Page 3 – Practical Gastro

Dispatches from the GUILD Conference, Series #65

Diagnosis and Management of Irritable Bowel Syndrome

December 2024 • Volume XLVIII, Issue 12

INTRODUCTION

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

Table 2. Alarm Features³⁹
GI: gastrointestinal; IBD: inflammatory bowel disease.

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)
Amitriptyline Desipramine Imipramine	Tricyclic Antidepressant	523 (8 RCT)	Variable	Constipation/sleep/High Withdrawal rate	RR 0.67 (0.5-0.8)
Fluoxetine Paroxetine	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

Drug	Class	N	Dose	Side Effects	Efficacy (Drug vs. Placebo)
Tenapanor	NHE3 channel Inhibitor	1372 (3 RCT)	50 mg bid	Diarrhea	34 vs. 27%, RR, 0.84 (0.79-0.94)
Plecanatide	Guanylate Cyclase C (GCC) agonist	1632 (3RCT)	3 mg daily	Diarrhea, bloating	RR, 0.87 (0.83-0.92)
Linaclotide	GCC agonist	2443 (3 RCT)	290 mcg/day	Diarrhea, bloating	RR, 0.81 (0.77-0.85)
Lubiprostone	CCI₂activator	1154 (3 RCT)	8 mcg bid	Nausea, diarrhea	RR, 0.88 (0.79-0.96)
Tegaserod	5 HT₄ agonist	2883 (4 RCT)	2 or 6 mg bid	Headache, nausea, diarrhea	35 vs. 24%, RR, 0.87 (0.81-0.93)
PEG	Osmotic	139 (1 RCT)	30 g daily	Bloating, diarrhea	RR, 0.9 (0.66-1.2)
Amitriptyline Nortriptyline Imipramine Desipramine Simipramine	TCA	523 (8 RCT)	Variable	Constipation, sleep	RR, 0.67 (0.54-0.82)
Paroxetine Citalopram	SSRI	7 RCT	Variable	Weight gain, dreams	RR, 0.74 (0.52-1.06)
12 drugs (Cochrane)	Antispasmodics	2983 (22 RCT)	Variable	Dry mouth	RR, 0.67 (0.55-0.80)

Table 4A. AGA Guidelines for IBS-C⁴⁶

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.

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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

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LIVER DISORDERS, SERIES #17

Drug-Induced Liver Injury (DILI): A Practical Review

December 2024 • Volume XLVIII, Issue 12

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 globally^24,7according 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

Risk Factor	Medications
Age
Children	Anticonvulsants Antimicrobials
Older Adults	Nitrofurantoin Amoxicillin-clavulanate Isoniazid
Female Sex	Minocycline Methyldopa Diclofenac Nitrofurantoin Nevirapine
Pregnancy	Tetracycline Methyldopa Hydralazine Antiretrovirals
Diabetes Mellitus	Methotrexate Antituberculosis medications
Alcohol Consumption	Acetaminophen (chronic alcohol use) Methotrexate Isoniazid Anabolic steroids
Drug-drug Interactions	Antituberculosis medications Anticonvulsants

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).

Pattern of Liver Injury	Compounds Associated with DILI
Hepatocellular R ratio ≥5	Fluoroquinolones Isoniazid Macrolides Nitrofurantoin Minocycline Phenytoin Lamotrigine Valproate NSAIDs Diclofenac INF-beta INF-alpha	Anti-TNF agents Immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab) Allopurinol Azathioprine Amiodarone Inhaled anesthetics Sulfasalazine
Cholestatic R ratio ≤2	Amoxicillin-clavulanate Androgen-containing steroids Trimethoprim/Sulfamethoxazole Azathioprine	Fluoroquinolones Phenytoin Sulfasalazine
Mixed R ratio = 2 to 5	Allopurinol Immune-checkpoint inhibitors (early) Fluoroquinolones	Phenytoin Sulfasalazine

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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Nutrition Reviews in Gastroenterology, SERIES #20

Patient-Centered Plant-Based Approach to Diets for Gastrointestinal Disorders

December 2024 • Volume XLVIII, Issue 12

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	Beta-glucan, pectin, guar gum	Guar beans, oats, barley, fruits, cereal brans, berries
Soluble	Non-viscous/ fermentable	– Strong pre-biotics potential – Produce SCFAs to stimulate immune system	Inulin, fructo-oligosaccharides, oligofructose, galacto-oligosaccharides	Chicory root, asparagus, garlic, onion, artichoke
Insoluble/ non-fermentable/ non-viscous	-Alleviate constipation	Cellulose, lignin	Skins of fruits, leafy greens, wheat bran, green beans, quinoa, nuts, flaxseed

Table 2. Roles and Types of Fiber^4,9-11

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
Metabolic dysfunction-associated steatotic liver disease	– Mediterranean diet – Any type of WFPBD	-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 PBD^{28,30,31,32,40,41,44,45,48}

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

Metabolic Dysfunction-Associated Steatotic Liver Disease

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).³⁹MASLD 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.³⁹Diet 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.⁴⁸In 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
Crohnscolitisfoundation.org/patientandcaregivers/gutfriendlyrecipes	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.⁵⁷Older 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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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #19

Gastrointestinal and Nutrition Implications in Cystic Fibrosis

November 2024 • Volume XLVIII, Issue 11

Catherine M. McDonald,

John F. Pohl

Read Article

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.^9,10,11,21Individualized advice and regular nutrition monitoring should continue as part of standard CF care across the lifespan.^{9,10,11,21,25}

Manufacturer	Supplement
Abbott	Ensure^®, Ensure Plus^®, Pediasure^®
Fairlife Elite	1.5 Core Power^®
Kate Farms	Kate Farms Standard^® and Peptide^®
Nature’s One	Pediasmart^®
Nestle	Boost^®, Boost Plus^®, Boost VHC^®, Boost Kid Essentials^®, Nutren Jr^®, Nutren 1.5^®, Nutren 2.0^®

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^®

Vitamin comparison chart available at: https://mvwnutritionals-assets.s3.amazonaws.com/wp-content/uploads/2024/04/11111124/Vitamin-Comparison-Chart-4_11_2024-FINAL.pdf
(last accessed 30 Sept 2024)

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.^10,63,64 Table 5 describes typical PERT dosing.⁶⁵No 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.¹Excessive 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 (Seracal^TM)
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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Dispatches from the GUILD Conference, Series #64

Beyond the Gut: Integrating Mental Health in the Management of Inflammatory Bowel Disease

November 2024 • Volume XLVIII, Issue 11

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.

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from the pediatric literature

Dermatologic Complications in Pediatric Inflammatory Bowel Disease

November 2024 • Volume XLVIII, Issue 11

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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.

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FRONTIERS IN ENDOSCOPY, SERIES #92

Endoscopic Management of Small Intestinal and Colorectal Anastomotic Strictures

November 2024 • Volume XLVIII, Issue 11

Michael B. Andrews,

Douglas G. Adler

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INTRODUCTION

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.^3,10Unfortunately, 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.^15,16However, 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.

References

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16 Santos-Fernandez J, Paiji C, Shakhatreh M, et al. Lumenapposing
metal stents for benign gastrointestinal tract strictures:
An international multicenter experience. World J
Gastrointest Endosc. 2017;9(12):571-578. doi:10.4253/wjge.
v9.i12.571
17 Ferrell M, Mounzer R, Pitea T, Gabbert C. Endotherapy
for distant anastomotic strictures with a twist: reaching new
depths in lumen-apposing metal stent placement. Gastrointest
Endosc. Published online April 8, 2024. doi:10.1016/j.
gie.2024.04.008
18 Axelrad JE, Lichtiger S, Sethi A. Treatment of Crohn’s
Disease Anastomotic Stricture With a Lumen-apposing
Metal Stent. Clin Gastroenterol Hepatol. 2018;16(3):A25-
A26. doi:10.1016/j.cgh.2017.05.016
19 Rejchrt S, Kopacova M, Brozik J, Bures J. Biodegradable
stents for the treatment of benign stenoses of the small
and large intestines. Endoscopy. 2011;43(10):911-917.
doi:10.1055/s-0030-1256405
20 Gkolfakis P, Siersema PD, Tziatzios G, Triantafyllou
K, Papanikolaou IS. Biodegradable esophageal stents for
the treatment of refractory benign esophageal strictures.
Ann Gastroenterol. 2020;33(4):330-337. doi:10.20524/
aog.2020.0482
21 Hong JT, Kim TJ, Hong SN, Kim YH, Chang DK, Kim ER.
Uncovered self-expandable metal stents for the treatment of
refractory benign colorectal anastomotic stricture. Sci Rep.
2020;10(1):19841. Published 2020 Nov 16. doi:10.1038/
s41598-020-76779-8
22 Clifford RE, Fowler H, Manu N, Vimalachandran D.
Management of benign anastomotic strictures following
rectal resection: a systematic review. Colorectal Dis.
FNRUTORNITTIIOENR SIS ISNU EESN DINO GSACSOTPRYO,E SNETRERIEOSL O#9G2Y, SERIES #174
Endoscopic Management of Small Intestinal and Colorectal Anastomotic Strictures
32 PRACTICAL GASTROENTEROLOGY • NOVEMBER 2024
2021;23(12):3090-3100. doi:10.1111/codi.15865
23 Di Giorgio P, De Luca L, Rivellini G, Sorrentino E, D’amore
E, De Luca B. Endoscopic dilation of benign colorectal anastomotic
stricture after low anterior resection: A prospective
comparison study of two balloon types. Gastrointest Endosc.
2004;60(3):347-350. doi:10.1016/s0016-5107(04)01813-9
24 Jain D, Sandhu N, Singhal S. Endoscopic electrocautery
incision therapy for benign lower gastrointestinal tract anastomotic
strictures. Ann Gastroenterol. 2017;30(5):473-485.
doi:10.20524/aog.2017.0163
25 He F, Yang F, Chen D, et al. Risk factors for anastomotic
stenosis after radical resection of rectal cancer: A systematic
review and meta-analysis. Asian J Surg. 2024;47(1):25-34.
doi:10.1016/j.asjsur.2023.08.209
26 Favuzza J. Risk Factors for Anastomotic Leak, Consideration
for Proximal Diversion, and Appropriate Use of Drains. Clin
Colon Rectal Surg. 2021;34(6):366-370. Published 2021
Nov 23. doi:10.1055/s-0041-1735266
27 Slesser AA, Pellino G, Shariq O, et al. Compression versus
hand-sewn and stapled anastomosis in colorectal surgery:
a systematic review and meta-analysis of randomized
controlled trials. Tech Coloproctol. 2016;20(10):667-676.
doi:10.1007/s10151-016-1521-8
28 Surek A, Donmez T, Gemici E, et al. Risk factors affecting
benign anastomotic stricture in anterior and low anterior
resections for colorectal cancer: a single-center retrospective
cohort study. Surg Endosc. 2023;37(7):5246-5255.
doi:10.1007/s00464-023-10002-3
29 Yang FF, Chan RH. Mucus Impaction Related to
Postoperative Anastomosis Site Obstruction: A Rare Case.
Cureus. 2024;16(4):e58048. Published 2024 Apr 11.
doi:10.7759/cureus.58048
30 Araujo SE, Costa AF. Efficacy and safety of endoscopic balloon
dilation of benign anastomotic strictures after oncologic
anterior rectal resection: report on 24 cases. Surg Laparosc
Endosc Percutan Tech. 2008;18(6):565-568. doi:10.1097/
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31 Biraima M, Adamina M, Jost R, Breitenstein S, Soll C.
Long-term results of endoscopic balloon dilation for treatment
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2016;30(10):4432-4437. doi:10.1007/s00464-016-4762-8
32 Thomas-Gibson S, Brooker JC, Hayward CM, Shah SG,
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meg.0000059110.41030.bc
33 Lamazza A, Fiori E, Schillaci A, Sterpetti AV, Lezoche
E. Treatment of anastomotic stenosis and leakage after
colorectal resection for cancer with self-expandable metal
stents. Am J Surg. 2014;208(3):465-469. doi:10.1016/j.amjsurg.
2013.09.032
34 Caruso A, Conigliaro R, Manta R, et al. Fully covered selfexpanding
metal stents for refractory anastomotic colorectal
strictures. Surg Endosc. 2015;29(5):1175-1178. doi:10.1007/
s00464-014-3785-2
35 Xu A, Banerjee D, Barlass U, Sánchez-Luna SA. Long-term
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2024;17(1):e257706. Published 2024 Jan 5. doi:10.1136/
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36 Kankotia RJ, Kwon RS, Philips GM, et al. Comparison of
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37 Repici A, Pagano N, Rando G, et al. A retrospective analysis
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s00464-012-2762-x
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40 Jain D, Sandhu N, Singhal S. Endoscopic electrocautery
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strictures. Ann Gastroenterol. 2017;30(5):473-485.
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Dispatches from the GUILD Conference, Series #63

