Ileus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
Ileus is defined as a temporary cessation of intestinal peristalsis in the absence of mechanical obstruction. The pathogenesis of ileus is based on its multifactorial etiology. Ileus is most commonly seen during the postoperative period (usually 3 days after surgery). When a patient undergoes a surgical procedure, it often puts the body under significant stress. It is thought that ileus is the result of a surgical stress-induced inflammatory process, that leads to the release of inflammatory and neuroendocrine mediators (such as nitric oxide, VIP and substance P). Additionally, manipulation of the intestine leads to activation of afferent pathways that travel to the brain stem, which leads to increased autonomic output to the sympathetic neurons and increased secretion of adrenergic neurotransmitters and subsequent decreased intestinal motility. Commonly used analgesics such as opiates and anesthesia may also aggravate the development of ileus. Enteric and autonomic nervous system disturbances can cause a severe form of ilues, called chronic intestinal pseudo-obstruction (CIPO) which may be related to some altered genes. Conditions commonly associated with ileus include diabetes mellitus, hypothyroidism, and hypoparathyroidism. Gross pathology findings of ileus include bowel contortion with a distended small and large intestine. On microscopic histopathological analysis, findings of ileus include inflammatory cells predominantly macrophages and mast cells.
Pathophysiology
Physiology
- The gastrointestinal tract is regulated by the enteric nervous system, autonomic nervous system and interacts with central nervous system.
- The enteric nervous system (ENS) is also known as an intrinsic neural network and consists of neurons located in the walls of Gastrointestinal tract.
- Enteric nervous system (ENS) includes the myenteric plexus (Auerbach's plexus) and submucosal plexuses (Meissner's plexus).
- The myenteric plexus is located in the muscular layer and is also known as the Auerbach's plexus.
- The submucosal plexuses is located in the submucosal layer and is also known as the Meissner's plexus.
- The autonomic nervous system (ANS) is also known as the extrinsic nervous system.
- The autonomic nervous system (ANS) consists of the sympathetic and parasympathetic nervous system, which control Gastrointestinal tract function.
- The sympathetic nervous system is inhibitory to visceral smooth muscle activity and decreases peristalsis and Gastrointestinal tract motility.
- The parasympathetic nervous system is stimulatory to visceral smooth muscle activity and increases peristalsis and Gastrointestinal tract motility.
- The afferent visceral sensory system of the GI tract is part of the parasympathetic nervous system, while the efferent visceral motor system is located in both sympathetic and parasympathetic autonomic nervous system.
- In addition, the extrinsic nervous system synapse with the enteric nervous system and relay information to the central nervous system.
Pathogenesis
- Ileus is defined as the temporary cessation of intestinal peristalsis in the absence of mechanical obstruction. The pathogenesis of ileus is based on its multifactorial etiology.[1][2][3]
- Intestinal peristalsis is primarily regulated by the enteric nervous system, autonomic nervous system and their interactions with the central nervous system (CNS). However, certain medications and metabolic products may also alter the normal intestinal equilibrium leading to temporary dysfunction in intestinal movements. Prolonged intestinal aperistalsis results in the accumulation of air and fluid in the intestinal lumen.
- The most common cause of ileus is abdominal surgery.[1][2][3]
- The risk of postoperative ileus depends upon the type of surgery; laparoscopic procedures have lower risk, compared to laparotomy which have the highest risk.
- The highest risk for postoperative ileus has been observed with colorectal surgeries.
- In fact, postoperative ileus (due to any surgery) is so common that it is sometimes regarded as a normal sequelae of surgery.
- Postoperative ileus that lasts longer than 3 days is termed as paralytic ileus or adynamic ileus.
- When a patient undergoes a surgical procedure, it often puts the body under significant stress.
- This surgical stress may lead to the release of inflammatory and neuroendocrine mediators (such as nitric oxide, VIP and substance P) that may result in the inhibition of intestinal motility and development of ileus.[4]
- Stress inducing conditions may lead to increased recruitment of dendritic cells, natural killer cells, monocytes, T cells, macrophages, and mast cells. The macrophages and mast cells are considered the key cells leading to the initiation and maintenance of the inflammatory process and release of chemical mediators.
- Recent research has shown that inhibition of inflammatory mediators (such as nitric oxide & VIP) may lead to improved gastrointestinal peristalsis and function.
- The site of the surgery is the most common affected part of the GI tract. However, recent research has shown that inflammation of the intestinal muscle may extend from the site of surgery to other parts of the intestinal tract.[5]
- Moreover, intestinal distention seen in ileus is contributed to serosal injury and may aggravate intestinal ischemia.
- Prolonged ileus leads to increased contact between various segments of intestine which predispose to fibrous adhesion formation, thereby further contributing to the severity of ileus. [6][7]
- Abdominal conditions such as gastroenteritis and peritonitis may also affect the intestinal motility leading to ileus.
