Page 10 – Practical Gastro

FRONTIERS IN ENDOSCOPY, SERIES #89

Disposable Endoscopes: Current Status and Future Directions

February 2024 • Volume XLVIII, Issue 2

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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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #10

Nitrogen Balance: Revisiting Clinical Applications in Contemporary Practice

February 2024 • Volume XLVIII, Issue 2

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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.

9. Estensen K, Shekar K, Robins E, McDonald C, Barnett AG, Fraser JF. Macro- and micronutrient disposition in an ex vivo model of extracorporeal membrane oxygenation. ICMx. 2014;2(1):29.

10. Dickerson RN. Using Nitrogen Balance in Clinical Practice. Hospital Pharmacy. 2005;40(12):1081-1085.

11. Hoffer LJ. Metabolic consequences of starvation. In: Modern Nutrition in Health and Disease. 11th ed. Lippincott William & Wilkins; 2012:660-677.

12. Munro HN. Energy and protein intakes as determinants of nitrogen balance. Kidney International. 1978;14(4):313-316.

13. Millward DJ. Identifying recommended dietary allowances for protein and amino acids: a critique of the 2007 WHO/FAO/UNU report. Br J Nutr. 2012;108(S2):S3-S21.

14. Shaw JHF, Wildbore M, Wolfe RR. Whole Body Protein Kinetics in Severely Septic Patients: The Response to Glucose Infusion and Total Parenteral Nutrition. Annals of Surgery. 1987;205(3):288-294.

15. Cerra F, Blackburn G, Hirsch J, Mullen K, Luther W. The Effect of Stress Level, Amino Acid Formula, and Nitrogen Dose on Nitrogen Retention in Traumatic and Septic Stress: Annals of Surgery. 1987;205(3):282-287.

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.

19. MacLean WC, Warwick P, Food and Agriculture Organization of the United Nations, eds. Food Energy: Methods of Analysis and Conversion Factors: Report of a Technical Workshop, Rome, 3-6 December 2002. Food and Agriculture Organization of the United Nations; 2003.

20. Yarandi SS, Zhao VM, Hebbar G, Ziegler TR. Amino acid composition in parenteral nutrition: what is the evidence?: Current Opinion in Clinical Nutrition and Metabolic Care. 2011;14(1):75-82.

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.

25. Inoue G, Fujita Y, Niiyama Y. Studies on Protein Requirements of Young Men Fed Egg Protein and Rice Protein with Excess and Maintenance Energy Intakes. The Journal of Nutrition. 1973;103(12):1673-1687.

26. Young VR, Hussein MA, Scrimshaw NS. Estimate of Loss of Labile Body Nitrogen during Acute Protein Deprivation in Young Adults. Nature. 1968;218(5141):568-569.

27. Irwin MI, Hegsted DM. A Conspectus of Research on Amino Acid Requirements of Man. The Journal of Nutrition. 1971;101(4):539-566.

28. Kim GH, Oh KH, Yoon JW, et al. Impact of Burn Size and Initial Serum Albumin Level on Acute Renal Failure Occurring in Major Burn. Am J Nephrol. 2003;23(1):55-60.

29. Zhu YB, Yao Y, Xu Y, Huang HB. Nitrogen balance and outcomes in critically ill patients: A systematic review and meta-analysis. Front Nutr. 2022;9:961207.

30. Dupuis C, Bret A, Janer A, et al. Association of nitrogen balance trajectories with clinical outcomes in critically ill COVID-19 patients: A retrospective cohort study. Clinical Nutrition. 2022;41(12):2895-2902.

31. Danielis M, Lorenzoni G, Azzolina D, et al. Effect of Protein-Fortified Diet on Nitrogen Balance in Critically Ill Patients: Results from the OPINiB Trial. Nutrients. 2019;11(5):972.

32. Ferrie S, Allman-Farinelli M, Daley M, Smith K. Protein Requirements in the Critically Ill: A Randomized Controlled Trial Using Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2016;40(6):795-805.

33. Waxman K, Rebello T, Pinderski L, et al. Protein Loss across Burn Wounds: The Journal of Trauma: Injury, Infection, and Critical Care. 1987;27(2):136-140.

34. Lehnhardt M, Jafari HJ, Druecke D, et al. A qualitative and quantitative analysis of protein loss in human burn wounds. Burns. 2005;31(2):159-167.

35. Mosteller RD. Simplified Calculation of Body-Surface Area. N Engl J Med. 1987;317(17):1098-1098.

36. Cheatham ML, Safcsak K, Brzezinski SJ, Lube MW. Nitrogen balance, protein loss, and the open abdomen: Critical Care Medicine. 2007;35(1):127-131.

37. Scheinkestel CD, Kar L, Marshall K, et al. Prospective randomized trial to assess caloric and protein needs of critically Ill, anuric, ventilated patients requiring continuous renal replacement therapy. Nutrition. 2003;19(11-12):909-916.

38. Levitt D, Levitt M. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. CEG. 2018;Volume 11:193-215.

39. Shekar K, Roberts JA, Mcdonald CI, et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care. 2015;19(1):164.

40. Pelekhaty SL, Galvagno SM, Lantry JH, et al. Are Current Protein Recommendations for the Critically Ill Adequate for Patients on VV ECMO: Experience From a High-Volume Center. J Parenter Enteral Nutr. 2020;44(2):220-226.

41. Pelekhaty S, Galvagno SM, Hochberg E, et al. Nitrogen Balance During Venovenous Extracorporeal Membrane Oxygenation Support: Preliminary Results of a Prospective, Observational Study. J Parenter Enteral Nutr. 2020;44(3):548-553.

42. Dresen E, Naidoo O, Hill A, et al. Medical nutrition therapy in patients receiving ECMO: Evidence-based guidance for clinical practice. J Parenter Enteral Nutr. 2023;47(2):220-235.

43. Zonies D, Codner P, Park P, et al. AAST Critical Care Committee clinical consensus: ECMO, nutritionExtracorporeal membrane oxygenation (ECMO)Nutrition. Trauma Surg Acute Care Open. 2019;4(1):e000304.

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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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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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FROM THE PEDIATRIC LITERATURE

Use of Pictograms to Help Diagnose Functional Abdominal Pain

January 2024 • Volume XLVIII, Issue 1

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Functional abdominal pain (FAP) is a common presentation in both general pediatric and pediatric gastroenterology clinics, and there is no specific test to diagnose this disorder. A clinical history helps in determining if FAP is present, and the authors of this study evaluated the utility of pictograms in assisting the diagnosis of pediatric FAP.

This study was prospective and occurred over one year at two academic medical centers in Europe. Patients with organic gastrointestinal (GI) disease or patients who could not complete a symptom questionnaire independently were excluded, and recruited patients were randomly given a questionnaire with or without associated explanatory pictograms. The child’s health care provider also filled out the questionnaire but was blinded to patient questionnaire results. In total, 144 patients participated in the study for which 62% of patients were female. The mean patient age was 13.7 ± 2.4 years. No significant difference was seen in concordance rates between the patient and healthcare provider when comparing individual GI symptoms, including any symptoms of abdominal pain. However, using a questionnaire with pictograms was statistically significant in determining symptoms of nausea and emesis with good interrater reliability for symptoms of nausea, emesis, and regurgitation as measured by Cohen’s kappa coefficient. Children between 8 – 12 years of age had significantly more concordance of nausea and emesis symptoms when using a questionnaire with pictograms compared to their healthcare provider questionnaire, but no other GI symptoms were statistically different. Most patients found the questionnaire easy to understand. Significantly more children found the questionnaire with pictograms easier to understand compared to the questionnaire alone regarding the symptom of regurgitation although the patients in this comparative group was small.

