Constipation pathophysiology: Difference between revisions

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{{CMG}}; {{AE}} {{M.P}}
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==Overview==
==Overview==
The underlying pathophysiology of constipation involves several processes such as hardening of the stool, paralysis or slow transit, constriction in the lower gastrointestinal system or psychomotor factors.
About 1.5 liter fluid enters the [[colon]] from [[small intestine]] every day. [[Colon]] only excrete out  200-400 mL [[stool]]. The [[defecation]] process consist of three important stages, include filling of the [[rectum]], sensation of [[rectum]] fullness, and relaxation of [[pelvic floor muscles]] in a coordinated fashion. Primary constipation is caused by [[anorectal]] and colonic problems, while secondary constipation is caused by organic and [[metabolic diseases]] or [[medications]]. [[Diseases]] that disturb the [[nervous system]] may lead to constipation, such as [[diabetes mellitus]], [[autonomic neuropathy]], [[Chagas' disease]], and [[Hirschsprung's disease]]. Chronic use of the [[laxative]] may lead to [[melanosis coli]], which is identified by [[hyperpigmentation]] and brownish discoloration of [[Colon|colonic]] [[mucosa]]. The primary [[histopathological]] finding in [[melanosis coli]] is brown granular [[pigment]] in [[lamina propria]].


==Pathophysiology==
==Pathophysiology==
* '''Hardening of the feces''': Improper [[mastication]], low [[dietary fiber]], [[dehydration]] and medications ([[aluminium]], [[calcium]], [[diuretic]], [[iron]]).
 
* '''Paralysis or slowed transit''': [[Hypothyroidism]], [[hypokalemia]], injured [[Anus|anal sphincter]], medications ([[loperamide]], [[codeine]], [[morphine]], [[tricyclic antidepressants]]) and severe systemic illness due to other causes.
=== Colonic Function ===
* '''Constriction, where part of the intestine or rectum is narrowed or blocked''': [[Diverticulosis]], [[pelvic masses]] and [[stenosis]].
* [[Water absorption]]
* '''Psychosomatic constipation''': [[Functional constipation]] and [[irritable bowel syndrome]].<ref>{{cite journal |author=Caldarella MP, Milano A, Laterza F, ''et al'' |title=Visceral sensitivity and symptoms in patients with constipation- or diarrhea-predominant irritable bowel syndrome (IBS): effect of a low-fat intraduodenal infusion |journal=Am. J. Gastroenterol. |volume=100 |issue=2 |pages=383–9 |year=2005 |pmid=15667496 |doi=10.1111/j.1572-0241.2005.40100.x}}</ref>
** About 1.5 liter fluid enters the [[colon]] from [[small intestine]] every day. [[Colon]] excrete out only 200-400 mL [[stool]].
** [[Colon]] absorb water and transit the [[stool]] into [[rectum]] to store and expel. The amount of [[water]] that is absorbed in [[rectum]] depends on the state of [[hydration]].<ref name=":0">{{cite book | last = Sleisenger | first = Marvin | title = Sleisenger and Fordtran's gastrointestinal and liver disease : pathophysiology, diagnosis, management | publisher = Saunders/Elsevier | location = Philadelphia | year = 2010 | isbn = 9781437727678 }}</ref>
** Both [[sodium]] and [[chloride]] are the key elements in reabsorbing [[water]] from [[colon]]. The more time [[stool]] remains in the [[colon]], the drier it becomes.<ref name="pmid22114753">{{cite journal| author=Andrews CN, Storr M| title=The pathophysiology of chronic constipation. | journal=Can J Gastroenterol | year= 2011 | volume= 25 Suppl B | issue=  | pages= 16B-21B | pmid=22114753 | doi= | pmc=3206564 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22114753  }}</ref>
* [[Motility]]
** There are two mechanism of gross [[motility]] in colon including:<ref name=":0" />
*** Repetitive non-propulsive [[contractions]]: The primary type of [[contraction]] responsible for mixing and absorption of contents.
*** High-amplitude propagated [[contractions]] (HAPCs): Large coordinated [[contraction]] responsible for pushing the [[stool]] forward. Increases in the morning and after drinking and/or eating.
** Normal colonic transit time is about 20-72 hours.<ref name="pmid19488763">{{cite journal |vauthors=Southwell BR, Clarke MC, Sutcliffe J, Hutson JM |title=Colonic transit studies: normal values for adults and children with comparison of radiological and scintigraphic methods |journal=Pediatr. Surg. Int. |volume=25 |issue=7 |pages=559–72 |year=2009 |pmid=19488763 |doi=10.1007/s00383-009-2387-x |url=}}</ref>
** HAPCs are usually decreased in [[constipation]] and maybe the main [[pathophysiology]] of constipation.<ref name="pmid19824935">{{cite journal |vauthors=Dinning PG, Smith TK, Scott SM |title=Pathophysiology of colonic causes of chronic constipation |journal=Neurogastroenterol. Motil. |volume=21 Suppl 2 |issue= |pages=20–30 |year=2009 |pmid=19824935 |pmc=2982774 |doi=10.1111/j.1365-2982.2009.01401.x |url=}}</ref>
** On [[molecular]] basis, the primary movements of the [[gut]] ([[peristalsis]]) are regulated through [[serotonin]] ([[5 hydroxytryptamine|5-hydroxytriptamine [5HT]]]). [[5HT]] is released from [[enterochromaffin]] [[cells]] when the [[bowel]] wall undergo traction (e.g., due to food or [[bolus]]). There are seven subtypes of the [[5-HT receptor|5HT receptors]], among which [[5HT4 receptor|5HT<sub>4</sub>]] and [[5-HT receptor|5HT<sub>3</sub>]] are the most important for peristalsis. [[5HT4 receptor|5HT<sub>4</sub>]] drives [[5HT]] effect on the gut and [[5HT|5HT<sub>3</sub>]] is responsible for the [[bowel]] sensation.<ref name="pmid16678554">{{cite journal |vauthors=Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Taché Y, Wood JD |title=Fundamentals of neurogastroenterology: basic science |journal=Gastroenterology |volume=130 |issue=5 |pages=1391–411 |year=2006 |pmid=16678554 |doi=10.1053/j.gastro.2005.11.060 |url=}}</ref>
 
