Zollinger-Ellison syndrome pathophysiology: Difference between revisions

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Zollinger-Ellison syndrome results from increased levels of [[gastrin]] due to an existing [[gastrinoma]] in the [[duodenum]] or [[pancreas]].
Zollinger-Ellison syndrome results from increased levels of [[gastrin]] due to an existing [[gastrinoma]] in the [[duodenum]] or [[pancreas]].


==Pathogenesis==
==Pathophysiology==
*Zollinger-Ellison syndrome is a disorder where the production of increased levels of [[gastrin]] causes the [[stomach]] to release excess amounts of [[hydrochloric acid]]. [[Gastrin]] then results in an excessive production of acid which often may lead to [[peptic ulcers]] (in almost 95% of patients).<ref name="wikipedia">wikipedia.2015.https://en.wikipedia.org/wiki/Zollinger%E2%80%93Ellison_syndrome</ref>
 
*Increased basal [[gastric acid]] output and [[hyperplasia|hyyperplasia]] of the fundic [[parietal cells]] occur as a result of excessive amounts of [[gastrin]] that secreted by the gastrinoma tumor cells. The excessive [[gastric acid]] output overrides the mucosal defense of the [[gastric]] and [[duodenal]] wall thereby causing [[ulceration]], and inactivation of [[pancreatic]] digestive enzymes which therefore results in fat [[malabsorption]] and [[diarrhea]]. Secretory nature of [[diarrhea]] is a result of the inhibition of absorption of [[sodium]] and water by the [[small intestine]]. <ref name="urlGastrinoma - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK441842/ |title=Gastrinoma - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
=== Physiology ===
*The pathophysiology of ZES is the stimulatory action of [[gastrin]] on the [[parietal cells]] of the gastric [[antrum]] resulting in hyper-secretory acid milieu. <ref name="pmid24319020">{{cite journal |vauthors=Epelboym I, Mazeh H |title=Zollinger-Ellison syndrome: classical considerations and current controversies |journal=Oncologist |volume=19 |issue=1 |pages=44–50 |year=2014 |pmid=24319020 |pmc=3903066 |doi=10.1634/theoncologist.2013-0369 |url=}}</ref>
 
*Majority of patients with ZES also develop [[peptic ulcers]] which are large and multiple in number, usually in the distal [[duodenum]] and proximal [[jejunum]] (which usually would be an uncommon location for [[ulcers]] arising due to [[Helicobacter pylori]] or by the use of [[nonsteroidal anti-inflammatory drugs]]). <ref name="pmid24319020">{{cite journal |vauthors=Epelboym I, Mazeh H |title=Zollinger-Ellison syndrome: classical considerations and current controversies |journal=Oncologist |volume=19 |issue=1 |pages=44–50 |year=2014 |pmid=24319020 |pmc=3903066 |doi=10.1634/theoncologist.2013-0369 |url=}}</ref>
* Chemotransmitters, which are delivered to the [[gastric mucosa]], have a main role in the stimulation and inhibition of [[gastric acid]] and [[pepsin]] production.<ref name="pmid18474247">{{cite journal| author=Schubert ML, Peura DA| title=Control of gastric acid secretion in health and disease. | journal=Gastroenterology | year= 2008 | volume= 134 | issue= 7 | pages= 1842-60 | pmid=18474247 | doi=10.1053/j.gastro.2008.05.021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18474247  }} </ref>
*[[Gastric acid]] is responsible for [[protein]] [[digestion]], absorption of [[calcium]], [[iron]], [[vitamin B12]], [[Thyroid hormone|thyroid hormones]] and some drugs ([[itraconazole]] and [[ketoconazole]]).<ref name="pmid25040647">{{cite journal| author=Irving SA, Vadiveloo T, Leese GP| title=Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). | journal=Clin Endocrinol (Oxf) | year= 2015 | volume= 82 | issue= 1 | pages= 136-41 | pmid=25040647 | doi=10.1111/cen.12559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25040647  }} </ref>
*[[Gastric acid]] is responsible for lowering [[Stomach|gastric]] [[pH]].
*[[Acid|Acidic]] [[pH]] kills [[Microorganism|microorganisms]], reduces [[bacterial growth]], and prevents [[Intestine|intestinal]] [[infection]] and [[bacterial peritonitis]].<ref name="pmid25151556">{{cite journal| author=Hegarty JP, Sangster W, Harris LR, Stewart DB| title=Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection. | journal=Surgery | year= 2014 | volume= 156 | issue= 4 | pages= 972-8 | pmid=25151556 | doi=10.1016/j.surg.2014.06.074 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25151556  }} </ref><ref name="pmid24674763">{{cite journal| author=Buendgens L, Bruensing J, Matthes M, Dückers H, Luedde T, Trautwein C et al.| title=Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. | journal=J Crit Care | year= 2014 | volume= 29 | issue= 4 | pages= 696.e11-5 | pmid=24674763 | doi=10.1016/j.jcrc.2014.03.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24674763  }} </ref>
*[[Gastric acid|Acid]] [[secretion]] has 3 phases:<ref name="pmid15703599">{{cite journal| author=Schubert ML| title=Gastric secretion. | journal=Curr Opin Gastroenterol | year= 2003 | volume= 19 | issue= 6 | pages= 519-25 | pmid=15703599 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15703599  }} </ref>
 