Functional Medicine and Inflammatory Bowel Disease: An Evolving New Approach to IBD Care

October 2024 • Volume XLVIII, Issue 10

Thomas M. Strobel,

Dawn B. Beaulieu

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Inflammatory bowel disease is a global disease with incidence and severity rising in Western and industrialized cultures. This increase in autoimmune diseases such as IBD can be influenced by many things: genetics, environment, nutrition, and lifestyle. Functional Medicine is a science-based, personalized approach to healthcare that focuses on understanding the underlying root causes of disease and illness. It seeks to uncover the complex connections between genetics, environmental factors and lifestyle choices contributing to disease manifestation and progression. The principles of Functional Medicine can be utilized to help patients with IBD by making connections between a person and modifiable lifestyle factors. Using a multi-modal functional medicine-based program for IBD, patients can experience improvement in both symptoms and gut inflammation. As the treatment of IBD patients evolves, Functional Medicine can play a significant role in the overall care of the IBD patient resulting in improvement in quality of life and patient outcomes.

Introduction

In the early 1990s, a group in Victoria, British Columbia, Canada, laid the groundwork for what would become The Institute for Functional Medicine. The goal was to merge traditional medical care with advanced scientific research. This initiative was inspired by the historical concept of functional medicine, dating back to the 19th century. Functional medicine is a holistic, science-based, personalized approach to healthcare that focuses on understanding the underlying causes of disease and illness. It views the body as an interconnected system rather than separate, individual parts. The principles of functional medicine are rooted in lifestyle choices and nutrition with the goal of restoring health and improving overall function. It is not a substitute for conventional medicine, but the principles can be applied as adjunct care to conventional medicine and serve as a model for the management of chronic, complex diseases. In functional medicine each patient is an n-of-1 and rejects the “one size fits all” concept of care.¹² Functional medicine care aims to improve clinical outcomes and quality of life, create balance and self-discovery, and guide the practice of preventative healthcare.

Inflammatory Bowel Disease (IBD) is an umbrella term that encompasses the diseases Crohn’s disease (CD) and ulcerative colitis (UC). It affects millions globally and presents a significant burden to individuals and healthcare systems alike. Traditional treatment modalities have predominantly focused on symptom management through pharmacological interventions. Recently, the use of functional medicine as a transformative approach to IBD management has begun emerging.

Conventional medicine focuses on arriving at a diagnosis and treating symptoms. It is disease-oriented, provider focused, and treatment is symptom-based and disease-specific. Functional medicine practitioners attempt to understand why the disease occurred and notice the linkages between lifestyle, nutrition, mental health, socioeconomic influences, and environmental factors. It treats the body and focuses on root causes while encouraging prevention. In functional medicine, every person has their own origin story.

We live in an era where chronic disease is an epidemic. Roughly 50% of adults have at least one chronic health condition and 25% have 2 or more.^1,2 With the rise in incidence of chronic disease, costs have risen as well. Chronic disease management accounts for 86% of all healthcare costs, and this figure continues to grow.³ The incidence and prevalence of IBD continues to rise globally in Western and newly industrialized Asian countries.⁴ It is becoming quite clear that pharmacologic treatment alone is not enough for this growing epidemic. Our pharmacologic advances in the treatment of IBD over the past 20 years have grown, but the disease is not slowing down. It is unlikely medications alone are going to reverse this trend.

Genetics, the Immune System, and the Environment

The pathogenesis of IBD is best described as an interplay of three domains: genetics (notably, first degree relatives), the innate and adaptive immune system, and environmental exposures. With this in mind, we can further divide these contributors into modifiable and non-modifiable factors. Diet and lifestyle can modify both the risk of developing IBD and overall severity of disease. Lifestyle choices, such as smoking and exercise, contribute to the environment you live in while your diet influences the biochemical makeup and microbiome of the gut. Both factors are the focal points of a functional medicine practitioner’s evaluation and management. Functional medicine challenges genetic determinism in that diet, lifestyle, and our environment can determine health outcomes.¹²

Disease Modifiers and Environmental Risk Factors

The increase in IBD prevalence may partially be explained by modifiable lifestyle factors. For example, changes in the composition of the gut microbiome can negatively or positively modify the risk for IBD. While certain strains such as Bifidobacterium and Firmicutes are protective, Escherichia coli and Enterobacteriaceae are known to increase the risk of IBD. Higher intake of ultra-processed foods such as cheeses, sweets, and pastries are associated with a higher risk of Crohn’s disease.⁵ Chen et al. showed a nearly 2-fold increase in the risk of CD in patients with higher intake of ultra-processed foods. Patients with pre-existing IBD have also been shown to have higher intake of ultra-processed foods and are four times as likely to have had an IBD-related surgery. Sasson and colleagues expertly described the causation between diet and inflammation.⁶ Certain dietary patterns and nutrition status can modify the diversity of the microbiome, increase gut permeability, and alter immune cell dysfunction. All of these contribute to the development and progression of IBD. In a functional medicine model, we think about things in relation to the mnemonic DIGIN: Digestion, Intestinal permeability, Gut microbiome, Inflammation, and Nervous system.

The Functional Medicine Roadmap: The 5 R’s

In addition to diet, other environmental triggers such as smoking, antibiotic use in childhood, oral contraceptives, history of appendectomy, and vitamin D deficiency have all been shown to increase the risk of IBD. Conversely, breastfeeding and tea or coffee consumption have been shown to be effective in lowering risk.^4,7 For children with CD, those who had exposure to maternal smoking were at higher risk of hospitalization within the first 3 years of diagnosis. Conversely, children with CD who were breastfed as infants were less likely to progress to structuring or penetrating phenotypes.⁸ These are just a few of the many examples of how modifiable lifestyle factors influence the risk and severity of IBD.

Functional medicine focuses on the effects of sleep, exercise, nutrition, stress, and human relationships and their contributions to the overall health of the human body. For IBD, a functional medicine model can promote microbiome diversity resulting in a healthy gut microenvironment. “The 5 R’s” is a functional medicine framework for gut restoration: Remove, Replace, Re-inoculate, Repair, and Re-balance.

In the REMOVE phase, the goals are to identify and remove dietary triggers, consider any current medications that can trigger dysbiosis or inflammation, and examine other dietary and lifestyle factors that drive dysbiosis. In some patients an elimination diet is helpful to promote body awareness of food, identify food triggers, use phytonutrients to heal the gut and support a healthy microbiome. The elimination diet focuses on common triggers of inflammation including dairy, eggs, gluten, peanuts, shellfish, beef/red meat, soy, corn, refined sugar, coffee/caffeine, and alcohol. Any diet changes or elimination diets should always be supervised by an experienced functional medicine provider or trained dietitian (Figure 2).

In the REPLACE phase, the goals are to support digestion and health by replacing nutrients that are essential to gut healing while focusing on dietary and lifestyle factors that promote wellness. This can be done through nutrients (example: vitamin D, zinc, magnesium, B12), supporting digestion, and focusing on dietary and lifestyle factors that promote health. In the REINOCULATE phase, the focus is to provide care plans to build a healthy microflora and look at the utility of using probiotics, prebiotics, synbiotics (prebiotics + probiotics), post biotics (inanimate microorganisms and their healthy byproducts), and short chain fatty acid as potential tools for care with the goal of supporting disordered intestinal permeability and reversing dysbiosis. It is helpful to remember that one cannot out supplement a bad diet and the “food first” approach should be step one when thinking in terms of how to REINOCULATE the gut.

