Potential Value of Biomarker-Based Approaches for Evaluation and Management of Costly Functional Gastrointestinal Diseases

Introduction

Functional gastrointestinal disorders including irritable bowel syndrome (IBS) are costly diseases associated with significant direct and indirect costs. This treatise deals predominantly with IBS and we apply the same principles to another example, functional dyspepsia. Strategies to control direct expenditure in IBS were proposed over two decades ago¹ and include the education of physicians that manage patients with IBS, education of the patients themselves, introduction of psychological treatments and addressing psychosocial issues early in the management process, curtailing unnecessary investigations, and developing effective doctor-patient relationships.² Since then, there has been significant documentation regarding the direct and indirect costs associated with IBS. A prior study had evaluated the cost effectiveness of tests for diarrhea-predominant IBS (IBS-D), but the biomarker tests pertained to investigations to exclude alternative diagnoses rather than focusing on biomarkers related to the etiopathogenesis of the IBS³. Since that report in 2018, there has been significant advance in the identification of biomarkers and potentially therapeutic reversal of the related mechanisms.

The purpose of this review is to introduce the potential of biomarker-based approaches for the evaluation and management of irritable bowel syndrome as an alternative to sequential therapeutic trials as proposed in recent guidelines.

IBS Is a Costly Disease from a Societal Perspective

There are several lines of evidence that document the high cost associated with IBS. First, a study from the United Kingdom⁴ has documented direct healthcare costs of Rome IV or Rome III-defined IBS. Thus, the mean annual direct cost of IBS per person among 752 patients with Rome IV IBS was £556.65 (SD £1023.92) and, for 995 patients with Rome III IBS, the mean annual direct cost was £474.16 (SD £897.86). It was also estimated that the annual direct healthcare cost of IBS in the UK is £1.27 billion (Rome IV IBS) and £2.07 billion (Rome III IBS). In fact, among patients with Rome IV IBS, mean annual costs were higher in those with opiate use (£907.90 vs £470.58, p <0.001), more severe symptoms (p <0.001 for trend), shorter duration of IBS (1 year, £1227.14 vs >5 years £501.60, p=0.002), lower quality of life (p <0.001 for trend), and higher depression, somatization, and gastrointestinal symptom-specific anxiety score.

Second, also from the United Kingdom, symptom subgroups in individuals with IBS predicted disease impact and burden.⁵ In this analysis, 7 clusters of patients with IBS were identified based on the presence of diarrhea, constipation, gastrointestinal symptoms, and psychological burden. It was demonstrated that high psychological burden was associated with worse quality of life (both IBS specific and generic), as well as reduced productivity, ability to work, manage affairs at home, engage in social and private leisure activities, and maintain close relationships. Moreover, high psychological burden was associated with higher IBS-related healthcare costs during the prior year, particularly in patients who had high degree of gastrointestinal symptoms as well as high psychological burden which were associated with greater than the equivalent of 1200 US dollars per person per year.

Third, a study from the Netherlands⁶ documented the socioeconomic impact of IBS including an analysis of direct and indirect healthcare costs. The total quarterly mean cost per IBS patient was estimated to be $2444, with $1354 indirect costs and $909 direct costs. Factors associated with significantly higher costs were age, male sex, unemployment, increased depressive symptoms, reduced IBS quality of life, and IBS subtypes other than constipation-predominant IBS (IBS-C).

Options in Management of IBS

Symptom-based diagnosis and therapeutic trials

Current guidelines for the management of IBS stress the importance of symptom-based diagnosis, as with the Rome criteria, followed by guideline-based treatment.^{7, 8} Given the variation in the iterations of the Rome criteria, as well as multiple deficiencies documented elsewhere⁹ that question the rationale for “splitting” the different syndromes identified by the criteria such as functional diarrhea and IBS-D, or functional constipation and IBS-C, there has been a plea for simpler identification of the classical symptoms of abdominal pain, bowel dysfunction, and bloating, and exclusion of alarm symptoms in identifying the clinical syndromes. An alternative approach to management is to apply the advances in the application of actionable biomarkers that identify the pathophysiologic mechanisms resulting in the generation of symptoms, followed by individualized therapy directed towards the mechanisms relevant to the individual patient (Figure 1).^{10, 11}

Figure 1.

