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EDITORIAL

Major Trends in Gastroenterology and Hepatology Between 2010 and 2019: An Overview of Advances From the Past Decade Selected by the Editorial Board of The American Journal of Gastroenterology

Bajaj, J.S. MD1; Brenner, D.M. MD, MSHS2; Cai, Q. MD3; Cash, B.D. MD4; Crowell, M. PhD5; DiBaise, J. MD5; Gallegos-Orozco, J.F. MD6; Gardner, T.B. MD7; Gyawali, C.P. MD8; Ha, C. MD9; Holtmann, G. MD10; Jamil, L.H. MD11; Kaplan, G.G. MD12; Karsan, H.A. MD13; Kinoshita, Y. MD14; Lebwohl, B. MD15; Leontiadis, G.I. MD16; Lichtenstein, G.R. MD17; Longstreth, G.F. MD18; Muthusamy, V.R. MD19; Oxentenko, A.S. MD20; Pimentel, M. MD9; Pisegna, J.R. MD21; Rubenstein, J.H. MD22,23; Russo, M.W. MD24; Saini, S.D. MD22,23; Samadder, N.J. MD20; Shaukat, A. MD, MPH25; Simren, M. MD, PhD26,27; Stevens, T. MD28; Valdovinos, M. MD29; Vargas, H. MD5; Spiegel, B. MD, MSHS, FACG9; Lacy, B.E. MD, PhD, FACG30

Author Information
The American Journal of Gastroenterology: July 2020 - Volume 115 - Issue 7 - p 1007-1018
doi: 10.14309/ajg.0000000000000709
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INTRODUCTION

A new decade has arrived. Dramatic changes in health care are already occurring, and continued changes will inevitably involve the practice of gastroenterology and hepatology. Sometimes, we can become so focused on the present (or the future) that it can be easy to lose track of the past, so before embarking on the next decade of research and innovation, we believe it important to briefly pause and reflect on some of the major developments that occurred in gastroenterology and hepatology between 2010 and 2019.

This article represents a first for The American Journal of Gastroenterology. It is written by the Associate Editors of the Journal, acknowledged experts in their respective fields. The Editors have reviewed the scientific literature over the past decade to identify major trends, developments, innovations, and practice changing ideas in 8 major areas of interest (endoscopy, esophagus, colorectal, small intestine, disorders of gut-brain interaction, hepatology, pancreatology, and inflammatory bowel disease). Key articles from gastroenterology and hepatology journals around the world have been summarized and cited; this review does not focus exclusively on the articles published in The American Journal of Gastroenterology. The following sections will briefly summarize these key trends. This article is not meant to serve as a comprehensive review of all of the important articles published in the past decade. In addition, this review will not discuss research on COVID-19, as this pandemic began in 2020. We know that you will benefit from this overview, and we hope that you enjoy reviewing the past decade of achievements as much as we enjoyed producing it.

ENDOSCOPY

Three major themes in the practice of endoscopy over the past decade include advances in the capabilities of interventional endoscopic ultrasound (EUS), the explosion of therapeutic procedures involving the submucosal or “third” space, and identification of the potential for infections to be transmitted by reprocessed duodenoscopes.

Interventional EUS

The practice of interventional EUS has evolved tremendously over the past decade. One of its major advances has been the use of lumen-apposing metal stents (LAMS), first reported in an ex vivo benchtop study. LAMS were initially designed to enable transluminal drainage of nonadherent extraintestinal fluid collections (1). It was US Food and Drug Administration (FDA) approved in 2013 for pseudocyst drainage (2), and in 2017, the AXIOS Stent and Electrocautery Enhanced Delivery System was FDA approved to facilitate transgastric or transduodenal endoscopic drainage of symptomatic pancreatic pseudocysts ≥6 cm in size and symptomatic walled-off necrosis ≥6 cm (3). In the past few years, its clinical use has greatly expanded allowing true lumen apposition, thereby revolutionizing interventional EUS-guided procedures. Its clinical use, supported by clinical studies, has evolved from pancreatic pseudocyst drainage to gall bladder drainage (4), bile duct drainage (5), gastroenterostomy (6), and creation of a transgastric fistula to access the excluded stomach in Roux-en-Y anatomy (7). The latter technique enables the endoscopist to perform endoscopic retrograde cholangiopancreatography and EUS on these anatomically challenging patients by advancing the endoscope through the LAMS.

Third space endoscopy/submucosal endoscopy

Routine luminal gastrointestinal endoscopy includes esophagogastroduodenoscopy, colonoscopy, and small bowel endoscopy. The gastrointestinal lumen is considered the primary or first space. Improvements in devices and techniques have enabled endoscopists to gain access into the second space (peritoneal cavity) over the past 2 decades and into the third space (submucosal space) in the past decade.