Diet can either drive dysbiosis or promote a healthy microbiome.⁹ In the REPAIR phase, we add back healthy nutrients to support cellular health and prevent inflammation. Vitamin D, L-glutamine, curcumin, botanicals, and immunoglobulins are a few examples that may repair damage from chronic inflammation. Increasing and optimizing phytonutrients are a key component of the REPAIR phase. These nutrients are derived from colorful fruits and vegetables. The aim should be for at least nine servings of phytonutrient-rich foods daily. This is much more than the average American, who gets 2-4 servings daily. Interestingly, each color of food comes with its own benefits in addition to anti-inflammation and vascular health. Eat the rainbow is a term often used in functional medicine. Red and orange foods typically confer anti-bacterial effects while promoting cardiovascular and brain health, prostate health, and cellular protection. Red foods also provide anti-cancer effects. Yellow foods promote digestive, immune, and eye health while supporting anti-inflammatory and protective cellular effects. Green foods support metabolic and hormonal health. Blue, purple, and black foods support liver and digestive health. White, tan, and brown foods support immunity, metabolism, and digestion. IBD patients often cannot tolerate a high fiber diet so this goal can be difficult in patients with active disease. Start slow and go slow should be the guidance given to patients with IBD. Be mindful that active inflammation and those IBD patients with strictures need to be on a low fiber diet. Each patient is unique in their inflammatory burden and disease severity, so each dietary plan should also be personalized to them.

If we can recognize that certain foods exert positive influence on overall health on a biochemical level, then such foods can be thought of as medicine. For example, quercetin and vitamin E are known inhibitors of phospholipase A2 – a precursor to arachidonic acid and prostaglandins, which promote inflammation. Quercetin, turmeric, ginger, green tea, and Boswellia are all inhibitors of 5-LOX, a precursor to leukotrienes. Other foods such as garlic, willow, and barberry are COX-2 inhibitors, which downregulates prostaglandin production. All of these are examples of the anti-inflammatory properties of certain foods. Some of these foods have been studied as treatment for IBD. Gut specific turmeric in combination with Qing Dai are examples that have shown promise as a gut-specific treatment for IBD.¹³

The last phase of the 5 R’s is REBALANCE, but this should be a focus throughout the IBD care plan from day one. IBD patients are often in a “fight or flight” mode with sympathetic overdrive. Trying to build resilience, reducing stress, and relaxation training should be a focus of care. Some examples of tools to rebalance and support a healthy gut microbiome are mindfulness, stress management, hypnotherapy, heart rate variability tools, and yoga nidra. Engaging in positive lifestyle modifications are the most cost-effective and safe treatments available and are often overlooked in traditional medical care.

Modifiable Lifestyle Factors

How a patient lives is often more important than any time spent with a provider. Chronic disease states often involve multi-system dysfunction. In addition to nutrition, the foundations of health in functional medicine are sleep and relaxation, exercise and movement, stress, and relationships. Data has shown that sleep loss appears to be associated with changes in the microbiota and insomnia can alter the gut microbiome. There are numerous physiologic changes associated with inactivity. Helping patients embrace an active lifestyle will benefit overall wellness. Moreover, stress management can help increase resilience and optimize immune function. Lastly, human relationships play a profound role in human biology. The social threads that connect us are often more impactful and powerful than the genetic threads.

A real-world example of functional medicine in practice is the Functional Medicine Clinic (FMC) at Vanderbilt University Medical Center. This program utilizes one-on-one and shared group visits to implement the principles of functional medicine. In the one-on-one visits, patients meet with an FMC provider, a wellness coach, and a dietician. During these visits, patients tell their own story of their health and disease. Clinicians elicit key factors predisposing to disease such as their genetic risk and environmental factors, looking for triggering events and mediators or perpetuators of inflammation, such as medication use or past infections. Focusing on modifiable lifestyle behaviors such as sleep, exercise, nutrition, stress, and relationships is the backbone of the program, emphasizing that how a patient lives is vital to their overall health and wellness.

In shared group visits, patients participate in group-based educational sessions every other week over 12-weeks. Each session includes a nutrition and a lifestyle intervention. Topics are described in Figure 3, and all of these are aimed at addressing the root causes of chronic disease. Another program available is a 6-week Nervous System Regulation Program (NSRP). Patients make weekly visits, and sessions are broken down into educational topics followed by an intervention (Figure 4).

The structured FMC program has demonstrated clinical improvement in IBD patient reported outcomes in measures of fatigue, sleep, global symptoms, and IBD-related symptoms.¹⁰ Additionally, a small cohort in the FMC program who had elevated fecal calprotectin levels (a marker of gut-specific inflammation), normalized following completion of the program, with each participant citing motivation to continue the changes they learned from the FM program.¹¹ In the NSRP, patients have demonstrated improvement in global fatigue and global symptoms.¹⁴

The benefits of functional medicine may best be described with the following clinical vignette: A woman who was diagnosed with UC after a diarrheal illness and while taking NSAIDs had poor clinical response to conventional mesalamine therapy. Per convention, she was offered escalation to biologic therapy, but she instead expressed willingness to try a functional medicine approach. Listening to her story and timeline, the fundamental issues that stood out were the following: she slept only 5-6 hours per night, was a chronic NSAID user, ate mostly processed foods and drank alcohol weekly. She had limited exercise and a long history of antibiotic use from recurrent UTIs. Additionally, she reported stress from her parents who divorced in high school, and she was bottle-fed as a baby. Upon completion of her personal 5R program, she had marked improvement in symptoms, normalization of a vitamin D deficiency, and normalization of inflammatory markers including fecal calprotectin.

Personalized Treatment Plans

A cornerstone of functional medicine is personalized treatment plans. In other words, it is tailored to the individual’s specific health needs and goals. This might include targeted supplementation to address nutrient deficiencies, nutritional changes to support gut health, and natural compounds with anti-inflammatory properties. These personalized interventions are designed to restore balance and functionality to the body and promote long-term remission and improved quality of life for IBD patients.

Functional Medicine and the Future of IBD Care

Functional medicine does not stand in opposition to conventional treatments, but rather complements them. It supports that a portion of health outcomes are influenced by the interaction between genes that are impacted by lifestyle, nutrition, environment, and human relationships. Research has shown thus far that functional medicine can improve outcomes in conditions such as irritable bowel syndrome, inflammatory arthritis, and Hashimoto’s thyroiditis. A synergistic approach that consists of pharmacological treatments and functional medicine strategies can provide the most comprehensive care for IBD patients. It gives patients a more proactive role in the management of their health. This model encourages collaboration between patients and healthcare providers.

References

1. Ward BW, Schiller JS, Goodman RA. Multiple chronic conditions among US adults: a 2012 update. Prev Chronic Dis. 2014;11: E62.

2. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459-1544.

3. Leroy L, Bayliss E, Domino M, et al. The Agency for Healthcare Research and Quality Multiple Chronic Conditions Research Network: overview of research contributions and future priorities. Med Care. 2014;52 Suppl 3:S15-22.

4. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-321.e2.

5. Chen J, Wellens J, Kalla R, et al. Intake of Ultra-processed Foods Is Associated with an Increased Risk of Crohn’s Disease: A Cross-sectional and Prospective Analysis of 187 154 Participants in the UK Biobank. J Crohns Colitis. 2023;17(4):535-552.

6. Sasson AN, Ananthakrishnan AN, Raman M. Diet in Treatment of Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2021;19(3):425-435.e3.

7. Ananthakrishnan AN, Kaplan GG, Bernstein CN, et al. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus. Lancet Gastroenterol Hepatol. 2022;7(7):666-678.

8. Lindoso L, Mondal K, Venkateswaran S, et al. The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn’s Disease in Children. Am J Gastroenterol. 2018;113(10):1524-1529.

9. Myles IA. Fast food fever: reviewing the impacts of the Western diet on immunity. Nutr J. 2014;13:61.

10. Strobel TM, Nguyen C, Riggs T, et al. Functional Medicine Approach to Patient Care Improves Sleep, Fatigue, and Quality of Life in Patients with Inflammatory Bowel Disease. Crohns Colitis 360. 2022;4(3).

11. Strobel, TM. A Functional Medicine Program for Patients with Inflammatory Bowel Disease Improves Fecal Calprotectin Levels. Poster presentation: American College of Gastroenterology Annual Meeting 2023; October 22, 2023; Vancouver, BC.

12. Bland J. S. (2022). Functional Medicine Past, Present, and Future. Integrative medicine, 21(2), 22–26.

13. Ben-Horin S, Salomon N, Karampekos G, Viazis N, Lahat A, Ungar B, Eliakim R, Kuperstein R, Kriger-Sharabi O, Reiss-Mintz H, Yanai H, Dotan I, Zittan E, Maharshak N, Hirsch A, Weitman M, Mantzaris GJ, Kopylov U. Curcumin-QingDai Combination for Patients with Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial. Clin Gastroenterol Hepatol. 2024 Feb;22(2):347-356.e6.

14. Emily Spring, Thomas Strobel, Sarah Campbell, Randi Robbins, Julia Carlson, Sydney Elliot, Stephanie Ardell, Dawn B. Beaulieu. Nervous System Regulation Program Improve Fatigue and Medical Symptoms in Inflammatory Bowel Disease Patients. Poster presentation: IFM AIC. May 2024; Las Vegas, NV

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Nutrition Reviews in Gastroenterology, SERIES #18

Management of CRBSI: How to Extend the Lifeline for Home PN Patients

October 2024 • Volume XLVIII, Issue 10

Yichun Fu,

Edwin McDonald

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Catheter-related bloodstream infections (CRBSI) are a dreaded complication for patients who require home parenteral nutrition (HPN) for survival. Patients with CRBSI usually present with fever, chills, and malaise. Clinicians should maintain a high level of suspicion for CRBSI to prevent severe illness and mortality. Healthcare providers should obtain blood cultures from both peripheral veins and the central venous access device (CVAD) at the first sign of infection. Antibiotic selection depends on the severity of the infection and antibiotic susceptibilities. Catheter salvage and preserving venous access have been proven successful in CRBSI. Establishing an institution-specific protocol for education, prevention, and treatment of CRBSI is essential for improving long-term outcomes of patients dependent on HPN.