Examples of actionable biomarkers and individualized therapies for rectal evacuation disorders, abnormal colonic transit, increased fecal bile acids, abnormal breath tests, inflammatory responses to dietary antigen injection into rectosigmoid colon mucosa, hypervigilance identified with validated questionnaires and altered fecal microbiome associated with increased H₂S or CH₄ excretion in breath (adapted from ref.¹⁰).

The guidance from the American Gastroenterological Association (AGA) Guidelines on the treatment of IBS^{7, 8} is essentially to pursue first the establishment of an optimal provider-patient relationship, education and reassurance, and lifestyle modifications including exercise, sleep, and stress reduction, as well as dietary modifications such as the introduction of fiber supplementation for patients who have constipation. After pursuing these general management strategies, patients with IBS-C are exposed to first- and second-line treatments directed at the constipation and abdominal pain, including osmotic laxatives and antispasmodics as first-line treatment for mild disease, and the introduction of secretagogues for moderate disease. In patients with IBS-D, the therapeutic approaches are treatment with loperamide and an empiric trial of bile acid sequestrant, and the same antispasmodic approach for the abdominal pain. For patients with moderately severe disease, central neuromodulators are applied, particularly tricyclic agents which also have an anticholinergic function. Alternative therapies for moderate disease include the nonabsorbable antibiotic, rifaximin, and the agent eluxadoline which has effects on different opioid receptors. The third-line treatment recommended for IBS-D is alosetron. If abdominal pain and or psychological symptoms are persistent, it is recommended that there would be additional focus on brain functions through use of central neuromodulators, as well as brain gut behavior therapies such as cognitive behavioral therapy or hypnosis.

A legitimate question that arises from such guidelines is: How expensive are these approaches for the insurer and the patient? Studies by Shah et al. have addressed several of the relevant questions for each subcategory of IBS. First, from an insurance perspective, starting with global treatments for IBS (central neuromodulators, dietician-directed low FODMAP diet, and cognitive behavioral therapy) is more cost saving than starting with on-label prescription drug treatments. In contrast, allowing on-label drugs first while reserving global IBS treatments for those patients who are refractory to the on-label drugs was associated with a total expense of $11,175.63, with an additional expense of $9034.59 in IBS-D compared to untreated IBS-D, and a total expense of $6858.31 and an additional expense of $2972.83 in IBS-C compared to untreated IBS-C.¹²

Second, from the perspective of calculating a cost-benefit analysis, societal insurer and patient perspectives in both IBS-D and IBS-C have been published^{13, 14} relative to the cost of no treatment. From the patient perspective and assuming approval by the individual patient’s insurance, the cost of no treatment for IBS-D was estimated to be $4789.13 with additional costs of treatments such as cognitive behavioral therapy, low FODMAP diet, tricyclic antidepressants, rifaximin, eluxadoline, and alosetron ranged from around $1900 to $2700.¹³ Similarly, for IBS-C, the cost of no treatment was estimated to be $5805, and the cost for treatments with linaclotide, lubiprostone, plecanatide, selective serotonin reuptake inhibitor, low FODMAP diet, and cognitive behavioral therapy from the patient perspective ranged from $2800 to $5800¹⁴ (Table 1).

Table 1.

Costs associated with different therapeutic strategies in patients with diarrhea- and constipation-predominant irritable bowel syndrome.

Therapeutic strategies (price in US dollars/year)	Insurer perspective ($)	Patient perspective ($)	Ref. #
Diarrhea-predominant irritable bowel syndrome
No treatment	2141.05	4789.13	13
CBT	1808.95	2734.14
Low FODMAP	1242.62	2730.29
Alosetron	15708.92	1868.03
Rifaximin	6144.53	2725.92
Eluxadoline	11567.00	1896.02
TCA	964.07	2049.97
Constipation-predominant irritable bowel syndrome
No treatment	3929.37	5805.00	14
CBT	2129.06	3275.79
Low FODMAP	2124.09	3230.31
Lubiprostone	7218.00	4596.04
Plecanatide	7139.64	3611.01
Linaclotide	6460.63	2822.20
SSRI	2046.58	3010.30

CBT: cognitive behavioral therapy; FODMAP: Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols; TCA: tricyclic antidepressant; SSRI: selective serotonin reuptake inhibitor

In summary, based on the direct and indirect costs of IBS as well as the cause of prescription medications, it is evident that the sequential application of these pharmacological agents based on tolerance of the medication, absence of adverse effects, and treatment choices based on symptoms of pain diarrhea or constipation involves significant expenditures.

