A CASE REPORT

Therapeutic Challenges in Afferent Loop Syndrome Presenting as Recurrent Acute Pancreatitis with Ascending Cholangitis

September 2022 • Volume XLVI, Issue 9
Michael Eiswerth,Fred Closson,Dipendra Parajuli

Read Article

Afferent loop syndrome (ALS) is a post-surgical complication associated with gastric resections with Billroth II, or Roux-en-Y reconstructions, and pancreaticoduodenectomies which result in the creation of a blind loop. ALS occurs when there is distal obstruction of the afferent limb that results in its distension secondary to the accumulation of bile, pancreatic fluid, or small bowel secretions. Our case demonstrates a rare presentation of afferent loop syndrome that posed both diagnostic and therapeutic challenges. Understanding the pathophysiology of ALS, its cause and the role of endoscopic interventions is crucial in diagnosing and managing ALS.

INTRODUCTION

Afferent loop syndrome (ALS) is a post- surgical complication associated with Billroth II, or Roux-en-Y reconstructions, and pancreaticoduodenectomies (Whipple procedure). The gastro-jejunal anastomosis creates an afferent and efferent limb to the stomach; for Roux- en-Y reconstruction, the afferent limb is the biliopancreatic limb. ALS is a rare complication, occurring in 0.2%-1.0% of patients with partial gastrectomy and Billroth II or Roux-en-Y reconstruction.1 Patients who undergo Whipple have a combination of afferent intestine loop and biliary-enteric anastomosis. The incidence of ALS is significantly higher in patients with Whipple and has been estimated up to 13%, rapidly increasing three years post-surgery.2

Etiologies for obstruction include adhesions, internal hernias, prior gastrojejunostomy ulceration, and recurrent malignancy in those who underwent surgery for cancer.3 Less common causes include intraluminal obstructions and afferent loop intussusception or volvulus, and radiation enteritis.3 We demonstrate the importance of a comprehensive evaluation for abdominal pain in patients with post- surgical anatomy and review management options for patients with ALS in the setting of an afferent limb stricture.

Case Report

A 59-year-old male with a history of peptic ulcer disease (PUD) status post remote gastric antrectomy with Billroth II, alcohol abuse, and recurrent admissions for acute pancreatitis secondary to alcohol use presented to the hospital with one day of abdominal pain, nausea, and vomiting. Vitals on admission were normal with heart rate of 84 bpm and blood pressure of 103/52 mmHg. Physical examination demonstrated mild distress with tenderness to light palpation in the epigastrium without distension or jaundice. Laboratory results showed a leukocytosis of 24.3 (4.1-10.8 cells/ mm3), lipase of 382 (10-50 units/liter), aspartate aminotransferase of 1,285 (12-38 units/liter), alanine aminotransferase of 560 (>31 units/liter), alkaline phosphatase of 289 (34-106 units/liter), and blood cultures grew E. coli.

Abdominal ultrasonography from a recent admission demonstrated a dilated common bile duct of 1.3 cm and a right upper quadrant (RUQ) cystic structure which appeared as a gallbladder filled with gallstones. On current admission, abdominal computed tomography (CT) demonstrated that this cystic structure was actually the duodenal blind limb dilation with stones. Magnetic resonance cholangiopancreatography (MRCP) redemonstrated a distended duodenal stump with intraluminal stones without interval worsening biliary dilatation (Figure 1). Treatment for cholangitis was initiated with ceftriaxone, with clinical improvement.

Esophagogastroduodenoscopy (EGD) showed evidence of previous Billroth II gastroenterostomy and duodenal stricture in the blind limb (Figure 2).

Liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) down-trended as well, this elevation was believed to be secondary to an obstructing stone that caused a transient obstruction at the site of the stricture and ultimately passed on its own. Endoscopic intervention was deferred due to clinical improvement with medical management and resolving liver enzymes levels. Patient is now following with surgery for possible revision of Billroth II.

Discussion

ALS occurs with distal obstruction of the afferent limb and subsequent distension secondary to the accumulation of bile, pancreatic fluid, and enteric secretions. Clinical presentation of ALS occurs across a wide spectrum depending on the acuity of the obstruction. Acute obstruction often presents as pancreatitis or ascending cholangitis.4 This most commonly occurs early in the post-operative course; abdominal pain is common and may be associated with sepsis or peritonitis. Chronic ALS occurs months to years after surgery with postprandial abdominal pain that may result in food avoidance, malabsorption, and weight loss.5 CT of the abdomen is the diagnostic gold standard for ALS, however MRCP can be a helpful adjunctive test in chronic ALS. An EGD was also performed to evaluate patency of the afferent loop in this case. Our patient posed a diagnostic challenge due to recurrent episodes of acute pancreatitis due to alcohol use and a new cholangitis that was present this admission. This case necessitated the use of multiple imaging modalities to appropriately identify the underlying cause of distal obstruction of the afferent limb, which was in our case a benign stricture. Our patient was particularly challenging given his remote surgical history, making a presentation of chronic ALS with both acute pancreatitis and acute cholangitis atypical. Given the numerous etiologies for developing chronic ALS, diagnostic accuracy is imperative to provide appropriate treatment, which historically has been surgical. By identifying the stricture, problem-directed treatment via endoscopicguided stenting or dilation is a potential therapy that may

not initially demand immediate surgical intervention.6 Newer, lumen-apposing metal stents (LAMS) are potentially useful in synchronous biliary and duodenal malignant obstruction. The advent of LAMS in the treatment of ALS has been precipitated by streamlining their use from a multiple, to one-step technique.

In one recent case report, two techniques were successfully used in deployment of  LAMS: one was placed across a gastroenterostomy, bypassing the stricture; another utilized intraluminal placement directly across a stenosis, placing a transmural stent.7 There are prior case reports documenting successful use of LAMS in the treatment of ALS,4 however only one study evaluates the efficacy and safety profile of LAMS in ALS.8 This trial had 18 patients, 100% technical success was reported and abdominal pain as an adverse event was reported in 16.7% of patients.8 Furthermore, patients with LAMS placement were compared

indirectly in this trial to patients with enteroscopyassisted luminal stenting, and patients with LAMS placement required fewer repeat interventions in this comparison.8

CONCLUSION

There is little in the literature regarding chronic ALS resulting in both acute pancreatitis and acute cholangitis. Prompt diagnosis of the underlying etiology precipitating ALS is crucial, as the landscape of management options is under evolving and under active research. CT of the abdomen remains the gold standard for the diagnosis of ALS, which is a post-surgical complication of multiple surgeries including Billroth II, or Rouxen-Y reconstructions, and Whipple procedures. The advent of LAMS as an endoscopic intervention in the treatment of ALS is promising, but longitudinal studies are needed to better understand the benefits and risk profile.

References

  1. Aoki, M., Saka, M., Morita, S., Fukagawa, T. and Katai, H., 2010. Afferent Loop Obstruction After Distal Gastrectomy with Roux-en-Y Reconstruction. World Journal of Surgery, 34(10), pp.2389-2392.
  2. Benallal, D., Hoibian, S., Caillol, F., Bories, E., Presenti, C., Ratone, J. and Giovannini, M., 2018. EUS–guided gastroenterostomy for afferent loop syndrome treatment stent. Endoscopic Ultrasound, 7(6), p.418.
  3. Grotewiel, R. and Cindass, R., 2022. Afferent Loop Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK546609/ [Accessed 1 March 2022].
  4. Monino, L., Barthet, M. and Gonzalez, J., 2019. Endoscopic ultrasound-guided management of malignant afferent loop syndrome after gastric bypass: from diagnosis to therapy. Endoscopy, 52(03), pp.E84-E85.
  5. RK, G. and R, C., 2022. Afferent Loop Syndrome. [online] PubMed. Available at: [Accessed 1 March 2022].
  6. Blouhos, K., 2015. Management of afferent loop obstruction: Reoperation or endoscopic and percutaneous interventions. World Journal of Gastrointestinal Surgery, 7(9), p.190.
  7. DuBroff, J., McDonough, S. and Adler, D., 2020. Afferent Limb Syndrome Treated via Lumen Apposing Metal Stents: Report of Two Different Approaches in Two Patients – Practical Gastro. [online] Available at: [Accessed 1 March 2022].
  8. Brewer Gutierrez, O., Irani, S., Ngamruengphong, S., Aridi, H., Kunda, R., Siddiqui, A., Dollhopf, M., Nieto, J., Chen, Y., Sahar, N., Bukhari, M., Sanaei, O., Canto, M., Singh, V., Kozarek, R. and Khashab, M., 2018. Endoscopic ultrasound-guided entero-enterostomy for the treatment of afferent loop syndrome: a multicenter experience. Endoscopy, 50(09), pp.891895

Download Tables, Images & References

FRONTIERS IN ENDOSCOPY, SERIES #83

Artificial Intelligence in Pancreaticobiliary Disease

September 2022 • Volume XLVI, Issue 9
Catherine Y. Wang,Tyler M. Berzin

Read Article

The rapid rise of artificial intelligence (AI) applications in the field of gastroenterology has led to the recent rollout of sophisticated hardware and software systems used to aid detection and diagnosis in the endoscopy suite. These systems have primarily been applied to esophagoduodenoscopies and colonoscopies. The literature is comparatively scant in the realm of pancreaticobiliary endoscopy. This review aims to discuss the few studies that have been published evaluating AI-assisted endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). While the preliminary data are encouraging the area as a whole demands further robust clinical study in addition to close consideration of the logistical and ethical challenges that machine (ML) and deep learning (DL) present.

INTRODUCTION

Artificial intelligence (AI) applied to medicine has seen a recent acceleration in both interest and clinical implementation after five decades of development, dating back to at least the 1970s.1 In that time AI has been deployed to aid in solving the diagnostic and prognostic questions in every field of medicine from radiology to dermatology.2

AI was born as a branch of computer science with the hope of creating computer systems that could perform tasks classically requiring human input or intelligence. Machine learning (ML) is a subset of AI in which computer algorithms “learn” from training data sets by performing specific tasks and analyses on said data. ML algorithms designed for certain tasks, for instance visual recognition (e.g., recognizing lung nodules on a chest x-ray), are trained on large data sets, and the resulting trained algorithm is termed a “model.” These models are then validated on different data sets to ascertain their positive and negative predictive value. Deep learning (DL) is a subset of ML that relies on an artificial neural network (ANN), which allows for multiple layers of features to be extracted from raw data to create more complex predictive outputs, often with even less human guidance than traditional ML algorithms. These DL systems learn through successive training data sets to produce outputs that are increasingly similar to

the target output typically predetermined by experts in the field. Other AI modalities include natural language processing (NLP) which gives computers the ability to understand both text and spoken word while ambient clinical intelligence (ACI) monitors and reacts to inputs from its environment akin to Siri or Alexa. 

Over the past two decades AI has become an increasingly important topic of discussion in gastroenterology.3–5 The applications of AI in this realm are wide in scope and in general fall into one of two categories: visual tasks and combination tasks. A typical approach to a visual task is first to develop a model based on a labeled test set of still images or video (e.g., a database of colon polyp images). The next step is to validate the model on a separate data set to measure performance, and in some cases “tune” the algorithm for optimal performance. Some of the early critical progress in computer vision for gastroenterology has been in the areas of esophagogastroduodenoscopy (EGD)6– 9 and colonoscopy10–12 where many academic and industry teams have developed computer-assisted detection (CADe) software for colon polyp detection and other indications. There is a smaller subset of studies evaluating the use of AI in video capsule endoscopy (VCE)13,14 to similarly aid in detection and diagnosis of small bowel pathology. While a great deal of progress has been made in computer vision for colonoscopy and upper endoscopy, with numerous randomized control trials (RCTs) evaluating clinical use of CADe and CADx systems in real-time, the same cannot yet be said for the field of pancreaticobiliary endoscopy. The development and implementation of AI tools for endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) is still in a nascent stage. This gap is likely explained by two key barriers: 1) pancreaticobiliary endoscopy relies on a broader mix of complex visual data (i.e., ultrasound, fluoroscopy, and endoscopy) therefore presenting a greater challenge for model development and 2) the total volume of pancreaticobiliary procedures is much smaller compared to general endoscopic procedures, making it more difficult to collect data for model development (and perhaps also less of a compelling investment for industry). This review

aims to highlight the AI systems in active development for advanced endoscopic procedures to treat pancreaticobiliary disease, highlighting some of the key barriers and opportunities that lie ahead.

Endoscopic Ultrasound

EUS has emerged as an impactful modality to evaluate conditions of the pancreas, gallbladder, and liver in addition to a wide variety of other indications. A particularly most common use is in fluid and tissue sampling to aid in diagnosing pancreatic cysts and malignancy. EUS interpretation appears to be operator-dependent15–17 with significant operator heterogeneity across various studies, highlighting a need for tools to help standardize diagnosis in difficult clinical scenarios.18 While the development of AI for EUS has been relatively limited in the past decade, there have been several important trials utilizing ML and DL systems to aid in detection and differentiation of various benign and malignant pancreatic lesions. EUS elastography has been one area of recent AI investigational efforts. Elastography measures the relative stiffness and density of tissue and has been used to help differentiate between pancreatic cancer and inflammatory changes (e.g., chronic pancreatitis). EUS elastography has been shown to have good sensitivity and specificity for differentiating cancer and chronic pancreatitis in one large meta-analysis.19 In 2008 Saftoiu and colleagues20 generated mean hue histograms from EUS elastography videos of 68 patients to which an extended neural network algorithm was applied to differentiate between chronic pancreatitis and pancreatic cancer. The algorithm reported an average training performance of 97% and an average testing performance of 95%. Sensitivity and specificity were 91.4% and 87.9% respectively, which is comparable to the sensitivity and specificity of previously published literature on the use of EUS elastography for diagnosis, with strong positive (88.9%) and negative (90.6%) predictive values. Major limitations of this study include its small sample size and use of normal pancreas cases with no definitive mass to train the algorithm. A follow up study21 expanded on their original dataset and designed a blinded prospective cohort study utilizing 774 EUS elastography recordings from

recorded for each patient. Hue histograms were then examined by an experienced operator and given a final clinical diagnosis. A mathematical model using ANN input of the hue video vectors and the known final diagnosis was then generated and the two compared. The study reported a training accuracy of 91.14% and a testing accuracy of 84.27%. Sensitivity and specificity were 87.59% and 82.94% respectively, with PPV and NPV 96.25% and 57.22%. While the study enrolled predominantly pancreatic cancer patients (47 patients with chronic pancreatitis and 211 patients with pancreatic cancer), it illustrates the usefulness of neural networks in accurate diagnosis of solid pancreatic masses using EUS elastography. These studies show the high diagnostic accuracy reported when incorporating artificial intelligence and neural networks to EUS elastography image interpretation. Continuing to add to these image databases and incorporate them into EUS elastography software may further enhance diagnostic differentiation of pancreatic parenchymal diseases. Zhu and colleagues22 designed a diagnostic prospective study including EUS data from 388 patients (126 with chronic pancreatitis and 262 with pancreatic ductal adenocarcinoma) utilizing a support vector machine (SVM) to build an algorithm that distinguishes benign and cancerous image samples. Classification performance was robust with a testing accuracy

of 94.2%. Sensitivity and specificity were 96.25% and 93.38% respectively, with a PPV and NPV of 92.21% and 96.68%. As with much of the work in this subfield the system was designed using a single classifier and no head-to-head comparison of different classifiers (e.g., ANNs) was performed. In addition, this form of image analysis was completed post hoc thereby limiting its general ability to be utilized as a dynamic tool in real-time clinical scenarios. Alongside the rise of ML and DL in medicine there has also been a movement towards utilizing more advanced imaging modalities (e.g., chromoendoscopy, magnification endoscopy, contrast enhanced EUS, etc.) to permit more subtle clinical interrogation of GI lesions. These advanced imaging modalities provide ample opportunity for AI innovation. In 2015 Saftoiu and colleages23 continued to expand their work with ANNs in pancreaticobiliary endoscopy by applying similar training and testing protocols to data captured with contrast-enhanced harmonic EUS (CEH-EUS). This study of 167 patients with intra-abdominal masses (55 with chronic pancreatitis and 112 with pancreatic cancer) trained an ANN with 94.64% sensitivity and 94.44% specificity. PPV and NPV were 92.21% and 96.68% respectively. While the majority of these data were obtained contemporaneously, roughly 25% of those patients had no fine needle aspirate (FNA) sample collected at the time of CEH-EUS. These cases required confirmatory testing by surgery (n=15) or followup (n=23). One source of additional bias in this study is the fact that the same investigators who performed the CEH-EUS also performed the EUS-guided investigator who was blinded to FNA results.

Larger studies focused on traditional EUS gained more traction in the mid-2010s. In 2016 Ozkan and colleagues24 created a CADx system using data from 172 patients with an imaging data set comprised of 130 non-cancer and 202 pancreatic cancer samples. Patients were further sub-divided into three different age groups: < 40, 40-60, and > 60 (as we know appearance of the pancreas on EUS changes throughout a person’s lifespan). The ANN processed 20 features and classified each sample as either benign or malignant. The testing accuracy of this CADx system for the < 40, 40-60, and > 60 age groups were 92%, 94.11%, and 91.66% respectively. Sensitivity and specificity for all age groups were 83.3% and 93.33% respectively. Limitations of this study include the small sample size utilized for the age < 40 subgroup in particular. There was also no differentiation between noncancerous pancreas pathologies (e.g., chronic pancreatitis, pseudocysts, polyps, etc.). As with the work of Zhu and colleagues this CADx system was designed to conduct post hoc analysis of the EUS images rather than providing real-time information to guide clinical decision-making. In 2019 two additional retrospective studies performed by Kuwahara and colleagues25 and Kurita and colleagues26 were performed to differentiate malignant IPMN from benign fine need aspiration (EUS-FNA) of the mass. Despite this limitation all computer analysis of CEH-EUS videos were performed by

pancreatic cystic lesions. The former included 50 patients (27 with low- or intermediate-grade dysplasia and 23 with high-grade dysplasia or invasive carcinoma) and utilized 3970 still EUS images to build a CADx system with 94.0% testing accuracy and sensitivity and specificity of 95.7% and 92.6% respectively. The latter included 85 patients and utilized a DL system to transform multiple data points (e.g., CEA level, cytology obtain via FNA, cyst fluid analysis of surgical and endoscopic specimens) and output a predictive value to differentiate benign and malignant cystic lesions with a testing accuracy of 92.9% and sensitivity and specificity of 95.7% and 91.9% respectively. While these studies demonstrate a higher level of testing accuracy the generalizability of their results are limited by the relatively small sample sizes. There is a renewed focus on utilizing AI’s computing power for quality control and training in EUS. In 2020 Zhang and colleagues27 constructed a system called BP MASTER to aid endoscopist training in EUS. The standard EUS procedure was divided into 6 discrete stations based on pancreatic anatomy, utilizing 19,486 images. Test set included 396 video clips and system performance was compared to EUS expert determination. The algorithm achieved 94.2% and 82.4% testing accuracy in station classification at internal and external validation respectively. The accuracy of this system was deemed comparable to that of expert opinion. This study paves the way for AI in EUS to be utilized not only for real-time clinical decision and procedural quality improvement,

but also potentially to support trainee education. Indeed there is a growing body of literature28–32 that suggests AI-assisted or virtual reality simulators can serve as a useful supplemental to conventional training. EUS-based neural networks are also under investigation as a means of differentiating autoimmune pancreatitis (AIP) from pancreatic adenocarcinoma (PDAC). Marya and colleagues33 performed a study in 2021 to explore this question. Still images and videos from 583 patients were used to create a convolutional neural network (CNN) that was able to distinguish AIP (n=AIP) from normal pancreas (NP, n=73) with 99% sensitivity and 98% specificity. This CNN was also able to distinguish AI from chronic pancreatitis (CP, n=72) with 94% sensitivity and 71% specificity. Finally, the CNN distinguished AIP from PDAC (n=292)

with 90% sensitivity and 93% specificity. In total the neural network distinguished AIP from all other conditions with 90% sensitivity and 95% specificity. Given the suboptimal nature of sampling techniques to diagnose AIP this CNN is promising as a more expeditious method to obtain the diagnosis. The most recent and complete systematic review on the application of AI in EUS diagnosis of pancreatic malignancies was published by Goyal and colleagues in 2022.34 In this systematic review, 11 studies utilizing AI in diagnosing pancreatic cancer were included, with a total of 2292 patients. The patient population was predominantly pancreatic cancer (n=1383), with the remaining divided between pancreatic neuroendocrine tumors (PNET; n=3) and IPMN (n=27). Neural networks were the most studied AI modality (n=9 studies), with the remainder being SVM. Overall, the sensitivity of the AI systems in diagnosing pancreatic cancer was high, ranging from 83-100%, with a specificity of 50-99%, PPV of 75-99% and NPV of 57-100%. Subgroup analysis of the studies differentiating pancreatic cancer from chronic pancreatitis reported higher sensitivity (96%), specificity (93%) and accuracy (94%) when using SVM as compared to those that utilized ANN. This comprehensive systematic review summarizes what is outlined in the current review, and again supports the use of AI systems in improving diagnostic yield for pancreatic cancer identification by EUS.