A major concern with performing third space endoscopy is ensuring secure closure of the entry point into the submucosa. The introduction of the mucosal flap safety valve (SEMF) technique in 2007 allowed endoscopists to safely access the second and third space with successful defect closure using the mucosal flap (8). The efficacy of the SEMF technique was first demonstrated in an endoscopic myotomy animal study in 2007 (9). Since then, submucosal endoscopy has been used for a variety of gastrointestinal diseases, including per oral endoscopic myotomy (POEM) for achalasia (10), submucosal tunnel endoscopic resection for submucosal tumors (11), gastric POEM for gastroparesis (12), and submucosal tunneling endoscopic septum division (Z-POEM) for Zenker diverticulum (13). Many studies have showed promising results for POEM (14–17), submucosal tunnel endoscopic resection (18–20), gastric POEM (21–23), and Z-POEM (24,25).

Endoscopic submucosal dissection was first described in 1988 as an endoscopic technique to resect early gastric neoplasia (26). It should be included as one of the submucosal endoscopy techniques because it resects both the mucosal and mucosal layers. However, it does not use the SEMF technique. Endoscopic submucosal dissection is worth mentioning as a notable advance because it has rapidly progressed from an uncommon experimental technique to a well-established, routinely performed procedure involving the endoscopic en bloc removal of gastrointestinal epithelial lesions (27).

Duodenoscope transmitted infections

The past decade bore witness to numerous reports of the transmission of multidrug-resistant bacteria, particularly carbapenem-resistant enterobacteriaceae, via duodenoscopes during endoscopic retrograde cholangiopancreatography procedures (28–31). In contrast to previous infectious outbreaks associated with endoscopic transmission, no breaches in the reprocessing protocol were identified in most of these outbreaks. These events led the FDA to mandate enhanced duodenoscope–reprocessing techniques, including double high-level disinfection, ethylene oxide sterilization, obtaining cultures postreprocessing, and the use of liquid chemical sterilization techniques (32). However, the utility of many of these techniques remains unclear (33,34). A subsequent FDA postmarket surveillance study found “high-concern” bacteria on up to 6.1% of the fully reprocessed duodenoscopes (35). These results led the FDA to recommend transitioning from fixed end-cap duodenoscopes to those with novel designs, involving disposable components that facilitate or eliminate the need for reprocessing (36). Recently, single-use duodenoscopes have been developed; their role is being actively evaluated (37,38). Future advances may include better mechanisms to validate adequate reprocessing and novel sterilization techniques, including low temperature reprocessing.

GASTROESOPHAGEAL DISORDERS

The 2010s witnessed major changes in the evaluation and management of esophageal disorders. Entering the decade, concerns over proton pump inhibitor (PPI) overuse challenged the dogma that chronic PPI use was safe. Throughout the 2010s, a near constant flow of publications reported weak associations between PPI use and an extensive list of potential adverse effects, including gastrointestinal cancer (39).

This prompted practitioners to discontinue PPIs in many patients, even those at high risk of acid-peptic complications and encouraged patients to self-discontinue PPIs without consulting their providers. These actions occurred despite publications released by gastroenterological societies designed to counter these potentially dangerous actions (40–42). At the close of the decade, the first large scale randomized trial did not confirm any of the purported PPIs adverse effects other than a small increase in enteric infections (1.4% vs 1.0% over 3 years of use) (42). The 2010s closed with information about a novel treatment option because potassium-competitive acid blockers were shown to have a faster onset of action, with dose-dependent and meal-independent acid suppression that is as efficacious if not better than PPIs in treating acid-peptic disorders (43).

Within the realm of acid-peptic disorders, pathologic esophageal acid exposure time was firmly established as the key metric from esophageal reflux monitoring that predicts the treatment outcome (44) and provides conclusive evidence for the diagnosis of gastroesophageal reflux disease (GERD) (45). For pH-impedance monitoring, the baseline impedance value measured during the nocturnal period (mean nocturnal baseline impedance) and a measure of the frequency of a primary peristaltic wave that clears and neutralizes refluxed acid (postreflux swallow–induced peristaltic wave index) were introduced as objective assessments that may predict GERD outcomes (46–48). Baseline impedance measurements can now be made using a novel device developed for use during sedated endoscopy, with 2 arrays of impedance sensors mounted on an esophageal balloon (49,50). Objective consensus criteria for conclusive evidence, equivocal evidence, and absence of GERD were published (45). Nonreflux etiologies for esophageal symptoms were demonstrated to outnumber-proven GERD in PPI nonresponders with objective testing (51), and superior management outcomes were demonstrated when targeted reflux therapies were offered to patients with proven GERD (44,51–53). Therefore, the diagnostic armamentarium for the clinician grew through the decade, allowing better precision in making or refuting a GERD diagnosis. On the therapeutic front, alternatives to PPI therapy continued to be evaluated. Magnetic sphincter augmentation (54,55) and transoral incisionless fundoplication (56) rose in prominence, each demonstrating short- and intermediate-term evidence of efficacy in well-selected patients.

The advent of endoscopic therapy for Barrett's esophagus and early esophageal neoplasia that began in the 2000s led to a management revolution in the 2010s. Guidelines shifted from recommending surveillance for low grade dysplasia to considering endoscopic therapy, from surveillance or esophagectomy for high grade dysplasia to endoscopic therapy, and from esophagectomy to endoscopic therapy for T1a adenocarcinoma (57). The long-awaited Aspirin and Esomeprazole Chemoprevention in Barrett's Metaplasia Trial was published in 2018, demonstrating decreased progression to the composite outcome of high grade dysplasia, cancer, or death among those randomized to taking full-dose aspirin and esomeprazole 40 mg twice daily compared with those taking no aspirin and esomeprazole 20 mg once daily (58).