Commonly used biomarkers to exclude organic diseases

It is relevant to emphasize that the commonly used biomarkers are intended predominantly to exclude underlying diseases such as celiac disease or colorectal cancer. A prospective real life cohort study demonstrated that these biomarkers do not contribute to IBS diagnosis. Thus, among 218 patients with Rome III positive IBS who were below the age of 50 years and had no red flags such as rectal bleeding or unintentional weight loss evaluated at a center of excellence for IBS patients,¹⁵the standard blood and fecal investigations, that is measurements of hemoglobin, TSH, celiac serology, and fecal calprotectin, during the first consultation contributed minimally to the diagnosis of patients who were followed for at least one year. Among these patients, 47 also underwent colonoscopy, and the final diagnoses were 210 IBS, 5 inflammatory bowel disease, 1 nonspecific ileitis, 1 hyperthyroidism, and 1 celiac disease. It was estimated that there were costs of €4900 to diagnose one patient with a diagnosis other than IBS.¹⁵

Actionable biomarkers in lower functional gastrointestinal disorders

In prior studies,¹¹ we documented the sensitivity, specificity, predictive values, and positive and negative likelihood ratios based on established cut-off values for rectal evacuation disorder, fast or slow colonic transit, bile acid diarrhea, and carbohydrate maldigestion. The specific tests are documented in Table 2.^16–29

Table 2.

Performance characteristics based on established cutoff values for rectal evacuation disorder, fast or slow colonic transit, bile acid diarrhea, and carbohydrate maldigestion (reproduced from ref.¹¹) and average costs of different biomarkers in selected cities in the United States (New York, NY, Los Angeles, CA, Chicago, IL, Miami, FL, Dallas, TX, Omaha, NE, St Louis, MS and Birmingham, AL) obtained from a publicly available website (https://www.fairhealthconsumer.org/) and including facility fees. Estimates are based on the 80^th percentile and correspond to in-network costs.

Biomarker	Cut-offs	Sn	Sp	PPV	NPV	+LR	−LR	Ref. #	CPT	Median charge US $
Rectal Evacuation disorders
Digital rectal exam (DRE)	>2 findings on DRE	83.9	68.1	49	92.8	2.6	0.2	16
Anorectal manometry: rectoanal pressure gradient	< −40 mm Hg	32.4	100	100	85.5	>10	0.7	17	91122	1194.5
Balloon expulsion test	22 seconds	77.8	69.8	39.2	92.6	2.6	0.3	18
Rectal gas volume	>20 mL	38.1	89.1	46.6	85.2	3.5	0.7	19
Rectal area on Scout film	>900 mm2	39.5	73.8	27.4	83.0	1.5	0.8	19	74018	294.5
Slow Transit Constipation
Stool burden score on abdo. x-ray	>7	86.9	54.5	27.1	95.5	1.9	0.2	20	74018	294.5
Colonic transit with scintigraphy: geometric center, GC	GC 48h <2.1	82	65	31.3	94.9	2.4	0.3	21	78266	2256.5
Fast transit diarrhea
Colonic transit with scintigraphy	GC 24h >3.8	31.6	87.2	21.5	91.9	2.5	0.8	22	78266	2256.5
Bile Acid diarrhea
75 SeHCAT retention	3-day 34%	100	94	33	77	1.7	0.9	23
48-hour fecal bile acid	1° BA >4% + total BA >1000μmol	46	97	83.6	84.3	15.3	5.1	24	82239	102
FGF-19	≤61.7pg/mL	29	83	29	78	1.3	0.9	25
7αC4	≥52.5ng/mL	29	78	33	79	1.7	0.8	25	82542	163
Carbohydrate maldigestion
Fructose breath test	peak rise in breath H2>20 ppm	98	86	26.9	99.9	7.0	0.02	26	91065	668.5
Lactose breath test	peak rise in breath H2 >20 μL/L	80	100	100	98.9	∞	0.2	27	91065	668.5
Upper GI Motor Dysfunctions
Gastric Emptying of Solids at 4 hr with Scintigraphy	> 25% retention	100	70	6.4	100	3.3	0	28
Gastric Accommodation with SPECT	Accommodation ratio >3.0	40.6	95	52.5	92.1	8.1	0.6	29

CPT: Current Procedural Terminology; NPV: Negative predictive value; PPV: Positive predictive value; Sn: Sensitivity; Sp: Specificity; + LR: Positive likelihood ratio; −LR: Negative likelihood ratio.