This study did not demonstrate that pictograms significantly improve how children with FAP describe GI symptoms except in the setting of nausea and emesis. More work is needed here as pictograms used to determine GI symptoms would be very helpful in pediatric patients who cannot read or are too young to read.

de Bruijn C, Rexwinkel R, Vermeijden N, Hoffman I, Tack J, Benninga M. The Use of Pictograms in the Evaluation of Functional Abdominal Pain Disorders in Children. J Pediatr 2023; 263: 113647

Medications and the Risk of Eosinophilic Esophagitis in Children

Eosinophilic esophagitis (EoE) is common in children, and the increase in incidence worldwide suggests a need to determine risk factors. Since antibiotic and acid-suppression medication can affect the intestinal microbiome and gut permeability, the authors of this study evaluated the long-term effects of these two medication classes in pregnant mothers as well as in infants to see if such medications led to a subsequent increased risk of EoE.

This study used Danish health registry data to collect information on pediatric patients with EoE and their mothers as well as control patients and their mothers. The Danish National Prescription Registry was analyzed to assess prescription type, frequency, and date of use. This data was combined with the Danish Medical Birth Register to determine pregnancy data. A total of 416 children with EoE (defined as ≤ 22 years of age at time of EoE diagnosis) was then compared 4160 age / sex- matched controls. The median age of patients with EoE was 11 years (range 6 – 15 years), and 68.8% of these patients were male. It was noted that most patients with EoE had a history of prematurity (11% versus 7.3%), were born by caesarean section (23.2% versus 19.6%) and had a history of newborn ICU admission (17.3% versus 10.2%).

The use of any antibiotic during a mother’s pregnancy was associated with an increased risk of their child developing EoE (adjusted odds ratio 1.5; 95% CI, 1.2-1.9) with this risk increasing with an increased number of maternal antibiotic prescriptions. The most common antibiotics prescribed were beta-lactam antibiotics and penicillins. The risk of antibiotics causing a mother’s child to have EoE was highest when used during the third trimester of pregnancy (adjusted odds ratio 1.5; 95% CI, 1.0-2.1). No such association was seen with single antibiotic use during the first or second trimester. This risk of EoE occurring in a patient who received antibiotics during infancy also was increased (adjusted odds ratio 1.4; 95% CI, 1.1-1.7), and the risk increased with an increased number of antibiotic prescriptions. Beta-lactam antibiotics and penicillins were the most commonly used prescriptions in these infants. Infants who received antibiotics closest to their birth date also had a higher risk for EoE (adjusted odds ratio 1.9; 95% CI, 1.1-3.1).

Similarly, use of maternal acid-suppression medication of any type during a mother’s pregnancy increased the risk of EoE in their children (adjusted odds ratio 1.7; 95% CI, 1.0-2.8) with the risk increasing with an increasing number acid- suppression medication prescriptions. A similar risk for developing EoE was present in children who received acid-suppression medications during infancy (adjusted odds ratio 15.9; 95% CI, 9.1- 27.7) with the risk increasing in children receiving more prescriptions for these medications. This risk was especially present in infants receiving proton pump inhibitors, in infants with a history of prematurity, and in infants who received such medications in late infancy (defined as 7 to 12 months of age) as opposed to early infancy (birth to 6 months of age).

This study is extremely important as it identifies potential risk factors for development of childhood EoE that may be preventable. Appropriate use of antibiotics and acid-suppression medication possibly could prevent EoE in specific scenarios. However, the increased use of acid-suppression medications in infants who went on to develop EoE in this study could have been due to early symptoms of not-yet diagnosed EoE.

Jensen E, Svane H, Erichsen R, Kurt G, Heide- Jorgensen U, Sorensen H, Dellon E. Maternal and Infant Antibiotic and Acid Suppressant Use and Risk of Eosinophilic Esophagitis. JAMA Pediatr 2023; 177: 1285-1293.

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology

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FRONTIERS IN ENDOSCOPY, SERIES #88

Radiofrequency Ablation for Indications Beyond Barrett’s Esophagus

January 2024 • Volume XLVIII, Issue 1

Douglas G. Adler,

Courtney Walker

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INTRODUCTION

Radiofrequency ablation (RFA) was first approved by the United States Food and Drug Administration in 2001 for the treatment of Barrett’s esophagus and for gastric hemostatic applications.¹ RFA uses alternating electrical currents in a closed circuit whereby tissues between two electrodes will become coagulated.² The acute coagulative necrosis occurs when temperatures within tissue are greater than 60 degrees Celsius and results in denaturing of proteins, melting of the plasma membrane, and near instantaneous cell death.³

Within the GI tract, RFA is perhaps best known for treating dysplastic lesions in the esophagus (typically Barrett’s esophagus with dysplasia), as well as pancreatic neoplasia, and malignant biliary obstruction.⁴

This review will focus on the application of RFA in the luminal GI tract for non-Barrett’s lesions.

Overview of Endoscopic RFA Technology

Unlike esophageal RFA treatment for Barrett’s esophagus, the coagulum that forms after RFA for benign luminal GI conditions is not scraped to minimize the risk of bleeding.⁴ In the U.S.A., RFA is performed with the Barrx Flex generator (Medtronic Inc, Sunnyvale, CA). The device is a bipolar radiofrequency (RF) generator which connects to various single-use RFA catheters. The generator measures tissue impedance during RF energy delivery and automatically adjusts energy output to obtain an equal depth of tissue ablation throughout the field.⁴ Catheters for use in the GI lumen include over the scope and through – the – scope (TTS) catheters.

RFA for Symptomatic Cervical Inlet Patches

Cervical inlet patches (CIP) are heterotropic gastric mucosa located in the proximal esophagus just below

the upper esophageal sphincter, usually 15-20 cm from the incisors and are considered a congenital condition.⁵ CIP is often an incidental finding, but in some patients, it can cause symptoms, and rarely may have evidence of Barrett’s esophagus and/or dysplasia necessitating treatment. Symptomatic patients most commonly present with dysphagia and cough, but ulcers, bleeding, and even peptic strictures can develop.⁶ Medical management of CIP begins with proton pump inhibitors and while this may improve some symptoms, it is at times ineffective and endoscopic therapy is warranted.⁷

Endoscopic therapy includes argon plasma coagulation (APC) and RFA. (Figure 1) Unlike APC, the uniform depth of ablation with RFA is felt to reduce the risk of adverse events such as stricture formation, perforation, and buried glands that may be seen following treatment with APC. One of the first studies to show safety and efficacy of RFA ablation for CIP was a ten-patient pilot study using a TTS RFA device. In this study by Dunn et al, all visible CIP was treated with three energy applications at 12 J/cm2 with a median of two RFA sessions and a total of 179 ablations. Follow up esophagogastroduodenoscopy (EGD) was performed at three and 12 months. Complete endoscopic and histologic resolution of CIP was seen in 80% of patients.⁸ RFA of the CIP also

had clinical success with improvement in globus sensation, sore throat, and cough. Treatment with RFA was durable as there was no recurrence of buried glands on biopsies or symptoms at 14 months follow up and no adverse events including strictures were reported.⁸

An additional study evaluated patients with large, symptomatic CIP (greater than 20 mm) and found that 80% of patients achieved macroscopic and histologic resolution of CIP after two RFA ablations. These patients had significant improvement in globus sensation, mental health scores, and laryngopharyngeal reflux. Similarly, no strictures or chronic adverse events were seen after mean follow up of 1.9 years.⁹ Overall, RFA for the treatment of CIP is effective for histologic removal of CIP and symptom improvement and with potentially less risk of deeper mucosal damage compared to APC.

