Biliary atresia (BA) is a progressive, obstructive cholangiopathy which is the leading cause of liver transplantation in children. Early detection of BA is essential as a Kasai hepatoportoenterostomy (“Kasai procedure”) can slow progression of hepatic fibrosis associated with BA which potentially allows a patient to be older when liver transplantation is needed. The Kasai procedure is most beneficial when performed before 45 days of age. Thus, it should be of utmost importance to develop accurate population screening methods allowing for the early diagnosis of BA. The authors of this study evaluated the feasibility of a BA screening program at a large United States Intermountain West healthcare system.
The authors utilized data from 4 of the 33 included healthcare system hospitals over a 15-month period. Newborns born 35 weeks or older and who were admitted to the newborn nursery were included, and all infants admitted to the newborn intensive care unit (NICU) were excluded. Infants who were supposed to undergo total bilirubin level serum testing had their orders modified to include a fractionated bilirubin level which included a direct bilirubin level. Any infant with an elevated direct bilirubin level was identified, and the parents or the child’s primary care provider subsequently was contacted so that consent could be obtained to check a second fractionated bilirubin level. All infants with a second elevation of the direct bilirubin level were then referred to the pediatric hepatology clinic at the tertiary children’s hospital involved in this study. A direct bilirubin level was considered elevated if it was ≥ 0.6 mg/dL.
In total, 12,276 newborns were eligible for this study, and 98.2% of these infants (12,055) underwent direct bilirubin testing. An elevated direct bilirubin level was identified in 100 infants for which 6 were excluded due to either underlying medical or social issues. Another 4 infants were lost to follow up. The remaining 90 infants were available to be screened with a second fractionated bilirubin level. The families of 70 infants could not be contacted or declined study participation. The primary care physicians of these infants were contacted so that follow-up fractionation of the total bilirubin level could be recommended. Only 20 infants underwent actual second screening of their direct bilirubin level for which an elevated direct bilirubin level was still present in 15 infants. Those 15 infants were evaluated by pediatric hepatology, and no BA cases were identified.
There was no statistically significant difference in sex or birthweight between infants with normal and elevated direct bilirubin levels although infants with an estimated gestational age greater than 39 weeks were significantly more likely to have an elevated direct bilirubin level. The authors note that during the study period, two newborns born at participating study hospitals were eventually diagnosed with BA. However, both infants had been admitted to the NICU and initially were excluded from study participation.
Although this feasibility study did not identify any newborn infants with BA, it did demonstrate the potential for BA screening in a large healthcare system. The study process used to screen for BA has the potential to be applied in other healthcare systems as well as with state newborn screening.
Guthery S, Jensen M, Esplin M, O＊Brien E, Krong J, Srivastava R. Feasibility of biliary atresia newborn screening in an integrated health network. Journal of Pediatric Gastroenterology and Nutrition 2024; 79: 954-961.
Long-Term Outcomes in Pediatric Ulcerative Proctitis
Ulcerative proctitis in children is a variant of ulcerative colitis, but unlike the adult population, treatment guidelines for pediatric ulcerative proctitis are not clear. The authors of this study performed a retrospective study to determine the disease course and treatment outcomes for pediatric patients with ulcerative proctitis.
Data from this study came from 10 pediatric treatment centers throughout Japan during the period between 2013 and 2022. All included patients were under 18 years of age and had a diagnosis of ulcerative colitis. Patients with inflammatory bowel disease (IBD) unclassified, monogenic IBD, and no IBD follow up were excluded. Patient demographics, clinical course, laboratory testing, and treatments for ulcerative proctitis were determined. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and the partial Mayo Endoscopic Score were utilized to assess disease. Ulcerative colitis was diagnosed per the Revised Porto Criteria, and ulcerative proctitis was defined as inflammation present from the rectosigmoid region extending to the anorectal junction.
A total of 54 patients were included in the study. The median age at diagnosis was 12 years, and 44% of patients were male. Median PUCAI at time of diagnosis was 20 (remission score was considered less than 10) with 62% of patients having a partial Mayo Endoscopic Score of 2 at diagnosis. The authors noted that C-reactive protein and albumin levels were typically normal at time of ulcerative proctitis diagnosis. The most common treatment after initial diagnosis was 5-aminosalicylic acid therapy (5-ASA) given as a suppository (40%). Oral 5-ASA therapy was used in 20% of patients while a combination of oral 5-ASA and topical 5-ASA therapy (suppository or enema) was used in 25% of patients. Long-term disease remission occurred in 95% of patients (62% during initial therapy) although 93% of patients required modification of therapy. Nonadherence to therapy occurred in 39% of patients.
Control of ulcerative proctitis symptoms using 5-ASA therapy monotherapy occurred in 63% of cases while 30% of patients had disease remission followed by symptom breakthrough requiring immunosuppression therapy. No initial disease remission with a subsequent need for immunosuppression occurred in 7% of cases. Patients requiring immunosuppression were statistically more likely to require more colonoscopies, have inflammation extending above the peritoneal reflection or rectosigmoid region, or have inflammation eventually extending past the left side of the colon compared to patients who responded to 5-ASA monotherapy. Patients who were unable to achieve disease remission after 3 months were more likely to require biologic therapy.
This study demonstrates that 5-ASA therapy appears to control ulcerative proctitis in most pediatric patients. However, disease extension, need for frequent diagnostic colonoscopies, and prolonged time to disease remission appear to be risk factors for requiring a step up in medical therapy. This study occurred in Japan, and similar studies are needed in other countries to see if similar outcomes to therapy exist in pediatric patients with ulcerative proctitis internationally.
Miyazawa A, Nambu R, Shimizu H, Kudo T, Nishizawa T, Kumagai H, Hagiwara S, Kaji E, Mizuochi T, Kurasawa S, Kakuta F, Ishige T, Shimizu T, Iwama I, Arai K. Long-term course and prognostic factors in pediatric ulcerative proctitis: a multicenter cohort study. Inflammatory Bowel Disease 2024; izae266.doi: 10.1093/ibd/izae266. Online ahead of print.
We extend our sincere appreciation to the reviewers of the 2024 Nutrition Reviews in Gastroenterology series for their thoughtful and scholarly critique of manuscripts.
Their expertise, time and thoughtful contributions are vital to the scientific publication process.
The term ‘sphincter’ likely has its origin in the legendary Sphinx (or sphynx), a prominent mythological figure in Egyptian and Greek mythology, a creature with the body of a lion and the head of a human that terrorized the people by demanding the trespassers to answer a riddle. Unlike the mythological Sphinx, which has a negative connotation, the sphincters in the human body are physiologically beneficial and needed to prevent several disorders. Of the sphincters in the gastrointestinal tract, several are made up of smooth muscle (lower esophageal, pyloric, sphincter of Oddi, ileocecal and internal), and striated muscle (upper esophageal and external anal sphincters). Sphincteric structure (striated or smooth muscle) and functions vary depending on the location. The individual dysfunctions are the pathophysiological basis of several common gastrointestinal disorders, such as transfer and transit/oropharyngeal dysphagia, gastroesophageal reflux disease (GERD), gastroparesis, pancreaticobiliary functional pain syndromes (sphincter of Oddi dysfunctions), small intestinal bacterial overgrowth (SIBO) and frequent constipation syndromes.
Introduction
Galen, the esteemed Greek physician of 129 CE, is credited with the first use of the term “sphincter,” meaning “band” or “lace.” A sphincter is a ring-like muscle that surrounds a lumen, regulating the flow of liquids, solids, or gases, which can contract or relax, shorten, or lengthen the lumen. Sphincters are classified as anatomical or functional, composed of smooth or striated muscle, voluntarily or involuntarily in regulation and they play a critical role in compartmentalization and directional movement in the gastrointestinal tract. The upper esophageal sphincter (UES), lower esophageal sphincter (LES), pyloric sphincter (PS), ileocecal sphincter (IS), the sphincter of Oddi (SO), and the external and internal anal (EAS & IAS) are the main sphincters of the gastrointestinal tract. The present review of the gastrointestinal tract sphincters (GIS) meant for clinicians summarizes the available data on the structure, function, and disorders. While discussing the individual sphincters, the role of the surrounding structures cannot be ignored.
Upper Esophageal Sphincter (UES)
Structure
The UES is a tonically active sphincter made up of several striated muscles, including the cricopharyngeus (CP), inferior pharyngeal constrictor (IPC), and the longitudinal fibers of the cervical esophagus. The CP comprises the majority of the posterior and lateral portions of the lower third UES. The Killian’s Triangle is located between the transverse fibers of the CP and the oblique fibers of the lower inferior constrictors. The glossopharyngeal (CN IX), vagus nerve (CN X), and its branches are the predominant nerves that supply the region. Acetylcholine is the neurotransmitter involved in the efferent pathway.1,2
Physiology
The UES is involved in various actions, such as swallowing, belching, retching, vomiting, and changes in respiration.1,2 The physiology of swallowing is a complex process that involves the coordinated efforts of various muscles in the oropharynx and the esophagus, including the sphincter regions of the UES and LES, to move food from the mouth into the stomach. When food is being swallowed, the nuclei of the brainstem that control the UES are inhibited, leading to a decrease in UES pressure. As a result, the UES opens to allow the passage of food. During belching, rumination, vomiting, and regurgitation, the UES permits a retrograde transportation of food, fluid, or air. To open the UES during swallowing, the CP relaxes, and the suprahyoid muscle contract, allowing for efficient opening.1 The stylopharyngeus muscle also shortens, widening the transverse diameter of the UES, while the infrahyoid muscle pulls the anterior wall forward for protection against aspiration. After the food passes through, the CP muscle returns to a contracted state and closes the UES. In the process of swallowing, in addition to the vagus and glossopharyngeal nerves, trigeminal (CN V), facial (VII), and hypoglossal nerves (XII) are involved. The factors influencing the resting UES pressure are tabulated in Table 1.
The UES pressure is impacted by its unique anatomy and physiology, which makes analyzing pressure difficult using traditional manometric systems. The recently available high-resolution manometry (HRM) that replaced the fluid-filled channels of traditional manometer has solid-state circumferential sensors which are closely spaced and can capture UES contractile and relaxation states more accurately.9 The pressure varies from 35 to 200 mm Hg in HRM studies. HRM is being utilized for a variety of UES disorders which include cricopharyngeal (CP) dysphagia, Zenker diverticulum, and globus. Few studies have evaluated UES function after stroke/neurological disorders with HRM.9
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
Globus pharynegeus (GP) is a recurrent sensation of a lump or tightness in the throat unrelated to swallowing or pain. Per Rome IV criteria, the sensation must occur between meals, and there must be no evidence of dysphagia or odynophagia, gastric inlet patch, gastroesophageal reflux, or eosinophilic esophagitis. The symptoms must have been present for at least three months, with symptom onset at least six months prior to diagnosis with a frequency of at least once a week.10 Additionally, major esophageal motor disorders such as achalasia/EGJ outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, and absent peristalsis must be absent.11
Temporary relief may be achieved by swallowing several times. The etiology is unclear. The risk factors considered in GP are stress factors, dysfunctional UES pressure, laryngopharyngeal reflux (LPR), conditions causing irritation or inflammation of the pharynx, and hypertrophy of the base of the tongue.
Globus is a possible esophageal disorder associated with GERD symptoms, but the role of GERD in causing globus is unclear. Previous studies have shown mixed results, with some finding GERD as a major cause of globus symptoms and others not finding a significant association.11 This may contradict the new guidelines observed in Rome IV. Globus symptoms may be associated with dysfunctional UES findings. Diagnostic methods such as neck ultrasound, video fluorography, and endoscopy are not useful in diagnosis or management. The utility of HRM is limited. There is not a specific treatment for Globus, but when warranted, an ENT examination to rule out neoplasm may be appropriate. Cognitive behavioral therapy and speech-language therapy may also assist with managing symptoms.
Cricopharyngeal dysphagia (CD), also referred to as transfer dysphagia or oropharyngeal dysphagia can lead to various symptoms such as globus sensation, coughing or choking while attempting to swallow solid or liquids, aspiration, odynophagia, regurgitation, fear of eating, avoiding social dining situations, and recurrent aspiration pneumonia. CD can occur due to either neuromuscular disorders or mechanical impairment of the UES. The underlying pathophysiology involves the failure of the cricopharyngeus muscle to relax and open during the initiation of swallowing, leading to difficulties in transferring the food bolus. Cerebrovascular accidents involving cranial nerves and associated brainstem nuclei V, VII, IX, X, and XII lead to impairment of muscle UES function, further leading to CD.12,13
During a videofluoroscopic examination, a cricopharyngeal bar or cricopharyngeal achalasia can be observed as a posterior impression on the esophagus, typically located at the C5 or C6 level. A CP bar refers to the enlargement or hypertrophy of the cricopharyngeal muscle. This bar-like structure may partially obstruct the UES passage.14 CP bar is a radiographic discovery found in around 5% to 19% of elderly individuals who undergo a barium upper gastrointestinal series.14 Among these patients, approximately 13% may experience dysphagia.14
In older adults, there may be a decline in the relaxation and flexibility of the UES, making swallowing more challenging and aspiration frequent. There might be a delay in initiating the swallowing process in the throat, a shorter duration of the swallowing action, and a reduced opening time of the CP.15,16 Age-related changes can lead to prolonged clearance times and potential exposure of the larynx, particularly in elderly patients with dysfunctional UES or swallowing mechanisms.16,17
Multiple treatment options are available for CD. One of these options is botulinum toxin injection, which is a popular and preferred option for treatment due to its low-risk and cost-effective profile compared to surgery.12 The success rates of botulinum toxin injection are slightly lower (69%) compared to myotomy (78%).18 Treatment of CP dysphagia secondary to stroke does not focus on managing the UES dysfunction alone but using functional therapy to assist in triggering the components of the swallowing reflex.
Zenker’s (pharyngoesophageal) diverticulum (ZD), named after the German Pathologist Friedrich Albert Von Zenker (1825-1898) in 1877, is the herniation of hypopharyngeal mucosa into the anatomical muscular weakness of the Killian’s Triangle due to the dysregulated contraction of pharyngeal muscles. The prevalence of ZD is 1.8-2.3% of patients with dysphagia who have a radiographic examination, highest in elderly populations in the seventh and eighth decades. Patients may have a sensation of a lump in the throat with mucous build-up. The associated symptoms include dysphagia to liquids and eventually solids, halitosis, aspiration episodes, cough, food regurgitation, or rarely weight loss.19 Modified barium swallow assists with the definitive diagnosis. HRM can reveal elevated residual UES pressures.20 In symptomatic patients, surgical options include diverticulectomy, diverticulotopexy, and myotomy. Endoscopic cricopharyngeal myotomy is becoming increasingly available in tertiary care centers.19
Lower Esophageal Sphincter
Structure
The primary function of the LES is to prevent the regurgitation of gastric contents back into the esophagus and allow the coordinated passage of food or fluid into the stomach. In addition, the LES allows for the venting of gas after meals, permitting belching.21 The LES spans 3-4 cm in length and is composed of intrinsic and extrinsic muscles. The LES should be considered in the context of the gastroesophageal junction (GEJ), an anatomically complex anti-reflux barrier. As a result of recent studies, it has been noted that the LES is only a part of the mechanism of GEJ, with several participants.22 The GEJ is the anatomical region, and the LES refers to the structures contributing to barrier function.22 The GEJ is defined by the Z line, which demarcates the termination of the esophageal mucosa (squamous) and the beginning of the gastric mucosa (columnar). The distal margin of the LES is situated about 2 cm below the Z line. Consideration of the components of the GEJ in the process of swallowing and the prevention of reflux is important rather than attributing all the functions solely to LES, as was done in the past.
The components of the GEJ involve 1) the sphincter itself, 2) the subdiaphragmatic segment of the esophagus, 3) the phrenoesophageal ligament, and 4) the acute angle of His (the angle of entry of the esophagus into the stomach).22,23 The diaphragm is critical to maintaining the GEJ competence; the hiatus in the diaphragm is formed by a loop of muscle, the right crus. The hiatus allows for the passage of the esophagus, vagal trunks, and blood vessels. The phrenoesophageal ligament is a circumferential connecting ligament that creates a union with the right crus to the structures passing through the hiatus. The ligament connects with the GEJ, causing brief shortening of the esophagus and superior displacement of the GEJ during swallowing. The phrenoesophageal ligament aids in keeping the LES intraabdominal. During inspiration, the right crus of the diaphragm contracts causing pressure to be applied to the esophagus proximal to the GEJ, leading to contraction of the intrinsic muscles. During periods of high abdominal pressure, the barrier function of the GEJ is maintained through this mechanism. The right portion of the GEJ is created by the angle of his. The angle of His is a union between the gastric cardia and distal esophagus which functions as a pinchcock to inhibit gastric reflux into the esophagus.
The LES receives innervation from the autonomic nervous system, specifically through parasympathetic (vagus) and sympathetic (splanchnic) inputs. Sensory signals from the LES are transmitted to the NTS through vagal sensory afferents, while vagal motor efferents originating from the preganglionic fibers of the dorsal motor nucleus project back down to the LES.24
Physiology
The components of GEJ participate in maintaining the tone of the LES. Resting tone in normal individuals ranges from 10 to 30 mm Hg compared to intragastric pressure, with the greatest pressure readings at night.23 This tone is achieved through a combination of transmitted intra-abdominal/thoracic pressures, passive muscle recoil, and active tone.21,23 During a swallow, the LES contracts to prevent reflux, and this contraction persists for a short period of time after swallowing due to the inhibitory pathway of the vagus nerve and postganglionic myenteric neurons that release nitric oxide.
Frequent transient LES relaxations (TLESR) are often mentioned as the predominant factor in promoting reflux contents and symptoms of GERD. TLSESRs are spontaneous and independent relaxation of the LES and diaphragm that lasts anywhere from 10-60 seconds and are vagally mediated.21,23 TLESRs occur without an associated pharyngeal contraction or esophageal peristalsis and are triggered by gastric distention, particularly of the cardia. TLESRs are responsible for most reflux events in healthy individuals. TLSERs occur without pharyngeal contraction or esophageal peristalsis and can last longer than LES relaxations induced by swallowing. However, not all TLESRs cause reflux. They play a significant role in belching and can be increased by gastric distention.
There is evidence for a myogenic basis of LES tone. Asoh and Goyal observed that the sphincter muscle shows a continuous electrical spike activity distinct from the esophageal body.24 The vagus nerve provides major inhibitory and excitatory innervation to the LES, with the sympathetic nerve minimally influencing LES tonic contraction and relaxation.25 The preganglionic fibers of the vagus nerve communicate with excitatory and inhibitory postganglionic myenteric neurons to innervate the LES smooth muscle. The preganglionic fibers release acetylcholine to the postganglionic fibers of the myenteric neurons. The postganglionic excitatory neurons release acetylcholine and substance P to cause constriction of the sphincter. The postganglionic inhibitory neurons release NO and lead to the relaxation of the LES, with neuronal nitric oxide synthase as a source of NO in the nerves. These inhibitory and excitatory nerves influence the myogenic tone of the LES. The lack of inhibitory innervation may lead to achalasia. Overactivity of the excitatory input can lead to hypertensive contraction of the LES at resting states.24
Several neurotransmitters and hormones influence the tone of the LES. LES tone is decreased by including nitric oxide (NO), vasoactive intestinal peptide (VIP), beta-adrenergic agonists, dopamine, possibly cholecystokinin (CCK), and secretin.23 On the other hand, substances like gastrin, alpha-adrenergic agonists, and muscarinic receptor agonists can increase LES tone. Other factors, such as peptides and hormones, may influence LES pressure, but the role in humans is not clear. Intraabdominal pressure and gastric distention also influence LES pressure.
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
Gastrointestinal Esophageal Reflux Disease (GERD) GERD has been extensively discussed in numerous publications by several experts (Katz, Goyal, Spechler, Yadlapati, and others). This topic is summarized substantially to limit the size of this article. The underlying cause of GERD involves the malfunction of one or more components of the GEJ. Other factors which complement the pathogenesis of GERD include excessive TLESR, hiatal hernia, hyposalivation, and dysmotility, including defects in secondary peristalsis involved in acid clearing. Studies have investigated the mechanism of TLESRs and the increased prevalence of reflux events in GERD patients, highlighting differences in the compliance or gradients of the GEJ and the localization of the acid pocket on top of the meal.25–27 Acid pocket, defined by Kahrilas et al., is a relatively new term in the concept of the pathogenesis of GERD.28 Acid pocket is an area of accumulated unbuffered gastric acid in the proximal stomach after meals and serves as a reservoir of acid in GERD patients. From the acid pocket, there is upward migration of acid film that contributes to mucosal injury in the squamocolumnar junction.
The role of several individual food items on LES is controversial in relation to GERD. In several studies, citrus and spicy food had little to no effect on LES pressure, although they are noted to exacerbate symptoms when esophagitis is present.29,30 The effect of caffeine on LES is variable. Alcohol, tobacco smoking, peppermint, high-fat foods, and chocolate influence the pathogenesis of GERD; in laboratory studies, these food items reduce LES tone. However, larger clinical trials are needed to investigate the association.
GERD symptoms include heartburn which is substernal burning from the epigastrium toward the neck. Heartburn and regurgitation are the main symptoms of GERD, but symptoms of GERD are non-specific and can overlap with those of other disorders of the LES sphincter, such as achalasia.31
The management of GERD is well discussed in a recent practice guideline article by the ACG, which primarily involves controlling gastric acid secretion but is not directed toward the pathophysiology of the GEJ.31 There are no medications available to increase LES pressure or prevent frequent TLESR contractions. Prokinetic therapy with propusid, a 5-HT4 receptor agonist, increases LES sphincter pressure and promotes esophageal peristalsis while decreasing the pyloric sphincter.32 The medication is unpopular in the US due to its cardiac side effects but is used in several countries as a supplementary option to PPI in the management of GERD. Other prokinetics, such as metoclopramide, are shown to increase LES pressure in addition to enhanced peristalsis of the esophagus and improved gastric emptying. Baclofen is a GABAb agonist that can reduce TLESR, enabling reflux episodes, decreasing postprandial acid and non-acid reflux events, and belching episodes.
Achalasia
The term achalasia was first used by Sir Arthur Hurst in 1927, derived from a Greek term meaning “lack of relaxation.” Primary achalasia is characterized by impaired relaxation of LES in response to swallowing and aperistalsis of the esophagus smooth muscle.33,34 The pathogenesis of primary achalasia involves the dysfunctional interplay of inhibitory neurotransmitters such as NO and VIP and excitatory neurotransmitters such as acetylcholine in the myenteric plexus, leading to increased LES pressure. Symptoms include progressive dysphagia from solids and liquid, and weight loss may be modest or non-existent.35,36
Secondary achalasia is characterized by the same symptoms but often of shorter duration, usually secondary to cardio-esophageal junctional cancer. Significant weight loss is a feature. Chagas disease, frequently seen in several parts of Central America, is due to infection by the parasite Trypanosoma cruzi. In Chagas disease, there is damage to the myenteric esophageal plexus leading to partial or absent LES relaxation accompanied by aperistalsis. As a result, there is the development of megaesophagus and megacolon in the gastrointestinal tract.37
To establish the diagnosis of achalasia, the standard procedures are barium esophagram, esophageal manometry, and endoscopy.33 The results are complementary and barium studies show a dilated esophagus with a classic bird beak sign. The main function of endoscopy is to exclude cardio esophageal junctional cancer by retroversion of the scope. Diagnosis of achalasia by HRM is the current standard gold test. Characterizing achalasia using Chicago classification subtypes is useful for the management of the patient.38 In all three subtypes, there is impaired GEJ relaxation with distinct esophageal pressurization and contraction. In types I and II, there is 100% failed peristalsis. Type I is characterized by the absence of pan esophageal pressurization to > 30 mm Hg. Achalasia type II is characterized by 100% failed peristalsis (aperistalsis) with pan-esophageal pressurization to > 30 mm Hg. Achalasia type III is characterized by spastic contractions because of abnormal lumen obliterating contractions with or without periods of pan-esophageal pressurization. Type I and II are associated with a good response to myotomy. Type III may require extensive myotomy.
The goal of the treatment of achalasia is to reduce the hypertonicity of the LES, which can improve esophageal emptying. Treatment options include pharmacologic, endoscopic, and surgical.
Botulinum toxin blocks the excessive unopposed cholinergic stimulation of the LES and only affects the neurogenic component of the sphincter with no influence on the myogenic tone. The treatment results only in a 50% reduction of basal LES pressure with short-acting benefits.33 Botulinum toxin injection, however, is a therapy of choice for patients unfit for definitive surgical therapy such as pneumatic dilation or laparoscopic Heller myotomy (LHM).33 Pneumatic dilation (PD) uses a balloon dilator which opens the muscularis propria of LES, leading to symptomatic relief. Surgical myotomy involves the division of the muscle fibers of the LES, circular layer, without disruption of the mucosal layer.33 The recently available laparoscopic myotomy has decreased morbidity and faster recovery.