- Abdominal incision leads to the activation of inhibitory spinal reflex which results in decreased movements of the intestine, as a regulatory mechanism.[8]
- The painful stimulates the spinal afferents that synapse in the spinal cord. The prevertebral adrenergic neurons in the spinal cord activate and inhibit intestinal motility via efferent nerves (sympathetic ANS).
- Additionally, manipulation of the intestine leads to the activation of afferent pathways that travel to the brain stem. In turn, the brain stem increases autonomic output to the sympathetic neurons located in the inter-medio-lateral column of the thoracic cord. The increased activity of sympathetic neurons results in increased secretion of adrenergic output and subsequent decreased intestinal motility.
- There is a chronic and severe form of ileus, known as chronic intestinal pseudo-obstruction (CIPO).[9][10][11]
- CIPO is a severe form of ileus resulting from disturbances in the enteric nervous system, autonomic nervous system and smooth muscle cell function.
- The cause of CIPO can be idiopathic, sporadic, or secondary to metabolic, connective tissue, endocrinologic, neurologic, and paraneoplastic disorders.[12]
- CIPO is often due to dysfunction in innervation of smooth muscle by the interstitial cells of Cajal resulting in partial or completely ineffective intestinal propulsion. However, any condition affecting the enteric nervous system, autonomic nervous system, smooth muscle cells and neuromuscular junction may lead to development of CIPO.
- The lack of propulsive intestinal movements may lead to increased intra-luminal pressure.
- The enhanced intra-luminal pressure leads to malabsorption and bacterial overgrowth. Over time, it can progress to present with malnutrition and sepsis.
- The other common cause of ileus are the drugs that affect intestinal motility and alteration in electrolyte levels.
- Drugs affecting intestinal motility primarily include antimotility agents and anesthetics.
- Anesthetic drugs: Anesthetic agents have a direct inhibitory effect on the intestinal motility. Long-acting anesthetic agents such as bupivacaine are more frequently associated with postopertaive ileus as compared to short-acting agents such as propofol.
- Opiates: The use of opiates for pain alleviation is not without side effects. In fact, opioid use has been associated with significant increase in the occurrence of postoperative ileus. Opioid medications that activate the µ (mu) receptors have been associated with decreased release of acetylcholine from cholinergic neurons, resulting in delayed intestinal motility. The most common opioid pain medication, morphine, initially activates the migrating myoelectric complex and later results in atony, resulting in inhibition of propulsion and delay in intestinal transit.
- Electrolyte abnormalities such as hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and metabolic acidosis may also lead to the development of intestinal ileus.
- Drugs affecting intestinal motility primarily include antimotility agents and anesthetics.
Genetics
There is no detected genetic disorder related to ileus, nevertheless, some cases of CIPO are related to alteration in FLNA and ACTG2 genes.
Associated Conditions
- Diabetes mellitus[13]
- Hypothyroidism[14]
- Hypoparathyroidism[15]
- Hirschsprung disease[16][17]
- Orthostatic hypotension[18]
- CNS neoplasms[19]
- Leiomyosarcomas[20]
- Radiation enteritis[21]
- Chagas disease[22]
Gross Pathology
Gross pathologic findings of ileus include:[23]
- Bowel contortion
- Distended small and large intestine
Microscopic Features
On microscopic histopathological analysis, findings of ileus include inflammatory cells predominantly macrophage and mast cells.
References
- ↑ 1.0 1.1 Kalff JC, Schraut WH, Simmons RL, Bauer AJ (1998). "Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus". Ann. Surg. 228 (5): 652–63. PMC 1191570. PMID 9833803.
- ↑ 2.0 2.1 Espat NJ, Cheng G, Kelley MC, Vogel SB, Sninsky CA, Hocking MP (1995). "Vasoactive intestinal peptide and substance P receptor antagonists improve postoperative ileus". J. Surg. Res. 58 (6): 719–23. doi:10.1006/jsre.1995.1113. PMID 7540700.
- ↑ 3.0 3.1 Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ (2000). "Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents". Gastroenterology. 118 (2): 316–27. PMID 10648460.
- ↑ Doherty TJ (2009). "Postoperative ileus: pathogenesis and treatment". Vet. Clin. North Am. Equine Pract. 25 (2): 351–62. doi:10.1016/j.cveq.2009.04.011. PMID 19580945.
- ↑ Bederman SS, Betsy M, Winiarsky R, Seldes RM, Sharrock NE, Sculco TP (2001). "Postoperative ileus in the lower extremity arthroplasty patient". J Arthroplasty. 16 (8): 1066–70. doi:10.1054/arth.2001.27675. PMID 11740765.
