Page 10 – Practical Gastro

Nutrition Reviews in Gastroenterology, SERIES #11

The Use of Curcumin in Ulcerative Colitis: Current Evidence and Practical Applications

March 2024 • Volume XLVIII, Issue 3

Although pharmacologic agents (mesalamine, immunomodulators, biologics, and small molecule inhibitors) have been established as safe and effective treatments for inflammatory bowel disease (IBD), patients with IBD report using nutraceutical supplements despite limited evidence on their safety and efficacy. Curcumin, a polyphenol derivative of the Curcuma longa rhizome, has received increasing attention due to its proposed anti-inflammatory, antioxidant, anticarcinogenic, and microbiome altering effects. This review highlights the current evidence for the use of curcumin in ulcerative colitis, its mechanisms of action, bioavailability, and safety data, as well as recommendations for use in clinical practice. Evidence of curcumin’s role in inducing clinical and endoscopic remission when used in combination with conventional treatment will be discussed, though larger scale and well-designed trials are still needed to fully establish its safety and efficacy.

Introduction

Ulcerative colitis (UC) is a relapsing and remitting immune-mediated chronic inflammatory bowel disease (IBD) with increasing global incidence and prevalence.^1,2 Patients often experience debilitating symptoms, including abdominal pain, diarrhea, rectal bleeding, and extraintestinal manifestations^2,3 as well as an increased risk of colorectal cancer.⁴ The pathophysiology of IBD has been attributed to a complex interplay between genetic factors, diet and environmental factors, and the gut microbiome resulting in intestinal barrier dysfunction, immune system dysregulation, and chronic intestinal inflammation.^1,2,5

Current pharmaceutical treatments target inflammation and include 5-aminosalicylic acid drugs, corticosteroids, immunomodulators, biologics, and novel small molecular inhibitors to improve clinical symptoms and induce remission.^2,3 However, these treatments carry an increased risk of serious adverse events (AEs) (e.g. infections, malignancy) and many patients relapse or require surgery despite treatment, highlighting the need for alternative therapeutic approaches.^2,6 Many patients with IBD turn to complementary and alternative medicine due to concerns about side effects and perceived lack of response to conventional treatment with up to 54% reporting nutraceutical use.^7,8

Curcumin is an active polyphenol found in the Curcuma longa rhizome that has been used medicinally for thousands of years in Ayurveda and Traditional Chinese Medicine and as a dietary spice and dye in the food industry.^3,9 Several in vitro and mouse models have demonstrated the anti-inflammatory, antioxidant, anticarcinogenic, and microbiome altering effects of curcumin, and clinical studies in a variety of diseases have reported promising results.¹⁰ In this review, we present the mechanisms of action, clinical evidence, and practical recommendations for curcumin use in UC.

Mechanism of Action

The primary mechanism by which curcumin ameliorates inflammation is through downregulation of inflammatory signaling pathways, which has been demonstrated in vitro and in dextran sodium sulfate (DSS)-induced colitis mouse models.^10–15 Curcumin also addresses immune system dysregulation by regulating Th1/Th2 expression,¹⁵ follicular helper T cell (Tfh) differentiation via Tfh-related nuclear transcription factor expression,¹⁶ toll-like receptor signaling,¹⁷ and macrophage polarization¹⁷ in colonic mucosa of DSS-induced colitis mice. Curcumin has demonstrated antioxidant effects by decreasing myeloperoxidase activity and inducible nitric oxide synthase expression in colonic mucosa of DSS-induced colitis mice,¹¹ increasing antioxidant enzyme levels in vitro,^15,18 and increasing serum total antioxidant capacity in human studies across a variety of diseases.¹⁹ Curcumin has been found to strengthen intestinal barrier function and decrease inflammatory circulating lipopolysaccharide levels by normalizing tight junction protein expression in DSS-induced colitis mice.^11,20 Ingestion of curcumin can alter gut microbiome composition and biodiversity^20–22 with an increase in short-chain fatty acid producing bacteria, which may decrease intestinal inflammation and improve mucosal protection.^20,22 Curcumin can induce apoptosis and autophagy in colon cancer cells via endoplasmic reticulum stress-mediated and caspase-dependent mechanisms, which may be of particular importance given the increased risk of colon cancer in UC.^18,23

Metabolism and Bioavailability

Although curcumin appears to have strong intrinsic activity, its oral bioavailability is limited by poor absorption, rapid metabolism, and low chemical stability¹⁴ resulting in low serum levels.²⁴ However, murine studies have suggested that curcumin after oral administration may concentrate in the gastrointestinal tract.^22,25 A study of humans with colorectal cancer taking oral curcumin 3.6g/d for 7 days reported curcumin concentrations of 12.7 ± 5.7nmol/g and 7.7 ± 1.7nmol/g in normal and malignant colorectal cells, respectively, with trace levels in peripheral circulation.²⁶ Curcumin undergoes phase I biotransformation via reduction and phase II biotransformation via glucuronidation and sulfation to metabolites primarily in the liver and intestines.^22,27,28 Studies suggest that Escherichia coli, Bifidobacteria longum, and other intestinal microorganisms are capable of reducing or deconjugating curcumin and its metabolites, suggesting that an individual’s intestinal microbiome can impact curcumin metabolism and its pharmacologic effects.^3,22,27 Given its low serum levels, curcumin’s activity has been potentially attributed to its metabolites and degradation products^25,28 although this requires further elucidation.³ Curcumin is rapidly eliminated from the body, primarily in feces.³

Table 1. Summary of Key Clinical Studies Investigating Curcumin in IBD

Author/Year	Population	Intervention	Control	Key Findings (intervention vs. control)
Lang et al., 2016	50 adults with mild-moderate UC (SCCAI 5-12) taking stable concomitant immunomodulators (AZA, 6-MP)	1.5g curcumin capsules PO BID (Cur-Cure, 95% pure curcumin preparation from Bara Herbs Inc., Israel) with 4g/d PO and 1g/4g enema or 1g suppository mesalamine daily for 4 weeks	Placebo capsules PO BID with 4g/d PO and 1g/4g enema or 1g suppository mesalamine daily for 4 weeks	– Clinical response (SCCAI reduction ≥3 points): 65.3% vs. 12.5% (p<0.001) – Clinical remission (SCCAI ≤2): 53.8% vs. 0% (p=0.01) – Endoscopic response (≥1 point reduction in Mayo endoscopic subscore): 45.4% vs. 0% (p<0.01) – Endoscopic remission (Mayo endoscopic subscore 0-1): 38% vs. 0% (p=0.043) – No significant difference in AEs. Severe AEs included peptic ulcer and worsening UC.
Banerjee et al., 2021	69 adults with mild-moderate UC (partial Mayo score 2-6 with endoscopic score>1) who were biologic and immunomodulator naïve	50 mg bioenhanced curcumin PO BID (VALDONE Curcumin 50 mg Softgel; Cadila Pharmaceuticals Ltd, India) self-micro-emulsifying drug delivery system containing 70:30 ratio of curcumin mixture (curcumin dry crystals and oils) to turmeric extract) with 4.8g/d PO + 1g/d PR mesalamine for 6 weeks	Placebo BID with PO 4.8g/d + PR 1g/d mesalamine for 6 weeks	– Clinical response (≥2 reduction in partial Mayo score): 52.9% vs. 14.3% (p=0.001) at 6 weeks; 58.8% vs. 28.6% at 3 months – Clinical remission (partial Mayo score ≤1): 44.1% vs. 0% (p<0.01) at 6 weeks; 55.9% vs. 5.7% at 3 months – Endoscopic remission (endoscopic Mayo score ≤1): 35.3% vs. 0% (p<0.01) at 6 weeks; 44% vs. 5.7% at 3 months – No significant difference in AEs. Severe AEs included worsening UC requiring study termination.
Sadeghi et al., 2020	70 adults with mild-moderate UC (SCCAI 5-12) taking concomitant salicylates, immunomodulators, or steroids; TNF-α inhibitors not permitted	500mg curcumin capsules PO TID with meals (Karen critical pharmaceutical and nutritional supplements company, Tehran, Iran) for 8 weeks	Placebo capsules PO TID with meals for 8 weeks	– Clinical response (reduction in SCCAI ≥3): 93.5% vs. 59.4% (p<0.001) – Clinical remission (SCCAI ≤ 2): 83.9% vs. 43.8% (p=0.001) – No significant difference in AEs
Masoodi et al., 2018	56 adults with mild-moderate UC (SCCAI 5-11); concomitant use of prednisolone, AZA, TNF-α inhibitors permitted	80mg curcuminoids nanomicelles (Sinacurcumin; contains curcuminoids and a hydrophilic portion) PO TID with 3g/d PO mesalamine for 4 weeks	Placebo PO TID with 3g/d PO mesalamine for 4 weeks	– Significantly greater reduction in urgency of defecation score (p=0.041) in treatment vs. control, but not in daily bowel movement frequency (p=0.13) or blood in stool (p=0.781) at 4 weeks. – No significant difference in change in mean SCCAI between groups (p=0.05) – No significant difference in AEs.
Kedia et al., 2017	62 adults with mild-moderate UC (UCDAI 3-9); 6.5% taking AZA	150mg purified curcumin capsules PO TID (Himalaya Drug Company, Bangalore, India) with mesalamine 2.4g/d PO for 8 weeks	Placebo PO TID with mesalamine 2.4g/d PO for 8 weeks	– Clinical response (reduction of UCDAI ≥3): 20.7% vs. 36.4% (p=0.18) – Clinical remission (UCDAI ≤2): 31.3% vs. 27.3% (p=0.75) – Endoscopic response: 34.5% vs. 30.3% (p=0.72) – Mild AEs reported in control group
Singla et al., 2014	45 adult subjects with mild to moderate distal UC (UCDAI 3-9); concomitant steroid, 5-ASA, and AZA use permitted	140mg NCB-02 enema QHS (Himalaya Drug Company, Bangalore, India) standardized extract with 72% curcumin, 18.08% dimethoxy curcumin, and 9.42% bis-dimethoxy curcumin) with 800mg mesalamine PO BID for 8 weeks	Placebo enema QHS with 800mg mesalamine PO BID for 8 weeks	– Clinical response (reduction in UCDAI ≥3): 56.5% vs. 36.4% (p=0.175) – Clinical remission (UCDAI <3): 43.4% vs. 22.7% (p=0.14) – Endoscopic response (decrease in mucosal appearance score ≥1): 52.2% vs. 36.4% (p=0.29) – No significant difference in AEs. Severe AEs included worsening UC requiring study termination.
Hanai et al., 2006	89 adult subjects with UC in remission only taking mesalamine or sulfasalazine	1g curcumin PO BID after breakfast and dinner (API Co, Ltd, Gifu, Japan containing 50% curcumin) with 1.5-3g mesalamine or 1-3g sulfasalazine daily for 6 months	Placebo PO BID with 1.5-3g mesalamine or 1-3g sulfasalazine daily for 6 months	– % recurrence at 6 months: 4.44% vs. 15.15% (p=0.049) – % recurrence at 12 months: 22.2% vs. 31.8% (p=0.4330) – Change in mean CAI: 1.3±1.1 to 1.0±2.0 (p=0.38) vs. 1.0±1.1 to 2.2±2.3 (p=0.003) at 6mo – Change in mean EI: 1.3±0.8 to 0.8±0.6 (p=0.0001) vs. 1.3±1.0 to 1.6±1.6 (p=0.0728) at 6mo – No serious AEs
Suskind et al., 2013	6 CD and 5 UC pediatric (age 11-18) subjects in remission or with mildly active disease taking mesalamine or TNF-α inhibitors	500mg curcumin capsule PO BID (Vital Nutrients Inc, Middletown, CT, USA) for 3 weeks followed by 1g BID for 3 weeks followed by 2g BID for 3 weeks	No control group	– 2 UC patients achieved clinical remission, 3 patients had lowering of PUCAI or PCDAI – No serious AEs reported – ESR, CRP, creatinine, alanine transaminase, and complete blood count remained stable

Abbreviations: 5-ASA (5-aminosalicylate), 6-MP (6-mercaptopurine), AE (adverse events), AZA (azathioprine), BID (twice daily), CAI (Clinical Activity Index), CD (Crohn’s Disease), CRP (C-reactive protein), EI (endoscopic index), ESR (erythrocyte sedimentation rate), g/d (grams/day), ITT (intention to treat analysis), PCDAI (Pediatric Crohn’s Disease Activity Index), PO (per oral), PR (per rectum), PUCAI (Pediatric Ulcerative Colitis Activity Index), QD (daily), QHS (at bedtime), SCCAI (Simple Clinical Colitis Activity Index), TID (three times daily), UC (ulcerative colitis), UCDAI (Ulcerative Colitis Disease Activity Index)

Studies have exhibited a wide range of serum curcumin concentrations after oral administration,²⁷ which may be due to variations in polyphenol concentration, intestinal microbiome, and diet. Dietary polyphenol concentration of curcumin can be influenced by seasonality, soil nutrients, plant stress, heating, drying, grinding, food storage, and food preparation.^22,27,29 Consumption with dietary lipids, such as lecithin-rich oil or eggs, can improve its absorption and solubility.^22,27 Piperine, an alkaloid found in black pepper, inhibits curcumin biotransformation and can increase its bioavailability by up to 2000%.^22,24,30 Bioenhanced delivery models, such as curcumin-piperine complexes, curcumin nanoparticles, and phospholipid complexes may improve bioavailability. NovaSol^〉, CurcuWin^〉, and LongVida^〉 reportedly have 100-fold higher bioavailability compared to unformulated curcumin.³¹

Ulcerative Colitis

Key studies evaluating curcumin in UC are described in Table 1. A randomized controlled trial (RCT) by Lang et al. garnered significant attention for curcumin use in combination with mesalamine to induce remission in UC.³² In this study, patients with active UC taking mesalamine and treated with 3g daily of curcumin had significantly higher rates of clinical response, clinical remission, endoscopic response, and endoscopic remission compared to placebo with mesalamine.³² Since then, three additional RCTs by Banerjee et al., Sadeghi et al., and Masoodi et al. with varying curcumin doses and formulations have supported similar findings.^9,33,34 However, a study by Kedia et al. reported no significant difference in clinical response, clinical remission, or mucosal healing rates in patients with active UC treated with curcumin in addition to mesalamine.³⁵ This was potentially due to a lower dose of curcumin than used in the aforementioned studies, suggesting that doses of 1500mg-3g/d may have better efficacy.

Singla et al. investigated the use of daily curcumin enemas in active ulcerative proctitis/proctosigmoiditis.³⁶ Although there were promising results in the per-protocol analysis, there was no significant difference in clinical response, clinical remission, or mucosal healing between groups in the intention-to-treat analysis.³⁶ This discrepancy was attributed to a small sample size and high attrition rate, which limits reliability and interpretation of the data.

Hanai et al. demonstrated a potential role for curcumin in maintenance of remission in UC, which showed that patients taking 2g oral curcumin daily had significantly lower rates of recurrence and clinical activity index scores compared to placebo.³⁷ There is limited data in pediatric patients with one small dose-escalation study reporting improvement in disease activity score in 5 patients with UC in remission.³⁸

Safety

The U.S. Food and Drug Administration (FDA) classifies nutraceuticals as food supplements, which are not required to undergo rigorous drug approval like pharmaceutical drugs.³⁹ Current Good Manufacturing Practices (CGMP) implemented by the FDA are intentionally flexible and manufacturers are responsible for determining their procedures for testing for environmental contaminants and identity, purity, strength, and quality of ingredients.⁴⁰ Supplement brands may source their ingredients from potentially unregulated sources or from outside of the U.S. This results in significant variation in purity, potency, and potentially safety between brands.³⁹ Online resources, such as ConsumerLab.com⁴¹ and Natural Medicines Comprehensive Database,⁴² can help providers learn about ingredients, potential drug interactions, testing for potency, and contaminants of specific supplements.

Curcumin is Generally Regarded as Safe (GRAS) as a food additive by the FDA.⁹ None of the aforementioned studies of curcumin in UC reported a significant difference in incidence of serious AEs, which were primarily disease flares, between treatment and control groups. This is supported by a review of 27 human studies using oral curcumin ranging from 150mg-4g/d to treat a variety of diseases for 4 weeks-6 months, which found no reports of major toxicity although headaches and mild gastrointestinal side effects (e.g. flatulence, diarrhea, nausea) were reported.⁴³

Drug-induced liver injury (DILI) is a growing concern associated with nutraceuticals.⁴⁴ A review of 10 patients enrolled in the Drug-Induced Liver Injury Network reported that turmeric-related liver injury presented as self-limited hepatocellular injury within 1-4 months of use with rapid improvement after cessation and only rare cases of severe injury or death.⁴⁴ Doses were not reported. Piperine in curcumin products may also contribute to hepatotoxicity as 50% of the cases included products containing piperine, although there has not been evidence of piperine alone causing DILI.⁴⁴ Kedia et al. did not report a significant change in laboratory parameters, including aspartate transaminase (AST), alanine transaminase (ALT), hemoglobin, or creatinine, with curcumin use³⁵ although this study used lower doses.

Table 2. Recommendations for Curcumin Use in Ulcerative Colitis

Patient population	Patients with active mild-moderate UC who have not achieved clinical remission with 5-aminosalicylic acid compounds Likely benefit in active UC or UC in remission taking other conventional therapies (e.g. azathioprine, steroids, biologics) Avoid in children, pregnancy, and lactation given limited data Monitor use in patients with history of bile duct obstruction and those susceptible to gallstones or nephrolithiasis
Dosing	Start with low dose (i.e. 500mg/d) and increase weekly as tolerated with goal of 1.5-3g/day in 2-3 divided doses daily
Bioavailability	Advise patients to take curcumin with black pepper and/or with a meal that has dietary fat (e.g., oil, avocado, nuts, dairy) Products that contain black pepper, piperine, or BioPerine^® or use a bioenhanced form of curcumin (e.g., NovaSOL^®) can increase the bioavailability of curcumin, but there are limited studies in UC
Adverse effects	Common: mild gastrointestinal side effects, yellow stool, and headaches Rare cases of drug-induced liver injury Theoretical risk of gallbladder contraction with curcumin and nephrolithiasis with turmeric Products containing piperine may cause gastric mucosal irritation and bleeding⁴¹
Drug monitoring and safety	May interact with amlodipine, anticoagulant/antiplatelet drugs, alkylating agents, diabetes medications, tacrolimus, sulfasalazine, tamoxifen, and topoisomerase inhibitors⁵³ Theoretically may impact levels of drugs metabolized by cytochrome P450 1A1,1A2, and 3A4⁵³ Products containing piperine may theoretically inhibit cytochrome P450 1A1, 2B1, 2D6, and 3A4 and interact with atorvastatin, lithium, phenytoin, carbamazepine, diclofenac, theophylline, and rifampin^41,53 Monitor transaminase levels at 1 and 3 months after initiation
Sample brands*	Puritan’s Pride Curcuminoids from Turmeric 538mg turmeric extract (500mg curcuminoids) per capsule Start with 2 capsules once daily with meals and increase to 2 capsules 2-3 times daily with meals as tolerated Pure Encapsulations Curcumin with Curcumin C3 Complex^® 500mg turmeric extract (475mg curcuminoids) per capsule Start with 2 capsules once daily with meals and increase to 2 capsules 2-3 times daily with meals as tolerated

*Not a brand endorsement. Listing of brands are for educational purposes only.

Two small studies with 12 subjects reported that curcumin can cause gallbladder contraction with potential concern for use in patients with gallstones or bile duct obstructions.^45,46 A study of 11 healthy subjects taking 2.8g turmeric daily for 4 weeks had increased urinary oxalate excretion, which may be of concern in patients susceptible to nephrolithiasis.⁴⁷ However, a murine study reported that curcumin may actually alleviate renal calcium oxalate crystal deposition.⁴⁸ This may be due to curcumin itself containing lower levels of oxalate as it is likely removed when isolated from turmeric.⁴¹

Evidence from animal and in vitro studies suggest that curcumin may have pharmacokinetic interactions, such as with anticoagulants, cardiovascular drugs, antidepressants, and antibiotics, through inhibition of some CYP450 subtypes and other drug metabolism pathways.^43,49 However, there is limited data in human studies, which may have different effects especially considering low serum levels of curcumin after oral administration of high doses.