Colonic transit could also be measured noninvasively with radiopaque markers³⁰ or wireless capsule, both of which are generally available.^{31, 32} In general, these methods have been validated more extensively in patients with constipation rather than in patients with chronic diarrhea. However, there are published data showing that radiopaque markers can also detect abnormal transit in diarrhea as well as in constipation.³³

In patients with chronic diarrhea, accelerated transit through the colon can be accurately measured with scintigraphy, which may not be generally available. For example, the location of isotope in the colon at 36 hours is significantly greater in descending colon, sigmoid and rectum, and in stool compared to healthy volunteers.³⁴ Indeed, the colonic geometric center at 24 hours >3.8 (where 0 represents the ileocecal valve, and 5 represents 100% of the isotope in stool) had a specificity of 87.2% to identify rapid transit diarrhea.²²Analysis of colonic transit at 48 hours by scintigraphy has also been shown to differentiate the colonic transit profile of patients with evacuation disorder compared to that of patients with slow transit constipation.²¹ Identification of accelerated or delayed transit provides an opportunity to institute treatment with medications such as new opioid agonists or 5-HT₃ antagonists for rapid transit, and chloride secretagogues (lubiprostone, linaclotide, plecanatide), inhibitors of sodium absorption (tenapanor) or 5-HT₄ agonists for slow colonic transit (Table 3). Indeed, it has been demonstrated that objectively delayed colonic transit with such agents in single-center, proof-of-concept studies correctly predicted responses to treatment in large scale clinical trials.³⁵

Table 3.

Examples of approved medications or combination probiotics for which pharmacogenomic measurements predicted clinical efficacy based on phase IIB and III trials (adapted from ref.³⁵).

Drug Class	Pharmacodynamics (intestine or colon)	Clinical Efficacy: Phase IIB or III Studies
5-HT3-antagonist, alosetron	1 mg BID delayed colonic transit diarrhea in IBS-D	IIB, III studies in thousands of patients with non-C-IBS or D-IBS adequate relief of pain and discomfort of IBS, bowel dysfunction (including diarrhea) and urgency
5-HT4-agonist, Prucalopride	Increases SB, colon transit in healthy and patients with CC	IIB and III in CC (thousands of patients): BM frequency and satisfaction with bowel function both improved
Bisacodyl	Accelerates colon transit in healthy	Relief of constipation after acute administration and CC
Cl-C2 channel activator, lubiprostone	Accelerates SB and colonic transit in healthy controls	Several phase III in several hundred CC and IBS-C patients: efficacious in relief of pain and bowel dysfunction
Guanylate cyclase-C agonist, linaclotide	Accelerated AC transit and induced looser bowel function in 36 women with IBS-C	Several IIA, IIB and III studies in CC or C-IBS (several hundred) patients: increased BM frequency, relief of bloating, and abdominal discomfort
Ileal bile acid transport inhibitor, Elobixibat	Accelerates colonic transit and loosens stool consistency in functional constipation patients	Phase IIB and III studies showed improved stool frequency, and improved constipation-related symptoms in idiopathic CC
VSL-3 combination probiotic	Retards colonic transit in IBS-D, improves flatulence and bloating in IBS-D	Meta-analyses demonstrate symptom relief of multiple symptoms in IBS: global IBS, abdominal pain, bloating, and flatulence scores

AC: ascending colon; BID: twice a day; BM: bowel movements; CC: chronic constipation; Cl⁻C2: chloride channel type 2; 5-HT: 5-hydroxytryptamine; IBS: irritable bowel syndrome; IBS-C: Constipation-predominant IBS; IBS-D: Diarrhea-predominant IBS; SB: small bowel