Introduction

Home parenteral nutrition (HPN) is an alternative form of nutrition when enteral nutrition is infeasible or insufficient.^1,2 HPN improves quality of life and disease outcomes by optimizing patients’ nutritional status.¹ In the United States, an estimated 20,883 adult patients received HPN in 2013 based on Medicare and Medicaid Services data.³ Catheter-related bloodstream infection (CRBSI) is a significant cause of morbidity and mortality in patients receiving parenteral nutrition (PN).^4–9 The infections develop after microbial biofilms form on the surface of the central venous access devices (CVAD).¹⁰ Studies have shown that patients receiving PN experience CRBSI at higher rates compared to other patients with chronic infusion needs.^3–5,11,12

Many interventions reduce CRBSI and its mortality in the HPN population. Further, several societies have issued CRBSI guidelines, including the European Society for Clinical Nutrition and Metabolism (ESPEN), the American Society for Parenteral and Enteral Nutrition (ASPEN), and the Infectious Diseases Society of America (IDSA).^2,9,13 This review aims to provide an overview of the standard practices in diagnosing, treating, and preventing CRBSI.

Epidemiology and Risk Factors

According to ASPEN’s Sustain registry of both adult and pediatric HPN populations, black and male patients were more likely to have at least one episode of CRBSI.¹⁴ Rates of CRBSI vary due to different diagnostic definitions, heterogeneity of study populations, and variability in institutional experience. In a meta-analysis, Reitzel et al. reported the incidence of CRBSI as 0.0-11.89 per 1000 CVAD days.¹² Known patient risk factors for CRBSI include having an ostomy or wound, underlying malignancy, and body mass index less than 18.5 kg/m.^2,^15,16 Similarly, a retrospective study of 155 HPN patients established male sex and underlying malignancy as independent risk factors for CRBSI (HR 1.69 and 2.38 respectively, p= 0.009, <0.001).¹⁷ In a Danish study of HPN patients, peripherally inserted central catheter (PICC) lines were associated with higher CRBSI rates (1.43 ± 0.20 vs. 0.95 ± 0.390, per 1000 CVAD days, p < .001) and shorter time intervals (83.91 ± 93.754 vs. 297.21 ± 386.910, p < .001) to a CRBSI episode compared to tunneled catheters.¹⁸ Additionally, using intravenous lipid emulsion (ILE) more than twice weekly and catheters with multiple lumens may increase CRBSI.¹⁶

Making the Diagnosis

Promptly diagnosing CRBSI is crucial. However, diagnosing CRBSI is challenging due to multiple factors, including variable bacteria culture methods and lack of CVAD tip cultures when attempting to salvage the CVAD. Practitioners should maintain a high suspicion for CRBSI when patients report fever, rigor, and malaise, especially within 30 minutes of initiating an infusion.⁴ However, clinical findings alone do not reliably establish a diagnosis. Fever and hypotension are sensitive but not specific. Purulent drainage at CVAD sites may solely indicate an exit-site infection without a concomitant bloodstream infection.¹³ Further, an observational study of 548 adult patients on HPN at a Danish center employed six strict microbiological criteria based on different sources of blood culture methods. Out of 3,188 blood culture episodes obtained for clinical signs of infection, a mean blood culture positivity rate was only 40%, with 30% fulfilling a CRBSI diagnosis.¹⁹

When there is concern for CRBSI, it is imperative to obtain blood cultures before initiating antibiotics to diagnose CRBSI definitively (Figure 1). According to the IDSA, patients should have two sets of blood cultures drawn, with at least one set drawn percutaneously.¹³ Notably, CVAD and percutaneous blood cultures have better negative predictive values than positive predictive values. Hence, a positive percutaneous culture must be interpreted within the clinical context, while a negative percutaneous culture is better at excluding a CRBSI (Table 1).^13,20

Culturing the CVAD tip with quantitative or semi-quantitative methods is the most reliable approach to diagnosing CRBSI, but it is not readily available in many laboratories. Quantitative cultures utilize the highly accurate pour plate method.^4,13 According to the pour plate method, CRBSI occurs when CVAD and percutaneous cultures yield the same organisms, with CVAD colony counts at least 3-fold greater than percutaneous counts.¹³ The differential time to positivity method is widely available among qualitative cultures. Microbial growth from the central CVAD blood sample occurring at least 2 hours earlier than the percutaneous blood sample provides a comparably accurate diagnosis to quantitative methods.^13,21,22 However, qualitative methods may falsely interpret contamination as an infection.⁴ The IDSA guidelines recommend culturing the tip or a segment of the CVAD only when CRBSI is confirmed.¹³ However, many patients require long-term access. A recent study showed that CVAD tip culture may not change antibiotic management when paired blood cultures confirm a CRBSI.²³ Therefore, septic shock or failed CVAD salvage should prompt performing CVAD tip cultures.

Finally, diagnosing certain pathogens requires specific blood culture protocols. A single blood culture growing coagulase-negative staphylococcus species necessitates additional blood samples from both the CVAD and a peripheral vein to rule out contamination. Patients with Corynebacterium, Bacillus, and Micrococcus species also require at least two positive blood cultures from different sites to secure a diagnosis.¹³ Malassezia furfur is a lipophilic fungus within normal skin flora that is difficult to detect with routine blood culture methods. For patients with unexplained septic shock, it is important to perform a catheter tip culture on Dixon agar to rule out Malassezia furfur fungemia.^24,25

Management of CRBSI

Antibiotic Selection and Duration

After the appropriate blood cultures are obtained, intravenous antimicrobials should be started immediately in patients with signs of sepsis. The initial therapy should be tailored to the severity of the patient’s clinical condition, the most likely pathogens, and the likelihood of resistant organisms based on the patient’s history and the local antimicrobial resistance patterns. Coverage for gram-positive and gram-negative species with vancomycin and a fourth-generation cephalosporin is generally necessary.¹³ Neutropenia, critical illness, or a history of multi-drug resistant pathogens warrant coverage for Pseudomonas aeruginosa. If the patient has a femoral CVAD and septic shock, empiric treatment should cover gram-negative bacilli and Candida species. Patients who develop severe sepsis should receive coverage for Candida.¹³

Following pathogen identification, the decision to remove or retain the CVAD should occur, as well as distinguishing complicated CRBSI from uncomplicated CRBSI. Complicated infections include those with suppurative thrombophlebitis, endocarditis, and osteomyelitis.

The IDSA guideline in 2009 provides detailed approaches to specific pathogens. Notably, the most common causes of CRBSI are coagulase-negative staphylococci. Most staphylococci exhibit methicillin resistance. Regardless of resistance, staphylococci infections can be generally treated with 14 days of antibiotics if the CVAD is retained and 5-7 days if the CVAD is removed.¹³ Staphylococcus lugdunesis and Staphylococcus aureus CRBSI require CVAD removal and generally 4-6 weeks of antibiotic treatment. Patients with S. lugdunesis and S. aureus are eligible for a shorter duration of antibiotics (2 weeks minimum) if they do not have diabetes, immunosuppression, prosthetic intravascular device, or complicated infections. These patients must resolve bacteremia within 72 hours of antibiotic initiation and a trans-esophageal echocardiogram (TEE) to ensure the absence of valvular vegetations. For CRBSI with Enterococcus species, ampicillin is the antibiotic of choice in non-resistant cases. In the presence of resistance, vancomycin is appropriate. The treatment is generally 7-14 days with CVAD retention. Signs or risks of endocarditis warrant evaluation with TEE. Critically ill patients with a history of gram-negative bacilli require two antibiotics of different classes with gram-negative activity to cover multidrug-resistant species. In addition, patients with a Candida CRBSI should have an ophthalmologic exam to assess for Candida endophthalmitis—patients on PN are at particular risk (odds ratio 6.02, interval 3.58-13.36).^26,27 Although societal guidelines recommended CVAD removal in S. aureus, Pseudomonas, and fungal species, many HPN patients struggle with limited vascular access sites. As such, there are cases of successful CVAD salvage in Staphylococcus aureus, Pseudomonas, and Candida species.^28,29

When narrowing the antibiotic coverage, one should take special consideration in patients with short bowel syndrome because of decreased absorption of many oral antimicrobial therapies. Some patients, such as those having sufficient length of jejunum in continuity with more than half of the colon, may have adequate medication absorption.^30,31 In general, micro-emulsified and liquid formulations have better absorption, while lipid-soluble medications are often poorly absorbed.^31,32 Certain medications with high solubility and high permeability, such as levofloxacin and metronidazole, have better absorption in patients with short bowel.³¹ Two systematic reviews similarly showed adequate absorption of metronidazole and fluconazole, whereas cephalexin, clindamycin, and trimethoprim-sulfamethoxazole had decreased absorption despite achieving therapeutic levels.^30,32,33 In contrast, ciprofloxacin and gentamicin had decreased bioavailability.^32,33 Comprehensive data in this area is limited as patients’ anatomy varies. Individualized drug monitoring and subsequent dose titration are recommended. In addition, patients with severe dysmotility or bowel obstruction may also have difficulty tolerating oral antibiotics and require intravenous alternatives.