Practical Applications

Based on the RCTs by Lang et al. and Sadeghi et al., 1.5-3g oral curcumin daily is likely a safe and effective dose in active UC.^32,33 Patients can be started on lower doses (e.g. 500mg/d) and increased weekly to a maximum of 3g/d as tolerated. Based on the evidence, a trial of 1-2 months is a reasonable treatment duration to observe for effect. Patients should be advised to use curcumin derived from the rhizome or extract of Curcuma longa⁴¹ and manufactured by reliable supplement brands that are transparent about sourcing, testing for purity and contaminants, and adherence to CGMPs. To optimize bioavailability, patients should take curcumin in 2-3 divided doses per day with meals that contain black pepper and dietary fat (e.g., avocado, oil, nuts, eggs, dairy).⁴¹ Patients may ask about using freshly grated or ground turmeric. However, 1g of ground turmeric only provides 33mg curcumin,⁴¹ so it would be difficult to obtain an adequate dose.

Many commercially available curcumin supplements contain piperine or are bioenhanced to increase bioavailability. Although Banerjee et al. and Masoodi et al. reported efficacy in UC with lower doses of bioenhanced formulations, the specific formulations used in these studies are not available in the U.S. None of the studies advised subjects to take curcumin with fat or black pepper nor used formulations containing piperine, although this combination has been studied in other conditions.^50–52 It is reasonable to conclude that the increased bioavailability of these methods may result in a lower minimal effective dose, but this requires further investigation.

Patients should be counseled about common side effects, including gastrointestinal symptoms, headaches, and yellow stool.⁴⁹ Given the lack of clarity about potential drug-drug interactions, it would be reasonable to exercise caution when using curcumin with drugs that have a narrow therapeutic window or potential for significant AEs, such as anticoagulants. Monitoring of liver function in patients using high dose curcumin supplements should be considered especially when combined with other medications.

Conclusion

The evidence suggests that oral curcumin can be used as an adjuvant treatment with conventional therapy in patients with UC (Table 2). Given that curcumin has primarily been studied in patients with active mild-moderate UC taking concomitant mesalamine, this is likely the ideal population although it can be considered in patients taking immunomodulators or steroids. There is some evidence to suggest benefit in patients in remission or those taking other UC medications.

Small sample sizes and heterogeneity among studies with regard to formulations, dosages, duration, clinical scoring systems, and concomitant medications limit high quality pooled analyses. This underlies the need for larger and higher quality clinical trials to establish appropriate doses, potential drug-drug interactions, and the role of nanoparticle-based delivery systems (e.g., NovaSol^®) and combination products with piperine. More stringent manufacturing practices and regulations in the nutraceutical industry are also needed. This is of particular importance given the prevalence of nutraceutical use and the strong potential for nutraceuticals, such as curcumin, in improving health outcomes in UC.

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43. Soleimani V, Sahebkar A, Hosseinzadeh H. Turmeric ( Curcuma longa ) and its major constituent (curcumin) as nontoxic and safe substances: Review. Phytotherapy Research. 2018;32(6):985-995.

44. Halegoua-DeMarzio D, Navarro V, Ahmad J, et al. Liver Injury Associated with Turmeric—A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN]. The American Journal of Medicine. 2023;136(2):200-206.

45. Rasyid, Lelo. The effect of curcumin and placebo on human gallbladder function: an ultrasound study. Aliment Pharmacol Ther. 1999;13(2):245-249.

46. Rasyid A, Rahman ARA, Jaalam K, Lelo A. Effect of different curcumin dosages on human gall bladder. Asia Pac J Clin Nutr. 2002;11(4):314-318.

47. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. The American Journal of Clinical Nutrition. 2008;87(5):1262-1267.

48. Li Y, Zhang J, Liu H, et al. Curcumin ameliorates glyoxylate-induced calcium oxalate deposition and renal injuries in mice. Phytomedicine. 2019;61:152861.

49. Bahramsoltani R, Rahimi R, Farzaei MH. Pharmacokinetic interactions of curcuminoids with conventional drugs: A review. Journal of Ethnopharmacology. 2017;209:1-12.

50. Tabanelli R, Brogi S, Calderone V. Improving Curcumin Bioavailability: Current Strategies and Future Perspectives. Pharmaceutics. 2021;13(10):1715.

51. Hosseini H, Ghavidel F, Panahi G, Majeed M, Sahebkar A. A systematic review and meta-analysis of randomized controlled trials investigating the effect of the curcumin and piperine combination on lipid profile in patients with metabolic syndrome and related disorders. Phytotherapy Research. 2023;37(3):1212-1224.

52. Mirhafez SR, Dehabeh M, Hariri M, et al. Curcumin and Piperine Combination for the Treatment of Patients with Non-alcoholic Fatty Liver Disease: A Double-Blind Randomized Placebo-Controlled Trial. Adv Exp Med Biol. 2021;1328:11-19.

53. Turmeric 1000mg by Kirkland Signature. Natural Medicines Comprehensive Database. Accessed December 12, 2023. https://naturalmedicines.therapeuticresearch.com/databases/commercial-products/commercial-product.aspx?cpid=287492

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Medical Bulletin Board

DUPIXENT® (DUPILUMAB) FDA APPROVED AS FIRST AND ONLY TREATMENT INDICATED FOR CHILDREN AGED 1 YEAR AND OLDER WITH EOSINOPHILIC ESOPHAGITIS (EOE)

Approval based on Phase 3 EoE KIDS trial showing a greater proportion of children taking Dupixent achieved histological remission compared to placebo

Expanded indication marks second disease for which Dupixent is approved in children this young, underscoring the commitment to bringing therapies to young patients with significant unmet needs

EoE is one of five FDA-approved indications for Dupixent in the U.S. for which type 2 inflammation is an underlying driver

TARRYTOWN, N.Y. and PARIS, Jan. 25, 2024 (GLOBE NEWSWIRE) – Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that the U.S. Food and Drug Administration (FDA) has approved Dupixent^® (dupilumab) for the treatment of pediatric patients aged 1 to 11 years, weighing at least 15 kg, with eosinophilic esophagitis (EoE). Dupixent is now the first and only medicine approved in the U.S. specifically indicated to treat these patients. This approval expands the initial FDA approval for EoE in May 2022 for patients aged 12 years and older, weighing at least 40 kg. The FDA evaluated Dupixent for this expanded indication under Priority Review, which is reserved for medicines that represent potentially significant improvements in efficacy or safety in treating serious conditions.

EoE is a chronic, progressive disease associated with type 2 inflammation that is thought to be responsible for damaging the esophagus and impairing its function. EoE can severely impact a child’s ability to eat, and they may experience heartburn, vomiting, abdominal discomfort, trouble swallowing, food refusal and failure to thrive. These symptoms can adversely impact their growth and development. Continuous treatment of EoE may be needed to reduce the risk of complications and disease progression. Approximately 21,000 children under the age of 12 in the U.S. are currently being treated for EoE with unapproved therapies. However, the actual prevalence of children with this disease is likely higher, given symptoms can be mistaken for other conditions and there are delays in diagnosis.

“Young children are some of the most vulnerable patients with eosinophilic esophagitis, or EoE, as this debilitating and progressive disease threatens their basic ability to eat. Until today, these children had no approved treatment options specifically for EoE, leaving many with unapproved medicines that failed to target the root cause of their disease,” said George D. Yancopoulos, M.D., Ph.D., Board co-Chair, President and Chief Scientific Officer at Regeneron, and a principal inventor of Dupixent. “With this approval, Dupixent becomes the first and only treatment option for EoE patients aged 1 and older, weighing at least 15 kg. By targeting the underlying type 2 inflammation that contributes to this disease, Dupixent has the potential to transform the standard of care for these children as it has for adults and adolescents with EoE.”

The FDA approval is based on data from the Phase 3 EoE KIDS trial with two parts (Part A and Part B) evaluating the efficacy and safety of Dupixent in children aged 1 to 11 years with EoE. At 16 weeks, 66% of children who received higher dose Dupixent at tiered dosing regimens based on weight (n=32) achieved histological disease remission (≤6 eosinophils/high power field), the primary endpoint, compared to 3% for placebo (n=29). Histological remission was sustained at week 52, with 17 of 32 (53%) children treated with Dupixent in Parts A and B. Histological remission was also achieved at week 52 in 8 of 15 (53%) children who switched to Dupixent from placebo in Part B. In addition, a greater decrease in the proportion of days with one or more signs of EoE based on Pediatric EoE Sign/Symptom Questionnaire-caregiver version (PESQ-C) was observed in children treated with Dupixent at 16 weeks compared to placebo.

“Young children with eosinophilic esophagitis have significant unmet medical needs; despite existing treatment options, 40% of these children in the U.S. under the age of 12 continue to experience symptoms of this disease,” said Naimish Patel, M.D., Head of Global Development, Immunology and Inflammation at Sanofi. “Today’s approval underscores our commitment to bringing therapies to young patients with unmet needs and also brings hope to these patients who are at a critical age where struggling to eat and maintain weight directly impacts their overall nutritional intake and development.”

The safety profile of Dupixent observed through 16 weeks in children aged 1 to 11 years weighing at least 15 kg was generally similar to the safety profile of Dupixent observed through 24 weeks in adult and pediatric patients aged 12 years and older with EoE. The most common adverse events (≥2%) more frequently observed with Dupixent than placebo were injection site reactions, upper respiratory tract infections, arthralgia (joint pain) and herpes viral infections. In EoE KIDS Part B, one case of helminth infection was reported in the Dupixent arm.

About the Dupixent Pediatric Eosinophilic Esophagitis Trial

The Phase 3 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of Dupixent in children aged 1 to 11 years, weighing at least 15 kg, with EoE, as determined by histological, endoscopic and patient- or caregiver-reported measures. At baseline, 97% of these patients had at least one co-existing type 2 inflammatory disease, such as food allergy, allergic rhinitis, asthma and atopic dermatitis.

Part A, a 16-week, double-blind treatment period, enrolled 61 patients and evaluated the safety and efficacy of Dupixent in a tiered, weight-based dosing schema. The primary endpoint was histological disease remission, which was defined as peak esophageal intraepithelial eosinophil count of ≤6 eosinophils (eos)/high power field (hpf). Changes in caregiver-reported symptoms (proportion of days with 1 or more EoE signs [e.g., stomach pain, vomiting, food refusal]) were evaluated using PESQ-C.

Part B was a 36-week extended active treatment period (n=47) in which eligible children from Part A in the Dupixent group continued to receive their dose level and those in the placebo group in Part A switched to Dupixent.

About Dupixent

Dupixent, which was invented using Regeneron’s proprietary VelocImmune^® technology, is a fully human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant. The Dupixent development program has shown significant clinical benefit and a decrease in type 2 inflammation in Phase 3 trials, establishing that IL-4 and IL-13 are key and central drivers of the type 2 inflammation that plays a major role in multiple related and often co-morbid diseases. These diseases include approved indications for Dupixent, such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), prurigo nodularis and EoE.

Dupixent has received regulatory approvals in one or more countries around the world for use in certain patients with atopic dermatitis, asthma, CRSwNP, EoE, and prurigo nodularis in different age populations. Dupixent is currently approved for one or more of these indications in more than 60 countries, including in Europe, the U.S. and Japan. More than 800,000 patients are being treated with Dupixent globally.

NOVARTIS LUTATHERA^® SIGNIFICANTLY REDUCED RISK OF DISEASE PROGRESSION OR DEATH BY 72% AS FIRST-LINE TREATMENT FOR PATIENTS WITH ADVANCED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS

In the Phase III NETTER-2 trial, Lutathera plus octreotide LAR significantly extended median PFS to 22.8 months vs. 8.5 months with high-dose octreotide LAR in patients with newly diagnosed grade 2 and 3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs)¹

NETTER-2 is the first and only positive Phase III trial for a radioligand therapy (RLT) in the first-line setting, demonstrating the potential of RLTs in earlier lines

Novartis, a leader in radioligand therapy, is investigating a broad portfolio of RLTs in advanced cancers, in addition to GEP-NETs, including lung, prostate, breast, colon, glioblastoma and pancreatic cancers to continue reimagining medicine for patients

Basel, January 19, 2024 – Novartis presented data from the Phase III NETTER-2 trial showing that Lutathera^® (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) plus long-acting release (LAR) octreotide reduced the risk of disease progression or death by 72% as first-line therapy in patients with somatostatin receptor-positive (SSTR+) well-differentiated grade 2/3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) versus high-dose octreotide LAR alone.¹ Data were presented at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.

“These positive results for Lutathera are practice-changing and offer new first-line treatment data for patients who have a significant unmet need. This study confirms the clinical benefit of first-line radioligand therapy for newly diagnosed patients living with these types of advanced GEP-NETs,” said Dr. Simron Singh, Associate Professor of Medicine at the University of Toronto and cofounder of the Susan Leslie Clinic for Neuroendocrine Tumours at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, Ontario, Canada. “These findings should instill confidence among physicians in using Lutathera as a first-line treatment for patients with this life-threatening type of cancer.”

“This is the first positive Phase III trial of a radioligand therapy in the first-line setting, and the overall efficacy and safety results are amongst the most clinically relevant observed to date in this kind of advanced cancer, addressing a significant unmet need for patients with newly diagnosed advanced GEP-NETs,” said Jeff Legos, Global Head of Oncology Development at Novartis. “The positive results are a significant advancement and further reaffirm our strategy to research and develop radioligand therapies in earlier lines of treatment or stages of disease to improve outcomes for patients.”

No new or unexpected safety findings were observed in the study and data are consistent with the already well-established safety profile of Lutathera.¹ Most patients (88%) in the Lutathera arm received all four cycles of Lutathera treatment. The most common all-grade AEs (≥20%) for the Lutathera arm vs. control arm were nausea (27.2% vs 17.8%), diarrhea (25.9% vs 34.2%) and abdominal pain (17.7% vs 27.4%), and the most common grade ≥3 AE (>5%) was lymphocyte count decreased (5.4% vs 0%).

NETs are a type of cancer that originate in neuroendocrine cells throughout the body and are commonly considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis and in many cases, diagnosis is delayed until patients have advanced disease.^2-4 Even though NETs are a rare (orphan) disease, their incidence has increased over the past several decades^2-5 and there is a need for continued research into treatment options for newly diagnosed patients.

The NETTER-2 trial is ongoing for further evaluation of secondary endpoints including overall survival and long-term safety.

About NETTER-2

NETTER-2 (NCT03972488) is an open-label, multi-center, randomized, comparator-controlled Phase III trial assessing whether Lutathera plus octreotide LAR when taken as a first-line treatment can prolong PFS in patients with high-proliferation rate tumors (G2 and G3), compared to treatment with high-dose (60 mg) long-acting octreotide.⁶Eligible patients were diagnosed with SSTR-positive advanced GEP-NETs within 6 months before enrollment.⁶

About Lutathera^®

Lutathera^® (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) is approved in the US for the treatment of adult patients with SSTR-positive GEP-NETs, including those in the foregut, midgut and hindgut, an indication which includes the NETTER-2 population. Lutathera is also approved in Europe for unresectable or metastatic, progressive, well-differentiated (G1 and G2), SSTR-positive GEP-NETs in adults,^7,8 and in Japan for SSTR-positive NETs.

Novartis and Radioligand Therapy (RLT)

Novartis is reimagining cancer care with RLT for patients with advanced cancers. By harnessing the power of radioactive atoms and applying it to advanced cancers, RLT is theoretically able to deliver radiation to target cells anywhere in the body.^9,10

Novartis is investigating a broad portfolio of RLTs, exploring new isotopes, ligands and combination therapies to look beyond gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and prostate cancer and into breast, colon, lung and pancreatic cancer.

With established global expertise, and specialized supply chain and manufacturing capabilities across the Novartis network, we are supporting growing demand for our RLT medicines. Our production capabilities continue to expand and now include sites in Millburn, US, Zaragoza, Spain, Ivrea, Italy and our new state-of-the-art facility in Indianapolis, US. We recently announced plans to expand our manufacturing capabilities and build additional points of supply in Sasayama, Japan, and Haiyan, Zhejiang, China, to produce RLTs for patients in Japan and China. We are continually evaluating additional opportunities to increase capacity around the world.

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products.. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us:

Visit us at:

novartis.com

NEWS FROM THE AMERICAN
COLLEGE OF SURGEONS

Colorectal Cancer Awareness Month: What to Know about the Rise of Colorectal Cancer in Younger Adults

Experts with the American College of Surgeons share colorectal cancer prevention tips and insights into the concerning rise of diagnoses in younger adults

CHICAGO (March 5, 2024): Rates of colorectal cancer have been rising consistently in younger adults — a trend that concerns surgeons and other medical professionals at the forefront of treating the disease.

“We’ve been noticing an alarming rise in colorectal cancer in adults under the age of 50. In fact, people born in the 1990s are two times more likely than people born in the 1950s to develop colorectal cancer,” said James T. McCormick, DO, FACS, FASCRS, a colorectal surgeon and American College of Surgeons Commission on Cancer (CoC) State Chair of the Pennsylvania chapter. “And that’s remarkably striking. We’re not quite sure why that’s happening or how to screen for it at such a young age. That’s the conundrum.”

For Colorectal Cancer Awareness Month this March, experts with the American College of Surgeons are available for interviews to share insights about the rise of colorectal cancer in younger adults and what steps people of all ages can take to reduce their risk of dying from the disease.

How much is colorectal cancer
increasing in younger adults?

Researchers have noted a 15% increase in colon cancer diagnoses in people aged 18-50 since 2004, according to hospital-based data from the National Cancer Database (NCDB). By comparison, there was only a 3% increase in colon cancer diagnoses in adults aged 45-55 during the same period.

The NCDB, a clinical oncology database jointly operated by the CoC and the American Cancer Society, captures approximately 74% of all newly diagnosed cancers in the U.S.

Colorectal cancer is also killing more young adults. According to the American Cancer Society, colorectal cancer is now the leading cause of cancer deaths in men younger than 50 and the second leading cause of cancer deaths in women of the same age group.

Why is colorectal cancer increasing among young people?

The exact causes behind the increase of colorectal cancer in younger people are not fully understood. However, most experts believe that the rise results from multiple factors, including environmental changes, potential exposure to toxins, genetic factors that may increase a person’s risk of developing the disease earlier in life, and lifestyle factors such as high consumption of ultra-processed foods. Research into all these areas is ongoing.

“We really don’t know one single cause, but it’s likely multifactorial, and risk factors may depend on where the patient lives, what they eat, their lifestyle habits, and other hereditary factors,” said Nitin Mishra, MBBS, MPH, FACS, CoC State Chair of the Arizona chapter, and an associate professor of surgery at Mayo Clinic in Phoenix, Arizona.

What can people do to prevent colorectal cancer?

Despite the unknown, there are several steps everyone can take to reduce their risk of developing the disease and/or dying from colorectal cancer.

First and foremost, ACS experts recommend that people of all ages remain vigilant and report any changes in bowel habits, including bleeding and persistent changes such as constipation or diarrhea, to their primary care physician. Be persistent, and don’t be afraid to ask questions.

“I think a lot of prevention starts with awareness,” said Paula Denoya, MD, FACS, FASCRS, CoC State Chair of the Eastern Long Island-NY chapter and a colorectal surgeon at the Stony Brook Cancer Center. “We’ve all seen patients who had rectal bleeding that was dismissed as hemorrhoids or IBS symptoms for a while before they were found to have colorectal cancer. Knowing your family history is also critically important.”

Starting at age 45, all people should be screened for colorectal cancer annually. Screening may need to start earlier for people with a family history of the disease or for people considered high-risk for

the disease due to other health factors.

The gold standard of colorectal cancer screening is with a colonoscopy, which can help physicians detect colorectal cancer at its earliest stage, when it’s more treatable, and even prevent colorectal cancer through the detection and removal of precancerous growths called polyps. Screening with colonoscopy may be one factor of many that has resulted in nearly 16,000 fewer colon cancer diagnoses among older adults per year, according to hospital-based data from the NCDB. Still, approximately 1 in 4 adults of screening age are not up to date with colorectal cancer screening recommendations, according to national data estimates.

Finally, exercising regularly to maintain a healthy body weight and eating a balanced diet high in lean meat, fiber, whole grains, vegetables, and fruits may also help reduce risk.

“Staying active even has other health benefits besides reducing the risk of colorectal cancer,” said Howard Kaufman, MD, FACS, CoC State Chair of the Southern California chapter and regional medical director of Huntington Cancer Center, an affiliate of Cedars-Sinai Cancer, in Pasadena, California. “For colorectal cancer, my main takeaway message is to get screened if you’re at the appropriate age or have other risk factors, and to see your doctor if you have any unusual bowel symptoms. If your symptoms persist and there’s not a plan to evaluate those symptoms from your doctor, then seek additional care. Don’t ignore symptoms.”