During the past decade, we have seen a reduction in the prevalence of peptic ulcer disease and Helicobacter pylori infection, primarily attributed to improved antibiotic and PPI regimens. A systematic review showed that concomitant therapy for 5 or 10 days was superior to PPI-amoxicillin-clarithromycin–based triple therapies administered for 5, 7, or 10 days but was not superior when triple therapy was administered for 14 days (59). The general prevalence of this infection declined from 11% to 9% by the end of the decade (60). Gastric intestinal metaplasia remains a significant issue in clinical practice, especially regarding concerns for the development of gastric cancer. Several risk factors have been identified, and these include advanced age, male sex, nonwhite race, ethnicity, and the use of cigarettes (61). Endoscopic grading of gastric mucosa remains an important determinant for identifying early gastric cancer. In patients who underwent eradication of H. pylori infection, mucosal atrophy was identified to be a critical risk factor for the development of gastric cancer (62).

Over the past decade, we have seen an increase in the recognition that eosinophilic gut disease is a significant clinical issue. Many factors have been investigated to account for this rise including the role of diet, the microbiome, and other lifestyle factors (63). Within the field of eosinophilic esophagitis (EoE), PPI responders were demonstrated to have similar demographic, clinical, and molecular characteristics as PPI nonresponders, prompting guidelines against requiring PPI nonresponse as a criterion for EoE diagnosis (64–67). Allergy testing (skin prick, patch, or serum) was determined to be inaccurate for identifying causative foods (67). Multicenter, randomized, controlled trials assessed clinical outcomes from topical steroids formulated specifically for EoE and biologics, positioning both of these options as medical therapies for EoE treatment in the next decade (68–72).

Updated versions of the Chicago Classification further enhanced characterization of esophageal motor disorders on high resolution manometry (HRM) (73). The role of adjunctive HRM-provocative maneuvers (multiple rapid swallows, rapid drink challenge, and standardized test meal) and adjunctive tests (functional lumen imaging probe) have been further established to avoid both over- and under-diagnosis of esophageal motor disorders using the existing HRM protocols (74). Targeted endoscopic myotomy (POEM) of aberrantly contracting esophageal smooth muscle and of a nonrelaxing lower esophageal sphincter was introduced as a niche procedure with excellent symptom outcomes, albeit with the risk of development of significant acid reflux in approximately half of the patients (75).

COLORECTAL

Advances in the field of colorectal disorders over the past decade have covered a range of topics, from the more modest and routine (increasing the efficiency of bowel preps) to the more advanced and less common (evaluating microsatellite instability). The following section briefly highlights some of these key advances.

Colonoscopy preparation

Effective bowel preparation before colonoscopy is essential for optimizing the detection of colon polyps and colorectal neoplasia. It has also become an important quality metric for colonoscopy (76,77). Noncompliance to dosing instructions has been shown to be a strong predictor of suboptimal bowel preparation (odds ratio [OR], 6.7; 95% confidence interval [CI], 3.2–14.2) (78). An analysis of average-risk patients who underwent routine screening colonoscopy showed that 86.7% of patients with poor bowel preparation had either failed to complete the preparation or failed to follow the written instructions on the timing of preparation or dietary restrictions (79). Split-dosing, with at least 50% of the bowel preparation consumed on the day of the examination, is recognized as superior in both efficacy and tolerability to the day-before dosing (80,81). A meta-analysis of 5 randomized trials reported that split-dosing of 4 L of a polyethylene glycol solution, compared with the day-before dosing, increased the number of adequate bowel preparations (OR 3.7; 95% CI, 2.8–4.9) and patient willingness to repeat the preparation for a subsequent colonoscopy (OR 1.8; 95% CI, 1.1–2.9) while decreasing the incidence of nausea (OR 0.6; 95% CI, 0.4–0.8) (82). The efficacy of the same-day bowel preparation is supported by a meta-analysis of 15 randomized studies, which noted similar bowel preparation quality (relative risk [RR], 0.95, 95% CI, 0.90–1.00), adenoma detection rate (ADR; RR, 0.97; 95% CI, 0.79–1.20), and patient willingness to repeat the process (RR, 1.14; 95% CI, 0.96–1.36) for the same day compared with split-dosing (83).

In addition, the likelihood of suboptimal preparation is increased for colonoscopies scheduled later in the day (OR, 1.9; 95% CI, 1.7–2.1) (84), which may be a function of the longer time between consumption of the bowel preparation and the procedure (runway time). A prospective analysis of 378 consecutive outpatients from a single practice found that every hour a patient waited between the last preparation dose and the start of colonoscopy translated to a nearly 10% decline in the likelihood of receiving a good or excellent bowel preparation quality rating (85). Thus, a shorter runway time may increase the chance of a good or excellent bowel preparation, which may, in turn, improve the detection of colorectal neoplasia. Recent guidelines strongly recommend split-dose bowel preparation, with the same-day preparation as an alternative to split-dosing, particularly for patients who schedule an afternoon colonoscopy, with the last bowel preparation dose beginning 4–6 hours before and completed ≥2 hours before the procedure time (80).