=== Defecation ===
* The [[defecation]] process consist of three important stages including:<ref name="pmid16771766">{{cite journal |vauthors=Bharucha AE |title=Pelvic floor: anatomy and function |journal=Neurogastroenterol. Motil. |volume=18 |issue=7 |pages=507–19 |year=2006 |pmid=16771766 |doi=10.1111/j.1365-2982.2006.00803.x |url=}}</ref>
*# Filling of the [[rectum]]
*# Sensation of [[rectum]] fullness
*# [[Relaxation]] of [[pelvic floor muscles]] in a coordinated fashion
* [[Anal sphincter|Anal sphincters]] and [[puborectalis]] [[muscle]] are anatomical contributors of normal [[fecal]] consistency.
* Resting [[anal sphincter]] tone is due to both involuntary [[Internal anal sphincter|internal]] (70%) and voluntary [[External anal sphincter|external]] (30%) anal [[sphincters]] tone.
* Rectoanal inhibitory reflex (RAIR) consist of relaxing the [[internal anal sphincter]] in response to [[rectal]] distention due to flatus or [[stool]]. RAIR is completely regulated by the [[gut]] and is not controlled by [[Peripheral nervous system|peripheral]] or [[central nervous system]]. Presence of RAIR rules out [[Hirschsprung's disease]] as a differential diagnosis.<ref name="pmid22114753" />
* When [[stool]] enters in [[rectum]], the [[Internal anal sphincter|internal sphincter]] is relaxed by [[reflex]]. If the [[defecation]] is inconvenient, the [[puborectalis muscle]] is contracted and [[External anal sphincter|external sphincter]] is closed.  In case [[defecation]] is desired, the [[puborectalis muscle]] is voluntarily relaxed and [[External anal sphincter|external sphincter]] is opened. Therefore, [[defecation]] may be assisted with [[valsalva maneuver]].<ref name="pmid20601142">{{cite journal |vauthors=Rao SS |title=Advances in diagnostic assessment of fecal incontinence and dyssynergic defecation |journal=Clin. Gastroenterol. Hepatol. |volume=8 |issue=11 |pages=910–9 |year=2010 |pmid=20601142 |pmc=2964406 |doi=10.1016/j.cgh.2010.06.004 |url=}}</ref>
 
=== Pathogenesis ===
* Primary constipation is caused by [[anorectal]] and colonic problems, while secondary constipation is caused by organic and [[metabolic diseases]] or [[medications]].
 