Additional resources:

Colorectal Cancer: What to Know
(American College of Surgeons)

facs.org/colorectalcancer/

References

References
Novartis Data on File.
Man D, Wu J, Shen Z, Zhu X. Prognosis of patients with neuroendocrine tumor: a SEER database analysis. Cancer Manag Res. 2018;10:5629-5638. Published 2018 Nov 13. doi:10.2147/CMAR.S174907Dasari.
A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017; doi:10.1001/jamaoncol.2017.0589.
Frilling A, Åkerström G, Falconi, M, et al. Neuroendocrine tumor disease: an evolving landscape. Endoc Related Cancer. 2012; 19: R163-815.
Lawrence B, Gustafsson BI, et al. The Epidemiology of Gastroenteropancreatic Neuroendocrine Tumors. Endocrinol Metab Clin N Am. 2011; 40:1–18.
ClinicalTrials.gov. NETTER-2 (NCT03972488). Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET (NETTER-2). Accessed January 2024.
Lutathera. Full Prescribing Information. 2018. Revised March 2023. https://www.novartis.com/us-en/sites/novartis_us/files/lutathera.pdf.
Lutathera. Summary of Product Characteristics (SmPC). 2018. Revised February 2023. https://www.ema.europa.eu/en/documents/product-information/lutathera-epar-product-information_en.pdf.
Jadvar H. Targeted radionuclide therapy: an evolution toward precision cancer treatment. AJR Am J Roentagenol. 2017;209(2);277-288.
Jurcic JG, Wong JYC, Knoc SJ, et al. Targeted radionuclide therapy. In: Tepper JE, Foote RE, Michalski JM, eds. Gunderson & Tepper’s Clinical Radiation Oncology. 5th ed. Elsevier, Inc. 2021;71(3):209-249.

References
Cotler J, Chan K, Zhu X. Colorectal cancer statistics, National Cancer Database, 2024.
American Cancer Society. Cancer Facts & Figures 2024. Atlanta: American Cancer Society; 2024.
Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal Cancer Incidence Patterns in the United States, 1974– 2013, JNCI: Journal of the National Cancer Institute, Volume 109, Issue 8, August 2017, djw322, https://doi.org/10.1093/jnci/djw322
“Key Statistics for Colorectal Cancer.” American Cancer Society, January 29, 2024, https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
“Health and Economic Benefits of Colorectal Cancer Interventions.” Centers for Disease Control and Prevention, December 21, 2022, https://www.cdc.gov/pcd/issues/2023/23_0071.htm

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Dispatches from the GUILD Conference, Series #57

Cardiovascular Risk in Inflammatory Bowel Disease: Another Reason to Control Disease Activity

March 2024 • Volume XLVIII, Issue 3

Edward V. Loftus Jr.

Read Article

“Major adverse cardiovascular events” (MACE) are an important endpoint for clinical trials of agents used in chronic inflammatory conditions. The risk of MACE and venous thromboembolism are elevated among patients with inflammatory bowel disease (IBD). Concerns about increased risk of MACE were noted in the ORAL Surveillance trial of tofacitinib versus anti-TNF agents in rheumatoid arthritis, but deeper analyses suggest that most of this risk is borne by a high-risk group older than 65 years who are current/former smokers. In IBD trials, the risk of MACE does not appear to be elevated.

INTRODUCTION

When we refer to the term “MACE,” we are not talking about the spice, the anti-personnel spray or the medieval weapon, we are talking about “major adverse cardiovascular events.” It is important to understand the definition of MACE used in a particular study. The classic definition of MACE is “3-point MACE”, which is non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. Some definitions of MACE include hospitalization for congestive heart failure (CHF), and some include both hospitalization for CHF and hospitalization for unstable angina. Thus, to compare risks across studies, you need to examine the specific definition of MACE used.¹

PATHOGENESIS OF ATHEROSCLEROSIS IN INFLAMMATORY DISORDERS

We are beginning to understand the role of inflammatory cytokines in atherosclerosis associated with inflammatory conditions. Most inflammatory conditions are throwing off pro-inflammatory cytokines such as interleukin (IL)-36, IL-1-beta (β), IL-6, and tumor necrosis factor-alpha (TNF-α). Some of these will amplify the T-cell adaptive response, and the TH1 effector cells will generate more TNF-α, which is pro-atherogenic, whereas the TH17 effector cells will produce IL-17, which, depending on the circumstances, can be either pro-or anti-atherogenic.² TNF-α plays a role in a prothrombotic state through various mechanisms, such as platelet aggregation and endothelial cell activation, whereas IL-1 can increase LDL cholesterol oxidation, and contribute to accelerated atherosclerosis and plaque rupture.³ The proposed mechanism of atherosclerotic cardiovascular disease in inflammatory bowel disease (IBD) is multifactorial, including genetic predisposition, environmental risk factors which contribute to a compromised gut microbiome, including bacterial overgrowth and disruption of the intestinal barrier, and then immune dysregulation, resulting in systemic inflammation including TNF-α, C-reactive protein (CRP), IL-1, and vascular epithelial growth factor. This leads to endothelial cell dysfunction with production of lipopolysaccharide, oxidase of damage, and macrophage activation. This, along with certain medications, as well as atherosclerotic cardiovascular disease (ASCVD) risk factors such as tobacco use, diabetes mellitus, poor diet, and obesity, lead to accelerated atherosclerosis.⁴

CARDIOVASCULAR RISK: SCOPE OF THE PROBLEM

A meta-analysis of five studies, with over 2400 cerebrovascular events, found that the relative risk of cerebrovascular disease was elevated in patients with IBD.⁵ The pooled risk for any IBD was 1.18 (95% CI, 1.09-1.27). For Crohn’s disease, the pooled risk was 1.26 (95% CI, 1.14-1.39), and for UC it was 1.13 (95% CI, 1.05-1.23). The relative risk was higher amongst women (1.28) than men (1.11). The relative risk was higher among patients younger than 40 or 50 years of age, with a relative risk of 1.84, than among older patients, with a relative risk of 1.11. The same meta-analysis examined the risk of ischemic heart disease in patients with IBD and included six studies with over 6400 cardiovascular events in over 123,000 IBD patients.⁵ For any IBD, the relative risk was 1.18 (95% CI, 1.07-1.31). For CD, the relative risk was 1.10 (95% CI, 1.03-1.17), and for UC it was 1.14 (95% CI, 1.03-1.25).

A population-based study of Olmsted County, Minnesota residents diagnosed with IBD between 1970 and 2011 assessed the risk of myocardial infarction in 736 IBD patients along with two matched controls per case.⁶ Despite lower rates of traditional ASCVD risk factors in the IBD patients, including family history of coronary artery disease, cigarette smoking, and hyperlipidemia, the cumulative risk of acute myocardial infarction was significantly higher among IBD patients compared to matched controls (P<0.001, log-rank tests). Overall, the adjusted hazard ratio for myocardial infarction was 2.82 (95% CI, 1.98-4.04). The hazard ratio was higher amongst users of corticosteroids relative to their matched controls, which indirectly suggests that inflammation may be one of the mechanisms of action behind the association. Similarly, the risk of heart failure was significantly higher among IBD patients compared to their matched controls (P<0.02).⁶ The adjusted hazard ratio for heart failure was 2.03 (95% CI, 1.36-3.03). Again, the hazard ratio was higher amongst steroid users relative to their matched controls, suggesting that inflammation may be playing a role.

In a prospective study of 361 unselected IBD patients who underwent coronary artery calcium scoring, 41% had a score of 0, 29% had a score between 1 and 99, 17% score between 103 and 199, and 13% scored greater than 400.⁷ Over half of the patients had an estimated 10-year ASCVD risk estimated greater than 7.5%. Patients with higher calcium scores were more likely to start a statin and more likely to start aspirin. The survival free of MACE was significantly higher among patients with a calcium score less than 76 relative to those greater than 76 (P<0.001, log-rank test).⁷ A calcium score greater than 76 was associated with a 4-fold increased risk of MACE.

A retrospective study of premature cardiovascular disease among U.S. military veterans was performed.⁸ Patients with extremely premature cardiovascular disease, defined as occurring under the age of 40 years, were significantly more likely to have IBD than their matched controls without cardiovascular disease (odds ratio [OR], 1.61; 95% CI, 1.34-1.94).

The United Kingdom Biobank is a large population-based prospective study of over half a million participants aged 40-69 years, with detailed data on cardiac risk factors, and outcomes from primary care visits, hospitalizations, and death registry.⁹ Patients in this biobank with IBD were matched to four non-IBD controls on the basis of age, sex, body mass index, ethnic background, smoking and alcohol usage, hypertension, diabetes mellitus, and hyperlipidemia. The primary outcome of this analysis was a composite of myocardial infarction, cerebrovascular accident, and cardiovascular death. Median follow-up was 12.4 years. The survival free of this endpoint was significantly higher in the non-IBD patients (P=0.011, log-rank test). Overall, patients with IBD had a 19% higher risk of acute arterial events relative to the non IBD patients (adjusted hazard ratio, 1.19; 95% CI, 1.08-1.32).⁹ When examining subtypes of acute arterial events, there was a significant association between IBD and ischemic heart disease. There were trends for myocardial infarction and peripheral arterial disease. For premature acute arterial events, IBD was independently associated with a 39% increased risk (adjusted hazard ratio, 1.38; 95% CI, 1.11-1.72). In addition to expected risk factors such as older age, male sex, hypertension, and diabetes mellitus, disease activity was an important predictor of acute arterial events. Patients with the highest quartile of CRP were 54% more likely to have an acute arterial event than patients in the lowest quartile of CRP values.⁹ Also, disease severity was significantly associated with events (hazard ratio, 5.40; 95% CI, 4.03-7.22).

A study from the U.S. National Inpatient Sample included 2.6 million patients with myocardial infarction, including over 3600 with ulcerative colitis and over 3700 with Crohn’s disease.¹⁰ In-hospital mortality was similar for patients with both IBD subtypes along with myocardial infarction and patients without IBD who had myocardial infarction. However, length of hospital stay was significantly longer among patients with concomitant IBD, and myocardial infarction compared to those with myocardial infarction alone. Additionally, hospital costs were significantly higher in the IBD patients.¹⁰

The incidence of acute arterial events in IBD patients was assessed in the French National database.¹¹ This included over 177,000 IBD patients with over 773,000 person-years of follow-up and included over 4000 acute arterial events. The incidence of acute arterial events with stratified into 3 categories by medication use (no thiopurine or anti-TNF, thiopurine, or anti-TNF). The total incidence of all acute arterial events was 5.4 cases per 1000 person-years, and when stratified by medication category, was 5.9 per 1000 in the no thiopurine/no anti-TNF group, 3.5 per 1000 in the thiopurine group, and 2.9 per 1000 in the anti-TNF group.¹¹ The hazard ratio for all acute arterial events was 0.79 in the anti-TNF group. Thus, it appeared the use of anti-TNF may be protective against the development of MACE.

Even microscopic colitis may be associated with increased risk of MACE. A population-based study from Sweden was recently published and included over 11,000 patients with microscopic colitis.¹² The unadjusted hazard ratio for MACE among the microscopic colitis patients was 1.51 (95% CI, 1.44-1.59). After adjusting for 10 risk factors, the hazard ratio was 1.27 (95% CI, 1.21-1.33), and after adjusting for these 10 risk factors plus the number of healthcare visits, the hazard ratio remained significantly elevated at 1.23 (95% CI, 1.17-1.29).¹²

THROMBOEMBOLISM RISK

It has been recognized for decades that the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) is elevated among patients with IBD. A landmark population-based study from Manitoba showed that the incidence of DVT was 31 cases per 10,000 person-years in Crohn’s disease and 30 per 10,000 in ulcerative colitis.¹³ When compared to 10 matched controls per case, the hazard ratio for DVT in Crohn’s disease was 4.7 and in ulcerative colitis was 2.8. For PE, the incidence rate was 10.3 cases per 10,000 person-years in Crohn’s disease and 19.8 per 10,000 in ulcerative colitis. When compared to matched controls, the hazard ratio for PE was 2.9 in Crohn’s disease and 3.6 in ulcerative colitis.¹³ The authors concluded that IBD patients have an at least threefold risk of developing thromboembolism.

In a retrospective single-center study of 98 patients with IBD and thromboembolism, we found that extensive colitis occurred in 76% of the ulcerative colitis patients, and ileocolonic or colonic disease occurred in almost 80% of Crohn’s disease patients.¹⁴ Thus, it appears that the extent of colonic inflammation may be a risk factor. When examining for specific thrombophilias, we found that about a third of IBD patients tested for thrombophilia were positive, with the most common thrombophilias being activated protein C resistance, factor V Leiden mutation, hyperhomocystinemia, and the presence of antiphospholipid antibodies.¹⁴ Risk factors for thromboembolism among this cohort included immobility or hospitalization in the majority, prior known thrombophilia or thromboembolism, followed by malignancy and recent surgery.

RISK WITH SPECIFIC MEDICATIONS

Janus Kinase Inhibitors

In placebo-controlled trials of tofacitinib for ulcerative colitis, higher increases in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density protein (LDL) cholesterol, and triglycerides were seen among tofacitinib-treated patients compared to those on placebo.¹⁵ Interestingly, decreases in serum CRP concentrations correlated significantly with increases in lipids. The incidence rate of MACE was less than 1 case per 100 person-years.

The ORAL Surveillance study was mandated by the FDA to further examine the safety of tofacitinib in patients with rheumatoid arthritis who were at least 50 years old and had at least 1 cardiovascular risk factor.¹⁶ These patients had already failed methotrexate. They were randomized in a 1:1:1 fashion to tofacitinib 5 mg b.i.d. plus methotrexate, tofacitinib 10 mg b.i.d. plus methotrexate, or either adalimumab 40 mg subcutaneously every two weeks plus methotrexate or etanercept 50 mg subcutaneously weekly plus methotrexate. The primary end points were all safety end points, including adjudicated MACE, defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and adjudicated malignancies excluding non-melanoma skin cancers (NMSC). The study continued until at least 1500 subjects had been followed for three years and at least 103 adjudicated MACE had occurred and at least 138 adjudicated malignancies excluding NMSC.¹⁶

The FDA in 2019 issued a drug safety communication warning about the potential hazards of thromboembolism of tofacitinib based on an interim analysis of this study. The incidence of DVT/PE was 0.49 cases per 100 person-years in the tofacitinib 10 mg b.i.d. group, versus 0.07 cases per 100 person-years in the anti-TNF treated group, with an incidence rate ratio of 7. The mortality rate in the high dose tofacitinib group was 1.16 cases per 100 person-years, versus 0.63/100 person-years in the anti-TNF treated group, yielding an incidence rate ratio of 1.8. A boxed warning about thromboembolism was added to the tofacitinib label, and for all approved indications, the use of tofacitinib were restricted to those who had failed anti-TNF therapy (FDA communication, July 26, 2019).

With the final results of the ORAL Surveillance study, over 4000 patients were enrolled, and the median follow-up was four years.¹⁶ A total of 3.4% of the tofacitinib-treated patients developed adjudicated MACE, versus 2.5% of the anti-TNF-treated patients. The incidence rate of MACE was 0.98 cases per 100 person-years with tofacitinib and 0.73 cases per 100 person-years with TNF inhibitors. The hazard ratio for MACE with tofacitinib relative to TNF inhibitors was 1.3 (95% CI, 0.9-1.9). Since the pre-specified endpoint for non-inferiority was that the upper limit of the 95% CI would be less than 1.8, non-inferiority for tofacitinib was not met.¹⁶ For adjudicated cancers, a total of 4.2% of the tofacitinib-treated patients developed malignancy, versus 2.9% of the TNF inhibitor-treated patients. The incidence rate of cancer was 1.13 cases per 100 person-years with tofacitinib and 0.77 per 100 with TNF inhibitors. The hazard ratio for malignancy excluding NMSC with tofacitinib was 1.48 (95% CI, 1.04-2.09), and therefore the primary endpoint of non-inferiority versus TNF inhibitors was not met for this endpoint, too.¹⁶

Several groups have examined in more detail the risk factors for MACE and malignancies within this study cohort. In one analysis, patients who were older than 65 years and were either current or former cigarette smokers were considered the high-risk group (n=2821), whereas patients who were younger than 65 years and had never smoked were considered low-risk patients (n=1541).¹⁷ In the low-risk category, there was no longer a significant increase in incidence rate of malignancies excluding NMSC, MACE, myocardial infarction, venous thromboembolism (VTE), or all-cause mortality. Furthermore, when the cumulative incidence of end points was stratified by the high-risk and low-risk categories, it was clear that the differences in cumulative risk between tofacitinib and anti-TNFs seen in the high-risk population were no longer seen in the low-risk population.¹⁷ This would suggest that there is a population of patients (younger than 65 years and nonsmokers) who would benefit from tofacitinib and not be at increased risk for these safety events.

In the OCTAVE Open clinical trial program for ulcerative colitis, a total of four PE events were seen, all of whom had at least one risk factor for PE, and 1 DVT event was seen in a patient who had at least 3 risk factors for DVT.¹⁸ In an integrated safety analysis of the entire global clinical program of tofacitinib in ulcerative colitis, which included phase 2 and phase 3 trials, and an interim analysis of a phase 3b/4 study, the mortality rate was 0.2 deaths per 100 person-years, and the incidence rates for MACE was 0.3 cases per 100, for malignancies excluding non-melanoma skin cancers was 0.8/100, for DVT was 0 cases per 100, and for PE was 0.2 cases per 100.¹⁹

In the upadacitinib clinical programs for ulcerative colitis and Crohn’s disease, there does not appear to be a strong signal for either VTE or MACE. In the phase 3 U-ACHIEVE maintenance study, there were no VTE events seen in patients treated with placebo or upadacitinib 15 mg daily.²⁰ There were two patients on the 30 mg dose of upadacitinib who had VTE, for an incidence rate of 1.5 cases per 100 person-years. There were no MACE events seen in patients treated with either dose of upadacitinib in this same study.²⁰ In the U-ENDURE maintenance study of upadacitinib in Crohn’s disease, there were no venous thromboembolic events seen in patients treated with placebo or upadacitinib 15 mg daily.²¹ There was a single case of hepatic vein thrombosis concurrent with an exacerbation of Crohn’s disease in a patient treated with 30 mg daily of upadacitinib, for an incidence rate of 0.6 cases per 100 person-years. There were no MACE events seen in U-ENDURE.²¹ An integrated analysis of MACE and VTE across the rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis phase 2b/3 clinical programs of upadacitinib was performed.²² The incidence rates of MACE ranged from 0.3 to 0.6 events per 100 person-years in the rheumatoid arthritis and psoriatic arthritis trials. There were no MACE events seen in the ankylosing spondylitis trials. Similarly, for VTE, incidence rates ranged from 0.2 to 0.4 cases per 100 person-years in these trials.²²

The comparative cardiovascular safety of tofacitinib and anti-TNF agents were compared in a United States insurance claims database, which included 305 IBD patients on tofacitinib and over 19,000 patients on anti-TNF therapy.²³ A total of 5% of tofacitinib-treated patients and 3% of anti-TNF-treated patients developed VTE. Four percent of tofacitinib-treated patients and 3% of anti-TNF-treated patients developed cardiovascular events. MACE occurred in 2% of tofacitinib-treated patients and 1% of anti-TNF-treated patients.²³ The hazard ratio for VTE with tofacitinib relative to anti-TNF therapy was 1.7 (95% CI, 0.7-3.0), and for cardiovascular events was 2.5 (95% CI, 0.4-6.2).

Anti-Interleukin Antibodies

In the psoriasis and psoriatic arthritis literature, there have been conflicting data as to whether or not cardiovascular events are associated with the use of ustekinumab. A different monoclonal antibody to interleukins-12 and -23, briakinumab, had demonstrated an increased risk of MACE.²⁴ For example, in a study of two U.S. commercial insurance claims databases, the incidence rates of atrial fibrillation and MACE were determined among over 60,000 patients with psoriasis or psoriatic arthritis treated with either ustekinumab or anti-TNF therapy.²⁵ Incidence rates of atrial fibrillation were 5.0 cases per 1000 person-years for ustekinumab-treated patients and 4.7 per 1000 for anti-TNF-treated patients. For MACE, the incidence rates were 6.2 cases per 1000 person-years for ustekinumab and 6.1/1000 for anti-TNF therapy.²⁵ The adjusted HR for atrial fibrillation among those treated with ustekinumab was 1.1 (95% CI, 0.8-1.52). The authors concluded that there was significantly different risk of atrial fibrillation of MACE.