Updates in colon and colon cancer prevention

The past decade has witnessed significant advances in our understanding of familial predisposition to colorectal cancer (CRC) and hereditary syndromes (86). Individuals with a family history of CRC are at increased risk for developing CRC. The magnitude of that increased risk depends on the number of relatives with CRC, the degree of biological relationship (first degree vs second degree relative), and the age at which the relatives were diagnosed with CRC (87–89). Recent studies now report pathogenic cancer susceptibility genes that involve both high and moderate penetrance genes in approximately 10%–15% of individuals with CRC (90–92). To diagnose these high-risk patients, healthcare institutions have begun to widely adopt “universal” tumor screening using microsatellite instability and/or immunohistochemistry showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) to identify patients with colorectal or endometrial cancers most likely to have Lynch syndrome. Advances in technology (modern next generation sequencing), combined with an increase in the number of testing laboratories, have made testing affordable (less than $500). Multigene panels can now test for dozens of genes in parallel, thereby offering comprehensive testing of genetic predisposition across multiple cancer types. In addition, precision therapy options linked to the genomic basis of CRC are on the rise. For example, treatment options for patients with CRC and pathogenic mutations in the Lynch syndrome mismatch repair genes are the best characterized and tailored therapy includes immune checkpoint inhibitors (93).

In the past decade, the terminology for carcinoid tumors has changed, and they have been renamed neuroendocrine tumors (NETs). Increased recognition of NETs has occurred in the past decade in part because of improved imaging techniques such as the DOTA-octreotate, oxodotreotide, DOTA-(Tyr3)-octreotate, and DOTA-0-Tyr3-Octreotate Gallium 68 Positron Emission Tomography/Computed Tomography. The overall incidence increased from 0.27 per 100,000 to 1.32 per 100,000 per year in England (94). Improvements in the management of NETs include the use of lanreotide, which has been shown to have a potent antitumor effect (95), and the recent approval of telotristat (96) and the use of a somatostatin receptor-based peptide receptor radionuclide therapy with 177Lut-DOTA-octreotate, oxodotreotide, DOTA-(Tyr3)-octreotate, and DOTA-0-Tyr3-Octreotate (97). The rectum is the third most common site for NETs and approximately 80% are small (<1 cm) and can be managed endoscopically (98).

Another key advance has been an increased emphasis on high quality colonoscopy, including monitoring key quality metrics such as the ADR and improved bowel preparation (99). The ADR goal has been increased to 30% for screening colonoscopy (99). Improved colonoscopy performance may be achieved through enhanced techniques (change in patient position, water exchange, and second look in the proximal colon), technology (high magnification scopes, accessory devices such as Endocuff, Endocap and Endorings, and use of artificial intelligence software), educational initiatives, and regular performance reviews (100,101).

SMALL INTESTINAL DISORDERS: CELIAC DISEASE AND SHORT BOWEL SYNDROME

Celiac disease

Our understanding of celiac disease epidemiology has evolved in the past decade. Previous studies found that fewer than 20% of patients with celiac disease in the United States had the diagnosis established (102). However, recent data from the National Health and Nutrition Examination Survey (2013–2014) found that more than 50% of people with celiac disease now have an established diagnosis, suggesting improved disease awareness and testing (103). Interestingly, although the prevalence of celiac disease in the US population is 0.7% (104), the adoption of the gluten-free diet (GFD) by people without celiac disease (whether because of nonceliac gluten sensitivity, irritable bowel syndrome (IBS), or as an albeit-unproven wellness strategy) has grown more rapidly and is now reported by nearly 2% of the US population (101). This had occurred despite a lack of strong evidence that empiric GFD improves clinical outcomes for many patients without gluten-related enteropathy.

Strategies for the prevention of celiac disease have focused on the timing of gluten introduction during infancy, and in 2014, 2 randomized trials tested the strategies of early (4 months) or delayed (12 months) gluten introduction, using 6 months as the comparator. Neither strategy resulted in a reduced risk of developing celiac disease (105,106). Subsequent to these negative trials, cohort and case-control studies found that a higher quantity of gluten consumed during the first 2 years of life was associated with a modest increase in the risk of celiac disease, suggesting that the quantity of gluten intake (as opposed to the timing of its introduction) may be the key factor, thus deserving of future studies (107).

The burden of the GFD has been documented in recent years, with self-reported treatment for celiac disease rated as more burdensome than that reported by individuals with diabetes mellitus or congestive heart failure (108). This difficulty is, in part, because of uncertainties surrounding the gluten-free status (and thus safety of) of the prepared foods. A crowd-sourced analysis of a portable gluten detection device found that pizza and pasta dishes at restaurants were particularly prone to gluten contamination (109). This treatment burden has spurred efforts to develop nondietary therapies for celiac disease. In addition to repurposing existing medications (such as open-capsule budesonide for refractory celiac disease) (110), drugs in various phases of clinical development include tight junction modulators (111), gluten degradation therapy (112), and tolerance-inducing peptide therapy (113).