CRBSI Complications and Disseminated Diseases

Several severe complications of CRBSI require additional testing and management, including suppurative thrombophlebitis, endocarditis, and osteomyelitis. Suppurative thrombophlebitis entails a venous thrombus with persistent bacteremia despite at least three days of antimicrobial therapy. Radiographic evidence of the thrombus is necessary for the diagnosis. Patients should receive a minimum of 3-4 weeks of antibiotics. If the superficial vein is purulent or the infection extends beyond the vessel wall, the vessel should be surgically resected. The benefit of antithrombotic agents such as heparin is not clear.¹³

Patients with persistent bacteremia and prosthetic valves or implanted cardiac devices (pacemakers) should have endocarditis excluded with a TEE. TEE should happen at least one week from the initial positive blood culture to ensure the test’s sensitivity. Notably, a negative transthoracic echocardiogram does not exclude endocarditis.¹³

Back pain, joint tenderness, or swelling raise the suspicion for osteomyelitis or septic arthritis in CRBSI. Serum biomarkers such as erythrocyte sediment rate and C-reactive protein are highly sensitive for osteomyelitis, but establishing the diagnosis requires radiographic studies such as magnetic resonance imaging.³⁴ In septic arthritis, synovial fluid analysis and cultures are necessary.³⁵ Treatment of osteomyelitis typically involves 6-8 weeks of parenteral or highly bioavailable oral antibiotics. Likewise, both 2-4 weeks of antibiotics and surgical drainage are necessary for managing septic arthritis.^34,36,37

Management of the CVADs

Septic shock, port abscesses, complicated CRBSI, or certain organisms, including S. aureus, P. aeruginosa, fungi, or mycobacteria, warrant removal of long-term CVAD.^2,13 Otherwise, IDSA and ESPEN guidelines support CVAD salvage since patients with HPN often require long-term venous access.^2,13 Of note, two studies did show comparable success rates of CVAD salvage in S. aureus infections.^28,29 Antibiotic lock therapy (ALT) may facilitate CVAD salvage. Ampicillin, cefazolin, and vancomycin locks are appropriate for gram-positive organisms. Cefazolin, ciprofloxacin, and gentamicin locks are usually suitable for gram-negative organisms. Tailoring line lock therapy to sensitivities from culture results is common.³⁸ In various institutional protocols, the duration of ALT ranged between 3 and 28 days.^29,38 The 2009 IDSA guidelines recommend ALT for 7-14 days in CVAD salvage with re-instillation every 24 hours, while the ESPEN guidelines in 2023 recommend 14 days of ALT with systemic antibiotics.^2,13 The success rates for salvage vary between 60% and 80%, with 53% of the patients CRBSI-free at one year.^38,39 Studies define successful salvage as clinical resolution of infection, negative blood cultures for 48 hours, and no evidence of CRBSI at 90 days after completing treatment.⁴ While it is possible to salvage CVADs, CVAD salvage is associated with higher rates of new infections than CVAD removal.³⁹

Salvage or wire exchange of a CVAD remains a viable option if patients have limited venous access sites or significant risks for procedural complications.⁴⁰ The overall success rate for CVAD salvage depends on the offending organisms: it ranges from 14.2% for Candida species, 26.7% in methicillin-resistant S. aureus, to 86.8% in methicillin-sensitive S. aureus.²⁸ The re-infection rate within 30 days was 4.4% in one study.²⁹ In the case of wire exchange, an antibiotic-impregnated CVAD is preferred.¹³ Therefore, salvaging or exchanging a CVAD is often a multidisciplinary decision with interventional radiology and infectious disease providers. Finally, inserting a new CVAD should occur after blood cultures are negative for 2-3 days in patients who underwent CVAD removal, per IDSA guidelines.¹³ Conversely, ESPEN recommends waiting 5-10 days after the first negative blood culture result or until the completion of the systemic antibiotic therapy before placing a new CVAD.²

Definition Met	Additional Criteria
Positive catheter tip culture	None required
Positive catheter blood culture and percutaneous culture with identical microorganisms	The colony count of the catheter specimen is at least 3-fold greater than the colony count from peripheral blood OR The catheter blood culture grows the organism at least two hours before the percutaneous culture
Percutaneous blood cultures and positive catheter tip with identical microorganisms	None required

Table 1. Criteria for CRBSI Diagnosis

Management of Parenteral Nutrition

During the initial evaluation for CRBSI, it is reasonable to hold PN and avoid accessing the retained CVAD. It is safe to resume PN after 72 hours of negative blood cultures following the initiation of appropriate antibiotic therapy.^29,38,39 Some institutions also withhold intravenous lipid emulsions (ILE) and continue a lipid-free PN solution when a patient has fever, leukocytosis, or sepsis but no evidence of bacteremia. The concern that ILE increases the risk of CRBSI or worsens CRBSI outcomes underlies this practice. Historical studies suggest intravenous sunflower and safflower oil promote the growth of bacteria and Candida. Several early prospective studies showed a higher odds ratio of infection with ILE containing PN.^41,42 Mundi et al. summarized several potential mechanisms for the increased risk of infection associated with ILE.³ Notably, ILE affects cell membrane fluidity and decreases the clearance capacity of the reticuloendothelial system, both of which can promote pro-inflammation.^43–45 However, in a prospective study with over 4000 patients, receiving ILE did not significantly contribute to bacteremia after adjusting for baseline characteristics.⁴⁶ Another retrospective study showed that ILE was not associated with higher rates of CRBSI, but patients with ILE had more frequent bloodstream infections from gastrointestinal translocation.⁴⁷ In addition, in a meta-analysis comparing the growth ratios of various species, only a portion of species survived exclusively in lipids. In contrast, some species rapidly grew in lipid-containing and lipid-free media.⁴⁸ Therefore, no substantial evidence supports withholding lipids in the case of suspected bacteremia or sepsis.

Topic	Teaching Points
Catheter Care	• Hand hygiene • Aseptic technique – catheter flushing, preparation of the infusion bag, connection, and disconnection • Cleansing the catheter hub • Catheter cap placement and removal • Catheter insertion site care – dressing and line securement • Recognition of catheter complications
Home Environment	• Setting up a clean, hard (non-porous) area for aseptic infusion bag preparation • Restriction of animals from the area • Sanitary water supply • Safe refrigerated storage and inspection of infusion bags • Clean storage of infusion supplies
Patient-Purchased Supplies	• Liquid hand soap • Hand sanitizer • Paper towels • Antibacterial wipes

Table 2. Sample Patient Education Checklist^54,55

Prevention of CRBSI

Strategies for preventing HPN-associated CRBSI target known risk factors for CRBSI. For example, using a tunneled CVAD with the lowest number of lumens necessary may decrease CRBSI.^14,49 Another strategy for mitigating CRBSI is minimizing the frequency of accessing CVAD lumens by designating their use solely for PN or antibiotics.¹⁶ ESPEN guidelines recommend taurolidine line locks for the primary prevention of CRBSI.² Several prospective studies demonstrate that taurolidine is superior to placebo and other line locks in preventing CRBSI and biofilm formation. Taurolidine is also cost-effective and has few adverse reactions.⁵⁰^–⁵² Taurolidine line locks are currently unavailable in the United States. Conversely, the IDSA and ESPEN guidelines recommended against using ethanol locks to prevent CRBSI due to systemic toxicity and its potential to occlude or damage the CVAD.^2,13 Studies of line locks against Candida biofilms are mostly still in the pre-clinical stage.⁵³

Clinician and patient education also play a crucial role in preventing CRBSI (Table 2).⁵⁰^–^52,54,55Keohane et al. showed that teaching from a trained nurse decreased CRBSI rates from 11.5% in patients with tunneled CVADs to 4%.⁴⁹ In an Italian center, detailed training for HPN patients reduced CRBSI by 50% (6/1000 CVAD days to 3/1000 CVAD days, p<0.005) compared with standard education. In a study by Reimund et al., CRBSI incidence decreased since the opening of a dedicated HPN center, and the rates were inversely related to the years of experience of the nutrition support team.⁵³

Conclusion

Clinicians should employ accurate and prompt diagnostic and management tools to diagnose, treat, and prevent CRBSI and its complications in patients with PN. CVAD salvage is an evidenced-based strategy for preserving venous access. There are ongoing studies regarding effective CRBSI prevention strategies. A dedicated nutrition support team and institution-specific protocols can significantly reduce the risk of CRBSI in patients with PN.

References

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16. Buchman AL, Opilla M, Kwasny M, Diamantidis TG, Okamoto R. Risk Factors for the Development of Catheter-Related Bloodstream Infections in Patients Receiving Home Parenteral Nutrition. J Parenter Enter Nutr. 2014;38(6):744-749.

17. Elfassy S, Kassam Z, Amin F, Khan KJ, Haider S, Armstrong D. Epidemiology and Risk Factors for Bloodstream Infections in a Home Parenteral Nutrition Program. J Parenter Enter Nutr. 2015;39(2):147-153.

18. Bech LF, Drustrup L, Nygaard L, et al. Environmental Risk Factors for Developing Catheter-Related Bloodstream Infection in Home Parenteral Nutrition Patients: A 6-Year Follow-up Study. J Parenter Enter Nutr. 2016;40(7):989-994.

19. Tribler S, Brandt CF, Hvistendahl M, et al. Catheter-Related Bloodstream Infections in Adults Receiving Home Parenteral Nutrition: Substantial Differences in Incidence Comparing a Strict Microbiological to a Clinically Based Diagnosis. J Parenter Enter Nutr. 2018;42(2):393-402.

20. DesJardin JA, Falagas ME, Ruthazer R, et al. Clinical Utility of Blood Cultures Drawn from Indwelling Central Venous Catheters in Hospitalized Patients with Cancer. Ann Intern Med. 1999;131(9):641.

21. Beekmann SE, Diekema DJ, Huskins WC, et al. Diagnosing and Reporting of Central Line–Associated Bloodstream Infections. Infect Control Hosp Epidemiol. 2012;33(9):875-882.

22. Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential Time to Positivity: A Useful Method for Diagnosing Catheter-Related Bloodstream Infections. Ann Intern Med. 2004;140(1):18.

23. Ulrich P, Lepak AJ, Chen DJ. Diagnostic and Therapeutic Utility of Positive Intravascular Catheter Tip Cultures. Carroll KC, ed. Microbiol Spectr. 2022;10(6):e04022-22.

24. Rhimi W, Theelen B, Boekhout T, Otranto D, Cafarchia C. Malassezia spp. Yeasts of Emerging Concern in Fungemia. Front Cell Infect Microbiol. 2020;10:370.

25. Iatta R, Battista M, Miragliotta G, Boekhout T, Otranto D, Cafarchia C. Blood culture procedures and diagnosis of Malassezia furfur bloodstream infections: Strength and weakness. Med Mycol. 2018;56(7):828-833.

26. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50.

27. Phongkhun K, Pothikamjorn T, Srisurapanont K, et al. Prevalence of Ocular Candidiasis and Candida Endophthalmitis in Patients With Candidemia: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2023;76(10):1738-1749.

28. Edakkanambeth Varayil J, Whitaker JA, Okano A, et al. Catheter Salvage After Catheter-Related Bloodstream Infection During Home Parenteral Nutrition. J Parenter Enter Nutr. 2017;41(3):481-488.

