater curvature of the stomach|greater curvature]]. From this pacemaker region, a band of activity is formed rapidly and propagated in an organized fashion towards the distal [[antrum]].<ref name="pmid25313679">{{cite journal| author=Cheng LK| title=Slow wave conduction patterns in the stomach: from Waller's foundations to current challenges. | journal=Acta Physiol (Oxf) | year= 2015 | volume= 213 | issue= 2 | pages= 384-93 | pmid=25313679 | doi=10.1111/apha.12406 | pmc=4405773 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25313679  }}</ref> Hence, tone of [[pyloric sphincter]] plays an important role in the regulation of [[gastric]] emptying.
*Non-[[adrenergic]], non-[[cholinergic]] (NANC) innervation to the [[pylorus]] is predominantly inhibitory and mediates [[relaxation]] of the sphincter.<ref name="pmid4152775">{{cite journal| author=Anuras S, Cooke AR, Christensen J| title=An inhibitory innervation at the gastroduodenal junction. | journal=J Clin Invest | year= 1974 | volume= 54 | issue= 3 | pages= 529-35 | pmid=4152775 | doi=10.1172/JCI107789 | pmc=301585 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4152775  }}</ref>
*A high density of [[nitric oxide synthase]]-immunopositive [[nerve cells]] and fibres have been been demonstrated in the [[pylorus]].<ref name="pmid7532815">{{cite journal| author=Ekblad E, Mulder H, Uddman R, Sundler F| title=NOS-containing neurons in the rat gut and coeliac ganglia. | journal=Neuropharmacology | year= 1994 | volume= 33 | issue= 11 | pages= 1323-31 | pmid=7532815 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7532815  }}</ref>
*They are called inhibitory nitrergic [[neurons]]. Expression of [[neuronal]] [[nitric oxide synthase]] (nNOS) activity from nitrergic [[neurons]] in [[gastric]] wall secrete [[nitric oxide]] ([[Nitric oxide|NO]]).  
*Major function of [[Nitric oxide|NO]] from these nitrergic [[enteric]] [[nerves]] include accommodation of the [[fundus]] and relaxation of [[pylorus]] through [[smooth muscle]] [[relaxation]].
*These [[enteric]] [[nerves]] also control the [[muscle tone]] of the [[lower esophageal sphincter]], the [[sphincter of Oddi]], and the [[anus]].<ref name="pmid18640116">{{cite journal| author=Sivarao DV, Mashimo H, Goyal RK| title=Pyloric sphincter dysfunction in nNOS-/- and W/Wv mutant mice: animal models of gastroparesis and duodenogastric reflux. | journal=Gastroenterology | year= 2008 | volume= 135 | issue= 4 | pages= 1258-66 | pmid=18640116 | doi=10.1053/j.gastro.2008.06.039 | pmc=2745304 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18640116  }}</ref> The most important mechanism behind the [[pathogenesis]] of gastroparesis appears to be:<ref name="pmid23350043" /> 
**Loss of expression of [[neuronal]] [[nitric oxide synthase]] (n[[Nitric oxide synthase|NOS]])
**Loss of [[Interstitial cell of Cajal|interstitial cells of Cajal]] (ICC)
==Genetics==
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*Recent studies suggest that the loss of [[antioxidant]] [[gene expression]] (NRF2 [[gene]]) can contribute to the development of gastroparesis. NRF2 regulates expression of phase II antioxidant [[genes]] such as HO-1, [[SOD1]], [[SOD2]], [[GCLC]], [[GCLM]], [[CAT]], and [[GPX1]].<ref name="pmid21605664">{{cite journal| author=Mukhopadhyay S, Sekhar KR, Hale AB, Channon KM, Farrugia G, Freeman ML et al.| title=Loss of NRF2 impairs gastric nitrergic stimulation and function. | journal=Free Radic Biol Med | year= 2011 | volume= 51 | issue= 3 | pages= 619-25 | pmid=21605664 | doi=10.1016/j.freeradbiomed.2011.04.044 | pmc=3129370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21605664  }}</ref>
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*Elevated expression of the [[enzyme]] [[heme oxygenase]]-1 may mitigate the development of gastroparesis.<ref name="pmid29161307">{{cite journal| author=Gibbons SJ, Grover M, Choi KM, Wadhwa A, Zubair A, Wilson LA et al.| title=Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis. | journal=PLoS One | year= 2017 | volume= 12 | issue= 11 | pages= e0187772 | pmid=29161307 | doi=10.1371/journal.pone.0187772 | pmc=5697813 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29161307  }}</ref> 
*The development of [disease name] is the result of multiple genetic mutations.
*High [[oxidative stress]] in [[Interstitial cell of Cajal|interstitial cells of Cajal]] and nitrergic [[enteric]] [[nerves]] are the potential cause of injury and decrease in their numbers.<ref name="pmid21605664" />