In a pooled safety analysis of phase 2 and phase 3 studies of ustekinumab for Crohn’s disease and ulcerative colitis, there were 2 adjudicated MACE events in the ulcerative colitis patients: one patient with nonfatal myocardial infarction and one nonfatal stroke.²⁶ Additionally, there was one patient with acute myocardial infarction perioperatively, who ultimately succumbed to acute respiratory distress syndrome (ARDS) and was categorized as a cardiovascular death. In Crohn’s disease, there was one adjudicated non-fatal stroke. DVT/PE events were reported in 13 ustekinumab patients for a total of 0.75 patients per 100 person-years.

In the FORTIFY phase 3 maintenance study of risankizumab for Crohn’s disease, there were no MACE events reported in either of the risankizumab-treated patient groups.²⁷

Sphingosine-1-Phosphate Receptor Modulators

Activating cardiac sphingosine-1-phosphate (S1P) receptors may affect heart rate and cardiac contractility, protect from ischemia, induced hypertrophy, and mobilize intracellular calcium. Conversely, blocking S1P receptor activation may disrupt potassium channels in cardiac myelocytes and interrupt cardiac conduction by hyper polarizing myelocytes.

There are two S1P receptor modulators that are now approved for moderately to severely active ulcerative colitis, ozanimod and etrasimod. Ozanimod selectively blocks the S1 P1 and S1 P5 receptors, whereas etrasimod blocks S1 P4 in addition to S1 P1 and S1 P5. There may be more cytochrome P 450 interactions with ozanimod versus etrasimod. The half-life of ozanimod is 21 hours, but there is an active metabolite with a half-life of 11 days. The half-life of etrasimod is approximately 33 hours. There appears to be first dose heart rate reduction with both medications. Ozanimod has a dose titration regimen for the first week, whereas there is no dosed titration with etrasimod. It is recommended that patients get an ophthalmic exam if they have risk factors for macular edema with ozanimod, and it is recommended that all patients starting etrasimod get a baseline ophthalmic exam. Fortunately, there were only a few MACE events or VTE events associated with ozanimod in the phase 2 and phase 3 ulcerative colitis studies, for a cumulative exposure of over 2200 person-years.²⁸ There were no myocardial infarctions, three patients with ischemic strokes, four patients with VTE, and one patient with sudden death. Ozanimod has been shown to be a weak monoamine oxidase inhibitor, and thus theoretically could cause serotonin syndrome in patients who are also on selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. In one analysis of adverse events which could theoretically be part of serotonin syndrome, including pyrexia, nausea, hypothermia, tremor, and tachycardia, the incidence of these events was not significantly higher among patients on SSRIs or SNRIs compared to those not on these medications.²⁹ In the multiple sclerosis literature, an open-label study of ozanimod demonstrated no increase in adverse events which theoretically were symptoms of serotonin syndrome in patients on SSRI/SNRI.³⁰

Recently, there have been several systematic reviews and meta-analyses of the risk of MACE among IBD patients, stratified by medications. In one systematic review, there were 22 randomized controlled trials involving over 12,000 patients with Crohn’s disease, and 32 randomized trials involving over 22,000 patients with ulcerative colitis. The authors concluded that there was no impact on the risk of MACE among Crohn’s disease patients with any of the biologics (i.e., anti-TNF agents, anti-integrins, anti-interleukins). Among 32 randomized trials involving over 22,000 ulcerative colitis patients, there was similarly no impact on the risk of MACE among the ulcerative colitis patients (anti-TNF, anti-integrin, anti-interleukin, JAK inhibitor).³¹ Another systematic review and meta-analysis examined the risk of MACE among patients treated with biologics or small molecules for multiple immune-mediated inflammatory disorders, including IBD, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.³² There were 36 randomized control trials and 4 cohort studies including over 126,000 patients. This analysis detected an increased risk of MACE with anti-IL-12/23 medications relative to placebo, with OR of 3.15 (credible interval [CrI], 1.01-13.35), with anti-TNF agents (OR, 2.49; CrI, 1.14-5.62), and with JAK inhibitors (OR, 2.64; CrI, 1.26-5.99). No increased risk of MACE was seen with the anti-p19 anti-IL-23 agents (OR, 2.65; CrI, 0.85-10.03). No difference in the risk of MACE was seen between drug classes or between disease states.

CONCLUSIONS

MACE will continue to be an important outcome in IBD trials. The definition of MACE can vary across studies so definitions need to be checked before making cross-comparisons. Despite fewer conventional coronary artery disease risk factors, there does appear to be an increased risk of cardiovascular and cerebrovascular events in IBD patients. Therefore, patients with chest pain probably need a thorough evaluation, even if they are younger, female, etc. In addition, thromboembolism occurs with more frequency in IBD patients, likely due to increased inflammation and more colonic involvement. There is no one specific thrombophilia that is increased. Hospitalized patients should be on VTE prophylaxis. Finally, there is no clear-cut signal of increased MACE with specific medications. The results of the ORAL Surveillance study in rheumatoid arthritis may not necessarily be translatable to the IBD population and may not be able to be extrapolated to JAK inhibitors as a whole. Certainly, there does not appear to be an increased risk of MACE among patients under the age of 65 years who are never smokers.

References

References
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Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004;99:97-101.
Sands BE, Taub PR, Armuzzi A, et al. Tofacitinib treatment is associated with modest and reversible increases in serum lipids in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2020;18:123-132.
Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386:316-326.
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From the Pediatric Literature

Zonulin and Pediatric Celiac Disease

March 2024 • Volume XLVIII, Issue 3

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Permeability of the intestinal tract is thought to play a role in the development of celiac disease (CD), and markers for intestinal permeability would be helpful in discovering the pathogenesis of this disorder. Zonulin is involved with tight junction function between intestinal epithelial cells, and high zonulin levels are associated with increased intestinal permeability. Thus, the authors of this study evaluated intestinal permeability changes in children prior to a diagnosis of CD.

This study used data from the Celiac Disease Genomic Environmental Microbiome and Metabolomic study (CD-GEMM). CD-GEMM is a prospective study following children who have a first degree relative with CD, and such children are followed over time with serial blood and stool samples as well as clinical information obtained. The authors used data from CD-GEMM study subjects enrolled between 2014 and 2022 from both Italy and the United States. All patients had blood samples obtained every 6 months for the first 3 years of life and then annually. Parental diaries and other clinical information, including a subject’s age at gluten introduction, number of respiratory and gastrointestinal viral infections, and antibiotic exposure were recorded. Celiac antibody and human leukocyte antigen genotype testing occurred in all subjects. Study subjects were diagnosed with celiac disease autoimmunity if they had elevated celiac antibody titers on at least two separate occasions. Study subjects were diagnosed with CD if they had histologic changes consistent with CD on endoscopic duodenal biopsy or had elevation of celiac antibody titers that met criteria for CD per recommendations from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Patients with celiac disease autoimmunity and CD were combined into one group labeled as “celiac disease autoimmunity” (or CDA). This group of patients with CDA was compared to matched controls, and serial serum zonulin levels were obtained in both study and control patients.

A total of 51 study subjects with CDA were compared to the same number of controls. It was noted that 63.7% of subjects were female with 31.4% of enrolled subjects being from the United States (68.6% being from Italy). Gluten introduction occurred at 7.9 months for controls and 8.3 months for patients with CDA. Follow-up time averaged 15.5 months for all study subjects.

Mixed effect longitudinal modeling demonstrated a steeper slope differential that was statistically significant for increased zonulin levels in patients with CDA compared to controls. This steeper slope indicating higher zonulin was present 6 to 78 months before a diagnosis of CDA. Study subjects from Italy had a higher mean zonulin level compared to children from the United States. A subject’s age at initial gluten introduction and amount of gluten ingested did not account for zonulin level changes. Although the number of viral infections did not increase the risk of CDA, the use of antibiotics significantly increased the risk of CDA occurring. Antibiotic use, especially multiple rounds of antibiotics, also increased zonulin levels more rapidly.

This study demonstrates that zonulin levels may be a useful marker for intestinal permeability in the setting of pediatric patients who are at risk of developing CD. Perhaps increasing zonulin levels also may prove to be a diagnostic technique to predict CD in pediatric patients. The association of antibiotic use and rising zonulin levels suggests that intestinal microbiome changes potentially can lead to CD which further enforces the importance of antibiotics stewardship.

DaFonte T, Valitutti F, Kenyon V, Locascio J, Montuori M, Francavilla R, Passaro T, Crocco M, Norsa L, Piemontese P, Baldassarre M, Fasano A, Leonard M, and the CD-GEMM Study Group. Zonulin as a Biomarker for the Development of Celiac Disease. Pediatrics 2024; 153: e2023063050.

Infant Symptoms are Often Misdiagnosed as GERD

Infants in the newborn intensive care unit (NICU) are often diagnosed with gastroesophageal reflux disease (GERD); however, symptoms such as back arching and irritability are non-specific and may not be associated with GERD events. This issue is important as gastroesophageal reflux (GER) is a normal physiological process which often does not correlate with GERD symptoms. The authors of this study used the technique of 24-hour pH / impedance monitoring to determine if symptoms of infant back arching and irritability were associated with acidic GERD.

This retrospective study from a U.S. tertiary children’s hospital evaluated all pH / impedance probe studies done at their institution over an 8-year period. All included studies had a minimum of 18 hours of recorded data. Infants older than 52 weeks postmenstrual age, infants on proton pump inhibitor therapy at the time of the pH-impedance study, and infants with no outcome data at one year were excluded. All included infants in the study underwent chest radiography to confirm probe placement, and all studies occurred with patients in the supine position. An infant in the study was considered to have frequent arching and irritability if greater than 72 such events occurred during a typical pH / impedance probe study. Symptom-associated probability between infant symptoms and documented GER events was determined by the Fischer Exact Test, and any acid GER event or bolus event occurring 2 minutes before a symptom of arching and irritability was considered a related GERD event.

In total, 516 infants were evaluated by pH / impedance monitoring for which 297 of infants in the NICU had arching and irritability. The median gestational age for study infants was 30.1 weeks, and the median age at the time of pH / impedance monitoring was 41.7 weeks. No significant difference in arching and irritability was present between male and female infants when comparing infants with less than 72 arching and irritability events and infants with 72 or more arching and irritability events. A total of 4456 out of a total 39,973 arching and irritability events were associated with a bolus-associated GERD (11.1% of events). A total of 3062 out of 39,962 arching and irritability episodes were associated with acidic GERD (sensitivity = 8%) while a total of 246,462 out of 262,534 events were not associated with acidic GERD (specificity = 94%). The authors noted a positive predictive value for arching and irritability episodes of 17% for bolus GERD events and 16% for acidic GERD events. The negative predictive value for both bolus GERD and acidic GERD events was 87%. Acidic GER events were not significantly different between infants with less than 72 arching and irritability episodes and infants with 72 or more arching and irritability episodes. However, infants with GERD episodes during a bolus feed were more likely to have arching and irritability episodes.

Infants with 72 or more arching and irritability episodes were statistically more likely to have a history of prematurity, history of oral feeding, neurologic disease, or chronic lung disease. At one year post study, such infants were significantly more likely to have undergone fundoplication.

This study provides further evidence that symptoms related to GERD in infants are over diagnosed. In NICU infants with excessive arching and irritability episodes, no significant correlation was noted in relation to increased acidic reflux during pH / impedance monitoring. Instead, infants with excessive arching and irritability episodes appeared to have other significant health issues not related to GERD. This study demonstrates that infants with perceived irritability and arching likely have other causes to their symptoms instead of GERD which should be considered. Additionally, this study provides evidence that acid suppression therapy likely was not needed in most of these infants as there was minimal correlation of GER to symptoms.

Njeh M, Helmick R, Alshaikh E, Marcano K, Alexander A, Osborn E, Jadcherla S. The Irritable Infant in the Neonatal Intensive Care Unit: Risk Factors and Biomarkers of Gastroesophageal Reflux Disease. J Pediatr 2023; 264: 113760.

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FRONTIERS IN ENDOSCOPY, SERIES #89

Disposable Endoscopes: Current Status and Future Directions

February 2024 • Volume XLVIII, Issue 2

Monique T. Barakat,

Douglas G. Adler

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Endoscopic retrograde cholangiopancreatography (ERCP) is a minimally invasive endoscopic procedure that allows visualization and therapeutic maneuvers to be performed in the bile and pancreatic ducts. ERCP has traditionally been performed by reusable duodenoscopes, but disposable duodenoscopes have been introduced to the field in efforts to decrease endoscope-related infections. Traditional duodenoscopes require high-level disinfection due to their complex design, but residual bacteria can persist despite reprocessing. Sterile, disposable duodenoscopes reduce the risk of potential outbreaks and infections due to transmission, but these disposable duodenoscopes are costly and are associated with significantly more environmental waste and greenhouse gas emissions. This review will discuss the safety and efficacy of disposable duodenoscopes, their environmental impact, and potential indications for their use. Disposable gastroscopes will also be discussed.

INFECTION CONCERNS OF TRADITIONAL REUSABLE DUODENOSCOPES

Contamination Rates of Duodenoscopes

The incidence of infection following an ERCP ranges from 2-4%, and a small number of these infections can be attributed to exogenous causes related to contaminated reprocessed duodenoscopes transmitting organisms between patients. A study by Rauwers et al. found that 22% of reprocessed duodenoscope were contaminated and 15% of the duodenoscopes grew microorganisms with gastrointestinal or oral origin, including Enterobacter cloacae, Escherichia coli, Klebsiella pneumonia, and yeasts, many of which are part of the normal flora of the gastrointestinal tract. Another study found that reprocessed duodenoscopes could be contaminated at a rate of 5.3% with high-concern organisms, such as gram negative rods, Staphylococcus aureus, Staphylococcus lugdunensis, β-hemolytic Streptococcus, and Enterococcus species.

Endoscopic procedures are not sterile, and while efforts should be made to minimize endoscopy-related infections, equipment harboring bacteria does not guarantee that potentially harmful organisms will be transmitted to a patient. Currently, reusable duodenoscopes are used to perform most ERCPs in the United States and around the world, but their intricate structural design, especially the elevator mechanism, makes them difficult to successfully disinfect between procedures. For example, swabs of the elevator, distal end cap, and biopsy/suction channel had a higher probability of being contaminated.²In addition to these factors related to the physical structure of a duodenoscope, Rauwers et al. identified miscommunication about reprocessing, undetected damaged parts, and inadequate repair of duodenoscope damage as potential reasons for outbreaks of multidrug resistant bacteria.

Post-Enhanced Surveillance and Reprocessing Techniques Rates

A meta-analysis conducted by Larson et al. found that there was a contamination rate of 15.25% for reprocessed, patient-ready duodenoscopes. Due to these contamination rates, in 2015 the United States Food and Drug Administration recommended enhanced surveillance and reprocessing techniques (ESRT) to improve disinfection. These additional reprocessing steps include microbiological culture, ethylene oxide sterilization, liquid chemical sterilant processing system, and double high-level disinfection. When ESRT protocols were followed, Bomman et al. found that the contamination rates were 5% and 0.8% for low and high-risk organisms, respectively.Although these enhanced techniques seem to lower contamination rates, reusable duodenoscopes are still unable to be completely sterilized, and disposable duodenoscopes have been developed as an alternative to mitigate this issue.

DISPOSABLE DUODENOSCOPES

Comparing Two Models

There are currently two disposable duodenoscopes commercially available in the United States, aScope Duodeno by Ambu Inc (Ballerup, Denmark) and EXALT Model D Single-Use Duodenoscope by Boston Scientific (Natick, Massachusetts), that are approved for clinical use by the FDA (Figures 1-7). Both are similar in design to currently available reusable duodenoscopes. A study completed by Shahid et al. compared the two disposable duodenoscopes and saw that they were rated similarly by endoscopists in terms of visualization quality, maneuverability, suction/air control, and elevator efficiency.This being said, however, endoscopists in this study rated both disposable duodenoscopes as inferior to their reusable counterparts.⁷

Safety and Efficacy

Both aScope Duodeno and EXALT Model D were found to have acceptable safety and efficacy.^,, Bang et al. found that disposable duodenoscopes were comparable in terms of overall safety and technical performance to reusable duodenoscopes when performing low-complexity ERCP procedures.⁸ Specifically, Bang and colleagues found that there was no difference in maneuverability and the ability to provide therapeutic interventions, but ease of passage through the stomach, image quality, image stability, and air-water button functionality were inferior for disposable duodenoscopes when compared to reusable instruments. Although disposable duodenoscopes and reusable duodenoscopes may not perform identically, the overall safety and performance were felt sufficient to make disposable duodenoscopes a viable alternative to reusable ones when performing ERCP.

A comparative bench simulation study by Ross et al. found that completion times for disposable versus reusable duodenoscopes were comparable across 4 different tasks and 14 subtasks on anatomic bench models.⁹ There were no significant differences in performance between the disposable duodenoscope and the reusable duodenoscopes that were used.While this study found no significant difference in the overall performance rating of the different duodenoscopes, they noticed that the navigation/pushability ratings for the disposable duodenoscope was significantly lower than that of its reusable counterpart.

Fully disposable duodenoscopes were also successful in providing therapeutic interventions. A meta-analysis of 7 studies by Ramai et al. found high rates of success in cannulation (95%), sphincterotomy (100%), bile duct stone clearance (100%), stent placement (97%), stent removal (100%), and balloon dilation (97%).¹⁰ Overall, disposable duodenoscopes were comparable to reusable duodenoscopes and were able to achieve high rates of technical success.

Performance of Disposable Duodenoscopes in Complex ERCPs

Disposable duodenoscopes have also been successfully used in high complexity ECRPs with disposable duodenoscopes used to complete ERCP cases across all 4 American Society for Gastrointestinal Endoscopy (ASGE) complexity grades with overall completion rates of 96.7% and high median overall satisfaction rates.The performance of disposable duodenoscopes was seen to be effective and safe even during technically complicated procedures in a multicenter, international, retrospective study which evaluated 47 grade 3 and 19 grade 4 ERCPs and saw technical success rates of 98.5%.

Success with Non-Expert Endoscopists

Procedural outcomes are another potential concern surrounding disposable duodenoscopes when used by endoscopists with varying degrees of experience. A study by Slivka et al. compared outcomes for expert (as defined by >2000 lifetime ERCPs) and “less-expert” (lifetime ERCPS ≤ 2000) endoscopists and reported similar mean procedural completion times, mean number of cannulation attempts, crossover rate (crossover from a disposable device to a reusable duodenoscope), and proportion of cases with high complexity. This study found that both expert and less-expert endoscopists were able to use disposable duodenoscopes to successfully complete ERCPs with a range of complexity (all 4 ASGE complexity grades). ERCP completion rate and median completion time for expert vs. less-expert endoscopists were 96.3% vs. 97.5% and 25.0 vs. 28.5 minutes, respectively. The median overall satisfaction with the disposable duodenoscopes were similar for the two groups as well.A study by Bruno et al. similarly found good ERCP procedural success and high-performance ratings for disposable duodenoscopes used by endoscopists with varying levels of experience across academic medical centers in 11 countries.

ADVERSE EVENTS REPORTED WITH DISPOSABLE DUODENOSCOPES

Infections

Disposable duodenoscopes are delivered in a sterile package. Endoscope-related infections, however, are not only caused by transmission of bacteria from reusable duodenoscopes and can also occur due to endogenous bacteria transmitted from a patient’s mouth or upper GI tract to their biliary tract. A meta-analysis including only studies of ERCPs completed with disposable duodenoscopes still included the adverse event of post-ERCP infection.¹¹As such, it should be emphasized that even completely sterile instruments do not eliminate the possibility of ERCP-related infection.

Other Adverse Events

Disposable duodenoscopes may decrease the chances of endoscope-related infections, but the differences in tactile feedback, navigation, and so-called “pushability” of these newer devices may also make them susceptible to contributing to other ERCP associated adverse events. This is evidenced by a case report of an esophageal perforation during an ERCP using a disposable duodenoscope performed by an experienced endoscopist at a community hospital.¹⁸ An analysis of post marketing surveillance data of disposable duodenoscopes from 2018 to 2021 also found 3 reports of internal organ perforation, 2 reports of tissue damage, and 2 reports of hemorrhage or bleeding.

In addition to patient-related adverse events, there are also reports of device failures. There were reports of optical problems, difficulty advancing the duodenoscope, fluid leaks, and use-of-device problems.¹⁶ Endoscopists should be aware of these issues when using disposable duodenoscopes. Differences in feel and device operational properties can lead to adverse patient events, and more research needs to be conducted to see if these are being caused by unfamiliarity with the device or due to differences in device design, tactile feedback, materials, or other characteristics.