29. Dibb MJ, Abraham A, Chadwick PR, et al. Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data. J Parenter Enter Nutr. 2016;40(5):699-704.

30. Severijnen R, Bayat N, Bakker H, Tolboom J, Bongaerts G. Enteral Drug Absorption in Patients with Short Small Bowel: A Review. Clin Pharmacokinet. 2004;43(14):951-962.

31. Meade U, Gabriel N, Patel R, et al. Drug Absorption in Patients with a Short Bowel. In: Nightingale JMD, ed. Intestinal Failure. Springer International Publishing; 2023:699-716.

32. Hong WBT, Tan WK, Law LSC, Ong DEH, Lo EAG. Changes of Drug Pharmacokinetics in Patients with Short Bowel Syndrome: A Systematic Review. Eur J Drug Metab Pharmacokinet. 2021;46(4):465-478.

33. Korzilius JW, Gompelman M, Wezendonk GTJ, et al. Oral antimicrobial agents in patients with short bowel syndrome: worth a try! J Antimicrob Chemother. 2023;78(8):2008-2014.

34. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adultsa. Clin Infect Dis. 2015;61(6):e26-e46.

35. Parvizi J, Tan TL, Goswami K, et al. The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J Arthroplasty. 2018;33(5):1309-1314.e2.

36. Gjika E, Beaulieu JY, Vakalopoulos K, et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial. Ann Rheum Dis. 2019;78(8):1114-1121.

37. Mathews CJ, Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm. Curr Opin Rheumatol. 2008;20(4):457-462.

38. Gompelman M, Paus C, Bond A, et al. Comparing success rates in central venous catheter salvage for catheter-related bloodstream infections in adult patients on home parenteral nutrition: a systematic review and meta-analysis. Am J Clin Nutr. 2021;114(3):1173-1188.

39. Ait Hammou Taleb MH, Mahmutovic M, Michot N, Malgras A, Nguyen-Thi PL, Quilliot D. Effectiveness of salvage catheters in home parenteral nutrition: A single-center study and systematic literature review. Clin Nutr ESPEN. 2023;56:111-119.

40. Martínez E, Mensa J, Rovira M, et al. Central venous catheter exchange by guidewire for treatment of catheter-related bacteraemia in patients undergoing BMT or intensive chemotherapy. Bone Marrow Transplant. 1999;23(1):41-44.

41. Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A Prospective, Randomized Trial of Intravenous Fat Emulsion Administration in Trauma Victims Requiring Total Parenteral Nutrition: J Trauma Inj Infect Crit Care. 1997;43(1):52-60.

42. McCowen KC, Friel C, Sternberg J, et al. Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications—A randomized clinical trial: Crit Care Med. 2000;28(11):3606-3611.

43. Calder PC, Yaqoob P, Harvey DJ, Watts A, Newsholme EA. Incorporation of fatty acids by concanavalin A-stimulated lymphocytes and the effect on fatty acid composition and membrane fluidity. Biochem J. 1994;300(2):509-518.

44. Wanten GJ, Naber AHJ. Human Neutrophil Membrane Fluidity After Exposure to Structurally Different Lipid Emulsions. J Parenter Enter Nutr. 2001;25(6):352-355.

45. Seidner DL, Mascioli EA, Istfan NW, et al. Effects of Long-Chain Triglyceride Emulsions on Reticuloendothelial System Function in Humans. J Parenter Enter Nutr. 1989;13(6):614-619.

46. Pontes-Arruda A, Dos Santos MCFC, Martins LF, et al. Influence of Parenteral Nutrition Delivery System on the Development of Bloodstream Infections in Critically Ill Patients: An International, Multicenter, Prospective, Open-Label, Controlled Study—EPICOS Study. J Parenter Enter Nutr. 2012;36(5):574-586.

47. Gavin NC, Larsen E, Runnegar N, et al. Association between parenteral nutrition–containing intravenous lipid emulsion and bloodstream infections in patients with single-lumen central venous access: A secondary analysis of a randomized trial. J Parenter Enter Nutr. 2023;47(6):783-795.

48. Austin PD, Hand KS, Elia M. Systematic review and meta-analyses of the effect of lipid emulsion on microbial growth in parenteral nutrition. J Hosp Infect. 2016;94(4):307-319.

49. Keohane PP, Attrill H, Northover J, et al. Effect of catheter tunneling and a nutrition nurse on catheter sepsis during parenteral nutrition. The Lancet. 1983;322(8364):1388-1390.

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51. Bisseling TM, Willems MC, Versleijen MW, Hendriks JC, Vissers RK, Wanten GJ. Taurolidine lock is highly effective in preventing catheter-related bloodstream infections in patients on home parenteral nutrition: A heparin-controlled prospective trial. Clin Nutr. 2010;29(4):464-468.

52. Wouters Y, Theilla M, Singer P, et al. Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition. Aliment Pharmacol Ther. 2018;48(4):410-422.

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54. Nickel B, Gorski L, Kleidon T, et al. Infusion Therapy Standards of Practice, 9th Edition. J Infus Nurs. 2024;47(1S):S1-S285.

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Fundamentals of ERCP, Series #14

Chronic Pancreatitis

October 2024 • Volume XLVIII, Issue 10

Thiruvengadam Muniraj

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Introduction

Chronic pancreatitis (CP) is a chronic progressive fibroinflammatory condition of the pancreas characterized by progressive scarring resulting in permanent loss of both exocrine (acinar) and endocrine (islet cells) tissue along with morphological changes in both the pancreatic duct and the parenchyma. The annual incidence of CP^1,2 ranges from 5 to 14 per 100,000; the prevalence of CP is about 50 per 100,000 persons.² (See Figure 1)

The clinical presentation of CP occurs as a large duct disease or a small duct disease and as variants of both, with and without calcifications. Most often, pain is the major clinical symptom and presents early in the course of the disease and significantly impacts quality of life. About 30-50% of CP patients develop chronic exocrine pancreatic insufficiency resulting in malabsorption and maldigestion, with a clinical presentation of steatorrhea and weight loss. Depending on the duration of follow-up and cohorts, 26-80% of CP patients develop diabetes mellitus due to progressive loss of islet cells.⁵ In this article, we mainly focus on the indications and techniques of endoscopic retrograde cholangiopancreatography (ERCP) endoscopic therapy in CP patients.

ERCP – Pancreatic Endotherapy

Pain associated with CP is multifactorial. One of the primary mechanisms for pain in CP is elevated intraductal pressures,⁶ along with other causes such as interstitial pressure, neural inflammation, ongoing acute pancreatitis with tissue inflammation, and the presence of fluid collections.

The main goal of ERCP-based endotherapy is to decompress the main pancreas duct (MPD), to achieve complete duct clearance by alleviating outflow obstruction of the MPD (from stones or strictures), evacuating focal fluid collections, and diverting the flow from a fistula or a pancreatic duct leak.^7-10 When MPD drainage is established via ERCP endotherapy, the flow of pancreatic juice to the duodenum increases and resistance to outflow decreases, thereby reducing or inhibiting the severity of exocrine pancreatic insufficiency and its symptoms such as steatorrhea. However, steatorrhea is not an indication to initiate ERCP unless the patient also has concomitant pain. While pain may improve with ERCP, improvement or preservation in pancreatic function is often uncertain and one does not guarantee the other. One prospective randomized trial of 41 patients showed endoscopic therapy with ERCP slowed the progression of exocrine insufficiency along with a reduction in pain but with no change in overt diabetes.¹¹

ERCP for ductal decompression therapy has become an established first-line method for the treatment of painful obstructive chronic pancreatitis. In a large prospective multicenter U.S. cohort (n = 521), 52% underwent endoscopic therapy, and pancreatic surgery was performed only on 18 % of patients.¹² The clinical response to endoscopic therapy is quite variable even if adequate duct clearance is achieved.¹⁰ In a cohort of >1000 CP patients with pain who underwent ERCP, MPD obstruction was caused by pancreatic stones alone, ductal strictures alone, and a combination of stones and strictures in 18%, 47%, and 32% of cases, respectively. Decompression of the MPD with ERCP yielded similar results in all these different categories of patients, with 51% of patients having no pain at all at a mean follow-up of 4.9 years.¹³

Management of MPD obstruction via ERCP can be achieved using pancreatic sphincterotomy, and removal of the ductal stones, with or without extracorporeal short-wave lithotripsy [ESWL] or mechanical lithotripsy, dilation of strictures, placement of pancreatic stents, and providing transpapillary drainage of pancreatic fluid collections.

Selection of Patients and Pre-ERCP Work Up

Proper patient selection results in a favorable long-term outcome with endoscopic management. Only patients with a clinical presentation of pain should be considered for ERCP. The presence of a MPD stricture in the head, neck, or proximal body of the pancreas with dilation of the upstream pancreas duct in a chronic disease with or without the presence of stone would be an indication for endoscopic therapy. ERCP should be avoided in asymptomatic patients even in the presence of MPD stricture unless malignancy is suspected and an intraductal tissue sampling is desired. Patients with an MPD obstruction located only in the tail of the pancreas are not considered candidates for ESWL and/or endoscopic therapy.¹⁴ Some studies have shown that favorable prognostic factors related to endoscopic therapy and/or ESWL include complete stone removal and MPD stricture resolution after stenting.^14,15

The risk of pancreas cancer is high among patients with CP. In addition to standard laboratory testing, the pre-ERCP workup should include cross-sectional imaging to rule out pancreatic cancer and to provide high quality images of the ductal anatomy. An abdominal Computed Tomography (CT) scan with and without IV contrast (Figure 2, Figure 3) and Magnetic resonance cholangiopancreatography (MRI/MRCP) (Figure 4) will help accurately delineate the location of calcified stones in relation to the duct, the presence of any mass lesion, and an excellent overview of the ductal anatomy. Some patients may have extensive parenchymal calcifications along with ductal calcifications that may not be amenable for any endoscopic therapy. (Figure 5) CT scan before and after the ERCP therapy can also help to accurately confirm the completeness of the stone extraction. (Figure 6)

Secretin-stimulated MRCP provides better information on pancreatic ductal anatomy and may also be used to quantify pancreatic exocrine function and predict the effects of pancreatic duct drainage procedures. A recent study by Sherman et al. found that S-MRI in comparison to MRCP may better identify patients who would benefit from therapeutic ERCP.¹⁶

Endoscopic Ultrasound (EUS) may be useful in selected CP patients, although the EUS-guided sampling seems to be less sensitive to diagnose a pancreatic cancer in the presence of CP vs. absence of CP (54 % vs. 89 %).¹⁷ The yield of EUS with contrast-enhanced harmonic EUS may improve the accuracy of EUS-guided sampling.¹⁸ Still, in current practice, EUS is the mainstay of technology for the diagnosis of pancreatic cancer.

