Acute pancreatitis is most commonly associated with gallstone disease, chronic alcohol use or hypertriglyceridemia while metabolic abnormalities such as hypercalcemia are far less frequent.1 Hypercalcemia accounts for only about 1% of acute pancreatitis cases, making it a cause that is not typically encountered in routine clinical practice.1 Among the causes of hypercalcemia-induced pancreatitis (HIP), primary hyperparathyroidism is the most common and accounts for approximately 90% of all hypercalcemia cases.3
Other causes of hypercalcemia include malignancy, particularly lung cancer, breast cancer, and multiple myeloma, granulomatous diseases (tuberculosis and sarcoidosis), vitamin A or D toxicity, hypothyroidism and medications like thiazide diuretics, lithium, and antacids.2,3
An under-recognized cause of hypercalcemia is chalk ingestion, which often occurs in the setting of pica. Chalk is primarily composed of calcium carbonate and can become a substantial calcium source for individuals who consume it regularly.5 This behavior can raise serum calcium to harmful levels, leading to metabolic disturbances and in this case, hypercalcemia-induced pancreatitis.
Case Presentation
A 52-year-old African American female with past medical conditions of hypothyroidism and newly diagnosed insulin-dependent type 2 diabetes mellitus, presented to the emergency department after a witnessed fall and several days of worsening fatigue and confusion. According to her family, she had been complaining of abdominal pain over the past two days. Additionally, the patient had been experiencing increased urinary frequency.
Her exam was notable for pale appearance and disorientation. The remainder of the physical examination was notable for diffuse abdominal tenderness with guarding. Her vital signs included a blood pressure of 90/60 mmHg, heart rate of 120 beats-per-minute, afebrile and oxygen saturation of 97% on room air.
Initial laboratory evaluation revealed serum calcium was markedly elevated at 25.4 mg/dL with an ionized calcium of 2.48 mmol/L. Additional findings included an albumin of 3.9 g/dL and an elevated lactate of 3.2 mmol/L. Her lipase was markedly elevated at 1,739U/L. Her liver enzymes, lipid panel and ethanol level were in normal range.
Computed tomography (CT) imaging of the abdomen and pelvis with contrast demonstrated acute interstitial pancreatitis without gallstones or biliary dilation [Imaging 1 & 2]. Additionally, large heterogeneous pelvic mass, suggestive of a uterine leiomyoma, was noted.
She was admitted to the intensive care unit for management of hypercalcemic crisis. The patient received empiric antibiotics, intravenous fluids and underwent two sessions of emergent hemodialysis. Patient’s hypercalcemia improved with hemodialysis and intravenous fluid, without the need for bisphosphonates, or calcitonin. Her calcium levels normalized from 25.4 to 9.4 mg/dL, accompanied by a gradual recovery in mental status. Serum calcium levels normalized within approximately 48 hours of initiating treatment. The patient’s pancreatitis gradually improved as she was able to tolerate oral intake.
A comprehensive metabolic evaluation demonstrated a suppressed PTH level (5.9 pg/mL) while phosphate, PTHrP, 25-hydroxy vitamin D, and 1,25-dihydroxy vitamin D were within normal limits. Serum and urine electrophoresis, serum free light chains, TSH, lithium, vitamin A level, and urine calcium were all unremarkable. Hematologic studies revealed microcytic anemia with hemoglobin level of 9 g/dl, MCV of 63 fL, low iron (8 µg/dL), a TIBC of 281 µg/dL, ferritin of 37.2 ng/mL, a reticulocyte count of 1.5%, and a peripheral smear showing microcytic, hypochromic red blood cells.
After resolution of her symptoms, the patient denied the use of diuretics, lithium, antacids, vitamin and calcium supplements. Her workup revealed no identifiable cause of hypercalcemia, raising concern about the source of her severe calcium elevation. It was only later in her hospitalization, when we specifically asked about her dietary habits, that she disclosed regularly consuming powdered chalk for almost three months. She consumed two bags of chalk (approximately four kilograms per day). She had not previously disclosed this due to embarrassment and a belief that the behavior was harmless to her health.
She received intravenous iron and was discharged on oral iron supplementation. She was evaluated by gynecology, and the uterine leiomyoma was removed. At an outpatient follow-up six weeks later, serum calcium (8.9 mg/dl) and hematologic studies returned to normal, and her chalk-ingestion behavior fully resolved.