DISPOSABLE GASTROSCOPES

In addition to disposable duodenoscopes, disposable gastroscopes are available. Reusable gastroscopes can also be contaminated with native flora of a patient, and the incidence of infectious transmission by gastroscope is reported to be between 1.6 and 3.7 per 1,000 gastrointestinal endoscopic procedures. Duodenoscopes are prone to reprocessing errors because of their complex designs, but Goyal et al. found that there was a 19.98% contamination rate unrelated to the elevator mechanism in gastrointestinal endoscopes. The authors’ meta-analysis including only studies evaluating gastroscopes found a contamination rate of 28.22% ± 0.076%. Like disposable duodenoscopes, disposable gastroscopes may decrease procedure-related infections. These devices may also be advantageous in the ICU, OR, or other settings beyond GI endoscopy suites.

A study by Li et al. reported that disposable endoscopes had similar rates of excellent and good image qualities when compared to the traditional endoscopes.¹⁵ The maneuverability satisfaction of disposable endoscopes was also not inferior to the conventional reusable endoscope. There was no significant difference observed in endoscopy outcomes or adverse events, but the procedure duration for the disposable endoscope was longer (8.40 ± 4.28 vs. 5.12 ±2.65). Han et al. conducted at pilot study of 30 patients who underwent diagnosis and/or treatment with a disposable esophagogastroduodenoscopy (EGD). Therapeutic EGD was performed on 13 of the patients and included hemostasis, foreign body retrieval, nasoenteric tube placement, and percutaneous endoscopic gastrostomy. All procedures were successfully completed without crossover to a conventional, reusable gastroscope, and the authors concluded that the EGD using the disposable scope may be a feasible alternative in emergency, bedside, and intraoperative settings.

COSTS AND EFFORTS TO CLEAN REUSABLE DUODENOSCOPES

Costs to Clean

One benefit of disposable duodenoscopes is that they eliminate the need for and cost of duodenoscope reprocessing. Compared to standard reprocessing techniques, Bomman et al. found that enhanced reprocessing costs were 2.6-fold higher with “culture and quarantine” and 3.7-fold higher with the EtO sterilization technique. More specifically, at these institutions, the adoption of double high-level disinfection (HLD) increased the costs by about 47% ($80 vs. $118) in comparison to single HLD. Culture and quarantine increased costs by 160% ($80 vs. $208) and ethylene oxide (EtO) gas sterilization increased costs by 270% ($80 vs. $296). Based on their analysis, the authors found that the implementation of enhanced-SRT would require an additional annual budget of $406,000 for high volume centers. In addition to the increased costs, enhanced-SRT introduced significant scope downtime, which created a 3.4-fold increase in the number of scopes needed to keep up with the procedural volume at these centers.While enhanced surveillance and reprocessing techniques lower contamination rates, they come with additional costs and labor.

Barakat et al. found that partially disposable duodenoscopes (duodenoscopes with disposable endcaps) were the most favorable from a cost utility standpoint when downstream costs associated with duodenoscope-transmitted infection were taken into account. They also noted that disposable duodenoscopes were a more favorable option from a cost utility standpoint when compared to single or double HLD, EtO sterilization, and culture and quarantine. Even in low-volume settings (centers performing fewer than 50 ERCPs a year), they found that partially disposable duodenoscopes were the most favorable in terms of cost-utility, followed by culture and quarantine, EtO sterilization, double HLD, single HLD as the least favorable.

Efforts to Clean

In addition to the high costs required to maintain reusable duodenoscopes, reprocessing them also takes considerable time and manual effort. A survey by Sivek et al. reported that it takes ≤ 10 minutes to finish pre-cleaning and 16 to 30 minutes to finish manual cleaning. This study found that the top 3 contributing factors to cleaning difficulty were time pressure, small cleaning areas, and uncomfortable height of work surfaces for operators. Factors contributing to reduced cleaning effectiveness similarly involved time pressure, uncomfortable height work surfaces, quality of training, and memory load (remembering all the steps of the cleaning process). Cleaning reusable duodenoscopes, depending on the model, takes about 18-23 steps for the pre-cleaning process and about 60-85 steps for the manual cleaning procedure. These cleaning procedures were also reported to cause body fatigue or discomfort for ≥75% of respondents. If reusable duodenoscopes continue to be the main type of duodenoscope used, these human factor issues should be addressed to provide a better work environment that can hopefully lead to lower contamination rates.

ENVIRONMENTAL EFFECTS OF DISPOSABLE DUODENOSCOPES

4.4% of total greenhouse gas emissions worldwide and 8% in the United States are due to the healthcare sector. Eighteen million endoscopic procedures are performed in the United States each year, and endoscopy has a considerable impact on the environment. While disposable duodenoscopes decrease concerns for procedure-related infections, increased utilization will also increase the amount of waste generated from disposable instruments.

After completing a 5-day cross-sectional study at two US academic medical centers, Namburar et al. reported that a single endoscopy (assuming disposable endoscopes have the same mass as reusable endoscopes) generated 2.1 kg of disposable waste (2.4 kg when including waste from reprocessing).²¹ 64% of the waste was destined for the landfill, 28% of waste was biohazard waste, and 9% was recycled. Over a five-day period, 278 endoscopies were performed at these two medical centers and the total waste produced amounted to a remarkable 619 kg.

When applying these estimates to all endoscopic procedures performed in the United States annually, the total waste produced from single-use supplies would weigh 38,100 metric tons, the equivalent of covering 117 soccer fields with waste coming up to 1 m.²¹ When adding the additional waste produced when reprocessing endoscopes, the total waste mass increases to 43,500 metric tons, and the total waste volume would cover 130 soccer fields.

If colonoscopies and ERCPs, to name just two endoscopic procedures, were performed solely by disposable endoscopes, the waste related to reprocessing would decrease, but the total net waste mass per endoscopic procedure would increase by 25%.²¹ Even after accounting for the lack of waste generated from reprocessing, using disposable endoscopes would increase the total net waste mass by 40%. The authors found that disposable endoscopes would create about 2 kg of waste per procedure, and only 10% of the waste was actually recycled. Disposable endoscopes would negatively impact the environment by creating more greenhouse gas emissions via the incineration of plastic material. The environment can also be expected to be impacted from the manufacturing of the disposable endoscopes.

For each reusable endoscope, approximately 2,000 disposable endoscopes need to be produced to perform an equal number of procedures.²¹ This is due to the fact that reusable endoscopes are designed to have a multi-year lifespan and are manufactured to stand up to repeated uses that involve significant mechanical forces. Le et al. estimated that performing an ERCP with a disposable duodenoscope releases between 36.6 and 71.5 kg CO₂ equivalent.²² This is a staggering 24 to 47 times more than the emissions emitted with the use of a reusable duodenoscope or a reusable duodenoscope with a disposable endcap. Manufacturing disposable duodenoscopes accounts for 91% to 96% of these emissions. Although reprocessing reusable duodenoscopes generates greenhouse emissions, the top contributor of emissions for these scopes is electricity use during the procedure. In comparison to reusable duodenoscopes, Le et al. estimated that disposable duodenoscopes have 4 times higher ecosystem impact (expressed as the number of potentially lost species) than reusable duodenoscopes and consume at least 26 times more resources, even after reprocessing was taken into account.

Reusable duodenoscopes carry a higher rate of contamination after reprocessing, but Le et al. found that disposable duodenoscopes have 13 to 26 times more impact than reusable duodenoscopes in terms of environmentally mediated human health impacts, 4 to 7.5 times more impact in regards to ecosystem quality, and 26 to 50 times more impact when looking at resource consumption.²¹ Disposable duodenoscopes can provide a public health benefit by decreasing potential infections and infectious transmissions between patients, but this comes at a higher cost to the environment.

INDICATIONS FOR DISPOSABLE DUODENOSCOPES

Low Volume Institutions

Bang et al. looked at the per-procedure cost of a disposable duodenoscope in the United Sates and found that the costs can vary from $797 to $1547 for centers performing at the 75^th percentile of ERCP procedure volume (125-150 ERCPs per year) and from $1318 to $2068 for institutions performing at the 25^th percentile of ERCP procedural volume (≤50 ERCPs per year) based on infection rates. When infections were not factored, the per-procedure cost decreased to $818 and $297 for centers performing at the 25^th and 75^th percentiles, respectively, suggesting that the cost of a disposable duodenoscope differs depending on both infection rates and procedure volume.

Based on this analysis, for a large-volume center to break even, disposable duodenoscopes would need to be priced much lower compared to low-volume centers. While this ‘per procedure cost’ will differ depending on the center, at the authors’ institution, a reusable duodenoscope purchased for $35,000 was used for 3 years to perform about 200 ERCPs each year. If a disposable duodenoscope was used in its place, it would cost about $367,200 ($612 per procedure), which would be over 10 times the costs to perform the same number of ERCPs using a reusable duodenoscope. Low volume centers that have technical expertise but that do not want to invest in capital equipment may be more inclined to incorporate the use of disposable duodenoscopes.

High Risk Patients

Reusable duodenoscopes may harbor bacteria even after reprocessing, but it is unclear how frequently this translates to patient infections. A majority of post-ERCP infections are likely due to suboptimal ductal drainage and residual microbes, so the number of infections directly caused by contaminated duodenoscopes is uncertain.²²

An analysis of Fee-for-Service Medicare patients undergoing ERCP identified 823,575 procedures between January 2015 and December 2021 and found that 3.5% (29,090) of these patients were hospitalized for infection within 7 days of the ERCP. Disposable duodenoscopes were billed for 711 of the procedures, and there was a 1.4% post-ERCP infection rate within 7 days. This study demonstrates that disposable duodenoscopes decrease the number of post-ERCP infections, but do not eliminate them completely. The analysis also found that ERCPs that were performed for urgent indications were the strongest risk factor for infections within the 7-day period. Chronic conditions, infection at time of ERCP, male sex, older age, and race were also risk factors. Disposable duodenoscopes did not fully eliminate post-ERCP infections in this study, but it may be appropriate to consider disposable duodenoscopes in patient populations that are at higher risk for post-ERCP infection, targeting these groups for specialized infection control prevention measures to avoid both duodenoscope-transmission of high-risk organisms to these patients and contamination of duodenoscopes.

CONCLUSION

Reusable duodenoscopes have been shown to harbor bacteria after reprocessing, and a small number of endoscope-related infections are thought to be due to transmission between patients via contaminated devices. Enhanced surveillance and reprocessing techniques can lower contamination rates significantly, but do not fully eliminate the risk. For this reason, disposable duodenoscopes have become available as a solution. Currently, two models are available and it is likely more will follow from other manufacturers.

Disposable duodenoscopes have acceptable safety and efficacy and can be considered as an alternative to reusable duodenoscopes for ERCP. However, the effects of disposable duodenoscopes on post-ERCP infection rates have not been clearly studied and larger studies are still needed.

Disposable duodenoscopes generate significantly more waste and greenhouse gas emissions than reusable duodenoscopes. Their effect on the environment will be determined by how widely they are adopted. Although studies have shown that low volume institutions may be more inclined to use disposable duodenoscopes and that certain patient populations may preferentially benefit from them, more time and research is needed to determine when disposable duodenoscopes should be used and if the incremental health benefit is worth the substantially higher cost to the environment.

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Goyal H, Larsen S, Perisetti A, Larsen NB, Ockert LK, Adamsen S, Tharian B, Thosani N. Gastrointestinal endoscope contamination rates – elevators are not only to blame: a systematic review and meta-analysis. Endosc Int Open. 2022 Jun 10;10(6):E840-E853. doi: 10.1055/a-1795-8883. PMID: 35692921; PMCID: PMC9187382.
Han ZL, Lin BT, Wang ZJ, Chen X, Xi YY, Wang JF, Qiao WG, Huang Y, Lin ZZ, Huang SH, Chua TY, Liu SD, Luo XB. Evaluation of a novel disposable esophagogastroduodenoscopy system in emergency, bedside, and intraoperative settings: Pilot study (with videos). Dig Endosc. 2023 Nov;35(7):857-865. doi: 10.1111/den.14548. Epub 2023 Apr 5. PMID: 36905288.
Bomman S, Kozarek RA, Thaker AM, Kodama C, Muthusamy VR, Ross AS, Krishnamoorthi R. Economic burden of enhanced practices of duodenoscopes reprocessing and surveillance: balancing risk and cost containment. Endosc Int Open. 2021 Aug 23;9(9):E1404-E1412. doi: 10.1055/a-1515-2591. PMID: 34466366; PMCID: PMC8382507.
Barakat MT, Ghosh S, Banerjee S. Cost utility analysis of strategies for minimizing risk of duodenoscope-related infections. Gastrointest Endosc. 2022 May;95(5):929-938.e2. doi: 10.1016/j.gie.2022.01.002. Epub 2022 Jan 10. PMID: 35026281.
Sivek AD, Davis J, Tremoulet P, Smith M, Lavanchy C, Sparnon E, Kommala D. Healthcare worker feedback on duodenoscope reprocessing workflow and ergonomics. Am J Infect Control. 2022 Sep;50(9):1038-1048. doi: 10.1016/j.ajic.2022.01.012. Epub 2022 Jan 30. PMID: 35108583
Namburar S, von Renteln D, Damianos J, Bradish L, Barrett J, Aguilera-Fish A, Cushman-Roisin B, Pohl H. Estimating the environmental impact of disposable endoscopic equipment and endoscopes. Gut. 2022 Jul;71(7):1326-1331. doi: 10.1136/gutjnl-2021-324729. Epub 2021 Dec 1. PMID: 34853058
Bang JY, Sutton B, Hawes R, Varadarajulu S. Concept of disposable duodenoscope: at what cost? Gut. 2019 Nov;68(11):1915-1917. doi: 10.1136/gutjnl-2019-318227. Epub 2019 Feb 12. PMID: 30772837; PMCID: PMC6839801.
Hutfless S, Shiratori Y, Chu D, Liu S, Kalloo A. Risk factors for infections after endoscopic retrograde cholangiopancreatography (ERCP): a retrospective cohort analysis of US Medicare Fee-For-Service claims, 2015-2021. BMJ Open. 2022 Sep 9;12(9):e065077. doi: 10.1136/bmjopen-2022-065077. PMID: 36691191; PMCID: PMC9472111.

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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #10

Nitrogen Balance: Revisiting Clinical Applications in Contemporary Practice

February 2024 • Volume XLVIII, Issue 2

Yichun Fu,

Dejan Micic

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Proteins play vital roles in metabolic reactions in both healthy and critically ill adults. Nitrogen balance (NB) studies serve as a key metric for protein metabolism. Despite its introduction in nutrition research in the early 20th century, NB studies remain underutilized in the hospital setting. The methodology of a NB calculation can be complex and there are specific limitations when it is applied in several clinical scenarios including burn injury, renal disease, and trauma. Overall, NB assessments remain a valuable tool in assessing the adequacy of nutrition support as achieving a positive NB has been associated with improved clinical outcomes. The aims of this review are to delineate NB calculations in hospitalized patients and provide insights into its limitations and adaptations in special populations.

Introduction

Proteins are composed of long chains of amino acids with functions ranging from catalyzing metabolic reactions to providing support for cellular structures.¹ Balancing adequate intake with protein degradation is therefore crucial to maintaining metabolic functions. Because proteins are the only macronutrient that contain nitrogen, NB studies serve as a surrogate for protein metabolism.² The earliest attempts to calculate daily protein requirements in health date back to the 1860s-1870s, although these reports were largely based on dietary surveys of working men.^2,3 Published in 1911, Chittenden was one of the first to utilize a NB assessment on 108 healthy subjects; he suggested 56 g of daily protein intake, close to modern-day recommendations.⁴ By the 1940s, NB was incorporated into many nutrition studies, including assessments of malnourished populations in postwar Denmark and Germany.⁵ In modern nutrition literature, NB or equilibrium is defined as a balance of protein degradation and accretion in most non-stressed adults.

Despite the abundant NB studies in unstressed populations, NB remains underutilized in critically ill and hospitalized patients. Yet, these patients experience significant physiologic stress and their protein requirements fluctuate frequently. NB assessment in these patients allows for more precise delivery of nutrition support. The critique of underlying methodology and applications of NB in specific clinical scenarios, such as hemodialysis and burn injury, have been published.^6–9 The aim of this review is to provide updated clinical insights in the interpretation of NB studies in hospitalized adults and to summarize its use in select patient populations.

Definition of Nitrogen Balance

As nitrogen is a fundamental component of amino acids, a NB study calculates the difference between nitrogen intake and output and reflects the loss or gain of total body proteins. When more nitrogen is excreted than taken in, this is considered negative NB or a catabolic process; the reverse is considered positive NB or anabolic. In an unstressed adult, the nitrogen intake is almost entirely from protein via an enteral or parenteral route. Nitrogen losses include the excretion of urine urea with additional losses via feces and dermal layers.¹

Goals for Nitrogen Balance

The general goal of NB is usually determined as -4 to +4 g nitrogen/day.¹⁰ This target is difficult to achieve in a hypercatabolic state. Hence, for critically ill patients, the goal is to provide enough nutrition support to minimize nitrogenous losses, which may blunt catabolism of lean tissue. Importantly, net balance or zero NB is not always the only target for protein supplementation, because patients suffering from chronic malnutrition or starvation may demonstrate pathologic adaption, where the body relies on muscle atrophy to provide amino acids for metabolic needs and to reestablish the balance.¹¹ Hence, one should assess a patient’s clinical state such as muscle atrophy, body composition and strength, to eliminate the possibility of a falsely positive balance study. Importantly, without meeting the global caloric requirements, patients with sufficient protein intake still experience muscle degradation, because the muscle breakdown provides metabolites for other tissues. Thus, both adequate protein and caloric supplementation is necessary to suppress muscle breakdown.¹²

There is no strong evidence to support unlimited protein supplementation. Apart from the deleterious effect of excess protein in liver disease, renal insufficiency, and inborn errors of urea metabolism, a high protein supplementation may cause false positivity in the NB calculation.¹³ Previous studies, as well as the 2016 and 2021 American Society of Parenteral and Enteral Nutrition (ASPEN) guidelines, have recommended 1.5-2 g/kg of actual body weight (ABW) of daily protein as sufficient for nitrogen retention.^14–17 In practice, protein support can be increased to 2.5 g/kg/d in critically ill trauma patients with severe nitrogen deficits and normal liver and renal functions.¹⁰ In non-obese patients receiving frequent intermittent hemodialysis or continuous renal replacement therapy, the protein goal can also be increased by 0.2 g/kg/d to a maximum of 2.5 g/kg of ABW per day. In obese critically ill patients, the protein goal is recommended as 2-2.5 g/kg of ideal body weight per day.¹⁷

In a dynamic patient, NB usually achieves a steady state after 48 hours of a constant nutritional regimen.¹⁸ Therefore, a steady intake or provision of calories and protein is required prior to NB assessment. To assess the adequacy of protein support, it is recommended to calculate a NB at 24 to 48 hours after the initiation of nutrition support with weekly assessments in those at risk for malnutrition, critically ill or with impaired healing.¹⁰

Calculation Methods

The classic formula to calculate NB is:

NB (g/d) = protein intake (g/d)/6.25 – urinary urea nitrogen (UUN)(g/d) – 4

Protein intake – In this formula, the estimated constants simplify the calculations, but carry inherent errors. The nitrogen input is calculated by dividing the protein intake in grams per day by 6.25, a constant based on the early determination that the average nitrogen content of proteins is approximately 16 percent (1/0.16 = 6.25).^10,19 There are two sources of error here. First, all foods contain non-protein nitrogen such as free amino acids, nucleotides, and choline, and only a small amount of these carry the same metabolic effects of protein.¹⁹ These nitrogen sources thus should be excluded for NB calculations; however, the exact proportion of these sources in the common diet and in nutritional supplements is not well understood. Secondly, the nitrogen content varies by the molecular weight of the amino acids taken in. Therefore, the actual nitrogen content of proteins range from 13 to 19 percent, which is equivalent to conversion factors of 5.26 to 7.69.¹⁹ It is undoubtedly impractical to comb through the protein sources for a patient ingesting varying food groups daily. One may consider altering the constant for patients who receive solely commercially available feeding formula or parenteral nutrition, because the commercially available formulas also vary by their amino acid contents.^10,20 However, in a classic review by Dickerson, the amino acid content in varying products would result in a 1g maximum error in NB for a patient with 120g daily protein intake, a relatively small impact unless patients have significantly high protein requirements.