Short bowel syndrome

There is great interest in the use of intestinal growth factors in patients with short bowel syndrome (SBS) who have been unable to achieve enteral independence despite optimization of diet and medical management. Teduglutide—a recombinant, degradation-resistant, longer-acting glucagon-like peptide-2 (GLP-2) analogue—was found to be safe and well-tolerated, with a doubling of the response rate in those receiving teduglutide compared with those on placebo (63% vs 30%, P = 0.002). In addition, 54% of those receiving teduglutide were able to reduce at least one parenteral nutrition (PN) infusion day/week compared with 23% for placebo (114). Longer-term data from an open-label extension study suggest continued improvement in PN weaning with continued use of teduglutide (115). More recently, a 24-week, phase III randomized, double-blind, placebo-controlled trial of teduglutide in pediatric patients with SBS demonstrated significant reduction in parenteral support (116). Teduglutide is now approved for both adult and pediatric patients with SBS as an aid to PN weaning. Longer-acting GLP-2 analoges with the potential advantage of less frequent administration are in development. The long-term benefits and risks, timing of administration in relation to the onset of SBS, optimal patient selection for use, duration of treatment, and cost effectiveness of teduglutide require further study.

There has also been recent interest in GLP-1 analoges in SBS. In an open-label pilot study, liraglutide was subcutaneously administered daily to 8 SBS patients with an end-jejunostomy and was found to reduce ostomy wet weight output and increase both intestinal wet weight and energy absorption (117). The use of a combined GLP-1 and GLP-2 agonist in SBS is being explored. In a study involving lean and diabetic mice, a GLP-1/GLP-2 agonist showed increased gut epithelial volume and mucosal surface area and beneficial glycemic effects (118).

DISORDERS OF THE GUT-BRAIN INTERACTION (PREVIOUSLY CALLED FUNCTIONAL GASTROINTESTINAL DISORDERS)

New definition and psychogastroenterology

Over the years, there have been many different terms to describe the functional gastrointestinal disorders. An important advance in the past decade is to rename functional gastrointestinal disorders as disorders of the gut-brain interaction (119), which replaces the less specific and potentially stigmatizing term “functional” and reflects concepts of pathogenesis derived from brain imaging (120) and other studies showing that gut and brain factors cumulatively influence symptom severity in IBS (121). This reconceptualization strengthens the rationale for practitioners to routinely incorporate psychotherapeutic best practices and to expand their knowledge of effective psychotherapies, qualified and accessible mental health practitioners, and neuromodulator therapies (122).

Accumulated data now indicate that cognitive behavioral therapy (CBT) can provide one-year improvement for IBS without psychopathology, yet this treatment can be difficult to obtain because of a limited number of therapists trained in gut-focused CBT paradigms. However, therapist-delivered telephone CBT and web-based CBT can increase availability with proven effectiveness in children, adolescents, and adults (123–125). Individual gut-directed hypnotherapy also improves symptoms, which is paralleled by normalization of abnormal central processing of visceral stimuli, further supporting the relevance of gut-brain interactions in these patients (126). Symptoms of IBS can improve for one year when administered to groups (127). Systematic review and network meta-analysis of traditional therapies for IBS revealed that low-to-modest dose tricyclic antidepressants are the most supported of central neuromodulators for intermediate-term chronic pain reduction and, compared with the benefits of compared therapies, rank first for decreasing pain and second for improving global symptoms (128).

Gut-directed drugs

A surge in new pharmacological treatments over the past decade now offers physicians and patients far more options than ever before.

The return of prokinetics.

Data collected over 10 years have mitigated claims of increased cardiovascular events associated with 5-HT4 agonists. Therefore, this past year witnessed the FDA reapproval of tegaserod for the treatment of IBS with predominant constipation in adult women younger than 65 years (129). Prucalopride was approved for adults with chronic idiopathic constipation (130), and it can improve symptoms in patients with gastroparesis (131).

Secretagogues.

Secretagogues have evolved with the advent of the guanylate cyclase C agonists, linaclotide (132) and plecanatide (133), and the sodium/hydrogen exchange 3 inhibitor tenapanor (134). All are FDA approved for treating IBS with predominant constipation, and the former 2 drugs are also approved for chronic idiopathic constipation. Improvements in global and individual IBS symptoms have been identified across a spectrum of clinical studies. The mechanisms of action for these agents have been well documented, and each offers advantage beyond its predecessors, mainly over-the-counter agents.

Miscellaneous.

Eluxadoline, an FDA-approved combination μ−k opioid receptor agonist δ-receptor antagonist reduces global, pain, and bowel symptoms in individuals with IBS with predominant diarrhea. Prospective studies have also shown that it is effective in individuals failing to respond to over-the-counter loperamide (135,136). Small-intestinal release peppermint oil reduces the pain of IBS (137) and ranked first in reducing global symptoms in a systematic review and network meta-analysis (128), although it should be noted that the quality of studies varied from treatment to treatment, making direct comparisons challenging. More than 25% of patients with IBS with predominant diarrhea have bile acid malabsorption (138), and practitioners can employ cholestyramine, although there is only very-low certainty evidence (139).