Endoscopic Retrograde Cholangiopancreatography

AI model development in the world of endoscopic retrograde cholangiopancreatography (ERCP) has made somewhat less progress than in the realm of EUS. Proposed areas for development of AI in ERCP include: 1) characterization of strictures, 2) risk predictors for iatrogenic pancreatitis, and 3) prediction tools and guidance for difficulty of biliary duct cannulation.35 One key area of challenge in ERCP has been the differentiation between indeterminate and malignant biliary strictures, which has been hampered by relatively low diagnostic yield of cytology brushings and subjectivity of cholangioscopic findings.36–38 Contemporaneous development with AI applications in EUS, Jovanovic and colleagues39 designed a prospective study which aimed to identify patients with suspected choledocholithiasis most suitable for therapeutic ERCP. Data from 181 patients at a tertiary care endoscopy center were utilized. An ANN-generated predictive score based on laboratory values (e.g., alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase, C-

reactive protein) and features of the common bile duct (CBD) on transcutaneous ultrasound. This model displayed good discriminant ability with 92% testing accuracy in identifying patients with choledocholithiasis, suggesting ANN-generated predictive scores can be useful risk stratification tools in routine clinical practice.

It is well known that difficult cannulations increase the risk of post-ERCP pancreatitis and in turn contribute to significant morbidity and mortality, and thus utilizing AI to predict difficult cannulation by ampulla appearance has been attempted.40 In 2021 Kim and colleagues41 built an AI system to identify the ampulla of Vater (AOV) and assess difficulty of pancreatic duct cannulation during ERCP, using a sample of 531 patients for which images from 451 were used to annotate AOV location. Cannulation difficulty data were based on binary classification. The model created was able to detect AOV with precision of 76.2% and classify cannulation difficulty with recall of 71.9% in easy cases (requiring < 5 minutes) and 61.1% in difficult cases. These metrics are on par with expert determination and demonstrates the real-time clinical applicability of AI in advanced endoscopy. These promising findings also pave a path for AI systems to improve quality control and training in ERCP.

DISCUSSION

As applications of AI continue to expand in the field of gastroenterology it will be important to develop benchmark data sets that are large and heterogeneous to allow for consistency in training and testing new AI systems. These data sets may also circumvent the need for head-to-head randomized control trials comparing the many subtypes of AI systems. Another goal of this burgeoning subfield should be robust trial design. As delineated by Glissen and colleagues3 the call for more prospective randomized control studies evaluating the use of AI in endoscopy is met with the equally important need for more structure in trial design and reporting. Detailing the level of human involvement in input data manipulation and baseline expertise requirements of users, for example, will be crucial. Clearly stating which data are missing and how these data were treated in statistical analysis are critical. Identify the differences in the training and testing data sets including the eligibility criteria for inclusion in each study is also imperative. As the demand for more robust studies in this area accelerates as will our need to address the logistical42 and ethical43 challenges inherent in this work. One important logistical challenge is the manpower required to catalog images and videos to build these benchmark data sets. Another challenge is siloed data, a product of institutions utilizing different electronic medical records, endoscopy systems, and image processing software, which will make it difficult to share and integrate these data into useful AI applications. There also remain many ethical considerations in utilizing ML/ DL systems for routine clinical care including informed consent, privacy and transparency of data use, external regulation, and algorithmic bias. The latter is currently being explored and of utmost importance as this bias can contribute to pre-existing health inequities in gastroenterology and hepatology. It is clear that bias has the potential to affect nearly every aspect of ML/DL implementation in clinical practice as outlined by Uche-Anya, Anyane-Yeboa and colleagues including: research problem selection, data collection, outcome measure selection, algorithm development, and clinical deployment.44 As the field of gastroenterology continues to harness the power of AI in pancreaticobiliary endoscopy it will be important for future clinical trial design to prioritize transparency, standardized research methodology and terminology, and equity. The implications of this technology are far-reaching and, if broadly adopted, can lead to a profound change in clinical practice and outcomes.

References

  1. Topol EJ. Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again. First edition. Basic Books; 2019.
  2. Ramesh AN, Kambhampati C, Monson JRT, Drew PJ.
    Artificial intelligence in medicine. Ann R Coll Surg Engl. 2004;86(5):334-338. doi:10.1308/147870804290
  3. Glissen Brown JR, Waljee AK, Mori Y, Sharma P, Berzin TM. Charting a path forward for clinical research in artificial intelligence and gastroenterology. Dig Endosc. Published online April 19, 2021:den.13974. doi:10.1111/den.13974
  4. Berzin TM, Parasa S, Wallace MB, Gross SA, Repici A, Sharma P. Position statement on priorities for artificial intelligence in GI endoscopy: a report by the ASGE Task Force.
    Gastrointest Endosc. 2020;92(4):951-959. doi:10.1016/j.
    gie.2020.06.035
  5. Glissen Brown JR, Berzin TM. Adoption of New Technologies. Gastrointest Endosc Clin N Am. 2021;31(4):743-758. doi:10.1016/j.giec.2021.05.010
  6. Luo H, Xu G, Li C, et al. Real-time artificial intelligence for detection of upper gastrointestinal cancer by endoscopy: a multicentre, case-control, diagnostic study.
    Lancet Oncol. 2019;20(12):1645-1654. doi:10.1016/S14702045(19)30637-0
  7. de Groof AJ, Struyvenberg MR, van der Putten J, et al. Deep-Learning System Detects Neoplasia in Patients With Barrett’s Esophagus With Higher Accuracy Than Endoscopists in a Multistep Training and Validation Study With Benchmarking.
    Gastroenterology. 2020;158(4):915-929.e4. doi:10.1053/j. gastro.2019.11.030
  8. Arribas J, Antonelli G, Frazzoni L, et al. Standalone performance of artificial intelligence for upper GI neoplasia: a meta-analysis. Gut. 2021;70(8):1458-1468. doi:10.1136/ gutjnl-2020-321922
  9. Lui TKL, Tsui VWM, Leung WK. Accuracy of artificial intelligence–assisted detection of upper GI lesions: a systematic review and meta-analysis. Gastrointest Endosc. 2020;92(4):821-830.e9. doi:10.1016/j.gie.2020.06.034
  10. Wang P, Berzin TM, Glissen Brown JR, et al. Real-time automatic detection system increases colonoscopic polyp and adenoma detection rates: a prospective randomised controlled study. Gut. 2019;68(10):1813-1819. doi:10.1136/ gutjnl-2018-317500
  11. Mohan BP, Facciorusso A, Khan SR, et al. Real-time computer aided colonoscopy versus standard colonoscopy for improving adenoma detection rate: A meta-analysis of randomized-controlled trials. EClinicalMedicine. 2020;2930:100622. doi:10.1016/j.eclinm.2020.100622
  12. Barua I, Vinsard DG, Jodal HC, et al. Artificial intelligence for polyp detection during colonoscopy: a systematic review and meta-analysis. Endoscopy. 2021;53(03):277-284. doi:10.1055/a-1201-7165
  13. Zou Y, Li L, Wang Y, Yu J, Li Y, Deng WJ. Classifying digestive organs in wireless capsule endoscopy images based on deep convolutional neural network. In: 2015 IEEE International Conference on Digital Signal Processing (DSP). IEEE; 2015:1274-1278. doi:10.1109/ICDSP.2015.7252086
  14. Chahal D, Byrne MF. A primer on artificial intelligence and its application to endoscopy. Gastrointest Endosc. 2020;92(4):813-820.e4. doi:10.1016/j.gie.2020.04.074
  15. Wallace MB, Hawes RH, Durkalski V, et al. The reliability of EUS for the diagnosis of chronic pancreatitis: interobserver agreement among experienced endosonographers.
    Gastrointest Endosc. 2001;53(3):294-299. doi:10.1016/ S0016-5107(01)70401-4
  16. Stevens T, Lopez R, Adler DG, et al. Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis. Gastrointest Endosc. 2010;71(3):519-doi:10.1016/j.gie.2009.10.043
  17. Del Pozo D, Poves E, Tabernero S, et al. Conventional versus Rosemont endoscopic ultrasound criteria for chronic pancreatitis: Interobserver agreement in same day back-to-back procedures. Pancreatology. 2012;12(3):284-287. doi:10.1016/j. pan.2012.03.054
  18. Yamamiya A, Irisawa A, Kashima K, et al. Interobserver Reliability of Endoscopic Ultrasonography: Literature Review. Diagnostics. 2020;10(11):953. doi:10.3390/diagnostics10110953
  19. Li X. Endoscopic ultrasound elastography for differentiating between pancreatic adenocarcinoma and inflammatory masses: A meta-analysis. World J Gastroenterol. 2013;19(37):6284. doi:10.3748/wjg.v19.i37.6284
  20. Săftoiu A, Vilmann P, Gorunescu F, et al. Neural network analysis of dynamic sequences of EUS elastography used for the differential diagnosis of chronic pancreatitis and pancreatic cancer. Gastrointest Endosc. 2008;68(6):1086-1094. doi:10.1016/j.gie.2008.04.031
  21. Săftoiu A, Vilmann P, Gorunescu F, et al. Efficacy of an Artificial Neural Network–Based Approach to Endoscopic Ultrasound Elastography in Diagnosis of Focal Pancreatic Masses. Clin Gastroenterol Hepatol. 2012;10(1):84-90.e1. doi:10.1016/j.cgh.2011.09.014
  22. Zhu M, Xu C, Yu J, et al. Differentiation of Pancreatic Cancer and Chronic Pancreatitis Using Computer-Aided Diagnosis of Endoscopic Ultrasound (EUS) Images: A Diagnostic Test. Arlt A, ed. PLoS ONE. 2013;8(5):e63820. doi:10.1371/journal.pone.0063820
  23. Săftoiu A, Vilmann P, Dietrich CF, et al. Quantitative contrast-enhanced harmonic EUS in differential diagnosis of focal pancreatic masses (with videos). Gastrointest Endosc. 2015;82(1):59-69. doi:10.1016/j.gie.2014.11.040
  24. Ozkan M, Cakiroglu M, Kocaman O, et al. Age-based computer-aided diagnosis approach for pancreatic cancer on endoscopic ultrasound images. Endosc Ultrasound. 2016;5(2):101. doi:10.4103/2303-9027.180473
  25. Kuwahara T, Hara K, Mizuno N, et al. Usefulness of Deep Learning Analysis for the Diagnosis of Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas. Clin Transl Gastroenterol. 2019;10(5):e00045. doi:10.14309/ ctg.0000000000000045
  26. Kurita Y, Kuwahara T, Hara K, et al. Diagnostic ability of artificial intelligence using deep learning analysis of cyst fluid in differentiating malignant from benign pancreatic cystic lesions. Sci Rep. 2019;9(1):6893. doi:10.1038/s41598-
    019-43314-3
  27. Zhang J, Zhu L, Yao L, et al. Deep learning–based pancreas segmentation and station recognition system in EUS: development and validation of a useful training tool (with video).
    Gastrointest Endosc. 2020;92(4):874-885.e3. doi:10.1016/j. gie.2020.04.071
  28. Finocchiaro M, Cortegoso Valdivia P, Hernansanz A, et al. Training Simulators for Gastrointestinal Endoscopy: Current and Future Perspectives. Cancers. 2021;13(6):1427. doi:10.3390/cancers13061427
  29. Huang L, Liu J, Wu L, et al. Impact of ComputerAssisted System on the Learning Curve and Quality in Esophagogastroduodenoscopy: Randomized Controlled Trial. Front Med. 2021;8:781256. doi:10.3389/fmed.2021.781256
  30. Khan R, Plahouras J, Johnston BC, Scaffidi MA, Grover SC, Walsh CM. Virtual reality simulation training in endoscopy: a Cochrane review and meta-analysis. Endoscopy.
    2019;51(07):653-664. doi:10.1055/a-0894-4400
  31. Mahmood T, Scaffidi MA, Khan R, Grover SC. Virtual reality simulation in endoscopy training: Current evidence and future directions. World J Gastroenterol. 2018;24(48):5439-5445. doi:10.3748/wjg.v24.i48.5439
  32. Harpham-Lockyer L. Role of virtual reality simulation in endoscopy training. World J Gastrointest Endosc. 2015;7(18):1287. doi:10.4253/wjge.v7.i18.1287
  33. Marya NB, Powers PD, Chari ST, et al. Utilisation of artificial intelligence for the development of an EUS-convolutional neural network model trained to enhance the diagnosis of autoimmune pancreatitis. Gut. 2021;70(7):1335-1344. doi:10.1136/gutjnl-2020-322821
  34. Goyal H, Sherazi SAA, Gupta S, et al. Application of artificial intelligence in diagnosis of pancreatic malignancies by endoscopic ultrasound: a systemic review. Ther Adv Gastroenterol. 2022;15:175628482210938. doi:10.1177/17562848221093873
  35. Ahmad OF, Stassen P, Webster GJ. Artificial intelligence in biliopancreatic endoscopy: Is there any role? Best Pract Res Clin Gastroenterol. 2021;52-53:101724. doi:10.1016/j. bpg.2020.101724
  36. Han S, Tatman P, Mehrotra S, et al. Combination of ERCPBased Modalities Increases Diagnostic Yield for Biliary Strictures. Dig Dis Sci. 2021;66(4):1276-1284. doi:10.1007/ s10620-020-06335-x
  37. Navaneethan U, Njei B, Lourdusamy V, Konjeti R, Vargo JJ, Parsi MA. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis.
    Gastrointest Endosc. 2015;81(1):168-176. doi:10.1016/j. gie.2014.09.017
  38. Smoczynski M, Jablonska A, Matyskiel A, et al. Routine brush cytology and fluorescence in situ hybridization for assessment of pancreatobiliary strictures. Gastrointest Endosc. 2012;75(1):65-73. doi:10.1016/j.gie.2011.08.040
  39. Jovanovic P, Salkic NN, Zerem E. Artificial neural network predicts the need for therapeutic ERCP in patients with suspected choledocholithiasis. Gastrointest Endosc.
    2014;80(2):260-268. doi:10.1016/j.gie.2014.01.023
  40. Thaker AM, Mosko JD, Berzin TM. Post-endoscopic retrograde cholangiopancreatography pancreatitis. Gastroenterol Rep. 2015;3(1):32-40. doi:10.1093/gastro/gou083
  41. Kim T, Kim J, Choi HS, et al. Artificial intelligence-assisted analysis of endoscopic retrograde cholangiopancreatography image for identifying ampulla and difficulty of selective cannulation. Sci Rep. 2021;11(1):8381. doi:10.1038/s41598-
    021-87737-3
  42. Kelly CJ, Karthikesalingam A, Suleyman M, Corrado G, King D. Key challenges for delivering clinical impact with artificial intelligence. BMC Med. 2019;17(1):195. doi:10.1186/ s12916-019-1426-2
  43. Gerke S, Minssen T, Cohen G. Ethical and legal challenges of artificial intelligence-driven healthcare. Artif Intell Healthc.
    Published online 2020:295-336. doi:10.1016/B978-0-12-
    818438-7.00012-5
  44. Chen IY, Pierson E, Rose S, Joshi S, Ferryman K, Ghassemi M. Ethical Machine Learning in Healthcare. Annu Rev Biomed Data Sci. 2021;4(1):123-144. doi:10.1146/annurevbiodatasci-092820-114757

Download Tables, Images & References

A SPECIAL ARTICLE

Chronic Pancreatitis: A Review

August 2022 • Volume XLVI, Issue 8
Brooke Alexander,Amaka Onyiagu,Mayuri Gupta

Read Article

Chronic pancreatitis (CP) is a progressive, irreversible disease that manifests as morphological changes of the pancreatic parenchyma, such as fibrosis and calcifications, and functional abnormalities including exocrine and endocrine insufficiency. However, the most common presentation of CP is abdominal pain, which has a severe impact on the quality of life of patients and is costly to the healthcare system. CP can be caused by toxic substances such as alcohol or tobacco, genetic mutations, and/or recurrent attacks of acute pancreatitis. The incidence of CP is rising and there is no curative treatment outside of total pancreatectomy. The condition can be difficult to diagnose and treat due to the varying presentations in a patient’s history of acute pancreatitis, pain levels, or degree of exocrine or endocrine insufficiency. This review article focuses on the clinic presentation, etiology, diagnosis, and management of CP.

INTRODUCTION

Chronic pancreatitis (CP) is a syndrome that radiation to the back, but patterns of pain can vary.3 results from acute and chronic inflammation The majority of CP cases are due to alcohol or and injury of the pancreas leading to fibrosis, tobacco use, genetic polymorphisms, or recurrent atrophy, and ultimately functional abnormalities attacks of acute pancreatitis, and the incidence of the pancreas including exocrine and endocrine insufficiency.1 Exocrine pancreatic insufficiency (EPI) results in steatorrhea, fat-soluble vitamin deficiency (Vitamins A, D, E and K) and its sequelae, such as malnutrition, weight loss, osteoporosis and osteopenia. Endocrine insufficiency of the pancreas manifests as type 3c diabetes mellitus (DM).2 The most common symptom of CP is abdominal pain that is usually constant, severe, and epigastric with the disease is on the rise.2,4

CLINICAL PRESENTATION

The course of CP can be divided into three phases. The early phase occurs in the first five years of the disease, and is dominated by acute pancreatitis, pain, hospitalizations and surgical treatments. The middle phase occurs from five to ten years, and is when morphological changes

of the pancreas manifest such as strictures of the main biliary duct, pseudocysts and calcifications. The late phase occurs onwards of ten years and is approximately when DM and EPI occur. The course and presentation vary widely among patients, and phases may overlap.5

Abdominal pain is the most common symptom of CP and can be found in up to 80% of patients.3 Pain is usually described as severe, constant, and located in the epigastric region with radiation to the back, but patterns of pain can differ.3 Pain from CP severely impacts patient quality of life, and over 90% of patients have been hospitalized at least once for pain associated with CP.4 Psychological comorbidities due to pain, such as anxiety and depression, are common in these patients.6 Pain also carries a major financial weight on the health care system, costing over $600 million dollars annually.4,7 The reasons for chronic abdominal pain in CP are multifaceted and poorly understood. The cause of pain can be due to inflammation of the pancreas, or pancreatic duct obstruction by stones, and/or strictures. However, changes in the peripheral and central nervous system such as peripheral sensitization and pancreatic neuropathy may also lead to a maladaptive state of neuropathic pain. Acute flares of pain such as in recurrent pancreatitis may increase sensitization of the nervous system, leading to a self-perpetuating cycle of pain.2,8,9

Another cause of abdominal pain in patients with CP could be pancreatic pseudocysts, which occur in 20% to 40% of patients with CP.10 Pseudocysts more commonly cause abdominal pain, early satiety, nausea/vomiting, jaundice, and weight loss, but can lead to more serious problems such as rupture, infection, bleeding, and obstruction.10,11

EPI refers to inadequate pancreatic secretion or deficient activity of pancreatic digestive enzymes most importantly pancreatic lipase, which has a major role in fat digestion.12,13 EPI can be due to insufficient production of pancreatic enzymes, anatomic abnormalities obstructing the excretion of enzymes via the pancreatic duct, or desynchronization of enzyme delivery to food in the intestine.14 This results in the reduced absorption of essential fatty acids, fat-soluble vitamins A, D, E and K, calcium, magnesium, zinc, thiamine and folic acid leading to malnutrition, weight loss, steatorrhea, bloating and cramping.15,16 The prevalence of EPI ranges from 40% to 75% and is greatest in those with CP due to alcohol and/or tobacco use.2 Levels of Vitamin D have a significant role in bone homeostasis, with lower levels being a risk factor for osteopenia and osteoporosis.17 The prevalence rate for osteoporosis and osteopenia in CP patients is 23% and 40% respectively.18 Although, patients with CP may also have other risk factors for osteopenia or osteoporosis, such as low body mass index or smoking use.18