Urinary nitrogen loss – The remainder of the NB equation accounts for the nitrogen losses via urine (UUN – 2 g) and other losses (- 2 g). To obtain the UUN, the patient’s urine is collected for a 24-hour period. Because of the various extrapolations used in a NB calculation, it is recommended to adhere to the 24-hour collection for accuracy. To assess the completeness of urine collection, one can calculate the estimated creatinine clearance (CrCl) and compare it with the one derived from the Cockroft-Gault equation. A significantly lower CrCl from urinary volume suggests incomplete collection.¹⁰

The UUN can be measured in most laboratories, but it underestimates total urinary nitrogen (TUN) excretion because TUN also includes molecules such as ammonia.^1,21 The classic formula assigns 2 grams as an estimation of the difference between UUN and TUN. However, in critically ill patients, the non-urinary nitrogen loss tends to increase due to increased protein catabolism.^10,22 Dickerson, et al. studied the TUN in trauma patients using pyrochemiluminescence and proposed that UUN/0.85 is a more accurate estimation of urine urea loss:²²

NB (g/d) = protein intake (g/d)/6.25 – UUN (g/d)/0.85 – 2

As 60% of non-urinary nitrogen loss is in the form of ammonia in critically ill patients,^21,23 this estimation does not apply for patients with significant open wounds, diarrhea, renal insufficiency or end stage liver disease.

Extrarenal losses – The final subtraction of 2 grams arises from nitrogen losses via skin, soft tissues, and feces. Skin and soft tissue loss is approximately 0.5 g/d in sedentary people, and an average of 1.6 g/d nitrogen is excreted in stool.¹ These generalized values, however, are based on small studies that measured nitrogen loss in non-stressed adults. Nitrogen loss from skin has been measured from desquamated cells, nail clippings and hair. It is directly correlated with body surface area and has been calculated as 5 mg/kg body weight in a comfortable environment.²⁴ In addition to cutaneous loss, there is also nitrogen loss from sweat, which varies by gender, race and ambient temperature. There have been several measurements reported via physiological studies in the 1960s and 1970s. An average dermal and sweat nitrogen loss of 6 mg/kg at temperatures of 6-22°C, and 15 mg/kg at 25-30°C.²⁵ For fecal nitrogen loss, it can differ based on the amount of nitrogen in dietary intake. Regardless, there is an obligatory nitrogen loss due to baseline metabolism and enzyme proteins, which was estimated to be 7-10 mg nitrogen per kg of body weight.^26,27

Nitrogen Balance and Clinical Outcomes

Table 1. Sample Calculation of Additional Nitrogen Loss in Burn Patients
Calculate additional nitrogen loss for a 5-foot-6-inch, 70kg adult patient with burn injuries of 20% BSA: • BSA is 1.82 m2	Day 1-3: 0.3 x 1.82 m2 x 20 = 10.9 g nitrogen loss per day
	Day 4 onward: 0.1 x 1.82 m2 x 20 = 3.6 g nitrogen loss per day

The objective of a NB measurement is to provide guidance on adequate protein supplementation to mitigate the hypercatabolism of illness. However, the actual effect of a positive NB on patient outcomes is difficult to study due to the heterogeneity of patient populations. Individual studies tend to have limitations of small study sizes or short study durations. In a retrospective study of 40 neurologic intensive care unit (ICU) patients, Kim, et al. found that a positive NB was associated with less neurological deterioration and shorter ICU and hospital stays.²⁸ Zhu, et al. conducted a meta-analysis that included eight observational studies of 1409 critically ill patients. A positive change in NB on subsequent studies was associated with patient survival, demonstrating the impact of repeated hospital measurements.²⁹ In a retrospective study of 99 critically ill patients with COVID-19 infections, both the survivor and the non-survivor groups had similarly negative NB, but the survivor group had consistently higher NB values than the non-survivor group.³⁰ However, in a small randomized controlled trial (RCT) of 40 ICU patients comparing a protein-fortified versus a standard diet, there was no difference of skin alterations (secondary outcome of interest) despite a higher NB in the protein-fortified group.³¹ Lastly, in a RCT of 120 ICU patients receiving standard (0.8 g/kg/day protein) or high protein (1.2 g/kg/day protein) parenteral nutrition, the high protein group had better forearm muscle mass, grip strength, and fatigue score on day 7 as well as a higher NB on day 3.³² Overall, the current data suggest a potential benefit in survival, hospital outcomes, and muscle preservation among individuals with a positive or improved NB, although more rigorous trials are needed.

Special Scenarios

Burn – In burn patients, body fluid and protein losses are highly dynamic in the first week post-injury, especially for those suffering burns on more than 15% of the body surface area (BSA).²⁸ The fluid loss tends to be the greatest in the first 24-48 hours post-burn, peaking at approximately 20 g per 10% total surface area.^33,34 Based on this, Waxman, et al. proposed that the average daily nitrogen loss on post-burn days 1-3 is estimated as nitrogen loss (g/d) = 0.3 (g/m²) x BSA (m²) x % burn; and on post-burn days 4 and onward as nitrogen loss (g/d) = 0.1 (g/m²) x BSA (m²) x % burn.³³ This equation can be used to calculate an additional nitrogen loss in the NB equation. Table 1 provides an example of calculated daily nitrogen losses with the BSA calculated using the Mosteller formula.³⁵

Table 2. Nitrogen Balance Calculations for Patients Receiving CRRT
Nitrogen loss on CRRT	Nitrogen losses (g/day) = effluent urea nitrogen losses (g/day) + amino acid loss via effluent (g/day) + urine urea nitrogen (g/day) + insensible nitrogen losses (0.031 g/kg/day x weight in kg) Effluent urea nitrogen = total effluent ultrafiltrate volume (L) Å~ average ultrafiltrate urea nitrogen (g/L) The total effluent ultrafiltrate volume = sum of dialysate volume + replacement fluid volume + removed ultrafiltration
In terms of calculating the average ultrafiltrate urea nitrogen concentration, Scheinkestel described a method of collecting 20 mL dialysate every eight hours and measuring the nitrogen concentration in the mixed 60 mL sample.37

Table 2. Nitrogen Balance Calculations for Patients Receiving CRRT

Nitrogen loss on CRRT

Nitrogen losses (g/day) = effluent urea nitrogen losses
(g/day) + amino acid loss via effluent (g/day) + urine
urea nitrogen (g/day) + insensible nitrogen losses
(0.031 g/kg/day x weight in kg)
Effluent urea nitrogen = total effluent ultrafiltrate
volume (L) Å~ average ultrafiltrate urea nitrogen (g/L)
The total effluent ultrafiltrate volume = sum of dialysate
volume + replacement fluid volume + removed
ultrafiltration

In terms of calculating the average ultrafiltrate urea nitrogen concentration, Scheinkestel described a method of
collecting 20 mL dialysate every eight hours and measuring the nitrogen concentration in the mixed 60 mL sample.37

Open abdomen – The open abdomen leads to abdominal fluid and protein loss from the exposed viscera. In a small cohort study of 25 critically ill surgical patients, the average abdominal fluid loss ranged from 2.2 to 3.0 L per day between post-operative day 1 and day 5 with a daily abdominal fluid nitrogen loss of 3.5 g + 1.7 g per 24 hours, or 1.9 g + 1.1 g per liter of abdominal fluid. This translated to an average underestimation of 3.5 g/d nitrogen loss in the study cohort when not accounting for the abdominal fluid losses.³⁶ Overall, one should consider nitrogen losses from abdominal and other body fluids when losses are significant.

Renal impairment – Patients with significant renal impairment accumulate nitrogen in the body as urea. Given its water solubility, the amount of urea in the body can be estimated by body water content and blood urea nitrogen (BUN).^10,21 Dickerson proposed an adjusted formula that takes BUN fluctuations into consideration:

Body urea nitrogen accumulation = 0.6 x weight x (BUN₂ – BUN₁) x 0.01

BUN₁ and BUN₂ are the two serum urea nitrogen values before and after the urine collection. Generally, a change in BUN greater than 5 mg/dL correlates to a meaningful change in NB.¹⁰ In this case, the final NB equation is:

NB (g/d) = protein intake (g/d)/6.25 – (UUN(g/d)/0.85) – (0.6 x weight x (BUN₂ – BUN₁) x 0.01)– 2

Renal replacement therapy – In patients receiving continuous renal replacement therapy (CRRT) or intermittent hemodialysis (iHD) the calculation of nitrogen losses requires an assessment of the protein and amino acid losses in the dialysate in addition to the accumulation of BUN (in iHD). Ostermann, et al. previously summarized the studies utilizing NB in hemodialysis patients.^6,8 During CRRT the amino acid losses can be estimated as 1.5 g/day for an ultrafiltration flow rate of 1 L/h and 2 g/day for an ultrafiltration flow rate of 2 L/h. In iHD, nitrogen loss is calculated through the urea nitrogen accumulation (UNA), because patients with renal insufficiency have decreased capacity to excrete urea and the change in BUN during the 24-hour urine collection requires assessment. Hence, the equation for nitrogen loss while on dialysis is listed below in Tables 2 and 3.^6,7,37

Compared to the UNA in a patient with renal disease but not on dialysis, the calculations above incorporate the accumulated urea that has been removed from dialysis and the weight change after dialysis.

Liver dysfunction and hyperammonemia – The liver captures serum ammonia and converts it to urea, which is then excreted mainly through the kidneys. In both acute and chronic liver dysfunction, there is marked decrease in ammonia uptake by the liver. The muscle uptake of ammonia increases roughly in a linear relationship to the arterial ammonia level and converts ammonia into glutamine.³⁸ Hence, it is expected that calculation of urinary nitrogen loss underestimates the total nitrogen loss. However, there are no clear studies on its significance in nutritional practice or NB measurement.

Metabolic acidosis – In metabolic acidosis, the kidneys secrete more ammonia into the renal tubules to bind hydrogen ions and increase hydrogen excretion. Consequently, the ammonia excretion can increase 5 to 10-fold from the baseline of 5-10% of total urine nitrogen.²¹ The NB equation therefore has additional losses that are not routinely measured. This process can be reversed by correcting the underlying acidosis.

Extracorporeal membrane oxygenation (ECMO) –
For patients receiving ECMO for circulatory support, there is a theoretic concern of protein sequestration in the ECMO circuit, thus affecting the calculation of NB and underestimating protein losses. Estensen, et al. conducted an ex vivo study on macro- and micronutrient disposition in ECMO models and concluded that there was no significant difference in protein concentration over 24 hours on ECMO versus in regular circuits.⁹ This indicates that the protein loss via ECMO is minimal. However, another ex vivo study found that among the medications of similar lipophilicity, there was significantly lower concentration of protein-bound medications after 24 hours of ECMO circulation, inferring protein loss via sequestration in the ECMO circuit.³⁹ Pelekhaty, et al. studied measured NB in two cohorts of patients on venovenous-ECMO (VV-ECMO) and found that both non-obese and obese patients on VV-ECMO had elevated urine nitrogen excretion and negative NB despite nutrition and protein supplementation based on 2016 ASPEN guidelines. This indicated that patients on VV-ECMO may have high levels of catabolism and require more protein supplementation than currently recommended.^40,41 Currently, there is no proposed adjustment of NB calculation in the critical care and nutrition society guidelines.^42,43 However, based on the studies, one may consider actively monitoring the NB in this population and supplement more than 2 g protein/kg per day from the standard recommendations.

Conclusions

Nitrogen balance has been widely used for decades to provide individualized nutrition support in highly dynamic patients with multiple acute and chronic medical conditions. This review highlights the various clinical circumstances that one may consider when applying the NB equations in acutely ill patients. While we acknowledge the inherent flaws and inaccuracy of NB calculation, this method still holds significant value for patients in complex metabolic states.

References

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2. Rand WM, Pellett PL, Young VR. Meta-analysis of nitrogen balance studies for estimating protein requirements in healthy adults. The American Journal of Clinical Nutrition. 2003;77(1):109-127.

3. Miller DS, Payne PR. Assessment of protein requirements by nitrogen balance. Biochemical Journal. 1969;113(2):2P-2P.

4. Chittenden R. Discussion On The Merits Of A Relatively Low Protein Diet. The British Medical Journal. 1911;2(2647):656-667.

5. Beattie J, Herbert PH, Bell DJ. Nitrogen Balances during Recovery from Severe Undernutrition. Br J Nutr. 1947;1(2-3):202-219.

6. Ostermann M, Lumlertgul N, Mehta R. Nutritional assessment and support during continuous renal replacement therapy. Seminars in Dialysis. 2021;34(6):449-456.

7. Masud T, Manatunga A, Cotsonis G, Mitch WE. The precision of estimating protein intake of patients with chronic renal failure. Kidney International. 2002;62(5):1750-1756.

8. Rao M, Sharma M, Juneja R, Jacob S, Jacob CK. Calculated nitrogen balance in hemodialysis patients: Influence of protein intake. Kidney International. 2000;58(1):336-345.

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16. Compher C, Bingham AL, McCall M, et al. Guidelines for the provision of nutrition support therapy in the adult critically ill patient: The American Society for Parenteral and Enteral Nutrition. J Parenter Enteral Nutr. 2022;46(1):12-41.

17. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2016;40(2):159-211.

18. Elwyn D, Gump F, Munro H, Iles M, Kinney J. Changes in nitrogen balance of depleted patients with increasing infusions of glucose. The American Journal of Clinical Nutrition. 1979;32(8):1597-1611.

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21. Weiner ID, Mitch WE, Sands JM. Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion. Clinical Journal of the American Society of Nephrology. 2015;10(8):1444-1458.

22. Dickerson RN, Tidwell AC, Minard G, Croce MA, Brown RO. Predicting total urinary nitrogen excretion from urinary urea nitrogen excretion in multiple-trauma patients receiving specialized nutritional support. Nutrition. 2005;21(3):332-338.

23. Burge JC, Choban P, Mcknight T, Kyler MK, Flancbaum L. Urinary Ammonia Plus Urinary Urea Nitrogen as an Estimate of Total Urinary Nitrogen in Patients Receiving Parenteral Nutrition Support. JPEN J Parenter Enteral Nutr. 1993;17(6):529-531.

24. Ashworth A, Harrower ADB. Protein requirements in tropical countries: nitrogen losses in sweat and their relation to nitrogen balance. Br J Nutr. 1967;21(4):833-843.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #56

A Review on the Management of Postoperative Crohn’s Disease

February 2024 • Volume XLVIII, Issue 2

Miguel Regueiro,

Benjamin Cohen,

Ravi S. Shah

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Postoperative Crohn’s disease recurrence often precedes the emergence of clinical symptomatology and requires detection and management strategies for early objective recurrence. A multidisciplinary approach to optimize patients for surgery via nutrition, smoking cessation, and immunosuppression management may not only prevent postoperative complications but also future Crohn’s disease recurrence. Postoperatively, a strategy to provide pharmacologic prophylaxis prior to the detection of objective recurrence and/or intensive monitoring via fecal calprotectin and endoscopy may alter the natural history of the disease and prevent a future surgery for complicated Crohn’s disease. In this review, the management of perioperative and postoperative Crohn’s disease is outlined for providers on the multidisciplinary team caring for these patients.

Introduction

Crohn’s disease (CD) is a chronic inflammatory bowel disorder that often leads to stricturing and fistulizing complications requiring surgery. Prior to the advent of biologics, approximately 50% of CD patients underwent ileocolonic resection (ICR) within 10 years.¹ Despite advances in the pharmacologic armamentarium against CD, surgical resection is still required in nearly 30% of patients by 10 years.² Although surgery may be an initial option for ileal CD, it is not curative and requires consideration of pharmacologic prophylaxis and/or a close monitoring protocol to prevent recurrence of disease (Figure 1).^3–5

Objective postoperative recurrence (POR) of CD (i.e. histologic, endoscopic, or imaging findings) is common and can be detected prior to the emergence of clinical symptomology.⁶ Before evidence of macroscopic disease arises, histologic recurrence on endoscopic biopsy pathology can be seen as early as one week after surgery.^7–9 Endoscopic recurrence, preceding either clinical or surgical recurrences, is estimated to happen in up to 70-90% of patients within one year postoperatively.^6,9 Medical providers have an opportunity to prevent surgical recurrence for stricturing or fistulizing complications by optimizing peri-operative care, aggressively monitoring these patients postoperatively, and providing pharmacologic prophylaxis in higher risk patients.

In the absence of objective CD recurrence, a broad differential including small intestinal bacterial overgrowth, bile acid diarrhea, fat malabsorption, infectious diarrhea, abdominal wall pain, amongst others should be considered for symptomatic recurrence.

Peri-Operative Management of Crohn’s disease

Opportunities to prevent postoperative complications begin in the perioperative period and include nutritional optimization, smoking cessation, immunosuppression management, and corticosteroid avoidance. Studies have found that postoperative intra-abdominal septic complications (IASC) are associated with POR.¹⁰ Malnutrition has been found to be associated with IASC, and various studies have shown the utility of enteral or parenteral nutrition in the weeks prior to surgery to prevent postoperative complications.^11–15 Exclusive enteral nutrition has the ability to reduce the risk of intra-abdominal septic complications which may indirectly decrease the risk of recurrence.^13,14 In a cohort study, four weeks of preoperative exclusive enteral nutrition compared to placebo was also associated with reduced endoscopic recurrence (11.9% vs. 28.4%, p=0.003).¹⁶ Multidisciplinary care to optimize nutrition and in some cases to delay surgery are required.

Tobacco use prior to ICR is also a known risk factor for postoperative complications and surgical recurrence.^17,18 Smoking cessation lowers this risk and may even have a role in altering specific microbiota that are associated with POR.^19,20 All efforts by clinicians caring for CD patients should make smoking cessation a priority in order to improve postoperative outcomes.

Multidisciplinary discussions to optimize immunosuppression management prior to surgery are necessary. Corticosteroid use has been found to be associated with IASC and surgical site infections. When possible, every attempt to avoid or taper corticosteroids prior to surgery is required.^21–23 In contrast, biologic utilization has not been found to be associated with IASC. In a prospective cohort study of inflammatory bowel disease patients undergoing surgery, anti-TNF exposed patients within twelve weeks of surgery had similar rates of infections postoperatively as patients who were not exposed (20.2% vs. 18.1%, p=0.47).²⁴ Importantly, detectable perioperative anti-TNF drug levels were not associated with infectious complications. Utilization of biologics in the peri-operative period should not delay surgical intervention.^24–28 If an indication for surgery such as a stricturing or fistulizing complication exists, a new start of a biologic is not indicated prior to surgery.

Operative Management

Various surgical techniques have been assessed to prevent POR. Although some anastomosis types were thought to be associated with reduced POR (end-end, side-side, end-side), the Kono-S anastomosis which provides limited mesenteric excision and reduced fecal stasis has been found to be associated with reduced POR.^29,30 In a randomized controlled trial (SuPREMe-CD), Kono-S compared to side-side anastomosis had a significantly lower rate of endoscopic recurrence (22.2% vs. 62.8%), clinical recurrence (8% vs. 18%), and surgical recurrence (0% vs. 4.6%).²⁹ However, the association between Kono-S and lower rates of endoscopic recurrence remains controversial.^31,32 There is growing interest and ongoing studies to surgically alter neural innervation, vasculature, and the mesentery, an active immune organ, to prevent POR.^33,3

Postoperative Crohn’s Disease Management Strategies: Intensive Monitoring versus Biologic Prophylaxis

Although surgery is not a cure for CD, early ICR as a first-line therapy for inflammatory ileitis has been shown be an effective management strategy. Up-front surgical resection for non-stricturing ileocecal CD compared to infliximab has a comparable quality of life (IBDQ score 178.1 vs. 172.0, p=0.25) and duration of treatment effect (33 vs. 34 months, p=0.52).^3,4 In a long-term follow up of the LIR!C study comparing laparoscopic ICR and anti-TNF (infliximab), a lower rate of anti-TNF use postoperatively (26% vs. 38%) and need for repeat surgery (0% vs. 48%) after five years was observed.^3,4 Similarly, a multicenter Danish study found that the risk of a composite outcome including: hospitalization, steroid use, surgery, and perianal disease was 33% lower with surgery compared to anti-TNF⁵ In this cohort study, approximately 50% of patients did not require any therapy five years after surgery.⁵ These studies may suggest that there is a subpopulation of postoperative CD patients who may not experience recurrence at rates that have previously been reported. It will be important to identify patients who experience surgical remission for an extended period of time in future studies.

Awareness and selection of a management strategy is imperative to prevent recurrence in patients who have undergone prior surgical resection. Current guidelines recommend considering either pharmacologic prophylaxis in patients who exhibit high-risk features or performing intensive monitoring in those who do not (Figure 2).^35,36 However, further research is ongoing to determine the optimal patient population benefiting from prophylaxis.