RFA for Gastric Antral Vascular Ectasia

Gastric antral vascular ectasia (GAVE), often referred to as “Watermelon stomach,” is the endoscopic appearance of erythematous stripes, which are visibly convoluted columns of vessels, extending from the pylorus into the distal gastric body.¹⁰ The dilated, fragile, and ectatic blood vessels are located within the superficial

submucosa and mucosa and, when disrupted, cause gastrointestinal bleeding, iron deficiency anemia, and need for red blood cell transfusion.10 GAVE is seen in 30% of patients with cirrhosis and is also associated with autoimmune conditions such as scleroderma, CREST syndrome, Raynaud’s, and chronic kidney disease.^11,12 The severity of GAVE has yet to establish a correlation with degree of chronic disease severity.¹³ Distinguishing GAVE from portal hypertension gastropathy (PHG) is critical as GAVE will not respond to therapy aimed at reducing portal pressures, unlike PHG.¹⁴

Prior to RFA, endoscopic treatment for GAVE was generally performed via thermal therapy with APC or the now obsolete laser therapy.¹⁵ The objective of thermal therapy is the eradication of the ectatic vessels that result in blood loss. APC has been widely used due to ease of use, low cost, and overall safety.¹³ However, unlike RFA, APC can be difficult to apply over large areas, and the depth of injury is highly variable. (Figure 2)

One of the first studies to evaluate RFA for treatment of GAVE was a pilot study of six patients with hemorrhagic GAVE and blood transfusion dependence.16 In this study, four of the six patients had failed prior APC. The HALO90 ablation system with over the scope RFA catheter fixed at the 12 0’clock position was used, four pulses per GAVE site were applied with a uniform depth of ablation created over 3 cm.² The maximum depth of ablation was limited to the superficial mucosa (14 J/cm2 of energy applied). Overall, there was an improvement in hemoglobin of 1.2 g/dL with only one patient still being transfusion dependent at the end of the study.¹⁶ No adverse events were reported.

Other studies also evaluated GAVE refractory to APC, treated with RFA, including use of the HALO90 ULTRA ablation catheter (with a surface area of 5.2 cm2).^17,18 Technical success was defined as complete eradication of endoscopic GAVE. In these prospective studies patients required a median number of 2 – 2.5 RFA sessions to achieve a goal of 90% technical success in one study and 100% in the other. In the study by Jana et al., 71% of patients achieved clinical success and were transfusion independent at 6 months follow-up.¹⁸

In addition to the classic flat, striped, watermelon appearance of GAVE there is a nodular phenotype. Nodular GAVE is seen in 30% of cases and described as endoscopically smooth, benign-appearing nodules in the antrum, often associated with cirrhosis.¹⁹ Previously, nodular GAVE was considered a distinct histopathologic entity, but now

is thought to be gastric hyperplastic polyps arising in a background of GAVE.^20,21 Similar to flat GAVE, nodular GAVE can also present with chronic iron deficiency anemia and gastrointestinal bleeding. Treatment involves APC, RFA, and the possible addition of endoscopic band ligation (EBL) for refractory nodular GAVE. Case series have shown that nodular GAVE may be more difficult to treat and multimodal therapy, either APC or RFA with banding have improved hemoglobin concentrations with less blood transfusions.^22,23,24

RFA versus APC for GAVE

A large, systemic review and meta-analysis of APC (24 studies, 508 patients) vs. RFA (9 studies, 104 patients) found those treated with RFA required fewer treatment sessions (2.10 vs. 3.39 for APC, p < 0.001) and had improved endoscopic ablation success (97% for RFA and 66% for APC, p < 0.001). Post-treatment pooled hemoglobin increase, and number of blood transfusions was statistically better in the APC group. However, 47% of the RFA patients had GAVE refractory to APC therapy, suggesting some heterogeneity in the samples between modalities. Overall, RFA was associated with fewer adverse events compared to the APC group.²⁵

Regarding adverse events of RFA, ulcerations and traumatic laceration to the gastric cardia, nausea, vomiting, and abdominal pain have been reported upon removal of the HALO90 ULTRA device.²⁶ Less common are reports of sepsis and bacteremia. A case report of a patient with cirrhosis and GAVE without evidence of infective endocarditis or spontaneous bacterial peritonitis developed streptococcus intermedius bacteremia almost two weeks after the fourth and final session of RFA with a total of 50 pulses, at least raising the possibility that these two events were related.²⁷ Mucosal injury from RFA was the suspected cause of bacterial translocation. While there are overall limited reports of RFA adverse events, perhaps the largest deterrent to RFA use is the overall cost, which is approximately five times greater per use than APC.²⁸ Furthermore, almost all endoscopy facilities have APC technology on hand, while RFA is in much more limited use.

RFA for Radiation Proctitis

RFA also has a role in the treatment of radiation proctitis. Approximately 5-20% of patients receiving radiotherapy for pelvic malignancies such as: prostate, cervical, vaginal, ovarian, and bladder cancer, etc., will develop radiation proctitis.^29,30 Cell death and apoptosis from radiation damage to DNA, lipids, and proteins occurs.³¹ This microvascular injury to the rectal mucosa gives rise to ischemia, fibrosis, and the development of fragile and friable neovascular lesions susceptible to hemorrhage.³² (Figure 3) Chronic rectal bleeding from radiation proctitis may result in iron deficiency anemia and blood transfusion dependence.