==== Primary constipation ====
* Primary constipation is considered when the secondary causes of [[constipation]] are ruled out. Without any certain causes or alarm signs, [[empiric therapy]] with [[Dietary fiber|dietary fibers]] and [[laxatives]] is administered. If the [[laxative]] treatment is successful, there will be no need to additional work up.
* Colonic transit test is needed if further work up is necessary for constipation. The procedure consist of [[ingestion]] of marker-contained capsule and taking an [[abdominal X-ray]] after 120 h (5 days).<ref name="pmid21138500">{{cite journal |vauthors=Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, Scott MS, Simren M, Soffer E, Szarka L |title=Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies |journal=Neurogastroenterol. Motil. |volume=23 |issue=1 |pages=8–23 |year=2011 |pmid=21138500 |doi=10.1111/j.1365-2982.2010.01612.x |url=}}</ref>
* After locating and counting the markers, if more than 20% of markers remains within the [[colon]], it is defined as slow transit [[disease]].
** '''Normal-transit constipation'''
*** The most common form of constipation referred to [[clinicians]] is normal transit constipation, which is also known as [[functional constipation]].<ref name="pmid16678561">{{cite journal |vauthors=Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC |title=Functional bowel disorders |journal=Gastroenterology |volume=130 |issue=5 |pages=1480–91 |year=2006 |pmid=16678561 |doi=10.1053/j.gastro.2005.11.061 |url=}}</ref>
*** Majority of the patients experience normal transit time and [[stool]] frequency. Numerous patients meet the criteria for [[Irritable bowel syndrome|irritable bowel syndrome with constipation (IBS-C)]] or [[Psychological|psychological disorders]].<ref name="pmid8561138">{{cite journal |vauthors=Ashraf W, Park F, Lof J, Quigley EM |title=An examination of the reliability of reported stool frequency in the diagnosis of idiopathic constipation |journal=Am. J. Gastroenterol. |volume=91 |issue=1 |pages=26–32 |year=1996 |pmid=8561138 |doi= |url=}}</ref>
*** '''''Rome III criteria''''' for [[functional constipation]] is presence of two or more than two of the followings for ≥ 3 months and onset ≥ 6 months before the [[diagnosis]]:<ref name="pmid16305718">{{cite journal |vauthors=Cash BD, Chey WD |title=Review article: The role of serotonergic agents in the treatment of patients with primary chronic constipation |journal=Aliment. Pharmacol. Ther. |volume=22 |issue=11-12 |pages=1047–60 |year=2005 |pmid=16305718 |doi=10.1111/j.1365-2036.2005.02696.x |url=}}</ref>
**** < 3 [[defecation]] per week
**** Straining during [[defecation]]
**** Lumpy or hard stool
**** Sensation if incomplete emptying of [[rectum]]
**** Sensation of in [[anorectal]] obstruction
**** Manual evacuation need for defecation
*** Most of the patients are cured with [[Dietary fiber|dietary fibers]], [[osmotic]] [[laxatives]], or enterokinetics.
** '''Slow-transit constipation'''
*** Slow-transit constipation is consisted of significant decreased number of [[Defecation|defecations]], less than once a week and the majority of times involve young women.<ref name="pmid3949236">{{cite journal |vauthors=Preston DM, Lennard-Jones JE |title=Severe chronic constipation of young women: 'idiopathic slow transit constipation' |journal=Gut |volume=27 |issue=1 |pages=41–8 |year=1986 |pmid=3949236 |pmc=1433176 |doi= |url=}}</ref>
*** The more severe form, called "colonic inertia", is the condition in which eating and [[Prokinetic|prokinetics]] does not lead to increase in motor activity and HAPCs.<ref name="pmid15300885">{{cite journal |vauthors=Bassotti G, Roberto GD, Sediari L, Morelli A |title=Toward a definition of colonic inertia |journal=World J. Gastroenterol. |volume=10 |issue=17 |pages=2465–7 |year=2004 |pmid=15300885 |pmc=4572142 |doi= |url=}}</ref>
*** The slow-transit constipation is due to decreased number of [[Interstitial cells of Cajal|interstitial cells of Cajal (ICC)]] and alteration of [[Myenteric plexus|myenteric plexus neurons]] which secretes [[substance P]].<ref name="pmid10611149">{{cite journal |vauthors=He CL, Burgart L, Wang L, Pemberton J, Young-Fadok T, Szurszewski J, Farrugia G |title=Decreased interstitial cell of cajal volume in patients with slow-transit constipation |journal=Gastroenterology |volume=118 |issue=1 |pages=14–21 |year=2000 |pmid=10611149 |doi= |url=}}</ref><ref name="pmid8980942">{{cite journal |vauthors=Tzavella K, Riepl RL, Klauser AG, Voderholzer WA, Schindlbeck NE, Müller-Lissner SA |title=Decreased substance P levels in rectal biopsies from patients with slow transit constipation |journal=Eur J Gastroenterol Hepatol |volume=8 |issue=12 |pages=1207–11 |year=1996 |pmid=8980942 |doi= |url=}}</ref>
*** Hypoganglionosis, [[inflammatory]] [[neuropathy]], and leiomyopathy are other causes of slow-transit constipation.
** '''Defecation disorder'''
*** Straining and spending long times in toilet are the main findings in patients with [[defecation]] disorder.
*** Patients with [[defecation]] disorder often have problems with both liquid and firm stools. Therefore, [[laxatives]] are not effective mostly.
*** [[Anorectal]] [[Manometry|manometery]] and balloon expulsion test are the [[Gold standard (test)|gold-standard]] tests for diagnosing functional defecation disorder.<ref name="pmid15984989">{{cite journal |vauthors=Rao SS, Ozturk R, Laine L |title=Clinical utility of diagnostic tests for constipation in adults: a systematic review |journal=Am. J. Gastroenterol. |volume=100 |issue=7 |pages=1605–15 |year=2005 |pmid=15984989 |doi=10.1111/j.1572-0241.2005.41845.x |url=}}</ref>
*** The majority of the functional defecation disorders are due to dyssynergia. Dyssynergia is an acquired condition due to disorganized toilet habits, chronic pain during [[defecation]], [[obstetrics]] and back injuries.<ref name="pmid187939972">{{cite journal |vauthors=Rao SS |title=Dyssynergic defecation and biofeedback therapy |journal=Gastroenterol. Clin. North Am. |volume=37 |issue=3 |pages=569–86, viii |year=2008 |pmid=18793997 |pmc=2575098 |doi=10.1016/j.gtc.2008.06.011 |url=}}</ref>
*** The primary defect in dyssynergia is lack of coordination among [[Abdominal muscles|abdominal]], [[Anorectal|rectoanal]], and [[pelvic floor muscles]] contractions during [[defecation]] process.<ref name="pmid187939972" />
 
