Zollinger-Ellison syndrome pathophysiology: Difference between revisions

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==Overview==
==Overview==
Development of Zollinger-Ellison syndrome is the result of 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 increased levels of [[gastrin]] are produced, causing the [[stomach]] to produce excess [[hydrochloric acid]]. Often, the cause is a [[tumor]] ([[gastrinoma]]) of the [[duodenum]] or [[pancreas]] producing the hormone [[gastrin]]. Gastrin then causes an excessive production of acid which can 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>
 
*The gastrinoma tumor cells secrete excessive amounts of gastrin which leads to hyperplasia of the fundic parietal cells and increased basal gastric acid output. The excessive gastric acid output breaches the mucosal defenses of the gastric as well as the duodenal wall, causes ulceration, and inactivates pancreatic digestive enzymes with resultant fat malabsorption and diarrhea. Inhibition of absorption of sodium and water by the small intestine results in a secretory component of the diarrhea. <ref name="pmid28722872">{{cite journal |vauthors=Cingam S, Karanchi H |title= |journal= |volume= |issue= |pages= |year= |pmid=28722872 |doi= |url=}}</ref>
=== Physiology ===
*Gastrin works on stomach [[parietal cell]]s causing them to [[Hydrogen potassium ATPase|secrete]] more [[hydrogen ion]]s into the stomach lumen. In addition, gastrin acts as a trophic factor for [[parietal cells]], causing [[parietal cell]] hyperplasia. Thus, there is an increase in the number of acid secreting cells and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of [[peptic ulcer]]s in the stomach and [[duodenum]]. High acid levels lead to multiple [[ulcer]]s in the [[stomach]] and [[small bowel]].
 
*The pathophysiology of ZES is related to the trophic action of gastrin on parietal cells of the gastric antrum and the resulting hypersecretory acid milleu. <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>
*An overwhelming majority of patients with this disease consequently develop [[peptic ulcers]], often large and multiple, frequently in distal [[duodenum]] and even proximal [[jejunum]] (an uncommon location for [[ulcers]] resulting from [[Helicobacter pylori]] or 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>
*[[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==
*Approximately 80% of the time, the primary causative lesion is thought to arise sporadically; in the remainder of recorded cases, this entity exists as part of [[Multiple endocrine neoplasia|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>
*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]]


==Gross Pathology==
==Gross Pathology==
*Gross pathology presents as enlarged fundic mucosal folds with cerebriform pattern.
*Gross pathology presents as enlarged [[Fundus (stomach)|fundic mucosal folds]] with cerebriform pattern.


==Microscopic Pathology==
==Microscopic Pathology==
*Histologically, well-differentiated neuroendocrine tumor (NET) has a typical organoid 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 round with regular bland nuclei and produce large amounts of secretory granules with diffuse immunoexpression of neuroendocrine markers. In contrast, the poorly differentiated NET has 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>
*An important feature for the diagnosis of neuroendocrine tumors is immunostaining for chromogranin A and synaptophysin. Gastrin immunostaining can be used to differentiate from other neuroendocrine tumors. Gastrinomas express a high density of somatostatin receptors, thus making somatostatin scintigraphy an effective localizing tool. <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.
</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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