APC has been the primary therapy for radiation proctitis for many years, but with limitations. Following APC, post-treatment ulcerations can develop from the deeper depth of thermal injury associated with this technology.^33,34Adverse events from APC for radiation proctitis include perforation and tissue necrosis in up to 14% of patients.34

With regards to RFA, the tightly spaced bipolar RFA catheter limits the RF energy penetration to the superficial mucosa, where the vessels of interest exist, reducing the risk of deep tissue injury as can occur with APC.³⁵

While less common, radiation-induced sigmoiditis is also seen following radiotherapy for pelvic malignancy. Radiation sigmoiditis may be more resistant to treatment with ablation therapy due to difficulty in targeting affected tissue with APC in the sigmoid colon.³⁶

RFA can potentially be used to treat radiation sigmoiditis as well. A retrospective study used 12 J/cm2 instead of 15 J/cm2 when radiation proctitis lesions were greater than 8 cm proximal to the dentate line.³⁷ No significant adverse events were seen. Mild to moderate anal pain was found in 34.2% of patients and controlled with acetaminophen or combined with non-steroidal anti-inflammatory drugs, or topical analgesics.³⁷ An initial proof of concept ex vivo study to evaluate RFA for the treatment of radiation proctitis was performed in 2011 by Trunzo et al. In this study, RFA was performed with two to four applications of energy applied to surgically resected left colon and rectum segments with a range of 12 to 20 J/cm.2 Sites receiving two applications of RFA showed no serosal alteration compared to 15% (p = 0.11) of sites receiving four applications. Histologic depth of ablation within the muscularis propria was seen in 25% of two-application sites and 63% of four-application sites (p < 0.05). Regardless of increasing energy density, there was no correlation with deeper ablation injury. This study suggested RFA for treatment of radiation proctitis was feasible and without significant risk of deep submucosal injury with only two RFA applications.³⁸

Other case studies evaluated patients with chronic radiation proctitis with hemorrhage using RFA HALO90 or HALO90 ULTRA catheters and found that broad areas of active bleeding could be treated in two to four RFA sessions to control rectal bleeding.^39,39 In one study, endoscopic optical coherence tomography (EOCT) was used to identify ectatic blood vessels in the rectum greater than 50 um in diameter. After RFA, EOCT showed re-epithelialization over the treated areas.40 Follow up after 2 sessions of RFA, 12-17 months later, showed new epithelium without development of ulcerations, strictures, or rebleeding.³⁹

One of the larger studies to investigate RFA therapy for radiation proctitis evaluated 39 Veteran’s Affairs patients. Enrolled patients had a history of endoscopically confirmed chronic radiation proctitis with recurrent hematochezia for at least three months and were treated with a mean number of 1.49 RFA sessions with the RFA catheter mounted in the 6 o’clock position on the endoscope. Rectal bleeding stopped in all patients at follow-up, and mean hemoglobin increased from 11.8 g/ dL to 13.5 g/dL (p < 0.001).⁴¹ Discontinuation of red blood cell transfusion and iron therapy was seen in 92% and 82% of patients respectively.⁴⁰ Endoscopic improvement was assessed via the rectal telangiectasia density score (range 0: normal mucosa to 3: two or more coalescing patches of rectal telangiectasias) with initial scores of 3 at the start of therapy, decreased to 0 (p < 0.0001) during follow-up.

Findings of improvement in radiation proctitis were reported in a retrospective single arm cohort study of 35 patients. In this study, the mean follow up was 18.6 months and rectal telangiectasia density score decreased from mean of 2.96 to 0.85 (p < 0.0001) at the end of follow up.³⁷ All patients in this study had resolution of hematochezia and statistically improved levels in hemoglobin at the end of the study. Rectal ulcers, fistulas, and strictures did not occur.⁴¹ A systematic review and metanalysis of six studies (71 patients) in which 38% of patients with chronic radiation proctitis had failed prior APC treatment, required a mean of 1.71 RFA sessions to achieve a pooled clinical and endoscopic success of 99% and 100% (p < .0001). Patients were followed for a mean of 19.73 months. There were no serious adverse events and there was a mean weighted difference of hemoglobin improvement post-RFA of 2.49 g/dL.42

CONCLUSION

The use of RFA has expanded well beyond the treatment of Barrett’s esophagus. RFA has shown great efficacy in the treatment of symptomatic cervical inlet patches, GAVE, and radiation proctitis in patients with and without other prior endoscopic treatments.

Among patients with symptomatic inlet patches, RFA was shown to effectively ablate endoscopic and histologic evidence of heterotropic gastric mucosa in most patients. Many patients had clinical resolution of globus, sore throat, and cough and without stricture formation or serious adverse events. Patients with GAVE also have high rates of endoscopic eradication following RFA and may be an alternative to patients with refractory GAVE previously treated with APC. RFA in radiation proctitis results in the development of new epithelium with decreased risk of bleeding or need for blood transfusions. Application of RFA for these indications is effective, with an acceptable level of adverse events.

References

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35. Sharma VK, Kim HJ, Das A, Dean P, DePetris G, Fleischer DE. A prospective pilot trial of ablation of Barrett’s esophagus with low-grade dysplasia using stepwise circumferential and focal ablation (HALO system). Endoscopy. 2008 May;40(5):380-7. doi: 10.1055/s-2007-995587. PMID: 18459074.

36. Tjandra JJ, Sengupta S. Argon plasma coagulation is an effective treatment for refractory hemorrhagic radiation proctitis. Dis Colon Rectum. 2001 Dec;44(12):1759-65; discussion 1771. doi: 10.1007/BF02234451. PMID: 11742157.

37. Tang CE, Cheng KC, Wu KL, Chen HH, Lee KC. A Retrospective Single-Arm Cohort Study in a Single Center of Radiofrequency Ablation in Treatment of Chronic Radiation Proctitis. Life (Basel). 2023 Feb 17;13(2):566. doi: 10.3390/ life13020566. PMID: 36836925; PMCID: PMC9958826.

38. Trunzo JA, McGee MF, Poulose BK, Willis JE, Ermlich B, Laughinghouse M, Champagne BJ, Delaney CP, Marks JM. A feasibility and dosimetric evaluation of endoscopic radiofrequency ablation for human colonic and rectal epithelium in a treat and resect trial. Surg Endosc. 2011 Feb;25(2):491- 6. doi: 10.1007/s00464-010-1199-3. Epub 2010 Jul 22. PMID: 20652324.

39. Pigò F, Bertani H, Manno M, Mirante VG, Caruso A, Conigliaro RL. Radiofrequency ablation for chronic radiation proctitis: our initial experience with four cases. Tech Coloproctol. 2014 Nov;18(11):1089-92. doi: 10.1007/ s10151-014-1178-0. Epub 2014 Jun 11. PMID: 24915942.

40. Zhou C, Adler DC, Becker L, Chen Y, Tsai TH, Figueiredo M, Schmitt JM, Fujimoto JG, Mashimo H. Effective treatment of chronic radiation proctitis using radiofrequency ablation. Therap Adv Gastroenterol. 2009 Jan 1;2(3):149- 156. doi: 10.1177/1756283×08103341. PMID: 20593010; PMCID: PMC2893353.

41. Rustagi T, Corbett FS, Mashimo H. Treatment of chronic radiation proctopathy with radiofrequency ablation (with video). Gastrointest Endosc. 2015 Feb;81(2):428-36. doi: 10.1016/j.gie.2014.04.038. Epub 2014 Jun 25. PMID: 24973172.

42. McCarty TR, Garg R, Rustagi T. Efficacy and safety of radiofrequency ablation for treatment of chronic radiation proctitis: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2019 Sep;34(9):1479-1485. doi: 10.1111/jgh.14729. Epub 2019 Jul 2. PMID: 31111527.