==== Secondary constipation ====
* Most of [[medications]] can lead to constipation as a [[side effect]]. Therefore, a comprehensive history of medications is needed in every patients with constipation.<ref name="pmid21332973">{{cite journal |vauthors=Fosnes GS, Lydersen S, Farup PG |title=Constipation and diarrhoea - common adverse drug reactions? A cross sectional study in the general population |journal=BMC Clin Pharmacol |volume=11 |issue= |pages=2 |year=2011 |pmid=21332973 |pmc=3049147 |doi=10.1186/1472-6904-11-2 |url=}}</ref><ref name="pmid21194659">{{cite journal |vauthors=Simonson W, Han LF, Davidson HE |title=Hypertension treatment and outcomes in US nursing homes: results from the US National Nursing Home Survey |journal=J Am Med Dir Assoc |volume=12 |issue=1 |pages=44–9 |year=2011 |pmid=21194659 |doi=10.1016/j.jamda.2010.02.009 |url=}}</ref><ref name="pmid20658791">{{cite journal |vauthors=Dolder C, Nelson M, Stump A |title=Pharmacological and clinical profile of newer antidepressants: implications for the treatment of elderly patients |journal=Drugs Aging |volume=27 |issue=8 |pages=625–40 |year=2010 |pmid=20658791 |doi=10.2165/11537140-000000000-00000 |url=}}</ref><ref name="pmid12809835">{{cite journal |vauthors=Talley NJ, Jones M, Nuyts G, Dubois D |title=Risk factors for chronic constipation based on a general practice sample |journal=Am. J. Gastroenterol. |volume=98 |issue=5 |pages=1107–11 |year=2003 |pmid=12809835 |doi=10.1111/j.1572-0241.2003.07465.x |url=}}</ref><ref name="pmid21375137">{{cite journal |vauthors=Rosti G, Gatti A, Costantini A, Sabato AF, Zucco F |title=Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment |journal=Eur Rev Med Pharmacol Sci |volume=14 |issue=12 |pages=1045–50 |year=2010 |pmid=21375137 |doi= |url=}}</ref>
{|
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Group
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Drug
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Alternatives
|-
| rowspan="3" style="background:#DCDCDC;" align="center" + |'''[[Antihypertensives]]'''
| style="background:#DCDCDC;" align="center" + |[[Clonidine]]
| rowspan="3" style="background:#F5F5F5;" + |
* [[Beta-blockers]]
* [[Angiotensin-converting enzyme inhibitors]]
* [[Angiotensin II receptor antagonists]]
|-
| style="background:#DCDCDC;" align="center" + |[[Calcium channel blockers]]
|-
| style="background:#DCDCDC;" align="center" + |[[Ganglionic blocker|Ganglionic blockers]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Antidepressants]]'''
| style="background:#DCDCDC;" align="center" + |[[Tricyclic antidepressants]]
| style="background:#F5F5F5;" + |
* [[Selective serotonin reuptake inhibitor|Selective 5HT reuptake inhibitors]]
* [[Serotonin-norepinephrine-dopamine reuptake inhibitor|5HT norepinephrine reuptake inhibitors]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Cations|Cation]]-containing drugs'''
| style="background:#DCDCDC;" align="center" + |Oral [[iron]] supplementation
| style="background:#F5F5F5;" + |
* [[Intravenous]] supplementation of [[iron]]
* Addition of a [[laxative]]
|-
| rowspan="2" style="background:#DCDCDC;" align="center" + |'''[[Aluminium|Aluminum]]-containing drugs'''
| style="background:#DCDCDC;" align="center" + |[[Sucralfate]] 
| rowspan="2" style="background:#F5F5F5;" + |
* [[Proton pump inhibitors]]
|-
| style="background:#DCDCDC;" align="center" + |[[Antacids]]
|-
| rowspan="2" style="background:#DCDCDC;" align="center" + |'''[[Analgesics]]'''
| style="background:#DCDCDC;" align="center" + |[[Opiates]]
| rowspan="2" style="background:#F5F5F5;" + |
* Different class of [[analgesic drugs]]
* Using an [[opiate]] in combination with a peripherally active [[Opioid antagonist|opiate receptor antagonist]], such as [[naloxone]] or [[methylnaltrexone]]
|-
| style="background:#DCDCDC;" align="center" + |[[Cannabinoids]]
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |'''[[Parkinson's disease medical therapy|Anti-Parkinson]]'''
| rowspan="3" style="background:#F5F5F5;" + |
* Regular use of [[laxatives]]
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Antiepileptics|'''Antiepileptic''']]
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Antipsychotic|'''Antipsychotic''']]
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Antihistamines|'''Antihistamines''']]
| rowspan="3" style="background:#F5F5F5;" + |
* Replaced with other groups
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Antispasmodics|'''Antispasmodics''']]
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Vinca alkaloids|'''Vinca alkaloids''']]
|}
* [[Diseases]] that disturb the [[nervous system]] may lead to constipation, such as [[diabetes mellitus]], [[autonomic neuropathy]], [[Chagas' disease]], and [[Hirschsprung's disease]].
* Both [[hyperglycemia]] and [[hypoglycemia]] may lead to [[bowel movement]] disturbance and constipation.<ref name="pmid12594591">{{cite journal |vauthors=Takahashi T, Matsuda K, Kono T, Pappas TN |title=Inhibitory effects of hyperglycemia on neural activity of the vagus in rats |journal=Intensive Care Med |volume=29 |issue=2 |pages=309–11 |year=2003 |pmid=12594591 |doi=10.1007/s00134-002-1580-3 |url=}}</ref>
 