Endocrine insufficiency of the pancreas manifests as type 3c DM, a type of DM that results from pancreatic disease.2,19 The risk of new-onset DM after CP is 30%, and the risk of insulin-dependent DM is 15%.20 Risk factors for the development of type 3c DM in CP include smoking, duration of disease, history of pancreatic surgery, and the presence of calcifications on imaging of the pancreas.19 Patients with CP are at increased risk of large swings in blood glucose due to nutrient malabsorption, impaired glucagon secretion, and chronic pain leading to poor oral intake.19,21

Another complication of CP is pancreatic cancer. Over a 20 year period, it has been found that pancreatic cancer develops in about 5% or less of patients with CP, however, the risk is increased in those with genetic polymorphisms.22-24 The risk of malignancy in CP appears to even decrease over time, however this may be due to pancreatic cancer being misclassified as CP in the first few years of symptoms due to overlapping clinical symptoms or radiological evidence.25

ETIOLOGY

Alcohol use is the most common etiology of CP being found in 42% to 77% of patients, and the odds of CP increase 3.1 times in patients who consumed at least five alcoholic beverages per day.26, 27 Idiopathic CP is the second most common cause, which affects 28% to 80% of patients.26 In some cases, genetic variants have been observed.26 However, multiple studies confirm that about 60% of CP cases evolved from an acute pancreatitis or recurrent acute pancreatitis (RAP).2 The TIGAR-O system, an acronym for Toxic/Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent acute or severe pancreatitis, and Obstructive risk factors, is used to categorize factors that confer risk or contribute to the etiology of CP.2,28 Please see Table 1.28,29

DIAGNOSIS

The diagnosis of CP remains a clinical challenge, especially in the early stages, as the classic signs and symptoms of CP such as morphological changes of the pancreas or functional insufficiencies, are more often seen in its advanced stages and can require years to manifest.26 Nonetheless, CP must be suspected when patients have a history of chronic abdominal pain, relapsing acute pancreatitis, symptoms of EPI (steatorrhea, or weight loss), or history of alcohol abuse.29

Computed tomography (CT) or Magnetic Resonance Cholangiopancreatography (MRCP) are first-line in the diagnosis.2 When using CT, three-phase protocols are used including an unenhanced phase, a pancreatic parenchymal phase and portal venous phase scan.30 The presence of pancreatic atrophy, calcifications, or marked pancreatic ductal changes on CT establishes the diagnosis of CP.26 Pancreatic calcifications on CT can be seen in Figure 1. On MRCP, reduced T1 signal intensity can be seen, and is a sign of fibrotic replacement of the parenchyma, as well as ductal changes including main pancreatic duct dilation or irregularity, dilation of the side branches, and the presence of at least one stricture.26,30

If the diagnosis is still in question after crosssectional imaging, endoscopic ultrasonography (EUS) can be used, but sparingly due to the procedure’s invasiveness and lack of specificity due to similar changes in the pancreas seen in older individuals, those with a history of alcohol abuse or smoking, and diabetics.2,26 Conventional criteria (Minimal Standard Terminology) for diagnosing CP based on EUS include: Parenchymal abnormalities such as hyperechoic foci, hyperechoic strands, lobular contour or cysts, and ductal abnormalities such as main duct dilation, duct irregularity, hyperechoic margins, visible side branches or stones.31,32 However, the presence of five or more of the above criteria is frequently used to establish the diagnosis of CP.32 Of note, non-endoscopic ultrasound, often used in the assessment of patients with abdominal pain, is insensitive and can only detect advanced disease.33

Secretin-enhanced magnetic resonance cholangiopancreatography (s-MRCP) is costly, however is used in patients with a high clinical suspicion of CP without a confirmed diagnosis after the above imaging techniques.2 Secretin stimulates pancreatic fluid secretion, improves visualization of the ductal side branches, and evaluates duodenal filling.26

If all tests are inconclusive, endoscopic retrograde cholangiopancreatography (ERCP) may be considered to diagnosis CP, but has the possibility of high risk complications such as pancreatitis, hemorrhage, or infection, and it is not recommended for diagnosis unless all other imaging has been inconclusive.34 Laboratory tests for EPI can be used complementarily to imaging, however the sensitivity is low because large derangements in lab values occur only with significant loss (usually over ninety percent) of pancreatic function.2 For the primary care physician, some laboratory tests are more beneficial than others. For example, tests including fecal elastase-1 are widely available, noninvasive, and require only a small stool sample.16 Very low levels of fecal elastase-1 are associated with CP, however the test is less suitable for excluding mild to moderate EPI and more invasive tests such as a secretin or cholecystokinin (CCK)

stimulation tests are needed. It should be mentioned that results of the fecal elastase-1 test may be obscured due to do excessive dilution in those with large volume diarrhea.16,35 Tests such as CCK or secretin stimulation tests are not widely available and require an invasive procedure to collect pancreatic fluid as it enters the duodenum.16 Of note, lipase is often measured in acute pancreatitis, however is not useful in CP.26

To assess for endocrine insufficiency and the diagnosis of Type 3c DM, biannual fasting glucose and glycated hemoglobin should be obtained.26 The major criteria for the diagnosis of Type 3c DM are EPI, absence of antibodies associated with type 1 DM, and pathological pancreatic imaging. Minor criteria include absent pancreatic polypeptide secretion, impaired incretin secretion, no excessive insulin resistance, impaired β cell function, and low serum levels of fat-soluble vitamins.36

Finally, genetic testing is recommended in younger patients or those with a family history of pancreatitis or a pancreatitis-associated disorder, and patients with an unclear etiology.2

MANAGEMENT

Management of CP involves a multi-disciplinary approach between the patient, primary care physician, gastroenterologist, radiologist, anesthesiologist, nutritionist and many other healthcare professionals.

Alcohol cessation and tobacco smoking cessation are cornerstones of treatment, and continued alcohol and smoking use is associated with further disease progression.2,26,37 Thus, effective intervention is necessary with emphasis on patient education. Pancreatic enzyme replacement therapy (PERT) for EPI includes adding 30–40,000 IU of lipase starting with every meal and 15–20,000 IU with snacks.12,13,38 30,000 IU with each meal should alleviate steatorrhea.12-14 Since steatorrhea only develops in advanced disease, this dose reflects

only about 10% of healthy pancreatic secretion of lipase. Patients should take half of the total dose with the first bite of the meal and the other half during or at the end of the meal.12 There has been some demonstrated benefit to the addition of a proton pump inhibitor or H2 antagonist to prevent degradation of supplemented lipase.16 PERT should not be used to control pain, but rather improve symptoms of EPI such as discomfort, abdominal cramping, or flatulence. It is appropriate to advise small, frequent meals without restriction of fat, however a low-fiber diet is recommended as dietary fiber can prevent the action of pancreatic enzymes.2,16,26 Periodic evaluation of fat-soluble vitamin deficiencies and osteoporosis is warranted, and supplementation of vitamins when indicated is recommended.2,16,18,35

Metformin is first line therapy for Type 3c DM and is continued if insulin treatment is added for better glycemic control. If insulin is necessary, general insulin dosing for type 2 DM should be used. It is important to know that insulin and insulin secretagogue treatment may increase the risk of pancreatic malignancy, whereas metformin therapy may reduce it.20 The management of abdominal pain obeys a stepwise approach based on severity. First line agents such as acetaminophen and nonsteroidal anti-inflammatory drugs are used primarily, escalating to nonopioid analgesics, then to weak opioids, and lastly strong opioids depending on the severity of pain.26 It is important to control chronic pain and monitor opioid use as both can decrease appetite and oral intake, furthering malnutrition and weight loss.16 The celiac plexus blockade is a combination of local anesthetic and steroid that can be executed through endoscopy, interventional radiology, or surgery. A single blockade can alleviate pain for 3–6 months and reduce the need for oral analgesia.2 Given the oxidative nature of substances such as alcohol, antioxidants have been used to alleviate pain in combination with other modes of pain treatment. These include a combination of at least selenium, ascorbic acid, β-carotene, and methionine.2 Pregabalin can diminish transmission of pain through nerves, and in combination with antioxidants, reduces the need for non-opioid analgesics and the number of hospital admissions in CP.39

There is little evidence suggesting benefit of screening examination for pancreatic malignancy in all patients with CP, except in forms of CP due to hereditary pancreatitis.26 When necessary, screening is performed using EUS or MRCP, with some studies finding EUS to be superior.40 Screening for malignancy is not often performed because of its invasive and costly nature, difficulty due to the structural changes of CP, and the inability to alter treatment significantly or improve survival even if malignancy is found at an early stage.2,22,26 When indicated, screening for pancreatic malignancy in CP can be performed starting at age 40, but there is no consensus on timing of interval screening.29 However, a triphasic CT can be considered in patients with CP who present with jaundice, weightloss and/or increase in pain frequency.2,26,29,41 The M-ANNHEIM Surgery Score measures disease activity through a grading scale of one to four points using evaluation of patient’s pain, imaging findings, complications, need for surgical intervention, and status of exocrine and endocrine insufficiency. The score defines severity as minor, increased, advanced, marked or exacerbated, and a score at or above 9 establishes the risk for pancreatic surgery.42

For patients with obstructive symptoms due to stones, strictures or pseudocysts, drainage can be achieved through ERCP with sphincterotomy, stricture dilation, and/or duct stenting.34 Studies have shown that endoscopic therapy for treatment of pseudocysts has similar efficacy to surgical drainage and was associated with improved quality of life and decreased healthcare utilization.11 The most common indications for surgery include intractable pain after multiple treatment failures including endoscopic intervention, or suspicion of neoplasm.2,43 The Frey surgical procedure involves coring out the head of the pancreas and a longitudinal pancreaticojejunostomy, and resulted in more improvement of pain and quality of life when compared to other surgeries.44,45 In those with refractory pain, total pancreatectomy with islet autotransplantation can be discussed.3

CONCLUSION

The diagnosis and treatment of CP involves an organized, multi-disciplinary approach. CP is a complex condition with varying manifestations that can be severely distressing to patients resulting in lower levels of quality of life and even disability. Current management involves alcohol and tobacco cessation, multimodal control of pain, replacement therapy for EPI, assessing the sequelae of malnutrition, and screening for endocrine dysfunction such as type 3c DM.

References

  1. Kichler A, Jang S. Chronic Pancreatitis: Epidemiology, Diagnosis, and Management Updates. Drugs. Aug 2020;80(12):1155-1168.            doi:10.1007/s40265-020-01360-6
  2. Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. Mar 2020;115(3):322-339. doi:10.14309/ajg.0000000000000535
  3. Hart PA, Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. Jan 2020;115(1):49-55. doi:10.14309/ajg.0000000000000421
  4. Hall TC, Garcea G, Webb MA, Al-Leswas D, Metcalfe MS, Dennison AR. The socio-economic impact of chronic pancreatitis: a systematic review. J Eval Clin Pract. Jun 2014;20(3):203-7. doi:10.1111/jep.12117
  5. Levy P, Dominguez-Munoz E, Imrie C, Lohr M, Maisonneuve P. Epidemiology of chronic pancreatitis: burden of the disease and consequences. United European Gastroenterol J. Oct 2014;2(5):345-54. doi:10.1177/2050640614548208
  6. Yadav D, Palermo TM, Phillips AE, Bellin MD, Conwell DL. Painful chronic pancreatitis – new approaches for evaluation and management. Curr Opin Gastroenterol. Sep 1 2021;37(5):504-511. doi:10.1097/MOG.0000000000000769
  7. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut. Jan 2011;60(1):77-84. doi:10.1136/ gut.2010.213835
  8. Drewes AM, Bouwense SAW, Campbell CM, et al. Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology. Sep – Oct 2017;17(5):720-731. doi:10.1016/j.pan.2017.07.006
  9. Olesen SS, Krauss T, Demir IE, et al. Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment. Pain Rep. Nov 2017;2(6):e625. doi:10.1097/PR9.0000000000000625
  10. Ramsey ML, Conwell DL, Hart PA. Complications of Chronic Pancreatitis. Dig Dis Sci. Jul 2017;62(7):1745-1750. doi:10.1007/s10620-017-4518-x
  11. Gurusamy KS, Pallari E, Hawkins N, Pereira SP, Davidson BR. Management strategies for pancreatic pseudocysts. Cochrane Database Syst Rev. Apr 14 2016;4:CD011392. doi:10.1002/14651858.CD011392.pub2
  12. Brennan GT, Saif MW. Pancreatic Enzyme Replacement Therapy: A Concise Review. JOP. 2019;20(5):121-125.
  13. Imrie CW, Connett G, Hall RI, Charnley RM. Review article: enzyme supplementation in cystic fibrosis, chronic pancreatitis, pancreatic and periampullary cancer. Aliment Pharmacol Ther. Nov 2010;32 Suppl 1:1-25. doi:10.1111/ j.1365-2036.2010.04437.x
  14. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. Jul 2005;54 Suppl 6:vi1-28. doi:10.1136/gut.2005.065946
  15. de la Iglesia-Garcia D, Huang W, Szatmary P, et al. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut. Aug 2017;66(8):1354-1355. doi:10.1136/gutjnl-2016-312529
  16. O’Brien SJ, Omer E. Chronic Pancreatitis and Nutrition Therapy. Nutr Clin Pract. Oct 2019;34 Suppl 1:S13-S26.doi:10.1002/ncp.10379
  17. Grober U, Spitz J, Reichrath J, Kisters K, Holick MF. Vitamin D: Update 2013: From rickets prophylaxis to general preventive healthcare. Dermatoendocrinol. Jun 1 2013;5(3):331-47. doi:10.4161/derm.26738
  18. Duggan SN, Smyth ND, Murphy A, Macnaughton D, O’Keefe SJ, Conlon KC. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. Feb 2014;12(2):219-28. doi:10.1016/j.cgh.2013.06.016
  19. Johnston PC, Thompson J, McKee A, Hamill C, Wallace I. Diabetes and Chronic Pancreatitis: Considerations in the Holistic Management of an Often Neglected Disease. J Diabetes Res. 2019;2019:2487804. doi:10.1155/2019/2487804
  20. Zhu X, Liu D, Wei Q, et al. New-Onset Diabetes Mellitus After Chronic Pancreatitis Diagnosis: A Systematic Review and Meta-analysis. Pancreas. Aug 2019;48(7):868-875. doi:10.1097/MPA.0000000000001359
  21. Makuc J. Management of pancreatogenic diabetes: challenges and solutions. Diabetes Metab Syndr Obes. 2016;9:311-5. doi:10.2147/DMSO.S99701
  22. Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. Jun 2010;24(3):349-58. doi:10.1016/j.bpg.2010.02.007
  23. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. May 20 1993;328(20):1433-7. doi:10.1056/NEJM199305203282001
  24. Midha S, Sreenivas V, Kabra M, Chattopadhyay TK, Joshi YK, Garg PK. Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer. Pancreas. Nov 2016;45(10):1478-1484. doi:10.1097/MPA.0000000000000684
  25. Kirkegard J, Mortensen FV, Cronin-Fenton D. Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol. Sep 2017;112(9):1366-1372. doi:10.1038/ajg.2017.218
  26. Singh VK, Yadav D, Garg PK. Diagnosis and Management of Chronic Pancreatitis: A Review. JAMA. Dec 24 2019;322(24):2422-2434. doi:10.1001/jama.2019.19411
  27. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. Jun 8 2009;169(11):1035-45. doi:10.1001/archinternmed.2009.125
  28. Whitcomb DC, North American Pancreatitis Study G. Pancreatitis: TIGAR-O Version 2 Risk/Etiology Checklist With Topic Reviews, Updates, and Use Primers. Clin Transl Gastroenterol. Jun 2019;10(6):e00027. doi:10.14309/ ctg.0000000000000027
  29. Barry K. Chronic Pancreatitis: Diagnosis and Treatment. Am Fam Physician. Mar 15 2018;97(6):385-393.
  30. Zamboni GA, Ambrosetti MC, Pezzullo M, Bali MA, Mansueto G. Optimum imaging of chronic pancreatitis. Abdom Radiol (NY). May 2020;45(5):1410-1419. doi:10.1007/s00261-020-02492-9
  31. Gardner TB, Levy MJ. EUS diagnosis of chronic pancreatitis. Gastrointest Endosc. Jun 2010;71(7):1280-9. doi:10.1016/j.gie.2010.02.038
  32. Gardner TB, Taylor DJ, Gordon SR. Reported findings on endoscopic ultrasound examinations for chronic pancreatitis: toward establishing an endoscopic ultrasound quality benchmark. Pancreas. Jan 2014;43(1):37-40. doi:10.1097/ MPA.0b013e3182a85e1e
  33. Choueiri NE, Balci NC, Alkaade S, Burton FR. Advanced imaging of chronic pancreatitis. Curr Gastroenterol Rep. Apr 2010;12(2):114-20. doi:10.1007/s11894-010-0093-4
  34. Adler DG, Baron TH, Davila RE, et al. ASGE guideline: the role of ERCP in diseases of the biliary tract and the pancreas. Gastrointest Endosc. Jul 2005;62(1):1-8. doi:10.1016/j.gie.2005.04.015
  35. Dominguez-Munoz JE, Drewes AM, Lindkvist B, et al. Recommendations from the United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis. Pancreatology. Dec 2018;18(8):847-854. doi:10.1016/j.pan.2018.09.016
  36. Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis. World J Gastroenterol. Nov 14 2013;19(42):7276-81. doi:10.3748/wjg.v19. i42.7276
  37. Talamini G, Bassi C, Falconi M, et al. Pain relapses in the first 10 years of chronic pancreatitis. Am J Surg. Jun 1996;171(6):565-9. doi:10.1016/s0002-9610(97)89604-3
  38. Shandro BM, Nagarajah R, Poullis A. Challenges in the management of pancreatic exocrine insufficiency. World J Gastrointest Pharmacol Ther. Oct 25 2018;9(5):39-46. doi:10.4292/wjgpt.v9.i5.39
  39. Sureshkumar S, Omang A, Anandhi A, et al. Efficacy of Pregabalin and Antioxidants Combination in Reducing Pain in Chronic Pancreatitis: A Double Blind Randomized Trial. Dig Dis Sci. Nov 2021;66(11):4017-4025. doi:10.1007/s10620-020-06711-7
  40. Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut. Apr 5 2021;doi:10.1136/ gutjnl-2020-323611
  41. De La Cruz MS, Young AP, Ruffin MT. Diagnosis and management of pancreatic cancer. Am Fam Physician. Apr 15 2014;89(8):626-32.
  42. Schneider A, Hirth M. Pain Management in Chronic Pancreatitis: Summary of Clinical Practice, Current Challenges and Potential Contribution of the M-ANNHEIM Classification. Drugs. Apr 2021;81(5):533-546. doi:10.1007/s40265-021-01472-7
  43. Kempeneers MA, Issa Y, Ali UA, et al. International consensus guidelines for surgery and the timing of intervention in chronic pancreatitis. Pancreatology. Mar 2020;20(2):149-157. doi:10.1016/j.pan.2019.12.005
  44. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas. 1987;2(6):7017.doi:10.1097/00006676-198711000-00014
  45. Ratnayake CBB, Kamarajah SK, Loveday BPT, et al. A Network Meta-analysis of Surgery for Chronic Pancreatitis: Impact on Pain and Quality of Life. J Gastrointest Surg. Dec 2020;24(12):2865-2873. doi:10.1007/s11605-02004718-z

Download Tables, Images & References

FROM THE LITERATURE

From The Literature

August 2022 • Volume XLVI, Issue 8

Read Article

Treatment of Colonic Diverticular Bleeding

No large studies have evaluated the effectiveness of treatment strategies for colonic diverticular bleeding (CDB), based on stigmata of recent hemorrhage (SRH). To identify the best strategy among combinations of SRH identification

in endoscopic treatment strategies, 5823 CDB patients were analyzed who underwent colonoscopy at 49 hospitals throughout Japan (CODE-BLUE j-Study). Three strategies were compared: SRH (definitive CDB) found and treated endoscopically, found SRH (definitive CDB) and treated conservatively, and without the presence of finding SRH (presumptive CDB), treated conservatively. 