==Associated Conditions==
==Associated Conditions==
The following conditions may be associated with gastroparesis:
* [[Diabetes]]
* Other motility disorders of [[gastrointestinal tract]] such as achalasia, [[irritable bowel syndrome]] and [[constipation]].<ref name="pmid29177065">{{cite journal| author=Triadafilopoulos G, Nguyen L, Clarke JO| title=Patients with symptoms of delayed gastric emptying have a high prevalence of oesophageal dysmotility, irrespective of scintigraphic evidence of gastroparesis. | journal=BMJ Open Gastroenterol | year= 2017 | volume= 4 | issue= 1 | pages= e000169 | pmid=29177065 | doi=10.1136/bmjgast-2017-000169 | pmc=5689484 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29177065  }}</ref>
* [[Neurological illness|Neurological diseases]] eg. [[Parkinson's disease]]
* [[Connective tissue disease|Collagen vascular disorders]]


==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On [[gross pathology]], no abnormalities seen on obtaining full thickness [[biopsy]] of [[gastric]] tissue.


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On [[microscopic]] [[histopathological]] analysis of full thickness biopsy of the [[gastric]] body. Decreased number of [[Interstitial cell of Cajal|interstitial cells of Cajal]] (also called fibroblast like cells) in circular muscle layer, [[immune cells]] infiltration of [[gastric]] tissue especially [[myenteric plexus]] predominantly consisting of [[lymphocytes]] and [[macrophages]] showing [[CD45]] and [[CD68]] immunoreactivity,<ref name="pmid25667023" /> and [[enteric]] [[nerve fiber]] loss within the circular [[Smooth muscle|smooth muscle layer]] are characteristic findings of gastroparesis.<ref name="pmid22339929">{{cite journal| author=Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC et al.| title=Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. | journal=Neurogastroenterol Motil | year= 2012 | volume= 24 | issue= 6 | pages= 531-9, e249 | pmid=22339929 | doi=10.1111/j.1365-2982.2012.01894.x | pmc=3353102 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22339929  }}</ref>


==References==
==References==

Latest revision as of 15:37, 20 February 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]

Overview

The exact pathogenesis of gastroparesis is not fully understood. However, gastric emptying process is the result of interaction of smooth muscles, extrinsic and enteric autonomic nervous system, and interstitial cells of Cajal (ICC). Loss of expression of neuronal nitric oxide synthase (nNOS) and loss of interstitial cells of Cajal (ICC) play pivotal role in the pathogenesis of gastroparesis. Recent studies suggest that the loss of antioxidant gene expression (NRF2 gene) can contribute to the development of gastroparesis. NRF2 regulates expression of phase II antioxidant genes such as HO-1, SOD1, SOD2, GCLC, GCLM, CAT, and GPX1. On microscopic histopathological analysis of full thickness biopsy of the gastric body. Decreased number of interstitial cells of Cajal (also called fibroblast like cells) in circular muscle layer, immune cells infiltration of gastric tissue especially myenteric plexus predominantly consisting of lymphocytes and macrophages showing CD45 and CD68 immunoreactivity, and enteric nerve fiber loss within the circular smooth muscle layer are characteristic findings of gastroparesis.