==Genetics==
*[[Genetic]] studies have shown the role of [[genetics]] in childhood constipation by various mechanisms.
*[[Genes]] involved in the [[pathogenesis]] of childhood constipation and related diseases are as following:<ref name="pmid21382580">{{cite journal |vauthors=Peeters B, Benninga MA, Hennekam RC |title=Childhood constipation; an overview of genetic studies and associated syndromes |journal=Best Pract Res Clin Gastroenterol |volume=25 |issue=1 |pages=73–88 |year=2011 |pmid=21382580 |doi=10.1016/j.bpg.2010.12.005 |url=}}</ref>
{|
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Group
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene
! style="background:#4479BA; color: #FFFFFF;" align="center" + |OMIM/Chromosome
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Syndrome
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Other manifestations
|-
| rowspan="9" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |'''Autonomic nervous system'''
| style="background:#DCDCDC;" align="center" + |[[GFAP]]
| style="background:#DCDCDC;" align="center" + |203450/17q21
| style="background:#F5F5F5;" align="center" + |[[Alexander disease]]
| style="background:#F5F5F5;" + |
* [[Seizures]]
* [[Neurodegeneration]]
* [[Spasticity]]
|-
| style="background:#DCDCDC;" align="center" + |[[LMNB2|LMNB1]]
| style="background:#DCDCDC;" align="center" + |169500/5q23
| style="background:#F5F5F5;" align="center" + |Cavitating [[leukodystrophy]] – autonomic failure
| style="background:#F5F5F5;" + |
* [[Cerebellar]] and [[pyramidal]] failure
* [[Orthostatic hypotension]]
* [[Bowel]] and [[bladder]] control problems
|-
| style="background:#DCDCDC;" align="center" + |[[PHOX2B]]
| style="background:#DCDCDC;" align="center" + |209880/4p12
| style="background:#F5F5F5;" align="center" + |[[Congenital central hypoventilation syndrome]]
| style="background:#F5F5F5;" + |
* [[Hypoventilation]]
* [[Ocular disease|Ocular abnormalities]]
* [[Hirschsprung disease]]
|-
| style="background:#DCDCDC;" align="center" + |[[HSN2]]
| style="background:#DCDCDC;" align="center" + |201300/12p13
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[Hereditary sensory and autonomic neuropathy 3|Hereditary sensory and autonomic neuropathy type II and III]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Autonomic dysfunction]]
* Defective [[lacrimation]]
* [[Incoordination]]
|-
| style="background:#DCDCDC;" align="center" + |[[IKBKAP]]
| style="background:#DCDCDC;" align="center" + |223900/9q31
|-
| style="background:#DCDCDC;" align="center" + |[[MECP2]]
| style="background:#DCDCDC;" align="center" + |300005/Xq28
| style="background:#F5F5F5;" align="center" + |[[MECP2]] duplication
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Hypotonia]]
* [[Seizure|Seizures]]
* [[Autonomic dysfunction|Autonomic dysfunctioning]]
* [[Spasticity]]
|-
| style="background:#DCDCDC;" align="center" + |[[SCN9A]]
| style="background:#DCDCDC;" align="center" + |167400/2q24
| style="background:#F5F5F5;" align="center" + |[[Paroxysmal extreme pain disorder]]
| style="background:#F5F5F5;" + |
* [[Rectal pain]]
* [[Sphincter]] [[hypertrophy]]
|-
| style="background:#DCDCDC;" align="center" + |[[TCF12 gene|TCF4]]
| style="background:#DCDCDC;" align="center" + |610954/18q21
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[Hopkins syndrome|Pitt-Hopkins syndrome]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Overbreathing]]
* [[Clubbing|Clubbing fingers]]
* Unusual face
* [[Hirschsprung disease]]
|-
| style="background:#DCDCDC;" align="center" + |[[NRXN1]]
| style="background:#DCDCDC;" align="center" + |610954/2p16.3
|-
| rowspan="4" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |'''Innervation'''
| style="background:#DCDCDC;" align="center" + |[[ATRX]]
| style="background:#DCDCDC;" align="center" + |301040/Xq13
| style="background:#F5F5F5;" align="center" + |[[Alpha-thalassemia X-Linked Mental Retardation|Alpha-thalassemia mental retardation syndrome]]
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Alpha-thalassemia]]
* [[Short stature]]
* [[Microcephaly]]
* Unusual face
* [[Hirschsprung disease]]
|-
| style="background:#DCDCDC;" align="center" + |[[RET gene|RET]]
| style="background:#DCDCDC;" align="center" + |162300/10q11
| style="background:#F5F5F5;" align="center" + |[[MEN, type 2b|MEN2B]]
| style="background:#F5F5F5;" + |
* [[Multiple endocrine adenomatosis]]
* Dysmorphic features
* [[Hirschsprung disease]]
* [[Gastrointestinal]] ganglioneuromatosis
|-
| style="background:#DCDCDC;" align="center" + |[[ZEB2]]
| style="background:#DCDCDC;" align="center" + |235730/2q22
| style="background:#F5F5F5;" align="center" + |[[Mowat-Wilson syndrome]]
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Microcephaly]]
* Unusual face
* [[Short stature]]
* [[Hirschsprung disease]]
|-
| style="background:#DCDCDC;" align="center" + |HPSE2
| style="background:#DCDCDC;" align="center" + |236730/10q24
| style="background:#F5F5F5;" align="center" + |[[Ochoa syndrome]]
| style="background:#F5F5F5;" + |
* Unusual [[facial expression]]
* Hydroureters
* [[Hydronephrosis]]
|-
| rowspan="13" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |'''Muscular'''
| style="background:#DCDCDC;" align="center" + |[[COL4A5]]
| rowspan="2" style="background:#DCDCDC;" align="center" + |308940/Xq22
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[Alport syndrome|Alport syndrome with diffuse leiomyomatosis]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Hematuria]]
* [[Leiomyomatosis]]
* [[Cataracts]]
* [[Deafness]]
|-
| style="background:#DCDCDC;" align="center" + |[[COL4A6]]
|-
| style="background:#DCDCDC;" align="center" + |PTRF-CAVIN
| style="background:#DCDCDC;" align="center" + |613327/17q21
| style="background:#F5F5F5;" align="center" + |[[Congenital generalized lipodystrophy|Congenital generalized lipodystrophy, type 4]]
| style="background:#F5F5F5;" + |
* [[Lipodystrophy]]
* [[Insulin resistance]]
* [[Pyloric stenosis]]
* [[Cardiac arrhythmia]]
|-