:1. Cephalic
 
:*Mediated by [[Vagus nerve|vagal]] stimulation during thinking about, smelling, and seeing food.
 
:2. Gastric
 
:*The major mediator for acid secretion due to [[stomach]] distension and [[chemical]] effects related to the food.
 
:3. Intestinal
 
:*Small mediator for acid secretion due to chemical effects of food
 
* Acid secretion mediated by some pathways:<ref name="pmid16149129">{{cite journal| author=Geibel JP| title=Role of potassium in acid secretion. | journal=World J Gastroenterol | year= 2005 | volume= 11 | issue= 34 | pages= 5259-65 | pmid=16149129 | doi= | pmc=4622792 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16149129  }} </ref><ref name="pmid17928547">{{cite journal| author=Heitzmann D, Warth R| title=No potassium, no acid: K+ channels and gastric acid secretion. | journal=Physiology (Bethesda) | year= 2007 | volume= 22 | issue=  | pages= 335-41 | pmid=17928547 | doi=10.1152/physiol.00016.2007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17928547  }} </ref>
**[[Parietal cell|Parietal cells]]
*** Contains the hydrogen-potassium-ATPase acid-secreting pump which controls acid secretion
**[[Gastrin]]<ref name="pmid24279703">{{cite journal| author=Waldum HL, Hauso Ø, Fossmark R| title=The regulation of gastric acid secretion - clinical perspectives. | journal=Acta Physiol (Oxf) | year= 2014 | volume= 210 | issue= 2 | pages= 239-56 | pmid=24279703 | doi=10.1111/apha.12208 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24279703  }} </ref>
*** Main [[hormone]] involved in acid secretion
***[[G cell|Gastrin-expressing cells (G cells)]] are located in the [[antrum]] and are responsible for [[gastrin]] [[secretion]].
***[[Gastrin]] stimulates [[gastrin]] [[secretion]] from [[Parietal cell|parietal cells]] by [[histamine]] release from [[Enterochromaffin cells|enterochromaffin-like (ECL) cells]].
***[[Gastrin]] activates [[Cholecystokinin receptor|cholecystokinin (CCK) 2 receptor]] and somatostatin-secreting D cells.<ref name="pmid2859810">{{cite journal| author=Soll AH, Amirian DA, Park J, Elashoff JD, Yamada T| title=Cholecystokinin potently releases somatostatin from canine fundic mucosal cells in short-term culture. | journal=Am J Physiol | year= 1985 | volume= 248 | issue= 5 Pt 1 | pages= G569-73 | pmid=2859810 | doi=10.1152/ajpgi.1985.248.5.G569 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2859810  }} </ref><ref name="pmid1373504">{{cite journal| author=Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY et al.| title=Expression cloning and characterization of the canine parietal cell gastrin receptor. | journal=Proc Natl Acad Sci U S A | year= 1992 | volume= 89 | issue= 8 | pages= 3605-9 | pmid=1373504 | doi= | pmc=48917 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1373504  }} </ref>
* Acid secretion is stimulated by [[histamine]] release, [[gastrin]] release, and [[acetylcholine]] release.<ref name="pmid7502535">{{cite journal| author=Sachs G, Prinz C, Loo D, Bamberg K, Besancon M, Shin JM| title=Gastric acid secretion: activation and inhibition. | journal=Yale J Biol Med | year= 1994 | volume= 67 | issue= 3-4 | pages= 81-95 | pmid=7502535 | doi= | pmc=2588922 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7502535  }} </ref>.
* Acid secretion is inhibited by somatostatin secretion from oxyntic glands and antral D cells.
 