The utility of a detailed digital rectal examination in the identification of defecation disorders in patients presenting with symptoms suggestive of irritable bowel syndrome with constipation or chronic constipation was documented 20 years ago.³⁶ Objective evidence of defecatory disorders is determined in clinical practice using high-resolution anorectal manometry and balloon expulsion testing.³⁷ An indication of possible defecatory disorder causing constipation can also be deciphered on review of a plain abdominal radiograph or abdominal CT scan which may have been performed for evaluation of constipation and abdominal pain. Thus, the identification of a rectal gas “bubble” situated above the pelvic floor and measuring at least 900 mm² has an almost 70% specificity for the presence of rectal evacuation disorder.^{19, 38} The importance of this finding is that it may alert the practicing gastroenterologist who does not have access to high-resolution manometry to the potential of a rectal evacuation disorder as a contributing factor if a patient’s constipation does not resolve with standard treatment for constipation including over-the-counter remedies as well as osmotic and secretory laxatives, or colonic prokinetic agents. Moreover, the results of the anorectal manometry test have been demonstrated to be useful in predicting the response to pelvic floor physical therapy in patients with chronic constipation based on a pragmatic clinical trial. Thus, for example, the combination of a balloon expulsion time greater than 6.5 seconds and inability to sustain 50% of squeeze pressure for more than 20 seconds at baseline predicted responsiveness to pelvic floor therapy³⁹. The overall clinical utility of a point-of-care test of rectal evacuation assessed by the patient inserting the balloon into the rectum, inflating the balloon, and measuring the time to expulsion in the left lateral position had significant diagnostic utility in addition to predicting 48.9% clinical response to physical therapy. The likelihood of response was even more accurately predicted (71.1%) when the balloon was retained greater than 13 seconds during attempted expulsion in the seated position⁴⁰.

With greater appreciation that approximately 1% of the people in the community have bile acid diarrhea and that this entity constitutes 25–50% of patients with functional diarrhea or IBS-D,⁴¹ the development of testing modalities for bile acid diarrhea opens opportunities for individualizing treatment in patients with these symptoms. The gold standard, available in many countries but not in the United States, is ⁷⁵SeHCAT retention at 3 or 7 days, as well as biochemical measurements in serum such as serum 7αC4 and serum FGF-19, and stool measurements of total, primary, and secretory bile acids. Receiver operating characteristic (ROC) curve analyses have demonstrated clinical utility of 48-hour stool collection for fecal total bile acid and primary bile acid measurements for the diagnosis of bile acid diarrhea. More recently, the same level of accuracy for the diagnosis of bile acid diarrhea has been documented with the combination of elevated serum 7αC4 >52.5 ng/mL and documentation of greater than 10% primary bile acids in a random stool sample.^42–44 This has the advantage of being more practical as it can be performed when the patient presents to the provider, and it has far greater sensitivity and specificity than the serum test alone. These tests are now offered by reference laboratories in the United States and therefore should be widely available.

An approach that still requires further evaluation and replication reflects the potential for dietary antigens taken up by the colonic mucosa to stimulate visceral pain in patients with irritable bowel syndrome.⁴⁵ Intramucosal injection of food antigens induced an immediate mucosal response in patients with IBS.⁴⁵ This novel finding is particularly relevant because of the evidence that antihistamine approaches are efficacious in reducing visceral pain in such patients.

Fecal microbiota and bacterial products as potential biomarkers

Gut dysbiosis is considered important in the pathogenesis of IBS,⁴⁶ and characterizing the composition of the fecal microbiome in patients with IBS may have diagnostic and therapeutic implications. However, because of significant heterogeneity observed in reports of fecal microbiome among studies, it has not been possible to identify a signature fecal bacterial profile for patients with IBS-D compared to IBS-C.⁴⁷

Given technical complexity of microbiome analysis and the absence of specific profiles in IBS-D and IBS-C, recent studies have focused on microbial byproducts such as short chain fatty acids (SCFA) or gases excreted in breath as possible biomarkers of altered microbiome. SCFA are produced by bacterial fermentation of non-absorbed carbohydrates; different bacteria use distinct fermentation pathways.^{48, 49} Hence, the concentrations of the diverse fecal SCFA could conceivably reflect the composition of the gut microbiome. A systematic review and meta-analysis showed that fecal SCFA concentrations were significantly different in patients with IBS and healthy volunteers, with increased butyrate in IBS-D and decreased propionate and butyrate in IBS-C.⁵⁰