Discussion
Hypercalcemia is an uncommon but recognized trigger of acute pancreatitis, accounting for approximately 1–2% of cases. Most HIP are attributed to primary hyperparathyroidism or malignancy-associated hypercalcemia.1 Literature on exogenous calcium leading to pancreatitis is extremely limited, with chalk ingestion described only in isolated cases. Hypercalcemia can precipitate pancreatitis by increasing intracellular calcium levels within pancreatic acinar cells, triggering premature trypsinogen activation and leads to autodigestion and inflammation.2
HIP is infrequently encountered, but hospitalist and gastroenterology management is pivotal for acute care and recurrence prevention. Priorities include confirming pancreatitis, excluding common pancreatitis etiologies, initiating lactated ringer’s-based resuscitation with adequate analgesia, and starting early enteral nutrition; contrast-enhanced CT is reserved for diagnostic uncertainty or lack of improvement after 48–72 hours, and ERCP is performed only for biliary indications. Close monitoring of electrolytes, with recognition that fat saponification can lead to secondary hypocalcemia as inflammation evolves. Preventing another episode requires addressing the underlying cause of hypercalcemia through a multidisciplinary approach, while counseling patients to avoid hidden or non-nutritive calcium sources.
Pica is often underreported and maybe normalized by patients who have engaged in the behavior for years. Although geophagia is a recognized form of pica in the DSM-5, psychiatric consultation was not obtained during this hospitalization. An additional consideration, in Central Georgia, kaolin (a form of chalk) is sometimes consumed as part of a cultural practice, particularly among African American women.6 However, both the patient and her family denied any cultural or personal use of kaolin or similar substances.
The current diagnostic algorithm for hypercalcemia begins by confirming elevated calcium levels and reviewing medications and supplements, including thiazide diuretics, lithium, vitamin D, vitamin A, calcium-containing antacids, and other over-the-counter products. Once hypercalcemia is established, intact PTH is measured to distinguish PTH-mediated from non–PTH-mediated causes. Elevated or inappropriately normal PTH levels suggest primary hyperparathyroidism or familial hypocalciuric hypercalcemia, while low PTH levels prompt evaluation for malignancy, granulomatous disease, vitamin D intoxication, and monoclonal gammopathies through testing such as PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, SPEP, UPEP, and serum free light chains. Although this algorithm captures the major etiologic categories, it does not include assessment of dietary or non-traditional calcium exposures.
Our case demonstrates that ingestion of calcium-rich substances, including chalk or culturally rooted forms of kaolin, can lead to significant hypercalcemia and may remain unrecognized without targeted questioning. Adding a step that evaluates dietary practices, cultural ingestion behaviors, and non-nutritive substances could improve detection of these overlooked causes and enhance diagnostic accuracy.
Pica is managed through a combination of education, nutritional counseling, and behavioral strategies implemented by an interdisciplinary team that may include physicians, nursing staff, psychologists, social workers, dietitians, and family members. Patients and families are taught to focus on understanding the behavior and adopt safer alternative coping skills.7
Conclusion
This case illustrates the importance of considering nontraditional and dietary sources of calcium in the evaluation of severe hypercalcemia and hypercalcemia-induced pancreatitis. Uncommon etiologies such as chalk ingestion can be easily overlooked without targeted questioning, particularly when the clinical picture remains unexplained after routine evaluation. Adding this step to clinical algorithms may facilitate earlier recognition of atypical causes, prevent delayed diagnosis, and improve patient outcomes.
References
1. G, Kui B, Hegyi P, et al. Hypercalcemia Causes More Severe Acute Pancreatitis: An International Multicenter Cohort Study. Journal of Clinical Medicine. 2025;14(17):6304. doi:10.3390/jcm14176304.
2. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67(9):1959–1966. PMID:12751656
3. Walker MD, Shane E. Hypercalcemia: A Review. JAMA. 2022;328(16):1624-1636. doi:10.1001/jama.2022.18331.
4. Danese A, Lippi G. Milk-alkali syndrome: a systematic review. Clin Cases Miner Bone Metab. 2012;9(3):122–125. PMID: 23269887
5. National Library of Medicine. Calcium Carbonate. Nih.gov. Published 2019. https://pubchem.ncbi.nlm.nih.gov/compound/Calcium-carbonate
6. Grigsby RK, Thyer BA, Waller RJ, Johnston GA Jr. Chalk eating in middle Georgia: a culture-bound syndrome of pica? South Med J. 1999 Feb;92(2):190-2. doi: 10.1097/00007611-199902000-00005. PMID: 10071665.