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MEDICAL BULLETIN BOARD

Phathom Pharmaceuticals Announces Commercial Availability of Voquezna® (Vonoprazan) Tablets

A Powerful First-In- Class Pcab for the Treatment of Erosive Gerd and Relief of Associated Heartburn

• VOQUEZNA, the first and only FDA-approved potassium-competitive acid blocker (PCAB), is now available through major retail pharmacies and BlinkRx, an end-to-end digital fulfillment channel

• VOQUEZNA tablets in 30-count bottles are now commercially available for the healing and maintenance of healing of all severities of Erosive GERD, and relief of heartburn associated with Erosive GERD1

FLORHAM PARK, N.J., Nov. 28, 2023 (GLOBE NEWSWIRE) – Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, today announced the U.S. commercial availability of VOQUEZNA® (vonoprazan). VOQUEZNA is now available for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD (gastroesophageal reflux disease), and the relief of heartburn associated with Erosive GERD.1 As the first and only approved potassium-competitive acid blocker (PCAB) in the U.S., this milestone brings the power of a new class of acid suppression treatment to a disease with high unmet need.

“We are thrilled to announce the commercial availability of our first-in-class medication, VOQUEZNA, now available for the millions of people in the U.S. suffering from Erosive GERD,” said Martin Gilligan, Chief Commercial Officer at Phathom Pharmaceuticals. “For over three decades, there has been no major innovation in this category. We are excited to introduce VOQUEZNA to patients and healthcare providers, as it has been shown to provide rapid, potent, and durable acid suppression and has the power to help heal Erosive GERD for patients seeking a new and effective treatment option.”

The U.S. Food and Drug Administration (FDA) recently approved VOQUEZNA for the healing of all severities (grades) of Erosive GERD, maintenance of healing of all severities of Erosive GERD, and relief of heartburn associated with Erosive GERD in adults.1 Its novel mechanism of action (MOA) provides rapid, potent, and durable acid suppression in a way that is distinct from other prescription and over-the-counter medications.2 Additionally,VOQUEZNA does not have the burden of mealtime dosing, whereas most PPIs must always be taken with food.1

In a Phase 3, randomized clinical study, VOQUEZNA 20 mg met the primary endpoint of non-inferiority for complete healing by Week 8 in patients with all severities of Erosive GERD, demonstrating a strong healing rate of 93% compared to 85% for lansoprazole 30 mg, with superior rates of healing demonstrated in a secondary endpoint in patients with moderate- to-severe disease at Week 2 compared to lansoprazole (70% for VOQUEZNA 20 mg and 53% for lansoprazole 30 mg). In the maintenance phase of the study, VOQUEZNA 10 mg was superior to lansoprazole 15 mg in maintaining healing at six months in all randomized patients (79% for VOQUEZNA 10 mg, compared to 72% for lansoprazole 15 mg).

The most common side effects of VOQUEZNA for the treatment of Erosive GERD include stomach inflammation, diarrhea, stomach bloating, stomach pain, nausea, indigestion, high blood pressure, and urinary tract infection.

“Erosive GERD is a highly prevalent condition affecting over 20 million people in the U.S.,3,4 many of whom experience troubling symptoms, including painful heartburn. When not properly treated, Erosive GERD can lead to complications such as scarring, narrowing of the esophagus, and bleeding,4” said Colin Howden, M.D., ProfessorEmeritus, University of Tennessee College of Medicine. “With many patients unsatisfied with their current therapy,5 the introduction of VOQUEZNA provides healthcare providers and patients with an important new treatment option that offers a novel mechanism of action and has demonstrated superiority in comparison to a standard-of-care PPI across several clinically meaningful endpoints.2”

Prescriptions for VOQUEZNA may be filled at major retail pharmacies and through BlinkRx, an end-to-end digital fulfillment channel. Phathom is offering programs for eligible patients who face coverage or affordability issues, including co-pay assistance for patients with commercial insurance. For more information, please visit www.voquezna.com/savings.

In addition, VOQUEZNA® TRIPLE PAK®(vonoprazan tablets, amoxicillin capsules, clarithromycin tablets) and VOQUEZNA® DUAL PAK® (vonoprazan tablets, amoxicillin capsules), two treatment regimens for adults with H. pylori infection, are expected to be commercially available in mid-December 2023. VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK each contain 14-days of VOQUEZNA-based treatment co-packaged with antibiotics in convenient blister packs.

VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. Please visit www.voquezna.com to learn more about VOQUEZNA.

INDICATION AND IMPORTANT SAFETY INFORMATION

What is VOQUEZNA?

VOQUEZNA® (vonoprazan) is a prescription medicine used in adults:
• for 8 weeks to heal acid-related damage to

the lining of the esophagus (called Erosive Esophagitis or Erosive Acid Reflux) and for relief of heartburn related to Erosive Acid Reflux.

• for up to 6 months to maintain healing of Erosive Acid Reflux and for relief of heartburn related to Erosive Acid Reflux.

It is not known if VOQUEZNA is safe and effective in children.

Do not take VOQUEZNA if you:

• are allergic to vonoprazan or any of the other ingredients in VOQUEZNA. Allergic reaction symptoms may include trouble breathing, rash, itching and swelling of your face, lips, tongue, or throat.

• are taking a medicine that contains rilpivirine (EDURANT, COMPLERA, JULUCA, ODEFSEY , CABENUV A) used to treat HIV-1 (Human Immunodeficiency Virus).

Before taking VOQUEZNA, tell your healthcare provider about all your medical conditions, including if you:
• have low magnesium, calcium, or potassium

in your blood, or you are taking a medicine to

increase urine (diuretic).
• have kidney or liver problems.
• are pregnant, think you may be pregnant, or

plan to become pregnant. It is not known if

VOQUEZNA will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if VOQUEZNA passes into your breast milk. You and your healthcare provider should decide if you will take VOQUEZNA or

breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

VOQUEZNA may affect how other medicines work, and other medicines may affect how VOQUEZNA works. Especially tell your healthcare provider if you take medicine that contains rilpivirine (EDURANT, COMPLERA,JULUCA, ODEFSEY, CABENUVA).

What are the possible side effects of VOQUEZNA?

VOQUEZNA may cause serious side effects including:
A type of kidney problem (acute tubulointerstitial nephritis): Some people who take VOQUEZNA may develop a kidney problem called acute tubulointerstitial nephritis. Call your healthcare provider right away if you have a decrease in the amount that you urinate or if you notice blood in your urine.
Diarrhea caused by an infection (Clostridioides difficile) in your intestines: Call your healthcare provider right away if you have watery stools,

stomach pain, and fever that does not go away. Bone fractures (hip, wrist, or spine): Bone

fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of another type of medicine that reduces acid in your stomach known as proton pump inhibitors (PPI medicines) for a long period of time (a year or longer). Tell your healthcare provider if you have a bone fracture, especially in the hip, wrist, or spine.

Severe skin reactions: VOQUEZNA can cause rare, but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening:

• Skin rash which may have blistering, peeling, or bleeding on any part of your skin.

• You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. • If you experience any of these symptoms, stop taking VOQUEZNA and call your healthcare provider right away. These symptoms may be

the first sign of a severe skin reaction.
Low vitamin B-12 levels: VOQUEZNA lowers the amount of acid in your stomach. Stomach acid is needed to absorb Vitamin B12 properly. Tell your healthcare provider if you have symptoms of low vitamin B12 levels, including irregular heartbeat, shortness of breath, lightheadedness, tingling or numbness in the arms or legs, muscleweakness, pale skin, feeling tired, or mood changes. Talk with your healthcare provider about the risk of low vitamin B12 levels if you

have been on VOQUEZNA for a long time. Low magnesium levels in the body can happen in people who take VOQUEZNA. Tell your healthcare provider right away if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, or spasms of hands, feet, or voice.
Stomach growths (fundic gland polyps): A certain type of stomach growth called fundic gland polyps may happen in people who take another type of medicine that reduces acid in your stomach known as proton pump inhibitors (PPI medicines) for a long time. Talk with your healthcare provider about the possibility of fundic gland polyps if you have been on VOQUEZNA for a long time.