Additionally, during fermentation of the complex carbohydrates^{51, 52} or proteins⁵³ that normally reach the colon by microorganisms, different types of gases are produced such as hydrogen sulfide (H₂S), hydrogen (H₂), or methane (CH₄). H₂S has been linked to disorders that present with diarrhea including experimental colitis⁵⁴ and stress-induced colonic hypermotility in rats.⁵⁵ Many microbial sources for intestinal H₂S production have been identified including Desulfovibrio and Desulfobulbus genera that utilize sulfate for energy production,⁵⁶ dissimilatory sulfate reduction (that is H₂S production under anerobic conditions) by Firmicutes and archaea species,⁵⁷ or degradation of sulfur-containing amino acids, cysteine, and methionine.^{58, 59} Methane is mainly produced by methanogenic archaea⁶⁰ and has been associated with slow small intestinal transit in dogs and with increased small intestinal contractile activity in patients with IBS with high methane production in response to a lactulose load.⁶¹ The degree of breath methane production in IBS correlates with the severity of constipation.⁶² In a recent study of 47 patients with IBS-D and 124 patients with IBS-C,⁵⁹ breath gas patterns were associated with distinct fecal microbial compositions, “microtypes”. Notably, patients with IBS-D had increased prevalence of Fusobacterium and Desulfovibrio, which are H₂S-producing bacteria, and higher breath H₂ and H₂S. Conversely, patients with IBS-C had increased fecal Methanobrevibacter smithii, a methanogenic archaea, and increased CH₄.⁵⁹

These findings suggest that the relative abundance of different gases identified on breath tests may serve as an indicator of the fecal microbial composition of patients with IBS. Subsequently, consistent with current treatment options being developed for Clostridium difficile infection, individualized treatment strategies could be developed for IBS through “microbiome replacement therapies”⁶³ or fecal microbiota transplantation.⁶⁴ Nevertheless, it is acknowledged that further validation studies are necessary before proposing these approaches directed at characterization of the exhaled gases, fecal SCFA, and other metabolome findings. These novel observations are very interesting, but they may not be sufficiently validated and ready for clinical application.

Pharmacogenomics

An ultimate measure of precision or individualized treatment would be the application of treatment for patients who manifest genetic variants in the target that would be associated with greater response, as reviewed elsewhere.⁶⁵ The literature remains sparse on this concept. The best examples are the effects of the 5-HT₃ antagonist, alosetron, in IBS-D and the 5-HT₄ agonist, tegaserod, in IBS-C. The activity of the serotonin-transporter protein (SERT), which is central to 5-HT neurotransmission, is impacted by the synthetic capacity of the gene involved in synthesis of SERT (also called SLC6A4). Polymorphism in the promoter region upstream of the coding sequence, documented by long variants (44 bp long insert in 5-HTTLPR or 5-HT transporter long polymorphic repeat) is associated with normal promoter-mediated transcription and synthesis of SERT in contrast to the short variant.⁶⁶ When there is sufficient SERT synthesized, there is reuptake of 5-HT from the synaptic cleft and avoidance of downstream overstimulation of serotonergic receptors. The presence of a single short allele in 5-HTT results in reduced SERT synthesis, leaving more 5-HT in the synaptic cleft. The clinical trials show that 5-HTTLPR was associated with greater efficacy of the 5-HT₃ antagonist, alosetron, in slowing colonic transit in IBS-D⁶⁷ and reduced efficacy of the 5-HT₄ agonist, tegaserod, on patient response outcomes.⁶⁸

Limitations

Table 2 lists some of the charges that are available for tests included in the list of actionable biomarkers, based on a searchable database for patients. While the costs of the diverse prescription therapies are well known (with societal insurer and patient costs identified), the precise charges for these tests are not always available in the public domain. The information in Table 2 illustrates that, with focused application of the tests, there may be potential cost savings with identification of the underlying mechanism contributing to IBS and targeted therapy. However, it is important to acknowledge that the efficacy of treatment directed at the actionable biomarker has been validated in relatively small, usually single-center studies, and that the efficacy was based predominantly on mechanistic endpoints such as colonic transit or biochemical markers of bile acid synthesis or excretion, rather than on patient response outcomes in large clinical trials with patients selected based on the biomarker. Unfortunately, it is perceived to be a commercial disincentive to combine a diagnostic and therapeutic for diseases such as IBS.