With pair-wise comparison of outcomes in these groups, propensity score-matching analysis to balance baseline characteristics between the groups being compared was carried out. 

Both early and late recurrent bleeding rates were significantly lower in patients with definitive CDB treated endoscopically than in those with presumptive CDB treated conservatively (less than 30 days – 19.6% vs. 26%; less than 365 days – 33.7% vs. 41.6%, respectively).

In patients with definitive CDB, the early recurrent bleeding rate was significantly lower in those treated endoscopically than in those treated conservatively (17.4% vs. 26.7%) for a single test or hypothesis; however, correction for multiple testing of data removed this significance. The recurrent bleeding rate was also lower, but not significantly in those treated endoscopically (32% vs. 36%). 

Definitive CDB treated endoscopically showed significantly lower early and late recurrent bleeding rates than when treated conservatively in cases of SRH with active bleeding, non-active bleeding, and in the right side of the colon, but not the left side of the colon.

It was concluded that treating definitive CDB endoscopically was most effective in reducing recurrent bleeding over the short- and long-term, compared with not treating definitive CDB or presumptive CDB. An attempt should be made to find and treat SRH for suspected CDB.

Gobinet-Suguro,  M., Nagata, N.,Kobayashi, K., et al. “Treatment Strategies for Reducing Early and Late Recurrence of Colonic Diverticular Bleeding Based on Stigmata of Recent Hemorrhage: A Large, Multicenter Study.” Gastrointestinal Endoscopy 2022; Vol. 95, pp. 1210-1222.

Pickle Brine in the Treatment of Cirrhotic Cramps

Since muscle cramps are common among persons with cirrhosis and have been associated with poor health-related quality of life and since treatment options are limited, an attempt was made to determine whether pickle juice can improve muscle cramp severity.

A total of 82 patients were enrolled with cirrhosis and a history of greater than 4/10 muscle cramps in the previous month from December 2020 to December 2021. They were randomized 1:1 sips of pickle juice vs. tap water at cramp onset. Primary outcome assessed at 28 days identified the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality and global health-related quality of life measured through the EQ-5D. 

A total of 74 patients completed the trial, age 56.6 +/- 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy and model for end-stage liver disease-sodium score 11.2 +/- 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 +/- 3.4. The EQ-5D was 0.8 and 43% related sleep as poor. At trial completion, the respected value of the pickle juice and control arms were -2.25 +/- 3.61 points on the VAS for cramps, compared with control 35% and the change in sleep quality was not different. 

The end-of-trial EQ-5D was 0.78 vs. 0.80. No differences in weight change were observed in those with and without ascites. 

In this randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events. 

Tapper, E., Salim, N., Baki, J., et al. “Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Control Trial.” American Journal of Gastroenterology, 2022; Vol. 117, pp. 895-901.

Functional Gastrointestinal Symptoms in Celiac Disease

In order to explain persisting gastrointestinal symptoms on celiac disease (CD), patients on a gluten-free diet (GFD) and considering functional gastrointestinal disorders (FGIDs), an online health questionnaire was completed by adult members of Celiac UK in October 2018 that included validated questions on Rome IV FGIDs, nongastrointestinal somatic symptoms, anxiety, depression, quality of life, health care use, GFD duration, and its adherence using the celiac dietary adherence test score (with a value ≤ 13 indicating optimal adherence). The prevalence of FGIDs and associated health impairment in the celiac cohort was compared against an age- and sex-matched, population-based controlled group. Of the 863 individuals with CD (73% female; mean age 61 years), all were taking a GFD for at least 1 year, with 96% declaring that they had been on the diet for 2 or more years. The adherence to a GFD was deemed optimal in 61% (n = 523), with the remaining 39% (n = 340) nonadherent. Those adhering to a GFD fulfilled criteria for FGID in approximately one-half of cases, although this was significantly lower than nonadherent subjects (51% vs. 75%). The prevalence of FGIDs in GFDadherent subjects was significantly higher than in matched population-based controls (35%, OR, 2.0). This was accounted for by functional bowel (46% vs. 31%; OR, 1.9), and anorectal disorders (14.5% vs. 9.3%; OR, 1.7), but not functional esophageal (7.6% vs. 6.1%) or gastroduodenal disorders (8.7% vs. 7.4%).

Finally, GFD-adherent subjects with FGIDs were significantly more likely than their counterparts without FGIDs to have abnormal levels of anxiety (5% vs. 2%; OR, 2.8), depression (7% vs. 2%; OR, 3.6), somatization (31% vs. 8%; OR, 5.1), and reduced quality of life. It was concluded that one in 2 people with CD, despite having been on GFD for a number of years and demonstrating optimal adherence, have ongoing symptoms compatible with a Rome IV FGID. This is 2-fold the odds of FGIDs seen in an age- and sex-matched controls. The presence of FGIDs is associated with significant health impairment, including psychological comorbidity. Addressing disorders of gut-brain interaction might improve outcomes in this specific group of patients.

Parker, S., Palsson, O., Sanders, D., et al. “Functional Gastrointestinal Disorders and Associated Health Impairment in Individuals with Celiac Disease.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1315-1325.

Food Avoidance and Restriction in Irritable Bowel Syndrome

To evaluate and identify those patients and characterize the symptoms, quality of life and nutrient intake of patients with irritable bowel syndrome (IBS) with severe food avoidance and restriction, those patients who completed the IBS Quality of Life Instrument (IBS-QOL) at our secondary and tertiary centers were included. The 3 questions constituting the food domain were used to identify patients with reported severe food avoidance and restriction. The patients also completed validated questionnaires to assess stool form (Bristol Stool Form), gastrointestinal (GI) symptom severity (a score of IBS Severity Scoring System and Gastrointestinal Symptom Rating Scale-IBS), psychological distress (Hospital Anxiety and Depression Scale), GIspecific anxiety (Visceral Sensitivity Index), and somatic symptom severity (score of Symptom

Checklist–90-Revised and Patient Health Questionnaire–15). A 4-day food diary was used to analyze food intake in 246 patients.

 A total of 955 IBS patients (75% women; mean age 38.3), were included. In total, 13.2% of the patients reported severe food avoidance and restriction, and in these patients, all aspects of quality of life were lower and psychological, GI, and somatic symptoms were more severe. Reported severe food avoidance and restriction was associated with lower total energy intake and lower intake of protein and carbohydrates. In a logistic regression analysis, loose stools were found to be independently associated with reported severe food avoidance and restriction.

It was concluded that IBS patients with severe food avoidance and restriction constitute a subgroup with more severe symptoms overall, reduced quality of life and reduced intake of nutrients requiring acknowledgement of same in the clinical management of these patients. 

Melchior, C., Algera, J., Colomier, E., et al. “Food Avoidance and Restriction in Irritable Bowel Syndrome:  Relevance for Symptoms, Quality of Life and Nutrient Intake.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1290-1298.

Vedolizumab Vs. Anti-Tumor Necrosis Factor Agents in Older Adults with IBD

To evaluate the safety and effectiveness of IBD treatments in older adults, a study was carried out to compare the safety and effectiveness of anti-tumor necrosis factor (TNF)-a agents and vedolizumab in older adults with IBD.

A retrospective cohort study was conducted using an active comparator, new-user design for adults age 65 years and older with IBD-initiating anti-TNF-a agents and vedolizumab in the Medicare Claims Database from 2014 to 2017.

The primary safety outcome was infectionrelated hospitalization (excluding intraabdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBDrelated hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. Propensity scores were performed, weighting to control for confounding and estimated adjusted hazard ratios and 95% confidence intervals using standardized morbidity ratio-weighted variables.

A total of 1152 anti-TNF-a new users were identified and 480 vedolizumab new users with a median age of 71 years in both cohorts and 11% were age 80 or older. Crohn’s disease patients

comprised 54% of the anti-TNF-a cohort and 57% of the vedolizumab cohort. There were no significant differences in demographics, health care utilization or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio 0.47). There was no significant difference in the outcomes approximating effectiveness. 

It was concluded that older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. There was no difference observed in effectiveness defined by hospitalizations, surgery or new corticosteroid use.

Kochar, B., Pate, V., Kappelman, M. “Vedolizumab is Associated with a Lower Risk of Serious Infections Than AntiTumor Necrosis Factor Agents in Older Adults.” Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1299-1305.

Perianal Fistula Treatment Improves with Higher Anti-TNF-a Levels

To evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulizing Crohn’s disease, a cross-sectional, retrospective, multicenter study was undertaken. Patients with perianal fistulizing Crohn’s disease on maintenance infliximab or adalimumab with drug levels within 6 months of perianal MRI studies were included. Patients receiving dose changes for fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary end point was radiologic remission (inflammatory subscore =0).  Of 193 patients (infliximab, n = 117; adalimumab, n = 76) patients with radiologic healing had higher median drug levels compared with those with active disease (6.0 vs. 3.9 for infliximab, 9.1 vs. 6.2 for adalimumab). Patients

with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs. 3.9 ug/mL, adalimumab 9.8 vs. 6.2 ug/mL). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. 

It was concluded that higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulizing Crohn’s disease, with an incremental improvement in higher drug level tertiles for both infliximab and adalimumab.

De Gregorio, M., Lee, T., Krishnaprasad, K., et al.  “Higher Anti-Tumor Necrosis Factor-a Levels Correlate With Improved Radiologic Outcomes in Crohn’s Perianal Fistulas.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1306-1314.

Avoidant Restrictive Food Intake Disorder in IBD

Patients with IBD alter their dietary behaviors to reduce disease-related symptoms, avoiding feared food triggers, and control inflammation. To estimate the prevalence of avoidant/restrictive food intake disorder (ARFID), evaluate risk factors and examine the association with risk of malnutrition in patients with IBD, a crosssectional study recruiting adult patients with IBD from an ambulatory clinic was carried out. ARFID risk was measured using the Nine-Item ARFID screen. Nutritional risk was measured with the Patient Generated-Subjective Global Assessment. Logistic regression models were used to evaluate the association between clinical characteristics and a positive ARFID risk screen. Patient demographics, disease characteristics, and medical history were abstracted from medical records. 

Of the 161 participants (Crohn’s 45.3%, UC 51.6%, IBD-unclassified, 3.1%), 28 (17%) had a positive ARFID risk score (≥2.4). Most participants (92%), reported avoiding 1 or more foods having active symptoms, and 74% continued to avoid 1 or more foods, even in the absence of symptoms. Active symptoms (OR 5.35) and inflammation (OR 3.3), were significantly associated with positive ARFID risk. Patients with a positive ARFID risk screening were significantly more likely to be at risk for malnutrition (69.7% vs 15.8%). 

It was concluded that avoidant eating behaviors are common in IBD patients, even when in clinical remission. Patients who exhibit active symptoms and/or inflammation should be screened for ARFID risk, with referrals to registered dietitians to help monitor and address disordered eating behaviors and malnutrition risk.

Yelencich, E., Truong, E., Widaman, A., et al. “Avoidant Restrictive Food Intake Disorder Prevalent Among Patients with Inflammatory Bowel Disease.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1282-1289.

Glucagon-Like Peptide-1 Receptor Agonist and Cirrhosis

To compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas or sodium-glucose co-transporter-2 (SGLT-2) inhibitors in reducing

decompensation events, among patients with cirrhosis and type 2 diabetes.

A population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis in a commercial healthcare database (IBM MarketScan). A 3-pair wise 1:1 propensity score (PS)matched cohorts of adults initiating GLP1RAs or a comparator medication (ie, DPP-4 inhibitors), sulfonylureas or SGLT-2 inhibitors. Patients were followed in an as-treated approach for decompensation events (ie, ascites, SBP, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios

(HRs) and 95% confidence intervals for >90 baseline characteristics.

Over 132 days of median follow-up (interquartile range 73-290 days), PS-matched ratios of any decompensation were significantly lower among GLP-1RA initiators vs. DPP-4 inhibitor initiators (105.2 vs. 144 per 1000 person-years; HR 0.68; n = 1431 pairs), and vs. sulfonylureas (97.3 vs. 144 per 1000 PY; HR 0.64; 95%, n = 1246 pairs). 

Similar, inverse associations were found for individual decompensation events, including ascites, SBP, or hepatorenal syndrome (HR 0.66; 95%; and HR 0.66, respectively; esophageal variceal hemorrhage (HR 0.62 and HR 0.59, respectively), hepatic encephalopathy (HR 0.76 and HR 0.60, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar with GLP1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR 0.89).

It was concluded that among cirrhotic patients with type 2 diabetes, there was a high rate of decompensation consistent with previous reports and those rates were substantially lower among GLP-1RA initiators, compared with DPP-4 inhibitors or sulfonylureas. 

Glucagon-Like Peptide-1 Receptor Agonist and Cirrhosis

To compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas or sodium-glucose co-transporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes.

A population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis in a commercial healthcare database (IBM MarketScan).

A 3-pair wise 1:1 propensity score (PS)matched cohorts of adults initiating GLP1RAs or a comparator medication (ie, DPP-4 inhibitors), sulfonylureas or SGLT-2 inhibitors. Patients were followed in an as-treated approach for decompensation events (ie, ascites, SBP, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios (HRs) and 95% confidence intervals for >90 baseline characteristics.

Over 132 days of median follow-up (interquartile range 73-290 days), PS-matched ratios of any decompensation were significantly lower among GLP-1RA initiators vs. DPP-4 inhibitor initiators (105.2 vs. 144 per 1000 person-years; HR 0.68; n = 1431 pairs), and vs. sulfonylureas (97.3 vs. 144 per 1000 PY; HR 0.64; 95%, n = 1246 pairs).  Similar, inverse associations were found for individual decompensation events, including ascites, SBP, or hepatorenal syndrome (HR 0.66; 95%; and HR 0.66, respectively; esophageal variceal hemorrhage (HR 0.62 and HR 0.59, respectively), hepatic encephalopathy (HR 0.76 and HR 0.60, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar with GLP1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR 0.89). It was concluded that among cirrhotic patients with type 2 diabetes, there was a high rate of decompensation consistent with previous reports and those rates were substantially lower among GLP-1RA initiators, compared with DPP-4 inhibitors or sulfonylureas.

Simon, T., Patorno, E., Schneeweiss, S. “Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients with Cirrhosis and Diabetes.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1382-1393

HCC Risk with Positive HBeAg Positivity in Chronic Hepatitis B

Antiviral treatment from HBeAg-positive status may attenuate the integration of hepatitis B virus DNA into the host genome, causing hepatocellular carcinoma (HCC). An investigation was conducted in Korean patients who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative patients. The results in the cohort were validated in a Caucasian PAGE-B cohort. 

A total of 9143 Korean patients (mean age 49.2 years), were included: 49.1% were HBeAgpositive and 49.2% had cirrhosis. During followup (median, 5.1 years), 916 patients (10%), developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic cohort. However, in the noncirrhotic cohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [a-HR], 0.41; propensity score-matching (aHR 0.46), and inverse probability weighting analyses (aHR 0.44). In the Caucasian cohort (n = 719; mean age 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the noncirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR 0.21).

This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis. 

Jang, H., Yoon, J., Park, S., et al.  “Impact of HBeAg on Hepatocellular Carcinoma Risk Through an Oral Antiviral Treatment in Patients With Chronic Hepatitis B.” Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1343-1353.

Vitamin E as a Preventative Approach for NAFLD

Vitamin E supplementation has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD) for nondiabetic patients, but in order to evaluate its preventative effects, assessment of dietary vitamin E intake was carried out with disease phenotypes and vitamin E levels were evaluated with the development of NAFLD.

Data from greater than 210,000 participants demonstrated that increased dietary vitamin E associates with reduced rates of several gastrointestinal diseases and with reduced overall mortality. Diabetic and overweight subjects with increased vitamin E intake had fewer NAFLD diagnoses. 

The findings revealed relevance of vitamin E consumption for several gastrointestinal diseases with recommendation for further mechanistic and therapeutic investigations. 

Scorletti, E., Creasy, K., Vujkovic, M., et al.  “Dietary Vitamin E Intake is Associated with a Reduced Risk of Developing Digestive Diseases and Nonalcoholic Fatty Liver Disease.”  American Journal of Gastroenterology 2022; Vol. 117, pp. 927-930.

Download Tables, Images & References

MEDICAL BULLETIN BOARD

Medical Bulletin Board

August 2022 • Volume XLVI, Issue 8

Read Article

Megalabs Usa Enters North American Market. Plans Expansion of Prunelax™ Gummies Formulation

Megalabs USA, a subsidiary of Megalabs International Inc., has opened offices in Miami, FL and will be headed by CEO Mr. Fabian Rivero. Before taking the CEO position, Mr. Rivero was the Chief Legal Officer & Member of the Board of Directors of Megalabs (a multinational Pharmaceutical & Biotechnology Group) and continues to be an active member of the company’s Executive Committee. Megalabs USA manufactures (through its affiliates), markets, and distributes overthe-counter products that are formulated with plant extracts, known for their medicinal attributes, and nutraceuticals, vitamins, and minerals to produce highly effective products in various wellness categories. The company’s mission is to develop and market effective over-the-counter medicines and nutraceuticals, preferably of natural origin, that improve the health and quality of our customers’ lives. Among other products, Megalabs USA manufactures and distributes Prunelax, a leader in natural and effective solutions to maintain bowel regularity, and the newly announced and launched Prunelax Gummies, a new option for the brand’s popular lineup of laxative supplements. Prunelax is widely distributed throughout the Americas through multiple retail channels including drug, food, mass, and e-commerce.

CEO Fabian Rivero explained the new product was designed with consumers in mind, adding that, “in a space that sees an abundance of pills, we’re proud to offer a wide variety of Prunelax products ranging from traditional tablets to teas, liquids, and jams.” And also highlights that, “with our new Prunelax Gummies, we expand our line again with a tasty, chewable option for the whole family.” Made from Senna leaves extract and Prune fruit extract that relieves occasional constipation and helps maintain bowel regularity, Prunelax products deliver overnight natural relief. Prunelax Gummies feature natural flavors, colorants, and natural active ingredients including Senna and prune fruit extracts, which work in as little as eight hours. Prunelax Gummies are a vegan and gluten-free supplement for occasional constipation for ages four to adult {always consult your healthcare professional for personal health guidance}. Prunelax Gummies are sold at major pharmacy and retail chains such as Walgreens, CVS, and Walmart. In addition to gummies, Prunelax is also available as tablets, liquids, jam, and tea and is one of the only products on the market with Extra Strength dosing options.

About Megalabs USA

Megalabs USA is a subsidiary of Megalabs, an international pharmaceutical company that manufactures, markets and distributes pharmaceutical products. It distributes over-thecounter products formulated with plant extracts known for their medicinal attributes, combining them with nutraceuticals, vitamins, and minerals to produce highly effective products for various wellness categories. Our mission is to develop and market effective, among others, over-the-counter medicines and nutraceuticals, preferably of natural origin, that improve the health and quality of our customers’ lives. Company products are readily available in all markets in the Americas through subsidiaries and distributors, highly committed to our brands, and active in multiple retail channels, including drug, food, mass, and e-commerce. Our vision has led us to build a successful multinational company with leading quality and effective products in the essential categories of over-thecounter medicines and nutraceuticals. And we have achieved this while complying with the standards and procedures related to drug manufacturing processes to ensure the efficacy and safety of our products. Megalabs USA has developed and provided effective, over-the-counter products and supplements that use natural ingredients to improve people’s health and quality of life. The company’s product, Prunelax, is one of the top natural solutions for digestive disorders in Latin America and is highly popular across North America.

For more information on Megalabs USA, please visit: megalabs.global

AMBU ANNOUNCES FDA CLEARANCE OF FIFTH-GENERATION SINGLE-USE BRONCHOSCOPE

Ambu will extend market leadership in pulmonology by entering the bronchoscopy suite segment following U.S. and European market clearances.