The microbiome and therapy

Alteration in the intestinal microbiome has been suggested to play a role in the pathogenesis of disorders of the gut-brain interaction, and research has increased markedly in the past decade. Persistent symptoms meeting the diagnostic criteria of IBS (140) and functional dyspepsia (141) each manifest in about 10% of patients after an acute gastrointestinal infection. The link between IBS and chronic alterations of the small intestinal microbiome, referred to as small intestinal bacterial overgrowth, continues to generate interest (142). Alterations in the stool microbial composition in patients with IBS have been demonstrated, although the findings vary between studies, possibly because of the heterogeneous nature of IBS. Although stool samples are simple to obtain, microbiome sampling from other sites, including the small bowel mucosa, could provide more clinically relevant insights.

Targeting the gut microbiome with the nonabsorbable antibiotic, rifaximin, significantly improves IBS symptoms (143) and also seems to benefit functional dyspepsia (144). However, only modest, transient changes in fecal microbiota occur with therapy, suggesting nonantibiotic contributions to its action (145). Probiotics can benefit IBS, but the individual species and strains that are the most beneficial remains unclear (146,147). Associations of brain structure and function have been associated with the gut microbiome (148,149), and brain activation changes accompany improved depression and quality of life with probiotic administration (150). Fecal microbiota transplantation has been studied in IBS, but the results have not met expectations to date (151). Although some data suggest a possible benefit (152), it is premature to routinely recommend this therapy for IBS outside of clinical trials despite attempts for the do-it-yourself fecal microbiota transplant programs (153).

Diet is an important extrinsic factor affecting the gut microbiome and seems to play a key role in symptom generation. Over the past decade, diet research has mainly focused on the role of a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) and a GFD for the relief of symptoms in IBS. A number of small randomized controlled trials suggest benefit of both the low FODMAP and GFD in IBS; however, a recent systematic review and meta-analysis concluded that there is insufficient evidence to recommend a GFD to reduce IBS symptoms and very low quality evidence that a low FODMAP diet is effective in reducing symptoms in patients with IBS (154).

HEPATOLOGY

Hepatitis C

Who could have foreseen that less than 30 years after the identification of the hepatitis C virus in 1989, well-tolerated therapies with virologic cure rates as high as 100% would be available? Initially labeled non-A non-B hepatitis, therapy consisted of interferon, followed by interferon and ribavirin and then pegylated interferon and ribavirin for up to 48 weeks. Sustained virologic response (SVR) rates of 30% were achieved in patients infected with genotype 1, the most common genotype. However, these successes came with considerable costs and side effects, including flu-like symptoms, depression, and occasional suicide. Initial excitement about one of the first direct acting antiviral agents, BILN2061, a protease inhibitor, was tempered by cardiac toxicity in animal studies and further development was abandoned (155).

It was not until the late 2000s that randomized clinical trials of the first protease inhibitors, telaprevir, and boceprevir were published, demonstrating the highest SVR rates yet to be seen, ∼70% (156,157). However, these proteases were used in combination with pegylated interferon and ribavirin, and discontinuation rates were double in the protease arms compared with pegylated interferon and ribavirin.

The next major advance was eliminating interferon from the treatment regimen. In 2013, a study that included an interferon-free regimen using the NS5B- polymerase inhibitor sofosbuvir demonstrated that high SVR rates could be achieved without interferon (158). The first interferon-free regimen with drugs from different classes, a polymerase and a protease, included sofosbuvir and simeprevir. This combination, frequently referred to as the COmbination of SiMeprevir and sOfoSbuvir in HCV-infected patients (COSMOS) study regimen, demonstrated extraordinary SVR rates of 90% in genotype 1 patients (159). Despite the success of this regimen, it was later replaced by other regimens, in part, because the drugs were made by 2 different pharmaceutical companies.

Subsequent advances focused on developing pangenotypic regimens that did not include ribavirin (160–163). Velpatasvir-sofosbuvir and glecaprevir-pibrentasvir are 2 pangenotypic regimens without ribavirin that have virologic cure rates as high as 100% and discontinuation rates of <1% (161,163). Velpatasvir-sofosbuvir can be prescribed to patients with decompensated cirrhosis, an especially challenging population. Duration of therapy can be as short as 8 weeks with glecaprevir-pibrentasvir in patients who meet the criteria. Importantly, virologic cure is associated with lower liver-related and all-cause mortality (164).