Hiatal Hernia (HH)
In the sliding type of HH, the LES is above the diaphragm reducing the function of the GEJ. In HH, there is a separation between the LES and crural diaphragm that can diminish the basal pressure of the GEJ and lead to a greater pressure gradient during relaxation, influencing the pathogenesis of GERD.23
Pyloric Sphincter
Structure
An excellent review by Ramkumar and Schulze provides clinically useful information on pyloric sphincter (PS).39 The gateway connecting the antrum of the stomach to the duodenum is known as the pyloric sphincter. The term “pylorus” comes from the Greek word “pylon,” which translates to “gatekeeper.” Essentially, the PS promotes forward flow from mechanical and chemical digestion (stomach) areas to the site of absorption of nutrients (duodenum and small intestine). The PS is a narrow zone 1cm wide, defined by thickened circular smooth muscle loops.
The PS connects the antrum to the duodenum through the proximal pyloric loop (PPL) and distal pyloric loop (DPL), respectively.39 DPL is rich in connective tissue that influences resting PS diameter and resistance. PPL is located 2-3 cm above the pyloric opening near the greater curvature of the stomach. The DPL and PPL join at the lesser curvature of the stomach, forming a connective tissue and layer of fat known as the pyloric torus.39 The contraction of the DPL and the PPL controls the pyloric diameter. The distal corpus and pyloric antrum serve as peristaltic pumps. The entire segment contracts as a unit with the distal antrum.40 See Figure 3.
Functionally the PS can be viewed in the context of other gastric segments. The fundus generates the tone, while the corpus and antrum process the food before emptying. The PS regulates the gastric emptying rate.41,42
The PS is under the influence of the autonomic nervous system. The vagus nerve supplies afferent and efferent signals from and to the pylorus. The afferents contain sensory nerve fibers, primarily stretch receptors, that respond to lower levels of a stretch compared to the antrum and proximal stomach. The parasympathetic nervous system, through CN X, causes the relaxation of the PS Motor fibers of vagal efferents and releases inhibitory responses through VIP and NO, leading to the relaxation of the sphincter. Several of these nerve fibers contain nitric oxide synthase (nNOS).43-45
The pylorus has an abundance of sympathetic nerve fibers. Through the greater and lesser splanchnic nerves from the celiac ganglion, the sympathetic nervous system causes constriction of the pylorus and the sphincter. Constriction of the pylorus is mediated by vagal efferent excitatory fibers that release acetylcholine. In addition, the pylorus has intrinsic innervation from the stomach’s myenteric plexus that extends through the pylorus into the duodenum, deeply integrating into the sphincter muscles and influencing contraction and relaxation.40
One must review the gastric motor functions to understand the pyloric sphincter function since they share integrated processes. Smooth muscle cells (SMC) of the stomach, with connective tissue interspersed between, play a significant role in the trituration of food and gastric emptying.42 SMC are coupled by gap junctions and transmit electrical impulses to neighboring cells leading to the synchronicity of contractions.42 SMCs are coupled with the Interstitial Cells of Cajal (ICC) by gap junctions, which help regulate the stomach’s motor patterns.
Physiology
The PS plays a vital role within the stomach’s migrating motor complex (MMC), a cyclical motor process that aims to eliminate undigested particles.40 The MMC encompasses four distinct phases. Phase 1, lasting 45-60 minutes, is characterized by slow waves independent of contraction. In Phase 2, slow waves occur with frequent phasic contractions. Phase 3, mediated by neural signals, involves contractions that persist for 5-15 minutes and move towards the pyloric sphincter, independent of slow waves. Throughout this process, the pylorus and duodenum remain relaxed and open, facilitating the movement of food remnants out of the stomach during phase III. In Phase 4, contractile activity is inhibited, merging with the subsequent phase of the digestive cycle. The absence of pyloric relaxation can result in gastric outlet obstruction. During the inter-digestive period, certain hormones such as motilin and ghrelin play a role in regulating the activity of gastric pumps and inhibition of PS contraction.40
Gastric emptying is a complex process that involves coordination from several intricate neuro-hormonal processes, from the smooth muscle cells, ICC, and parasympathetic and sympathetic nervous systems. The PS and duodenum function in a synchronized manner. Prior to gastric emptying, the terminal antrum and PS serve as grinders and filters, respectively.40
During the digestive phase, the fundus of the stomach can hold large volumes of food without an increase in pressure, known as accommodation.40 In this filling phase, gastric smooth muscles are not contracted. Liquids leave the stomach much faster than solids. Solids that remain in the stomach then move to the antrum and become triturated into chyme of particles less than 2mm in size and leave 2-3 hours after a meal.46 Following the filling phase, a pumping phase is present with contraction of the fundus and increased peristaltic contractions in the antrum. Through this process, undigested food is mixed with gastric acid and pepsin, and the antrum is filled to a threshold prior to food entering the duodenum.40
The pylorus plays a major role in preventing the regurgitation of duodenal contents while regulating the emptying of chyme.39,40 Following stimulation from the pacemaker and activation of ICC, gastric motility begins. The peristaltic contraction from the fundus propels digested food and chyme from the proximal to the distal antrum, where the PS is relaxed. A small portion of chyme moves into a relaxed pylorus into the duodenum, with some chyme moving back into the proximal antrum. The peristaltic contraction becomes more vigorous and faster and reaches the terminal antrum, constricting the pylorus and restricting emptying. These contents are retropulsed back into the stomach leading to shearing forces that break down food particles into smaller pieces. The PS continues to be contracted and provides a sieve/filter function to reduce food particles to less than 2mm before emptying occurs. The contractions in the pylorus lead to an anterograde flow of chyme into the duodenum and a retrograde flow of food that escapes grinding.39,40,42 During the digestive period, PS can influence gastric emptying. Failure of the antral contractions or pyloric relaxation can decrease gastric emptying.42
The soluble fiber in the diet influences gastric motility, creating a gel formation with liquid in the stomach, resulting in a substantial delay in gastric emptying.47 Slower gastric emptying is associated with lower postprandial blood glucose levels.47
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
Gastroparesis & the Pyloric Sphincter
Gastroparesis is a functional disorder defined by delayed gastric emptying without mechanical obstruction associated with nausea, vomiting, early satiety, bloating, and abdominal pain.48 While idiopathic gastroparesis is seen in 30% of cases, several etiologies contribute to symptoms ranging from neuromuscular diseases affecting the non-sphincter gastric muscles to post-surgical complications and pyloric dysfunction. Patients with gastroparesis may also have pyloric dysfunction. Pyloric dysfunction can consist of pylorospasm or intermittent contractions that cause increased baseline tone at the pylorus and sphincter. Diabetes contributes to the significant pathogenesis of gastroparesis. Patients with gastroparesis are found to have abnormal interstitial cells of Cajal and neuropathy of the myenteric plexus, leading to loss of gastric pacemaker activity.
Diabetic gastroparesis patients are shown to have lower PS distensibility and higher pyloric sphincter pressures.48 Distensibility refers to an elastic tissue’s ability to stretch and expand in response to applied pressure.49 The term applies to ring-shaped sphincters compared to similar terms such as compliance, which refers to a hollow organ. PS distensibility is inversely correlated to gastric emptying, and studies have shown that pyloric distensibility was altered in 30-50% of patients with gastroparesis.48
Modality
Effect
Comments
Prokinetic Agents: Erythromycin Metoclopramide * Other medications in development include: felcistetag (5-HT4 agonist) tradipitant (NK1 antagonist) relamorelin (ghrelin agonist) trazpiroben (dopamine D2/D3 receptor agonist)42
Erythromycin is a commonly used antibiotic that accelerates gastric emptying through activation of the MMC42 Metoclopramide, a peripheral cholinergic and antidopaminergic agent, peripherally improves gastric emptying and central action resulting in an anti-emetic effect54
Erythromycin prokinetic effects are limited by tachyphylaxis42 Metoclopramide has serious central nervous system adverse effects, partially irreversible tardive dyskinesia54
Diet modification
Appropriate glycemic control, especially for patients with diabetes36 Avoidance of alcohol and tobacco Low fat, low soluble fiber diet of small portions
Increased blood glucose can slow gastric emptying, especially in diabetics Alcohol and tobacco can modify gastric emptying Fat, soluble fiber, and large volume can slow gastric emptying
Intrapyloric botulinum toxin
Neurotoxic protein that leads to relief of pylorospasm & improvement of gastric emptying53
No current systematic evidence evaluating its effectiveness55
Surgical pyloroplasty
Surgery that widens the pylorus to promote short-term gastric emptying53
No current randomized trials evaluating its effectiveness for gastroparesis53
Endoscopy pyloromyotomy (G-Poem)
Division of the pylorus from the mucosal surface with incision of the circular muscular layer to improve gastric emptying56
More studies are needed to evaluate its effectiveness
Gastric electrical stimulation
Direct stimulation of the pacemaker to improve gastric emptying36
No current systematic evidence evaluating its effectiveness36
Table 2. Treatment Modalities for Gastroparesis
Gastric emptying study using scintigraphy is an available test in many institutions and is considered to be the gold standard for diagnosing gastroparesis.50,51 Radioactive tracers, such as technetium-99 m, are added to liquid and solid foods. Other tests to diagnose gastric emptying include a breath test with carbon 13-octanoic acid or acetic acid.52 However, these are more time-consuming compared to scintigraphy. Intraduodenal/pyloric manometry and Functional Luminal Imaging Probe (FLIP) can help to assess the PS but are available only in tertiary care centers and at this time of limited clinical interest.
The role of the PS in gastroparesis and management has been discussed and reviewed in the following articles.42,53 A summary is shown in Table 2.
Hypertrophic Pyloric Stenosis
Hypertrophic pyloric stenosis (HPS) involves a thickening of the pyloric lumen to greater than 1-3mm, associated with rigid and overlapping mucosal folds that create a point of obstruction. HPS is seen in young infants 1 to 2 months after birth. Ultrasound is the preferred diagnostic test choice due to its ease of use with no contrast or no radiation exposure.40 Laparoscopic pyloromyotomy, involving the hypertrophied pyloric muscle incision, is the treatment of choice.39,57
Ileo-Cecal Sphincter
Structure
The junctional region between the ileum and colon, the Illeo-colonic junction (ICJ), has been dubbed the ‘apothecary barrier’ due to its role in reinforcing water absorption in the colon.58 This segment, also known as the ileocecocolonic segment, consists of the ileocecal sphincter (ICS) and cecum and behaves similarly to the LES region discussed earlier. The ICS has an episodic and intermittent propagating motor activity and functions to transfer digestive contents and residue from the ileum to the cecum, leading to the early concept of the ICS as an intestinal stomach.58
The ICS exhibits several features of other sphincters. Anatomically the site is marked by considerable thickening of the circular muscle coat.59 The terminal ileum and cecum join at an acute angle. The ileum’s muscular components merge with the layers of the cecum and colon, creating an ileal papilla, further supported by ligamentous connections between all three structures. The smooth muscle in the distal portion of the ileum wall thickens to create a sphincter. This intricate relationship between the structures of this region may play a role in the ICS’s competency.59,60 The vagus and splanchnic nerves innervate the ICS. The vagal efferent stimulation reduces the sphincteric pressure and increases motor activity of the ileum.
Physiology
ICS maintains a sustained isometric tone of myogenic origin.59,59,61 Manometry studies have been unable to assess the position of the manometric pressures of the ICS.62
The ICS controls forward and backward flow through integration with the distal ileum and proximal colon motility. The gastro-ileal and ileocolonic reflexes involving the ICS affect the sphincter’s overall motility. The ICS tone increases immediately after a meal and lessens during the inter-digestive phase.58
The ileocolonic reflex involves colonic distension, which is followed by ICS contraction.63 Higher distending pressures cause higher excitatory responses. Ileal distension can have variable responses of the ICS; distention closer to the ICS causes excitatory and inhibitory responses likely due to descending excitatory and inhibitory pathways.58
The distal ileum synthesizes several hormones that influence digestive motility, including peptide YY (PYY), glucagon-like peptides, and neurotensin.Neurotensin is a hormone and neurotransmitter that functions as a hormone in the distal ileum.64 We are not discussing in depth the absorptive features of the terminal ileum; however, the terminal ileum plays a significant role in B12 absorption and entero-hepatic circulation of bile acids.
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
Small Intestinal Bacterial Overgrowth Syndrome (SIBO)
Clinically the role of the ICS in preventing small intestinal bacterial overgrowth syndrome (SIBO) has been discussed previously.65 The ICS separates the small and large bowel, which have distinct physiological properties, especially in bacterial content. The ICS limits colo-ileal reflux, which can prevent the colonization of the ileum by colonic microflora. Surgical removal of the ICS may enhance the development of SIBO due to retrograde bacterial migration from the large to the small bowel.
The Sphincter of Oddi
Structure
The sphincter of Oddi (SO) consists of three layers of smooth muscle surrounding the common bile duct, main pancreatic duct, and ampulla of Vater.
Function
The SO plays a role in preventing duodenal reflux, regulating bile and pancreatic flow, and facilitating retrograde gallbladder filling. The SO has a basal pressure of 10mm Hg in humans, and pressure gradients dictate the flow.
Functional Biliary Sphincter of Oddi Dysfunction
Functional Pancreatic Sphincter of Oddi Dysfunction
1. Criteria for biliary pain include: Pain located in the epigastrium and/or right upper quadrant and all of the following: Builds up to a steady level and lasts 30 minutes or longer Occurring at different intervals (not daily) Severe enough to interrupt daily activities or lead to an emergency department visit Not significantly related to bowel movements Not significantly relieved by postural change or acid suppression 2. Elevated liver enzymes or dilated bile duct, but not both 3. Absence of bile duct stones or other structural abnormalities Additional Supportive Criteria: 1. Normal amylase/lipase 2. Abnormal sphincter of Oddi manometry 3. Hepatobiliary scintigraphy
1. Documented recurrent episodes of pancreatitis (typical pain with amylase or lipase >3 times normal and/or imaging evidence of acute pancreatitis) 2. Other etiologies of pancreatitis excluded 3. Negative endoscopic ultrasound 4. Abnormal sphincter manometry Diagnostic criteria must include all of the above
Table 3. SOD Classification, Biliary and Pancreatic(Adapted from Rome IV Criteria)10,68,69
Anterograde phasic contractions at the SO propel bile and pancreatic secretions into the duodenum. This is followed by a relaxation phase allowing the passive filling of bile into the SO. Increasing basal pressure leads to resistance to flow into the duodenum, allowing the gallbladder to fill. Bile and pancreatic juices flow into the duodenum when basal pressure decreases below CBD and PD pressure.
The filling of the SO triggers varying phasic contractions during different digestive phases. A meal stimulates the release of CCK, causing gallbladder contraction and relaxation of the SO. CCK also directly stimulates SO smooth muscle. Somatostatin, released from endocrine cells throughout the digestive tract, causes gallbladder contraction and SO relaxation.66
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
Sphincter of Oddi dysfunction (SOD)
Sphincter of Oddi dysfunction (SOD) is commonly present in females ages 20-50, with a general population prevalence of 1.5%. The biliary or pancreatic sphincter may become stenotic, causing blockage of bile and pancreatic juice flow. Furthermore, the sphincter’s smooth muscle may have an inappropriate response to neuronal or hormonal stimuli that normally cause contraction.66,67
The disease presentation and clinical findings are on a spectrum, and the ROME IV criteria can assist in describing the clinical features.10,68,69 The diagnostic criteria for SOD dysfunction are tabulated.
Patients with idiopathic recurrent pancreatitis (IARP) may have a prevalence of SOD as high as 72%.70 Toouli et al. observed 57% of patients with IARP had elevated SO pressures in a study with 28 patients with IARP.71 In the pathogenesis of acute pancreatitis, however, it is well-recognized that a stone at the ampulla can initiate pancreatic injury.
Once, the most widely used Milwaukee classification for SOD was carefully re-evaluated in Rome IV criteria, and as a result, type III SOD was eliminated to avoid unnecessary or unwanted sphincterotomy as the diagnosis was based solely on patient history. Thus, SOD is divided into two types using a structural perspective based on symptoms, radiographic findings, and laboratory abnormalities. Type I SOD has abnormal chemistries and dilated biliary or pancreatic duct imaging. Type II SOD has abnormal biochemical markers or abnormal imaging.72
Risk factors for SOD include patients who underwent cholecystectomy, irritable bowel syndrome (IBS), and use of exogenous agents such as opiates. As mentioned previously, CCK relaxes the SO in patients with intact gallbladders. In patients six months after cholecystectomy, CCK can fail to relax the SO. Patients with postcholecystectomy may have elevated basal SO pressures with increased retrograde SO phasic contractions. The gallbladder may act to prevent sudden increases in retrograde intraductal pressures from ductal obstruction. The incidence of SOD after cholecystectomy is variable, with approximately 1.5% of patients developing the disorder.73
Patients with IBS may have an association with SOD. Patients with IBS who undergo cholecystectomy may exhibit a diminished response to CCK compared with postcholecystectomy patients without IBS, leading to the pathogenesis of SOD. Opiates are known to alter flow through the SO, with morphine increasing the amplitude and frequency of the phasic wave through the mu receptor.66
Manometry is the gold standard for diagnosing SOD, especially diagnosing SOD type I. The therapy is only offered at select tertiary care centers due to its time-consuming nature, technical expertise requirements, and potential complications such as post-ERCP pancreatitis.66,74
Certain exogenous agents reduce the pressure and resistance of the SO, leading to the relaxation of the sphincter. These agents include calcium-channel blockers, botulinum toxin, and glyceryl trinitrate, showing some evidence of symptomatic relief.75–77 There currently is a lack of large, randomized, and controlled trials to demonstrate the efficacy of these pharmacological agents for the treatment of SOD.
For both types of SOD, endoscopic sphincterotomy is the best treatment option with significant pain reduction. Roughly 90% of patients with type I biliary SOD and 60–94% of SOD type II patients have had improvement in pain following a biliary sphincterotomy.66 ,67
Anal Sphincter
Structure
Internal Anal Sphincter (IAS)
The IAS and EAS are the two sphincters of the anal canal. The IAS, an extension of the circular ring of the involuntary smooth muscle of the rectum, terminates 10mm above the anal verge and is 2.5cm long, 2-5mm thick in size, and is comprised of both circular and longitudinal muscle separated by connective tissue. The IAS is surrounded superiorly by the levator ani muscle and is encased by the EAS, comprised of skeletal muscle, and is under voluntary control.78,79
The IAS is under dual innervation from the autonomic and enteric nervous systems. The sympathetic nerve fibers arise from the lower thoracolumbar ganglion to form the superior hypogastric plexus.80 Parasympathetic fibers arising from spinal cord levels S2-S4 form the inferior hypogastric plexus giving rise to the superior, middle, and inferior rectal nerves that supply the anal canal.80 The parasympathetic input is primarily inhibitory in nature, prompting relaxation mainly through muscarinic receptor stimulation. The sympathetic nervous system is shown to have both an inhibitory and excitatory influence, dependent on receptor activation. Alpha and beta adrenoreceptors are present in the IAS, with stimulation of alpha adrenoreceptors leading to excitation and stimulation of the beta receptors leading to an inhibitory effect.81–83 Anal pressure and tone are primarily influenced through the parasympathetic nervous system.
Pathology Associated with Low Resting IAS Pressure
Comment
Obstetric anal sphincter injury during childbirth
A significant correlation between IAS injury is observed during childbirth and fecal incontinence
Advances in surgical techniques have decreased iatrogenic injuries
Rectal prolapse
Pathogenesis is not clearly understood but may involve IAS dilation and altered RAIR mechanisms
Radiation toxicity
Following radiotherapy significant reduction in RAP and physiological sphincter length in patients, indicating IAS dysfunction
Scleroderma
Affects the anorectal region Low IAP
Pathology Associated with Low Resting IAS Pressure
Comment
Anal fissure
Elevated resting pressure in the anal canal greater than 90mm Hg leads to ischemia of the anal lining
Internal sphincter achalasia
A rare and multifactorial disorder
Table 4. IAS Pathology and IAS Pressure Adapted from Kumar & Emmanuel et al.78
The enteric nervous system affects the IAS through neurotransmitters, mainly NO. The circular muscle layer is embedded with inhibitory neurons that release NO, leading to relaxation. VIP is also shown to influence inhibitory responses in the IAS.84
Due to the specialized cell properties of the smooth muscle, the basal tone is myogenic, with tone and phasic contractile activity being independent of nervous system input.85
External Anal Sphincter (EAS)
The EAS is composed of striated muscles, voluntary, and encompasses the IAS, extending to the anal verge. The subcutaneous and superficial muscle bundles make up the EAS. The nervous system innervation comes from the perianal branch of S4 and the inferior rectal branch of the internal pudendal nerve, while sensation comes from the inferior rectal nerve, a branch of the pudendal nerve.80 The EAS is under conscious input from higher cortical centers.
Physiology
The anal sphincter play an important role in maintaining continence, controlling defecation, and passing flatus. The complex process is accomplished through the integrated motor functions of the anal sphincter muscles, rectum, pelvic floor muscles, the sensory visceral somatic components of the pelvic nerves, and higher cortical centers.85
Low Pressure
Modality
Effect
Lifestyle Modification
Promotion of improved stool consistency and stable bowel movements through dietary modification and reflex mechanisms
Medication
Anti-diarrheal medications
Surgical Repair
Direct repair
Augmentation Techniques
Unclear mechanism
Artificial anal sphincters
Biofeedback
Rectal sensitivity training involving the patient to squeeze EAS on activation of RAIR reflex
Relaxation of IAS smooth muscle through activation of NO or blockade of calcium channels
Botulinum Toxin
Neurotoxin causes a reduction in resting anal pressure and an increase in blood flow.
Lateral Sphincterotomy
Division of IAS to reduce RAP
Table 5. Treatment Options for Low and High Resting Anal Pressure States of the IASAdapted from Kumar & Emmanuel et al.78
The IAS is a complex muscle responsible for maintaining continence and is divided into upper and lower portions. The lower portion contributes significantly to the basal anal resting tone, responsible for 50-85% of the resting anal pressure (RAP).85 The control of the IAS involves intrinsic and extrinsic neurons and myogenic neurons. The lower IAS has a high resting pressure to prevent leakage of fecal contents or flatus and is coordinated with the contraction of the EAS to maintain continence. The upper IAS relaxes reflexively during rectal filling/distention, a process known as recto anal inhibitory reflex (RAIR) plays a critical role in maintaining continence. The RAIR permits the passage of feces from the rectum to the upper anal canal, allowing the anal sensory epithelium to “sample” and distinguish luminal contents of solid, liquid, and gaseous origin. The volume of distension/filling can affect RAIR, with larger volumes contributing to prolonged relaxation periods of the IAS. Relaxation of the IAS occurs during the RAIR, which is a direct evaluation of IAS function. The contraction of IAS is mediated by sympathetic nerves through alpha adrenoreceptors and relaxation through Beta receptors.
Unlike the IAS, the EAS only contributes to a small portion of the anal resting tone. EAS is unique compared to other striated muscles as it has continuous tonic activity even at rest. However, changes in posture and increased intra-abdominal pressure can trigger an anal reflex, increasing the resting tone of the EAS. The second sacral spinal segment enables the EAS to have integrated activity, resulting in voluntary contraction that can last between 40-60 seconds. This contraction is vital for deferring defecation and facilitating rectal accommodation. Additionally, higher cortical signals can also transmit inhibiting signals that can cause relaxation of the EAS, allowing for the fecal bolus to pass.86,87
Clinical Disorder(s): Pathogenesis, Diagnosis, and Management
An excellent and exhaustive review by Kumar and Emmanuel highlights the IAS pathology in the context of anal pressure.78 Insufficient IAS pressure at rest can result in different degrees of fecal incontinence, often accompanied by diarrhea. High-pressure states generated in the IAS can cause the inability to defecate. Understanding these causes is crucial for the appropriate diagnosis and treatment of individuals with low and high internal anal sphincter pressure. Due to space limitations, the following important topics are summarized in Table 4.