Endoscopic Pancreatic Sphincterotomy (EPS)

MPD cannulation and endoscopic pancreatic sphincterotomy (EPS) are the initial steps in the endoscopic therapy. EPS is a well-known mode of therapy and can offer symptomatic relief even without stenting in a subset of patients with papillary stenosis and allow access to removal of stones in the MPD. In a small retrospective study of 11 early onset CP patients, more than 2/3^rd of patients had good pain relief following EPS alone.¹⁹ In patients with chronic pancreatitis, EPS with a standard sphincterotome or with a needle-knife offers an effective and reliable approach to both access and decompress the pancreatic duct system and the complication rate of EPS in CP patients appears to be lower than the complication rate of biliary sphincterotomy for other indications.²⁰

When performing EPS for pain relief in CP, a routine biliary sphincterotomy is not indicated unless the common bile duct is dilated or there is an elevation of alkaline phosphatase or other clinical indication.²¹ An endoscopic biliary sphincterotomy (EBS) is performed prior to EPS in the setting of obstructive jaundice, cholangitis or when it is technically easier to have biliary sphincterotomy to facilitate access to the MPD. If EPS is performed after EBS, the MPD orifice is usually located between the 2 and 6 o’clock position to the right margin of the sphincterotomy. (Figure 7)

After contrast injection and obtaining a pancreatogram, the guidewire is maneuvered through into the MPD, crossing strictures as needed. (Figure 8) EPS is then performed over the guidewire using either standard or taper pull type sphincterotome. When compared to EPS with a pull sphincterotome (followed by pancreatic stenting) or a needle knife over a pancreatic stent, EPS is safer when performed with a needle knife over a pancreatic stent.²² The common expected complication of EPS are post-ERCP pancreatitis, bleeding, perforation and restenosis. Using pure cutting current for the EPS incision would avoid coagulative injury, thereby decreasing the risk of pancreatitis, although most endoscopists currently used alternating cutting and coagulating currents as are common on modern electrosurgery generators for ERCP. In a large study of 398 patients who underwent EPS, post-ERCP pancreatitis was minimized with either pancreatic duct stent placement or nasopancreatic drainage.²³ EPS in CP patients has shown to have a 14% restenosis rate during a 4 year follow up.²⁴

Minor Papilla Sphincterotomy in CP Patients

The benefit of minor papilla sphincterotomy is dependent upon the clinical setting. Lehman et al. reported that minor papilla sphincterotomy helps patients with acute recurrent pancreatitis more frequently than those with chronic pancreatitis (76.5% vs. 27.3%, p = 0.01).²⁵ Vitale et al. followed 24 CP patients with pancreas divisum and reported significant pain relief on 2-year follow up following minor papilla sphincterotomy and stenting.²⁶ A recent Japanese study showed that endoscopic balloon dilation (EBD) of the minor papilla is feasible and effective for the management of symptomatic pancreas divisum in CP patients.²⁷ The same technique as EPS with a tapered pull type sphincterotome can be utilized to perform minor papilla sphincterotomy or a stent can be placed in the dorsal pancreas duct and minor papilla sphincterotomy performed over a needle knife. (Figure 9)

Pancreatic Duct Stone Management

Pancreatic duct calculi are often seen in patients with CP and cause pain by obstructing the pancreatic ducts and producing upstream ductal hypertension. Pancreatic stones may appear either as calcified stones or as radiolucent protein plugs that may or may not become calcified. A majority of the pancreatic stones are calcified and radiopaque. Although alcoholic CP often presents with calcified pancreatic stones, the stones seen in tropical pancreatitis and hereditary pancreatitis can be larger in size than those seen in the setting of alcoholic CP. Larger stone size often makes endotherapy difficult, whereas stones < 5mm are more amenable to endoscopic extraction after pancreatic sphincterotomy alone. However, in 70–90% of cases, pancreatic stones cannot be extracted without pre-ERCP fragmentation (by mechanical and/or extracorporeal shock wave lithotripsy [ESWL]).^7,28 If the pancreatic duct stone is larger than 5mm, it is often preferable to perform stone extraction after ESWL or intra-ductal lithotripsy.

Extracorporeal Shock Wave Lithotripsy

ESWL is now accepted as the standard of care in the management of large MPD calculi >5 mm not amenable to routine endotherapy.^29,30 ESWL is very effective in fragmenting both radio-opaque and radio-lucent calculi in the MPD. European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend ESWL prior to ERCP for large MPD calculi.² A meta-analysis of 17 studies with a total of 588 patients looked at pain relief and duct clearance as the primary end point. They noted a duct clearance rate of 37%-100% and good pain relief, and a mean effect size (weighted correlation coefficient) for pain was 0.6215 and for duct clearance was 0.7432 (indicates moderate to high practical significance).³¹

ESWL is routinely used in Urology for clearance of nephrolithiasis. In many U.S. centers, Urologists perform ESWL for PD stones. Components of ESWL machines include (1) a shock wave generator, (2) a focusing system, (3) a coupling mechanism, and (4) a localization unit.³² Shock waves are generated via piezoelectric technology and the focusing system concentrates shock waves into a precise target volume where fragmentation of hard structures will take place. The coupling mechanism between the shock wave generator and the patient’s body currently consists of a cushion surrounding the shock wave generator, which is closely applied onto the patient’s skin (with a special gel similar to that used in transabdominal ultrasonography). The localization unit allows maintaining the target stone inside the target volume, using simultaneous fluoroscopy. Localization of stones using fluoroscopy is more reliable than using ultrasound. If the stone is not radiopaque, then placing a pancreatic duct stent that terminates at the level of the stone often helps in the localization of the target for ESWL. The patient is positioned prone or supine with a slight tilt to prevent the spine from being in the target volume.

If there are several stones present, the one located inside the MPD closest to the papilla is targeted first; and then the focus is gradually moved to more proximal MPD stones once distal ones have been fragmented. Usually, the stones in the tail and the side branches are not targeted as they do not significantly impede the outflow of pancreatic fluid and, if targeted, resulting stone fragments can potentially migrate into the MPD and cause worsening obstruction.³²

High energy shock waves are delivered until the stone is fragmented (as seen via fluoroscopy) and although there is limited evidence on the maximum number of shock waves that may be administered per session, 5000-6000 are typically performed per session and patients are scheduled for further supplementary sessions as needed. In most centers, ESWL is done as an ambulatory procedure under general anesthesia and an abdominal radiograph is obtained 1 to 2 weeks later to assess the need for further ESWL. The most common complication of ESWL is acute pancreatitis, and this has been reported in 4.2% in a meta-analysis.³³ (Figure 10)

Combining ERCP with ESWL at the Same Time

In some centers, the extracorporeal lithotripter is located within the endoscopy unit and ERCP is used in combination with ESWL and is performed by the endoscopist during same anesthesia session. In a study of 55 patients randomized to ESWL alone or ESWL combined with endoscopy, both groups had similar rates of pain relief (62% vs. 55%) and the authors concluded that combining systematic endoscopy with ESWL adds to the cost of patient care, without improving the outcome of pancreatic pain.²⁹ A study by Cotton et al. that combined use of ESWL with endotherapy was shown to prevent pancreatic surgery in the majority of patients.³⁴ In most studies of ESWL (alone or combined with endoscopic drainage), more than 70 to 80% patients had short term pain relief and about 60% had long term pain relief (2 to 5 years).^35-37 ESWL is a relatively safe and well-tolerated procedure.³⁸

Secretin ESWL

Injection of human secretin increases bicarbonate rich pancreatic fluid secretion. To see if this could facilitate excretion of pulverized pancreatic stones during ESWL, Choi et al. studied 233 consecutive cases and observed that secretin use resulted in significantly higher rate of complete MPDS clearance (63% vs. 46%, p = 0.021).³⁹

Intraductal Lithotripsy

Lithotripsy is commonly used for biliary stones, but occasionally mechanical lithotripsy is also used in treating pancreatic calcifications (prior to referring patients to undergo ESWL). Standard lithotripter-compatible baskets can be used in the pancreatic duct during ERCP and, if these baskets can capture and crush stones more aggressive treatments may be obviated.²⁸ Intraductal lithotripsy via a pancreatoscope can be performed using per oral pancreatoscopy (POP)-guided intracorporal lithotripsy using either of the two techniques: Electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). A recent meta-analysis, showed high clinical success rates with EHL (67%) and LL (88%).⁴⁰ (Figures 11,12,13)

Stone Extraction

After stone fragmentation with ESWL and pancreatic sphincterotomy, tiny stone fragments may pass spontaneously through the papilla and ERCP may not be even necessary. Endoscopic therapy is needed in patients without spontaneous clearance of pancreatic stones after adequate fragmentation by ESWL.² If the stone is located upstream from a stricture, the stricture is generally dilated first using a dilation balloon (Hurricane; Boston Scientific, Natick, MA) or a graduated dilating catheter (Soehendra dilators; Cook Endoscopy, Winston-Salem, NC) to facilitate the stone removal.Then a small Dormia basket or stone extraction balloon is used to remove the stone fragments. (Figures 14a,b,c,d,e)

If the stones are visible on fluoroscopy, a guidewire is introduced in the duct and with minimal or no contrast injection, a basket or balloon introduced, manipulated to extract the stones starting with those closer to papilla and progressing upstream. A dormia basket may be more useful than a stone extraction balloon as often the fragmented pancreatic stones are sharp and frequently rupture the balloon.