===Pathogenesis===
 
*[[Embryology|Embryologic]] [[endoderm]] produces [[enteroendocrine cells]] and these [[Cell (biology)|cells]] are considered as the origin of [[Gastrinoma|gastrinomas]].<ref name="pmid7904550">{{cite journal| author=Norton JA| title=Neuroendocrine tumors of the pancreas and duodenum. | journal=Curr Probl Surg | year= 1994 | volume= 31 | issue= 2 | pages= 77-156 | pmid=7904550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7904550  }}</ref>
* Symptoms of Zollinger-Ellison syndrome are related to hypergastrinemia.<ref name="pmid17108778">{{cite journal| author=Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT| title=Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. | journal=Medicine (Baltimore) | year= 2006 | volume= 85 | issue= 6 | pages= 295-330 | pmid=17108778 | doi=10.1097/01.md.0000236956.74128.76 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17108778  }}</ref>
*[[Hypertrophy (medical)|Hypertrophy]] of [[gastrin]] [[Mucous membrane|mucosa]] results in hypergastrinemia.
*[[Gastric acid]] [[secretion]] increases four to six-fold.
* Hypergastrinemia results from increase activity of parietal cells and histamine-secreting enterochromaffin-like cells.
*Gastric acid secretion overrides the mucosal defense of the [[gastric]] and [[duodenal]] wall which may cause [[ulceration]] and inactivation of [[pancreatic]] enzymes.
*The majority of patients have large and multiple peptic ulcers located in distal duodenum and proximal jejunum.<ref name="pmid7439637">{{cite journal| author=McGuigan JE, Wolfe MM| title=Secretin injection test in the diagnosis of gastrinoma. | journal=Gastroenterology | year= 1980 | volume= 79 | issue= 6 | pages= 1324-31 | pmid=7439637 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7439637  }}</ref>
*Inactivation of pancreatic enzymes leads to fat [[malabsorption]] and [[diarrhea]].<ref name="urlGastrinoma - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK441842/ |title=Gastrinoma - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*High gastric acid secretion does not reabsorb in small intestine and colon; therefore, it results in chronic diarrhea.<ref name="pmid17108778" />
*Sodium and water do not reabsorb in presence of high volume of gastric acids which results in secretory diarrhea.
*The major factors related to fat malabsorption are as following:<ref name="pmid6824402">{{cite journal| author=King CE, Toskes PP| title=Nutrient malabsorption in the Zollinger-Ellison syndrome. Normalization during long-term cimetidine therapy. | journal=Arch Intern Med | year= 1983 | volume= 143 | issue= 2 | pages= 349-51 | pmid=6824402 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6824402  }} </ref>
** Gastric mucosal damage
** Inactivation of Pancreatic enzymes
** Bile salts precipitation