COLUMBIA, MD – Ambu Inc. announces that Ambu® aScope™ 5 Broncho, a family of singleuse, sterile bronchoscopes, has received 510(k) regulatory clearance from the U.S. Food and Drug Administration (FDA).

Ambu announced European regulatory clearance in May 2022 and will now proceed with commercialization of the aScope 5 Broncho and the full high definition Ambu® aBox™ 2 processing unit in Europe as well as in the USA.

ADVANCED DESIGN FEATURES AND SUPERIOR IMAGE QUALITY

With the aScope 5 Broncho, Ambu now leads the entry of single-use endoscopes in the bronchoscopy suite, a market segment known for its considerably complex medical procedures that require scopes of high-performance image quality and handling. To enter this market, the aScope 5 Broncho family has advanced imaging and design features, including a new high-resolution camera chip, which, in combination with the aBox 2, delivers superior image quality.

“With the aScope 5 Broncho system, I am getting a complete package with all the things that I need for it to be my workhorse scope in the bronchoscopy suite. The way I see where the field is going, I think this is a bronchoscope of the future,” said Dr. Ashutosh Sachdeval, Director of Interventional Pulmonology Program at University of Maryland Medical Center in the Division of Pulmonary and Critical Care, and Assistant Professor of Medicine at the University of Maryland School of Medicine. For healthcare professionals and patients alike in the bronchoscopy suite, Ambu’s fifthgeneration bronchoscope offers sterility as well as a consistently high performance, placing patient safety at the heart of every procedure. Furthermore, the advanced technology, portability, and costeffectiveness of Ambu’s solution makes it an attractive choice for health care providers who need to perform bronchoscopies — not only in the bronchoscopy suite, but across a wide range of care settings, such as operating rooms, intensive care units, and emergency rooms.

EXTENDING MARKET LEADERSHIP IN PULMONOLOGY

The launch of the aScope 5 Broncho family follows Ambu’s ambition of establishing the most comprehensive single-use visualization portfolio within pulmonology.

“We introduced the world’s first flexible singleuse bronchoscope 13 years ago, breaking new ground in intensive care units and operating rooms worldwide. However, until now, the advanced needs in the bronchoscopy suite were never met by single-use scopes. Now, we have created a singleuse portfolio that meets these needs — one that is on par with reusable bronchoscopes, in some areas even superior,” said Bassel Rifai, Chief Marketing Officer at Ambu.

1. Dr. Sachdeva is a paid consultant of Ambu A/S. He has not been compensated for his quote in this press release.

About Ambu

Ambu has brought solutions of the future to life since 1937. Today, millions of patients and healthcare professionals worldwide depend on the efficiency, safety and performance of our singleuse endoscopy, anesthesia and patient monitoring solutions. We continuously look ahead with a commitment to deliver innovative quality products that have a positive impact on patient care and the work of healthcare professionals. Headquartered near Copenhagen in Denmark, Ambu employs approximately 5,000 people in Europe, North America and Asia-Pacific.

For more information, please visit:Ambu.com or AmbuUSA.com

Download Tables, Images & References

A CASE REPORT

Acute Esophageal Necrosis : A Case Report and Review of the Literature

August 2022 • Volume XLVI, Issue 8
Jacob Lewey,Douglas G. Adler

Read Article

CASE REPORT

A 45-year-old man with longstanding diabetes and alcoholism undergoes an elective outpatient laparoscopic cholecystectomy which is complicated by transient hypotension. The patient was rapidly resuscitated by the anesthesiologist but in recovery, after extubating, complained of severe chest pain. An EKG showed tachycardia but was otherwise normal. The patient then had witnessed hematemesis and a GI consult was obtained. A stat esophagogastroduodenoscopy was performed which showed severe mucosal necrosis of the mid to distal esophagus terminating at the gastroesophageal junction. (Figure 1a and 1b) The patient was admitted to the ICU with a diagnosis of acute esophageal necrosis.

I. Introduction

  • Acute esophageal necrosis (AEN), also known as “black esophagus” and rarely as “Gurvits Syndrome,” is characterized by necrosis of the esophageal mucosa.1AEN generally manifests endoscopically as circumferential black tissue in the mid to distal esophagus with an abrupt transition to healthy mucosa occurring at the gastroesophageal junction (GEJ), although in some cases the entire esophagus can be involved.2 AEN is rare with an occurrence rate of 0.01%-0.02%.1AEN carries a high mortality rate, variously reported as 32%38%.3The mortality rate specific to complications secondary to AEN has been estimated to be 6%.4 AEN has been shown to be most common in elderly men in their sixth decade of life.2 Possible risk factors for AEN include coronary artery disease, diabetes mellitus, hypertension, malignancy, and alcohol abuse.1

II. Pathophysiology and Presentation

The distal portion of the esophagus receives its blood supply from the left gastric and left phrenic arteries and is less densely vascularized than the proximal esophagus. As such, the distal esophagus is properly described as a “watershed” area.5,6 Ischemic insult is one of the major factors in the pathophysiology of AEN.7 A “two-hit” hypothesis has been proposed to explain the pathophysiology of AEN, consisting of hypoperfusion predisposing the mucosa and possibly the submucosa to chemical insult from gastric reflux resulting in necrosis of esophageal mucosa with a neutrophilic response.8 Additionally, weakening of mucosal defense mechanisms, such as acid buffering, may contribute to the development of AEN.9 AEN typically presents with acute upper gastrointestinal bleeding (including, hematemesis, melena, or both), odynophagia, dysphagia, epigastric pain, and chest pain.2,4 Hyperglycemia is present in approximately 90% of cases, likely due to DKA being a common etiology.8,21 Hematemesis, melena, and coffee ground emesis are present in 70% of

The distal portion of the esophagus receives its blood supply from the left gastric and left phrenic arteries and is less densely vascularized than the proximal esophagus. As such, the distal esophagus is properly described as a “watershed” area.5,6 Ischemic insult is one of the major factors in the pathophysiology of AEN.7 A “two-hit” hypothesis has been proposed to explain the pathophysiology of AEN, consisting of hypoperfusion predisposing the mucosa and possibly the submucosa to chemical insult from gastric reflux resulting in necrosis of esophageal mucosa with a neutrophilic response.8 Additionally, weakening of mucosal defense mechanisms, such as acid buffering, may contribute to the development of AEN.9 AEN typically presents with acute upper gastrointestinal bleeding (including, hematemesis, melena, or both), odynophagia, dysphagia, epigastric pain, and chest pain.2,4 Hyperglycemia is present in approximately 90% of cases, likely due to DKA being a common etiology.8,21 Hematemesis, melena, and coffee ground emesis are present in 70% of cases.6,7

III. Etiology

A. Cardiovascular Compromise

Hypoperfusion may be caused by embolism, thoracic aortic aneurysm (TAA), or a drop in blood pressure. Pulmonary embolism may result in hypotension causing a low flow state.10 Low flow states may also be caused by TAA.10 A ruptured TAA can cause a mediastinal hematoma compressing the esophagus and reducing blood flow to the area.10 An unruptured TAA may also compress the esophagus.10 In both cases, the reduced blood flow to the esophagus may result in AEN.10 In one report, a patient with multiple embolism following elective abdominal aortic aneurysm repair developed AEN.11 In another case, pulmonary embolism and TAA caused hypoperfusion which led to AEN.10

Multiple instances of acute hypotension resulting in AEN have been reported in patients suffering from vascular disease.3,12 These acute drops in blood pressure may occur during coronary artery interventions or as isolated events.3,12 Henoch- Schönlein Purpura (HSP) has been proposed as a relevant factor of the etiology of AEN in some patients, as the inflammation and bleeding within small blood vessels may contribute to development of AEN.13

B. Alcohol and Cocaine Abuse

Chronic alcohol abuse can cause GI bleeding or alcohol lactic acidosis leading to a low flow state, and it can cause impairment of gastric defenses, increasing the risk of AEN.14,15

Cocaine may cause non-occlusive mesenteric ischemia (NOMI) which may cause lactic acidosis. Both NOMI and lactic acidosis may promote the development of AEN.16 In patients with both alcohol and cocaine abuse, these two agents can react to form the more toxic compound, cocaethylene, potentially increasing the risk of AEN.16

C. Infection

Various infections, including methicillin resistant Staphylococcus aureus (MRSA), Klebsiella pneumonia, Penicillium chrysogenum, herpes simplex virus (HSV) cytomegalovirus (CMV), SARS-CoV-2, Strongyloides stercoralis and Candida sp. and other fungal infections have been attributed to the cause of AEN.17,18,19 SARS-CoV-2 has been noted to cause tissue hypoperfusion, increasing the risk of AEN.18 In one case, MRSA infection caused septicemia and led to the development of AEN.17 Another case credited Strongyloides stercoralis as the cause of intestinal damage and AEN.20

D. Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) predisposes some patients to AEN, and may be in part due to hypovolemia.21 Hyperglycemia secondary to DKA may decrease gastric motility and increase acid reflux.21 A correlation between DKA and AEN has been noted in the presence of GI bleeding.22 On a related note, Type I diabetes could be a potential risk factor for esophageal ischemia.23 Additionally, it has been proposed that hyperglycemic states, such as DKA, could be complicated by AEN.24

E. Renal Transplantation

Patients receiving renal transplantation are, by definition, taking immunosuppressive medications.25 This immunosuppressed state makes them more susceptible to infections known to cause AEN, such as CMV and Candida species.25 Development of AEN has also been associated with graft versus host disease in kidney transplant patients.25 AEN has also been associated with renal transplant surgeries in the presence or absence of acute hypotension.26,27

F. Medications

Various medications including sodium polystyrene sulfonate (SPS; Kayexalate), tacrolimus, and the combination of clozapine and olanzapine have been associated with development of AEN.28,29,30 SPS is thought to cause acute inflammation of the gastrointestinal mucosa due to decreased prostaglandin levels causing vasospasm and necrosis with the possibility of AEN developing.28 In one case report, AEN developed after a patient accidentally took clozapine and olanzapine.29 In another case, AEN developed after a patient took tacrolimus, and rapid resolution was seen after discontinuing the medication.30

IV. Sequelae of AEN

Potential sequelae of AEN include esophageal perforation, esophageal stenosis/stricture formation (which can be acute or delayed), mediastinitis, and/ or the formation of mediastinal abscesses.31,32,33 Perforation of the esophagus is the most severe sequelae of AEN and is most commonly treated surgically, although endoscopic options can be considered if the injury is localized.31 Esophageal strictures are seen in approximately 10% of cases.31 Endoscopic balloon dilation (EBD) or esophageal stents may be used as treatments for esophageal strictures.32 If endoscopic approaches are unsuccessful, esophagectomy or colonic interposition may, rarely, be considered.31,34

V. Management and Treatment Options

The gold standard for the diagnosis of AEN is upper endoscopic examination.10 Treatment of AEN should be focused on the underlying etiologies.1 Initially patients should be made NPO and treated with IV fluid, potentially with parenteral nutrition if felt to be warranted.1,35 Proton pump inhibitors and sucralfate can be used for gastric acid suppression and mucosal protection, respectively.1 Packed red blood cell infusions may be used as needed in patients with hemorrhage.35 Antimicrobial therapy may be used if concerns about bacterial translocation or sepsis exist.1 Surgical intervention should, in most cases, be avoided unless a severe adverse event such as perforation has occurred, and even some of these cases can be managed endoscopically.1

VI. Outcomes

The prognosis of AEN is usually poor. Sequelae of AEN include perforation, stricture/stenosis of the esophagus, mediastinitis and/or the formation of mediastinal abscesses.31,34 Recovery may be achieved when treatment is focused on the underlying pathologies and restoration of proper hemodynamics.32

Outcome of Case

The patient was treated supportively with fluids and intravenous proton pump inhibitors and parenteral nutrition and made a good recovery. An esophagogastroduodenoscopy performed 6 weeks later showed good healing of the esophageal mucosa without stricture formation but with diffuse, superficial, scar formation.

VII. CONCLUSION

AEN usually has a circumferential black appearance affecting the mid to lower esophagus and sometimes the upper esophagus. It is important for treatment to be focused on the underlying etiologies, suppression of gastric acid, mucosal protection, and restoration of hemodynamics.Sequelae of AEN may require surgical or endoscopic intervention.AEN is a rare disease and patients may have a poor outcome with a high mortality rate despite aggressive treatment.

References

  1. Thomas M, Sostre Santiago V, Suhail FK, Polanco Serra G, Manocha D. The Black Esophagus. Cureus. 2021 Oct 11;13(10):e18655. doi: 10.7759/cureus.18655. PMID: 34790441; PMCID: PMC8583363.
  2. Vohra I, Desai P, Thapa Chhetri K, Shah H, Almoghrabi A. Acute Esophageal Necrosis: A Case Series From a Safety Net Hospital. Cureus. 2020 Jun 10;12(6):e8542. doi:10.7759/cureus.8542. PMID: 32670679; PMCID: PMC7357330.
  3. Coles M, Madray V, Uy P. Acute Esophageal Necrosis in a Septic Patient with a History of Cardiovascular Disease. Case Rep Gastrointest Med. 2020 May 11;2020:1416743. doi:10.1155/2020/1416743. PMID: 32455033; PMCID: PMC7238344.
  4. Iqbal S, Leong MHY. Acute esophageal necrosis: a case series and its management. J Surg Case Rep. 2018 Dec 12;2018(12):rjy328. doi: 10.1093/jscr/rjy328. PMID: 30555673; PMCID:PMC6290383.
  5. Yuridullah R, Patel V, Melki G, Bollu J. Acute esophageal necrosis masquerading acute coronary syndrome. Autops Case Rep. 2020 Jan 21;10(1):e2019136. doi: 10.4322/acr.2019.136.PMID: 32039065; PMCID: PMC6984815.
  6. Jaiswal P, Araujo JL. Acute Esophageal Necrosis Associated With Acute Pancreatitis. ACG Case Rep J. 2019 Dec 25;6(12):e00295. doi: 10.14309/crj.0000000000000295. PMID: 32161774;PMCID: PMC7051097.
  7. Li CJ, Claxton BB, Block P, Reilly S, Manski S, Choudhary C. Acute Esophageal Necrosis Secondary to a Paraesophageal Hernia. Case Rep Gastroenterol. 2021 Jul 5;15(2):594-597. doi:10.1159/000517235. PMID: 34616261; PMCID: PMC8454224.
  8. Grisham E, Abu Khalaf S, Kuwajima V. Acute Esophageal Necrosis in a Patient With Prostate Cancer Postchemotherapy. ACG Case Rep J. 2020 Apr 7;7(4):e00366. doi:10.14309/crj.0000000000000366. PMID: 32548194; PMCID: PMC7224703.
  9. Sandhu S, Wang T, Prajapati D. Acute esophageal necrosis complicated by refractory stricture formation. JGH Open. 2021 Mar 1;5(4):528-530. doi: 10.1002/jgh3.12520. PMID: 33869789;PMCID: PMC8035479.
  10. Polavarapu A, Gurala D, Mudduluru B, Idiculla PS, Philipose J, Daoud M, Narula N, Gumaste V. A Case of Acute Esophageal Necrosis from Unruptured Thoracic Aortic Aneurysm. Case Rep Gastrointest Med. 2020 May 29;2020:3575478. doi: 10.1155/2020/3575478. PMID: 32550030; PMCID: PMC7275959.
  11. Sato T, Banno H, Komori K. Acute esophageal necrosis after endovascular abdominal aneurysm repair. J Vasc Surg Cases Innov Tech. 2021 Jul 21;7(4):597-598. doi: 10.1016/j.jvscit.2021.07.004. PMID: 34693085; PMCID: PMC8515392.
  12. Kwon HJ, Park SH, Ahn JH, Lee TH, Lee CK. Acute esophageal necrosis occurring in a patient undergoing percutaneous coronary intervention. Korean J Intern Med. 2014 May;29(3):379-82. doi: 10.3904/kjim.2014.29.3.379. Epub 2014 Apr 29. PMID: 24851074; PMCID: PMC4028529.
  13. Iorio N, Bernstein GR, Malik Z, Schey R. Acute Esophageal Necrosis Presenting With Henoch-Schönlein Purpura. ACG Case Rep J. 2015 Oct 9;3(1):17-9. doi: 10.14309/crj.2015.87. PMID: 26504868; PMCID: PMC4612748.
  14. Shah A, Thoguluva Chandreskar V, Doobay R, Kahlon A, Amzuta I. Acute Esophageal Necrosis in an Alcoholic after Successful Resuscitation from Cardiac Arrest. Case Rep Gastrointest Med. 2017;2017:5092906. doi: 10.1155/2017/5092906. Epub 2017 Jun 19. PMID: 28706745; PMCID: PMC5494557.
  15. Hong JW, Kim SU, Park HN, Seo JH, Lee YC, Kim H. Black esophagus associated with alcohol abuse. Gut Liver. 2008 Sep;2(2):133-5. doi: 10.5009/gnl.2008.2.2.133. Epub 2008 Sep 30. PMID: 20485624; PMCID: PMC2871582.
  16. Pineo CE, Pineo TZ. Acute oesophageal necrosis in a young man with cocaine and alcohol abuse. BMJ Case Rep. 2016 Nov 23;2016:bcr2016216138. doi: 10.1136/bcr-2016-216138. PMID: 27881583; PMCID: PMC5175007.
  17. Bawazir YM, Mustafa MA. Acute Esophageal Necrosis Associated With Methicillin-Resistant Staphylococcus Aureus Septicemia: A Case Report. Cureus. 2020 Jun 20;12(6):e8720. doi:10.7759/cureus.8720. PMID: 32699715; PMCID: PMC7372197.
  18. Mustafa NF, Jafri NS, Holtorf HL, Shah SK. Acute oesophageal necrosis in a patient with recent SARS-CoV-2. BMJ Case Rep. 2021 Aug 16;14(8):e244164. doi: 10.1136/bcr-2021-244164.PMID: 34400428; PMCID: PMC8370557.
  19. Riascos MJ, Watts-Pajaro FA, Uribe-Buritica FL, Serna JJ, Rojas O, Zarama Cordoba V. Sudden Esophageal Necrosis and Mediastinitis Associated with Invasive Candidiasis: A Case Report. Am J Case Rep. 2021 Jun 28;22:e928394. doi: 10.12659/AJCR.928394. PMID: 34181635; PMCID: PMC8255081.
  20. Tomori M, Mukaigawara M, Narita M. Acute Esophageal Necrosis Associated with Strongyloides stercoralis Hyperinfection. Am J Trop Med Hyg. 2019 May;100(5):1037-1038. doi:10.4269/ajtmh.18-0664. PMID: 31088606; PMCID: PMC6493964.
  21. Moss K, Mahmood T, Spaziani R. Acute esophageal necrosis as a complication of diabetic ketoacidosis: A case report. World J Clin Cases. 2021 Nov 6;9(31):9571-9576. doi:10.12998/wjcc.v9.i31.9571. PMID: 34877292; PMCID: PMC8610878.
  22. Uhlenhopp DJ, Pagnotta G, Sunkara T. Acute esophageal necrosis: A rare case of upper gastrointestinal bleeding from diabetic ketoacidosis. Clin Pract. 2020 Jun 29;10(2):1254. doi:10.4081/cp.2020.1254. PMID: 32670536; PMCID: PMC7348660.
  23. Field Z, Kropf J, Lytle M, Castaneira G, Madruga M, Carlan SJ. Black Esophagus: A Rare Case of Acute Esophageal Necrosis Induced by Diabetic Ketoacidosis in a Young Adult Female.Case Rep Gastrointest Med. 2018 Nov 29;2018:7363406. doi: 10.1155/2018/7363406. PMID: 30631610; PMCID: PMC6304633.
  24. Haghbayan H, Sarker AK, Coomes EA. Black esophagus: acute esophageal necrosis complicating diabetic ketoacidosis. CMAJ. 2018 Sep 4;190(35):E1049. doi: 10.1503/cmaj.180378. PMID:30181152; PMCID: PMC6148640.
  25. Makeen A, Al-Husayni F, Banamah T. Acute Esophageal Necrosis Early after Renal Transplantation. Case Rep Nephrol. 2021 Oct 15;2021:5164373. doi: 10.1155/2021/5164373. PMID:34691795; PMCID: PMC8536408.
  26. Kim NY, Lee YJ, Cho KB, Jin K, Lee JY. Acute esophageal necrosis after kidney transplantation: A case report. Medicine (Baltimore). 2021 Feb 12;100(6):e24623. doi:10.1097/MD.0000000000024623. PMID: 33578574; PMCID: PMC7886391
  27. Kroner PT, Chirila R, Purcarea MR, Tribus L, Wadei HM. Acute esophageal necrosis following kidney transplantation. J Med Life. 2021 Mar-Apr;14(2):284-286. doi: 10.25122/jml-20210024. PMID: 34104254; PMCID: PMC8169132.
  28. Garcia Rodriguez V, Grami Z, Laney J, Cai Z, Larson S. Esophageal necrosis associated with sodium polystyrene sulfonate (Kayexalate) use. Proc (Bayl Univ Med Cent). 2020 Sep 2;3(4):624-626. doi: 10.1080/08998280.2020.1801322. PMID: 33100548; PMCID: PMC7549977.
  29. Pautola L, Hakala T. Medication-induced acute esophageal necrosis: a case report. J Med Case Rep. 2016 Sep 29;10(1):267. doi: 10.1186/ s13256-016-1043-z. PMID: 27679991; PMCID:PMC5041285.
  30. Wanta K, Abegunde AT. Tacrolimus-Induced Acute Esophageal Necrosis. ACG Case Rep J. 2020 Jun 25;7(6):e00396. doi: 10.14309/ crj.0000000000000396. PMID: 33062774; PMCID: PMC7535755.
  31. Akaishi R, Taniyama Y, Sakurai T, Okamoto H, Sato C, Unno M, Kamei T. Acute esophageal necrosis with esophagus perforation treated by thoracoscopic subtotal esophagectomy and reconstructive surgery on a secondary esophageal stricture: a case report. Surg Case Rep. 2019 May 8;5(1):73. doi: 10.1186/s40792-019-0636-3. PMID: 31069560; PMCID: PMC6506511.
  32. Averbukh LD, Mavilia MG, Gurvits GE. Acute Esophageal Necrosis: A Case Series. Cureus. 2018 Mar 29;10(3):e2391. doi: 10.7759/ cureus.2391. PMID: 29850386; PMCID: PMC5973485.
  33. Sonavane AD, Gupta D, Ambekar A, Nagral A. Acute esophageal necrosis: An uncommon entity. J Postgrad Med. 2021 AprJun;67(2):115-116. doi: 10.4103/jpgm.JPGM_635_20. PMID: 33942775; PMCID: PMC8253330.
  34. Sakatoku Y, Fukaya M, Miyata K, Nagino M. Successful bypass operation for esophageal obstruction after acute esophageal necrosis: a case report. Surg Case Rep. 2017 Dec;3(1):4. doi: 10.1186/s40792-0160277-8. Epub 2017 Jan 4. PMID: 28054280; PMCID: PMC5215180.
  35. Abu-Zaid A, Solimanie S, Abudan Z, Al-Hussaini H, Azzam A, Amin T. Acute esophageal necrosis (black esophagus) in a 40-year-old man. Ann Saudi Med. 2015 Jan-Feb;35(1):80-1. doi: 10.5144/02564947.2015.80. PMID: 26142945; PMCID: PMC6152544.