7. Sayetta RB. Pica: an overview. Am Fam Physician. 1986; 33:181–185.
Musculoskeletal injuries are prevalent among healthcare workers. Proceduralists, such as gastroenterology (GI) endoscopists, require repetitive and often unnatural movements while maneuvering endoscopes and colonoscopes. The frequent stress and forces naturally lead to injuries and pain. Currently the one-size-fits-all endoscopes do not accommodate for the various hand sizes and body types of endoscopists. Proper ergonomics during procedures are recommended to both prevent and ameliorate endoscopy related injuries. The purpose of this article is to review the current literature on published studies and recommendations for gastroenterologists regarding ergonomics in endoscopy.
Injuries in Endoscopy
The most common sites of pain among endoscopists varied between studies. The most frequent sites of pain were low back, hand and wrist, fingers, neck, right shoulder, and left thumb. The left thumb is particularly exerted during both colonoscopy and ERCP, of note. In an electronic survey sent to 72 GI physicians and 104 non-GI physicians employed by Mayo Clinic, frequency of overall musculoskeletal (MSK) pain was not significant between the two groups, but frequency of pain in left thumb, hand, and wrist were significantly higher in the GI group.2 Endoscopists in practice less than 39 months experienced more left thumb and finger pain, while endoscopists practicing longer most commonly experienced left shoulder pain.1 In a Canadian survey of 133 physicians practicing ERCP in Ontario, 74% of endoscopists attributed their pain to procedure work, and yet only 18% of participants modified their work based on their pain or injuries.3
Injuries from endoscopy can be serious and debilitating. In a survey of 171 endoscopists of the Portuguese Society of Gastroenterology, missing work due to musculoskeletal injury was reported by 10.1% of respondents and 33.6% required a reduction in physical activity outside of work.
Risk Factors
The literature suggests a higher risk for injury in females compared to males, although studies seem to differ on statistical significance. This may be due to physical differences in hand sizes between males and females, as the endoscope is of constant size regardless of the user. (Figure 1) With the increasing number of women entering the field of gastroenterology, in 2020, Bhatt et al. distributed an electronic survey which sought to evaluate the subtle gender differences in endoscopy ergonomics. They found a statistically higher incidence of injury in females compared to males (p = 0.02) and a higher incidence of wrist pain in females compared to males (p = 0.02). This was the first study to show, with statistical significance, differences in injury by gender. It was attributed to disproportionately smaller hand/glove size, and lesser muscle mass and upper body strength compared to males. On the other hand, in a large electronic survey of 1,698 members of the American College of Gastroenterology, the authors found no significant differences in prevalence of endoscopy related injury in men compared to women (p = 0.77). The authors did find that females were more likely to have upper extremity and upper back pain.
During endoscopy, the proceduralist must often hold and repeat difficult movements again and again, frequently in awkward positions, alternately pinching, gripping, pushing, pulling, and torquing the endoscope and its accessories for the entirety of the procedure. Bhatt et al. also found that females, compared to their male counterparts, tended to hold the endoscope umbilical cord outside the forearm (p = 0.00), use the right hand to turn the small wheel (p = 0.03), and were more likely to use a pediatric colonoscope in smaller patients (p = 0.01). (Figure 2) This was likely attributed to females with smaller body and hand sizes needing to bear the weight and diameters of the endoscope and apply adequate force during the procedure. Regarding turning and stabilizing the endoscope shaft itself, they found no significant difference in technique between men and women (p = 0.26). To turn the scope, most endoscopists (94.5%) favored torquing or twisting the shaft. Other less frequently used techniques included turning the left forearm which holds the endoscope control head (47.4%), using the small wheel for left or right deflection (45.8%), and turning their entire body (41.1%). To stabilize the endoscope shaft, most endoscopists chose to either place the shaft on the bed (67.3%) or stabilize the shaft with their body (65.4%). Other less common techniques to stabilize the shaft included holding it between the fingers of the left hand (49.5%) and asking for assistance from a technician or nurse (28%).5
These maneuvers place significant strain on the endoscopist’s musculoskeletal system. Shergill et al. quantified this strain by measuring the thumb force and forearm muscle loads of the extensor carpi radialis and flexor digitorum superficialis during colonoscopy insertion versus withdrawal. Tactile thumb pads were used to measure thumb force and bilateral muscle electromyography (EMGs) were used to measure muscle loads. They evaluated 12 attending gastroenterologists from the University of California, San Francisco and found that forearm loads were significantly greater during insertion even though more time was spent during withdrawal (p <0.05). Highest thumb forces also occurred during colonoscopy insertion compared to withdrawal.