Risk-Stratification

Multiple risk factors associated with POR have been identified. These include patient, disease, operative, histologic, microbiome, genetic, and metabolomic risk factors. Current guidelines suggest dichotomizing patients into higher or lower illustrative risk profiles based on clinical risk factors. Higher risk features associated with surgical recurrence, including ≥2 surgeries, penetrating +/- perianal disease, and smoking, benefit from pharmacologic prophylaxis.^18,35 In a prospective cohort study, male gender, non-white race, and active smoking, but not penetrating disease or prior surgeries, were associated with endoscopic recurrence.³⁷ Broadening of risk factors associated with endoscopic recurrence and individualizing postoperative risk may further refine patients benefiting from prophylaxis.^18,37,38 Various real-world studies assessing risk stratification have suggested that prophylaxis may benefit patients irrespective of risk group, however this remains controversial and future prospective studies are required.^18,38,39

Non-clinical risk factors for recurrence are being explored. Histologic features such as positive resection margins, plexitis, and transmural inflammation are associated with POR.⁴⁰ Microbiome analysis is not widespread but dysbiosis, including recolonization and depletion of various bacteria, is increasingly being recognized as a risk factor.^20,41,42 Serologic markers and metabolomics may play a role in the identification of high risk patients.^43–45 Furthermore, as precision medicine advances, important genetic features such as NOD2/CARD15 and CARD8 expression may identify higher risk patients.^46,47 Ultimately, efforts for precision medicine to identify patients who are highest risk based on all of these potential risk factors are necessary.

Intensive Monitoring Irrespective of Risk Profile

Irrespective of risk profile, monitoring of disease activity is the cornerstone of postoperative management. It is imperative for clinicians to understand that objective recurrence precedes the rise of symptoms in patients. In the first year postoperatively, it is recommended to incorporate fecal calprotectin and colonoscopy into a monitoring strategy. Emerging evidence may soon support the use of cross-sectional imaging and intestinal ultrasound (IUS) as well.

Endoscopy

Ileocolonoscopy remains the gold standard test to identify early POR prior to the onset of symptoms. The modified Rutgeerts’ score is an endoscopic score of the neoterminal ileum graded from i0-i4 that correlates to future clinical and surgical recurrence (Table 1).⁴⁸ Endoscopic recurrence is determined based on a modified Rutgeerts’ score of ≥i2b. A score of i2b correlates to 19% surgical and 40-80% clinical recurrence. Severe recurrence scores of i3 and i4 correlate to 28-50% surgical and 60-100% clinical recurrence in 2 years from surgery. In contrast, low-grade mucosal inflammation defined as i0 and i1 correlate to only 5-8% surgical and 10-50% clinical recurrence.^9,48 Refinement of this score to delineate the significance of i2a versus i2b disease is ongoing and a subset of patients with i2a recurrence may benefit from treatment.⁴⁹

Active endoscopic management to step-up therapy has been well supported by the pivotal Postoperative Crohn’s Endoscopic Recurrence (POCER) trial. In this multicenter randomized controlled trial, patients in the active (colonoscopy at 6 months with opportunity to step up therapy) versus standard (no colonoscopy) care groups had lower rates of endoscopic recurrence at 18 months (49% vs. 67%; p=0.03)⁵⁰ In another study, the risk of developing late endoscopic recurrence past one year is up to 40% despite initial monitoring at 6 months, and therefore ongoing active monitoring with colonoscopy after the initial assessment approximately every one to two years may be reasonable.⁵¹ Endoscopy at 3-12 months postoperatively is recommended and especially for those not receiving prophylaxis.

Fecal Calprotectin

Fecal calprotectin is a fast, reliable, and noninvasive tool that should be used to monitor for CD recurrence after ICR.^52,53 In a prospective, multicenter, randomized, controlled trial, fecal calprotectin at 6 and 18 months postoperatively correlated to the presence (r=0.42; p<0.001) and severity (r=0.44; p<0.001) of CD recurrence.⁵⁴ With escalation of therapy, fecal calprotectin responds similarly to endoscopic disease activity. Various studies have found that fecal calprotectin has a high sensitivity and negative predictive value for detecting recurrence.^54–56 Recent guidelines suggest that a fecal calprotectin <50 µg/g in asymptomatic patients with CD who are considered low risk or on prophylaxis and are in surgically induced remission within 12 months are unlikely to have recurrence of CD. Patients may therefore consider avoiding a colonoscopy within the first year from surgery. In patients with an elevated fecal calprotectin or with high-risk features not on prophylaxis, colonoscopy should be used as a screening method to detect early recurrence within 3-12 months postoperatively.⁵³

Intestinal Ultrasound

In addition to fecal calprotectin, intestinal ultrasound is a newer, adjunctive, and noninvasive tool that assesses transmural inflammation and can detect recurrence. In regards to postoperative disease assessment, the combination of the presence of lymph nodes or bowel wall thickness ≥3mm plus a fecal calprotectin ≥50 mcg/g correctly classified 56% and 75% of patients as having endoscopic recurrence.⁵⁷ The sensitivity and specificity of IUS is >85% for detecting POR^58,59 Contrast-enhanced ultrasound of the neoterminal ileum has also correlated to the Rutgeerts’ score indicating that this modality may be used as an early and noninvasive method to detect recurrence.⁶⁰ Though prospective studies are needed, in centers where intestinal ultrasound is available, monitoring for neoterminal disease at 3-6 months postoperatively in combination with fecal calprotectin with confirmatory endoscopy may be an effective strategy.

Enterography

Although enterography (CT or MR) is not recommended to screen for recurrence, it may have a role in detecting recurrence (intestinal wall thickening, luminal narrowing, mural hyperenhancement, and length of disease) in symptomatic patients even in the absence of endoscopic activity.⁶¹ Enterography has also been found to be associated with subsequent endoscopic recurrence even in the absence of activity on the index endoscopy.⁶¹

Medical Prophylaxis in Patients with High Risk Profile

A multidisciplinary approach perioperatively is necessary to determine if initiation of pharmacologic prophylaxis is indicated after surgery. High risk patients benefit from prophylaxis ideally within one month of surgery.⁶² Anti-TNF and vedolizumab, an anti-integrin, specifically have been found to reduce recurrence in prospective randomized control trials.^63,64 In the seminal PREVENT trial, infliximab compared to placebo reduced endoscopic but not clinical recurrence (30.6% vs. 60.0%; P<0.001).⁶⁴ Even in patients who have been on anti-TNFs prior to surgery, reutilization of anti-TNF prophylaxis after surgery may still be a viable option as long as they did not develop antibodies.^65,66 Adalimumab, another anti-TNF, likely has a similar effect in the prevention of recurrence.⁶⁷ Anti-TNF drug level and antibody monitoring may be indicated to achieve adequately therapeutic levels to optimize prevention of recurrence.^68,69 Vedolizumab within four weeks of surgery is also effective in reducing POR based on a prospective randomized trial.⁶³ Although these two agents have the strongest evidence behind them, it is also reasonable to utilize other biologics (interleukin 12/23 and 23 inhibitors) and presumably small molecules if there had been true failure or adverse events from anti-TNF and vedolizumab.^70,71 While on prophylaxis, it is imperative to continue to monitor with noninvasive tools as well as performing an ileocolonoscopy every 1-2 years.

Alternatives to advanced therapies for postoperative Crohn’s Disease prevention

Alternatives to biologics and small molecules to prevent recurrence have been explored, however many of these agents are hindered by tolerability, adverse events, or a paucity of data.

Thiopurines have been shown to reduce postoperative recurrence. In a Cochrane meta-analysis, thiopurines were more effective than placebo in preventing clinical POR at 12-36 months [51% vs. 64%, RR 0.79, 95% CI 0.67-0.92] but not endoscopic POR.⁷² Compared to mesalazine, azathioprine seems more effective in preventing endoscopic POR. Biologics are favored over thiopurines due to better efficacy and more favorable safety profiles.

Microbiome dysbiosis in the neoterminal ileum has a role in the development of CD at this site. Therefore, the utility of either probiotics or antibiotics has been postulated. Of these, nitroimidazoles have been shown to reduce endoscopic recurrence. Metronidazole 20 mg/kg (13% vs. 43%, p=0.02) and ornidazole 1g/day (OR 0.31, 95% CI 0.10-0.94, p=0.04) compared to placebo reduced endoscopic recurrence at 3 months and 1 year, respectively.^73,74 Despite the obvious efficacy, the utility of these agents are limited by their adverse effects including neuropathies and dysgeusia.⁷⁵ Probiotics, including Lactobacillus and VSL#3, to modify the microbiome as a method to prevent POR have been fraught with disappointing evidence thus far and future studies to alter the microbiome are required.^24,76,77

Modulation of the microbiome via nutritional means has also been explored. Although not standard of practice, there is promising data to support the use of enteral nutrition as a means to prevent recurrence. Postoperative enteral nutrition plus a low fat diet compared to placebo has been found to be associated with a decrease in recurrence rate (10% vs. 45%, p=0.03).¹² An inherent barrier to adopting enteral nutrition as a means to reduce recurrence is the adherence to this modality of therapy. Future studies to assess methods of partial enteral nutrition and other nutritional studies are required.

Future Directions of Postoperative Crohn’s Disease

Significant advances have been made in the management of postoperative CD including the understanding of the natural history and pathogenesis, risk factor assessment, and strategies to prevent POR. Despite these, several questions remain unanswered and future work is required. Personalization of risk for patients utilizing clinical, environmental, microbiome, histologic, genetic, and “-omics” data may provide unique pathways for management strategies. Further assessment of non-invasive monitoring via intestinal ultrasound and biomarkers requires established data to integrate these methods into clinical practice. Data on newer biologics and small molecules in the prevention and treatment of postoperative CD are needed as well. Innovative methods of managing POR and incorporation of artificial intelligence may help standardize the care of these patients. Postoperative CD remains a significant challenge and efforts to optimize care are ongoing.

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52. Tham YS, Yung DE, Fay S, et al. Fecal calprotectin for detection of postoperative endoscopic recurrence in Crohn’s disease: systematic review and meta-analysis. Therap Adv Gastroenterol. 2018;11:1756284818785571. doi:10.1177/1756284818785571

53. Ananthakrishnan AN, Adler J, Chachu KA, et al. AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Crohn’s Disease. Gastroenterology. 2023;165(6):1367-1399. doi:10.1053/j.gastro.2023.09.029

54. Wright EK, Kamm MA, De Cruz P, et al. Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn’s disease after surgery. Gastroenterology. 2015;148(5):938-947.e1. doi:10.1053/j.gastro.2015.01.026

55. Lobatón T, López-García A, Rodríguez-Moranta F, Ruiz A, Rodríguez L, Guardiola J. A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn’s disease. J Crohns Colitis. 2013;7(12):e641-51. doi:10.1016/j.crohns.2013.05.005

56. Qiu Y, Mao R, Chen B, et al. Fecal calprotectin for evaluating postoperative recurrence of Crohn’s disease: a meta-analysis of prospective studies. Inflamm Bowel Dis. 2015;21(2):315-322. doi:10.1097/MIB.0000000000000262

57. Furfaro F, D’Amico F, Zilli A, et al. Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’s Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2023;21(12):3143-3151. doi:10.1016/j.cgh.2022.11.039

58. Yung DE, Har-Noy O, Tham YS, et al. Capsule Endoscopy, Magnetic Resonance Enterography, and Small Bowel Ultrasound for Evaluation of Postoperative Recurrence in Crohn’s Disease: Systematic Review and Meta-Analysis. Inflamm Bowel Dis. 2017;24(1):93-100. doi:10.1093/ibd/izx027

59. Rispo A, Imperatore N, Testa A, et al. Diagnostic Accuracy of Ultrasonography in the Detection of Postsurgical Recurrence in Crohn’s Disease: A Systematic Review with Meta-analysis. Inflamm Bowel Dis. 2018;24(5):977-988. doi:10.1093/ibd/izy012

60. Paredes JM, Ripollés T, Cortés X, et al. Contrast-enhanced ultrasonography: usefulness in the assessment of postoperative recurrence of Crohn’s disease. J Crohns Colitis. 2013;7(3):192-201. doi:10.1016/j.crohns.2012.03.017

61. Bachour SP, Shah RS, Lyu R, et al. Test Characteristics of Cross-sectional Imaging and Concordance With Endoscopy in Postoperative Crohn’s Disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. Published online December 2021. doi:10.1016/j.cgh.2021.12.033

62. De Cruz P, Kamm MA, Hamilton AL, et al. Efficacy of thiopurines and adalimumab in preventing Crohn’s disease recurrence in high-risk patients – a POCER study analysis. Aliment Pharmacol Ther. 2015;42(7):867-879. doi:10.1111/apt.13353

63. D’Haens G, Taxonera C, Lopez-Sanroman A, et al. OP14 Prevention of postoperative recurrence of Crohn’s disease with vedolizumab: First results of the prospective placebo-controlled randomised trial REPREVIO. J Crohn’s Colitis. 2023;17(Supplement_1):i19-i19. doi:10.1093/ecco-jcc/jjac190.0014

64. Regueiro M, Feagan BG, Zou B, et al. Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After Ileocolonic Resection. Gastroenterology. 2016;150(7):1568-1578. doi:10.1053/j.gastro.2016.02.072

65. Le Cosquer G, Altwegg R, Rivière P, et al. Prevention of post-operative recurrence of Crohn’s disease among patients with prior anti-TNFα failure: A retrospective multicenter study. Dig liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2023;55(6):727-734. doi:10.1016/j.dld.2022.09.004

66. Ten Bokkel Huinink S, Beelen EMJ, Ten Bokkel Huinink T, et al. Retreatment with anti-tumor necrosis factor therapy in combination with an immunomodulator for recurrence of Crohn’s disease after ileocecal resection results in prolonged continuation as compared to anti-tumor necrosis factor monotherapy. Eur J Gastroenterol Hepatol. 2023;35(1):45-51. doi:10.1097/MEG.0000000000002474

67. Cañete F, Mañosa M, Casanova MJ, et al. Adalimumab or Infliximab for the Prevention of Early Postoperative Recurrence of Crohn Disease: Results From the ENEIDA Registry. Inflamm Bowel Dis. 2019;25(11):1862-1870. doi:10.1093/ibd/izz084

68. Pan Y, Ahmed W, Mahtani P, et al. Utility of Therapeutic Drug Monitoring for Tumor Necrosis Factor Antagonists and Ustekinumab in Postoperative Crohn’s Disease. Inflamm Bowel Dis. 2022;28(12):1865-1871. doi:10.1093/ibd/izac030

69. Wright EK, Kamm MA, De Cruz P, et al. Anti-TNF Therapeutic Drug Monitoring in Postoperative Crohn’s Disease. J Crohns Colitis. 2018;12(6):653-661. doi:10.1093/ecco-jcc/jjy003

70. Mañosa M, Fernández-Clotet A, Nos P, et al. Ustekinumab and vedolizumab for the prevention of postoperative recurrence of Crohn’s disease: Results from the ENEIDA registry. Dig liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2023;55(1):46-52. doi:10.1016/j.dld.2022.07.013

71. Buisson A, Nancey S, Manlay L, Rubin DT, Hebuterne X, Pariente B, Fumery M, Laharie D, Roblin X, Bommelaer G, Pereira B, Peyrin-Biroulet L VL. Ustekinumab is More Effective than Azathioprine to Prevent Endoscopic Postoperative Recurrence in Crohn’s Disease. United Eur Gastroenterol J. 2020;8((8_suppl)):84-85. https://doi.org/10.1177/2050640620927344

72. Gjuladin-Hellon T, Iheozor-Ejiofor Z, Gordon M, Akobeng AK. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn’s disease. Cochrane database Syst Rev. 2019;8(8):CD010233. doi:10.1002/14651858.CD010233.pub3

73. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108(6):1617-1621. doi:10.1016/0016-5085(95)90121-3

74. Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005;128(4):856-861. doi:10.1053/j.gastro.2005.01.010

75. Glick LR, Sossenheimer PH, Ollech JE, et al. Low-Dose Metronidazole is Associated With a Decreased Rate of Endoscopic Recurrence of Crohn’s Disease After Ileal Resection: A Retrospective Cohort Study. J Crohns Colitis. 2019;13(9):1158-1162. doi:10.1093/ecco-jcc/jjz047

76. Marteau P, Lémann M, Seksik P, et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut. 2006;55(6):842-847. doi:10.1136/gut.2005.076604

77. Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut. 2002;51(3):405-409. doi:10.1136/gut.51.3.405

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #55

Liver Masses: Work up and When to Worry

January 2024 • Volume XLVIII, Issue 1

Elliot B. Tapper

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Liver lesions are common. A nodule found on ultrasound could be benign without the need for follow-up or malignant requiring urgent attention. This review examines the differential diagnosis, epidemiology, and management of common liver lesions. We review the imaging (particularly contrast-enhanced magnetic resonance imaging) characteristics and management considerations for cystic lesions, hemangiomas, adenomas, and focal nodular hyperplasia. We also review the diagnostic approach to solid lesions in patients with cirrhosis where hepatocellular carcinoma is more common.

ELpidemiology
Liver lesions are common. The best data on population-based prevalence comes from incidental findings in scans ordered for reasons unrelated to the risk of liver lesions. For example, among 17,309 people receiving cross- sectional imaging ordered for lung cancer screening, 6.1% had liver lesions. Of these 1,064 lesions, one in three were potentially significant and 8 (0.8% of lesions) were found to be malignant.¹ Among 4,691 patients who received abdominal imaging during a trauma evaluation, 93 (3%) had liver cysts and 10 (0.3%) had potentially significant lesions requiring further evaluation.² There is variation depending on the population and the imaging modality selected. In general, when examining ultrasounds of the abdomen, cysts are detected in 6-8%, hemangiomas in 3-5%, focal nodular hyperplasia in 0.2-0.8%, and adenoma in 0.04%.³

Cystic Liver Lesions

Cystic lesions range from simple cysts which have no malignant potential to complex pre-malignant lesions. Simple cysts contain clear fluid, do not communicate with the biliary tree, and are smooth but occasionally contain septations, particularly if they have been complicated by hemorrhage (often after trauma). On ultrasound, there is often acoustic shadowing in the parenchyma distal to the cyst. Occasionally, when very large, simple cysts can cause abdominal symptoms and can be treated surgically.⁴ Hydatid cysts have thicker, frequently calcified walls with hypoechoic contents. On cross- sectional imaging, daughter cysts can be observed in the periphery.

Cystadenomas are cystic structures that have the potential for malignancy. Cross-sectional imaging is indicated when the cyst is irregular, with multiple septations, or very large. These have thick or irregular linings with papillary projections that often enhance during contrast phases, septations, and frequently contain heterogeneous fluid. Cystadenomas require monitoring or intervention given the risk of cystadenocarcinoma.

Solid liver lesions

General principles

If a patient has a small (<3cm), smooth, and stable (if prior imaging is available) lesion, it is likely to be benign. Many such lesions can be fully characterized by ultrasound, but cross-sectional imaging is usually definitive. Patients with cirrhosis (or hepatitis B) or known (or suspected) extrahepatic malignancy, and those with new or enlarging lesions (if prior imaging is available) require cross-sectional imaging for evaluation.