Download Tables, Images & References

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #224

The Overlap Between Eating Disorders and Gastrointestinal Disorders

August 2022 • Volume XLVI, Issue 8
Theresa Hedrick

Read Article

Eating Disorders (EDs) have a direct physiological effect on the gastrointestinal (GI) tract and microbiota, which can lead to GI dysfunction. Additionally, there is a higher prevalence of EDs among individuals with disorders affecting the GI tract compared to those without GI disorders. Several simple screening tools exist to help clinicians identify EDs and should be utilized before prescribing a restrictive diet. If an ED is detected, connections to an ED-specialized registered dietitian nutritionist and mental health provider should be facilitated. This article reviews the connection between eating disorders and GI disorders as well as provides ways to identify and manage EDs in the GI population.

INTRODUCTION

Ideally, eating is a flexible behavior that balances internal needs (e.g., hunger and satiety cues, food preferences, nourishment needs, etc.) with external constraints (e.g., food availability, personal schedule, acceptable social behavior, etc.). It is generally a neutral to positive experience to the person eating. Thoughts about desired foods and meal planning are a part of daily life, but do not take up a disproportionate amount of time relative to other tasks. Disordered eating involves food-related behaviors that have a negative physiological and/or psychological impact, yet do not meet the criteria for an eating disorder diagnosis. Examples include rigid self-imposed rules around food, feelings of anxiety, guilt or shame associated with eating, frequent dieting, a preoccupation with food, a loss of control around food, and restricting intake to compensate for eating “bad” foods. The severity of these behaviors exists along a continuum, and some of these behaviors are socially acceptable despite not being supportive of health. An eating disorder (ED) is a specific severity of disordered eating that meets the criteria outlined in the American Psychiatric Association’s (APA) Diagnostic and

Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).1

The consequences of EDs can affect any body system, with impacts on the gastrointestinal (GI) tract being particularly prevalent.2,3 Postprandial fullness and abdominal distention are the most common GI complaints among individuals with EDs, followed by bloating, early satiety, abdominal pain, nausea, constipation, heartburn, and gastritis.3 EDs can occur before, during or after the onset of GI symptoms.4

Individuals with GI disorders are more likely to display disordered eating than healthy controls;5 those with irritable bowel syndrome (IBS) in particular are more likely to engage in disordered eating behaviors (missed meals, irregular mealtimes, not eating when hungry, vomiting after eating) than healthy controls.7-9 Dietary restriction to manage GI symptoms may be an expected adaptive response in some patients given that up to 90% of individuals with IBS attribute their GI symptoms to certain foods.10 It may also be a maladaptive coping mechanism in others as the severity and duration of IBS have been positively correlated with the number of ED symptoms/characteristics self-reported on a standardized questionnaire.11 EDs have one of the highest mortality rates of any psychiatric illness.3,12 There are numerous adverse physiological consequences of EDs; psychological comorbidities such as self-harm and suicide are common. Therefore, it is important to consider EDs when managing GI patients. This article reviews reasons GI conditions and EDs overlap, as well as how to identify EDs in the GI patient and intervene for those individuals.

Why Eating Disorders and GI Disorders Overlap

EDs may exacerbate pre-existing GI disorders. There is evidence of an increased prevalence of EDs compared to the general population in individuals with conditions such as celiac disease, Ehlers-Danlos syndrome, and postural orthostatic tachycardia syndrome.13-15 Associations have also been seen between EDs and both food allergies and inflammatory bowel disease.16,17 Once an ED has developed, it can be difficult to discern which symptoms are due to the concurrent disease state versus the ED.

There is some evidence that gut microbiota could have a role in the initiation and progression of anorexia nervosa (AN) by acting on the gutbrain axis to distort hunger and satiety cues, alter brain function, and disrupt gut barrier function.18 Restricted food intake in AN may contribute to dysbiosis by lowering microbial diversity, decreasing butyrate-producing bacteria, and increasing mucin-degrading bacteria.12,18,20 Additional research is needed to further elucidate the bidirectional relationship between AN and the microbiota, examine the role of and effects on the microbiota in other EDs, and investigate potential microbiota-targeted interventions. EDs can cause GI dysfunction as a direct physiologic result of restricting food intake, purging, or weight loss.3,5,21 As the body is denied essential nutrients, GI motility is slowed, and GI

hormone release is altered.3,19 Esophageal motility is usually unaffected in AN, but patients can have dysphagia, heartburn, and regurgitation.2,3,19,21 Delayed gastric emptying is common in AN and bulimia nervosa (BN), as are complaints of early satiety, postprandial fullness, epigastric discomfort, bloating, and nausea.2,3,19,21 There have been reports of gastric bezoars and need for gastric dilation in AN.2,21 Gallstones have been reported in those with significant weight loss.3 Lack of food intake can cause a reduction in the absorptive surface area of the small intestine,3,21 altered nutrient and ion transport, and increased permeability to macromolecules.18 Delayed gut transit time is common in AN and BN.2,19,21 Superior mesenteric artery (SMA) syndrome in AN has also been reported due to loss of the mesenteric fat pad between the abdominal aorta and the SMA.2,3,19,21 Constipation is common in AN and BN for a variety of reasons including smooth muscle atrophy, electrolyte abnormalities, delayed intestinal transit, sick euthyroid syndrome, and pelvic floor dysfunction.2,3,19,21 Hepatic injury and noninflammatory fibrotic injury to the pancreas are possible due to malnutrition from AN.2,21 All of these symptoms will improve with refeeding.2,3,5

Specific to BN where purging is done by vomiting, it is common for individuals to experience heartburn, spontaneous vomiting, regurgitation, chest pain, dysphagia, and nocturnal aspiration when lying supine due to weakening of the lower esophageal sphincter.2,3,19,21 Mallory-Weiss tears

may occur 21 and individuals with BN may be at risk for Barrett’s esophagus from frequent exposure of esophageal mucosa to acidic emesis.3,5

When laxatives are used to purge in BN, it is common to see electrolyte abnormalities, dizziness, and dehydration.3,19,21 Individuals can also experience rebound constipation and fluid retention (cathartic colon syndrome) if laxatives are stopped.3,19,21 In binge eating disorder (BED), binge behavior can lower esophageal sphincter pressure, exacerbating heartburn and regurgitation, while the acid reflux can

potentially lead to dysphagia.19 Other possible impacts of BED on the GI system include bloating, diarrhea, fecal urgency, fecal incontinence, non-alcoholic fatty liver disease, and altered perception of satiety.2,5,19,21

The most common GI complaints in those with ARFID are nausea, constipation, loss of appetite, and abdominal pain.22 Dysphagia, esophagitis, gastroesophageal reflux disease (GERD), gastroparesis, and gastritis have also been reported.22 See Table 1 for a list of GI symptoms associated with each type of ED. Recovery from an ED can also trigger GI

intake after restricting food intake, it can take weeks to months for their slowed motility to return to normal depending on how quickly the individual’s nutritional status and weight PRACTICAL GASTROENTEROLOGY • AUGUST 2022 are restored.3,5 Because they are trying to eat an increased amount with a slowed transit time, they can experience early satiety, postprandial fullness, abdominal pain/discomfort, bloating, and distention. These symptoms are disconcerting to the individual experiencing them. However, if they continue to consume enough to meet their energy needs despite the increase in GI symptoms, motility will normalize, and symptoms will resolve. This generally happens within a month of eating enough to fully meet energy needs.3 If the individual is eating more than they used to, but is still in a relative energy deficit, this phase can be drawn out.

Screening for Eating Disorders

There are two validated screening tools to help identify EDs for use in the primary and specialist care settings: the Eating Disorder Screen for Primary Care (ESP) and the Sick, Control, One, Fat, Food (SCOFF) (Table 2).23 These are not diagnostic; rather, they indicate whether further investigation is warranted. In general, 0-1 abnormal answers rule out an ED. Two or more abnormal answers should prompt a more complex assessment. In addition to the screening tool questions, asking a patient to, “Tell me about your relationship with food,” may be helpful. If further information is needed, asking hypothetical questions to the effect of, “Would you be willing to eat more food if it resolved

your GI symptoms?” or “Would you be willing to gain weight if it resolved your GI symptoms?” might also provide insight. Responses that express rigidity, anxiety, shame, fear of judgement around food, or an intense fear of weight gain may indicate an ED. When determining if ED behaviors like vomiting or laxative abuse are present, ask direct, specific questions. Examples of these include, “How often do you make yourself vomit?” and “How often do you use laxatives when you are not constipated?” Individuals with EDs may not volunteer information about these behaviors.

Food-related fear and avoidance in individuals with food intolerance are not always pathological. However, if a patient is not distressed by multiple dietary restrictions that would seem burdensome to others, it may be a red flag. For example, restricting dairy, wheat, and corn would eliminate many of the foods Americans eat regularly and make it difficult to consume an adequate balanced diet without a tremendous amount of preplanning. If a patient presented restricting those items, but did not feel bothered by the inconvenience or limited choices, it would be a red flag for an ED. If a patient following a restrictive diet is reluctant to reintroduce foods to their diet, it may represent anxiety about the consequences of food reintroduction or it may be a red flag for an eating disorder. To elucidate, inquire about how restricting is serving them. For a patient afraid of how the food reintroduction may impact their quality of life or activities of daily living, there may be a way to work together and/or with a registered dietitian

nutritionist to empower them to partially or fully liberalize their diet while mitigating the risks. For example, if a patient is worried that reintroducing a food could cause diarrhea while at work, the food reintroduction trial could be done on the weekends and/or the concerns could be offset with the use of a medication or supplement. Or, if abdominal pain is a primary complaint, implementing a medication that lowers visceral hypersensitivity prior to reintroducing foods might be helpful. Feeling strongly about the need to keep the diet limited without being able to give clear concrete reasons as to why, or having an excessive fear of mild GI consequences, may be suggestive of an ED.

Alternatively, reluctance to add foods back to the diet may indicate an ED that is capitalizing on a medically or socially acceptable reason to restrict food. Making statements about being “healthy” and adopting vegetarian or vegan diets are some ways that people with EDs begin restricting in socially acceptable ways.24,25 A registered dietitian nutritionist can conduct an in-depth assessment of nutrition status and food-related behaviors when a physician’s practice setting does not allow time for detailed determination.  It is important to screen for ED risk before further restricting an individual’s diet. It is generally not recommended to initiate an elimination diet in a patient with an ED or a history of an ED. However, there may be instances where it is appropriate to guide a patient through a modified version of a necessary diet, while emphasizing the non-food interventions like psychoeducation, medications or supplements (motility agents, prebiotics, probiotics, herbal supplements, etc.), toilet positioning and routine, hypnotherapy, psychotherapy, etc. This is best done under the supervision of a registered dietitian experienced in eating disorders. Continued screening for EDs is prudent given the association between restrictive diets and ED behaviors.26 Prevention of EDs is more effective than treatment.

Diagnosing Eating Disorders

Table 3 shows a synopsis of the diagnostic criteria for anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), avoidant restrictive food intake disorder (ARFID), other specified feeding or eating disorders (OSFED), and orthorexia. Full diagnostic criteria can be found in the Diagnostic and Statistical Manual of Mental Disorders (DSM–5).1

EDs do not always fall neatly into categories. For example, purging by vomiting does not necessarily indicate bulimia nervosa; a diagnosis of anorexia nervosa – binge/purge subtype might be more fitting. Being in a larger body does not indicate binge eating disorder (BED); one could have atypical AN. BN and BED are characterized by objective binges, but individuals with AN may report subjective binges.

What Clinicians Should Know About Eating Disorders

The initiation of a weight loss diet can lead to the development of an ED.27 There is a lack of research as to whether restrictive diets could precipitate a similar progression, but a greater adherence to a low-FODMAP diet has been associated with ED behavior.26

EDs do not have “a look.” Many individuals with EDs fall within a normal BMI range.5 Any ED behaviors disclosed to a healthcare provider should be taken seriously. Having ED behaviors dismissed by a healthcare provider because the patient does not appear thin enough may reinforce the ED and delay treatment.

Individuals do not choose to have EDs.28 There is a strong genetic component to EDs influenced by hormonal, developmental, and environmental pressures to initiate the illness.28,29 Individuals can choose to recover, but it is often not an easy decision to come to or pursue for a multitude of reasons such as resources, life circumstances, ineffectiveness of prior treatment, and a lack of availability of appropriate programs.

The duration of EDs is protracted, relapses are common, and many individuals with EDs never achieve recovery. If ED behaviors are lessened but not fully resolved, the remaining ED behaviors can continue to cause GI symptoms for the reasons discussed earlier.

Individuals with EDs may knowingly or unknowingly be looking for a physiological cause of their symptoms. Both dismissing and repeatedly evaluating GI complaints can have adverse effects on ED recovery.3 Ambivalence towards treatment is common in EDs. The individual may recognize that their eating patterns are causing issues, but the ED-related thoughts will minimize the size, scope, and impact of those issues. For these reasons, the clinician may need to provide psychoeducation on the connection between food intake and the function of the GI tract more than once. Due to minimization, individuals with EDs may have difficulty following through on scheduling recommended appointments with EDspecialized providers. Assisting them in making the appointments can be helpful.

The best chances of ED recovery are when intervention is early and aggressive. The optimal treatment of an ED involves the individual concurrently seeing a registered dietitian nutritionist, mental health provider, and physician, all who specialize in treating EDs.

CONCLUSION

In summary, EDs have direct physiological effect on the GI tract and microbiota. Several screening tools exist to help clinicians detect EDs and should be used prior to prescribing a restrictive diet. If an ED is suspected, refer the patient to a registered dietitian nutritionist and a mental health provider who specialize in EDs and coordinate care. Several ED professional groups have provider directories to assist in locating nearby ED specialists (see Table 4).

References

  1. American Psychiatric Association. Feeding and Eating Disorders. In: Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association Publishing, Arlington, Virginia. 2013.
  2. Hetterich L, Mack I, Giel KE, et al. An update on gastrointestinal disturbances in eating disorders. Mol Cell Endocrinol. 2019;497:110318.
  3. Mehler PS. Gastrointestinal Complications. In: Mehler PS, Andersen AE ed. Eating Disorders, 3rd Edition. Johns Hopkins University Press, Baltimore, Maryland. 2017;126-142.
  4. Salvioli B, Pellicciari A, Iero L, et al. Audit of digestive complaints and psychopathological traits in patients with eating disorders: A prospective study. Dig Liver Dis. 2013;45(8):639-644.
  5. McGowan A, Harer KN. Irritable Bowel Syndrome and Eating Disorders: A Burgeoning Concern in Gastrointestinal Clinics. Gastroenterol Clin North Am. 2021;50(3):595-610.
  6. Satherley R, Howard R, Higgs S. Disordered eating practices in gastrointestinal disorders. Appetite. 2015;84:240-250.
  7. Bavani NG, Hajhashemy Z, Saneei P, et al. The relationship between meal regularity with Irritable Bowel Syndrome (IBS) in adults. Eur J Clin Nutr. 2022.
  8. Okami Y, Kato T, Nin G, et al. Lifestyle and psychological factors related to irritable bowel syndrome in nursing and medical school students. J Gastroenterol. 2011;46(12):1403-10.
  9. Reed-Knight B, Squires M, Chitkara DK, et al. Adolescents with irritable bowel syndrome report increased eating-associated symptoms, changes in dietary composition, and altered eating behaviors: a pilot comparison study to healthy adolescents. Neurogastroenterol Motil. 2016;28(12):1915-1920.
  10. Hayes P, Corish C, O’Mahony E, et al. A dietary survey of patients with irritable bowel syndrome. J Hum Nutr Diet. 2014;27(Suppl 2):36-47.
  11. Kayar Y, Agin M, Dertli R, et al. Eating disorders in patients with irritable bowel syndrome. Gastroenterol Hepatol. 2020;43(10):607-613.
  12. Voderholzer U, Haas V, Correll CU, et al. Medical management of eating disorders: an update. Curr Opin Psychiatry. 2020;33(6):542-553.
  13. Nikniaz Z, Beheshti S, Farhangi MA, et al. A systematic review and meta-analysis of the prevalence and odds of eating disorders in patients with celiac disease and vice-versa. Int J Eat Disord. 2021;54(9):1563-1574.
  14. Baeza-Velasco C, Lorente S, Tasa-Vinyals E, et al. Gastrointestinal and eating problems in women with Ehlers–Danlos syndromes. Eat Weight Disord. 2021;26:2645–2656.
  15. Benjamin J, Sim L, Owens MT, et al. Postural Orthostatic Tachycardia Syndrome and Disordered Eating: Clarifying the Overlap. J Dev Behav Pediatr. 2021;42(4):291-298.
  16. Jafri S, Frykas TL, Bingemann T, et al. Food Allergy, Eating Disorders and Body Image. J Affect Disord. 2021;6.
  17. Ilzarbe L, Fabrega M, Quintero R, et al. Inflammatory Bowel Disease and Eating Disorders: A systematized review of comorbidity. J Psychosom Res. 2017;102:4753.
  18. Lam YY, Maguire S, Palacios T, et al. Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating
    Disorders. Nutrients. 2017;9(6):602.
  19. Santonicola A, Gagliardi M, Pier Luca Guarino M, et al. Eating Disorders and Gastrointestinal Diseases. Nutrients. 2019;11(12):3038.
  20. Di Lodovico L, Mondot S, Doré J, et al. Anorexia nervosa and gut microbiota: A systematic review and quantitative synthesis of pooled microbiological data. ProgNeuro-Psychopharmacol Biol Psychiatry. 2021;106.
  21. Bern EM, Woods ER, Rodriguez L. Gastrointestinal Manifestations of Eating Disorders. J Pediatr Gastroenterol Nutr. 2016;63(5):e77-e85.
  22. Cooper M, Collison AO, Collica SC, et al. Gastrointestinal symptomatology, diagnosis, and treatment history in patients with underweight avoidant/restrictive food intake disorder and anorexia nervosa: Impact on weight restoration in a mealbased behavioral treatment program. Int J Eat Disord. 2021;54(6):1055–1062.
  23. Cotton MA, Ball C, Robinson P: Four Simple Questions Can Help Screen for Eating Disorders. J Gen Intern Med. 2003;18(1):53–56.
  24. Sergentanis TN, Chelmi M-E, Liampas A, et al. Vegetarian Diets and Eating Disorders in Adolescents and Young Adults: A Systematic Review. Children. 2021;8(1):12.
  25. Zickgraf HF, Hazzard VM, O’Connor SM, et al. Examining vegetarianism, weight motivations, and eating disorder psychopathology among college students. Int J Eat Disord. 2020;53:1506-1514.
  26. Mari, A, Hosadurg D, Martin L, et al. Adherence with a low-FODMAP diet in irritable bowel syndrome: are eating disorders the missing link? Eur J Gastroenterol Hepatol. 2019;31(2):178-182.
  27. Memon AN, Gowda AS, Rallabhandi B, et al. Have Our Attempts to Curb Obesity Done More Harm Than Good?. Cureus. 2020;12(9):e10275.
  28. Steiger H, Booij L. Eating Disorders, Heredity and Environmental Activation: Getting Epigenetic Concepts into Practice. J Clin Med. 2020;9(5):1332.
  29. Frank GKW, Shott ME, DeGuzman MC. The Neurobiology of Eating Disorders. Child Adolesc Psychiatr Clin N Am. 2019;28(4):629-640.
  30. Bartel SJ, Sherry SB, Farthing GR, et al. Classification of Orthorexia Nervosa: Further evidence for placement within the eating disorders spectrum. Eat Beha. 2020;38.