Injury may start as early as gastroenterology fellowship and becomes more likely over time. These early stages of training and introduction to endoscopy are crucial for learning proper posturing and techniques to reduce physical strain. In a study attempting to assess the prevalence of MSK injuries among GI fellows across the United States, 47% of 156 survey participants experienced new endoscopy-related MSK injury during fellowship and 85% occurred within the first 12 months. In a similar survey analyzing the prevalence of endoscopy-related overuse injuries in GI fellows (n = 165), 20% reported a musculoskeletal injury with female gender as the only factor associated with a higher rate of injury. These injuries may be subsequent results of improper positioning of the patient and/or the monitor, and/or improper endoscopic technique.
Working as an attending in a fellowship program may be a protective factor, as Bhatt et al. found that working with GI fellows decreased the risk of injury significantly, suggesting a decreased endoscopy workload may be beneficial.5
In a Japanese web-based survey focusing on sites of injuries and risk factors among 352 Japanese endoscopists, they found that greater than or equal to 28 endoscopy procedures per week and age older than 36 years old were associated with endoscopy related injury. Endoscopist height taller than or equal to 172 cm was associated with neck injuries in males. Specifically, for hand injuries, risk factors included glove size greater than or equal to 7 in males and age above 36 in females. Authors suggested that in males, hand size does not always match the standard size of endoscope. Additionally, their study showed that most females were also dissatisfied with the size and shape of the endoscopes. As age increases in females, arthritis is precipitated or worsened by frequent pinching and gripping. They concluded that changing the endoscope design and operability may be essential in preventing endoscopy-related injury.
Proper Ergonomics
To follow proper endoscopy ergonomics, the American Society of Gastroenterology Endoscopy (ASGE) suggests ergonomic education to reduce risk of endoscopy related injury. Hansel et al. recommends aiming to reduce twisting and bending during procedures, having adjustable table heights to allow the endoscopist’s elbows to be gently flexed at approximately 90 degrees, video monitors side by side with the endoscopist’s eyes at three-quarters the way up the screen, using two-piece lead aprons (as opposed to one-piece aprons), scheduled breaks between procedures, and floor padding.2 Similarly, Khan et al. recommended that the video monitor should be directly in front of the endoscopist, 15-25 degrees below eye level, the bed height between elbow height and 10 cm below elbow height, keeping foot pedals in front of the endoscopist’s body, cushioned floor mats, two-piece lead aprons, endoscopists keeping in neutral position and square to monitor with feet hip-width apart, and finger grip 15-30 cm from anorectum when colonoscopy was being performed. (Figures 3 and 4) Markwell et al. created individualized wellness plans for eight Duke University gastroenterologists at an ambulatory surgical center. They recommend a monitor height 15 degrees below the horizontal visual field, monitor placement directly in front of the physician to reduce cervical strain while maintaining clarity, bed at a height to allow the right hand to be at elbow height to 10 cm below elbow height, ergonomic floor mats, and closed toe footwear with arch support.
Prevention
Making Modifications
Modifications can, and should, be made to prevent and treat endoscopic injuries. Comparing the 109 endoscopists to the 120 non-endoscopists in Kuwabara et al.’s study, the endoscopists chose to make fewer modifications to their daily practices to prevent musculoskeletal pain. The reasons for this were unclear, but it was speculated to be due to limited time, busier schedules, or a lack of willingness. In this study, the endoscopists’ most common request to improve endoscope design was making parts of the endoscope lighter and smaller.1 In a survey by Bhatt et al. more female participants, as compared to male participants, were willing to try a pre-procedure posture checklist, wear a posture sensor to signal the endoscopists to stand up straight, and use braces at sites of pain. This may be attributed to the significantly higher rate of injury in the females included in this study.5
Hansel et al. found that although gastroenterologists and hepatologists employed by Mayo Clinic experienced musculoskeletal injury, nearly a third made no modifications to their practice despite these injuries. Of those who chose to make modifications, the most common choices were stretching, using adjustable height beds, standing on rubber mats, and reducing the overall time spent performing endoscopies.2 The ASGE’s website includes links to the videoGIE journal for stretching suggestions.