Pathophysiology

Pathogenesis

Genetics

Associated Conditions

The following conditions may be associated with gastroparesis:

Gross Pathology

On gross pathology, no abnormalities seen on obtaining full thickness biopsy of gastric tissue.

Microscopic Pathology

On microscopic histopathological analysis of full thickness biopsy of the gastric body. Decreased number of interstitial cells of Cajal (also called fibroblast like cells) in circular muscle layer, immune cells infiltration of gastric tissue especially myenteric plexus predominantly consisting of lymphocytes and macrophages showing CD45 and CD68 immunoreactivity,[3] and enteric nerve fiber loss within the circular smooth muscle layer are characteristic findings of gastroparesis.[11]

References

  1. 1.0 1.1 Oh JH, Pasricha PJ (2013). "Recent advances in the pathophysiology and treatment of gastroparesis". J Neurogastroenterol Motil. 19 (1): 18–24. doi:10.5056/jnm.2013.19.1.18. PMC 3548121. PMID 23350043.
  2. Camborová P, Hubka P, Sulková I, Hulín I (2003). "The pacemaker activity of interstitial cells of Cajal and gastric electrical activity". Physiol Res. 52 (3): 275–84. PMID 12790758.
  3. 3.0 3.1 Parkman HP (2015). "Idiopathic gastroparesis". Gastroenterol Clin North Am. 44 (1): 59–68. doi:10.1016/j.gtc.2014.11.015. PMC 4324534. PMID 25667023.
  4. Cheng LK (2015). "Slow wave conduction patterns in the stomach: from Waller's foundations to current challenges". Acta Physiol (Oxf). 213 (2): 384–93. doi:10.1111/apha.12406. PMC 4405773. PMID 25313679.
  5. Anuras S, Cooke AR, Christensen J (1974). "An inhibitory innervation at the gastroduodenal junction". J Clin Invest. 54 (3): 529–35. doi:10.1172/JCI107789. PMC 301585. PMID 4152775.
  6. Ekblad E, Mulder H, Uddman R, Sundler F (1994). "NOS-containing neurons in the rat gut and coeliac ganglia". Neuropharmacology. 33 (11): 1323–31. PMID 7532815.
  7. Sivarao DV, Mashimo H, Goyal RK (2008). "Pyloric sphincter dysfunction in nNOS-/- and W/Wv mutant mice: animal models of gastroparesis and duodenogastric reflux". Gastroenterology. 135 (4): 1258–66. doi:10.1053/j.gastro.2008.06.039. PMC 2745304. PMID 18640116.
  8. 8.0 8.1 Mukhopadhyay S, Sekhar KR, Hale AB, Channon KM, Farrugia G, Freeman ML; et al. (2011). "Loss of NRF2 impairs gastric nitrergic stimulation and function". Free Radic Biol Med. 51 (3): 619–25. doi:10.1016/j.freeradbiomed.2011.04.044. PMC 3129370. PMID 21605664.
  9. Gibbons SJ, Grover M, Choi KM, Wadhwa A, Zubair A, Wilson LA; et al. (2017). "Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis". PLoS One. 12 (11): e0187772. doi:10.1371/journal.pone.0187772. PMC 5697813. PMID 29161307.
  10. Triadafilopoulos G, Nguyen L, Clarke JO (2017). "Patients with symptoms of delayed gastric emptying have a high prevalence of oesophageal dysmotility, irrespective of scintigraphic evidence of gastroparesis". BMJ Open Gastroenterol. 4 (1): e000169. doi:10.1136/bmjgast-2017-000169. PMC 5689484. PMID 29177065.
  11. Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC; et al. (2012). "Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium". Neurogastroenterol Motil. 24 (6): 531–9, e249. doi:10.1111/j.1365-2982.2012.01894.x. PMC 3353102. PMID 22339929.

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