When a pancreatic duct stricture is tight, catheter (balloon or bougie) passage may be impossible. In this setting a Soehendra stent retriever with a screw tip (8.5Fr) can be spanned through the stricture to enable subsequent passage of the dilating balloon or bougie, although this maneuver carries with it some risk of pancreatic injury.

Pancreatic duct strictures

Management of strictures secondary to CP is often challenging. Along with pancreatic duct strictures, patients often present with distal biliary strictures resulting from ongoing inflammation and fibrotic reactions in the pancreatic head, which can in turn produce a biliary stricture. The most important aim is to rule out malignancy during the initial work up if there is any concern r.e. cancer. As CP is associated with an increased risk of pancreas cancer, the emphasis should be to reasonably exclude pancreatic cancer if a MPD stricture is detected, particularly in the absence of pancreatic calcifications and in the presence of exocrine insufficiency or new late onset diabetes, without smoking or alcohol history.^41,42 It has been shown that approximately 5% of patients with pancreatic cancer are initially misdiagnosed as CP.⁴³

MPD strictures are defined as dominant strictures by the presence of at least one of the following characteristics: upstream MPD dilatation ≥ 6 mm in diameter, prevention of contrast medium outflow alongside a 6-Fr catheter inserted upstream from the stricture, or abdominal pain during continuous infusion of a naso-pancreatic catheter inserted upstream from the stricture with 1 L saline for 12 – 24 h.² The latter maneuver is virtually never performed in modern practice, and this classification system is often not put into practice. (Figures 15a,b,c)Technical success in the management of such a dominant stricture would be defined by some as stent insertion across a dominant MPD stricture or up to the tail MPD if multiple strictures occur in the MPD. Before a stent is placed, if malignancy is still suspected, a brush cytology could be obtained. Although a clear definition for short term clinical success is lacking, the absence of pain during a full year following the stent removal implies clinical success. Refractory MPD strictures are defined as symptomatic dominant strictures that persist or relapse after 1 year of single pancreatic stent placement, or can be diagnosed in patients who cannot function without an indwelling pancreatic duct stent.²

Stricture Dilation and a Single Plastic Stent

ERCP intervention (endotherapy) is ideal for single strictures in the head while isolated strictures in the tail or multiple strictures in the body with a chain of lake appearance have unfavorable outcomes with the endotherapy.⁴⁴

Historically, stricture dilation alone was used to treat single MPD strictures, but in current endoscopy practice dilation alone is not felt to represent an adequate treatment. Dilation is routinely followed by placement of a plastic pancreatic stent. MPD strictures are single in >80% of CP patients and a placement of a single plastic stent has been widely used as the initial endoscopic therapy.⁴⁵

On relieving MPD stricture obstruction, pain relief was reported at short and long-term follow-up in 70–94% and 52–82% of patients, respectively.^32,44 In a meta-analysis of 9 studies, long-term pain relief (24 months) was reported in 67.5 % of 536 patients (95 % confidence interval [CI] 51.5 % – 80.2 %).⁴⁶

Leaving the PD stent in place for periods of up to 6 months does not always yield an adequate clinical response and stents are often needed for a longer duration.⁴⁷ Prior to stent placement, tight strictures sometimes need to be dilated with Teflon bougies, a Soehendra stent retriever or a balloon dilator.⁴⁸

Plastic stents are placed across the stricture and typically exchanged every 2 to 6 months or “on-demand” when the symptoms recur. Large bore stents of size 7Fr to 10Fr are progressively used when treating MPD strictures, if possible. The stent size is usually limited by the unaffected downstream duct (close to the pancreas head). In general, stent exchanges are performed for about 24 months. There is no clear consensus data on whether or not a pancreatic sphincterotomy should be performed prior to placement of plastic MPD stent, but most patients with CP often find their way to undergoing this maneuver as well.⁴⁹

Criteria used for ‘definitively’ removing a stent (with no intent to replace the stent again) usually consist of (1) adequate outflow of contrast medium into the duodenum within 1 to 2 min after ductal filling upstream from the dilated stricture, immediately after stent removal plus the extraction of ductal debris, and (2) easy passage of an ERCP catheter through the dilated stricture.⁸

After definitive stent removal, recurrence of symptoms and strictures was reported in 27 to 38% of patients after 2 years of follow up. Mean time to recurrence of pain after definitive removal is around 2.1 years.⁴⁵ The most important factor associated with higher re-stenosis rates in CP patients is the presence of concomitant pancreas divisum.⁴⁵ (Figure 16)

Multiple Plastic Stenting

MPD stricture management has evolved from single stents to the placement of multiple side-by-side stents. Two 7Fr or 8.5Fr plastic stents can be placed once the stricture is dilated to 6mm with a balloon. The number of stents can be increased based on the degree of dilation in the upstream MPD beyond the stricture. Such multiple stent placements are facilitated by having two guidewires in the pancreas duct across the stricture subsequently followed by successive stent placements.

Costamagna et al. who initially proposed using multiple plastic stenting for MPD strictures not responding to a single stent placement, reported a study of 19 patients who had a MPD stricture that persisted immediately after removal of a single pancreatic stent, multiple plastic stents (8.5-11.5Fr diameter) were placed. A mean of 3 stents were used and the stents were removed after a mean of 7 months. Stricture resolution was seen in 95% and pain relief in 84% on a 38 month follow up.⁵⁰ The main advantages of this technique include a low number of ERCP sessions (two) and a large dilation diameter that might account for the absence of pain relapse during a relatively long follow-up. However, further prospective controlled studies are needed to confirm these promising results.

Self-Expandable Metal Stents

Fully covered self-expanding metal stents (FCSEMS) were initially developed for palliation of malignant biliary strictures, and have subsequently been used in benign biliary strictures. Placement of FCSEMS in the MPD may be an alternative to placing multiple plastic stents or when the stricture is refractory despite several sessions of plastic stent placements. Due to tissue in-growth, only FCSEMS are used in PD strictures and FCSEMS used in this manner are applied in an “off label” manner. FCSEMS can be used only in strictures close to the papilla in the head of the pancreas and reachable by a single stent. The MPD should be large enough to accommodate 8 to 10mm stents and the stents should be shorter so that they do not extend beyond the stricture site and seal the side branches. (Figure 17)

Poley et al., in a study of 13 CP patients, demonstrated better results using FCSEMS when compared with progressive plastic stenting protocols.⁵¹ A major limitation of FCSEMS is frequent stent migration (5-33%). To reduce the risk of migration, anti-migration features such as anchoring flaps and flared ends were introduced, and these modified stents have been studied in MPD strictures in CP patients by Moon et al.⁵² In a systematic review of 4 prospective case series (n=61), placement of FCSEMS provided pain improvement in 85 %.⁵³ A study of 10 patients with follow-up period of 19.8 months showed the use of FCSEMS in MPD strictures feasible, safe and effective.⁵⁴ Similarly, in a U.S multicenter retrospective study of 33 CP patients with MPD strictures that were refractory to plastic stents, FCSEMS were shown to be effective, with a clinical success rate of 93%.⁵⁵ The recurrence rate for treated strictures with FCSEMS was 0 % after a median follow-up of 8 months (range 5 – 14).⁵⁵ About 20% of patients who receive FCSEMS for PD strictures may not tolerate these implants and develop significant post-procedure pain. This post-procedure pain is hypothesized mainly due to the greater stent diameter, and if a smaller-diameter (6 mm) FCSEMS is available, that should be further investigated regarding the post-procedure pain and development of iatrogenic strictures when using over-sized stents.

Due to the lack of controlled data, further trials are needed to assess the long-term safety and efficacy of using FCSEMS in intrapancreatic strictures in the setting of CP before this method can be adopted in routine clinical practice, but it is within the standard of care to consider and use these devices in this setting.

Transpapillary Endoscopic Drainage of Pancreatic Fluid Collections and Leaks

Pancreatic Fluid Collections (PFC) may be drained via a transpapillary or transmural approach or, sometimes, a combination of both. Transpapillary endoscopic drainage with plastic stent placement is recommended for pseudocysts communicating to the MPDs, ductal leaks in CP, and if the site of MPD disruption could be reached or site of obstruction could be bypassed. However, if bridging the ductal obstruction or disruption is unsuccessful, then transmural or percutaneous drainage would typically be necessary.

The main advantage of transpapillary drainage of PFCs and leaks is a near-total avoidance of bleeding. If a symptomatic PFC communicates with the MPD and is not approachable transmurally, placement of a plastic pancreatic stent with or without EPS is a helpful approach. The upstream end of the stent, if unable to bridge the site of the leak then, should terminate in the PFC itself. An ideal approach would be to bridge the disruption site as that would restore the duct into continuity. A successful resolution of PD disruption by transpapillary stent placement depends on the ability to bridge the disrupted duct with a stent.⁵⁶ If there is an obstructive lesion such as a stone or stricture between the leak site and the duodenal papilla, it is prudent to place a stent bridging across the obstruction. In a retrospective study of 110 patients, a combined transpapillary PD stenting improves treatment outcomes in patients undergoing endoscopic transmural drainage of PFC, although in practice if transmural drainage is performed then transampullary drainage is not usually warranted.⁵⁷

While transpapillary stenting helps with improved outcomes in walled-off necrosis, a large multicenter retrospective study showed that transpapillary stenting may have no added benefit in the treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts.⁵⁸ Most endoscopists perform ERCP with pancreatic duct stenting in patients with pancreatic duct disruption during endotherapy for walled-off pancreatic necrosis but not during transmural drainage in patients with pancreatic pseudocysts, even in cases of confirmed main pancreatic disruption as it negatively affects treatment outcomes. However, large prospective randomized trials are necessary to confirm these conclusions.

Biliary Strictures Secondary to CP

Biliary strictures occur secondary to CP in 3% – 23% of patients.⁵⁹ Clinical presentation of biliary strictures in CP varies widely from asymptomatic lab abnormalities (elevated alkaline phosphatase) to jaundice with or without cholangitis. Patients with persistent biliary obstruction would benefit from biliary decompression with dilation and stent placement.

Summary

In patients with symptomatic obstructive chronic pancreatitis with a dilated pancreatic duct, ERCP is the first line of management to treat stones and strictures. Further studies are needed in using FCSEMS for pancreatic duct strictures and EUS-guided novel interventions.

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