- ↑ Lundin C, Sullins KE, White NA and al. Induction of peritoneal adhesions with small intestinal ischaemia and distention in the foal. Equine Vet J 21: 451, 1989
- ↑ Vachon AM, Fisher AT. Small intestinal herniation through the epiploic foramen: 53 cases (1987-1993). Equine Vet J 27: 373, 1995
- ↑ Barquist E, Bonaz B, Martinez V, Rivier J, Zinner MJ, Taché Y (1996). "Neuronal pathways involved in abdominal surgery-induced gastric ileus in rats". Am. J. Physiol. 270 (4 Pt 2): R888–94. doi:10.1152/ajpregu.1996.270.4.R888. PMID 8967419.
- ↑ Di Nardo, G.; Di Lorenzo, C.; Lauro, A.; Stanghellini, V.; Thapar, N.; Karunaratne, T. B.; Volta, U.; De Giorgio, R. (2017). "Chronic intestinal pseudo-obstruction in children and adults: diagnosis and therapeutic options". Neurogastroenterology & Motility. 29 (1): e12945. doi:10.1111/nmo.12945. ISSN 1350-1925.
- ↑ Iida H, Ohkubo H, Inamori M, Nakajima A, Sato H (2013). "Epidemiology and clinical experience of chronic intestinal pseudo-obstruction in Japan: a nationwide epidemiologic survey". J Epidemiol. 23 (4): 288–94. PMC 3709546. PMID 23831693.
- ↑ Yeung AK, Di Lorenzo C (2012). "Primary gastrointestinal motility disorders in childhood". Minerva Pediatr. 64 (6): 567–84. PMID 23108319.
- ↑ Stanghellini V, Cogliandro RF, De Giorgio R, Barbara G, Morselli-Labate AM, Cogliandro L, Corinaldesi R (2005). "Natural history of chronic idiopathic intestinal pseudo-obstruction in adults: a single center study". Clin. Gastroenterol. Hepatol. 3 (5): 449–58. PMID 15880314.
- ↑ Hoeffel JC, Senot P, Champigneulle B, Drouin P (November 1980). "Gastric retention and gastric ileus in diabetes mellitus". Radiologe. 20 (11): 540–2. PMID 7208886.
- ↑ Rodrigo C, Gamakaranage CS, Epa DS, Gnanathasan A, Rajapakse S (February 2011). "Hypothyroidism causing paralytic ileus and acute kidney injury - case report". Thyroid Res. 4 (1): 7. doi:10.1186/1756-6614-4-7. PMC 3041782. PMID 21303532.
- ↑ Lord, Reginald V. N.; Sillin, Lelan F. (2010). "Motility Disorders of the Small Bowel": 17–26. doi:10.1007/978-1-84996-372-5_2.
- ↑ Kubota A, Imura K, Yagi M, Kawahara H, Mushiake S, Nakayama M, Kamata S, Okada A (December 1999). "Functional ileus in neonates: Hirschsprung's disease-allied disorders versus meconium-related ileus". Eur J Pediatr Surg. 9 (6): 392–5. doi:10.1055/s-2008-1072290. PMID 10661850.
- ↑ EHRENPREIS T (May 1951). "Meconium ileus and Hirschsprung's disease". Acta Paediatr. 40 (3): 227–32. PMID 14837740.
- ↑ Izumi Y, Masuda T, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N (October 2017). "Chronic Intestinal Pseudo-obstruction and Orthostatic Hypotension Associated with Small Cell Lung Cancer that Improved with Tumor Reduction after Chemoradiotherapy". Intern. Med. 56 (19): 2627–2631. doi:10.2169/internalmedicine.8574-16. PMC 5658530. PMID 28883237.
- ↑ Stengel A, Taché Y (December 2014). "Brain peptides and the modulation of postoperative gastric ileus". Curr Opin Pharmacol. 19: 31–7. doi:10.1016/j.coph.2014.06.006. PMC 4254047. PMID 24999843.
- ↑ Deck KB, Silverman H (July 1979). "Leiomyosarcomas of the small intestine". Cancer. 44 (1): 323–5. PMID 455259.
- ↑ Moeschl P, Miholic J (January 1989). "[Ileus following radiotherapy: importance and therapeutic aspects of surgery for late radiation injuries of the intestine]". Wien. Klin. Wochenschr. (in German). 101 (2): 84–7. PMID 2916344.
- ↑ Ferreira JA, Giani CA, Buiatti JB (October 1965). "[Megacolon. Complications]". Prensa Med Argent (in Spanish; Castilian). 52 (36): 2069–71. PMID 5879587.
- ↑ Batke M, Cappell MS (2008). "Adynamic ileus and acute colonic pseudo-obstruction". Med. Clin. North Am. 92 (3): 649–70, ix. doi:10.1016/j.mcna.2008.01.002. PMID 18387380.