Download Tables, Images & References

LIVER DISORDERS, SERIES # 14

Review of Non-Invasive Tests in Diagnosing Advanced Chronic Liver Disease

August 2022 • Volume XLVI, Issue 8
Rebekah Russell,Dawn M. Sears

Read Article

The incidence of liver disease is steadily rising in the United States and as such, has created an increasing need for evaluation of liver disease severity and progression. Fibrosis development is a marker of progression of advanced liver disease and prognosis of many liver diseases is determined by degree and severity of fibrosis, which, if left untreated, may progress to cirrhosis. Liver biopsy has long been the standard for assessment of fibrosis; however it is expensive, invasive, and requires expert evaluation. Given these limitations, non-invasive tests (NITs) are frequently used due to their non-invasive properties, relatively cheaper cost, and repeatability, which allows for closer monitoring of changes in liver disease progression. In this paper, we review recent clinical practice guidelines to determine the differences, if any, between the recommendations regarding use of NITs.

INTRODUCTION

As the incidence of liver disease continues to increase in the Unites States,1 increasing interest has turned to the evaluation of liver disease severity and progression, with a special emphasis placed on fibrosis development and progression. The development of fibrosis marks worsening of advanced chronic liver disease (ACLD) and prognostication depends on determining the degree and severity of cirrhosis. Liver biopsy has long been the standard for assessment of fibrosis, however it is expensive, invasive, can lead to serious complications and must be evaluated by experts to provide information.2,3 Given these limitations, non- invasive tests (NITs) have become the subject of increased scrutiny for their non-invasive properties, relatively cheaper cost, and repeatability- allowing for closer monitoring of changes in fibrosis and liver disease progression.4 In this paper, we review recent clinical practice guidelines to determine the differences, if any, between the recommendations regarding use of NITs.

Non-Invasive Tests

As previously mentioned, NITs are repeatable, cheaper, and able to be performed by general practitioners. These characteristics make them more attractive as tools to be used to determine diagnosis and progression of liver fibrosis. Limitations of these tests, however, include: an inability to discriminate between stages of fibrosis, applicability across different etiologies of liver disease, and in some cases, overestimation of degree of fibrosis.4,5 All NITs can be divided into serum markers or imaging and elastography. Caution should be exercised when using these tests, as the context in which they were studied varies and may influence results.

Serum Markers

Serum markers that function as NITs include blood-based laboratory tests and serology-based scoring systems. These include, but are not limited to: aspartate aminotransferase (AST), alanine transaminase (ALT), platelets, international normalized ratio (INR), albumin, FibroTest (FT), the NAFLD Fibrosis Score (NFS), AST to Platelet Ratio Index (APRI), and Fibrosis-4 (FIB-4) score. These patented and non-patented serum tests and scoring systems have been found to have high applicability and reproducibility, however they can be influenced by extrahepatic causes and care should be taken to ensure that there are no confounding factors.6,7 For example, the FT has been widely validated, however it relies on bilirubin measurement and in the presence of hemolysis or cholestasis, may yield falsely elevated results.6

Imaging and Elastography

Imaging and elastography modalities include methods that assess liver stiffness and anatomy of the liver and adjacent structures. Liver stiffness measurement (LSM) can be obtained from a variety of modalities such as transient elastography (TE), point shear wave elastography (pSWE), bidimensional shear wave elastography (2D-SWE), and magnetic resonance elastography (MRE). A common measurement of fibrosis is kPa and values >15 kPa strongly suggestive of ACLD. However, cutoff values vary with different disease states (Table 1). Of these modalities, TE is the most used and most widely available.5,6 LSM, however, can be falsely elevated in the presence of inflammation, venous congestion, or recent food intake and, if possible, all confounding factors should be removed for accurate results. MRE is also routinely used, but expense, limited availability, presence of metal foreign devices all limit this modality. In a few studies, MRE and computerized tomography (CT) techniques were not accurate when used to diagnose initial stages of fibrosis.4,5 Of note, MRE values are approximately one-third the value of TE and readings >5.2kPa suggest the presence of ACLD.23

Applicability in Hepatitis C and B

With the advent of direct-acting antivirals (DAAs), more patients with Hepatitis C virus has overtaken viral hepatitis as an indication for liver transplant and cause of liver related death.24 Several scores, SteatoTestTM, the fatty liver index (FLI), the hepatic steatosis index (HSI), the lipid accumulations product, and the index of NASH and nonalcoholic fatty liver disease (NAFLD)

(HCV) are achieving sustained virological response (SVR),8 which results in a decrease in fibrosis. As post- SVR liver biopsies are not routinely performed, the importance of NITs to accurately assess fibrosis regression and stage fibrosis has become a topic of increasing interest. A meta-analysis showed a 28% median decline in LSM with TE from baseline to 6-12 months after SVR compared to non-SVR

patients.9,10 Other studies with paired liver biopsies have shown that LSM decrease is greater in patients with fibrosis regression, but the degree of LSM decrease does not predict fibrosis regression.11 Overall, the consensus appears to be that NITs are poor predictors of fibrosis regression after SVR6 and further studies are needed to validate their role in the monitoring of Hepatitis C patients. Serum markers for fibrosis are not routinely used in the presence of chronic Hepatitis B (CHB) infection, as multiple variables, including immune activity and inflammatory flare affect their reliability.12,13 Fibrotest was inaccurate in identification of severe fibrosis and APRI and Fib-4 do not reflect changes in fibrosis and have limited ability to accurately diagnose fibrosis in moderately advanced disease. TE has a strong prognostic role in CHB, but the correlation between improvement in fibrosis and LSM have yet to be studied.6

Applicability in NAFLD/ NASH

The diagnosis of nonalcoholic steatohepatitis (NASH) is important, as NASH is associated with increased liver fibrosis progression and liver fat score (NAFLD-LFS) have been proposed to diagnose steatosis.14 Although many of these have been independently validated, they were all designed and validated against different modalities15 and, thus, it is difficult to compare diagnostic performance. Quantification of steatosis with controlled attenuation parameter (CAP) is a potential point-of-care technique (which can be bundled with Fibroscan) that requires further study, as results are influenced by metabolic factors and type of probe used.6 CAP also performed poorly when compared to MRI-proton density fat fraction (MRI-PDFF).4 Although, European Association for the Study of the Liver (EASL) recommendations are that TE may be used to rule out advanced fibrosis, other reviews argue that TE thresholds require further validation in more heterogenous cohorts6 and the AGA review on elastography did not give specific recommendations on the TE LSM that would diagnose cirrhosis.16 None of the available imaging modalities can consistently determine when simple steatosis transforms into NASH. Thus, liver biopsy remains the gold standard for diagnosis of NASH, though it is infrequently used due to limitations of the procedure and highrisk status of the patients.5 However, despite the differences regarding diagnostic thresholds, the majority of TE are performed on NASH/NAFLD patients and many point of care studies are ongoing due to the increased benefits of frequent evaluation of fibrosis development.5

Applicability in Alcoholic Hepatitis

Alcoholic liver disease (ALD) is the leading cause of liver related morbidity and mortality worldwide and patients with alcoholic cirrhosis are diagnosed at later stages and die earlier than patient with liver disease from other etiologies.17  With this in mind, the implementation of NITs for early disease detection and lifestyle changes including alcohol cessation, improved nutrition, and sarcopenia modification, are attractive prospects. TE has been shown to have good diagnostic accuracy in significant and advanced fibrosis and has been proven superior to serum markers.6 In many studies, cut-off values for advanced cirrhosis range from 11.5 to 25.8 kPa and EASL recommends ruling out advanced fibrosis with TE values below 8-10 kPa.6,18 Fib-4 and Forn’s (age, total cholesterol, gamma-glutamyl transferase and platelet count) can also be used to rule out advanced fibrosis in lowprevalence populations and their affordability and easy accessibility make them attractive modalities. Lastly, use of NITs is not recommended in patients with suspected alcoholic hepatitis as only 3 studies have evaluated use of NITs in this disease and they vary in definition of alcoholic hepatitis and patient cohorts.19

Applicability in Cholestatic and Autoimmune Liver Disease

As with other liver diseases, progression of fibrosis is associated with poor prognosis. In primary biliary cholangitis (PBC), liver biopsy is no longer included in work up, except in specific circumstances, and LSM with TE and point shear wave elastography (pSWE) have shown promise in predicting advanced fibrosis.21 Serum biomarkers of liver fibrosis and non-invasive scores have limited ability to accurately differentiate between stages of fibrosis and thus, should not be used for fibrosis staging.21 pSWE, MRE, and spleen length measurement by ultrasound have all shown promising results in the diagnosis of significant and advanced fibrosis,6,21,22 but further studies are needed for validation. Primary sclerosing cholangitis (PSC) is progressive in nature and patients have unpredictable fluctuations in bilirubin due to cholangitis, stones, or strictures. This characteristic complicates prognostication with classic models, such as model for end-stage liver disease (MELD) score and Child-Pugh score.4 TE is the most commonly used, validated NIT, but care should be taken to exclude biliary obstruction as obstructive cholestasis is known to falsely elevate LSM.6

In autoimmune hepatitis (AIH), TE has been found to have superior performance to serum markers, including APRI and FIB-4 and is able to detect advanced fibrosis and cirrhosis.4 Hepatic inflammation is a known confounder that falsely elevates LSM and thus, liver aminotransferases should be taken into account when assessing LSM in patient with AIH.6,20

In PBC, PSC, and AIH, TE is the best NIT in terms of diagnostic and prognostic ability, performance, and validation.6

CONCLUSION

All NITs, both serum markers and imaging elastography, are able to more accurately diagnose cirrhosis and less able to differentiate between stages of fibrosis leading to cirrhosis. The accuracy of the various tests depends on the patient population and etiology of the fibrosis. While these tests are inexpensive and generally available to most practitioners, care should be taken to ensure that they are being used in the appropriate context and that confounding factors are not affecting results.

References

  1. Scaglione S, Kliethermes S, Cao G, et al. The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol. 2015;49(8):690-696.
  2. Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449-1457.
  3. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044.
  4. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update. J Hepatol. 2021;75(3):659689.
  5. Castera L. Non-invasive tests for liver fibrosis in NAFLD: Creating pathways between primary healthcare and liver clinics. Liver Int. 2020;40 Suppl 1:77-81.
  6. Patel K, Sebastiani G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Rep. 2020;2(2):100067. Published 2020 Jan 20.
  7. Fraser JR, Gibson PR. Mechanisms by which food intake elevates circulating levels of hyaluronan in humans. J Intern Med. 2005;258(5):460-466.
  8. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol. 2020;73(5):1170-1218.
  9. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients with Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(1):27-38.e4.
  10. Persico M, Rosato V, Aglitti A, et al. Sustained virological response by direct antiviral agents in HCV leads to an early and significant improvement of liver fibrosis. Antivir Ther. 2018;23(2):129-138.
  11. Mauro E, Crespo G, Montironi C, et al. Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C. Hepatology. 2018;67(5):1683-1694.
  12. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-283.
  13. Salkic, N., Jovanovic, P., Hauser, G. and Brcic, M., 2014. FibroTest/Fibrosure for Significant Liver Fibrosis and Cirrhosis in Chronic Hepatitis B: A Meta-Analysis. American Journal of
    Gastroenterology, 109(6), pp.796-809.
  14. Stern C, Castera L. Non-invasive diagnosis of hepatic steatosis. Hepatol Int. 2017;11(1):70-78.
  15. Poynard T, Lassailly G, Diaz E, et al. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS One. 2012;7(3):e30325.
  16. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute Technical Review on the Role of Elastography in Chronic Liver Diseases. Gastroenterology. 2017;152(6):1544-1577.
  17. Kim D, Adejumo AC, Yoo ER, et al. Trends in Mortality from Extrahepatic Complications in Patients with Chronic Liver Disease, From 2007 Through 2017. Gastroenterology. 2019;157(4):10551066.e11.
  18. Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021;74(5):1109-1116.
  19. Bissonnette J, Altamirano J, Devue C, et al. A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis. Hepatology. 2017;66(2):555-563.
  20. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172.
  21. Park DW, Lee YJ, Chang W, et al. Diagnostic performance of a point shear wave elastography (pSWE) for hepatic fibrosis in patients with autoimmune liver disease. PLoS One. 2019;14(3):e0212771.
  22. Osman KT, Maselli DB, Idilman IS, et al. Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated with Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients with Primary Biliary Cholangitis. J Clin Gastroenterol. 2021;55(5):449457.
  23. Asrani SK. Noninvasive diagnosis of liver fibrosis in adults. Clin Liver Dis (Hoboken). 2017;9(5):121-124. Published 2017 May 26. doi:10.1002/cld.632
  24. Shetty A, Giron F, Divatia MK, Ahmad MI, Kodali S, Victor D. Nonalcoholic Fatty Liver Disease after Liver Transplant. J Clin Transl Hepatol. 2021;9(3):428-435. doi:10.14218/JCTH.2020.00072
  25. Tapper EB, Lok AS. Use of Liver Imaging and Biopsy in Clinical Practice. N Engl J Med. 2017;377(8):756768. doi:10.1056/NEJMra1610570

Download Tables, Images & References

A SPECIAL ARTICLE

Update in Cyclical Vomiting Syndrome

July 2022 • Volume XLVI, Issue 7
Bedoor Alabbas,Kerian Dodds,Marie L. Borum,Joyce M. Koh,David B. Doman

Read Article

Cyclical vomiting syndrome (CVS) is a functional idiopathic gastrointestinal disorder characterized by recurrent episodes of severe emesis with periods of remission in between. Since initially termed in 2004, experts continue to try to define the disorder although it is still poorly understood in terms of pathophysiology. Diagnostic evaluation for underlying GI disorder is negative. Treatment has centered around disease recognition including: antiemetics, management coexistent migraine, and cognitive behavioral therapy. Emerging research has investigated the gut axis and neural pathways that may lead to future therapeutic opportunities.

INTRODUCTION

Cyclical vomiting syndrome (CVS) was first described in 1882. Previously thought to only occur in children, CVS has subsequently been described in all age groups. A recent population- based study shows CVS is prevalent in 2% of adults in America.1 Cyclical vomiting syndrome can be misrecognized and is probably underdiagnosed causing significant impact on health and quality of life leading to multiple emergency visits and increasing morbidity. Comorbidities such as migraines, trauma, or functional syndromes may help aid in the diagnosis. This paper will review new CVS insights pathophysiology, diagnostic evaluation, and therapeutic opportunities.

Pathophysiology

The pathophysiologic process of CVS is unclear. Current theories center around multiple functional disorders involving the brain-gut pathways with central and peripheral nervous system manifestations.2 Several mechanisms have been implicated in the development of CVS. In a study using functional brain MRI, the author concluded that although CVS patients had increased connectivity between salience network and mid/ posterior insult, CVS and migraine patients displayed close similarities with diminished insular connectivity with the sensorimotor cortex compared to healthy controls.22

Neuroendocrine Dysfunctions

It is hypothesized that activation of the hypothalamic-pituitary-adrenal axis (HPA) as a result of psychological or physical stress leads to the release of corticotropin-releasing factor (CRF). The release of CRF stimulates the inhibitory motor nerves in the dorsal motor nucleus of the vagus resulting in delayed gastric emptying. Elevated levels of adrenocorticotropic hormone (ACTH), antidiuretic hormone, cortisol, prostaglandin E2, antidiuretic hormone, cortisol, prostaglandin E2, and serum and urinary catecholamines during episodes of CVS was also described by Sato and associates.19

Autonomic Dysfunction

Autonomic mediated symptoms such as pallor, flushing, drooling, diarrhea, and dysmotility are common during episodes of CVS. Role of autonomic dysfunction in the pathophysiology CVS has been studied in the literature. It was suggested that patients with CVS have impairment of the sympathetic nervous system with intact parasympathetic nerve function.16 Rapid gastric emptying at baseline, which may be related to autonomic dysfunction, and delayed gastric emptying during episodes have been demonstrated in adults with CVS.20

Mitochondrial Dysfunction

The maternal inheritance of both migraine and CVS suggest mitochondrial dysfunction. CVS was linked to maternal mitochondrial dysfunction in the pediatric population such as mitochondrial DNA (mtDNA) polymorphisms: 16519T, 3010A.17 However, the significance of these single nucleotide polymorphisms (SNPs) remains unclear. These mitochondrial associations have not been identified in adults with CVS suggesting other genetic factors in adults. Mitochondrial dysfunction is exacerbated by cellular energy depletion during stressors such as fasting, anxiety and illnesses. This again suggests association between CVS and migraine.

Clinical Presentation

Manifestations usually begin in adolescence however they can persist into adulthood complicating care as well. The hallmark of this disease is recurrence of nausea and vomiting cycles with complete resolution between episodes. Exam findings are nonspecific but often showed signs of dehydration such as dry mucous membranes, tachycardia, and poorly localized abdominal tenderness.

The Rome committee redefined CVS in 2016 as episodes of vomiting with at least two acute episodes over a six-month period and these episodes must occur at least one week apart but last no longer than one week. CVS has been shown to have four phases.8 Beginning with the well phase in which patients are at baseline health without symptoms of nausea or vomiting. Followed by a prodromal phase lasting minutes to hours. It is characterized by nausea, fatigue, insomnia, change in temperature, diaphoresis and abdominal pain. The acute emetic phase follows with severe nausea and vomiting persisting even after evacuation of all stomach contents. Abdominal pain is present in up to 71% of adults.12 Many patients also experience classic migraine headache with photophobia and phonophobia. A recovery phase during which the patient returns to normal health without nausea occurs at varying lengths of time after the episode either occurring immediately in some patients while others struggle to recover over a period of hours or days.

Several physical and psychological stressors are known to precipitate episodes such as emotional events, lack of sleep, physical exhaustion, dietary triggers (e.g., caffeine intake) and menstrual cycle in women.