| style="background:#DCDCDC;" align="center" + |[[DES]]
| style="background:#DCDCDC;" align="center" + |601419/2q35
| style="background:#F5F5F5;" align="center" + |[[Desmin-related myopathy]]
| style="background:#F5F5F5;" + |
* [[Muscle weakness|Skeletal muscle weakness]]
* [[Cardiac disease|Cardiac problems]]
|-
| style="background:#DCDCDC;" align="center" + |[[SCN4A]]
| style="background:#DCDCDC;" align="center" + |170500/17q23
| style="background:#F5F5F5;" align="center" + |[[Hyperkalemic periodic paralysis|Hyperkalemic periodic paralysis (HYPP)]]
| style="background:#F5F5F5;" + |
* Episodic flaccid generalized muscle weakness
|-
| style="background:#DCDCDC;" align="center" + |[[ZNF3|ZNF9]]
| style="background:#DCDCDC;" align="center" + |160900/3q21
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[Myotonic dystrophy]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Myotonia]]
* [[Muscular dystrophy]]
* [[Cataract]]
* [[Hypogonadism]]
* [[Baldness|Frontal balding]]
|-
| style="background:#DCDCDC;" align="center" + |[[DMPK]]
| style="background:#DCDCDC;" align="center" + |602668/19q13
|-
| style="background:#DCDCDC;" align="center" + |[[SMN1]]
| style="background:#DCDCDC;" align="center" + |253300/5q12
| style="background:#F5F5F5;" align="center" + |[[Spinal muscular atrophy]]
| style="background:#F5F5F5;" + |
* [[Spinal muscular atrophy|Acute spinal muscular atrophy]]
* Severe [[hypotonia]]
|-
| style="background:#DCDCDC;" align="center" + |AXPC1
| style="background:#DCDCDC;" align="center" + |609033/1q31
| style="background:#F5F5F5;" align="center" + |[[Posterior column]] [[ataxia]] with [[retinitis pigmentosa]]
| style="background:#F5F5F5;" + |
* [[Posterior column]] [[ataxia]]
* [[Retinitis pigmentosa]]
* [[Esophageal achalasia]]
|-
| style="background:#DCDCDC;" align="center" + |[[CBP-1011|CBP]]
| style="background:#DCDCDC;" align="center" + |180849/16p13
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[Rubinstein-Taybi syndrome]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* Broad [[thumbs]]
* Broad [[Hallux|halluces]]
* Unusual face
* [[Growth retardation]]
|-
| style="background:#DCDCDC;" align="center" + |[[EP300]]
| style="background:#DCDCDC;" align="center" + |180849/22q13
|-
| style="background:#DCDCDC;" align="center" + |[[HUWE1]]
| style="background:#DCDCDC;" align="center" + |300706/Xp11
| style="background:#F5F5F5;" align="center" + |Turner mental retardation syndrome
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Macrocephaly]]
* [[Contractures]]
* [[Holoprosencephaly]]
|-
| style="background:#DCDCDC;" align="center" + |[[UPF3B]]
| style="background:#DCDCDC;" align="center" + |300676/Xq25
| style="background:#F5F5F5;" align="center" + |[[Fragile X syndrome|X-linked syndromic mental retardation -14]]
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Hypotonia]]
* Slender body build
* Long face
|-
| rowspan="5" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |'''Electrolyte disturbance'''
| style="background:#DCDCDC;" align="center" + |[[SLC12A3]]
| style="background:#DCDCDC;" align="center" + |263800/16q13
| style="background:#F5F5F5;" align="center" + |[[Gitelman syndrome]]
| style="background:#F5F5F5;" + |
* [[Metabolic alkalosis|Hypokalemic metabolic alkalosis]]
* Salt wasting
|-
| style="background:#DCDCDC;" align="center" + |[[SLC6A8]]
| style="background:#DCDCDC;" align="center" + |300036/Xq28
| style="background:#F5F5F5;" align="center" + |[[Creatinine]] transporter defect
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Hypotonia]]
* [[Seizure|Seizures]]
* [[Behavioral]] problems
|-
| style="background:#DCDCDC;" align="center" + |CASR
| style="background:#DCDCDC;" align="center" + |239200/3q21
| style="background:#F5F5F5;" align="center" + |[[Hyperparathyroidism]] – [[neonatal]] [[familial]]
| style="background:#F5F5F5;" + |
* [[Hypotonia]]
* [[Respiratory distress]]
* [[Irritability]]
* [[Polyuria]]
|-
| style="background:#DCDCDC;" align="center" + |[[AVP|AVPR2]]
| style="background:#DCDCDC;" align="center" + |304800/Xq28
| style="background:#F5F5F5;" align="center" + |[[Nephrogenic diabetes insipidus]]
| style="background:#F5F5F5;" + |
* [[Vomiting]]
* [[Anorexia]]
* [[Failure to thrive]]
* [[Fever]]
|-
| style="background:#DCDCDC;" align="center" + |[[SPINK5]]
| style="background:#DCDCDC;" align="center" + |256500/5q32
| style="background:#F5F5F5;" align="center" + |[[Netherton's syndrome|Netherton syndrome]]
| style="background:#F5F5F5;" + |
* [[Ichthyosis]]
* [[Eczema]]
* Brittle hair
* [[Alopecia]]
|-
| rowspan="5" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |'''Malformation'''
| style="background:#DCDCDC;" align="center" + |HLXB9
| style="background:#DCDCDC;" align="center" + |176450/7q36
| style="background:#F5F5F5;" align="center" + |[[Currarino syndrome]]
| style="background:#F5F5F5;" + |
* [[Anal atresia]]
* [[Sacral agenesis|Sacral anomalies]]
* Presacral mass
|-
| style="background:#DCDCDC;" align="center" + |[[MED12]]
| style="background:#DCDCDC;" align="center" + |305450/Xq13
| rowspan="2" style="background:#F5F5F5;" align="center" + |[[FG syndrome]]
| rowspan="2" style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Macrocephaly]]
* [[Anal]] malformation
* [[Pyloric stenosis]]
* [[Hypotonia]]
|-
| style="background:#DCDCDC;" align="center" + |FLNA
| style="background:#DCDCDC;" align="center" + |305450/Xq28
|-
| style="background:#DCDCDC;" align="center" + |[[SIX3]]
| style="background:#DCDCDC;" align="center" + |157170/2p21
| style="background:#F5F5F5;" align="center" + |[[Holoprosencephaly]]
| style="background:#F5F5F5;" + |
* [[Mental retardation|MR]]
* [[Microcephaly]]
* [[Cleft lip]]
* [[Cleft palate]]
* Hypotelorism
* [[Sacral agenesis]]
* [[Holoprosencephaly]]
|-
| style="background:#DCDCDC;" align="center" + |VANGL1
| style="background:#DCDCDC;" align="center" + |600145/1p13
| style="background:#F5F5F5;" align="center" + |[[Sacral]] defect with anterior [[meningocele]]
| style="background:#F5F5F5;" + |
* [[Caudal]] [[dysgenesis]]
|}
 