Alcoholic hepatitis and liver transplantation

There is a burgeoning epidemic of alcohol-related liver disease that is now being increasingly recognized in younger individuals (165). The specter of alcoholic hepatitis looms large over the mortality statistics in alcohol-related liver disease. Patients with alcoholic hepatitis are prone to infections, complications of portal hypertension, and liver synthetic failure, and they have a poor prognosis (166). Although medical therapies such as corticosteroids and N-acetylcysteine can help in the short term, liver transplant remains the only curative option (166). Liver transplant in alcoholic hepatitis represents a unique comingling of ethical, medical, and psychosocial questions, and it was hardly ever performed until recently. A game-changing, small study from Europe showed that in <2% of patients evaluated for alcoholic hepatitis, there was satisfactory post-transplant survival, which was significantly better than historical controls (167). This was then replicated in a US-based study and then across multiple centers (168). Additional studies showed that the rate of significant alcohol relapse post-transplant remained similar to those who had alcoholic cirrhosis but had followed the 6-month pretransplant abstinence rule (168). With donated livers being a precious resource, this topic has ignited debate and has led several transplant centers to formulate policies that focus on patients who fulfill medical and ethical priorities for liver transplant while also reducing the potential for alcohol relapse in patients who have not been abstinent for 6 months.

Nonalcoholic fatty liver disease

With the ever-expanding national obesity epidemic, it has become apparent that approximately half of the adult population in the United States will be obese by 2030 (169). Obesity directly correlates to nonalcoholic fatty liver disease (NAFLD) and has now become the most common cause of chronic liver disease in the world, affecting ∼30% of adults (170). It is estimated that there will be 100,000 million people with NAFLD by 2030 in the United States, including 25 million with non-alcoholic steatohepatitis (NASH) and 2.5 million with cirrhosis, hepatocellular carcinoma, and liver transplant (171). Patients with NASH and fibrosis have an increased rate of liver-related and all-cause mortality, with cardiovascular disease as the most common cause of death in patients with NAFLD (172). With ongoing chronic liver damage in NASH, it has also been recognized that hepatocellular carcinoma occurs at an increased rate in patients with NASH even without cirrhosis (173). In fact, NASH has become the fastest-growing indication for liver transplantation in the United States and has replaced cirrhosis from hepatitis C (174). It has been shown that 7%–10% of body weight loss improves NASH, including fibrosis; however, this is often difficult for patients to sustain. There is no FDA-approved therapy for NASH, although current guidance from American Association for the Study of Liver Diseases recommends vitamin E and pioglitazone in select patients with biopsy-proven NASH (175). Over the past decade, there has been significant growth in our understanding of the pathophysiology of NAFLD, which has fueled the search for new pharmacologic options. Because the pathogenesis of NAFLD is complex, multiple targets are available and most likely we will need to address several targets simultaneously to arrest the progression of liver disease. Although there is a long list of agents undergoing preclinical and early clinical research, only 3—obeticholic acid, elafibranor, and cenicriviroc—are in advanced phase 3 clinical trials (176). In a recent interim analysis, obeticholic acid achieved improvement in liver fibrosis among patients with NASH and stage 2–3 fibrosis compared with placebo (177). It is very likely that there will be approved therapies for NASH and fibrosis within the next 5 years. Clearly, pharmacotherapy alone will not be the solution; we will need to continue preventative efforts to curtail the obesity epidemic and reduce its metabolic complications. We will also need to develop reliable, accessible, and noninvasive tools to diagnose and risk-stratify patients with NAFLD.

PANCREATOLOGY

The 2 major developments of the past decade in clinical pancreatology have been the refinement of the diagnosis and management of autoimmune pancreatitis (AIP) and the explosion of minimally invasive techniques to manage pancreatic fluid collections (PFCs), particularly walled off pancreatic necrosis.

Autoimmune pancreatitis

Recent observations have clarified the immunologic basis of type I AIP and suggested potential therapeutic targets. Humoral immunity is certainly a critical factor, based on patients' responses to B-cell depletion therapy. However, recent studies have suggested an equal or even greater role for T-cells, as evidenced by TH1/TH2 imbalance (178), abnormal T-regulatory cell expression (179), and increased lymphotoxin expression (180). Further experimental evidence suggests a potential role for T-cell directed therapy (e.g., cyclosporine) (181).

Clinically, the classification of AIP has been further refined. Type 2 AIP (idiopathic duct-centric) is now acknowledged as a disease process distinct from type I AIP. Comparative studies have led to a consensus highlighting the differences (182,183). Patients with type 2 AIP are younger, lack other organ involvement, and have normal serum IgG4 levels as compared to those with type 1. Unfortunately, the pathogenesis of type 2 remains unclear, hampering the development of diagnostic markers and targeted treatments.

Consensus criteria for the diagnosis of AIP are now available, and these unify clinical, serologic, and pathologic features. In select patients lacking serum IgG4 elevations or typical imaging findings, pancreatic biopsies are sometimes required. A randomized trial of 110 patients with suspected type 1 AIP showed that EUS-guided core-biopsy needles are superior to standard cytology needles, providing adequate tissue in 78% of patients with AIP.

Owing to its rarity, AIP treatment is based on small observational studies and clinical experience; helpful treatment algorithms have been proposed in recent years (184–186). Corticosteroids remain the mainstay for the induction of remission. Rituximab has also shown success in steroid-refractory disease and for steroid-intolerant patients (187). Strategies for maintenance therapy to prevent relapse need further study. A randomized trial showed significantly fewer relapses in patients treated with maintenance corticosteroids compared with those who discontinued steroids (188).