It has been suggested that endoscopists do not take enough breaks in prevention of injury. In O’Sullivan et al.’s survey of ERCP endoscopists, more than half of respondents did not take any breaks between procedures.3
The endoscopists in the study by Shergill et al. were invited to perform simulated colonoscopy using a novel antigravity support arm (zeroG system, Equipois, Manchester, NH, USA). They found that during simulation the support arm decreased muscle activity of the left wrist extensors when evaluated with EMG.7 Another small study of three experienced endoscopists in Bologna, Italy evaluated the advantages of using a lighter, single-use duodenoscope compared with standard reusable ones. They measured upper limb postures and muscle activity, which found that a lighter endoscope could decrease static and dynamic load during ERCP procedures and lower muscle activity.
Multiple studies have attempted to start ergonomics education as early as possible in training. In Pawa et al., gastroenterology fellows who reported no musculoskeletal injuries were significantly more likely to have had previous ergonomics training.8 Khan et al. created a simulation-based ergonomics curriculum studying general surgery, internal medicine, and gastroenterology trainees rotating at St. Michael’s Hospital in Toronto, Canada. This cohort of trainees were compared to a similar group without ergonomics training. In order to quantify musculoskeletal injury, the authors used the “Rapid Entire Body Assessment” (REBA) and “Rapid Upper Limb Assessment” (RULA). These are ergonomic worksheet assessment tools developed to evaluate whole body (REBA) and upper extremity (RULA) ergonomic musculoskeletal injuries., They saw significantly higher REBA scores in clinical colonoscopy (p <0.001) but not significant in simulated colonoscopy. Those without ergonomic training had worse REBA and RULA scores six weeks after training (p<0.001). Similarly, Gala et al. created a six-month curriculum for 37 general GI and fourth year advanced GI fellows. This curriculum included a didactics session based on the ASGE guidelines on ergonomics for prevention of musculoskeletal injury, followed by a session practicing stretches, resistance bands, and ideal postures with a physical therapist. Participants were provided with a lifelong subscription code to the website with home exercises and stretching. They were evaluated with a pre and post curriculum survey. From those who completed post-curriculum surveys, those individuals felt that the interactive session with the physical therapist was the most impactful part of the curriculum. Although there are many studies with a positive response to ergonomics training during fellowship, Villa et al. found differing results. Their 168-participant electronic survey to GI trainees found that 85% of respondents received ergonomics training but found no relation between training and endoscopic related injury.9
Treatment of Endoscopic Injury
In the study by O’Sullivan et al., the most commonly used treatment for pain and injury from endoscopy included medication (36%), physiotherapy (15%), and massage therapy (13%).3 The University of Miami also created an ergonomics training curriculum for GI fellows incorporating a physical therapist for active practice of exercises and an introduction to a “microbreaks” model. The “microbreaks” model was taken from studies for general surgeons trialing scheduled 1.5-minute breaks at appropriate 20-40 minutes intervals throughout surgical cases. During these breaks, the physician completes exercises and stretches targeting the neck, shoulders, upper back, lower back, wrists, hands, knees, and ankles. This study found that 100% of fellows reported reduction of pain immediately after implementing the “microbreaks” model.,
Conclusion
Improper ergonomics in GI endoscopy has left many proceduralists with injuries, most commonly in the upper extremity. The literature is mixed on whether females are disproportionately affected by endoscopy related injury, potentially due to smaller statures and hands. Many females report a desire for alternative techniques to accommodate such maneuvers. Injuries from endoscopy start as early as in fellowship training and should be addressed early on. An ergonomic curriculum during training is likely beneficial. During procedures, the patient beds should be at a height allowing the endoscopists elbows bent to approximately 90 degrees, positioning the screen to reduce cervical strain, using floor mats and using two-piece lead aprons when possible. Although there is widespread recognition of ergonomic injury, many gastroenterologists do not make any adjustments to their practice. Proper ergonomics may include making those adjustments before and during procedure, but also planning for microbreaks with stretching and exercises during and after the procedure. In conclusion, GI endoscopists are at risk of experiencing endoscopy-related injuries, and the literature suggests the solution may be multifactorial. The endoscope itself should be modified to accommodate the unique hand and body shapes of endoscopists. Body positioning and equipment positioning should minimize strain or extra force. Breaks and stretching should be incorporated into the proceduralist’s schedule. Finally, formal education on ergonomics should be implemented early in training.