Diagnostic Evaluation

No specific diagnostic test exists to diagnose cyclic vomiting syndrome but rather it remains a diagnosis of exclusion. Diagnosing CVS can be challenging due to the clinical overlap with conditions. The differential diagnosis is broad and includes gastroparesis, biliary disease, Crohn’s disease, intestinal pseudo-obstruction, mechanical obstruction, mitochondrial disease, eating disorder or other nervous system diseases. Due to this clinical overlap, these patients often undergo extensive negative workups with various providers over the course of many years. Patients presenting during the CVS “well phase” can be burdened by multiple and exhaustive evaluations given their seemingly healthy state during physician evaluations. Workup usually includes normal imaging of the abdomen and head, blood work, gastric emptying studies and even endoscopy.

Comorbidities

Cyclic vomiting syndrome shares many similarities with neurological disease such as migraines. In fact, a personal or family history of migraines can be a leading factor in determining the diagnosis. Relationships between migraine disorders, menses, autonomic dysfunction and mitochondrial diseases are shown but not fully understood. These disorders have been established and treatments could be linked to potential therapies for CVS as well.

Migraines

Either a personal or family history of migraine has been shown to have a strong correlation with cyclic vomiting syndrome. Episodic syndromes such as functional dyspepsia, irritable bowel syndrome, or chronic/functional abdominal pain syndromes have been associated with migraine disorders. In fact, in 1922 the first associated “Abdominal Migraine” was termed in children who were observed with episodic gastrointestinal upset that later developed migraine headaches.9 Abdominal migraine is another disorder that shares in episodic gastrointestinal pain that is poorly localized as well as nausea and vomiting. However, this differs from cyclic vomiting in that there is less of a predominance of nausea and vomiting and more of a diagnosis that focuses on abdominal pain that persists after thorough clinical evaluation.

Mental Health Conditions

Anxiety, depression, and panic are mental health conditions that can plague patients with CVS. Anxiety is the most common mental health disorder that accompanies CVS. Studies differ in the prevalence of the disease, but some have estimated as much as 84% of those affected by CVS suffer from anxiety.13,14 Anxiety can be centered around anticipation of another event and exacerbated by an unclear diagnosis.

Cannabinoid Hyperemesis Syndrome

Cyclic vomiting syndrome can be mistaken with the similar symptoms seen in cannabinoid hyperemesis syndrome (CHS). Cannabis is often used for nausea, pain control, and control of seizures given it’s sedative effects. Legalization has increased cannabis use worldwide with the advent and steady incline in cannabis use disorders, including cannabinoid hyperemesis syndrome. In a 2015 study by emergency medicine physicians in New York, one third of patients with regular cannabis use, defined as 20 days out of a month, met the criteria for CHS.6 However, chemicals in cannabis such as THC have been proposed to have irritative effects on the gastrointestinal tract. A greater percentage of THC has been found in recreational cannabis and therefore hypothesized to cause a link between the two.23 Cannabinoid hyperemesis syndrome is defined by the Rome IV criteria as chronic cannabis use followed by intractable emesis episodes similar to CVS. There is increasing overlap between cyclical vomiting syndrome as well as cannabinoid hyperemesis syndrome. However, as the name suggests, cannabinoid hyperemesis syndrome is characterized by the significant use of cannabis prior to episodes of nausea and vomiting. While cannabis may be beneficial in the nausea of cyclic vomiting syndrome, it is known to instigate an episode in cannabinoid hyperemesis syndrome.24 The two differ slightly in that termination of hyperemesis syndrome in CHS is achieved with the cessation of cannabis use. Patients have also been shown to have relief with “hot bathing” with frequent hot baths or showers.5 The reason for this CHS relief is unclear. Interestingly, patients with CVS get similar relief with hot showers.

Treatment

Recommendations for treatment of CVS are limited given no placebo-controlled study has yet to examine any preventative or acute treatment measures. However, case studies have shown that lifestyle modification should be of prime consideration. A study in Ireland came to an interesting conclusion as well: when pediatric patients were diagnosed with CVS, the majority of patients’ utilization of medical services started to decline, thought to be a direct indication of proper diagnosis and education of disease and triggers.10 This further emphasizes the necessity of a team based approach no matter the age of the patient with both primary treatment team, emergency treatment team, and patient working together to developed a treatment plan.

Most patients report reaching for a heating pad, hot shower, or quiet place as a first line treatment in treating an attack.14 This compulsive bathing is a key treatment noted in cannabinoid hyperemesis as noted above.

CVS has been shown to be a disorder of the brain-gut axis as discussed above. Events that induce stress such as infection or menses (known as catamenial cyclic vomiting syndrome) have been shown to precipitate an event. Therefore, focusing on lowering the level of stress and identifying potential psychosocial triggers has been shown to be beneficial in patients with CVS.

Migraine and CVS Overlap

Therapy used for preventing or aborting migraines may be used for CVS given the overlap. Migraine triggers may be involved in CVS as well, therefore avoiding them may be beneficial to patients. Foods such as alcohol, chocolate, milk, cheese, and caffeine have been shown to predispose patients to migraines and functional disorders.21 Avoidance of such foods may not work for everyone but should be discussed with patients as first line therapy for the disorder.

Nonspecific treatments for migraine such as nonsteroidal anti-inflammatory drugs (NSAIDS) ironically may be useful providing symptomatic CVS relief. Nonselective beta blockers (e.g., propranolol) useful to prevent migraine headache may also have a role in preventing frequent CVS episodes. In certain countries, a combination of metoclopramide and paracetamol is used for migraines that are accompanied by nausea and vomiting. The most popular class of migraine abortive and preventative medication is known as the triptans. These are vasoconstrictors that largely replaced the ergot class as the most highly effective medications for migraines and have been shown to be effective in CVS.

Guidelines for Treatments of CVS

The American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association published guidelines outlining the distinction between mild versus moderate or severe episodes. These distinctions help further guide proposed management of disease. A moderate or severe disorder was characterized by the occurrence of equal or greater than four episodes a year, lasting over two days, with a long recovery period, as well as requiring emergency medical care or hospitalization. With this distinction, moderate or severe disease was proposed to be treated

with preventative medications such as a tricyclic antidepressant/topiramate or CoQ10. Treatment with abortive medications in acute episodes was proposed with all disease phenotypes.11 Aprepitant is a substance P/neurokinin 1 receptor (NK1) antagonist. Although lacking extensive study due to its relative new emergence in 2003, aprepitant has been shown to be beneficial in chemotherapy induced nausea and post operative nausea and vomiting. Due to these advances, The American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association recommend its use as a second line prophylactic agent when tricyclic antidepressants (TCA) or topiramate has failed to show improvement in moderate to severe CVS.11

In any acute episode either managed at home or with the care of medical services, adequate fluid resuscitation is of utmost importance. Additionally, antiemetics such as promethazine or zofran may be applicable based on the patient’s underlying comorbidities. In small case series and retrospective trials, medications such as nasal sumatriptan, amitriptyline, riboflavin, and aprepitant (a neurokinin-1 antagonist) have been shown to have partial or complete resolution of symptoms in pediatric patients.9

CONCLUSION

Cyclic vomiting syndrome (CVS) has been historically underdiagnosed, leading to patient physical and psychological stress. This lack of clinical insight has led to a burden on the health care system in the US with cost estimated to be up to $200 million annually.18  The future, however, is bright due to growing clinician CVS awareness and earlier diagnosis. Once CVS is diagnosed targeted therapy can be prescribed. In addition, new insights in the CVS risk polymorphisms cannabinoid hyperemesis syndrome overlap, and ongoing brain gut axis research may lead to new, novel therapeutic opportunities.

References

  1. Aziz I, Palsson OS, Whitehead WE, Sperber AD, Simren M, Törnblom H. Epidemiology, Clinical Characteristics, and Associations for Rome IV Functional Nausea and Vomiting Disorders in Adults. Clin Gastroenterol Hepatol 2018. Large, cross sectional health survey from U.S., Canada and United Kingdom documenting a 2% prevalence of adult CVS in the U.S.
  2. Sunku, Bhanu. “Cyclic Vomiting Syndrome: A Disorder of All Ages.” Gastroenterology & Hepatology vol. 5,7 (2009): 507–515.
  3. Hayes, William J et al. “Cyclic vomiting syndrome: diagnostic approach and current management strategies.” Clinical and experimental gastroenterology vol. 11 77-84. 26 Feb. 2018, doi:10.2147/CEG.S136420
  4. Galli, Jonathan A et al. “Cannabinoid hyperemesis syndrome.” Current drug abuse reviews vol. 4,4 (2011): 241-9. doi:10.2174/1874473711104040241
  5. Venkatesan, Thangam et al. “Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome.” Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society vol. 31 Suppl 2,Suppl 2 (2019): e13606. doi:10.1111/nmo.13606
  6. Habboushe J, Rubin A, Liu H, Hoffman RS. The Prevalence of Cannabinoid Hyperemesis Syndrome Among Regular Marijuana Smokers in an Urban Public Hospital. Basic Clin Pharmacol Toxicol. 2018 Jun;122(6):660-662. doi: 10.1111/bcpt.12962. Epub 2018 Feb 23. PMID: 29327809.
  7. Hasler, WL, Levinthal, DJ, Tarbell, SE, et al. Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions. Neurogastroenterol Motil. 2019; 31(Suppl. 2):e13607. https://doi.org/10.1111/ nmo.13607
  8. Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic vomiting syndrome in 41 adults: the illness, the patients, and prob- lems of management. BMC Med. 2005;31:20.
  9. Irwin, S., Barmherzig, R. & Gelfand, A. Recurrent Gastrointestinal Disturbance: Abdominal Migraine and Cyclic Vomiting Syndrome. Curr Neurol Neurosci Rep 17, 21 (2017). https://doi.org/10.1007/s11910-017-0731-4
  10. Drumm, B.R., Bourke, B., Drummond, J., Mcnicholas, F., Quinn, S., Broderick, A., Taaffe, S., Twomey, J. and Rowland, M. (2012), Cyclical vomiting syndrome in children: a prospective study. Neurogastroenterolog & Motility, 24: 922-927. doi:10.1111/j.1365-2982.2012.01960.x
  11. Venkatesan, T, Levinthal, DJ, Tarbell, SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association. Neurogastroenterol Motil. 2019; 31(Suppl. 2):e13604. https://doi.org/10.1111/nmo.13604
  12. Abell TL, Adams KA, Boles RG et al (2008) Cyclic vomiting syndrome in adults. Neurogastroenterol Motil 20:269–284
  13. Bhandari S, Venkatesan T. Clinical Characteristics, Comorbidities and Hospital Outcomes in Hospitalizations with Cyclic Vomiting Syndrome: A Nationwide Analysis. Dig Dis Sci. 2017 Aug;62(8):2035-2044. doi: 10.1007/ s10620-016-4432-7. Epub 2017 Jan 3. PMID: 28050780.
  14. Namin F, Patel J, Lin Z, Sarosiek I, Foran P, Esmaeili P, McCallum R. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy. Neurogastroenterol Motil. 2007 Mar;19(3):196-202. doi: 10.1111/j.13652982.2006.00867.x. PMID: 17300289.
  15. Taché Y. Cyclic vomiting syndrome: the corticotropinreleasing-factor hypothesis. Dig Dis Sci. 1999 Aug;44(8 Suppl):79S-86S. PMID: 10490044.
  16. Venkatesan T, Prieto T, Barboi A, Li B, Schroeder A, Hogan W, Ananthakrishnan A, Jaradeh S. Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study. Neurogastroenterol Motil. 2010 Dec;22(12):1303-7, e339. doi: 10.1111/j.13652982.2010.01577.x. PMID: 20667005.
  17. Wang Q, Ito M, Adams K, Li BU, Klopstock T, Maslim A, Higashimoto T, Herzog J, Boles RG. Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome. Am J Med Genet A. 2004 Nov 15;131(1):50-8. doi: 10.1002/ajmg.a.30323. PMID: 15368478.
  18. Bhandari S, Venkatesan T. Clinical characteristics, comorbidities and hospital outcomes in hospitalizations with cyclic vomiting syndrome: a nationwide analysis. Dig Dis Sci. 2017;62:2035-2044Bhandari S, Venkatesan T. Clinical characteristics, comorbidities and hospital outcomes in hospitalizations with cyclic vomiting syndrome: a nationwide analysis. Dig Dis Sci. 2017;62:2035-2044
  19. Sato T, Igarashi M, Minami S, Okabe T, Hashimoto H, et al. Recurrent attacks of vomiting, hypertension, and psychotic depression: a syndrome of periodic catecholamine and prostaglandin discharge. Acta Endocrinol. 1988;117:189–197
  20. Autonomic abnormalities in cyclic vomiting syndrome. Chelimsky TC, Chelimsky GG.J Pediatr Gastroenterol Nutr. 2007 Mar; 44(3):326-30 Hindiyeh, N.A., Zhang, N., Farrar, M., Banerjee, P., Lombard, L. and Aurora, S.K. (2020), The Role of Diet and Nutrition in Migraine Triggers and Treatment: A Systematic Literature Review. Headache: The Journal of Head and Face Pain, 60: 1300-1316. https://doi. org/10.1111/head.13836
  21. Ellingsen DM, Garcia RG, Lee J, Lin RL, Kim J, Thurler AH, Castel S, Dimisko L, Rosen BR, Hadjikhani N, Kuo B, Napadow V. Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: A cross-comparison with migraine and healthy adults. Neurogastroenterol Motil. 2017 Jun;29(6):10.1111/nmo.13004. doi: 10.1111/nmo.13004. Epub 2016 Dec 1. PMID: 27910222; PMCID: PMC5423835.
  22. Siddiqui, MT, Bilal, M, Singh, A, et al. Prevalence of cannabis use has significantly increased in patients with cyclic vomiting syndrome. Neurogastroenterol Motil. 2020; 32:e13806. https://doi.org/10.1111/ nmo.13806
  23. Rosen, S., Diaz, R., Garacci, Z. et al. Hot-Water Bathing Improves Symptoms in Patients with Cyclic Vomiting Syndrome and Is Modulated by Chronic Cannabis Use. Dig Dis Sci (2020). https://doi.org/10.1007/s10620-02006343-x

Download Tables, Images & References

FROM THE PEDIATRIC LITERATURE

From the Pediatric Literature

July 2022 • Volume XLVI, Issue 7

Read Article

The Placebo Effect and Pediatric Functional Abdominal Pain

The placebo effect is a well-described phenomenon in medicine, and the possibility of open-label placebo use has been studied for disorders involving brain-gut interaction (DBGI). The authors of this study evaluated the use of open-label placebo for pediatric DBGI, specifically children with functional abdominal pain and irritable bowel syndrome defined using Rome III criteria. Children (8-18 years old) with functional abdominal pain/ irritable bowel syndrome were recruited from two tertiary children’s hospitals in the United States in a prospective crossover randomized clinical trial, and every study subject had normal laboratory testing, including a negative lactose breath test (or no clinical response to a lactose free diet). Each patient was given an explanation of the placebo effect in the setting of the brain-gut axis before starting a 7-day observational study in which they recorded their abdominal pain using a visual analog scale (0 mm to 100 mm pain score). If a patient had a mean daily pain score of 25 mms or higher, they were randomized into 2 groups. One group (the control group) filled out an initial questionnaire, was given a daily symptom diary, and was given a rescue medicine as needed for abdominal pain (hyoscyamine). The other group (the open-label placebo group) took a placebo (85% sucrose) immediately in the office setting followed by an initial questionnaire, a daily symptom diary, and a rescue medicine (again, hyoscyamine) as needed for abdominal pain. After 3 weeks, these patient groups were crossed over, and after another 3 weeks, the study concluded, and questionnaires were returned. A total of 30 patients out of the 31 patients enrolled were able to complete the study. Both study groups had significantly improved mean pain scores when participating in the open-label placebo arm compared to the control arm (39.9 [18.9] vs. 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03); and in total, 70% of patients had lower pain scores while participating in the open-label placebo arm. Additionally, study subjects took significantly more hyoscyamine while participating in the control group compared to the open-label placebo group (P = 0.001). Global improvement (based on the question,

“Overall, how do you feel your problem is (better, same, or worse)?”) was not significantly different between groups. There was a significantly greater belief in the patient group receiving the open-label placebo (based on the pre-randomization question, “How well do you think the treatment will work (excellent, good, fair, poor, or not at all)?”) that the placebo would be beneficial (P=0.045).

In summary, children with functional abdominal pain/irritable bowel syndrome may have a significant response to an open-placebo intervention and understanding this concept in the setting of DBGI should be a caution for the practitioner to avoid unnecessary testing and medication in such a setting. More research is needed in understanding the neural mechanisms between the brain and intestinal tract.

Nurko S, Saps M, Kossowsky J, Zion S, Di Lorenzo C, Vaz K, Hawthorne K, Wu R, Ciciora S, Rosen J, Kaptchuk T, Kelley J.  Effect of open-label placebo on children and adolescents with functional abdominal pain or irritable bowel syndrome: a randomized clinical trial.  JAMA Pediatrics 2022; 176: 349-356.

Endoscopic Gastrojejunal Tube Placement in Children

In some children, direct gastric feeding is unsafe, and in such a scenario, gastrojejunal tube (GJT) placement subsequently can be performed through an initial one-step procedure or via a pre-existing gastric button site to allow for direct access to both the stomach and small intestine. This retrospective study evaluated all children undergoing GJT over a 10-year period at a tertiary children’s hospital in France. Children with a pre-existing jejunostomy or nasoduodenal tube were excluded from this study. Patient demographics, including reason for GJT intervention, response to GJT placement, and GJT complications were included. Weight for height z-scores and weight for age z-scores were determined 1 month after GJT placement, 6 months after GJT placement, and at the time of weaning from jejunal feeding. A z-score less than -2 was defined as malnutrition. 

In total, 107 patients (48.6% female) who underwent GJT were included in the study. Median patient age was 10 months with 55% of patients being less than one year of age. The mean weight for height z-score was -1.0 ± 1.6, and the mean weight for age z-score was -2.6 ± 1.8. The main indication for GJT placement was gastroesophageal reflux disease; 95% of patients had at least one comorbidity. Patients who underwent an initial onestep GJT placement were significantly younger and had a significantly lower weight compared to patients who received GJT placement through a pre-existing gastrostomy site. Peri-procedure complications occurred in 8 patients with one of these patients developing a complication as a direct result GJT placement (pneumoperitoneum). A total of 85 patients (79%) experienced at least one minor post-procedural complication with the most common minor complications being tube breaking, tube dislodgement, and tube blockage. A total of 6 patients (5.6%) experienced a late complication including jejunal intussusception, intestinal perforation, and pneumoperitoneum. Major complications were significantly more likely to occur in children who were younger (< 12 months, P=0.03) and underweight (<6 kg, P=0.03).

The average number of GJT changes after placement was 2.1 ± 2.3 (range 0 – 10), and the median time that a GJT remained in place was 70 days (range 1 – 558 days). GJT feeds were weaned in 87% of patients with most of these patients transitioning to some type of gastric tube feedings. Weight for age z-score significantly improved from -2.4 to -1.7 throughout the duration of GJT feeds (P<0.001) although the weight for height z-score did not significantly change through the duration of GJT feeds (P=0.2). 

Thus, the authors state that GJT placement is a feasible option for children with complex medical issues. Minor complications were frequent, but the weight for age z-scores improved over time and many patients were able to convert to other type of enteral feeds. We need more research comparing this type of feeding access to patients receiving feeds via direct jejunostomy or fundoplication. 

Elmehdi S, Ley D, Aumar M, Coopman S, Guimber D, Nicolas A, Antoine M, Turck D, Kyheng M, Gottrand F. Endoscopic gastrojejunostomy in infants and children. Journal of Pediatrics 2022; 244: 115-119.

Download Tables, Images & References

Jojobet GirişjojobetmeritbetcasibomCasibom girişcasibomromabetJojobet GirişcasibomcasibomcasibomjojobetMadridbetMadridbetcasibom giriştaraftarium24justin tvbetgaranti girişganobetpokerklasjojobetjojobetromabetMarsbahis GüncelCasibommatbetJojobetGrandPashaBet destekDeneme bonusu veren siteler 2026GrandPashaBet Şikayetjojobet girişholiganbetCasibom GirişJojobet GirişJojobet Giriş