The most common side effects of VOQUEZNA for treatment of Erosive Acid Reflux include: • stomach inflammation
• diarrhea
• stomach bloating
• stomach pain
• nausea
• indigestion
• high blood pressure
• urinary tract infection

These are not all the possible side effects of VOQUEZNA. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects.

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NUTRITION REVIEWS IN GASTROENTEROLOGY

Nutrition Care for Patients with Upper GI Malignancies: Part 2 – Gastric Cancer

December 2023 • Volume XLVII, Issue 12

Greta Macaire

Read Article

Gastric cancer is a leading cause of cancer and cancer related deaths worldwide. While accounting for only 1.5% of cancers in the United States, gastric cancer has one of the highest incidences of disease-associated malnutrition. Understanding the nutrition challenges from tumor related symptoms, side effects of treatments, and post gastrectomy syndrome allows for effective patient care. More studies are needed to understand how to best manage the unique nutritional needs of this patient population as it is well established that better nutrition contributes to improved quality of life and greater overall survival for patients with gastric cancer. The goal of this review is to outline gastric cancer-associated malnutrition, treatment related gastrointestinal symptoms, considerations for perioperative and postoperative nutrition for patients undergoing surgery for gastric cancer, and to provide recommendations aimed at optimizing nutrition care for this at-risk patient population.

INTRODUCTION

Gastric cancer is the fifth most common malignancy and fourth leading cause of cancer death worldwide.^1-2 Although gastric cancer rates have declined in the United States over the past decade, prevalence rates are rising in other parts of the world, especially East Asia. It is estimated that 26,380 Americans were diagnosed and 11,090 died from the disease in 2022.³ Early diagnosis results in a 5-year relative survival rate of 72%, unfortunately only 28% of gastric cancers in the U.S. are localized at diagnosis dropping the overall survival rate to 35%.^2,3 Malnutrition and nutrient deficiencies often develop throughout the disease course. Studies show that nutrition monitoring and timely interventions lead to improved quality of life (QoL) and better survival for patients with gastric cancer.⁴ This review will discuss nutrition care for gastric cancer-associated malnutrition, treatment related gastrointestinal symptoms, and for perioperative and postoperative nutrition for patients undergoing surgery for gastric cancer.

Diagnosis and Treatment

Risk factors for gastric cancer are listed in Table 1 and include hereditary diffuse gastric cancers, Helicobacter pylori infection, diets high in salt-preserved foods, heavy alcohol intake, and low intake of fruits and vegetables. Data analysis from 25 studies in the Stomach cancer Pooling Project (StoP) observed a 39% lower risk of gastric cancer associated with the highest versus lowest intake of fruits and vegetables.^1-3,5 Over the past 20 years the most common location of gastric cancers has shifted from the body and antrum of the stomach to the proximal stomach and esophagogastric junction. The cause for this change is unclear, however it correlates with the rise in obesity.³ Of note, proximal stomach tumors are considered to be more aggressive with worse prognosis than distal gastric cancers.

In the early stages of gastric cancer symptoms may be vague and include indigestion, early satiety, postprandial bloating, and nausea. As the disease progresses symptoms can include weight loss, dysphagia, vomiting, anemia, ascites, and jaundice.^6,7 See Table 2.

When gastric cancer is suspected, an upper endoscopy with biopsy is performed. If detected, further testing may check for HER2 genes and H. pylori infection. After diagnosis, staging studies may include endoscopic ultrasound, computed tomography scan (CT scan) of chest, abdomen, and pelvis (if not previously performed), positron emission tomography scan (PET scan), magnetic resonance imaging (MRI), and laparoscopy.^7,8 Staging follows the American Joint Committee on Cancer (AJCC) Tumor, Lymph node, Metastasis (TNM) classification system.⁷

Treatments for gastric cancer depend on the location and disease stage as well as an individual’s overall health and goals of care. For early-stage, surgery with regional lymphadenectomy is standard therapy. For locoregional disease, multimodal treatment regimens are typically used and may include surgery, chemotherapy, radiation, targeted drug therapy, and immunotherapy.^7,8 Endoscopic mucosal resection can be used for very early-stage gastric cancers; however, partial, and total gastrectomy are the primary surgeries for gastric cancers. Types of surgical reconstruction include Billroth I, Billroth II, and Roux-en-Y.^7,8 Non-surgical candidates and patients with widely metastatic disease may be treated with multimodal therapy or best supportive care.

Nutrition and Lifestyle	Other
Cigarette smoking Diets high in salted, smoked, or preserved foods Diets low in fruits and vegetables Alcohol (3 or more drinks per day) Obesity (cardia region)	Advanced age Male sex H. pylori gastric infection Epstein-Barr virus infection Chronic atrophic gastritis Intestinal metaplasia Pernicious anemia Gastric adenomatous polyps Family history of gastric cancer Ménétrier’s disease Familial syndromes

Table 1. Risk Factors for Gastric Cancer

The primary goals for medical nutrition therapy for patients undergoing cancer treatment are to prevent or resolve nutrient deficiencies, achieve, or maintain a healthy weight, preserve lean body mass and function, minimize nutrition-related side effects, and maximize QoL.⁹

Malnutrition in Gastric Cancer

It is estimated that 60-80% of gastric cancer patients experience malnutrition at some point in their cancer journey.⁴ The side effects from treatment make it difficult for patients to eat and drink to maintain their nutritional status. Treatment side effects include decreased appetite, nausea, vomiting, diarrhea, and altered taste. Gastric cancer surgery is associated with a 10-30% weight loss, most of which occurs in the first 6 months after surgery; greater weight loss and sarcopenia are significantly associated with postoperative complications and shorter survival.^10-13 Nutrition counseling has been found to be an effective intervention to improve nutritional status and QoL post-gastrectomy. Compared to patients that did not receive nutrition counseling, patients that received individualized dietary counseling post-gastrectomy met their calorie and protein goals at a higher rate, had less weight loss, and had significantly lower levels of fatigue.¹⁴ See Table 3.