==Genetics==
==Genetics==
*The primary causative lesion is  assumed to develop sporadically in approximately 80% of the cases and in the rest of the recorded cases, this entity exists as a part of [[MEN, type 1|MEN-1]]; an [[Autosomal dominant inheritance|autosomal dominant]] disorder characterized by tumors of the [[pituitary]], the [[parathyroid]], and the [[pancreas]]. <ref name="pmid22723327">{{cite journal| author=Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR et al.| title=Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2990-3011 | pmid=22723327 | doi=10.1210/jc.2012-1230 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22723327  }} </ref>
*Approximately 75% of Zollinger-Ellison syndrome (ZES) patients develop sporadically. <ref name="pmid22723327">{{cite journal| author=Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR et al.| title=Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2990-3011 | pmid=22723327 | doi=10.1210/jc.2012-1230 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22723327  }} </ref>
*ZES occurs in 20–30% of patients as part of the [[MEN, type 1|Multiple Endocrine Neoplasia-type 1 syndrome]] ([[MEN1]] which is an an [[autosomal dominant]] disorder as a result of [[mutations]] in an 10-exon [[gene]] at 11q13. <ref name="pmid23363383">{{cite journal |vauthors=Ito T, Igarashi H, Uehara H, Jensen RT |title=Pharmacotherapy of Zollinger-Ellison syndrome |journal=Expert Opin Pharmacother |volume=14 |issue=3 |pages=307–21 |year=2013 |pmid=23363383 |pmc=3580316 |doi=10.1517/14656566.2013.767332 |url=}}</ref>
*Approximately 25% of patients are associated with [[MEN, type 1|Multiple Endocrine Neoplasia-type 1 syndrome]].<ref name="pmid171087783">{{cite journal| author=Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT| title=Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. | journal=Medicine (Baltimore) | year= 2006 | volume= 85 | issue= 6 | pages= 295-330 | pmid=17108778 | doi=10.1097/01.md.0000236956.74128.76 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17108778  }}</ref>
*[[MEN, type 1|MEN-1]]<nowiki/> is considered as an [[Autosomal dominant inheritance|autosomal dominant]] disorder defining by tumors of the [[pituitary]], the [[parathyroid]], and the [[pancreas]].<ref name="pmid171087782">{{cite journal| author=Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT| title=Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. | journal=Medicine (Baltimore) | year= 2006 | volume= 85 | issue= 6 | pages= 295-330 | pmid=17108778 | doi=10.1097/01.md.0000236956.74128.76 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17108778  }}</ref>
*[[MEN1]] results from [[mutations]] in an 10-exon [[gene]] at [[chromosome 11]]q13. <ref name="pmid23363383">{{cite journal |vauthors=Ito T, Igarashi H, Uehara H, Jensen RT |title=Pharmacotherapy of Zollinger-Ellison syndrome |journal=Expert Opin Pharmacother |volume=14 |issue=3 |pages=307–21 |year=2013 |pmid=23363383 |pmc=3580316 |doi=10.1517/14656566.2013.767332 |url=}}</ref>


==Associated Conditions==
==Associated Conditions==
*[[Multiple endocrine neoplasia type 1]] ([[MEN 1]])  
*[[Multiple endocrine neoplasia type 1]] ([[MEN 1]])<ref name="pmid9354421">{{cite journal| author=Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C et al.| title=Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. | journal=Cancer Res | year= 1997 | volume= 57 | issue= 21 | pages= 4682-6 | pmid=9354421 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9354421  }}</ref>
*[[Gastrinoma]]
*[[Gastrinoma]] (duodenal gastrinoma and pancreatic gastrinomas)<ref name="pmid79045502">{{cite journal| author=Norton JA| title=Neuroendocrine tumors of the pancreas and duodenum. | journal=Curr Probl Surg | year= 1994 | volume= 31 | issue= 2 | pages= 77-156 | pmid=7904550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7904550  }}</ref>
*Usually these gastriomas are small (less < 1 cm), multiple ones,less often to metastasize to liver rather than pancreatic gastrinomas.
*[[Peptic ulcer disease]]
*[[Peptic ulcer disease]]


Line 26: Line 73:
==Microscopic Pathology==
==Microscopic Pathology==
*A well-differentiated [[neuroendocrine tumor]] (NET) histologically typically shows an organ like arrangement of cells with nesting, trabecular, or gyriform patterns. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
*A well-differentiated [[neuroendocrine tumor]] (NET) histologically typically shows an organ like arrangement of cells with nesting, trabecular, or gyriform patterns. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
*The tumor cells are usually round with regular bland nuclei which produce large number of secretory granules with diffuse immunoexpression of [[neuroendocrine]] markers.Where as, the poorly differentiated [[neuroendocrine tumor]] (NET) shows a atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
*The tumor cells are usually round with regular bland nuclei which produce large number of secretory granules with diffuse immunoexpression of [[neuroendocrine]] markers where as, the poorly differentiated [[neuroendocrine tumor]] (NET) shows a atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
*Immunostaining for [[chromogranin A]] and [[synaptophysin]]  is an important step in the diagnosis of [[neuroendocrine]] tumors. In order to differentiate from other [[neuroendocrine tumors]] gastrin immunostaining may be used. [[somatostatin]] [[scintigraphy]] is considered an effective localizing tool as [[Gastrinoma|gastrinomas]] tend to express a high density of [[somatostatin]] receptors. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
*Immunostaining for [[chromogranin A]] and [[synaptophysin]]  is an important step in the diagnosis of [[neuroendocrine]] tumors. In order to differentiate from other [[neuroendocrine tumors]] [[gastrin]] [[immunostaining]] may be used. [[somatostatin]] [[scintigraphy]] is considered an effective localizing tool as [[Gastrinoma|gastrinomas]] tend to express a high density of [[somatostatin]] receptors. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>