==Associated Conditions==
Associated conditions with constipation are included:
* [[Diabetes mellitus]]
* [[Hypothyroidism]]
* [[Systemic sclerosis]]
* [[Parkinson's disease]]
* [[Depression]]
* [[Eating disorders]]
* [[Colon cancer]]
* External compression from [[malignant]] lesion
* [[Strictures]]: [[diverticular]] or postischemic
* [[Rectocele]] (if large)
* [[Postsurgical]] abnormalities
* [[Megacolon]]
* [[Anal fissure]]
* [[Hypercalcemia]]
* [[Hypokalemia]]
* [[Hypomagnesemia]]
* [[Uremia]]
* [[Heavy metal poisoning]]
* [[Myopathies]]
* [[Parkinson's disease]]
* [[Spinal cord injury]] or [[tumor]]
* [[Cerebrovascular disease]]
* [[Depression]]
* [[Degenerative joint disease]]
* [[Autonomic neuropathy]]
* [[Cognitive impairment]]
* [[Immobility]]
* [[Cardiac disease]]
 
==Gross Pathology==
*On gross [[pathology]], there is no finding related to constipation.
==Microscopic Pathology==
*On microscopic [[histopathological]] analysis, there is no finding related to constipation.
*Chronic use of the [[laxative]] may lead to [[melanosis coli]], which is identified by [[hyperpigmentation]] and brownish discoloration of [[Colon|colonic]] [[mucosa]].
*The primary [[histopathological]] finding in [[melanosis coli]] is brown granular [[pigment]] in [[lamina propria]].
{| align: " right
|[[image:Melanosis coli (4130655629).jpg|thumb|200px|Melanosis coli with brown granular pigments, By Ed Uthman from Houston, TX, USA - Uploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30104213]]
|
[[image:Colon melanosis. 1.jpg|thumb|500px|Melanosis coli, By myself (Alex_brollo) - Slide files from Hospital of Monfalcone (Italy), CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1221399]]
|
[[image:Melanosis coli (4130655593).jpg|thumb|560px|Melanosis coli in laxative abusing patient, By Ed Uthman from Houston, TX, USA - Melanosis coliUploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30104214]]
|}


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}


[[Category:Needs content]]
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Latest revision as of 21:08, 29 July 2020

Constipation Microchapters

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Overview

Historical Perspective

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Differentiating Constipation from other Diseases

Epidemiology and Demographics

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

Overview

About 1.5 liter fluid enters the colon from small intestine every day. Colon only excrete out 200-400 mL stool. The defecation process consist of three important stages, include filling of the rectum, sensation of rectum fullness, and relaxation of pelvic floor muscles in a coordinated fashion. Primary constipation is caused by anorectal and colonic problems, while secondary constipation is caused by organic and metabolic diseases or medications. Diseases that disturb the nervous system may lead to constipation, such as diabetes mellitus, autonomic neuropathy, Chagas' disease, and Hirschsprung's disease. Chronic use of the laxative may lead to melanosis coli, which is identified by hyperpigmentation and brownish discoloration of colonic mucosa. The primary histopathological finding in melanosis coli is brown granular pigment in lamina propria.

Pathophysiology

Colonic Function

Defecation

Pathogenesis

Primary constipation

Secondary constipation

Group Drug Alternatives
Antihypertensives Clonidine
Calcium channel blockers
Ganglionic blockers
Antidepressants Tricyclic antidepressants
Cation-containing drugs Oral iron supplementation
Aluminum-containing drugs Sucralfate
Antacids
Analgesics Opiates
Cannabinoids
Anti-Parkinson
Antiepileptic
Antipsychotic
Antihistamines
  • Replaced with other groups
Antispasmodics
Vinca alkaloids

Genetics

  • Genetic studies have shown the role of genetics in childhood constipation by various mechanisms.
  • Genes involved in the pathogenesis of childhood constipation and related diseases are as following:[24]
Group Gene OMIM/Chromosome Syndrome Other manifestations
Autonomic nervous system GFAP 203450/17q21 Alexander disease
LMNB1 169500/5q23 Cavitating leukodystrophy – autonomic failure
PHOX2B 209880/4p12 Congenital central hypoventilation syndrome
HSN2 201300/12p13 Hereditary sensory and autonomic neuropathy type II and III
IKBKAP 223900/9q31
MECP2 300005/Xq28 MECP2 duplication
SCN9A 167400/2q24 Paroxysmal extreme pain disorder
TCF4 610954/18q21 Pitt-Hopkins syndrome
NRXN1 610954/2p16.3
Innervation ATRX 301040/Xq13 Alpha-thalassemia mental retardation syndrome
RET 162300/10q11 MEN2B
ZEB2 235730/2q22 Mowat-Wilson syndrome
HPSE2 236730/10q24 Ochoa syndrome
Muscular COL4A5 308940/Xq22 Alport syndrome with diffuse leiomyomatosis
COL4A6
PTRF-CAVIN 613327/17q21 Congenital generalized lipodystrophy, type 4
DES 601419/2q35 Desmin-related myopathy
SCN4A 170500/17q23 Hyperkalemic periodic paralysis (HYPP)
  • Episodic flaccid generalized muscle weakness
ZNF9 160900/3q21 Myotonic dystrophy
DMPK 602668/19q13
SMN1 253300/5q12 Spinal muscular atrophy
AXPC1 609033/1q31 Posterior column ataxia with retinitis pigmentosa
CBP 180849/16p13 Rubinstein-Taybi syndrome
EP300 180849/22q13
HUWE1 300706/Xp11 Turner mental retardation syndrome
UPF3B 300676/Xq25 X-linked syndromic mental retardation -14
Electrolyte disturbance SLC12A3 263800/16q13 Gitelman syndrome
SLC6A8 300036/Xq28 Creatinine transporter defect
CASR 239200/3q21 Hyperparathyroidism – neonatal familial
AVPR2 304800/Xq28 Nephrogenic diabetes insipidus
SPINK5 256500/5q32 Netherton syndrome
Malformation HLXB9 176450/7q36 Currarino syndrome
MED12 305450/Xq13 FG syndrome
FLNA 305450/Xq28
SIX3 157170/2p21 Holoprosencephaly
VANGL1 600145/1p13 Sacral defect with anterior meningocele

Associated Conditions

Associated conditions with constipation are included:

Gross Pathology

  • On gross pathology, there is no finding related to constipation.