Anal rectal manometry (ARM) is the gold standard for assessing sphincter and anorectal function. ARM involves evaluating resting and squeeze pressures of the anal sphincter, RAIR, rectal sensation, changes in anal and rectal pressures during attempted defecation, rectal compliance, and a balloon expulsion test. However, there is currently no standardized protocol for interpreting or performing the test, and variations exist in manometry probes and study populations. High-resolution manometry (HRM) can be utilized to measure circumferential pressures, providing additional information in the evaluation of anal rectal function.78
Dyssynergic defecation (DD) is a condition characterized by a lack of coordination of muscle contractions of the anorectal region, specifically puborectalis, and EAS, leading to difficulties in evacuating stool. Diagnosing DD involves ruling out underlying abnormalities and considering factors such as inadequate fiber and liquid intake, immobility, medications, and metabolic, neurological, or structural disorders. The balloon expulsion test (BET) and anorectal manometry ARM help to evaluate the pressure activity in the rectoanal region and aid in the diagnosis of DD.88
Conclusion
The gastrointestinal sphincters are gatekeepers that regulate the flow of solids, liquids, and gases in the digestive system. They are made up of both striated and smooth muscles and are influenced by nerves and hormones. These essential sphincters permit unidirectional or bidirectional flow. However, apart from the LES and anal sphincters, technical difficulties have prevented a thorough examination of the UES, PS, SO, and Ileocecal sphincters, resulting in gaps in our knowledge regarding their neuro-motility and disease prevention roles. Recent advances in technology and increased interest in their study offer hope for a better understanding of their structure, function, and impact on clinical disorders. With current advances in neuro-motility physiology and the technical feasibility of studying previously inaccessible sphincters, we can gain a better understanding of their roles in physiology and disease.
Acknowledgment: The authors acknowledge Shree Swapna Kalapatapu for her contribution to the anatomical diagrams included in this article.
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51. Camilleri M, Zinsmeister AR, Greydanus MP, Brown ML, Proano M. Towards a less costly but accurate test of gastric emptying and small bowel transit. Dig Dis Sci. 1991;36(5):609-615. doi:10.1007/BF01297027
52. Choi MG, Camilleri M, Burton DD, Zinsmeister AR, Forstrom LA, Nair KS. Reproducibility and simplification of 13C-octanoic acid breath test for gastric emptying of solids. Am J Gastroenterol. 1998;93(1):92-98. doi:10.1111/j.1572-0241.1998.092_c.x
53. Clarke JO, Snape WJJ. Pyloric sphincter therapy: botulinum toxin, stents, and pyloromyotomy. Gastroenterol Clin North Am. 2015;44(1):127-136. doi:10.1016/j.gtc.2014.11.010
54. Al-Saffar A, Lennernäs H, Hellström PM. Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2019;31(11):e13617. doi:10.1111/nmo.13617
55. Bai Y, Xu MJ, Yang X, et al. A systematic review on intrapyloric botulinum toxin injection for gastroparesis. Digestion. 2010;81(1):27-34. doi:10.1159/000235917
56. Gastric Peroral Endoscopic Myotomy for Refractory Gastroparesis: First Human Endoscopic Pyloromyotomy (with Video). Vol 78.; 2013. doi:10.1016/j.gie.2013.07.019
58. Malbert CH. The ileocolonic sphincter. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2005;17 Suppl 1:41-49. doi:10.1111/j.1365-2982.2005.00657.x
59. Quigley EM, Phillips SF. The ileocecal (ileocolonic) sphincter. Z Gastroenterol. 1983;21(2):47-55.
60. Pollard MF, Thompson-Fawcett MW, Stringer MD. The human ileocaecal junction: anatomical evidence of a sphincter. Surg Radiol Anat SRA. 2012;34(1):21-29. doi:10.1007/s00276-011-0865-z
61. Faussone Pellegrini MS, Manneschi LI, Manneschi L. The caecocolonic junction in humans has a sphincteric anatomy and function. Gut. 1995;37(4):493-498. doi:10.1136/gut.37.4.493
62. Nasmyth DG, Williams NS. Pressure characteristics of the human ileocecal region–a key to its function. Gastroenterology. 1985;89(2):345-351. doi:10.1016/0016-5085(85)90335-x
63. Dinning PG, Bampton PA, Kennedy ML, et al. Basal pressure patterns and reflexive motor responses in the human ileocolonic junction. Am J Physiol. 1999;276(2):G331-340. doi:10.1152/ajpgi.1999.276.2.G331
64. Allescher HD, Fick H, Schusdziarra V, Classen M. Mechanisms of neurotensin-induced inhibition in rat ileal smooth muscle. Am J Physiol. 1992;263(5 Pt 1):G767-774. doi:10.1152/ajpgi.1992.263.5.G767
65. King CE, Toskes PP. Small intestine bacterial overgrowth. Gastroenterology. 1979;76(5 Pt 1):1035-1055.
66. Afghani E, Lo SK, Covington PS, Cash BD, Pandol SJ. Sphincter of Oddi Function and Risk Factors for Dysfunction. Front Nutr. 2017;4:1. doi:10.3389/fnut.2017.00001
67. Villavicencio Kim J, Wu GY. Update on Sphincter of Oddi Dysfunction: A Review. J Clin Transl Hepatol. 2022;10(3):515-521. doi:10.14218/JCTH.2021.00167
68. Drossman DA, Hasler WL. Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology. 2016;150(6):1257-1261. doi:10.1053/j.gastro.2016.03.035
69. Schmulson MJ, Drossman DA. What Is New in Rome IV. J Neurogastroenterol Motil. 2017;23(2):151-163. doi:10.5056/jnm16214
70. George J, Baillie J. Biliary and gallbladder dyskinesia. Curr Treat Options Gastroenterol. 2007;10(4):322-327. doi:10.1007/s11938-007-0075-2
71. Toouli J, Roberts-Thomson IC, Dent J, Lee J. Sphincter of Oddi motility disorders in patients with idiopathic recurrent pancreatitis. Br J Surg. 1985;72(11):859-863. doi:10.1002/bjs.1800721104
72. Silverman WB, Slivka A, Rabinovitz M, Wilson J. Hybrid classification of sphincter of Oddi dysfunction based on simplified Milwaukee criteria: effect of marginal serum liver and pancreas test elevations. Dig Dis Sci. 2001;46(2):278-281. doi:10.1023/a:1005692530034
73. Behar J, Corazziari E, Guelrud M, Hogan W, Sherman S, Toouli J. Functional gallbladder and sphincter of oddi disorders. Gastroenterology. 2006;130(5):1498-1509. doi:10.1053/j.gastro.2005.11.063
74. Smithline A, Hawes R, Lehman G. Sphincter of Oddi manometry: interobserver variability. Gastrointest Endosc. 1993;39(4):486-491. doi:10.1016/s0016-5107(93)70156-x
75. Khuroo MS, Zargar SA, Yattoo GN. Efficacy of nifedipine therapy in patients with sphincter of Oddi dysfunction: a prospective, double-blind, randomized, placebo-controlled, cross over trial. Br J Clin Pharmacol. 1992;33(5):477-485. doi:10.1111/j.1365-2125.1992.tb04074.x
76. Pasricha PJ, Miskovsky EP, Kalloo AN. Intrasphincteric injection of botulinum toxin for suspected sphincter of Oddi dysfunction. Gut. 1994;35(9):1319-1321. doi:10.1136/gut.35.9.1319
77. Staritz M, Poralla T, Ewe K, Meyer zum Büschenfelde KH. Effect of glyceryl trinitrate on the sphincter of Oddi motility and baseline pressure. Gut. 1985;26(2):194-197. doi:10.1136/gut.26.2.194
78. Kumar L, Emmanuel A. Internal anal sphincter: Clinical perspective. Surg J R Coll Surg Edinb Irel. 2017;15(4):211-226. doi:10.1016/j.surge.2016.10.003
79. Barleben A, Mills S. Anorectal anatomy and physiology. Surg Clin North Am. 2010;90(1):1-15, Table of Contents. doi:10.1016/j.suc.2009.09.001
80. Raizada V, Mittal RK. Pelvic floor anatomy and applied physiology. Gastroenterol Clin North Am. 2008;37(3):493-509, vii. doi:10.1016/j.gtc.2008.06.003
81. Rattan S. Sympathetic (adrenergic) innervation modulates but does not generate basal tone in the internal anal sphincter smooth muscle. Gastroenterology. 2008;134(7):2179-2181; author reply 2181-2182. doi:10.1053/j.gastro.2008.05.017
82. Parks AG, Fishlock DJ, Cameron JD, May H. Preiminary investigation of the pharmacology of the human internal anal sphincter. Gut. 1969;10(8):674-677. doi:10.1136/gut.10.8.674
83. Ballester C, Sarriá B, García-Granero E, et al. Relaxation by beta 3-adrenoceptor agonists of the isolated human internal anal sphincter. Life Sci. 2010;86(9-10):358-364. doi:10.1016/j.lfs.2010.01.005
84. Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9(5):286-294. doi:10.1038/nrgastro.2012.32
85. Bajwa A, Emmanuel A. The physiology of continence and evacuation. Best Pract Res Clin Gastroenterol. 2009;23(4):477-485. doi:10.1016/j.bpg.2009.06.002
86. Kumar D, Waldron D, Williams NS, Browning C, Hutton MR, Wingate DL. Prolonged anorectal manometry and external anal sphincter electromyography in ambulant human subjects. Dig Dis Sci. 1990;35(5):641-648. doi:10.1007/BF01540414
87. Varma KK, Stephens D. Neuromuscular reflexes of rectal continence. Aust N Z J Surg. 1972;41(3):263-272.
88. Rao SSC, Patcharatrakul T. Diagnosis and Treatment of Dyssynergic Defecation. J Neurogastroenterol Motil. 2016;22(3):423-435. doi:10.5056/jnm16060
Irritable bowel syndrome (IBS) often presents with recurring abdominal pain, bloating, diarrhea, or constipation with an estimated pooled prevalence of 4.1% to 10.1%,1,2 respectively. In the western world IBS is twice more common in females than males.1,2
IBS has a substantial impact on healthcare burden, both to patients and society, in terms of daily symptoms, quality of life (QoL), work productivity, and healthcare costs.3-5 Many patients experience chronic, disruptive symptoms for many years prior to seeking health care, and typically report lengthy and complex treatment histories.4,6,7 Results from the IBS in America survey indicate that most patients with constipation-predominant IBS (IBS-C) experience symptoms at least 4 to 6 days per week,7 while another survey found that over half of patients with diarrhea-predominant IBS (IBS-D) reported experiencing fecal urgency most of the time.6 Abdominal pain is an important symptom and a key driver of health care seeking behavior.4 The main QoL domains affected by IBS includes general health, social functioning, and mental health.8,9
IBS may be caused by multiple pathophysiological mechanisms, including disordered gut-brain interactions, abnormalities in gastrointestinal (GI) motility, visceral hypersensitivity (a cardinal dysfunction), altered intestinal permeability, immune dysfunction, and gut dysbiosis.9-13 Genetic polymorphisms and environmental factors, including dietary and enteric, also play a role.12 Acute viral or bacterial gastroenteritis remains a strong risk factor for IBS, with 10% of patients reporting IBS after acute infections (i.e., post-infectious IBS).12 Whether IBS symptoms arise because of abnormal stress response to infectious and/or inflammatory gut responses, or from gut dysbiosis causing release of inflammatory mediators that affect the gut-brain axis merits further studies.12 The diagnostic approach and management of IBS, under the three main subcategories of IBS-D and IBS-C, and bloating, will be discussed. An overlap between these categories and other forms of IBS including IBS-M (mixed IBS with diarrhea and constipation) and IBS-U (undifferentiated IBS) may also exist.9,10
Clinical Approach to IBS-D
Diagnostic tests
IBS-D can usually be diagnosed with the help of Rome diagnostic criteria (Table 1, 2) without performing an array of diagnostic tests, although selected testing is appropriate in some patients to distinguish organic diseases from lower gastrointestinal motility disorders.9,10 (Figure 1) Key organic conditions that should be excluded in patients with suspected IBS-D include inflammatory bowel disease (IBD), hormonal disturbances, enteric infections, colorectal cancer, and disorders associated with malabsorption such as celiac disease, bile acid diarrhea, or carbohydrate maldigestion.9,10,13 A complete blood count is recommended to identify elevated white blood cell count, or anemia, while measures of systemic inflammation such as C-reactive protein (CRP) or fecal calprotectin can help discriminate between IBS and IBD.9,14 Given its low yield in this setting,15 routine colonoscopy is not recommended in the absence of alarm features.9 A small proportion of patients with suspected IBS-D may have microscopic colitis.14,15 Hence, colonoscopy with random colon biopsies is recommended.14
Hydrogen and methane breath tests can be useful in diagnosing various food intolerance syndromes, small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO), which are commonly associated with IBS-like symptoms.16,17 Despite significant heterogeneity in test performance, preparations, and indications, a recent consensus of experts and the American College of Gastroenterology (ACG) clinical practice guidelines concluded that breath hydrogen and methane testing can be useful in diagnosing not only carbohydrate maldigestion and SIBO, but also in assessing patients with bloating and methane-associated constipation.16,17 Since 25% of patients with IBS-D have evidence of bile acid diarrhea, regardless of cholecystectomy,18 tests such as 23-seleno-25-homotaurocholic acid retention test (75SeHCAT) or testing for 7-C4, a bile acid precursor, may be useful, especially to identify patients who may benefit from bile acid binding resins.
The value of celiac screening remains unclear. Current ACG guidelines recommend screening patients with tissue transglutaminase antibody (TtG) test,19 which is supported by a recent meta-analysis demonstrating a significantly higher prevalence of biopsy-proven celiac disease among all subtypes of IBS compared with controls.20 Likewise on a case-by-case basis, for example recent foreign travel, or antibiotic use, appropriate consideration should be given for stool evaluation of ova, parasites, culture and C. difficile toxin evaluation.
Management of IBS-D
A diet low in fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs) has become popular and has been evaluated.10,21,22 Meta-analysis of 7 RCTs found a significant effect of a low FODMAP diet in improving overall symptoms of IBS,10 with overall improvement in about half to two-thirds of patients.22 The most likely symptoms to respond include bloating and abdominal pain, and diarrhea is more likely to improve than constipation.22 A two-to-four-week trial is usually sufficient to assess response, with many patients responding within the first two weeks of FODMAP restriction. A recent network meta-analysis showed that low FODMAP diet was as superior to BDA/NICE diet for bloating and distension, and it is better than habitual diet for global gas symptom, although here was a higher risk of bias.23
Further, the long-term efficacy of this diet is unknown. A low FODMAP diet is not intended to be a long-term treatment strategy, but rather a tool for identifying patients who are sensitive to FODMAPs so that some of these foods can be systematically reintroduced to determine which foods are triggers and individualize diets accordingly.22,23 This process is best guided by a dietitian with expertise in caring for patients with GI disorders. An alternative approach is to perform fructose, lactose, fructan or sucrose breath tests,24,25 and/or disaccharidase mucosal enzyme assay26 to precisely determine the underlying etiology with one or more enzyme deficiency or food intolerance(s), and then provide tailored nutrition advice.25
Antidiarrheals and antispasmodics: Loperamide, a peripheral µ-opioid receptor agonist, is often recommended for patients with IBS-D.27 Although an effective antidiarrheal, there is no evidence supporting its efficacy in relieving abdominal pain, bloating, or global IBS symptoms.10 (Table 3) Similarly, despite being used for decades to treat abdominal pain associated with IBS, the evidence supporting the use of antispasmodics is modest.9,27 However, these agents do appear to provide some short-term benefit in IBS, but their use can be limited by dose-dependent anticholinergic adverse effects (e.g., constipation, fatigue, dry mouth, dizziness, blurred vision).27 Peppermint oil, which causes smooth muscle relaxation by blocking calcium channels, has been found to improve IBS symptoms in a small number of trials.10 In particular, an enteric-coated, sustained-release formulation of peppermint oil, IB Gard®, improved symptom scores in an RCT involving 72 patients with IBS-D/M, with significant improvement compared to placebo, and within 24 hours 28. Overall, the AGA guidelines gave this class a conditional and either low or very low evidence. (Table 3D)
Recurrent abdominal pain, on average, ≥1 day per week in the last 3 months, associated with ≥2 of the following criteria:
1. Related to defecation 2. Associated with a change in frequency of stool 3. Associated with a change in form (appearance) of stool
Criteria fulfilled for the last 3 months with symptom onset ≥6 months
Table 1. Rome IV Diagnostic Criteria for IBS9
Antidepressants: Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are useful in relieving pain and overall symptoms in IBS.27 These medications work centrally and peripherally via pain perception, visceral hypersensitivity, and GI motility. Although the efficacy of antidepressants according to predominant stool pattern has not been well studied, TCAs may be most appropriate in IBS-D given their ability to slow colonic motility and their mildly constipating effects.27 The serotonin and norepinephrine reuptake inhibitors (SNRIs) have not been studied adequately in this population. Given the diarrhea-predominant symptoms, a trial of low-dose TCA would be an appropriate option as these neuromodulators are very effective for treatment of pain. The AGA guidelines gave a conditional, low evidence recommendations for these agents. (Table B) A recent large community based RCT showed that a titrating dose of amitriptyline (10-30 mg/day) for 6 months, was superior to placebo in improving IBS symptoms.29
Management of bloating: Bloating is intricately linked and often associated with IBS.10,17,30 To that end, restriction of dietary FODMAPs has been found in studies of varying design to decrease bloating in a large proportion (50-82%) of patients.10,30 Another strategy is the use of probiotics, which are defined as attenuated bacteria or bacterial products that are beneficial to the host. Based on data from 37 RCTs involving 4403 patients, the ACG Task Force on IBS determined that probiotics have low quality of evidence and therefore gave a weak recommendation for treatment of IBS, with possible benefit on bloating and flatulence, rather than on bowel urgency or function.10 However, due to the poor quality and heterogeneity of the evidence, recommendations regarding the use of particular strains or species, or the subtype of IBS most likely to respond, could not be made.10 Also, a recent study cautioned against indiscriminate probiotic use as it may lead to colonization of probiotic organisms in the small bowel causing small intestinal bacterial overgrowth (SIBO), D-lactic acidosis, bloating and brain fog.31
Recent change in bowel habit (< 3 months) Age ≥50 years, no previous colon cancer screening, and presence of symptoms Unintentional weight loss Evidence of overt GI bleeding(i.e., melena or hematochezia) Nocturnal pain or passage of stools Family history of colorectal cancer, celiac disease or IBD Palpable abdominal mass or lymphadenopathy Evidence of iron-deficiency anemia Positive test for fecal occult blood
Rifaximin, an oral, non-absorbable, broad-spectrum antibiotic, has been extensively evaluated in IBS and found to improve bloating.10,32 Based on data from 6 RCTs involving 2441 non-constipated IBS patients, the ACG Task Force recommends rifaximin for improvement of global IBS symptoms as well as bloating.10 Although the precise mechanism for its benefit in IBS remains unclear, rifaximin appears to have beneficial effects on GI symptoms of diarrhea, pain and bloating, mucosal inflammation, and stabilization of the gut microbiota. Further, preclinical evidence suggests that the effects of rifaximin in IBS may involve mechanisms beyond the gut microbiota, including the modulation of proinflammatory cytokines and intestinal permeability.32
Rifaximin is approved in a 14-day regimen for the treatment of IBS-D and up to two retreatments in those who experience recurrence. Rifaximin is well tolerated, with a safety profile similar to that of placebo.32 The potential for an increased risk for Clostridium difficile infection and/or the emergence of microbial resistance has been reassuring.10,32 The AGA guidelines gave Rifaximin a conditional, moderate evidence recommendation.27 (Table 3D)
Specific therapies for IBS-D: Alosetron is a selective serotonin 5-HT3 receptor antagonist that improves global IBS symptoms and abdominal pain.10,27 Recently, a network meta-analysis of 18 RCTs involving various therapies (alosetron, ramosetron, rifaximin, eluxadolione) ranked alosetron first in efficacy for achieving the composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms, and effect on stool consistency in patients with IBS-D/M.27,33 However, it’s use has been limited by the small risk of ischemic colitis (1.03 cases per 1000 patient-years) and serious complications of constipation (0.25 cases per 1000 patient-years),34 leading to the restriction of its use to women with severe IBS-D who have not responded to conventional therapies.34 Although marketed under a Risk Evaluation and Mitigation Strategy program, requirements for the program have been updated to make it less onerous for prescribers than when it was first initiated.27 Alosetron was afforded a conditional recommendation with moderate certainty in evidence by the AGA.27 (Table 3B)
Eluxadoline is an oral, locally acting, mixed μ- and κ-opioid agonist/δ-opioid receptor antagonist approved for use in adults with IBS-D.35,36 Unlike pure µ-opioid receptor agonists, this agent reduces visceral hypersensitivity without completely disrupting intestinal motility, theoretically decreasing the potential for medication-related constipation.35,36 Meta-analysis of data from three large RCTs demonstrated significant benefits of eluxadoline on stool consistency and overall symptom improvement IBS-D patients but failed to demonstrate a clear effect on abdominal pain.10 However, subsequent analysis of the pivotal trials37 and a phase 4 study36 found eluxadoline to be effective in improving abdominal and stool consistency in IBS-D patients reporting inadequate symptom response to loperamide. Eluxadoline has been relatively well tolerated in clinical trials, with the most common adverse effects being constipation, nausea, and vomiting.10,36,38 However, due to the risk of pancreatitis, this agent is contraindicated in patients without a gallbladder, known or suspected biliary duct obstruction or sphincter of Oddi disease/dysfunction, alcohol use, history of pancreatitis, severe hepatic impairment, and severe constipation or its sequelae.38 The AGA assessment gave eluxadoline a conditional recommendation with moderate certainty.27,35 (Table 3B)
Drug
Class
N
Dose
Side Effects
Efficacy(Drug vs. Placebo)
Eluxadoline
Mixed μ/κ Agonist & Antagonist
1617 (2 RCT)
75/100 mg qd
Constipation, nausea, pain
27.2 vs 16.7 %, RR 0.87 (0.8-0.9)
Rifaximin
Nonabsorbable Broad Spectrum antibiotic
1258 (3 RCT)
550 MG TID
Nausea, URI, UTI
RR 0.85% (0.8-0.9)
Rifaximin
GCC agonist
2438/636 (1 RCT – 2 PHASES)
550 mg/tid
Nausea, URI, UTI N. Pharyngitis
38% vs 31%; RR 0.9 (0.8-1)
Alosetron
5 HT3 antagonist
4227 (8 RCT)
0.5-1 mg bid
Ischemic Colitis, constipation
RR 0.6 (0.5-0.67)
Loperamide
μ agonist
2883 (2 RCT)
2 or 6 mg bid
Headache, nausea, diarrhea
RR 0.4 (0.2-0.8)
AmitriptylineDesipramineImipramine
Tricyclic Antidepressant
523 (8 RCT)
Variable
Constipation/sleep/High Withdrawal rate
RR 0.67 (0.5-0.8)
FluoxetineParoxetine
SSRI
7 RCT
Variable
Weight gain, dreams
RR 0.74 (0.5-1.06
12 drugs(Cochrane)
Antispasmodics
2983 (22 RCT)
Variable
Dry mouth, Dizziness, vision
RR 0.74 (0.59-0.9)
Table 3A. Efficacy and Safety of Drug Treatments for IBS-D Based on AGA Guidelines AGA Guidelines for IBS-D35 5 HT3 = 5 Hydroxy Tryptamine 3; SSRI = Selective Serotonin receptor inhibit. RCT = Randomized controlled trial; qd = once/day; Bid = twice a day; TID = three times/day. UTI = Urinary tract infection; RR = Relative risk ratio
Clinical Approach to IBS-C
Diagnostic Tests for IBS-C: A first step is to obtain a detailed clinical history, and perform a digital rectal exam,40 and physical examination, combined with selected tests to exclude organic disease. (Figure 1). Further, evaluation of the pathophysiology of constipation may prove useful.9,41 It is important to characterize what a patient means by the term constipation; is it altered stool frequency or is it difficulty with defecation or both. Assessment of incomplete evacuation and stool consistency using a Bristol stool scale is important as well as associated features, such as degree of straining during defecation and use of digital maneuvers to assist defecation.9 It is essential to perform a digital rectal exam,40 which can help identify fecal impaction, anal stricture, rectal mass, and/or dyssynergia.9,39,42 Patients with paradoxical anal contraction on straining or inadequate push effort or anal/puborectalis relaxation should be referred for anorectal physiologic testing.39,42
Again, the presence of key alarm symptoms (e.g., unintentional weight loss, rectal bleeding) and whether patient has undergone recent screening colonoscopy per national recommendations are important. Assessment for hypothyroidism or hypercalcemia with a serum TSH and serum calcium may be useful.9 Although IBS-C and CIC are among the most common overlapping disorders associated with chronic constipation, it is important to exclude secondary causes of constipation such as drugs, metabolic disorder, neurological disorders and others.42
Once alarm features and secondary causes for a constipation have been excluded, the Rome IV criteria can be useful to diagnose IBS-C.9 (Tables 2,3)
General Management and Diet
Patient should be educated about IBS and advised to increase fluid intake, and maintain a fiber-rich diet, and regular exercise and reduce daily stressors. Poorly fermentable, soluble fiber (e.g., psyllium) is a recommended, evidence-based treatment for IBS-C.9,41 In contrast, insoluble fiber (e.g., bran) has no significant effect on IBS symptoms and on the contrary, may increase pain and bloating.10,41 Although an appropriate first-line treatment, fiber supplementation should be introduced gradually, starting with low doses and titrating slowly as tolerated to minimize unwanted GI effects (bloating, flatulence, and abdominal discomfort).10,44 Patients should also be educated that, unlike stimulant laxatives, response to fiber may take several weeks.42
New or Updated Recommendations
Strength of Recommendation
Certainty in Evidence
1. In patients with IBS-D, the AGA suggests using eluxadoline Implementation remark; eluxadoline is contraindicated in patients without a gallbladder, or those who drink more than 3 alcoholic beverages per day
Conditional
Moderate
2a. In patients with IBS-D, the AGA suggests using rifaximin
Conditional
Moderate
2b. In patients with IBS-D with initial response retreatment with rifaximin recurrent symptoms, the AGA suggests retreatment with rifaximin
Conditional
Moderate
3. In patients with IBS-D, the AGA suggests using alosetron
Conditional
Moderate
4. In patients with IBS-D, the AGA suggests using loperamide
Conditional
Moderate
5. In patients with IBS, the AGA suggests using TCAs
Conditional
Moderate
6. In patients with IBS, the AGA suggests against using SSRIs
Conditional
Moderate
7. In patients with IBS, the AGA suggest using antispasmodics
Conditional
Moderate
Table 3B. AGA Guidelines for IBS-D *For all recommendation statements, the comparator was no drug treatment.