<div align="left">
[[image:ZES_NET_Duodenum.jpg|thumb|500px|center|By Ed Uthman from Houston, TX, USA [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons]]
<gallery heights="175" widths="175">
Image:NET_Duodenum.jpg|Well-differentiated neuroendocrine tumor of the duodenum.
Image:NET_Pancreatic.jpg|Pancreatic neuroendocrine tumour.
Image:400px-Gastric neuroendocrine tumour - high mag.jpg|Gastric neuroendocrine tumour - high magnification
Image:400px-Gastric_neuroendocrine_tumour_-_intermed_mag.jpg|Gastric neuroendocrine tumour - intermed_magnification
Image:800px-Gastric neuroendocrine tumour - low mag.jpg|Gastric neuroendocrine tumour - low magnification
Image:Gastrinoma.jpg|Gastrinoma
</gallery>
</div>


==References==
==References==

Latest revision as of 01:55, 12 September 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2] Mohamad Alkateb, MBBCh [3]

Overview

Zollinger-Ellison syndrome results from increased levels of gastrin due to an existing gastrinoma in the duodenum or pancreas.

Pathophysiology

Physiology

1. Cephalic
  • Mediated by vagal stimulation during thinking about, smelling, and seeing food.
2. Gastric
  • The major mediator for acid secretion due to stomach distension and chemical effects related to the food.
3. Intestinal
  • Small mediator for acid secretion due to chemical effects of food

Pathogenesis

  • Embryologic endoderm produces enteroendocrine cells and these cells are considered as the origin of gastrinomas.[12]
  • Symptoms of Zollinger-Ellison syndrome are related to hypergastrinemia.[13]
  • Hypertrophy of gastrin mucosa results in hypergastrinemia.
  • Gastric acid secretion increases four to six-fold.
  • Hypergastrinemia results from increase activity of parietal cells and histamine-secreting enterochromaffin-like cells.
  • Gastric acid secretion overrides the mucosal defense of the gastric and duodenal wall which may cause ulceration and inactivation of pancreatic enzymes.
  • The majority of patients have large and multiple peptic ulcers located in distal duodenum and proximal jejunum.[14]
  • Inactivation of pancreatic enzymes leads to fat malabsorption and diarrhea.[15]
  • High gastric acid secretion does not reabsorb in small intestine and colon; therefore, it results in chronic diarrhea.[13]
  • Sodium and water do not reabsorb in presence of high volume of gastric acids which results in secretory diarrhea.
  • The major factors related to fat malabsorption are as following:[16]
    • Gastric mucosal damage
    • Inactivation of Pancreatic enzymes
    • Bile salts precipitation

Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

By Ed Uthman from Houston, TX, USA [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