Management of pancreatic fluid collections

The revised 2013 Atlanta classification of acute pancreatitis defined PFCs into 4 distinct entities based on etiology, duration, presence of solid debris, and development of an encapsulated wall (189). This more refined definition enables clinicians to more accurately diagnose, manage, and predict the outcomes of each type of PFC, including acute fluid collection, acute necrotic collection, pancreatic pseudocyst, and walled-off necrosis.

The overriding principle for the management of acute fluid and acute necrotic collections is to delay intervention to allow for either resolution or encapsulation. Acute fluid collections will sometimes develop into pseudocysts that typically resolve spontaneously. Acute necrotic collections will usually develop into walled-off necrosis, which are much less likely to resolve.

Minimally invasive endoscopic techniques to drain or debride pseudocysts and walled-off necrosis were refined throughout the decade, with a major advance being the use of lumen-opposing metal stents to facilitate the easy creation of a cystenterotomy (190). A multicenter trial demonstrated the superiority of minimally invasive approaches to manage necrosis and pseudocysts compared with surgery (191).

INFLAMMATORY BOWEL DISEASE

Over the past decade, epidemiological data have revealed changing trends that have transformed IBD into a global disease (192,193). Newly industrialized countries in Asia, Africa, and Latin America have reported a rapidly increasing incidence of IBD that mirrors the incidence of IBD in the Western world during the latter half of 20th century (192,194,195). By contrast, the incidence of IBD in North America, Europe, and Oceania has begun to stabilize and, in some regions, decline (192). However, countries of the Western world are experiencing compounding prevalence, whereby the total number of patients living with IBD has climbed steadily (193,196). Prevalence data from Canada and Scotland suggest that the prevalence of IBD is 0.7% in 2020 and is forecasted to climb to 1% of the population by 2030 (196–198). Moreover, the IBD population is aging; gastroenterology clinics over the next decade will need to contend with caring for aging IBD population with comorbidities of the elderly (198,199). The global burden of IBD will stress healthcare systems worldwide, necessitating innovations in the delivery of healthcare and personalized approaches to monitoring and managing IBD (200).

One of the most important changes within the past decade has been the shift away from using primarily clinical symptoms to assess treatment response and the shift toward endpoints of mucosal healing. Clinical trial outcome measures have been adapted to include coprimary endpoints of patient-reported outcomes and objective assessments including fecal calprotectin, serum inflammatory markers, and endoscopy (201). This strategy has demonstrated efficacy as the Effect of tight control management on Crohn's disease (CALM) trial showed that early treatment optimization using biomarkers (C-reactive protein or calprotectin) resulted in superior clinical outcomes, mucosal healing, and cost-effectiveness over clinical assessments alone (202). However, even with early optimization of treatment based on risk stratification, many patients still do not respond or lose response to treatment. The burgeoning field of biomarkers, genetics, and precision medicine in IBD holds potential for personalizing strategies based on factors beyond the generic assessments currently available with the goal to increase the likelihood of early and sustained remission (203).

Over the past decade, we have gained a better understanding of the complex, intricate pathophysiological pathways that underlie the inflammatory cascade present in patients afflicted with IBD. Our currently approved biologic agents and small molecules inhibit tumor necrosis factor (Infliximab, adalimumab, golimumab, and certolizumab pegol), integrin (vedolizumab), interleukin-12/23 (ustekinumab), and Janus Kinase (JAK) kinase (tofacitinib) and are effective for the treatment of patients with moderate-to-severe active IBD when other options have failed (204,205). However, these agents heal the mucosa in less than half of patients with IBD (206).

Given the unmet need that exists, numerous novel therapeutics are being targeted for future therapy to treat patients with IBD. Different promising mechanisms have been identified and are undergoing evaluation in various phases in clinical trials. Several of these agents with novel mechanisms include the following:

  • Blockade of the downstream signalling pathways—such as JAK Kinase inhibitors—including filgotinib [JAK 1], upadacitinib [JAK 1], baricitinib [JAK 1,2], TD-1473 [JAK 1,2,3], peficitinib [JAK 1,2,3], PF-06651600 [JAK 3 and TEC Kinase], itacitinib [JAK 1], PF-06700841 [JAK 1 and Tyk-2], and BMS-986165 [Tyk-2];
  • blockade of proinflammatory cytokines—such as anti-interleukin-23 agents—including brazikumab (MEDI2070), risankizumab (BI 655066), guselkumab (Tremfya), mirikizumab (LY3074828), and tildrakizumab (MK-3222);
  • antiadhesion molecules—such as leukocyte trafficking inhibitors—including etrolizumab, anti-mucosal vascular addressin cell adhesion molecule ontamalimab (SHP 647, PF00547659), abrilumab, and AJM 300—as well as spingosine-1-phosphate modulators, including ozanimod and etrasimod (207).

The emergence of new biological agents targeting specific pathways in IBD has led to a variety of novel treatments and opportunities for more individualized therapy for patients with IBD. The careful evaluation and testing of the aforementioned, and other, novel agents will expand our medical armamentarium, thus enabling us to provide further treatment options for patients with IBD.

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