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Thank you to the 2025 Peer Reviewers of the Nutrition Reviews in Gastroenterology Series We extend our sincere appreciation to the reviewers of the 2025 Nutrition Reviews in Gastroenterology series for their thoughtful and scholarly critique of manuscripts. Their expertise, time, and thoughtful contributions are vital to the scientific publication process.
Honoring Five Decades of Progress, Commitment, and Support for Liver Patients
(Fairfield, NJ – Jan. 5, 2026) – American Liver Foundation (ALF) proudly announces its 50th anniversary, marking five decades of unwavering commitment to advancing liver health, empowering liver patients and their families, providing groundbreaking public health initiatives and programs, and funding close to $30 million in critical research that supports and educates the 100 million Americans living with some form of liver disease. Since its founding in 1976, ALF has evolved into a leading voice at the forefront of the fight against liver disease, by educating patients and medical professionals through community events, fundraisers and educational webinars and advocating on Capitol Hill for liver health policies. ALF boldly strives to continue forging 50 years forward advancing liver health programs and initiatives that illustrate our continued dedication to liver patients each and every day.
“ALF has achieved numerous milestones that have shaped the landscape of liver health over the past 50 years, and we’re committed to driving progress 50 years forward to educate and support those battling a liver condition and help end liver disease,” said Lorraine Stiehl, Chief Executive Officer of American Liver Foundation. “As we look 50 years forward, we are excited for each milestone that represents 50 years of stepping stones dedicated to improving the lives of liver patients and their families.”
Key highlights through five decadesof innovative growth include:
In the 1980s – ALF established a Research Awards Program that has since awarded close to $30 million to 923 scientists; $2.5M of which was awarded in the last two years alone. ALF unveiled a National Toll-Free helpline, 1.800.GO.Liver (1.800.465.4837), that provides trusted liver health information and support in 50 states today and in over 100 languages; and ALF launched Love Your Liver, its first community education program that taught elementary school children about liver health, resisting peer pressure, and saying no to drugs.
In the 1990s – The first Irwin M. Arias Symposium: Bridging Basic Science & Liver Disease launched, uniting global scientists and physicians to bridge basic science and liver disease. Now in its 35th year, this one-day event has featured breakthroughs in diagnosing and treating liver diseases in children and adults worldwide; ALF convened a Scientific Advisory Council of leading hepatitis and liver disease researchers to draft the nation’s first research agenda, setting priorities for Congress to accelerate cures; ALF published the Children’s Liver Research Agenda: A Scientific Blueprint to help guide families coping with pediatric liver disease; and ALF launched Liver Life Walks to bring communities across the country together to raise awareness and funds regarding liver disease in a fun, inspiring way and to provide education and support services to those living with the disease.
In the early 2000s – ALF launched a multi-year, nationwide community education campaign to raise awareness about Hepatitis B (Hep B) called THINK (The Hepatitis Information You Need to Know); ALF’s Board Chair Dr. James Boyer testified before Congress, advocating for increased funding for the National Institutes of Health (NIH), Center for Disease Control’s (CDC) Viral Hepatitis, and Health Resources and Services Administration’s (HRSA) Organ Transplantation; and ALF launched its third national community education program titled FLIP (Fatty Liver Information Program), which laid the groundwork for what would become ALF’s Liver Wellness Program.
In 2010 to 2020 – Music legends Gregg Allman and Natalie Cole joined ALF’s nationwide Hepatitis C virus (HCV) campaign called “Tune in to Hep C”, to raise awareness about HCV; ALF formed its first-ever National Patient Advisory Committee (NPAC) to train liver patients across the nation to use their voices to advocate for change and raise awareness on Capitol Hill about many liver conditions. Today, ALF hosts an annual advocacy day amplifying many voices to fight for liver health policies during our “Liver Life Advocacy Summit.”; ALF launched a live educational series called Ask the Experts, which brings liver health specialists into communities across the country to raise awareness and answer questions about liver health; ALF honored 2020 Nobel Laureates Charles M. Rice, PhD, Harvey Alter, MD, and Michael Houghton, PhD, DSc, at ALF’s 45th Anniversary Leadership Celebration for their discovery of the hepatitis C virus and transformative contributions that led to a cure.