Perioperative Nutrition for Gastric Cancer Surgery

Perioperative nutrition recommendations for gastrectomy are addressed by the Enhanced Recovery After Surgery (ERAS®) Society’s 2014 consensus guidelines.¹⁵ ERAS is a single program that incorporates a multimodal perioperative care pathway designed to achieve early recovery for patients undergoing major surgery. The nutrition guidelines focus on preoperative nutrition, early advancement of postoperative diet, and indications for enteral and parenteral nutrition. Preoperative enteral nutrition (EN) in malnourished patients was associated with improved 3-year overall survival when compared to patients with inadequate dietary intake before surgery.¹⁵ Routine use of EN is discouraged, however, failure to meet 60% of nutrient requirements after one week warrants evaluation for EN support. Parenteral nutrition (PN) should be reserved for those with a non-functional or inaccessible gut.¹⁵

The use of Enhanced Recovery Protocols (ERPs) in Asian patients with gastric cancer has demonstrated improved outcomes.¹⁶ Recent studies comparing gastric cancer surgery outcomes before and after implementation of ERPs in two U.S. hospitals found ERPs were safe, feasible, and potentially decrease postoperative length of stay without increasing complications.^15-17

Postoperative Nutrition After Gastric Cancer Surgery

Normally, the stomach sends hunger signals to the brain, accommodates a large quantity of food, mechanically grinds food for absorption, and controls the rate of chyme emptying into the small intestine. The extent of diet modifications needed after gastric cancer surgery will depend on the volume of remnant stomach and the type of reconstruction.^{4, 18,19} The ERAS 2014 consensus guidelines provide recommendations for early initiation and patient-directed intake of food and drink with cautious increase according to tolerance (Table 4); allowing food from post op day 1 is supported and has not been associated

with any adverse events in trials with patient status post total gastrectomy. The traditional post-operative clear liquid diet that includes high sugar, hyperosmolar fluids such as juice, soda, Jell-OTM, and popsicles may not be well tolerated following gastrectomy and should be avoided.

Early Onset Symptoms	Late Onset Symptoms
Decreased appetite • Early satiety • Abdominal pain or vague abdominal discomfort • Heartburn and indigestion • Nausea • Fatigue	Unintentional weight loss Dysphagia Vomiting Heme-positive stools Anemia Ascites Jaundice

Table 2. Symptoms of Gastric Cancer

Post Gastrectomy Syndrome

Post gastrectomy syndrome refers to complications that may occur with a partial or total gastrectomy and it includes dumping syndrome, maldigestion and malabsorption, delayed gastric emptying, bile acid reflux, and micronutrient deficiencies.^18,19

Dumping syndrome (DS) results from partial or total loss of the stomach reservoir capacity and rapid gastric emptying of hyperosmolar contents into the proximal small intestine. Incidence of DS ranges from 20-50% depending on the type of reconstruction.²⁰ There are two types of DS, early and late, that are classified by the timing of onset and constellation of symptoms. Early DS occurs within 10-30 minutes after eating and is characterized by abdominal cramping, bloating, nausea, diarrhea, and vasomotor symptoms of postprandial weakness, flushing, dizziness, and sweating. Late DS occurs 1-3 hours after eating and is characterized by weakness, sweating, nausea, hunger, and tremors.

Side Effect	Strategies
Decreased Appetite	Schedule small, frequent meals. Increase intake when appetite is at its best. Eat nutritious, high calorie, high protein foods and fluids. Examples: nuts/nut butters, avocado, yogurt, tofu, eggs, smoothies Consume most liquids between meals to prevent dumping and exceeding the gastric remnant’s volume capacity. Engage in light physical activity such as walking to help stimulate the appetite.
Nausea/Vomiting	Eat small meals every few hours. Include well tolerated foods such as oatmeal, rice, boiled potatoes, toast, skinless poultry, yogurt, soft, mild fruits, and vegetables – melons, bananas, grapes, cucumber, cooked carrots, zucchini, and winter squash. Sip on clear liquids – diluted juice, broth, ginger, and peppermint tea. Avoid strong odors (allow fresh air inside to clear odors). Relax and stay upright after meals. Limit fried, greasy, and rich foods.
Diarrhea	Drink plenty of fluids throughout the day – well tolerated fluids include water, diluted juice, broth, chamomile tea, and oral rehydration solutions. Eat small meals every few hours. Add a food rich in soluble fiber at each meal – oatmeal, barley, bananas, applesauce, peeled fruits, peeled, and cooked vegetables such as carrots, zucchini, and sweet potatoes.
Altered Taste	Practice good oral hygiene. Rinse mouth with a baking soda, salt, and water rinse before eating. Add strong flavors to foods with the addition of spices, herbs, marinades, lemon juice, and sauces. Use plastic utensils, cups, and plates in place of metal if with a metallic taste.

Table 3. Nutrition Strategies for Managing Side Effects from Chemotherapy and Radiation

Diet Guidelines for Post Gastrectomy
Eat on a schedule with 6 – 8 small meals a day. ■ Immediately after surgery, start with 2-4 oz of food per meal ■ Slowly increase portion sizes over time as tolerated Eat slowly and chew food thoroughly. Sit upright during meals and for an hour after meals. Eat the last meal of the day 2 hours before bedtime. Separate fluids from solids by 30-60 minutes. Include protein with each meal (e.g., eggs, skinless poultry, fish, legumes, lean meats, dairy products, high protein drinks or protein powder with less added sugars (<5 grams of added sugar per serving)). Include calorie dense foods such as avocado, smooth nut butter, or a sprinkle of cheese. Limit foods and drinks with added sugars to small amounts (e.g., sodas, desserts, candy). For the first 6 weeks after surgery limit fibrous meats and foods high in insoluble fiber in whole form. Raw fruits and vegetables with thick skins Nuts, seeds, and legumes After six weeks can gradually add fibrous foods into the diet as tolerated Include foods with fiber in small particle size as tolerated (e.g., blended vegetable soups, fruit and vegetable smoothies, canned fruits, creamy nut butters, instant oatmeal, tofu, and hummus). If there is gastrointestinal discomfort after eating, keep a short-term food diary to identify problematic foods and eating patterns.

Diet Guidelines for Post Gastrectomy

Eat on a schedule with 6 – 8 small meals a day.
■ Immediately after surgery, start with 2-4 oz of food per meal

■ Slowly increase portion sizes over time as tolerated Eat slowly and chew food thoroughly. Sit upright during meals and for an hour after meals. Eat the last meal of the day 2 hours before bedtime. Separate fluids from solids by 30-60 minutes. Include protein with each meal (e.g., eggs, skinless poultry, fish, legumes, lean meats, dairy products, high protein drinks or protein powder with less added sugars (<5 grams of added sugar per serving)). Include calorie dense foods such as avocado, smooth nut butter, or a sprinkle of cheese. Limit foods and drinks with added sugars to small amounts (e.g., sodas, desserts, candy). For the first 6 weeks after surgery limit fibrous meats and foods high in insoluble fiber in whole form. Raw fruits and vegetables with thick skins Nuts, seeds, and legumes
After six weeks can gradually add fibrous foods into the diet as tolerated Include foods with fiber in small particle size as tolerated (e.g., blended vegetable soups, fruit and vegetable smoothies, canned fruits, creamy nut butters, instant oatmeal, tofu, and hummus). If there is gastrointestinal discomfort after eating, keep a short-term food diary to identify problematic foods and eating patterns.

Table 4.