Laxatives and fruits: Stimulant laxatives (senna, bisacodyl, castor oil, cascara, and aloe) help to produce bowel movements by decreasing water absorption and stimulating intestinal motility, either directly or indirectly through release of prostaglandins.42,44 These agents are often used on a rescue basis, such as in patients who have not defecated in several days, or more regularly if required.45 Based on data from 2 RCTs, the AGA considers sodium picosulfate and bisacodyl to be effective for CIC,46 although their use can be limited by poor tolerability, particularly regarding diarrhea and abdominal cramping. There is insufficient evidence to recommend the use of other stimulant laxatives for CIC, and similarly, there are no RCTs of stimulant laxatives in IBS-C.41
Polyethylene glycol (PEG) is an osmotic laxative that extracts fluid into the intestinal lumen to soften stools and accelerate colon transit. 47 The short- and long-term efficacy of PEG has been well-established in patients with CIC,47 with efficacy and safety established up to 6 months in an RCT47 and 24 months in a retrospective trial. Its efficacy in IBS-C, however, is less clear. (Table 4A) Data from two small RCTs found that PEG improved stool frequency in patients with IBS-C, but not pain or other IBS-related symptoms.10,48 Based on these data, the ACG recommends against the use of PEG for overall symptom improvement in IBS patients.10 Recently Kiwi fruit has been shown to be useful in improving IBS symptoms in an RCT.49
Antidepressants: Both TCAs and SSRIs are effective in relieving pain and overall symptoms in IBS.46 Given their prokinetic and anxiolytic effects, an SSRI is more appropriate option for constipation-related symptoms. These agents should be initiated at low doses and takes 4 to 8 weeks to achieve therapeutic response.46 (Table 4A)
Specific Therapies for IBS-C: Several specific therapies, (lubiprostone, linaclotide, plecanatide, and tenapanor) have been FDA approved over the last decade for the treatment of IBS-C.46,50-56 These therapies include secretagogues that act on intestinal enterocytes to stimulate net efflux of ions and water into the intestinal lumen, accelerate intestinal transit, and facilitate ease of defecation. These agents significantly improve bowel and abdominal symptoms in IBS-C,46 and are approved for this use.46,50-56 These agents were afforded a conditional recommendation with moderate certainty by the AGA guidelines. (Table 4B)
Lubiprostone was the first compound approved in 2006. It is a prostaglandin E1 derivative that acts on type 2 chloride channels (ClC2) of small intestinal enterocytes to increase secretion of chloride and fluid into the intestinal lumen.10 This agent is approved at dosages of 8 µg twice daily. The most common adverse effect with lubiprostone is dose-related nausea, occurring in 8% of patients receiving 8 µg and 24 µg twice daily, in pivotal trials of IBS-C and CIC compared with 4% and 3% of patients receiving placebo.50 Lubiprostone should be taken with food and water to minimize nausea and treatment can be initiated at lower doses and titrated upward as needed.46
Linaclotide and plecanatide are guanylate cyclase (GC)-C agonists that produce cyclic GMP intracellularly leading to activation of chloride ion secretion through the cystic fibrosis transmembrane regulator (CFTR), increasing fluid secretion into the GI tract and accelerating intestinal transit.51,52 Additionally, because GC-C pathways are involved in modulating pain fiber activity,53 these agents have effects on the abdominal pain and sensory symptoms of patients with IBS-C.54,55 In clinical trials, however, improvement in stool frequency tends to occur earlier (i.e., within a week of treatment initiation) with linaclotide compared with improvement in abdominal pain and bloating, which make take up to 8 to 12 weeks.51 A recent placebo controlled RCT study showed that linaclotide improves abdominal pain in patients IBS-C by improving rectal hypersensitivity and attenuating the signals from the rectum to the brain.55
Both linaclotide and plecanatide are approved at once-daily doses for use in IBS-C and CIC.46 (Table 9) Diarrhea is the most common adverse effect, which is usually mild and leads to few treatment discontinuations. Diarrhea can be managed by administering linaclotide 30 to 60 minutes before breakfast,46 or by starting with a low dose (72 µg/day) and titrating up to 290 mg/day.
New or Updated Recommendations
Strength of Recommendation
Certainty in Evidence
1. In patients with IBS-C, the AGA suggests using tenapanor
Conditional
Moderate
2. In patients with IBS-C, the AGA suggest using plecanatide
Conditional
Moderate
3. In patients with IBS-C, the AGA recommends using linaclotide
Strong
High
4. In patients with IBS-C, the AGA suggests using tegaserod Implementation remark: Tegaserod was reapproved for women under the age of 65 years without a history of cardiovascular ischemic events (such as myocardial infarction, stroke, TIA, or angina)
Conditional
Moderate
5. In patients with IIBS-C, the AGA suggests using lubiprostone
Conditional
Low
6. In patients with IIBS-C, the AGA suggests using PEG laxatives
Conditional
Low
7. In patients with IBS, the AGA suggests using TCAs
Conditional
Low
8. In patients with IBS, the AGA suggest against using SSRIs
Conditional
Low
9. In patients with IBS, the AGA suggests using antispasmodics
Conditional
Low
Table 4B. AGA Guidelines for IBS-C *For all recommendation statements, the comparator was no drug treatment. TIA: Transient ischemic Attack; PEG: Polyethylene Glycol; TCA: Tricyclic Antidepressants; SSRI: Selective Serotonin Receptor Reuptake Inhibitor.
Tenapanor is a new class of drug and is a sodium hydrogen exchanger 3 blocker that inhibits sodium absorption in the intestinal lumen.46,56 In 2 large clinical trials, tenapanor 50 mg BID was superior to placebo in improving IBS-C symptoms. It has been approved for IBS-C.46,56 Its main side effect is diarrhea.
CONCLUSIONS
IBS is a common disorder that imposes considerable health care burden. Dissatisfaction with current therapies remained but progress has been made on several fronts. Advances in understanding of the pathogenesis of these disorders have paved the way for new treatments. Recent evidence on the role of certain foods causing symptoms, and carefully planned dietary intervention, particularly the low-FODMAP diet, as a therapeutic strategy may be useful for many IBS patients. The best clinical trial evidence for IBS-D supports the use of alosetron, TCAs, peppermint oil, rifaximin, and eluxadoline. Although the predominance of abdominal pain differentiates IBS-C from chronic constipation, significant overlap exists, and treatment options are largely similar. First-line treatment of IBS-C/chronic constipation typically consists of diet and lifestyle modifications, along with nonprescription laxatives (soluble fiber, PEG). High-quality evidence supports the efficacy of prosecretory agents (lubiprostone, linaclotide, plecanatide), and NHE3 blocker tenapanor for the treatment of IBS-C. Cognitive behavioral therapy, especially using home-based APPs is gaining popularity and its wider availability will improve access to this therapy along with the stress-reduction therapies such as yoga and meditation, but these interventions need more evidence.
References
1. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology 2021;160(1):99-114.e3. doi:10.1053/j.gastro.2020.04.014
2. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatoll 2012;10(7):712-721.e4. doi:10.1016/j.cgh.2012.02.029
3. Buono JL, Carson RT, Flores NM. Health-related quality of life, work productivity, and indirect costs among patients with irritable bowel syndrome with diarrhea. Health Qual Life Outcomes 2017;15(1):35. doi:10.1186/s12955-017-0611-2
4. Heidelbaugh JJ, Stelwagon M, Miller SA, Shea EP, Chey WD. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol 2015;110(4):580-7. doi:10.1038/ajg.2015.67
5. Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm. 2013;19(9):755-64. doi:10.18553/jmcp.2013.19.9.755
6. Sayuk GS, Wolf R, Chang L. Comparison of Symptoms, Healthcare Utilization, and Treatment in Diagnosed and Undiagnosed Individuals With Diarrhea-Predominant Irritable Bowel Syndrome. Am J Gastroenterol. 2017;112(6):892-899. doi:10.1038/ajg.2016.574
7. Ballou S, McmahonC, Lee HN, et. al. Effects of irritable bowel syndrome on daily activities vary among subtypes based on results from the IBS in America survey. Clin Gastro Hepatol 2019; 17:2471-78.
8. Taylor DCA, Abel JL, Doshi JA, et al. The Impact of Stool Consistency on Bowel Movement Satisfaction in Patients With IBS-C or CIC Treated With Linaclotide or Other Medications: Real-World Evidence From the CONTOR Study. J Clin Gastroenterol. 2019;53(10):737-743. doi:10.1097/mcg.0000000000001245
9. Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology. 2016;150(6):1393-1407.e5. doi:10.1053/j.gastro.2016.02.031
10. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1-18. doi:10.1038/s41395-018-0084-x
11. Pimentel M, Lembo A. Microbiome and Its Role in Irritable Bowel Syndrome. Dig Dis Sci. 2020;65(3):829-839. doi:10.1007/s10620-020-06109-5
12. Barbara G, Grover M, Bercik P, et al. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46-58.e7. doi:10.1053/j.gastro.2018.07.011
13. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 Suppl 1:S1-35. doi:10.1038/ajg.2008.122
14. Banerjee A, Srinivas M, Eyre R, et al. Faecal calprotectin for differentiating between irritable bowel syndrome and inflammatory bowel disease: a useful screen in daily gastroenterology practice. Frontline Gastroenterol. 2015;6(1):20-26. doi:10.1136/flgastro-2013-100429
15. Chey WD, Nojkov B, Rubenstein JH, Dobhan RR, Greenson JK, Cash BD. The yield of colonoscopy in patients with non-constipated irritable bowel syndrome: results from a prospective, controlled US trial. Am J Gastroenterol. 2010;105(4):859-65. doi:10.1038/ajg.2010.55
16. Rezaie A, Buresi M, Lembo A, et al. Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus. Am J Gastroenterol. 2017;112(5):775-784. doi:10.1038/ajg.2017.46
17. Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020;115(2):165-178. doi:10.14309/ajg.0000000000000501
18. Slattery SA, Niaz O, Aziz Q, Ford AC, Farmer AD. Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2015;42(1):3-11. doi:10.1111/apt.13227
19. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-76; quiz 677. doi:10.1038/ajg.2013.79
20. Irvine AJ, Chey WD, Ford AC. Screening for Celiac Disease in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-analysis. Am J Gastroenterol. 2017;112(1):65-76. doi:10.1038/ajg.2016.466
21. van Lanen AS, de Bree A, Greyling A. Efficacy of a low-FODMAP diet in adult irritable bowel syndrome: a systematic review and meta-analysis. European Journal of Nutrition 2021: 60; 3505-3522.
22. Chey WD. Food: The Main Course to Wellness and Illness in Patients With Irritable Bowel Syndrome. Am J Gastroentero. 2016;111(3):366-371. doi:10.1038/ajg.2016.12
23. Black CJ, Staudacher HM, Ford AC. Efficacy of a low FODMAP diet in irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2022;71(6):1117-1126. doi:10.1136/gutjnl-2021-325214
24. Amieva-Balmori M, Coss-Adame E, Rao NS, Dávalos-Pantoja BM, Rao SSC. Diagnostic Utility of Carbohydrate Breath Tests for SIBO, Fructose, and Lactose Intolerance. Dig Dis Sci. 2020;65(5):1405-1413. doi:10.1007/s10620-019-05889-9
25. Rao SS, Yu S, Fedewa A. Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Aliment Pharmacol Ther. 2015;41(12):1256-70. doi:10.1111/apt.13167
26. Viswanathan L, Rao SSC, Kennedy K, Sharma A, Yan Y, Jimenez E. Prevalence of Disaccharidase Deficiency in Adults With Unexplained Gastrointestinal Symptoms. J Neurogastroenterol Motil. 30 2020;26(3):384-390. doi:10.5056/jnm19167
27. Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea. Gastroenterology. 2022;163(1):137-151. doi:10.1053/j.gastro.2022.04.017
28. Cash BD, Epstein MS, Shah SM. A Novel delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Symptoms. Dig Dis Sci. 2016;61(2):560-71. doi:10.1007/s10620-015-3858-7
29. Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023;402(10414):1773-1785. doi:10.1016/S0140-6736(23)01523-4
30. Foley A, Burgell R, Barrett JS, Gibson PR. Management Strategies for Abdominal Bloating and Distension. Gastroenterol Hepatol (N Y). 2014;10(9):561-71.
31. Rao SSC, Yu S, Tetangco EP, Yan Y. Probiotics can Cause D-Lactic Acidosis and Brain Fogginess: Reply to Quigley et al. Clin Transl Gastroenterol. 2018;9(11):207. doi:10.1038/s41424-018-0077-5
32. Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39(10):1161-8. doi:10.1111/apt.12735
33. Black CJ, Burr NE, Camilleri M, et al. Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Gut. 2020;69(1):74-82. doi:10.1136/gutjnl-2018-318160
34. Tong K, Nicandro JP, Shringarpure R, Chuang E, Chang L. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol. 2013;6(5):344-57. doi:10.1177/1756283×13491798
35. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. N Engl J Med. 21 2016;374(3):242-53. doi:10.1056/NEJMoa1505180
36. Brenner DM, Sayuk GS, Gutman CR, et al. Efficacy and Safety of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: RELIEF Phase 4 Study. Am J Gastroenterol. 2019;114(9):1502-1511. doi:10.14309/ajg.0000000000000327
37. Lacy BE, Chey WD, Cash BD, Lembo AJ, Dove LS, Covington PS. Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use. Am J Gastroenterol. 2017;112(6):924-932. doi:10.1038/ajg.2017.72
38. Viberzi (eluxadoline)[prescribing information]. Allergan USA IM, NJ; 2020.
39. Ford AC, Lacy BE, Talley NJ. Irritable Bowel Syndrome. N Engl J Med. 2017;376(26):2566-2578. doi:10.1056/NEJMra1607547
40. Rao SSC. Rectal Exam: Yes, it can and should be done in a busy practice! Am J Gastroenterol. 2018;113(5):635-638. doi:10.1038/s41395-018-0006-y
41. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109 Suppl 1:S2-26; quiz S27. doi:10.1038/ajg.2014.187
42. Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol. 2016;13(5):295-305. doi:10.1038/nrgastro.2016.53
43. Ramkumar D, Rao SS. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol. 2005;100(4):936-71. doi:10.1111/j.1572-0241.2005.40925.x
44. Rao SSC, Brenner DM. Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review. Am J Gastroenterol. 2021;116(6):1156-1181. doi:10.14309/ajg.0000000000001222
45. Bharucha AE, Pemberton JH, Locke GR, 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology. 2013;144(1):218-38. doi:10.1053/j.gastro.2012.10.028
46. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation. Gastroenterology.l 2022;163(1):118-136. doi:10.1053/j.gastro.2022.04.016
47. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol. 2007;102(7):1436-41. doi:10.1111/j.1572-0241.2007.01199.x
48. Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol. 2013;108(9):1508-15. doi:10.1038/ajg.2013.197
49. Gearry R, Fukudo S, Barbara G, et al. Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort—Results of an International Multicenter Randomized Controlled Trial. Official journal of the Am J Gastroenterol. 2023;118(6):1058-1068. doi:10.14309/ajg.0000000000002124
50. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome–results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29(3):329-41. doi:10.1111/j.1365-2036.2008.03881.x
51. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714-24; quiz p.1725. doi:10.1038/ajg.2012.255
52. Rao SSC. Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol. 2018;11:1756284818777945. doi:10.1177/1756284818777945
53. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′-monophosphate. Gastroenterology. 2013;145(6):1334-46.e1-11. doi:10.1053/j.gastro.2013.08.017
54. Rao SS, Quigley EM, Shiff SJ, et al. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014;12(4):616-23. doi:10.1016/j.cgh.2013.09.022
55. Rao SSC, Xiang X, Yan Y, et al. Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis. Aliment Pharmacol Ther. 2020;51(12):1332-1341. doi:10.1111/apt.15772
56. Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. doi:10.14309/ajg.0000000000000516
Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States1. DILI can be caused by a wide variety of compounds, including antibiotics, anticonvulsants, antidepressants, and herbal supplements. The risk of DILI is increased in patients with underlying liver disease, alcohol use, and certain genetic polymorphisms.
The diagnosis of DILI is based on a history of drug exposure, liver enzymes, and, less commonly, liver biopsy. Clinical and histologic presentation can mimic other causes of liver injury, which can make diagnosis challenging. The treatment of DILI, however, is supportive and includes stopping the offending drug and treating any complications. The prognosis of DILI is variable, but most cases are mild and resolve with discontinuation of the offending drug. Accurate diagnosis is paramount to prevent further unnecessary testing, therapies, complications, and lengthy hospital stays.
Background
Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States.1 It is estimated that DILI occurs in 1-6% of hospitalized patients and liver injury may occur 10-15% of patients taking new medications. A study by Chalasani et al. conducted in a large academic medical center in the US found that DILI accounted for 13% of cases of acute liver injury in hospitalized patients between 1994 and 2006.18 Additionally, DILI remains the leading reason for the post-market withdrawal of medications by the Federal Drug Administration (FDA) in the United States.2,16 Compounds commonly implicated in DILI include antimicrobials, antidepressants, anticonvulsants, analgesics, and herbal and dietary supplements. In Western countries, acetaminophen remains the leading cause of DILI.3
The incidence of DILI ranges between 2.4 in 100,000 to 19 in 100,000 persons per year globally24,7 according to population studies in the UK, France, and Sweden. A recent study by Björnsson et al. encompassing the population of Iceland utilizing a national healthcare database revealed an incidence of non-acetaminophen DILI of 19 in 100,000 per year8 in that population. The true incidence of DILI, however, is difficult to accurately determine. Liver injury is a significant consideration during drug development given the vast number of medications metabolized in the liver. Adverse effects of medications, including DILI, often can be discovered in clinical trials prior to regulatory approval and drug marketing. These clinical trials, however, are generally comprised of a limited number of subjects. Given the low incidence of DILI, the majority of cases are only discovered after regulatory approval and increased use of a medication in the general population. In a prospective survey to physicians in France performed over a 3-year period, the incidence of symptomatic DILI was found to be 14 in 100,000 patients per year.7 Notably, this number was 16 times greater than adverse hepatic events reported to the French regulatory authority.7 Similarly, in the United States, the post-market Adverse Events Reporting System established by the FDA is voluntary, may be incomplete, and may skew attribution of causality, ultimately underestimating true incidence of DILI25 in the general population.
Pathophysiology
The pathophysiology of DILI is complex and not fully understood. However, it is thought to involve a combination of genetic, environmental, and drug-related factors. Liver injury related to drugs or herbal and dietary supplements can generally be subdivided into two types of DILI—intrinsic or idiosyncratic.
Intrinsic DILI is defined as a direct, dose-dependent, and predictable hepatotoxicity. These compounds are generally thought to cause predictable liver injury in patients regardless of risk factors in a mainly dose-dependent fashion. Injury commonly arises from the drug itself or an active metabolite. This results in a series of events resulting in cell death. Mechanisms include production of free radicals, reactive oxygen species, interfering with native cellular components and cellular functions.36 This can subsequently lead to entities such as acute hepatitis or sinusoidal obstruction syndrome. Many intrinsically hepatotoxic compounds are identified in pharmaceutical trials or removed by regulatory agencies after post-market reporting.37 Some compounds, however, normally limited to therapeutic doses, are known to cause intrinsic hepatotoxicity in higher doses. The most common and well-studied example is acetaminophen (APAP), which is the leading cause of drug-induced liver failure in the US. In supratherapeutic doses, the accumulation of the hepatotoxic APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) causes direct oxidative cellular injury.3 Other compounds implicated with intrinsic liver injury in high doses include niacin and iron sulfate as well as those naturally occurring in some mushrooms such as Amanita phalloides.
Idiosyncratic DILI, however, is unpredictable and liver injury may not be dose dependent. The difficulty in identifying idiosyncratic DILI arises from its variable presentation and unpredictability. The incidence of idiosyncratic reactions to medications is low and, as a result, often escapes identification in preclinical and clinical pharmaceutical trials.36,38 Idiosyncratic DILI is thought to affect a predisposed population based on risk factors that are not well understood.
Risk Factors
Several risk factors for DILI have been proposed in the medical literature, however there is no clear evidence to suggest that they represent major risk factors for the development of all-cause DILI independent of a specific compound.40
Certain risk factors, however, may predispose an individual to injury with specific medications. Children are thought to be at higher risk of developing DILI with certain medications such as anticonvulsant and antimicrobial medications whereas older adults are more likely to develop liver injury with amoxicillin-clavulanate, nitrofurantoin, and isoniazid.39,40 Females may have an increased risk with minocycline, methyldopa, diclofenac, nitrofurantoin, and nevirapine. Risk for DILI in pregnancy may be increased with methyldopa, hydralazine, and antiretrovirals.42
Table 1. Risk Factor Associated with DILI Related to Particular Compounds
Other chronic comorbidities have been seen associated with higher risk of liver injury in combination with specific agents. In particular, diabetes mellitus may be related to a higher risk of DILI with methotrexate and antituberculosis medications as seen in a publication by the US DILI Network (DILIN).9
Environmental risk factors such as chronic alcohol use may be an additional risk factor for DILI, particularly with methotrexate and isoniazid41. Chronic alcohol use also increases the risk of liver injury from acetaminophen overdose. Interestingly, acute coingestion of alcohol with an acetaminophen overdose has been seen to confer a lower risk of DILI due to suspected substrate competition for metabolism of both compounds.43
Drug-drug interactions, particularly with antituberculosis medications and anticonvulsants, may potentially increase the risk for DILI.41
R ratio =
ALT ÷ ALT ULN _________________ Alk Phos ÷ Alk Phos ULN
Table 2. Calculation of R Ratio47 ALT: alanine aminotransferase, ULN: upper limit of normal of resulting laboratory, Alk Phos: alkaline phosphatase
Gender may also be associated with different outcomes following acute liver injury. Notably, acute liver injury in females was more likely to progress to acute liver failure as seen in several DILI registries.4,18,29
Other risk factors have been proposed which may increase the risk of DILI, such as other underlying liver disease, smoking, obesity, and malnutrition, however there is no clear evidence to suggest that these are major independent risk factors.41
Another risk factor proposed in the medical literature is race, however there remains no convincing evidence to suggest this as an independent risk factor due to confounding socioeconomic variables. Data from the US DILIN cohort saw that DILI in African-Americans was noted to occur in a younger age group and was associated more frequently with chronic symptoms when compared to Caucasians despite no significant difference in patterns of injury and recovery time. African Americans in that cohort, when compared to Caucasians, were seen to be twice as likely to develop severe liver injury leading to worse outcomes.19 Reasons for these outcomes are unclear, but may be related to unaccounted-for disparities in access to healthcare and reporting of adverse effects as well as other socioeconomic biases.51
Clinical presentation
The clinical presentation of DILI is variable and depends on the severity of the injury. Patients with mild DILI may have no symptoms or only mild symptoms, such as fatigue, nausea, and vomiting. With increasing severity of DILI, patients may exhibit jaundice, abdominal pain, and ascites. In very severe cases, DILI can present with coagulopathy and encephalopathy (signifying acute liver failure) and can subsequently lead to death.8
Clinically, DILI can be subcategorized based on the pattern of injury to the liver—hepatocellular, cholestatic, or mixed hepatocellular and cholestatic injury.44 Hepatocellular injury can be identified by a disproportionate increase in serum aminotransferases when compared to alkaline phosphatase. Cholestatic injury is identified by a disproportionate increase in alkaline phosphatase when compared to aminotransferases. In both cases, serum bilirubin may be elevated and synthetic function of the liver may be affected. These patterns can typically be differentiated by the calculation of the R ratio (Table 2) which compares the values of ALT and alkaline phosphatase. Typically, certain medications have been found to be more commonly associated with a specific pattern of hepatic injury (Table 3).