Application of These Principles to Another Disorder of Gut-Brain Interaction, Functional Dyspepsia

The same principles observed with IBS also apply to functional dyspepsia (FD), another DGBI that is characterized most commonly by symptoms of bothersome epigastric pain or burning, postprandial nausea, fullness and/or early satiety which are often grouped as either epigastric pain syndrome (EPS) or postprandial distress syndrome (PDS).⁶⁹

Available guidelines

The British Society of Gastroenterology (BSG) published guidelines for both the diagnosis and management of FD.⁷⁰ The guideline recommends a trusting physician-patient relationship with an open and empathetic communication, taking a focused history and performing a physical exam for patients presenting with symptoms compatible with FD. The next step is targeted testing including full blood count in patients >55 years of age, celiac serology if there are overlapping IBS-like symptoms, and breath or stool or gastric biopsy testing for Helicobacter pylori infection. Additionally, esophagogastroduodenoscopy, abdominal CT scan and abdominal ultrasound are considered in patients with alarm features such as unintentional weight loss or symptoms that suggest other etiologies such as biliary colic. Table 4 differentiates the tests and treatments applied in uninvestigated dyspepsia, typically esophagogastroduodenoscopy and screening for Helicobacter pylori infection, before considering the diagnosis of functional dyspepsia. There is evidence that, in uninvestigated dyspepsia, prompt endoscopy maximizes cost-, and patient-satisfaction from the patient and insurance perspectives compared with alternative strategies.⁷¹

Table 4. Average costs of different therapeutic options for functional dyspepsia.

Prices of screening and diagnostic tests performed in Washington, DC (selected as an example) were obtained from a publicly available website (https://www.fairhealthconsumer.org/) and include facility fees. Estimates are based on the 80^th percentile and correspond to in-network costs. Prices of medications were obtained from a publically available website (https://www.goodrx.com/) that offers discounted coupons.

Methods to exclude or treat organic dyspepsia
	CPT code/example of treatment	US $
Helicobacter pylori
Breath test	83013	374
Stool	87338	158
Gastric biopsy by	43239	2751
EGD
EGD	43235	2635
Clarithromycin triple treatment for Hp	Pantoprazole (40 mg QD) Clarithromycin (500 mg BID) Amoxicillin (1 g BID)	9.5 / 2 weeks 10.5 / 2 weeks 13 / 2 weeks
Bismuth quadruple therapy for Hp	Pantoprazole (40 mg QD) Bismuth subsalicylate (524 mg QID) Tetracycline (500 mg, QID) Metronidazole (250 mg QID)	9.5 / 2 weeks 8.3 / 2 weeks 50.2 / 2 weeks 11.5 / 2 weeks
Methods for diagnosis and treatment of functional dyspepsia
	CPT code/example of treatment	US $
Gastric emptying scintigraphy	78264	1962
Gastric emptying breath test	0106U	150 to 450
Gastric Accommodation test	78262	2261
Proton pump inhibitor	Pantoprazole (40 mg BID)	19 / month
H2 receptor antagonist	Famotidine (20 mg BID)	11.7 / month
Metoclopramide	Metoclopramide (5 mg TID)	4.0 / month
Central Neuromodulator: TCA or SSRI	Amitriptyline (25 mg QD)	1.6 / month
Pyridostigmine	Pyridostigmine (60 mg TID)	17.0 / month
Buspirone	Buspirone (5 mg TID)	2.7 / month
Ondansetron	Ondansetron (4 mg TID)	25.4 / month
Promethazine	Promethazine (12.5 mg QID)	13.5 / month
FDgard	2 tabs TID	149.7 / month

BID: twice a day; CMS: Centers for Medicare and Medicaid services; CPT: Current Procedural Terminology; EGD: Esophagogastroduodenoscopy; Hp: helicobacter pylori; QD: once a day; QID: four times a day; NA: not available; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressants; TID: three times a day.