While the exact mechanism is unknown, late DS is attributed to reactive hypoglycemia. It is thought that the rapid absorption of carbohydrates exaggerates the glucose-mediated insulin response. Dietary modification is recommended as the initial treatment for DS. Patients are advised to:^{4, 18-20}

Reduce meal size
Eat slowly
Chew well
Wait at least 30 minutes after eating to drink fluids
Increasing fiber and protein rich foods
Limit rapidly absorbed carbohydrates present in sweets, sugar sweetened beverages, and fruit juices

Maldigestion along with malabsorption may occur after a partial or total gastrectomy. Contributing factors include a decrease in hormonal stimulation of pancreatic secretion, rapid transit time, poor mixing of chyme and bilio-pancreatic secretions, and small intestine bacterial overgrowth (SIBO). Clinical signs of fat malabsorption are steatorrhea and weight loss with symptoms such as bloating, foul-smelling gas, and diarrhea or large floating stool. In addition to poor mixing of chyme with bile and pancreatic enzymes, pancreatic exocrine insufficiency (PEI) is thought to impact digestion in a total gastrectomy with an estimated incidence of 47- 100%; the greatest prevalence is in patients with Roux-en-Y reconstruction.²¹ Common diagnostic tests for PEI include quantitative or qualitative fecal fat and fecal elastase 1 (FE-1). In some clinical practices, pancreatic enzyme replacement therapy (PERT) is empirically commenced when symptoms of fat malabsorption are present. Two randomized controlled trials evaluating the effectiveness of PERT use after gastric cancer surgery have been conducted.²_^2,23 After starting PERT patients reported feeling better overall and improved stool consistency was seen in cases of severe steatorrhea. Despite these positive findings, the studies concluded the effect of PERT on post gastrectomy malabsorptive symptoms was marginal. In cases of partial gastrectomy when there is potential for gastric acid to inactivate lipase, concomitant use of an acid suppressing agent or buffered enzyme product may improve PERT efficacy.^{21, 24} See Table 5.

Gastric stasis may occur with a partial gastrectomy from damage to the vagus nerve during surgery. Symptoms may include postprandial bloating and fullness that can last for many hours after meals. Delayed gastric emptying increases risk for SIBO, bezoar formation, nausea, vomiting, weight loss, and ultimately malnutrition. In addition to following general post-gastrectomy diet recommendations, patients with delayed gastric emptying can be counseled to select calorie and protein containing liquids and foods in small particle size for improved tolerance. While more research is needed, a small particle size diet has been shown to reduce upper gastrointestinal symptoms in patients with gastroparesis via increasing the rate of gastric emptying. Foods in small particle size are easily mashed into small pieces such as pureed fruits and vegetables, hummus, blended soups, smoothies, mashed avocado, mashed boiled eggs, and soft tofu.^4,18,19,25

Bile acid reflux occurs when bile flows back into the esophagus or the gastric remnant. It is caused by loss of the pylorus and is most frequently found after Billroth II reconstruction. This complication may not occur until 1-3 years after gastrectomy and is often triggered by physical positioning. Symptoms include burning epigastric pain, nausea, and bilious vomiting. In addition to following the post-gastrectomy diet, sleeping with the head of the bed elevated at least 30°, bending at the knees rather than leaning forward, and avoiding constipation may improve bile reflux symptoms. Acid suppressing medications are ineffective for bile reflux in patients with achlorhydria after total gastrectomy. Mucosal protectants and bile acid sequestrants may be helpful to protect the mucosal lining and reduce the caustic effects of the bile acids, but these must be balanced to prevent worsening fat malabsorption.^{4, 18,19}

Initial Dose	500-2,500 lipase units/kg/meal 250-1,250 lipase units/kg/snack
Timing of Dose	Take with meals and snacks. If taking several capsules, take ½ the dose with the first bite and the other ½ during or at the end of the meal.
Follow Up	Monitor response to treatment. If symptoms of malabsorption persist, use strategies for optimization of PERT (below).
Step Wise Optimization of PERT	Assess compliance of dosing with all meals and snacks. Double PERT dose. Not to exceed 10,000 units of lipase/kg per day. Trial a different PERT product. For partial gastrectomy, concomitant acid suppressing agent or buffered enzyme product may improve efficacy.

Table 5. Guidelines for Pancreatic Enzyme Replacement Therapy 21,24
PERT: pancreatic enzyme replacement therapy

Vitamin B12 Malabsorption due to lack of gastric acid and intrinsic factor Occurs within 1 year for total gastrectomy Deficiency can cause irreversible neurological symptoms	Maintenance 1000 mcg of vitamin B12 subcutaneous once monthly or 1,000 mcg orally daily Sublingual preparation preferred in patients with diarrhea, vomiting, or difficulty taking oral medications
Folate Secondary to malabsorption	Maintenance 400-800 mcg of folate daily Repletion 5 mg of folate daily for 3-4 months
Iron Malabsorption due to lack of gastric acid and bypass of the absorption sites in the duodenum and proximal jejunum Occurs in 50% of patients More common after total gastrectomy and Roux-en-Y reconstruction	Maintenance Total gastrectomy – 45-60 mg of elemental iron daily* with 500 mg vitamin C to improve absorption Repletion 200 mg elemental iron* daily for 3-4 months Take at least 2 hours apart from calcium
Calcium Malabsorption due to lack of gastric acid and bypass of the duodenum and proximal jejunum Possible postoperative lactose intolerance Metabolic bone disease may occur in up to 69% of gastrectomy patients 3-5 years after surgery	Maintenance 400-500 mg, three times daily (total 1200-1500 mg daily) Take at least 2 hours apart from iron supplements Note: Calcium citrate is less dependent on gastric acid for absorption and therefore the preferred form, take with or without food.*
Vitamin D Decreased absorption with maldigestion and malabsorption	Maintenance Recommended dose is based on serum levels Repletion 3000 – 4000 IU D3 daily until levels are greater than sufficient (30 ng/mL) Note: Vitamin D3 is the preferred form.

Table 6. Nutrient of Concern and Supplement Recommendations after Gastrectomy18,19, 26-33
*Needs to be crushed or chewed for the first 3 months

Micronutrient deficiencies are expected after gastrectomy; however, the degree of deficit depends on the extent of resection. Total gastrectomy poses the greatest risk for deficiencies. Established guidelines for nutrient monitoring and supplementation after gastric cancer surgery are lacking.18,19 However, given the extensive body of literature available for micronutrient deficiencies and repletion therapies after bariatric surgery, it is recommended to reference the American Society of Metabolic and Bariatric Surgery (ASMBS) guidelines when treating patients with gastric cancer. Ongoing monitoring of nutritional status at 1,3,6, and 12 months after surgery, then annually and monitoring bone mineral density via dual-energy X-ray absorptiometry (DEXA) scan within two years after surgery is advised. Recommended blood tests include vitamin B12, methylmalonic acid, red blood cell folate, iron panel with ferritin, and 25-hydroxy-vitamin D.^{18,19, 33} See Table 6.

CONCLUSION

Gastric cancer, and the available treatments, put patients at a high risk of developing malnutrition and micronutrient deficiencies. Patients that undergo gastric cancer surgery may face additional nutritional challenges resulting from post gastrectomy syndrome and weight loss. However, evidence shows that nutrition therapy interventions can improve patient outcomes, function, and QoL. Nutrition counseling, close monitoring, treatment of gastrointestinal symptoms, and identifying and supplementing nutrient deficiencies are key elements of optimizing care for patients with gastric cancer.

References

Stomach Cancer Statistics. World Cancer Research Fund. Updated March 23, 2022. Accessed March 7, 2023. https://www.wcrf.org/cancer-trends/stomach-cancer-statistics/

Stomach Cancer Prevention – Health Professional Version. National Cancer Institute. Updated February 7, 2022. Accessed March 8, 2023. https://www.cancer.gov/ types/stomach/hp/stomach-prevention-pdq

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