Table 3. Pattern of Liver Injury Associated with Common Culprits of DILI *Note: some compounds can produce multiple patterns of injury or can initially cause one pattern and later cause another pattern. These compounds are listed several times in this table
A poorly understood mechanism of injury, however, is immune-mediated DILI. This pattern of injury, thought to be related to an immune-mediated attack of the liver as a result of a specific metabolite, can often be associated with symptoms of hypersensitivity such as fever, rash, joint pains, lymphadenopathy, and eosinophilia.45 This symptomatic presentation may also resemble infectious mononucleosis. This pattern of injury has been associated with amoxicillin-clavulanate, diclofenac, phenytoin, and allopurinol.46
Another specific pattern includes drug-induced autoimmune hepatitis (DI-AIH). This presents with features of autoimmune hepatitis (AIH) such as elevated gamma-globulins, antibodies against smooth muscle, and/or antinuclear antibodies.46 Interestingly, this entity is responsive to treatment with corticosteroids and, as such, it is important to differentiate this entity from other injury patterns of DILI, where steroids may be less efficacious. Particularly, minocycline use in children can be seen to have a delayed pattern of injury resembling AIH.
Globally, the most common medications implicated in DILI are antibiotics, with the most common culprit in Western countries being amoxicillin-clavulanate (Table 4).8,19,48 More recently, however, with the increased use of herbal/dietary supplements (HDS), incidence of liver injury attributed to these agents has also been increasing.59,60 The most common cause of injury among HDS are bodybuilding supplements.60 Clinically, this can present with prolonged jaundice in otherwise healthy young men. Liver injury related to non-bodybuilding supplements is more commonly seen in females, usually presents with a hepatocellular pattern of injury and is associated with worse outcomes and higher rates of transplantation.60
Diagnosis
Despite its low incidence, DILI should always be included in a differential diagnosis of liver injury. Diagnosis of DILI poses significant difficulty to the clinician given the variability of objective markers of liver injury and the difficulty to assign causality to a certain medication. One of the earliest definitions of DILI, specifically that with an hepatocellular pattern of injury, was developed by Dr. Hyman Zimmerman based on observations published in 1968 and again in 1999, suggesting that elevation of aspartate transaminase (AST) or alanine transaminase (ALT) more than three times the upper limit of normal (ULN) along with an elevation of total bilirubin more than two times the ULN in the absence of cholestasis (elevation of alkaline phosphatase < 2x the ULN) is a predictor of severe liver injury and poor outcomes (with a mortality of 10-50%, in pre-transplant days).26,27 Later dubbed Hy’s law, these parameters, in the absence of other etiologies of liver injury, signaled the potential for a drug to cause liver injury and have comprised part of the recommendations by the FDA for pharmaceutical trials.
Spanish Registry (n = 843)48
DILIN (n = 899)19
Icelandic Study (n = 96)8
Amoxicillin-clavulanate (22%)
Amoxicillin-clavulanate (10%)
Amoxicillin-clavulanate (22%)
Anti-tuberculosis (4.5%)
Isoniazid (5.3%)
Diclofenac (6.3%)
Ibuprofen (3%)
Nitrofurantoin (4.7%)
Nitrofurantoin (4%)
Flutamide (2.6%)
Sulfam-trimeth (3.4%)
Azathioprine (4%)
Atorvastatin (1.9%)
Minocycline (3.1%)
Infliximab (4%)
Diclofenac (1.8%)
Cefazolin (2.2%)
Isotretinoin (3%)
Ticopidine (1.4%)
Azithromycin (2%)
Atorvastatin (2%)
Azathioprine (1.3%)
Ciprofloxacin (1.8%)
Doxycyline (2%)
Fluvastatin (1.3%)
Levofloxacin (1.4%)
Imatinib (1%)
Simvastatin (1.3%)
Diclofenac (1.3%)
Isoniazid (1%)
HDS (3.4%)
HDS (16.1%)
HDS (16%)
Table 4. The Most Common Implicated Agents Causing DILI in Three Prospective Studies on DILI Abbreviations: DILI, drug-induced liver injury; HDS, herbal and dietary supplements; Sulfam-trimeth, sulfamethoxazole-trimethoprim Reproduced from: Björnsson ES. Clinical management of patients with drug-induced liver injury (DILI). UEG Journal. 2021 Sep;9(7):781-6.
In an effort to further delineate causality based on objective measurements, the Roussel Uclaf Causality Assessment Method (RUCAM) system was developed in 1993 as an assessment score reflecting the likelihood that liver injury can be attributed to a specific compound.30 This system was validated on findings of a consensus meeting of experts (including Drs. Benhamou, Bircher, Dana, Maddrey, Neuberger, Orlani, Tygstrup and Zimmerman) and uses a combination of serologic, clinical, and radiologic features of liver injury assigned to a point system. This study found that scores usually agreed among the experts, with only 16% of scores being more than 1 point divergent.30,47
History
DILI should be considered amongst a wider differential diagnosis of more common causes of liver injury, as it largely remains a diagnosis of exclusion. Obtaining an accurate and thorough history is paramount to making a diagnosis of DILI. This should particularly involve a comprehensive review of medications with respect to the timing of their initial dosing, onset and chronicity of symptoms, and liver chemistry abnormalities. Additionally, care should be taken to inquire about the use of herbal and dietary supplements as these are increasingly more common causes of DILI.13
Figure 1. A diagnostic workflow for assessing cases of suspected DILI 49. Reproduced from Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017 Jun 1;66(6):1154-64: Figure 3. Used with permission from BMJ Publishing Group Ltd.
A particularly useful tool for clinicians developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) along with the National Library of Medicine is LiverTox (https://www.ncbi.nlm.nih.gov/books/NBK547852). This is a publicly available and easily accessible online textbook which maintains continuously up-to-date information on the likelihood and pattern of hepatotoxicity of over 1200 compounds.50 The aim of the LiverTox resource is to consolidate information that is not readily available and is dispersed throughout multiple publications in multiple disciplines throughout the world. This repository is constantly updated as new medications are introduced and their hepatotoxic side effects are brought to light through more frequent use.
Laboratory Investigations
After a thorough history is obtained, liver chemistry abnormalities should be analyzed for their pattern of injury. This can be objectively accomplished by calculating an R ratio (Table 2). This in turn will help differentiate between hepatocellular injury, cholestatic injury, or a mixed injury. The pattern of injury can then guide further workup.
For a hepatocellular pattern of injury (R ratio ≥5), causes of acute hepatitis should be further investigated. Preliminary testing should include serologies for acute viral hepatitis (including HCV RNA), serologies for autoimmune hepatitis, as well as imaging studies of the liver such as ultrasonography. If first-line testing is unrevealing, a hepatocellular pattern of injury should be further explored with ceruloplasmin and serologies for less common etiologies of viral hepatitis such as CMV, EBV (quickly assessed with monospot testing), and COVID, and possibly liver biopsy.
For a cholestatic pattern of injury (R ratio ≤2), primary testing should involve imaging studies, such as abdominal ultrasound. If unrevealing, further testing by cholangiography, serologies for primary biliary cholangiopathy (PBC), and liver biopsy can be considered.
A mixed pattern of liver injury (R ratio 2-5) should primarily involve workup for acute viral hepatitis (as detailed above), serologies for autoimmune hepatitis, as well as imaging studies of the liver with ultrasonography. If this is unrevealing, further testing for ceruloplasmin levels, serologies for less common causes of viral hepatitis, and liver biopsy can also be considered.
If thorough testing and history can reasonably exclude a non-DILI etiology of liver injury, a literature review utilizing the LiverTox database should be performed to reexamine the likelihood of liver injury by reported medications and/or dietary or herbal supplements.
Ultimately the final diagnosis of DILI is based on clinical judgment and clinical suspicion. Consultation with an expert should be sought if there remains a doubt about the diagnosis or if specialized assistance is needed for further workup such as with endoscopic cholangiography.
Liver Biopsy
The diagnosis of DILI typically does not require a liver biopsy. Biopsy findings may be supportive of DILI but are rarely diagnostic. Nearly every type of histologic abnormality can be mimicked by certain drugs, although each individual drug is typically associated with a histologic pattern characteristic to that drug. Review of every drug’s histologic pattern is beyond the scope of this article. Histologic evaluation may be useful, however, to exclude an alternate etiology of liver injury, particularly if there is no initial resolution of liver injury (i.e., persistently abnormal liver chemistries) following withdrawal of a suspect agent (dechallenge).
Acute liver failure
Clinical symptoms should be closely evaluated during presentations with acute liver injury. Particular care should be taken to monitor for progression to ALF based on diagnostic indicators, namely an INR >1.5 and signs of hepatic encephalopathy (altered mental status/asterixis). A timely diagnosis of ALF should prompt immediate referral to a liver transplant center in order to begin evaluation for liver transplantation, particularly in the setting of DILI, due to the high associate mortality rate.
Treatment
Once the diagnosis of DILI has been established, the mainstay of treatment is the removal of the offending compound/medication. Dechallenging results in a complete resolution of liver injury without the need for additional treatment in a vast majority (>90%) of cases.52,53 Furthermore, a successful dechallenge suggests the potential causality of a medication to liver injury and care should be taken to avoid re-exposure. Although care for DILI is mainly supportive, there are certain directed therapies which have shown to improve outcomes in liver injury by specific agents.
Although treatment of liver injury related to acetaminophen with N-acetylcysteine (NAC) has been well-established, evidence has suggested that treatment of non-acetaminophen liver injury with NAC should be considered in patients presenting with ALF related to idiosyncratic DILI. A randomized trial by the US ALF study group revealed a two-fold increase in transplant-free survival in patients who received NAC vs a placebo infusion.54
Treatment of DILI related to terbinafine and leflunomide with a bile-acid binder has been shown to facilitate clearance of these compounds.52,55 Valproic acid hepatotoxicity can be treated with carnitine, which regulates fatty acid uptake and mitochondrial beta-oxidation.52,56 In patients undergoing myeloablative hemopoietic stem cell transplant (HSCT), ursodiol has shown good results as prophylaxis against sinusoidal obstruction syndrome (SOS, formerly veno-occlusive disease). Similarly, defibrotide can be considered not only as a treatment for severe SOS but also as prophylaxis for those at high risk.57
The use of corticosteroids in idiosyncratic DILI remains controversial, and corticosteroids are mainly reserved for use in the setting of drug-induced AIH, severe hepatitis related to immunotherapy, or in hypersensitivity. In patients with severe liver injury, lower survival was seen in patients treated with corticosteroids.58 Close monitoring is essential during treatment with corticosteroids. In the absence of a response to treatment, corticosteroid treatment should be discontinued in order to prevent steroid-related adverse effects, and an alternate diagnosis should be considered.51 In the event of response to corticosteroid treatment, steroids should be withdrawn in a gradual manner. This should be paired with close follow up and monitoring of liver chemistries for the reappearance of liver injury in order to detect an AIH component, which would require ongoing treatment.
Conclusion
Drug-induced liver injury (DILI) is a serious condition that can lead to severe liver injury, acute liver failure, and even death. Although the incidence of DILI is relatively low, it is important for clinicians to be aware of DILI and its general workup in order to recognize and manage this condition early. Diagnosis is mostly clinical, with the assistance of resources such as LiverTox. The approach to suspected DILI involves recognizing general signs and symptoms, careful history taking, excluding alternative causes of liver injury, assessing severity, identifying and discontinuing the offending drug. It is similarly important to monitor for ALF in order to provide a timely referral to a liver transplant center.
The most common cause of DILI in the US remains acetaminophen and the use of NAC is well-established in its treatment, but NAC should be considered in use for idiosyncratic DILI given data on improved outcomes in non-acetaminophen related DILI. In most cases, removal of the offending medication results in resolution.
The best way to prevent DILI, however, is to avoid agents that are known to cause liver injury, particularly in those individuals who are susceptible. Providers should be aware of the increased use of herbal and dietary supplements and the increasing incidence of liver injury related to their use.
Aftermarket reporting of DILI remains extremely important in providing ongoing data regarding the hepatotoxicity of medications. Providers should strongly consider reporting hepatotoxic effects of medications to regulatory agencies. In the US, reports to the FDA Adverse Events Reporting System (FAERS) database can be submitted by anyone, including healthcare professionals, patients, and consumers.
In some cases, it may be necessary to rechallenge a patient with the suspected drug if it is the only effective treatment for a particular condition, however this should only be done after careful consultation with a hepatologist.
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Over the past decade, whole food plant-based diets (WFPBDs) have gained popularity as evidence has emerged regarding their association with improved morbidity and mortality for many patient populations, including those with gastrointestinal diseases. Multiple factors contribute to the benefits of a WFPBD, including the impact of fiber on the gut microbiome, reduction of the additives found in processed foods such as emulsifiers and stabilizers, and the anti-inflammatory properties of plant-based foods compared to animal-based foods. This review discusses general components and benefits related to WFPBDs, with an evidence-based focus on their role in managing and preventing gastrointestinal disorders. In addition, we offer practical guidance and tools for healthcare providers to help their patients adopt and sustain a WFPBD.
Introduction
Whole food plant-based diets (WFPBDs) emphasize maximizing the intake of plant-based foods while minimizing highly processed and animal-based foods. Over the last decade, WFPBDs have been emerging with strong evidence regarding their impact on morbidity and mortality in various diseases.1 Current evidence has highlighted the positive effect of WFPBDs on not only gastrointestinal (GI) diseases but also metabolic syndrome, cardiovascular diseases, cognitive function, and overall mortality risk.1-3 WFPBDs encourage a high-fiber intake to influence the diversity and composition of the gut microbiome, a key connection between diet and metabolic health.4 Ultra-processed foods may play a role as a significant contributor to the development of GI disorders such as inflammatory bowel disease (IBD), colorectal cancer, and metabolic dysfunction-associated steatotic liver disease (MASLD).2,5,6 WFPBDs aim to address and mitigate the underlying factors that may contribute to these disorders.1-3,5,6
Despite the increasing popularity of WFPBDs, there are still inconsistencies in its definition, leading to confusion about its composition among patients and healthcare providers. This review explores the core principle of WFPBDs and their multifaceted connections to various GI disorders. We will also outline a patient-centric approach for providers to help patients adopt new dietary habits while addressing the potential challenges of WFPBDs.
What is a Whole Food Plant-based Diet?
The WFPBD focuses on the consumption of vegetables, fruits, whole grains, and legumes in their most natural form while reducing or eliminating animal products.7 This emphasis on whole foods inherently decreases the intake of emulsifiers and stabilizers, which are standard components of ultra-processed foods. Emulsifiers, often used to improve texture and shelf life, have been associated with increased inflammation and detrimental changes to the microbiome composition.8 Similarly, stabilizers, such as maltodextrins, have been linked to intestinal protective mucus layer damage and the subtle development of intestinal inflammation.8
WFPBD can be tailored to fit individual preferences, offering flexibility in food choice while maintaining its core principle of whole, minimally processed plant-based diet. Patients may adopt various forms of WFPBD, such as vegan, lacto-ovo-vegetarian, pescatarian, or Mediterranean diets (MD).7 (See Table 1) With guidance from registered dietitians and healthcare providers with expertise in WFPBD, patients can choose a dietary pattern that best matches their health goals and cultural preferences, all while supporting long-term health benefits and managing their GI diagnosis.
Fiber and the Gut Microbiome
Fiber is traditionally defined as the non-digestible components that make up the plant cell wall.9 It remains a critical part of the diet today, with plants serving as the primary source. Dietary fiber has various properties – solubility, fermentability, and viscosity – that influences its health benefits within the GI tract.10 Solubility refers to the ability of the fiber to dissolve in water. Fermentability indicates the ability of the gut bacteria to digest fiber. Viscosity refers to fiber’s capacity to hold water and form a thick, gel-like substance.4 As such, fiber can be categorized into many types: soluble/fermentable/viscous (e.g., pectin, galactomannans, beta-glucans), soluble/fermentable/non-viscous (e.g., inulin, oligofructose, fructo-oligosaccharides), and insoluble/non-fermentable/non-viscous (e.g., lignin, cellulose).10,11 (See Table 2)
Types
Definition
Whole food plant-based diet
Whole food ingredients comprised primarily of vegetables, minimally processed fruits, whole grains, legumes, nuts, or seeds. Covers a wide range of other diets including vegan, lacto-ovo-vegetarian, pescatarian, and Mediterranean diet.
Vegan diet
Strictly excludes meat, poultry, eggs, dairy, and any food that contains them.
Lacto-ovo-vegetarian diet
Include eggs and dairy. Excludes meat, poultry, and fish.
Pescatarian diet
Includes seafood but excludes meat and poultry. May or may not include eggs and dairy.
Mediterranean diet
Primarily fruits, vegetables, whole grains, and fish. Poultry, eggs, and dairy are eaten in moderation. Meat and added sugars are consumed infrequently.
Table 1. Definitions of Whole Food Plant-Based Diets7
Gut microbiota is a community of microorganisms, including bacteria, archaea, fungi, and viruses, that reside within the GI tract, shaping our gut immune system by regulating the expression of colonic regulatory T cells.12 Soluble, non-viscous, and fermentable fibers, once fermented by colonic bacteria, help generate short-chain fatty acids (SCFAs) such as butyrate and acetate, which are the preferred energy sources for colonic mucosa cells.13 SCFAs also promote the growth of beneficial gut bacteria, such as Bifidobacteria and Lactobacilli. Subsequently, they increase the immune reactive myenteric neurons and inhibit the signaling pathway for colonic inflammation.4 In contrast, a low-fiber diet can disrupt this process, resulting in dysbiosis, a harmful imbalance in the gut microbiota characterized by reduced bacterial diversity and an overgrowth of harmful microorganisms.14,15
Properties
Benefits
Types
Food Sources
Soluble
Viscous/ fermentable
– Moderate pre-biotics potential – Produce SCFAs to stimulate immune system
Skins of fruits, leafy greens, wheat bran, green beans, quinoa, nuts, flaxseed
Table 2. Roles and Types of Fiber4,9-11
Meanwhile, insoluble/poorly fermentable fiber irritates gut mucosa, stimulates mucous, and water secretion. An osmotic load is then formed to improve absorption and decrease gastrointestinal transit time, alleviating chronic constipation.11
Polyphenols and the Gut Microbiome
Polyphenols are natural metabolites synthesized exclusively by plants. Most polyphenols come from fruits, vegetables, grains, spices, herbs, and teas. Extensive studies on these compounds have highlighted their beneficial roles in promoting antioxidant, anti-inflammatory properties and healthy gut microbiome.16 Upon consumption, only a small fraction of polyphenols is absorbed in the small intestine.17 The remaining polyphenols are metabolized by the colon and undergo a transformative process facilitated by gut microbes. This process promotes a shift in the composition of the gut microbiota from harmful species, such as Clostridium spp. and Bacteroides spp., to beneficial bacteria, including Lactobacillus spp. and Bifidobacterium spp.18,19 These beneficial species produce butyrate and promote anti-inflammation through a reduction in C-reactive protein.18
Other studies have noted the ability of polyphenols to interact and cause apoptosis of harmful cell membranes via hydrogen bonding with lipid bilayers.20 This antimicrobial property allows polyphenols to inhibit the growth of pathogenic bacteria such as Escherichia coli and Klebsiella pneumoniae while providing protective effects against tumor cells.17,20 Moreover, the antioxidant and anti-inflammatory effects of polyphenols are likely related to their ability to inhibit pro-inflammatory cytokines such as TNF-alpha and IL-6 and suppress free radical generation by activated neutrophils in the GI lumen.21 One of the most well-known polyphenols is curcumin, a natural compound found in turmeric. It has shown potential benefit for IBD patients. One study has demonstrated that daily intake of 2 grams of curcumin, combined with sulfasalazine or mesalamine, was more effective in preventing clinical relapse in patients with ulcerative colitis compared to treatment with sulfasalazine or mesalamine and placebo compound.22
GI Disorders
Diets
WFPBD Foods
Inflammatory bowel disease
– Mediterranean diet – Lacto-ovo-vegetarian diet – For strictures or active flares: foods in small particle size
– Fruit. If stricturing: soft fruits (banana, berries, avocado), fruits in small particle size, no peels – Vegetables. If stricturing: small particle size for cooked vegetables, no peels – Protein: fatty fish, creamy peanut butter, ground flaxseed – Add olive oil to meals, smoothies, hummus and crackers, yogurt, and berries
Irritable bowel syndrome
-Soluble fibers -Low- FODMAP
-Fruits: kiwi, banana, blueberries, cantaloupe, grapes – Vegetables: bok choy, carrots, green beans, zucchini, lettuce – Dairy/Dairy Substitutes: lactose-free milk or yogurt, hard cheeses such as cheddar or swiss, almond or coconut milk -Protein: chicken, fish, egg, tofu
Gastroparesis
– Small and frequent meals with a small particle size diet
– Fruits: soft fruits such as cantaloupe, honeydew, or kiwi with no peel – Vegetables: should be cooked or mashed, blended into small particle size, no peel – Protein: ground chicken or turkey, fish, creamy nut butter, tofu -Dairy: milk, sprinkle of cheese, yogurt
-Fruits: all -Vegetables: all -Whole grains: all -Legumes: all -Proteins: fatty fish, flax seed, chia seeds, nuts
Celiac disease
-Gluten-free diet
-Fruits: any fresh or frozen -Vegetables: any fresh or frozen -Milk and/or dairy: milk, plain cheese, yogurt – Gluten-free grains: quinoa, millet, sorghum, amaranth, buckwheat, teff, and wild rice – Proteins: lean meats, eggs, beans, chickpeas, edamame, tofu
Gastroesophageal reflux disease
-WFPBD – minimize chocolate, peppermint, coffee, citrus, and spicy food
-Fruits: non-citrus fruit only -Vegetables: fresh and raw -Whole grain: oatmeal, whole-grain bread, rice -Dairy: any – Protein: lean meats that are grilled/ poached, broiled or baked -Use fresh herbs instead of spice for flavors
We recommend incorporating a variety of plant-based food in all meals, with portion sizes and frequency tailored to individual tolerance and preferences. As a starting point, patients can create a balanced plate using the My Plate method (https://www.myplate.gov/) or Mediterranean diet pattern (www.oldwayspt.org). From there, adjustments can be made based on personal needs, to further meet nutritional needs and ensure sustainability overtime.