After treatment of Helicobacter pylori and lifestyle modifications, first line therapies recommended without any specific testing include acid suppression with proton pump inhibitors (PPI) or H₂ receptor antagonists, a prokinetic followed by central neuromodulators (tricyclic antidepressants). According to the guideline, failure of medical therapy should prompt referral for psychological therapy.⁷⁰ While the guideline reflects a commonly applied algorithm for uninvestigated dyspepsia,⁷² it had been suggested that the identification of symptoms consistent with PDS rather than EPS⁷² should lead to valid measurements of gastric emptying, gastric accommodation, or postprandial satiation during a nutrient drink test to individualize treatment. In fact, the combined United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on FD⁷³ also recommended identification of these two subsets of patients with FD after excluding Helicobacter pylori infection as the cause of dyspepsia. In addition to diet and PPI therapy, the algorithm proposes the use of medications such as prokinetic, 5 HT_1A agonist, and mirtazapine in patients with PDS, or tricyclic antidepressants and behavioral interventions for patients with EPS.⁷³

Health care costs

Despite the presence of such well-developed diagnostic and therapeutic algorithms, FD is associated with high societal burden. In a study that analyzed trends in healthcare utilization, patients who reported functional gastric disorders had more office visits, emergency room visits, hospital admissions, and prescriptions compared to the reference cohort. The mean annual healthcare expenditure cost for patients with functional gastric disorders was estimated to be $12,985, with many expenditures incurred in the management of co-existing medical conditions.⁷⁴ Given that FD is predominantly based on clinical diagnosis in accordance with algorithms in BSG as well as UEG/ESNM guidelines, patients are often offered sequential therapeutic trials in an attempt to identify clinical response. Unfortunately, this approach may lead to prolonged symptoms and decreased quality of life.

The costs of the diverse approaches that may be incurred in patients with functional or uninvestigated dyspepsia are summarized in Table 4 with medication costs discounted as based on prices partly subsidized according to a publicly available website.

Actionable biomarkers in FD

An alternative approach, as in IBS, is to utilize diagnostic tests aimed at ruling out structural conditions as well as identification of abnormal gastric emptying and accommodation which are actionable biomarkers with good performance characteristics¹¹ (Table 2). These test results could then guide the management of patients with FD. While patients with FD could have normal, accelerated, or delayed gastric emptying as well as normal or decreased accommodation, up to 70% of 1,287 patients with symptoms of upper gastrointestinal symptoms had at least one of those abnormalities.⁷⁵ A systematic review of the literature⁷⁶ also documented significant association of slow gastric emptying with the symptoms of nausea, vomiting, bloating, and early satiety/fullness. Patients with slow gastric emptying could benefit from a prokinetic^{77, 78} whereas central neuromodulators such as buspirone⁷⁹ or mirtazapine⁸⁰ might be preferred in patients with decreased accommodation or increased postprandial satiety and weight loss.

Conclusions

IBS and FD are costly diseases; societal, insurer and patient expenditures associated with trials of approved therapies have been well documented in IBS, and it is evident that, from the insurance perspective, starting with global treatments for IBS (central neuromodulators, dietitian-directed low FODMAP, and cognitive behavioral therapy) is more cost saving than starting with on-label prescription drug treatments. Societal guidelines propose first to third tier therapeutic trials with costly medications in IBS. Unfortunately, such prescription drug treatments may not be appropriate or available for some patients.

The costs of treatments for FD are lower unless the patient undergoes upper GI endoscopy to exclude Helicobacter pylori infection even in the absence of alarm symptoms. The alternative utilization of actionable biomarkers is attractive as it may lead to individualized treatment. However, the tests need to be simplified, made more widely available, and validated in terms of their utility based on multicenter trials focused on patient response outcomes in addition to the proof-of-concept studies using biomarkers as pharmacodynamic endpoints emanating from single centers. There is evidence in lower DBGI that a valid biomarker, specifically colonic transit measurement in response to diverse medications that accelerate or delay transit. is predictive of the patient response outcomes measured in phase 2B or phase 3 large multicenter clinical trials³⁵ (Table 3).

In the future, the availability of funding for such validation studies would provide definitive evidence regarding whether the best approach is based on sequential therapeutic trials or use of actionable biomarkers that identify targets for individualized therapy. Such validation would be anticipated to ultimately reduce diverse societal costs including health care utilization and indirect costs of ill health and reduced productivity.