Understanding the biology across the differential diagnosis of solid liver lesions is key to ensuring accurate assessment and management. There are three central factors to consider: vascular supply, cellular components, and hormone sensitivity. (Table 1)

TABLE 1: Liver Lesion Basics

Lesion	Biology	Imaging Features	What to Do	When to Worry	What it Could Be	Next Step
Cyst	Clear fluid.	Smooth, occasional septations. Acoustic shadow on ultrasound.	No monitoring needed for simple cysts.	Ultrasound with nodular cyst wall, heterogeneous fluid, multiple septations, or calcifications.	Cystadenoma can transform into malignancy. Hydatid cysts may require therapy.	MRI with contrast.
Hemangioma	Septate clusters of vascular endothelium fed with hepatic arterial supply.	Ultrasound: hyperechoic with sharp margins. MRI: strong signal intensity on T2-weighted sequences and early peripheral arterial contrast enhancement with progressive centripetal filling on later phases.	No monitoring needed.	If >10 cm, can cause abdominal symptoms. If >20cm, rarely can cause coagulopathy.	Cavernous (large) hemangiomas can cause pain or, very rarely, Kasabach-Merrit Syndrome.	Multidisciplinary management with a surgeon and liver tumor board.
Focal nodular hyperplasia (FNH)	Proliferative hepatocytes with intact portal triads surrounding a central scar.	Ultrasound: subtle, if any differences from surrounding tissue. Doppler may see ‘spoke-wheel’ arterial flow. Cross-sectional: arterial enhancement, isointensity in later phases. Scar will appear hypointense on T1, hyperintense on T2, and hyperintense on delayed contrast-enhanced phases.	No monitoring needed after diagnosis by MRI.	If Gadolinium- Eovist enhanced MRI is not conclusive.	Without conclusive imaging features, biopsy may be needed to exclude adenoma.	Biopsy or multidisciplinary management at liver tumor board.
Adenoma	Hepatocytes that are less functional than those in FNH. They lack portal tracts and are fed by arteries. When caused by HNF1-A mutations, there is significant fatty infiltration. B-catenin mutations do not cause specific features. Inflammatory subtypes have vessel clusters and dilated sinusoids.	Variable by subtype. Dilated vascular structures can be seen on ultrasound if present. If fatty infiltration, signal dropout on T1-weighted MRI sequences. HNF1a: arterial enhancement which fades on delayed phases. Inflammatory lesions with telangiectatic arteries are hyperintense on T2 with persistent enhancement on delayed phases. B-catenin lesions often appear the same. Noninflammatory lesions are isointense on T1 and T2 with arterial enhancement and delayed washout.	Stop oral contraceptives. Consider 6 or 12 month follow up to determine growth pattern.	Men, pregnancy, >5cm or growing.	Large lesions can rupture and bleed or transform into hepatocellular carcinoma. Lesions with b-catenin mutations are more likely to transform into malignancy.	Biopsy if lesion is inconclusive or needed for decision making. Resection for high-risk lesions (men, >5cm, growing, b-catenin mutation). Monitor each trimester in pregnancy and 12-weeks post-partum. Bland embolization if >5cm and pregnant.
Hepatocellular Carcinoma (HCC)	Malignant transformation of hepatocytes with preference for arterial blood supply. Arises in patients with cirrhosis, hepatitis B, and rarely in non-cirrhotic livers.	Solitary or multi-nodular lesions. Ultrasound cannot distinguish from other lesions. Arterial hyperenhancement with ‘washout’ on portal veinous phases.	Refer for multidisciplinary tumor board review.	All patients require urgent evaluation.	HCC is fatal if untreated.	Multidisciplinary selection of therapeutic modalities.

MRI = magnetic resonance imaging

Benign lesions

Hemangioma

A hemangioma is mass consisting of septate clusters of vascular endothelium fed with hepatic arterial supply. The classic ultrasound appearance is homogenously hyperechoic and sharp margins. On MRI, hemangiomas display strong signal intensity on T2-weighted sequences and enhance strongly with contrast.⁵ The pattern of enhancement is early/arterial enhancement in the periphery with progressive opacification through the portal and delayed phases. They are more common among women, can be large (>5cm), but do not grow or transform into malignancy.⁶ There is no need for further monitoring on oral contraceptives or during pregnancy.⁷ Rarely, the so-called ‘cavernous hemangioma’ (>5-10cm) can cause symptoms or rupture. Abdominal symptoms are common irrespective of the presence of liver lesions and attribution of abdominal symptoms to hemangiomas is therefore challenging and must be done carefully. Surgical resection or embolization is successful in highly selected cases. Among patients with hemangiomas >20cm, there have been case reports of Kasabach-Merrit Syndrome, a consumptive coagulopathy that improves with resection of the lesion.⁸

Focal Nodular Hyperplasia (FNH)

The vast majority of FNH occur in females. It is generally a solitary lesion. FNH consists of a proliferation of hyperplastic hepatocytes surrounding a central stellate scar with abnormal biliary drainage. There is no portal veinous supply and enlarged arterial branches are presented, coursing through the central fibrosis toward the lesion’s rim. To distinguish FNH from adenomas, contrast-enhanced cross-sectional imaging may be required. Specifically, multiphasic MRI with a contrast agent that is readily taken up by hepatocytes such as Eovist is useful.⁹ The enhancement issignificant during the arterial phase and it persists through the delayed phase because the hepatocytes are functional but the biliary drainage is abnormal. FNH are not hormone sensitive and need no additional monitoring during pregnancy or when patients receive oral contraceptives.7

Adenomas

Hepatocellular or hepatic adenomas are mostly benign but understanding several key features is needed to discern benign from risky lesions. Adenomas are clusters of nonfunctional hepatocytes without portal tracts – they are fed by arteries and lack portal venules or bile ducts – and often are diffusely infiltrated with steatosis. These features often lead to accurate diagnoses by MRI. When infiltrated by steatosis, there will be signal dropout on T1-weighted sequences. Many adenomas, particularly the common inflammatory subtype which has telangiectatic arteries, possess a strong hypersignal on T2-weighted images and display persistent enhancement on delayed phases. Notably, adenomas do not take up the MRI contrast agent Eovist because it is selective for (functional) hepatocytes.

Adenomas can arise and grow in association with estrogen exposure. The epidemiology of adenomas is derived from case-control studies and suggest that the lower doses of estrogen in modern contraceptives are linked to a lower risk of adenoma development. Discontinuation of contraceptives results in regression or stability of the lesion.¹⁰ Of note, intrauterine devices, depoprogestin injections, and progestin-only pills are considered safe. Given the risk of growth during high estrogen states, pregnancy is a high-risk period for patients with adenomas. Women with adenomas should undergo ultrasound surveillance each trimester and at week 12 post-partum. The risk of hemorrhage and rupture is highest for lesions >5cm and therefore to prevent complications, bland transarterial embolization is indicated when lesions reach this size. Adenomas will also grow when exposed to and regress after discontinuation of anabolic steroids taken by men.¹¹ Finally, adenomas arise in those with obesity and the metabolic syndrome. There is limited evidence to suggest that some adenoma will stabilize or shrink in response to weight loss.¹²

Two key features characterize the risk of complications, namely hemorrhage and malignancy. First, lesions >5cm, particularly those in men or those which do not regress with discontinuation of estrogen, are high risk. Second, there are multiple histological subtypes of adenomas, and one is more likely to become cancer. The most common adenoma subtypes are the inflammatory, HNF1A mutated, and, comprising 10%, the beta-catenin mutated adenoma. Beta-catenin mutations pose the greatest risk of malignancy, are more common among men, and therefore molecular diagnostics from lesional biopsies can inform decision making. Specifically, this information guides the frequency of follow-up imaging and the benefit of early treatment particularly when size is <5cm or when patient is unsure of their next steps. Generally, resection is indicated when adenomas are growing during surveillance, when beta-catenin is detected, and for men. Surveillance can be short-term (6 months) when observing following cessation of estrogen therapy or at 1-year when tracking progression for lesions <5cm.

Hepatocellular Carcinoma

Cirrhosis is the primary risk factor for HCC, according for 80-90% of HCC with an annual incidence of 2-4%.^13,14 The highest incidence are among people with uncured/viremic hepatitis C and uncontrolled hepatitis B infections.^{15, 16} Hepatitis B can cause HCC in the absence of cirrhosis. As such, people with cirrhosis should undergo screening for HCC. Among those with HBV, men >40 years old, females >50 years old, and those with a family history of HCC should be screened.¹⁷ Screening should involve liver ultrasounds and AFP testing semiannually, however cross-sectional imaging can be used. When a liver mass is detected in someone with cirrhosis or HBV, prompt diagnostic evaluation is needed to improve outcomes.¹⁸ Although it is a cancer, HCC can be diagnosed by imaging without the need for biopsy. When a suspicious lesion is found, patients should undergo cross-sectional diagnostic imaging with a multiphasic CT or MRI. Owing to the differential blood supply of the liver (primarily portal veinous blood) and HCC (primary arterial), the timing of contrast phase can identify lesions as HCC or not. Liver lesions are categorized and interpreted according to the American College of Radiology criteria for Liver Imaging Reporting and data system (LI-RADS).¹⁹ Lesions are classified from definitely benign (LI-RADS 1) to definitely HCC (LI-RADS 5), as well as non-HCC malignancy (LI-RADS M) and noncategorizable (LI-RADS NC). For LI-RADS 4 lesions and above, the AASLD recommends a multidisciplinary discussion, with biopsy in select cases, or follow up imaging in 3 months.

Cholangiocarcinoma

Intrahepatic cholangiocarcinoma is a rare (9 per 1,000,000 people) lesion with poor survival. Risk factors are poorly defined but there are some high-risk groups: primary sclerosing cholangitis, recurrent pyogenic cholangitis, liver flukes, Caroli’s disease, and age >65 years. Though often diagnosed when symptomatic and advanced, cholangiocarcinoma can be diagnosed as a solitary lesion. On ultrasound, they can be indistinguishable from other lesions but are occasionally irregular with associated capsular retraction. Cross-sectional contrast-enhanced imaging displays slow centripetal enhancement and the draining bile ducts are frequently dilated.

CONCLUSION

Liver lesions are frequently encountered incidentally. We review approaches in Table 1. The key principles guiding their diagnosis are fourfold. First, all decisions must be considered in the context of whether the patient has underlying chronic liver disease such as cirrhosis or sclerosing cholangitis. Second, many lesions can be diagnosed by ultrasound if cystic or small and smooth. Third, most lesions will require an MRI with contrast which provides the greatest detail based on the underlying physiology of the lesion. Fourth, where doubt remains following an MRI, follow-up imaging or discussion at a multidisciplinary tumor board are reasonable approaches. Following a diagnosis, management is often conservative apart from hepatic adenomas and lesions in patients with chronic liver disease.

References

1. Nguyen XV, Davies L, Eastwood JD, Hoang JK. Extrapulmonary Findings and Malignancies in Participants Screened With Chest CT in the National Lung Screening Trial. J Am Coll Radiol. Mar 2017;14(3):324-330. doi:10.1016/j.jacr.2016.09.044

2. Ekeh AP, Walusimbi M, Brigham E, Woods RJ, McCarthy MC. The prevalence of incidental findings on abdominal computed tomography scans of trauma patients. J Emerg Med. May 2010;38(4):484-9. doi:10.1016/j.jemermed.2008.11.019

3. Kaltenbach TE-M, Engler P, Kratzer W, et al. Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients. Abdominal radiology. 2016;41:25-32.

4. Tapper EB, Martin D, Adsay NV, Kalb B, Kooby D, Sarmiento JM. Symptomatic bile duct hamartomas: surgical management in an MRI driven practice. Journal of Gastrointestinal Surgery. 2010;14:1265- 1270.

5. Liver EAftSot. EASL Clinical Practice Guidelines on the management of benign liver tumours. Journal of hepatology. 2016;65(2):386-398.

6. Gandolfi L, Leo P, Solmi L, Vitelli E, Verros G, Colecchia A. Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut. 1991;32(6):677- 680.

7. Sarkar M, Brady CW, Fleckenstein J, et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;73(1):318-365. doi:10.1002/hep.31559

8. Liu X, Yang Z, Tan H, et al. Giant liver hemangioma with adult Kasabach-Merritt syndrome: case report and literature review. Medicine. 2017;96(31)

9. Grazioli L, Morana G, Kirchin MA, et al. MRI of focal nodular hyperplasia (FNH) with gadobenate dimeglumine (Gd-BOPTA) and SPIO (ferumoxides): an intra-individual comparison. J Magn Reson Imaging. May 2003;17(5):593-602. doi:10.1002/jmri.10289

10. Haring MP, Gouw AS, de Haas RJ, Cuperus FJ, de Jong KP, de Meijer VE. The effect of oral contraceptive pill cessation on hepatocellular adenoma diameter: A retrospective cohort study. Liver International. 2019;39(5):905-913.

11. Socas L, Zumbado M, Pérez-Luzardo O, et al. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. British Journal of Sports Medicine. 2005;39(5):e27-e27. doi:10.1136/ bjsm.2004.013599

12. Gevers TJ, Marcel Spanier B, Veendrick PB, Vrolijk JM. Regression of hepatocellular adenoma after bariatric surgery in severe obese patients. Liver International. 2018;38(12):2134-2136.

13. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology. 2011;140(4):1182-1188. e1.

14. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5):S35-S50.

15. Jhaveri R. Screening for hepatitis C virus: how universal is universal? Clinical therapeutics. 2020;42(8):1434- 1441.

16. Owens DK, Davidson KW, Krist AH, et al. Screening for hepatitis C virus infection in adolescents and adults: US Preventive Services Task Force recommendation statement. Jama. 2020;323(10):970-975.

17. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, S taging, and M anagement of H epatocellular C arcinoma: 2018 P ractice G uidance by the A merican A ssociation for the S tudy of L iver D iseases. Hepatology. 2018;68(2):723-750.

18. Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology. 2015;61(1):191-199.

19. Tang A, Bashir MR, Corwin MT, et al. Evidence supporting LI-RADS major features for CT-and MR imaging–based diagnosis of hepatocellular carcinoma: a systematic review. Radiology. 2018;286(1):29-48.

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MEDICAL BULLETIN BOARD

Redhill and U.s. Army Announce Opaganib and Rhb-107 Combinations with Remdesivir Show Distinct Synergistic Effect Against Ebola

Investigational drugs opaganib and RHB-107 (upamostat) demonstrate distinct synergistic effect when combined individually with remdesivir, significantly improving potency while maintaining cell viability, in a new U.S. Army-funded and conducted in vitro Ebola virus study

Opaganib and RHB-107 are both novel, oral, host-directed, small molecule investigational drugs that are easy to administer and distribute, with demonstrated activity against multiple viral targets, including COVID-19, and are expected to be effective against emerging viral variants

Opaganib is believed to be the first host-directed molecule to show activity in Ebola virus disease, having recently delivered a statistically significant increase in survival time in a separate U.S. Army-funded in vivo Ebola virus study. RHB-107 was recently accepted for inclusion in the ACESO PROTECT adaptive platform trial for early COVID-19 outpatient treatment

TEL-AVIV, Israel / RALEIGH, NC, December 20, 2023, RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company, today announced that its two novel, oral host-directed investigational drugs, opaganib¹ and RHB-107 (upamostat),² demonstrated robust synergistic effect when combined individually with remdesivir (Veklury®),³ significantly improving viral inhibition while maintaining cell viability, in a new U.S. Army-funded and conducted Ebola virus in vitro study.

“These encouraging in vitro results for opaganib and RHB-107 show a distinct synergy in terms of viral inhibition while maintaining cell viability (i.e., not increasing toxicity), when either is added to remdesivir, with opaganib showing the greatest synergistic effect in combination with remdesivir,” said Jeffrey Kugelman, Ph.D., Major(P), US Army MSC, Branch Chief Synthetic Biology & Surveillance, Molecular Biology Division, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), who led the bioinformatics analysis of the study. “The results suggest that opaganib and upamostat may have potential or use in combination with direct antiviral agents,

such as remdesivir, to improve treatment outcome, increasing efficacy while maintaining safety.”

“Opaganib is believed to be the first host-directed molecule to show activity in Ebola virus disease, and these results add to a recent U.S. Army Ebola virus study in which opaganib delivered a statistically significant increase in mice survival time in vivo,” said Reza Fathi, Ph.D., RedHill’s SVP R&D. “Opaganib and RHB-107 are both novel, oral, host-directed, small molecule investigational drugs with demonstrated activity against multiple viral targets, including COVID-19, and are expected to be effective against emerging viral variants. This, together with their growing safety and tolerability databases, presents a compelling hypothesis for further study of their potential in treating Ebola virus.”

Utilizing a checkerboard design to test the study compounds in combination, the study cell lines were pretreated and then infected with Ebola virus. The cells were fixed, washed and subjected to immunofluorescence staining using a virus-specific antibody. The raw data for the combination was analyzed to determine synergistic, additivity or antagonistic effects on viral inhibition while taking into account cell viability.

Twice daily administered opaganib has previously demonstrated benefit in late-stage clinical studies of patients hospitalized with moderate to severe COVID-19 and was selected by the NIH Radiation and Nuclear Countermeasures Program (RNCP) for Acute Radiation Syndrome development.

RHB-107 successfully met its U.S. Phase 2 study primary endpoint of safety and tolerability and delivered promising efficacy results, including marked reduction in hospitalization due to COVID-19. RHB-107 was recently accepted for inclusion in the ACESO PROTECT adaptive platform trial for early COVID-19 outpatient treatment. The 300-patient PROTECT Phase 2 RHB-107 arm, fully funded by non-dilutive external funding sources including the U.S. government,4 has received FDA clearance to start, with the first patient expected to be enrolled in the coming weeks. The study is being conducted in the U.S., Thailand, Ivory Coast, South Africa and Uganda, and is estimated to be completed by end of 2024.

GIE MEDICAL ANNOUNCES FIRST PATIENT ENROLLED IN PATENT-E BENIGN ESOPHAGEAL STRICTURE TREATMENT STUDY

The large, multicenter randomized controlled clinical trial is evaluating the safety and efficacy of the ProTractX3™ TTS drug coated balloon for the treatment of benign esophageal strictures

MINNEAPOLIS – December 7, 2023. GIE Medical, a clinical stage company developing solutions for patients suffering from benign stricture(s) of the esophagus or bowel, announced today that enrollment has begun in its Paclitaxel Coated Balloon for the Treatment of Chronic Benign Stricture – Esophagus (PATENT-E) study. The study is evaluating the safety and efficacy of the first of its kind ProTractX3™ TTS drug coated balloon (DCB) and the first patient was enrolled at the University of North Carolina School of Medicine.

“We are excited to be testing this promising new technology,” said Nicholas J. Shaheen, MD, MPH, Chief, Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine. “Our patients with difficult-to-treat strictures need treatment options that are effective and safe. We hope to show that this innovative approach provides a new direction for them.”

Earlier this year, the Food and Drug Administration Center for Devices and Radiological Health (CDRH) granted GIE Medical the Breakthrough Device Designation to expedite development of its ProTractX3™ TTS DCB for patient access because it has a reasonable chance of providing more effective treatment of life-threatening or irreversibly debilitating human disease or conditions than the current standard of care.

“We are pleased to be enrolling the randomized cohorts in PATENT-E, our treatment for esophageal stricture IDE study, and look forward to the results,” said GIE Medical Vice President Drew McClure. “We sincerely thank our clinical partners and internal GIE Medical team for achieving this significant milestone.”

People who may qualify to participate in the PATENT-E study:
Are 22 years of age or older
Are failing to respond to conventional dilation (have had at least one previous dilation in the past 12 months with diagnosis of stricture recurrence)

GIE Medical’s ProTractX3™ 3-Stage TTS DCB is a balloon coated with the anti-restenotic agent paclitaxel. It is an investigational device in the U.S.

ABOUT GIE MEDICAL

GIE Medical is a clinical stage company conducting trials in the U.S. to help patients suffering from benign stricture(s) of the esophagus or bowel (small intestine, colon, and rectum).

The ProTractX3™ Through the Scope Drug Coated Balloon could offer a new solution for treating GI strictures, potentially creating sustained long-term patency and reducing the number of treatments.

For more information, visit: GIEMedical.com

References

References
1. Opaganib is an investigational new drug, not available for commercial
distribution.
2. RHB-107 is an investigational new drug, not available for commercial
distribution.
3. Remdesivir, a leading COVID-19 therapy, is sold under the
brand name Veklury® by Gilead Sciences, Inc. (Nasdaq:
GILD)
4. https://www.redhillbio.com/news/news-details/2023/RedHill-
Announces-New-Non-Dilutive-External-Funding-of-Entire-
RHB-107-COVID-19-300-Patient-Phase-2-Study/default.
aspx
More information about the company
is available at:
www.redhillbio.com / twitter.com/RedHillBio

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INTRODUCTION: DISPATCHES FROM THE GUILD CONFERENCE

Introduction: Dispatches from the GUILD Conference 2024

January 2024 • Volume XLVIII, Issue 1

Uma Mahadevan

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Welcome to the eighth annual Dispatches from GUILD Conference series. The Gastrointestinal Updates-Bowel-Liver Inflammatory Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February (GUILD 2024: February 18-21). We are delighted to offer a hybrid meeting with over 250 health care providers attending live. GUILD again provides cutting edge updates in gastroenterology by world class speakers. Our topics this year include 2 days of IBD updates, a day of hepatology and a day devoted to general gastroenterology. We understand that trainees are our future. Ten Gastroenterology fellows were selected to attend the meeting and receive daily mentoring and networking from our star faculty. GUILD also recognizes the role played by nurse practitioners and physician assistants in the care of IBD and Liver patients and introduced a boot camp in 2019, awarding 10 scholarships to APPs to attend the meeting.

To share our learning with the gastroenterology community at large, we are happy to continue our series beginning with the following article , “Liver Masses: Work up and When to Worry”.

We look forward to providing informative and educational articles covering IBD, Hepatology and special topics in GI in Practical Gastroenterology over the following months. We hope to see you all in person for GUILD 2024 in Maui February 18-21.

For more information on the GUILD Conference, visit: guildconference.com

Uma Mahadevan MD, Professor of Medicine, Director, UCSF Colitis and Crohn’s Disease Center

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