Table 3. A Summary of Recommended Diets for Gastrointestinal Disorders and Sample PBD28,30,31,32,40,41,44,45,48
WFPBDs and Gastrointestinal Disorders
Inflammatory Bowel Disease
The Western diet is recognized as a predominant environmental risk factor in IBD.23,24 A prospective study of long-term dietary fiber intake (median of 24.3g/day, mainly from fruits) demonstrated a reduced risk of Crohn’s disease in individuals who consumed higher quantities of fiber, particularly from fruit sources.24 Likewise, a trial of 92 patients with ulcerative colitis (UC) showed lower clinical relapse rates with the regimen of a WFPBD and induction therapy compared to induction therapy alone.25
Another small two-year clinical study examined remission rates in Crohn’s disease (CD) patients, who had initially achieved remission through medical or surgical intervention. They were advised to maintain a semi-vegetarian diet and avoid processed foods. Among the sixteen patients who adhered to the diet, 100% remained in remission after 1 year, and 92% maintained remission after two years. In contrast, remission rates were only 67% at one year and 25% at two years among the six patients who did not follow the diet.26 Finally, the Diet to Induce Remission in Crohn’s Disease (DINE-CD) trial compared MD to the Specific Carbohydrate Diet and found no significant difference in symptomatic remission or inflammation reduction at six weeks between the two diets.27 Thus, data suggest that recommending less restrictive diets, like the MD, would be reasonable for symptom control in IBD. (See Table 3)
Patients with symptomatic or significant fibro-stricturing IBD often have concerns about fiber consumption. For these individuals, the quantity, type, and particle size of fiber are critical to ensure optimal tolerance.28 There is limited evidence on complete fiber restriction in individuals with strictures or active flares. Soluble fibers such as bananas, avocados, and most berries tend to be better tolerated.29 In contrast, insoluble fiber, such as raw kale or apple skin, may need modification to small particle size into blended, mashed, and minced forms.30 As an example, patients can replace apples with applesauce and garbanzo beans with hummus, and blend fruits and vegetables into a smoothie.31
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a common GI disorder involving the gut-brain interaction. The 2021 American College of Gastroenterology (ACG) Clinical Guidelines recommend whole food soluble fiber such as oat bran and barley to treat global symptoms of IBS.32
As a highlight, controlled trials have demonstrated a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is effective in improving disease-specific quality of life, anxiety, and activity impairment in IBS patients with diarrhea predominance.33 However, more studies are still needed to evaluate its efficacy in patients with IBS-constipation.32 The low-FODMAP approach involves 3 phases. The first is the elimination phase, during which all high-FODMAP foods are replaced with low-FODMAPs for 4-6 weeks. In the reintroduction phase, patients gradually reintroduce a high-FODMAP food one at a time to learn foods that exacerbate their symptoms. The last phase, personalization, is for patients to customize their diet based on what was learned from the trials of reintroduction. Patients can then retain the well-tolerated high-FODMAP items and limit the portions of those that were not.33
A WFPBD can be tailored to fit the low-FODMAP with a few strategic adjustments. Low-FODMAP whole grains (e.g., oatmeal, quinoa), fruits (e.g., blueberries, kiwi), and vegetables (e.g., spinach, zucchini) can be included in WFPBD meals throughout the day. Research also shows that certain food processing methods can significantly reduce FODMAP content.34 For example, pickling artichokes, onion, or garlic lowered their FODMAP content by 80-90%, while canning and simmering beans or lentils reduces their oligosaccharide content, increasing options for patients personalizing their WFPBD to a low-FODMAP diet.34
Gastroparesis
Gastroparesis (GP) is defined by symptoms suggestive of gastric food retention and objective evidence of delayed gastric emptying without mechanical obstruction.35 Traditionally, the dietary treatment for GP is low-fat and low-fiber meals 4-5 times daily, which came with its limitations such as malnutrition and digestive issues.35,36 In the recent years, the recommendation has shifted to modifying food consistency to small particle size by blending, mincing, mashing, or chopping.35,37 A 2018 experimental study explored how the particle size of food influenced gastric emptying. The study compared two solid meals with identical components but different gastric sizes, demonstrating that the smaller particle size diet significantly increased gastric emptying rates.38 Further supporting this, a 2014 randomized controlled trial showed a significant reduction of GP symptoms with use of a small particle size diet.37
For GP patients following a WFPBD, small and frequent meals in small particle size are often recommended to optimize tolerance. Plant foods with large particle sizes, such as food with husks or peels (e.g., pineapple, corn, and cabbage), foods with membranes (e.g., oranges and apples), raw vegetables, seeds, and grains should be cooked, ground, or blended.35
MASLD is a spectrum of diseases, including steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma.39 The MASLD term replaced what was formerly known as non-alcoholic fatty liver disease (NAFLD).39 MASLD is thought to be the result of excess triglyceride storage in the liver in addition to at least one cardiometabolic risk factor.5 Obesity and diabetes mellitus strongly correlate with the development and progression of MASLD. MASLD/MASH and alcohol-associated liver disease are the two most common indications for liver transplantation among patients without hepatocellular carcinoma in the United States.39 Diet modification has been recommended to prevent and treat MASLD.5,40
A longitudinal analysis involving 1521 participants conducted from 1998-2011 demonstrated that adherence to a MD or a WFPBD over a six-year period led to reductions in liver fat accumulation and risk of MASLD.41 Like WFPBD, MD emphasizes minimally processed foods, with key elements including legumes, whole grain, healthy fats (from extra virgin olive oil and fats), vegetables and fruits, while limiting red meat and sweets. MD also encourages the intake of omega-3 fatty acid (EPA and DHA) from fish.27 These healthy components collectively improve insulin resistance, decrease central obesity, and reduce MASLD risk regardless of genetic susceptibility.42
Celiac Disease
Treatment of celiac disease consists of a lifelong gluten-free diet (GFD). Strict adherence is necessary for improving the health of duodenal mucosa, alleviating symptoms, and normalizing celiac-specific antibodies. Microscopic mucosa recovery occurs six months to three years after initiating the GFD.43 For those following a WFPBD, providers can recommend gluten-free whole grains such as quinoa, millet, sorghum, amaranth, buckwheat, teff, and wild rice.44 These grains offer higher protein and fiber contents compared to wheat and are also rich in antioxidants like carotenoids, and essential vitamins and minerals such as iron, calcium, and thiamine.44-46 Furthermore, gluten-free grains and plant-based protein sources like soy milk, yogurt, tofu and flour from nuts, seeds, or legumes can enhance the nutritional value of WFPBD for individuals with celiac.44,46
Gastroesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) is highly prevalent, with a global burden that has increased by 77.53% from 1990 to 2019, making it critical for clinicians and healthcare systems to prioritize preventative and management strategies.47 Acid suppression therapy and dietary changes are considered first-line medical therapies.48
The 2022 ACG Clinical Guidelines suggests that alcohol, smoking, chocolate, peppermint, and high-fat foods reduce lower esophageal sphincter pressure, thereby worsening GERD symptoms. Additionally, coffee, citrus, and spicy food can irritate the esophageal lining, evoking symptoms.48 In 2023, Rizzo et al. conducted an online survey of the dietary habits of 4352 Italian individuals and found that those adhering to strict WFPBDs such as a vegan diet, had a reduced incidence of GERD compared to those following animal-based dietary patterns.49 WFPBDs provide a higher concentration of fiber and other nutrients such as vitamin C, β-carotene, folate, and vegetable protein, which have preventative and protective effects for GERD as well as esophageal and gastric cancers.50
Making the Transition to a WFPBD
Patients often express concerns that plant-based meals will be less enjoyable, difficult to prepare, or ingredients may not be as readily available.51 Tools such as motivational interviewing with open-ended questions and collaborative discussions, can help healthcare providers assess patients’ current attitudes towards food and their motivations to explore the transition to a WFPBD.52 Dietitians, upon referral, play a key role in providing primary education and counseling on the benefits of a plant-based diet. They can also offer patient-specific ongoing guidance for WFPBD implementation that respects cultural and financial factors while aiming to treat and manage GI disorders.53
Resources
Description
Lifestylemedicine.org
Culinary medicine curriculum that is free to download on the American College of Lifestyle Medicine culinary medicine website
Culinarymedicine.org
A virtual culinary medicine curriculum from the culinary medicine program at Tulane university. Many medical schools, nursing schools and residency programs utilize this curriculum
Healthykitchens.org
Healthy Kitchen Healthy Lives is an annual culinary conference by Harvard Medical School in collaboration with the Culinary Institute of America. The goal is to empower healthcare providers to become advocates for lifestyle changes and culinary medicine
Culinary Health Education Fundamentals (CHEF) Coaching
The Institute of Lifestyle Medicine along with the Spaulding Rehabilitation Hospital and Harvard Medical School provide a virtual culinary medicine curriculum that includes coaching technique to promote behavior changes
Culinary Connections
“Culinary Connections” is a column of ACG magazine with culinary contributions from members of the gastroenterology community. Use #ACGfoodie to follow the content on social media
Plantforwardkitchen.org
Culinary institute of America and Harvard T.H. Chan School of public health launched the Plant Forward Kitchen, providing guidance to plant-forward food preparation and education
Crohn’s & Colitis Foundation Association (CCFA) gut friendly recipe database for IBD
Monashfodmap.com/recipe/
Database for low-FODMAP recipes (with plant-based recipes)
Oldwayspt.org
Database for Mediterranean diet plant-based recipes
Forksoverknives.com
Database for gluten-free plant-based recipes
Vegetariantimes.com
Database for gluten-free and dairy-free recipes
Table 4. Culinary Resources for Whole Food Plant-Based Diets
A practical technique to initiate patients on a new diet involves having them practice sectioning a plate into various plant-based food groups for at least one meal a day. For example, using the MD pattern, providers can recommend that half of the plate be filled with vegetables, while the other half is divided between plant-based protein (such as tofu or legumes) and whole grains, with a portion for dessert.54 This structure supports managing GI or liver disorders while ensuring a balanced meal. Animal-based protein such as poultry and fish are meant to be consumed in moderation, ideally 2-3 times per week.55 Online resources, food pyramids, smartphone apps, and social media can provide patients with culinary support and education.56 (See Table 4) Community and patient group cooking classes can also be a valuable tool for recipe demonstration, easing the transition to a WFPBD. (See Table 5)
Nutrient Challenges for WFPBDs
Protein
Protein consumption while on a WFPBD is often of concern, especially in the geriatric population, as they must consume adequate high-quality dietary protein to prevent age-related muscle loss. A meta-analysis using sixty-four studies across Europe, Asia, and North America showed a lower average protein intake in vegetarians and vegans; however, it was well within the recommended intake level.57 Older vegetarians should include high-protein foods such as soy products, legumes, nuts, and seeds two to three times daily. In patients with GI disorders such as IBS, plant-based protein sources such as quinoa and certain soy products like tempeh and soy cheese are low-FODMAP and may be better tolerated.58
Makes 1 individual serving Ingredients ½ cup oats ½ cup oat milk or almond milk 1 teaspoon chia seeds 2 teaspoons pure grade A maple syrup 1 teaspoon honey ¼ cup blueberries
Instructions Mix all ingredients together in a mason jar or other container with a lid. Place sliced kiwi and extra blueberries on top of mixture. Refrigerate overnight (requires at least 4 hours minimum). Eat cold or microwave for 1-2 minutes in the morning. Stays fresh in the refrigerator for approximately 3 days.
This recipe can be customized for various GI disorders. Ensure the oats are gluten-free for those with celiac disease as oats are not always gluten-free depending on how they are processed. The recipe can be also tailored to the low-FODMAP diet by replacing honey with extra pure maple syrup up to 2 tablespoons. Any fruit can be substituted for new combinations such as blueberries and bananas, strawberries and kiwis, or apple pieces and a sprinkling of cinnamon. Oatmeal versus overnight oats with a peeled kiwi and mashed blueberries can be used for those with gastroparesis.
Table 5. Overnight Oat, Blueberry, and Kiwi Recipe
Vitamin and Mineral Deficiencies
Individuals on WFPBD tend to have the same, if not higher, levels of key vitamins and minerals, including vitamin A, vitamin B1, vitamin B12, folate, vitamin C, vitamin E, calcium, magnesium, and phosphorus.59 However, strict versions of WFPBD, such as a vegan diet, which exclude animal-based, fish, and dairy products, can put patients at risk for vitamin D and calcium deficiencies. To counter this, patients on vegan WFPBD should ensure they consume calcium fortified plant-based dairy alternatives like fortified almond or soy milk or consider calcium supplements if necessary.59 Leafy greens, especially the low-oxalate ones like bok choy or kale have higher calcium bioavailability than cow’s milk, although they contain less total calcium.60 Therefore, compared to dairy products, though patients need a larger quantity to match the daily required calcium, leafy green can be a more efficient source for absorption.60 Amaranth, adzuki beans, navy beans, quinoa, and firm tofu are plant-based sources that also provide good sources of calcium and zinc.44,46
Another major concern is vitamin B12, which is primarily found in animal products. Hence, WFPBD patients should incorporate plant-based B12 sources such as fortified grains like breakfast cereals, or plant-based dairy. Supplementation of B12 is an important consideration for patients with a strict vegan WFPBD.61
Iron consumption is another concern regarding the adoption of a WFPBD. There are two primary forms of iron in food: heme iron (in animal products, well-absorbed 13-35%) and non-heme iron (in plant and animal products, lower absorption rate 2-20%). In addition, legumes and nuts contain phytate, one of the most potent iron absorption inhibitors.62 Vegetarian men are generally iron-sufficient in studies. Iron insufficiency is detected more frequently in premenopausal women. Iron study monitoring should, therefore, be considered in this population.62
Conclusion
WFPBDs have seen a surge in popularity over the past decade, primarily driven by increasing health awareness among patients and a growing body of scientific evidence that supports the role of WFPBDs in disease prevention and management. For patients with GI disorders, adopting the WFPBD can offer numerous health benefits, including GI symptom reduction, promoting diversity and composition of the gut microbiome, and modulating inflammation. Dietary recommendations must be patient-centered and tailored to meet individual needs to ensure sustainability and improve long-term outcomes. Achieving these outcomes is most effective when approached by a multidisciplinary team, including primary care providers, gastroenterologists, and dietitians.
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The management of cystic fibrosis (CF) care continues to evolve rapidly with new medications and treatments. The advancements in specialized CF care have added years of life as well as improved life quality for people with cystic fibrosis (pwCF). Currently, more than half of the CF population is over the age of 18 years. As life expectancy for CF increases, the importance of overall physical and mental health maintenance has received more attention. Medical nutrition therapy (MNT) for children and adults with CF has shifted away from the so-called “CF legacy diet” with high fat, high energy foods to higher quality, individualized dietary patterns. Despite considerable improvements in respiratory function for many pwCF, gastrointestinal (GI) complications and nutritional deficiencies may persist. Effective management of GI symptoms assists in achieving nutrition goals and improving quality of life in this patient population.
Introduction
Cystic fibrosis (CF) is a genetic, multi-organ disorder affecting nearly 40,000 children and adults in the United States (US) and an estimated 105,000 people across 94 countries worldwide.1 Mutations in the CF transmembrane conductance regulator (CFTR) gene result in dysfunctional CFTR protein in the cell. Over 1,700 CF-causing CFTR mutations have been identified. Different mutations impact the production and function of the CFTR protein in a variety of ways, but the outcome is essentially similar for all mutations. Abnormally functioning CFTR protein limits chloride movement across cell surfaces, causing the presence of thick sticky mucus in the lungs, pancreas, liver, and GI tract resulting in significant morbidity and mortality.1
This review addresses practical nutritional guidance for pwCF as follows: 1) current recommendations in MNT in the era of CFTR modulator therapy and 2) management of common GI issues.
CFTR Modulator Therapy
The treatment and prognoses of pwCF have changed dynamically since the 2012 introduction of CFTR modulator therapy (CFTRm).2 CFTRm can be “potentiators” (i.e., keeps the chloride channel open) or “correctors” (i.e., fixes the CFTR structure). These medications enable more normal chloride transfer across cell surfaces, thus treating the underlying causes of CF rather than just symptoms. At present, four CFTRm combinations are approved by the US Food and Drug Administration with more therapies under investigation (see Table 1).3-7 As of 2022, 86% of adults and an increasing number of children with CF in the US are receiving CFTRm therapies.2
CFTRm improves or alleviates respiratory symptoms and may also improve non-respiratory symptoms associated with other organ systems in pwCF. Overall, median predicted survival for pwCF has increased while pulmonary exacerbations requiring intravenous antibiotics and lung transplants have decreased.2 People with CF receiving CFTRm are leading longer and healthier lives. Reported pregnancies in women with CF doubled between 2019 and 2022.2
The percentage of underweight adults with CF declined to 4.4% in 2022. Conversely, >40% of adults with CF are now categorized using body mass index (BMI) as overweight (BMI between 25 to < 30 kg/m2) with 12.8% classified as obese (BMI ≥ 30 kg/m2).2,8 MNT is evolving rapidly to individualize nutrition and dietary intervention for pwCF in the era of CFTRm.9-11 An emphasis on a nutrient-rich, healthy diet is important to prevent obesity and associated co-morbidities. Despite advances in CF care and therapies, there remain pwCF with advanced lung disease as well as pwCF who are not eligible for, cannot access, or do not tolerate CFTRm.2 Individualized nutrition therapies with the assistance of a dietitian with expertise in CF care must be employed to address specific needs for each pwCF in accordance with therapies received. 9-11
Although pulmonary manifestations of CF respond well to CFTRm, pwCF continue to experience a high gastrointestinal symptom burden.12 Common GI symptoms in pwCF, regardless of age, include constipation, bloating, distension, early satiety, abdominal pain, and gastroesophageal reflux disease (GERD). Symptoms can be chronic and can negatively impact nutritional status and quality of life.2,12
Historical Perspective
In the early days of treatment for CF, MNT aimed to control malabsorption and associated GI symptoms by limiting dietary fat intake.13 Consequently, poor weight gain and growth stunting in children were common.14 In 1988, an epidemiological study compared two accredited CF centers one in Canada (Toronto) and the other in the US (Boston).15 The pwCF seen at the Canadian center received a more liberalized diet and pancreatic enzyme replacement therapy (PERT) regimen compared to those at the CF center in the US. As a result, the pwCF at the Canadian center were taller, weighed more, and had a survival advantage of nine years.15
With this substantial difference in survival, the nutritional guidance for pwCF shifted from a low-fat to a high-fat and high calorie diet (the so-called “CF legacy diet”) to promote weight gain and to potentially extend survival. As a result, diet quality for pwCF received less attention. Subsequent dietary intake studies in pwCF indicated a reliance on energy-dense, nutrient-poor foods.16,17
CFTR Medication Brand
Chemical Name
Mechanism
Kalydeco® (Vertex)
Ivacaftor
CFTR potentiator for patients with G551D mutation
Orkambi® (Vertex)
Lumacaftor/ivacaftor
CFTR potentiator / corrector for patients with homozygous F508del mutation
Symdeko® (Vertex)
Tezacaftor/ivacaftor
CFTR potentiator / corrector for patients with homozygous F508del mutation, heterozygous F508del mutation / residual CFTR function
Trikafta® (Vertex)
Elexacaftor/tezcaftor/ivacaftor
CFTR potentiator / corrector for patients with at least one F508del mutation or 177 other mutations
Table 1. Current CFTR Modulators
Current Nutrition Guidance
No evidence exists that pwCF require routine modification from a healthy, well-balanced, age-appropriate diet although energy needs may vary.9-11 A wide variety ofculturally acceptable foods associated with positive health outcomes in the general population should be emphasized for pwCF.10 It is reasonable to advise supplementation with energy and/or protein dense foods and/or oral or enteral nutritional supplements as needed to achieve or to maintain normal growth in children and a normal BMI status in adults (18.5-24.9 kg/m2).10,18,19 High nutrient density oral supplements are listed in Table 2. The use of these supplements should be tailored to the individual’s preferences, clinical status, nutritional needs, GI tolerance, and reimbursement options.18
Vitamins and Minerals
Malabsorption of fats in pwCF is associated with deficiencies in fat-soluble vitamins (A, D, E, and K), calcium, and zinc.1 Most pwCF benefit from CF-specific vitamin/mineral supplementation (see Table 3).20,21.
All forms of multivitamin supplements designed for pwCF include vitamin K, but not all over-the-counter multivitamins do. Most CF specific multivitamin supplements contain zinc. No CF-specific multivitamins contain either calcium or iron. Initiation of CFTRm may impact vitamin/ mineral absorption, but further data are needed. Annual serum levels for fat soluble vitamins are recommended to guide supplementation.1,9,10,21
Fiber
The dietary fiber intake recommended for the general population does not increase the risk of constipation, distal intestinal obstruction syndrome or other GI symptoms for pwCF. Low amounts of dietary fiber may increase the risk of constipation and abdominal pain. Increased fiber intake above usual guidelines may exacerbate GI symptoms such as constipation, gas, and bloating in some pwCF. Dietary fiber recommendations should be adjusted according to individual tolerance and GI symptoms.10,11,21
Sodium
Excessive salt loss in sweat can cause electrolyte imbalances and hyponatremia in pwCF, and growth failure in infants and children with CF.19,21 Salt requirements are affected by physical activity, climate, and GI losses. The usual recommendation for pwCF is to eat salty foods and to use the saltshaker freely at meals and snacks.1,9,10,21 Guidelines from Australia and New Zealand suggest salt (sodium) supplementation for all pwCF (up to 500-1000 mg sodium/day for infants, 1000 mg sodium/day for children, and 6000 mg sodium/day for adolescents and adults) to compensate for loss in sweat.21 Individual requirements are guided by signs and symptoms of sodium depletion, exercise levels, and rate of sweat.9,11,21
Salt recommendations are being re-evaluated for pwCF who receive CFTRm as such patients may experience reduced salt and chloride excretion in their sweat. Decreased salt losses along with high salt intake may cause hypertension in some pwCF who use CFTRm.9 Blood pressure should be monitored at all clinical encounters for pwCF.9 Hypertension has been noted to range between 2.2 and 11.8% of adults with CF in the US, UK, and internationally.2,21
Salt recommendations may need to be modified on an individual basis, especially for pwCF who receive CFTRm or for individuals who are post-organ transplant and on immunosuppressive therapy.9,10,11,21
Adiposity
Nutritional quality of diet has been associated with body composition and clinical outcomes in adults with CF.22 A significant, positive association has been observed between fasting blood glucose concentration and visceral adipose tissue.23 Excess dietary sugar is significantly and positively associated with visceral adipose tissue in adults with CF.24
In pwCF, a normal BMI and body composition with sex- and age-appropriate fat mass and fat-free mass should be achieved and maintained to improve lung function and to prolong survival.4,5,10,22 Obesity should be avoided as it is associated with an increased risk of hypertension, hypercholesterolemia, liver steatosis, and diabetes.9,24,25 Gradual weight reduction is appropriate in cases of overweight or obesity.10 Rapid or extreme weight loss should be discouraged for pwCF as there can be detrimental effects on pulmonary function.