References

  1. ↑ Schubert ML, Peura DA (2008). "Control of gastric acid secretion in health and disease". Gastroenterology. 134 (7): 1842–60. doi:10.1053/j.gastro.2008.05.021. PMID 18474247.
  2. ↑ Irving SA, Vadiveloo T, Leese GP (2015). "Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS)". Clin Endocrinol (Oxf). 82 (1): 136–41. doi:10.1111/cen.12559. PMID 25040647.
  3. ↑ Hegarty JP, Sangster W, Harris LR, Stewart DB (2014). "Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection". Surgery. 156 (4): 972–8. doi:10.1016/j.surg.2014.06.074. PMID 25151556.
  4. ↑ Buendgens L, Bruensing J, Matthes M, Dückers H, Luedde T, Trautwein C; et al. (2014). "Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea". J Crit Care. 29 (4): 696.e11–5. doi:10.1016/j.jcrc.2014.03.002. PMID 24674763.
  5. ↑ Schubert ML (2003). "Gastric secretion". Curr Opin Gastroenterol. 19 (6): 519–25. PMID 15703599.
  6. ↑ Geibel JP (2005). "Role of potassium in acid secretion". World J Gastroenterol. 11 (34): 5259–65. PMC 4622792. PMID 16149129.
  7. ↑ Heitzmann D, Warth R (2007). "No potassium, no acid: K+ channels and gastric acid secretion". Physiology (Bethesda). 22: 335–41. doi:10.1152/physiol.00016.2007. PMID 17928547.
  8. ↑ Waldum HL, Hauso Ø, Fossmark R (2014). "The regulation of gastric acid secretion - clinical perspectives". Acta Physiol (Oxf). 210 (2): 239–56. doi:10.1111/apha.12208. PMID 24279703.
  9. ↑ Soll AH, Amirian DA, Park J, Elashoff JD, Yamada T (1985). "Cholecystokinin potently releases somatostatin from canine fundic mucosal cells in short-term culture". Am J Physiol. 248 (5 Pt 1): G569–73. doi:10.1152/ajpgi.1985.248.5.G569. PMID 2859810.
  10. ↑ Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY; et al. (1992). "Expression cloning and characterization of the canine parietal cell gastrin receptor". Proc Natl Acad Sci U S A. 89 (8): 3605–9. PMC 48917. PMID 1373504.
  11. ↑ Sachs G, Prinz C, Loo D, Bamberg K, Besancon M, Shin JM (1994). "Gastric acid secretion: activation and inhibition". Yale J Biol Med. 67 (3–4): 81–95. PMC 2588922. PMID 7502535.
  12. ↑ Norton JA (1994). "Neuroendocrine tumors of the pancreas and duodenum". Curr Probl Surg. 31 (2): 77–156. PMID 7904550.
  13. ↑ 13.0 13.1 Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT (2006). "Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature". Medicine (Baltimore). 85 (6): 295–330. doi:10.1097/01.md.0000236956.74128.76. PMID 17108778.
  14. ↑ McGuigan JE, Wolfe MM (1980). "Secretin injection test in the diagnosis of gastrinoma". Gastroenterology. 79 (6): 1324–31. PMID 7439637.
  15. ↑ "Gastrinoma - StatPearls - NCBI Bookshelf".
  16. ↑ King CE, Toskes PP (1983). "Nutrient malabsorption in the Zollinger-Ellison syndrome. Normalization during long-term cimetidine therapy". Arch Intern Med. 143 (2): 349–51. PMID 6824402.
  17. ↑ Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR; et al. (2012). "Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)". J Clin Endocrinol Metab. 97 (9): 2990–3011. doi:10.1210/jc.2012-1230. PMID 22723327.
  18. ↑ Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT (2006). "Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature". Medicine (Baltimore). 85 (6): 295–330. doi:10.1097/01.md.0000236956.74128.76. PMID 17108778.
  19. ↑ Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT (2006). "Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature". Medicine (Baltimore). 85 (6): 295–330. doi:10.1097/01.md.0000236956.74128.76. PMID 17108778.
  20. ↑ Ito T, Igarashi H, Uehara H, Jensen RT (2013). "Pharmacotherapy of Zollinger-Ellison syndrome". Expert Opin Pharmacother. 14 (3): 307–21. doi:10.1517/14656566.2013.767332. PMC 3580316. PMID 23363383.
  21. ↑ Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C; et al. (1997). "Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas". Cancer Res. 57 (21): 4682–6. PMID 9354421.
  22. ↑ Norton JA (1994). "Neuroendocrine tumors of the pancreas and duodenum". Curr Probl Surg. 31 (2): 77–156. PMID 7904550.
  23. ↑ 23.0 23.1 23.2 Cingam S, Karanchi H. PMID 28722872. Missing or empty |title= (help)

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