Microscopic Pathology

Melanosis coli with brown granular pigments, By Ed Uthman from Houston, TX, USA - Uploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30104213
Melanosis coli, By myself (Alex_brollo) - Slide files from Hospital of Monfalcone (Italy), CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1221399
Melanosis coli in laxative abusing patient, By Ed Uthman from Houston, TX, USA - Melanosis coliUploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30104214

References

  1. ↑ 1.0 1.1 Sleisenger, Marvin (2010). Sleisenger and Fordtran's gastrointestinal and liver disease : pathophysiology, diagnosis, management. Philadelphia: Saunders/Elsevier. ISBN 9781437727678.
  2. ↑ 2.0 2.1 Andrews CN, Storr M (2011). "The pathophysiology of chronic constipation". Can J Gastroenterol. 25 Suppl B: 16B–21B. PMC 3206564. PMID 22114753.
  3. ↑ Southwell BR, Clarke MC, Sutcliffe J, Hutson JM (2009). "Colonic transit studies: normal values for adults and children with comparison of radiological and scintigraphic methods". Pediatr. Surg. Int. 25 (7): 559–72. doi:10.1007/s00383-009-2387-x. PMID 19488763.
  4. ↑ Dinning PG, Smith TK, Scott SM (2009). "Pathophysiology of colonic causes of chronic constipation". Neurogastroenterol. Motil. 21 Suppl 2: 20–30. doi:10.1111/j.1365-2982.2009.01401.x. PMC 2982774. PMID 19824935.
  5. ↑ Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Taché Y, Wood JD (2006). "Fundamentals of neurogastroenterology: basic science". Gastroenterology. 130 (5): 1391–411. doi:10.1053/j.gastro.2005.11.060. PMID 16678554.
  6. ↑ Bharucha AE (2006). "Pelvic floor: anatomy and function". Neurogastroenterol. Motil. 18 (7): 507–19. doi:10.1111/j.1365-2982.2006.00803.x. PMID 16771766.
  7. ↑ Rao SS (2010). "Advances in diagnostic assessment of fecal incontinence and dyssynergic defecation". Clin. Gastroenterol. Hepatol. 8 (11): 910–9. doi:10.1016/j.cgh.2010.06.004. PMC 2964406. PMID 20601142.
  8. ↑ Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, Scott MS, Simren M, Soffer E, Szarka L (2011). "Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies". Neurogastroenterol. Motil. 23 (1): 8–23. doi:10.1111/j.1365-2982.2010.01612.x. PMID 21138500.
  9. ↑ Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC (2006). "Functional bowel disorders". Gastroenterology. 130 (5): 1480–91. doi:10.1053/j.gastro.2005.11.061. PMID 16678561.
  10. ↑ Ashraf W, Park F, Lof J, Quigley EM (1996). "An examination of the reliability of reported stool frequency in the diagnosis of idiopathic constipation". Am. J. Gastroenterol. 91 (1): 26–32. PMID 8561138.
  11. ↑ Cash BD, Chey WD (2005). "Review article: The role of serotonergic agents in the treatment of patients with primary chronic constipation". Aliment. Pharmacol. Ther. 22 (11–12): 1047–60. doi:10.1111/j.1365-2036.2005.02696.x. PMID 16305718.
  12. ↑ Preston DM, Lennard-Jones JE (1986). "Severe chronic constipation of young women: 'idiopathic slow transit constipation'". Gut. 27 (1): 41–8. PMC 1433176. PMID 3949236.
  13. ↑ Bassotti G, Roberto GD, Sediari L, Morelli A (2004). "Toward a definition of colonic inertia". World J. Gastroenterol. 10 (17): 2465–7. PMC 4572142. PMID 15300885.
  14. ↑ He CL, Burgart L, Wang L, Pemberton J, Young-Fadok T, Szurszewski J, Farrugia G (2000). "Decreased interstitial cell of cajal volume in patients with slow-transit constipation". Gastroenterology. 118 (1): 14–21. PMID 10611149.
  15. ↑ Tzavella K, Riepl RL, Klauser AG, Voderholzer WA, Schindlbeck NE, Müller-Lissner SA (1996). "Decreased substance P levels in rectal biopsies from patients with slow transit constipation". Eur J Gastroenterol Hepatol. 8 (12): 1207–11. PMID 8980942.
  16. ↑ Rao SS, Ozturk R, Laine L (2005). "Clinical utility of diagnostic tests for constipation in adults: a systematic review". Am. J. Gastroenterol. 100 (7): 1605–15. doi:10.1111/j.1572-0241.2005.41845.x. PMID 15984989.
  17. ↑ 17.0 17.1 Rao SS (2008). "Dyssynergic defecation and biofeedback therapy". Gastroenterol. Clin. North Am. 37 (3): 569–86, viii. doi:10.1016/j.gtc.2008.06.011. PMC 2575098. PMID 18793997.
  18. ↑ Fosnes GS, Lydersen S, Farup PG (2011). "Constipation and diarrhoea - common adverse drug reactions? A cross sectional study in the general population". BMC Clin Pharmacol. 11: 2. doi:10.1186/1472-6904-11-2. PMC 3049147. PMID 21332973.
  19. ↑ Simonson W, Han LF, Davidson HE (2011). "Hypertension treatment and outcomes in US nursing homes: results from the US National Nursing Home Survey". J Am Med Dir Assoc. 12 (1): 44–9. doi:10.1016/j.jamda.2010.02.009. PMID 21194659.
  20. ↑ Dolder C, Nelson M, Stump A (2010). "Pharmacological and clinical profile of newer antidepressants: implications for the treatment of elderly patients". Drugs Aging. 27 (8): 625–40. doi:10.2165/11537140-000000000-00000. PMID 20658791.
  21. ↑ Talley NJ, Jones M, Nuyts G, Dubois D (2003). "Risk factors for chronic constipation based on a general practice sample". Am. J. Gastroenterol. 98 (5): 1107–11. doi:10.1111/j.1572-0241.2003.07465.x. PMID 12809835.
  22. ↑ Rosti G, Gatti A, Costantini A, Sabato AF, Zucco F (2010). "Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment". Eur Rev Med Pharmacol Sci. 14 (12): 1045–50. PMID 21375137.
  23. ↑ Takahashi T, Matsuda K, Kono T, Pappas TN (2003). "Inhibitory effects of hyperglycemia on neural activity of the vagus in rats". Intensive Care Med. 29 (2): 309–11. doi:10.1007/s00134-002-1580-3. PMID 12594591.
  24. ↑ Peeters B, Benninga MA, Hennekam RC (2011). "Childhood constipation; an overview of genetic studies and associated syndromes". Best Pract Res Clin Gastroenterol. 25 (1): 73–88. doi:10.1016/j.bpg.2010.12.005. PMID 21382580.

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