The effect of CFTRm upon body weight and BMI varies according to the genetic variants of the individual with CF and the specific CFTRm prescribed. Increased weight gain and BMI in some pwCF have been documented with each of the CFTRm currently available, especially the triple combination elexacaftor/tezacaftor/ivacaftor. Anticipatory MNT should be provided prior to starting CFTRm with discussions of possible weight gain and potential body image concerns.9,10,11,25 Incorporation of healthy dietary patterns, and exercise routines should be encouraged.9,10,11,21 Individualized advice and regular nutrition monitoring should continue as part of standard CF care across the lifespan.9,10,11,21,25
Table 2. Examples of High Nutrient Density Oral Supplements
CF-Related Diabetes and Glucose Impairment
Current guidelines recommend screening pwCF for glucose intolerance and CF-related diabetes (CFRD) with annual oral glucose tolerance tests beginning at age 10 years if not previously diagnosed with CFRD.24,25,26 The prevalence of CFRD is increased across the lifespan, reaching above 40% in pwCF ≥40 years.2 Consultation with an endocrinologist who has expertise in CFRD is recommended.9,11,21
The primary nutrition goals for CFRD are to achieve and to maintain healthy weight and body composition with normalized blood glucose levels.21,23,24,26
1. Fat-soluble vitamins: A, D, E, K 2. Iron 3. Sodium 4. Zinc 5 Calcium 6. Magnesium 7. Essential fatty acids 8. Water-soluble vitamins
*Supplements are available in drops, softgels, chewables and gummies with variable vitamin D levels ranging from 19 mcg to 125 mcg per dose including MVW Complete Formulation®, MVW Modular Formulation® and DEKAsPlus®
Table 3. Potential Vitamin and Mineral Deficiencies in Cystic Fibrosis
Common Gastrointestinal Complications of Cystic Fibrosis
GI symptoms, including fecal straining, abdominal distension, and abdominal pain, are quite common in pwCF but often go unrecognized.12 GERD with potential erosive esophagitis and aspiration have an estimated prevalence of 35% to 81% in pwCF.27,28 Thus, GI disorders and its associated symptoms are a significant burden for pwCF (see Table 4).12
Mouth
The sense of smell is impaired in many pwCF due to inflammation of the olfactory cleft which is the predominant location of olfactory neurons. Thus, pwCF experience an impaired sense of taste which can decrease food enjoyment and caloric intake.29 Factors such as oral aversion can lead to feeding problems and resultant weight loss common to many children with CF.30
Esophagus and Stomach
As food is masticated and passed into the esophagus, pwCF can experience GERD which leads to classic “heartburn” symptoms, increased cough, aspiration, and in severe cases, weight loss. GERD appears commonly in pwCF with up to 90% of patients potentially having associated symptoms.31,32 Other esophageal diseases such as eosinophilic esophagitis (EoE) may be increased in pwCF compared to the general population, especially in the pediatric age group.33,34
Although GERD is common, it is unclear if acid suppression therapy, including proton pump inhibitor (PPI) therapy, is beneficial in pwCF. Gastroesophageal reflux of bacteria-containing gastric fluid due to aggressive acid blockage from PPI use may increase risk for pneumonia and CF pulmonary exacerbations.35,36 It is unclear if anti-reflux surgery such as fundoplication is beneficial in reducing lung function decline in pwCF who have GERD, especially in children.37 Adult pwCF have an increased risk of Barrett’s esophagus.38
Gastric issues tend to be less concerning in pwCF compared to other aspects of GI physiology although gastroparesis and dumping syndrome can occur in this population. No increased risk of H. pylori infection is associated with pwCF.39,40 Gastroparesis may be more common in pwCF although research studying this phenomenon has not been standardized.41 Conversely, pancreatic enzyme replacement therapy (PERT) may be effective in slowing rapid gastric emptying (thus, reducing dumping syndrome risk) in pwCF via increasing levels of glucagon-like peptide 1 (GLP- 1).42
Small Intestine
CFTR is present throughout the small intestine, and CFTR mutations impair transport of small intestinal fluid leading to inflammatory and obstructive intestinal mucous, similar to CF pathologic processes in the lungs.43 As a result, malabsorption and symptoms of small intestinal bacterial overgrowth (SIBO) can occur. SIBO is common in pwCF presenting as abdominal pain, diarrhea, malabsorption, and distention.44,45 PPI use may precipitate SIBO due to the associated lack of gastric acid production leading to overgrowth of pathogenic bacteria.46 Antibiotics with enteral efficacy and minimal systemic absorption, such as rifaximin, can be used to treat SIBO.47
CF enteropathy is associated with enterocyte inflammation and probable intestinal dysbiosis which affects lung function through the “gut-lung axis.”48 CF enteropathy is associated with an elevated fecal calprotectin level, and adult patients with this disorder have a negative correlation between fecal calprotectin levels and pulmonary function. Exocrine pancreatic insufficiency (EPI), CFRD, and use of PPIs also are risk factors for CF enteropathy.49 CF enteropathy is not a type of inflammatory bowel disease such as Crohn’s disease, but use of azathioprine has been reported as effective for some pwCF with this disorder.50
Although seemingly unrelated, celiac disease (CD), an autoimmune disease of the small bowel associated with gluten exposure, has been noted in pwCF. Research suggests that CD may be more common in pwCF compared to the rest of the population.51-53 The association between CF and CD is unclear, but the production of sticky, inflammatory mucous in CF and the increased response in inflammatory GI conditions such as CD suggest that changes in the intestinal microbiome to more pathogenic bacteria such as Escherichia coli may be causative.34,51-54
Diagnosis of CD in pwCF does not differ from the rest of the population. Typically, CD diagnosis requires tissue transglutaminase IgA antibody (TTG IgA) serum testing with or without confirmatory duodenal biopsies (depending on TTG IgA level of elevation).55,56,57 The treatment of CD in pwCF is life-long adherence to a gluten free diet, and consultation with a dietitian who has expertise in CD is of paramount importance.55,58
Pancreas
The most well-known aspect of the GI tract in CF occurs with the pancreas in the setting of EPI; EPI is present in at least 85% of pwCF and presents as malabsorption, fat soluble vitamin insufficiency, and poor growth.59 Additionally, EPI is associated with worse lung function outcomes long-term.60 Due to CFTR malfunction, pwCF and EPI experience pancreatic ductal obliteration, pancreatic fibrosis, and pancreatic fatty infiltration.61 Diagnosis of EPI for pwCF typically is made through testing of fecal elastase-1 levels.62
Treatment of EPI requires appropriate PERT, fat soluble vitamin replenishment, and adequate fat intake. Consultation with a dietitian with expertise in CF is essential.10,63,64Table 5 describes typical PERT dosing.65 No evidence exists for the timing of PERT dosing relative to intake, but PERT is commonly dosed immediately prior to the ingestion of fat-containing food or beverages. If meals are longer than 30 minutes, PERT can be dosed half at the beginning of the meal and the other half midway through the meal.1 Excessive PERT dosing (≥10,000 lipase units/kilogram/day) is associated with the rare but serious complication of fibrosing colonopathy.66,67 It should be noted that pwCF with endocrine pancreatic sufficiency can develop associated endocrine pancreatic insufficiency or CFRD as pancreatic damage progresses.65
CFTRm has reversed EPI in young children with CF, but not in older pwCF, although this issue remains under investigation as recovery of pancreatic function after CFTRm may occur after several years. Currently, no evidence-based algorithms exist for adjusting PERT with CFTRm for pwCF.68 Measurement of fecal elastase-1 after CFTRm initiation in young children or anyone suspected of a change in pancreatic status is clinically appropriate.4,69
Although less common than EPI, pwCF can develop pancreatitis (acute, acute recurrent, and chronic) in the setting of less severe CFTR genotypes. Pancreatitis also has been reported in the setting of CFTRm use in pwCF who have EPI. In such clinical scenarios, pancreatitis should be considered in pwCF presenting with severe abdominal pain.70,71
Nutrition/GI Disorder
Possible Therapies
Vitamin / mineral deficiency risk
Supplementation and monitoring
Fiber
Same use as general population
Essential fatty acid deficiency
Serum fatty acid profile with triene:tetraene ratio monitoring, adjust PERT, EFA supplementation with absorbable structured lipid (SeracalTM)
Sodium
Increased salt use need compared to general population
Adiposity
Prevention of underweight/overweight over time
CFRD
Annual oral glucose tolerance test Insulin/consultation with endocrinology
Esophagus (GERD, EoE, Barrett’s esophagus)
PPI use, therapies for EoE Consider upper endoscopy with biopsy
Stomach (gastroparesis, dumping syndrome)
Treatments for gastroparesis (prokinetics, pyloric botulinum toxin) Treatments for dumping syndrome (PERT, dietary changes)
Small intestine (SIBO, CF enteropathy, celiac disease)
Judicious enteral antibiotic use Judicious PPI use TTG IgA antibody titer Upper endoscopy with biopsy
Pancreas(EPI, pancreatitis)
Treatments for EPI (PERT, fat soluble vitamin supplementation, appropriate fat intake) Treatments for pancreatitis (diagnostic amylase/lipase, diagnostic imaging including abdominal ultrasound or magnetic resonance cholangiopancreatography) Typical medical/surgical treatments for pancreatitis, as warranted
Terminal ileum (meconium ileus, DIOS)
Hyperosmolar enemas Surgical intervention if warranted
Colon (constipation, increased colon cancer risk)
Laxative therapy Early colon cancer screening
Gallbladder (delayed emptying, cholelithiasis)
Cholecystectomy if warranted
Liver (CFLD spectrum)
Screening for progression of liver disease Consultation with hepatology /liver transplant program if warranted
Table 4. Common Nutrition and GI Disorders in CF and Potential Therapy
Terminal Ileum/Colon
The terminal ileum is the site of early manifestations of CF in the setting of meconium ileus occurring during infancy. Dehydrated and acidic mucous due to CFTR dysfunction can lead to abdominal distention, emesis, and GI obstruction in the neonatal setting.72 Such patients typically are diagnosed by barium enema in which the obstruction is noted, and many of these neonates with CF will have an associated microcolon due to ileal blockage and colon disuse. Treatment is urgent removal of the obstruction either through the use of hyperosmolar enemas observed by fluoroscopy for stable infants or surgical intervention in unstable infants or infants who do not respond to enema therapy.73,74
Distal intestinal obstructive syndrome (DIOS) may manifest after the neonatal period and potentially can occur at any stage in life in pwCF. Fecal obstruction of the terminal ileum and colon occurs with DIOS and presents with severe constipation, signs and symptoms of a bowel obstruction, and a palpable right lower quadrant mass that can be demonstrated radiographically.75 Most cases of DIOS can be managed by high-volume osmotic therapy (such as with polyethylene glycol 3350) with surgical intervention required for severe cases.Constipation prevention via routine use of osmotic laxatives, especially polyethylene glycol 3350, is critical in reducing risk of DIOS in pwCF.76,77
Constipation, associated with hard stools, abdominal distention, and pain with defecation, is extremely common in pwCF affecting up to 41%.78,79 Such patients have associated prolonged colonic transit time.78 Treatment is supportive using osmotic laxative therapy (typically daily polyethylene glycol 3350).77 Fiber intake in line with the dietary reference intake for the general population and adequate hydration are recommended for pwCF for the prevention and management of constipation.10
Age
Range
Upper Limit
Infants
1000-2500 lipase units/kg/feed
10,000 lipase units/kg/day
1-4 years
1000-2500 lipase units/kg/meal*
10,000 lipase units/kg/day
4+ years
500-2500 lipase units/kg/meal*
10,000 lipase units/kg/day
Table 5. PERT Dosing Guidelines
The risk of colorectal cancer in adults with CF is 5-10 times greater than the general population and is even higher in pwCF who receive a lung or other solid organ transplant.80 Colonic adenomas with the risk of malignant transformation occur in pwCF at a younger age compared to the general population.81 It is recommended that pwCF undergo screening colonoscopies no later than 40 years of age with repeat screening every 5 years. Such patients should undergo screening within 3 years if adenomas are noted.82 If a pwCF has undergone a solid organ transplantation, they should undergo screening at age 30 years if they are within 2 years of transplantation.82
Gallbladder and Liver
Abnormal gallbladder anatomy such as micro-gallbladder formation occurs in pwCF. Delayed gallbladder emptying and cholelithiasis (typically black pigmented stones from bile acidification) are common in pwCF.83 Most pwCF who have gallbladder abnormalities require simple observation over time, although cholecystectomy is warranted for symptomatic cholelithiasis.83,84
Liver manifestations in pwCF are defined as “cystic fibrosis-related liver disease” (CFLD), occurring in up to 30% of pwCF.82,85 CFLD is caused by CFTR mutations which decrease bile transport disrupting the intestinal microbiome changes leading to hepatic inflammation. Risk factors for CFLD include male sex, history of meconium ileus, and history of EPI.85,86 CFLD can vary from rare entities (neonatal cholestasis and sclerosing cholangitis) to more common presentations (steatosis). Hepatic fibrosis in pwCF can progress over time from focal biliary cirrhosis to multinodular biliary cirrhosis with associated portal hypertension and potential liver failure.87-90
Treatment of pwCF with CFLD requires optimizing nutrition status, including normal weight and muscle stores, and appropriate vitamin and mineral stores, in a manner necessary for all pwCF, and treating end-stage complications of liver disease such as treatment of portal hypertension and potential liver transplantation.90 It is unclear if ursodeoxycholic acid use in pwCF with associated CFLD prevents progression to more severe liver disease.91
Conclusion
As the future for many pwCF anticipates less severe respiratory disease, longer lifespan, and less risk of undernutrition, more attention should be focused on preventive health management.92 Many challenges remain for both clinicians and pwCF to achieve optimal nutrition in an era of CFTRm.9,10,11,20,92 Not all pwCF are eligible for CFTRm, and some pwCF still face severe respiratory disease and many GI complications.2 Some individuals are at risk of malnutrition with increased medical needs, especially pwCF not eligible for CFTRm. Others are at risk of overweight/obesity and associated metabolic and cardiovascular complications as well as oncological sequelae such as colon cancer.92
As described above, pwCF now are at an increased risk of major adverse cardiovascular events with associated obesity, diabetes, and hypertension.19 In aging CF populations, individualized nutritional interventions, adequate hydration, and physical activity should aim to improve fat-free mass or to prevent its loss.9,10,11,20,92
Historically, these long-term complications were infrequently described due to the shortened life span for most pwCF. In the era of CFTRm, specific metabolic and cardiovascular screening programs need to be established. In the absence of specific recommendations for pwCF, standard screening guidelines for the general population should be employed.9,10,11,20,92
The future health of children and adults with CF, whether receiving or not receiving CFTRm, benefit from individualized MNT and GI management conducted in collaboration with pwCF, their family, and the entire healthcare team. Nutritional management for infants, children, and adults with CF continues to evolve but remains essential for optimal outcomes for all pwCF.
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Mental health and sleep disorders are common in inflammatory bowel disease (IBD), and have been associated with a bidirectional relationship with intestinal symptoms and gut inflammation. Studies show that mental health is an important contributor to quality of life and clinical outcomes in IBD patients, and thus it has been recommended to be addressed as a part of routine clinical care. This review discusses simple tools that can be used by primary care and specialist clinicians to screen for mental health and sleep disorders. It also describes the approach for preliminary treatment in cases when such disturbances are detected, and briefly reviews some of the emerging research in the field of gut and brain health, which may have important clinical implications in the future.
Introduction
From the early days of medicine, gastrointestinal (GI) function and mental health were known to be very closely associated. This led to the presumption and belief that many GI symptoms were psychosomatic in nature. Over the years, as our understanding of diseases deepened, this psychosomatic conceptualization of GI disease has been critically re-evaluated and, in many cases, abandoned in favor of biological and neurochemical models of brain and gut interactions. Research in recent decades has started to decipher the biological basis of brain-gut communications, establishing a model of the “gut-brain axis”. The gut-brain axis is a bidirectional communication network that involves immunological, metabolic, neuronal, hormonal, and microbial components, all of which play an important role in both physiological and pathophysiological processes.1 It is now believed that psychological morbidities that commonly accompany GI disease, including IBD, may be reactive and associated with symptoms, but also have a “biological” component that is independent of symptoms. The growing interest in this gut-brain communication has laid the foundation for extensive clinical, translational, and basic research in the field. It has also highlighted the importance of the clinical aspects of the crosstalk between GI diseases and mental health. Specifically, in the field of IBD, it has led to the acknowledgment that psychological and social factors such as mood and sleep are important aspects of the disease which significantly affect quality of life and should be assessed and treated as a part of a holistic approach to patient care.
Here, we review common psychosocial health issues in IBD and the bidirectional relationship of gastrointestinal diseases and psychological morbidities. We discuss an approach to screening for mental health issues in the setting of primary care and GI clinics, and suggest preliminary approaches to treatment. We also introduce some of the ongoing research in the field which may have important clinical implications.
Common Psychosocial Issues in IBD
Patients with IBD face numerous psychosocial challenges that compound the physical symptoms of the disease (Figure 1). These issues, including mental health disorders, sleep disturbances, social stigma, and others significantly impact patients’ quality of life and well-being (definitions of common psychosocial issues outlined in Table 1).
Anxiety and depression are highly prevalent among IBD patients, though often undiagnosed and untreated. Approximately 20-32% of IBD patients experience symptoms of anxiety and 22-25% show symptoms of depression.2,3 Disease activity increases the risk, and patients with Crohn’s disease (CD) may be at greater risk than those with ulcerative colitis (UC). GI symptom-specific anxiety is also common, though its exact prevalence remains unclear.
Sleep disturbances are another major concern, with over half of IBD patients meeting the criteria for insomnia.4,5 Patients with active IBD, mood disorders, disability, and lower quality of life are particularly affected. Fatigue is also widespread, affecting 40-80% of IBD patients with active disease and 40-60% of those in remission.6,7
Stress and stigma greatly impact patients with IBD. Stress worsens disease activity, and patients with IBD experience higher stress levels than the general population. Around 10% of these patients may meet criteria for PTSD, often due to their disease experiences.8 In addition, many patients with IBD experience stigmatization, embarrassment and shame due to the unpredictable nature of bowel symptoms and potential social implications. Body image is also a concern for patients, with most patients reporting some form of concern about an aspect of their body image.9
Issues related to sexual function and satisfaction are common among patients with IBD, due to a combination of factors including active disease or surgical factors, body image concerns, or mental health comorbidities. Although sexual dysfunction is prevalent in IBD, it is infrequently discussed with their healthcare providers.
Concerns related to fertility is another common source of distress among individuals with IBD. While most IBD treatments do not impact fertility directly, voluntary childlessness is higher in this population, which may be, in part, due to misconceptions about disease heritability and transmission risks.10
In addition, patients with IBD have a significantly higher prevalence of disordered eating behaviors than the general population. Disordered eating may or may not be related to body image and in many cases, is thought to result from restrictions and modifications of diet resulting from attempts to control IBD and its symptoms.
Untreated psychosocial issues negatively impact quality of life and complicate IBD management for both the patient and their healthcare team. It is therefore imperative that we address these issues in our management strategies and care for our patients. Moreover, further research is needed to explore less-studied mental health conditions in the IBD population (e.g., obsessive-compulsive disorder, panic disorder) in order to better identify and address them.
The Impact of Mental Health on IBD
The nature of the association between IBD and psychological comorbidities remains an area of ongoing, active research, with many unanswered questions. Clinical and epidemiological studies in this field have been limited by the lack of a robust methodology, and results are therefore quite heterogeneous, as are the types and severities of IBD. Nonetheless, existing evidence supports a reciprocal relationship between IBD and mental health disorders, where one can trigger and modify the other.11
A study that evaluated patients with new-onset depression found that their risk to develop IBD within a mean follow-up time of 6.7 years was more than twice as high as the risk of patients with no depression.12 This was true for both CD and UC. Similarly, data from the U.S. Nurses’ Health Study showed that patients with CD were more likely be those with a prior diagnosis of depression compared to those without depression (HR 2.36; 95% CI 1.40-3.98).13 Interestingly, a similar association was not found in patients with UC in this study.
Conversely, some studies show that patients with IBD have an increased risk of developing mental health disorders after their diagnosis. Population-based studies from Canada and Sweden showed that the risk of patients with IBD developing depression or anxiety in the years following their diagnosis is about 50% greater than healthy matched controls.14,15 This was shown in adult-onset as well as in pediatric-onset IBD.
In patients with IBD, mental health disorders were shown to adversely affect the disease course of the IBD. In a meta-analysis of 12 longitudinal studies, IBD patients with depressive symptoms were at increased risk of flare, hospitalization, need for therapy escalation, and IBD-related surgery.16 Psychological stress was also identified to have adverse effects on IBD. In a prospective study that included 124 patients with IBD, disease activity after highly stressful life events was monitored. It was found that patients who experienced the death of a family member or close friend, change in residence or job status, birth of a child, personal or familial health concern, marriage or divorce, were more than twice as likely to present with active disease within a 6-month follow-up period compared to patients who did not experience such an event.17 A study that followed 677 patients with IBD in Japan after the Great East Japan Earthquake in 2011 found an increased risk for disease flare in the 2 months after the earthquake, compared to a corresponding period in the 1 and 2 years after the earthquake.18 Together, these data show that IBD disease course can both affect and be affected by mental health disorders and psychological stress. These studies highlight the importance of psychological assessment in IBD care.
Psychosocial Assessment in IBD Patients
Both self-report questionnaires and the clinical interview are valuable tools for the assessment of psychosocial concerns among patients with IBD. Direct patient-provider communication via the clinical interview lacks the uniformity of self-report questionnaires but is nonetheless a quick and useful method. This may require only a few questions, such as “How have you been coping with everything?” and “How has your IBD affected your life recently?” Direct communication strengthens the patient-provider relationship, demonstrates care to the patient, and can be easily integrated into the clinic visit (Table 2).
While self-report questionnaires offer a valid, uniform system of measurement that can be tracked over time both within and between patients, they are not without logistical and ethical burdens. Integration is challenging for many practices due to the time and personnel needed to administer, score, and document the assessments. Finally, the GI provider must have the time to review this information with the patient during the visit in order to have clinical utility, rather than become just a data point. Patients who are found to have more severe anxiety or depression, especially those who express suicidal ideation or plan, require an immediate action plan and intervention for the practice, resources that are not readily available or currently considered part of most primary or specialty practices.
There are several validated tools for the screening of mental health symptoms in IBD. The Patient Health Questionnaire-9 (PHQ-9) for depression,19 and the Generalized Anxiety Disorder scale-7 (GAD-7) for anxiety,20 are easy to administer and score on paper or virtually. These measures have scoring ranges that can be used to indicate the severity of symptoms and the likelihood of a clinical diagnosis. GI symptom-specific anxiety refers to anxiety and fear related to the disease, its symptoms, or the context in which the symptoms occur. This is a common form of anxiety seen among IBD patients and is best captured by the Visceral Sensitivity Index (VSI).21 Keefer and colleagues present a comprehensive list of suggestions on the assessment of other psychosocial issues.22
Management of Mental Health Disorders in IBD
The success of a screening program is dependent on what happens after a positive screen: ideally, a referral for comprehensive assessment and treatment with a mental health professional. New research highlights the bidirectionality of IBD and mental health conditions; psychological interventions may improve both mental health and inflammatory markers in IBD,23 while psychotropic medications may have protective effects in IBD.24
For many patients, and particularly those with more severe or longstanding depression or anxiety, a referral for psychotherapy with a general mental health therapist and/or a psychotropic medication evaluation with a psychiatry provider, is appropriate. If the GI provider is aware of a more specific issue such as an eating disorder or substance abuse, this may warrant referral to a more specialized clinic or provider. Developing relationships with mental health providers either within the institution, or with community partners, is paramount to referring patients appropriately.
For patients whose depression, anxiety, or overall stress level is closely related to their IBD experience, a gastrointestinal psychologist is an ideal referral. The growing specialty of gastrointestinal psychology includes psychologists who typically work with patients with IBD to develop stress management and adaptive coping strategies, reduce symptoms of anxiety and depression, and to utilize behavioral tools to cope with and reduce ongoing GI symptoms. IBD-specific virtual support programs exist and can help fill this gap if a gastrointestinal psychologist is not part of your practice.
Sleep Disturbances in IBD
Sleep is a major contributor to health and good quality of life. Increasing evidence shows that sleep disturbances are linked to dysfunction of multiple body systems, including the function of the immune system and the GI tract.25 This prompted further investigation into the effect of sleep on the course of IBD. The prevalence of sleep disorders in patients with IBD is believed to be high but is not well-defined. A study that prospectively screened 166 IBD patients found that 67.5% of them suffered from sleep disturbance.26 Studies assessing sleep quality in patients with IBD identified active IBD as a contributor to sleep deprivation. This may, in turn, trigger further immune activation and perpetuate a vicious cycle of worsening symptoms that would further adversely affect patients’ quality of life.25 In CD, poor sleep quality has been associated with disease activity and higher risk of hospitalization and surgery.27 Patients with active IBD were shown to have fewer episodes of deep sleep compared to patients in remission. Interestingly, patients in clinical remission who report abnormal sleep have a high likelihood of subclinical disease activity, indicating that poor sleep is not only driven by symptoms such as nocturnal diarrhea, but also may be affected by abnormal immune function.28 There are validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) that can be used for assessing sleep quality. However, in everyday clinical practice, simple questions can be used, such as: “How do you sleep at night?”, “Any trouble falling asleep or staying asleep?” and “Do you wake up feeling refreshed?” (Table 2). All patients who report poor sleep quality should be educated on sleep hygiene practices. Referral to a sleep specialist for evaluation of specific sleep conditions, such as obstructive sleep apnea or restless legs syndrome (which may also be associated with iron deficiency), should be considered if clinically relevant. In patients with active disease, poor sleep may be a symptom of active inflammation, and should prompt optimization of the anti-inflammatory treatment. For patients with insomnia, cognitive behavioral therapy for insomnia (CBT-I) is a highly effective treatment, and should be considered in patients with insomnia related to IBD as well.29
Future Directions in Mental Health and IBD Research
Current research on the interface between gut and mental health focuses on elucidating a better understanding of the biological mechanisms and careful investigation of novel clinical interventions. A major interest in this field is the changes in gut-derived metabolites, which may mediate gut-brain interaction. Tryptophan is an example of such a mediator. It is metabolized by both host cells and the gut microbiome; both are affected by gut inflammation. It is a precursor of multiple neuroactive metabolites, including serotonin and melatonin, metabolites that play a central role in controlling mood and sleep. It was shown that tryptophan metabolism is altered in patients with active IBD.30 Whether it influences mental health in these patients is yet to be determined. Interestingly, it has been found that the penetrance of the blood-brain barrier31 and the choroid plexus32 changes in response to gut inflammation, which may alter the exposure of the central nervous system (CNS) to various peripheral compounds. Identifying key mediators that are relevant in this context may open the door for therapeutic interventions that target specific mediators and compounds.
Several studies have shown the benefits of incorporating psychological treatment into medical care in IBD patients.33 The growing number of GI-specialized therapists may significantly contribute to patient care and quality of life. Interestingly, there are ongoing studies that utilize virtual reality and artificial intelligence technologies to treat symptoms in patients with irritable bowel syndrome (IBS).34 Using these tools in IBD may increase the accessibility of psychological care and may be a novel approach to more effectively and extensively address mental health concerns.
Conclusion
Mental health conditions and sleep disorders are very common among patients with IBD. They have a bidirectional relationship with gut inflammation and intestinal symptoms, and current evidence supports the notion that one may trigger and modify the other. Given its clear impact on quality of life and the evolving understanding of the biological connection between the brain and gut, addressing psychosocial issues should be part of the comprehensive care for our patients with IBD. While standardized questionnaires may be time-consuming, simple questions can be easily incorporated into routine clinical practice and serve as a preliminary screening method. Identification of mental health conditions and sleep disorders in patients with active inflammation of the bowel should prompt optimization of their IBD treatment. Referral to a specialized GI therapist should be strongly considered when appropriate, but there is a clear need for additional research and resources for treatment and management in this evolving and clinically important field.
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26. Marinelli C., Savarino E V., Marsilio I., Lorenzon G., Gavaruzzi T., D’Incà R., et al. Sleep disturbance in Inflammatory Bowel Disease: prevalence and risk factors – A cross-sectional study. Sci Rep 2020;10(1):507. Doi: 10.1038/s41598-020-57460-6.
27. Sofia MA., Lipowska AM., Zmeter N., Perez E., Kavitt R., Rubin DT. Poor Sleep Quality in Crohn’s Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery. Inflamm Bowel Dis 2020;26(8):1251–9. Doi: 10.1093/ibd/izz258.
28. Erondu A., Singer J., Yi Y., Sossenheimer PH., Rubin DT. Sa1801 INFLAMMATORY BOWEL DISEASE PATIENTS WITH ACTIVE DISEASE HAVE FEWER EPISODES OF DEEP SLEEP COMPARED WITH PATIENTS IN REMISSION. Gastroenterology 2020;158(6):S-430. Doi: 10.1016/S0016-5085(20)31761-3.
29. Salwen-Deremer JK., Godzik CM., Jagielski CH., Siegel CA., Smith MT. Patients with IBD Want to Talk About Sleep and Treatments for Insomnia with Their Gastroenterologist. Dig Dis Sci 2023;68(6):2291–302. Doi: 10.1007/s10620-023-07883-8.
30. Nikolaus S., Schulte B., Al-Massad N., Thieme F., Schulte DM., Bethge J., et al. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology 2017;153(6):1504-1516.e2. Doi: 10.1053/j.gastro.2017.08.028.
31. Logsdon AF., Erickson MA., Rhea EM., Salameh TS., Banks WA. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Exp Biol Med (Maywood) 2018;243(2):159–65. Doi: 10.1177/1535370217743766.
32. Carloni S., Bertocchi A., Mancinelli S., Bellini M., Erreni M., Borreca A., et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 2021;374(6566):439–48. Doi: 10.1126/science.abc6108.
33. Li C., Hou Z., Liu Y., Ji Y., Xie L. Cognitive-behavioural therapy in patients with inflammatory bowel diseases: A systematic review and meta-analysis. Int J Nurs Pract 2019;25(1). Doi: 10.1111/ijn.12699.
34. Lacy BE., Cangemi DJ., Spiegel BR. Virtual Reality: A New Treatment Paradigm for Disorders of Gut-Brain Interaction? Gastroenterol Hepatol (N Y) 2023;19(2):86–94.
Children with inflammatory bowel disease (IBD) can have associated dermatologic disease. Erythema nodosum (EN) and pyoderma gangrenosum (PG) are two such common skin lesions seen in this setting. The authors of this study attempted to determine rates of EN and PG in pediatric patients with IBD and evaluated for IBD complications in the setting of EN and PG.
This study was longitudinal and evaluated patient data from the international pediatric IBD registry, ImproveCareNow™. Deidentified patient data were evaluated to determine patient baseline characteristics as well as follow-up clinic visit characteristics, duration of IBD, presence of EN or PG, and other factors associated with IBD. The following disease activity scales also were used in this study: Physician Global Assessment (PGA), the short Pediatric Crohn’s Disease Activity Index (PCDAI), and the Pediatric Ulcerative Colitis Activity Index (PUCAI). Patients were characterized as having Crohn’s disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). It should be noted that IC also is known as Inflammatory Bowel Disease – Unclassified (IBD-U). Pediatric patients with IBD with associated EN or PG were compared to pediatric patients with IBD who had no skin manifestations.
A total of 285,913 clinic visits from 32,497 pediatric patients (≤ 21 years of age) were included in the study. A diagnosis of EN was made in 509 patients (401 CD, 90 UC, and 18 IC), and the rate of EN in this patient population was 1.57% (95% confidence interval (CI), 1.43-1.71%). A diagnosis of PG was made in 291 patients (203 CD, 67 UC, and 21 IC), and the rate of PG in this patient population was 0.90% (95% CI, 0.80-1.00%). Co-occurrence of EN and PG was present in 99 patients, and the rate of both diseases occurring simultaneously was 0.30% (95% CI, 0.25-0.37%). Most patients (90%) with simultaneous EN and PG had both diseases occurring during at least one clinic visit.
Significantly more patients with EN or PG were female compared to pediatric patients with IBD and no skin disease. There was no statistical difference between patients with IBD and EN or PG versus pediatric patients with IBD and no skin disease regardless of age, gender, or age of IBD diagnosis. Higher scoring (indicating worse disease) using the PGA, short PCDAI, and PUCAI was significantly increased in patients with associated EN and PG. Poor growth and nutrition were significantly associated with a higher rate of EN and PG while continuous disease remission was significantly associated with a reduced rate of EN and PG. A history of ileostomy or colostomy, peri-anal disease, uveitis, or arthritis was associated with a significantly increased risk of EN or PG. An elevated erythrocyte sedimentation rate (ESR), an elevated C-reactive protein level (CRP), and a reduced albumin level were all significantly associated with a higher risk of EN or PG while improving albumin levels at follow-up clinic visits significantly reduced the risk of having EN or PG. In terms of IBD treatment, only corticosteroid use was significantly associated with the presence of EN or PG. Multivariable analysis demonstrated that CD, high PGA score, arthritis, uveitis, elevated ESR, low albumin level, and corticosteroid use were associated with EN while a high PGA score, history of colectomy/colostomy/ileostomy, arthritis, uveitis, and low albumin level were associated with UC.
This study provides new information about the frequency of important dermatologic manifestations seen in pediatric IBD, specifically EN and PG. The authors have identified specific risk factors in the pediatric IBD population associated with EN and PG. Once EN and PG are identified in a pediatric patient with IBD, concern should be raised that the patient may have a more severe IBD phenotype.
Yousif M, Ritchey A, Mirea L, Patel A, Price H, O＊Haver J, Montoya L, Gonzalez-Llanos L, Smith J, Zeblisky K, Pasternak B. The Association Between Erythema Nodosum and Pyoderma Gangrenosum and Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2024; doi: 10.1002/jpn3.12370. Online ahead of print.
Can Abnormal Weight be Associated with Child Maltreatment?
Pediatric gastroenterologists are in a unique position to address nutrition issues in children, while at the same time, discovering social challenges in families. The authors of this study determined if child maltreatment or exposure to intimate partner violence affected both childhood weight and diagnosis type.
This retrospective study occurred at a pediatric center specializing in child maltreatment, and data over a 3-year period were collected. Only children 17 years or younger with ICD-10 codes for child maltreatment were studied. Five types of child maltreatment were considered: physical, sexual, neglect, psychological/emotional, and exposure to intimate partner violence. Patients with neonatal abstinence syndrome or an organic disease that could affect weight were excluded. Patients were determined to be underweight, normal weight, overweight, or obese based on weight-for-length z scores if a child was under 24 months of age or based on body mass index (BMI) z scores if a child was equal to or older than 24 months of age.
A total of 855 subjects were included in the study, and the median age was 29 months (interquartile range 5-83 months). Normal weight classification was present in 59.4% of children while classifications of underweight, obese, and overweight was present in 15.3%, 12.9%, and 12.4%, respectively. All types of child maltreatment were significantly associated with all weight types. Patients with one type of child maltreatment were statistically younger while patients with more than one type of child maltreatment were statistically older. Neglect was the most common type of child maltreatment (68.7%), and neglect was significantly associated with children who were normal weight and underweight. Physical abuse (33.6% of children) was significantly lower in normal weight children. Sexual abuse (16.8%) increased significantly as patient weight increased and was most common in children characterized as obese. Psychological/emotional abuse (10.8%) was most common in children characterized as obese while children exposed to intimate partner violence (9.8%) were more likely to be characterized as overweight. Finally, having one category of child maltreatment was significantly associated with normal weight. The presence of more than one category of child maltreatment was associated with abnormal weight, but the association was not statistically significant.
This study provides a potential way to screen for risk factors for abuse in children by considering their weight, weight-for-length z score, or BMI z score, especially if the provider suspects child maltreatment is occurring. This study occurred at a single center in Pennsylvania, and more research is needed in other parts of the United States to see if such findings can be more universalized.
Esernio-Jenssen D, Morrobel A, Hansen S, Kincaid H. Exploring Associations Between Abnormal Weight Classifications and Child Maltreatment Diagnoses. Clin Pediatr 2024; 63: 1056-1061.
Small intestinal and colorectal anastomotic strictures are often difficult-to-treat post-surgical adverse events. Surgical re-intervention was previously first-line therapy, but advancements in endoscopic techniques have made endoscopy the first-line treatment approach. This review will assess the efficacy and adverse events of the currently available endoscopic management techniques for the treatment of small intestine and colorectal anastomotic strictures.2,3
Small Intestinal Anastomotic Strictures
Etiology
Small intestinal anastomotic strictures are post-surgical adverse events following small bowel resection for malignant or benign conditions including perforation, ischemia, and Crohn’s disease.1 Surgical resection is required in 50-80% of patients with Crohn’s disease within the first 10 years of diagnosis, and approximately one-third of patients will require at least a second surgery due to development of an anastomotic stricture.2,3
Risk Factors
Risk factors for anastomotic complications have been studied extensively in patients with Crohn’s disease and show an increased risk with pre-operative poor nutritional status, weight loss, steroid use, and longer duration of disease.4 However, more studies are needed to identify the patient risk factors specifically for small bowel anastomotic stricture development.
Choy et al. performed a meta-analysis comparing surgical anastomotic closure techniques among 1,125 patients which showed no difference in anastomotic stricture rates between hand-sewn and linearly stapled anastomoses.5
Clinical Manifestations
Patients commonly present with obstructive symptoms including abdominal pain, distention, bloating, nausea, and/or vomiting.6
Endoscopic Balloon Dilation
Technique
Endoscopic balloon dilation (EBD) is most commonly performed using inflatable through-the-scope (TTS) balloon dilators available in various lengths (3-8cm) and diameters (6-20mm).2,3,7,8 The balloon dilator is positioned across the stricture with or without guidewire assistance followed by inflation using a handheld device to inject saline or contrast.7 The main challenge using EBD to treat small intestinal anastomotic strictures compared to more proximal anastomotic strictures is reaching the stricture, which often requires push enteroscopy or balloon-assisted enteroscopy.8
Efficacy
Clinical success rates for EBD for small intestinal anastomotic strictures across multiple studies range from 44-89% following a mean of approximately two sessions.2,3,9,10 Ding et al. performed a retrospective cohort study of 54 patients with Crohn’s disease-related anastomotic strictures and observed a decrease in repeat EBD with escalation of medical therapy, strictures <40mm long, and shorter disease duration at the time of initial EBD.2 Hassan et al. and Ferreira-Silva et al. reported similar improved outcomes (higher success rates with decreased need for surgical re-intervention) when anastomotic strictures were <40mm long.3,10 Unfortunately, stricture recurrence remains a problem following EBD, occurring in 46-62% of patients and requiring use of other endoscopic therapies or surgical re-intervention.3,10
Adverse Events
Perforation was the most frequent adverse event with Ding et al. reporting perforation in 1.85% (1/54) of patients and 0.6% (1/151) of procedures whereas Hassan et al. reported perforation in 3.7% (13/347) of patients and 1.9% (13/695) of procedures.2,3
Self-Expandable Metal Stents
Technique
Self-expandable metal stents (SEMS) are composed of metal mesh which can be covered with overlying silicone or plastic to resist tumor or tissue ingrowth. SEMS for small intestinal use are either uncovered (UCSEMS) or partially covered (PCSEMS).11 These include the uncovered Wallstent and Wallflex stents (Boston Scientific, Natick, Massachusetts, United States) and the uncovered or partially covered Hanarostents (M. I. Tech, Seoul, Korea) available in various diameters (20-22mm) and lengths (60-170mm).11,12 SEMS work by exerting constant radial force against the anastomotic stricture until removal during a subsequent endoscopic procedure.11
Efficacy
Branche et al. and Das et al. published case series with a combined 26 patients, all having anastomotic stricture lengths <6cm treated with the partially-covered Hanarostent, and observed clinical success rates of 100% and 81%, respectively.12,13 However, Branche et al. noted recurrence in 33% of patients at six-month follow-up.12 Ferreira-Silva et al. reported clinical success rates of 36-100% in 71 total patients across case reports and series.10
Adverse Events
Migration was the most reported adverse event seen in as many as 15.8% (3/19) of patients in Das et al.’s case series using PCSEMS.10,12,13 It is important to understand stent migration is not always a true adverse event and instead may occur following stricture resolution as there is no stenosis to anchor the stent in place. Nonetheless, anchoring techniques have been used to reduce migration rates including endoscopic suturing and TTS or over-the-scope (OTS) clips attaching the stent to adjacent mucosa. In a case series of seven patients, Senol. et al. described successful use of TTS clips to affix jejunal SEMS with a 0% migration rate.14
Lumen-Apposing Metal Stents
Technique
The AXIOS stent (Boston Scientific, Natick MA, United States) is the only commercially available lumen-apposing metal stent (LAMS) in the United States and was originally designed with FDA approval for draining pancreatic fluid collections.15,16 However, LAMS are commonly used in an off-label manner for the treatment of luminal strictures, including small intestinal anastomotic strictures.15 LAMS are 8-15mm long with diameters of 6, 8, 10, 15, and 20mm.15,16 LAMS are deployed across the anastomotic stricture using a guidewire under a combination of endoscopic and fluoroscopic visualization.15
The AXIOS catheter is often not long enough to reach distal small intestinal anastomotic strictures. Ferrell et al. reported a modified technique to assist in reaching distal small intestinal anastomotic strictures. The AXIOS stent was deployed into sterile water followed by twisting the ends in opposite directions and backloading the stent into the distal end of the working channels of a colonoscope and double-balloon enteroscope.17 Once the stricture was reached, the stent was manually deployed using biopsy forceps. In general, LAMS are deployed across strictures within reach of an upper endoscope, which includes duodenal and proximal jejunal strictures.
Efficacy
Ferrell et al. utilized the modified technique described above to reach distant small intestinal anastomotic strictures in two patients with strictures <1cm long that were previously refractory to EBD.17 Both patients remained asymptomatic without signs of stricture recurrence at three-month follow-up.17 Axelrad et al. reported a case with successful use of LAMS in a patient with a 1cm small intestinal anastomotic stricture refractory to EBD. The stent was removed after 60 days, and the patient remained asymptomatic without signs of stricture recurrence at 90-day follow-up.18
Adverse Events
Neither Ferrell et al. nor Axelrad et al. reported adverse events in the three cases.17,18
Biodegradable Stents
Technique
Biodegradable stents (BDS) were designed to treat esophageal strictures but have been used off-label for treatment of other luminal strictures, including small intestinal anastomotic strictures.19,20 The SX-ELLA BDS (ELLA-CS, Hradec Kralove, Czech Republic) is the only commercially available BDS but is not approved for use in the United States. BDS range in diameter (18-25mm) and length (60-135mm) with flared ends (23-27mm wide) designed to reduce stent migration.10,19,20 BDS are constructed of synthetic polymers which supply radial force against the stricture for 4-6 weeks before degrading and fragmenting over the next 6-24 weeks, after which they spontaneously pass.10,19
BDS require assembly prior to placement. These devices are advanced across a stricture using a guidewire under endoscopic and/or fluoroscopic visualization.19,20 Positioning of the stent is facilitated by locating the radiopaque ends of the stent with fluoroscopy.19 The main limitation to using BDS for small intestinal anastomotic strictures is the potential inability of the BDS delivery system to reach distal strictures.19
Efficacy
Rejchrt et al. performed a case series with 11 patients including 8 who had small intestinal anastomotic strictures treated with BDS.19 All patients underwent EBD prior to stent placement.19 62.5% (5/8) of patients were asymptomatic at follow-up ranging from 12-26 months, and complete BDS degradation was noted at a mean of four months.19
Adverse Events
Rejchrt et al. reported stent migration in 37.5% (3/8) of patients.19 No other adverse events were reported.19
Colorectal Anastomotic Strictures
Etiology
Colorectal anastomotic strictures may result following partial or complete colonic and/or rectal resection. (Figure 1) Common indications for resection include malignant or benign conditions including diverticulitis, inflammatory bowel disease, perforations, and ischemic bowel. Post-operative colorectal anastomotic strictures occur in 2-30% of patients.21,22,23,24 Jain et al. noted most colorectal anastomotic strictures are diagnosed within one year of surgery.24
Risk Factors
Patients are at increased risk of developing colorectal anastomotic strictures if they are male, smoke tobacco, underwent neoadjuvant or adjuvant radiation therapy, or experienced perioperative anastomotic leakage.22,24,25 Anastomotic leaks increase the risk for anastomotic stricture formation by promoting local inflammation with resultant fibrosis and stenosis.24 Risk factors for anastomotic leakage include male sex, diabetes, obesity, kidney disease, cardiovascular disease, radiation therapy, smoking, heavy alcohol use (>35 drinks/week) and the use of immunosuppressive medications such as steroids.26
Slesser et al. performed a meta-analysis of 10 randomized controlled trials with 1,969 patients examining the risk for colorectal anastomotic strictures among different surgical anastomotic closure techniques.27 They reported no difference in colorectal anastomotic stricture rates between hand-sewing, stapling, or using compression rings to create anastomoses.27 One surgical technique shown to reduce risk of colorectal anastomotic strictures is mobilization of the splenic flexure which was observed by Surek et al. in a retrospective cohort study of 375 patients.28
Clinical Manifestations
Patients may experience abdominal pain, bloating, distention, nausea, vomiting, constipation, and/or weight loss.29 While symptoms often occur within the first year following surgery, there have been reports of onset as early as one month after surgery and as late as 12 years after surgery.24
Endoscopic Balloon Dilation
Technique
EBD is first-line therapy for treating colorectal anastomotic strictures using the same techniques described previously for small intestinal anastomotic strictures.8,23,30 Most colorectal anastomotic strictures are reachable with standard colonoscopes, but, rarely, strictures may require push enteroscopy or balloon-assisted enteroscopy in certain cases such as patients with tortuous colons.8 Klag et al. cautioned dilation beyond 25mm due to a perceived increased risk of perforation.8
Efficacy
Hong et al. noted clinical success rates of 88-100% using EBD with recurrence rates of 30-88%.21 Clifford et al. performed a systematic review including ten studies with 380 patients treated with EBD which showed clinical success rates of 80.6-100% after a mean range of 1-3 dilation sessions.22 Araujo et al.’s case series of 24 patients and Di Giorgio et al.’s prospective cohort study of 30 patients observed clinical success in 91.7% and 100% of patients following a mean of 2.3 and 2.6 dilation sessions, respectively.23,30
Despite initial clinical success rates that are high, stricture recurrence is common after EBD. Biraima et al., in a retrospective cohort study of 76 patients, found that 49% of patients required more than two dilation sessions to achieve clinical success, and stricture recurrence occurred in 11% of patients at 12 months, 22% of patients at 24 months, and 25% of patients at 60 months.31
Thomas-Gibson et al. performed a retrospective cohort study of 53 patients with Crohn’s disease related colorectal anastomotic strictures and observed initial success in 82% of patients. However, long-term clinical success (remaining asymptomatic after six months) was observed in only 42% of patients at mean follow-up of 21 months.32 58% of patients required another surgery within a median of 4.9 months following EBD.32
Adverse Events
Perforation was reported in 1.18% (6/509) of patients across multiple studies.22,31,32 Other infrequently reported adverse events included minor bleeding and fever.22
Self-Expandable Metal Stents
Technique
SEMS for colorectal use were originally designed for, and continue to be used for, treatment of malignant large bowel obstruction.21 Because these stents were intended to either be left in place as a palliative device or to be removed by surgery, they are only available as UCSEMS in the United States. Epithelization of these stents commonly occurred but was not considered an adverse event.21 As their use expanded to include treatment of benign strictures, including colorectal anastomotic strictures, fully covered (FCSEMS) colorectal stents were manufactured which reduced epithelialization and made stent removal feasible, but these are not available in the United States.21
Commercially available SEMS include Wallflex colonic stents (Boston Scientific, Natick MA, United States) available in various diameters (22-25mm) and lengths (60-120mm).11 The colonic Z-stent and Evolution stents (Cook Medical, Winston-Salem, NC) are also available in various lengths (40-120mm) with a 25mm diameter.11 Stent placement near the dentate line should be avoided to reduce the risk of tenesmus and pain.33
Efficacy
Clinical success rates using SEMS ranged from 25-70% across three case studies with a combined 48 patients.21,33,34 Caruso et al. performed a case series of 16 patients in Italy and observed a significant difference (p-value 0.035) in clinical success rates between patients treated with smaller FCSEMS 20-22mm in diameter (17%) compared to larger FCSEMS 24-26mm in diameter (80%).34
Adverse Events
Stent migration was the most common adverse event reported among the 48 patients.21,33,34 Caruso et al. and Lamazza et al. treated anastomotic stricture patients with FCSEMS and noted stent migration in 19% and 37.5% of patients, respectively.33,34 Hong et al. and Lamazza et al. treated patients with UCSEMS and noted stent migration in 17% and 0% of patients, respectively.21,33 Hong et al. also noted UCSEMS epithelialization in 17% of patients with a median follow-up time of 16.7 months.21 Other reported adverse events included pain and minor bleeding without any reports of perforation.21,33,34
Lumen-Apposing Metal Stents
Technique
Using the previously described technique, LAMS can be used in an off-label manner to treat short (<1-1.5cm long) colorectal anastomotic strictures.34,35 (Figure 2) Pre-stent or in-stent dilation may be utilized at the discretion of the operator.
Efficacy
Xu et al. described successful use of LAMS with in-stent dilation to treat a <1cm long malignant colorectal anastomotic stricture previously refractory to EBD.35 The LAMS remained patent at six months, and the patient remained asymptomatic at 14-month follow-up, the last follow-up prior to the case report’s publication.35
Kankotia et al. performed a retrospective cohort study of 29 patients comparing EBD (N=18) and LAMS (N=11) for treatment of benign colorectal anastomotic strictures.36 They observed no significant difference in clinical success (EBD 66.7% vs. LAMS 81.8%; p-value 0.67) or stricture recurrence (EBD 33.3% vs. LAMS 11.1%; p-value 0.35), but the trend favored LAMS overall.36
Adverse Events
The most common adverse event reported by Kankotia et al. was LAMS migration seen in 46% (5/11) of patients.36 However, stent migration is not always a true adverse event and may instead be a surrogate marker of stricture resolution. There were no reports of perforation, bleeding, or pain in the LAMS group.36
Biodegradable Stents
Technique
BDS have been used outside the United States in an off-label manner to treat colorectal anastomotic strictures via the previously described technique.36,37
Efficacy
Repici et al. and Janik et al. performed case series with a combined 14 anastomotic stricture patients treated with BDS following pre-stent dilation.37,38 Repici et al. observed a less-than-ideal clinical success rate of 45% (5 of 11 patients) whereas Janik et al. observed clinical success in 100% (3/3) of patients with stent degradation noted at 4-5 months.37,38
Adverse Events
Janik et al. reported no adverse events.38 Repici et al. noted BDS migration in 36% (4/11) within two weeks.37 No other adverse events were reported.37
Endoscopic Incisional Therapy
Technique
Endoscopic incisional therapy (EIT) is a commonly utilized modality to treat esophageal strictures and has been successfully used to treat colorectal anastomotic strictures.22,38,39 Multiple radial incisions of operator-dependent length and depth are made around the stricture with or without excision of the fibrosed mucosal tissue in-between incisions.40 Operators have an array of instruments available to create the incisions including sphincterotomes, needle knives, insulation-tip (IT) knives or other endoscopic submucosal dissection (ESD) knives, and even polypectomy snares with argon plasma coagulation (APC) as seen in one study.40
Efficacy
Clifford et al. performed a systematic review including three retrospective cohort studies with a combined 455 patients treated with EIT which showed clinical success rates ranging from 71.4-100%.22 Jain et al. performed a meta-analysis with 186 patients treated with EIT alone or in combination with other modalities such as EBD or steroid injection.40 95.5% of patients treated with EIT alone achieved clinical success with stricture recurrence in 2.8% of patients.40 87.8% of patients treated with combined EIT and EBD achieved clinical success with stricture recurrence in 12.5% of patients.40 91.2% of patients treated with combined EIT and steroid injection achieved clinical success.40
Adverse Events
Jain et al. reported pain in 3.8% (7/186) of patients.40 Clifford et al. did not report any adverse events among their 455 patients.22
Conclusion
Small intestinal and colorectal anastomotic strictures pose a significant clinical challenge, and endoscopic management techniques continue to advance providing many solutions, each with varying efficacies and associated adverse events. For both small intestinal and colorectal anastomotic strictures, endoscopic balloon dilation remains first-line therapy but is hindered by high recurrence rates. Stenting with SEMS, LAMS, or BDS serves as another treatment option while endoscopic incisional therapy is another solution for small bowel and colorectal anastomotic strictures.
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