In 2020 to the present – ALF launched Think Liver Think Life, it’s first nationwide public health initiative to screen U.S. adults for metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer, raising awareness and connecting communities to the care they need. See if you’re at risk today by taking our free liver health quiz at thinkliverthinklife.org/quiz; ALF created the Bili the Brave toolkit, complete with a plush lion, children’s book, and resources to support children and families affected by biliary atresia; ALF’s Living Donor Network was recently launched to connect non-directed (altruistic) liver donors with transplant centers nationwide to help children and adults in need of a transplant; and ALF launched a Patient Registry to help researchers find better treatments and cures for liver disease.
“ALF expresses profound gratitude to its donors, volunteers, medical partners, scientists and researchers and the liver health community for their steadfast support of our mission for the past 50 years,” said Emmanual Thomas, MD, PhD, FAASLD, ALF Board Chair and Tenured Professor at University of Miami School of Medicine and member of the Sylvester Comprehensive Cancer Center and the Schiff Center for Liver Diseases at University of Miami. “As ALF celebrates its legacy, we look 50 years forward with renewed commitment to fostering hope, advancing innovative breakthroughs, and supporting millions affected by liver disease.”
In honor of our 50th Anniversary milestone, ALF invites all its supporters to join the Liver of Life Society with a monthly donation of $15 or more. By becoming a monthly donor, you can make a lasting difference in the fight against liver disease that will help us sustain vital programs year-round. As a token of our appreciation, all Liver of Life Society members will receive ALF’s commemorative 50th Anniversary tote bag.
“For the past 50 years, ALF has continued to be a beacon of hope for liver patients across the country living with some form of liver disease,” said Dan Weil, immediate past Board Chair of ALF, and spouse to a liver patient for over 25 years. “ALF’s goal is to create a world free from the challenges of liver disease, but we can’t do it without your continued support of our ongoing mission to promote education, advocacy, support services and research for the prevention, treatment and cure of liver disease. Supporting ALF today means you’re helping millions in the future to lead healthier lives and achieve optimal liver health.”
For more information about ALF, go to www.liverfoundation.org and for details regarding the Monthly Donor Campaign, please visit Liver of Life Society – American Liver Foundation. Read ALF’s entire 50th Anniversary timeline. If you have any questions or concerns regarding liver disease, please call our FREE helpline at 1.800.GO.LIVER (800.465.4837).
About the American Liver Foundation
American Liver Foundation (ALF) is a national community of patients, caregivers and medical professionals dedicated to helping people improve their liver health. Providing guidance and life-saving resources, we are a beacon for the 100 million Americans affected by liver disease. We advocate for patients and families, fund medical research and educate the public about liver wellness and disease prevention. We bring people together through our educational programs and events and create a network of support that lasts a lifetime. ALF is the largest organization focused on all liver diseases and the trusted voice for patients and families living with liver disease.
For more information visit:
www.liverfoundation.org
or call:1 800 GO LIVER (800-465-4837)
SafeHeal® Announces Successful Launch of SAFE-3CV IDE Study for Colovac® Anastomosis Protection Technology
Breakthrough device promises significantly improved patient recovery after colorectal surgery
PARIS, France/Tampa, FL – SafeHeal®, a leading innovator in the field of colorectal cancer surgery, today announced the first patient enrollment in its pivotal IDE study of Colovac®, a groundbreaking endoluminal bypass sheath. Colovac® is intended as an alternative to a temporary diverting ostomy for patients undergoing colorectal resection. Up to 20 U.S. and European sites will enroll patients in the SAFE-3CV study led by Principal Investigator Patricia Sylla, MD, and EU Principal Investigator Prof. Jérémie Lefevre, which is expected to complete enrollment by late 2026. SAFE-3CV serves as the final phase of a comprehensive study for U.S. market approval and EU post-market surveillance. This two-phase study will enroll up to 252 patients to compare the safety and efficacy of the Colovac® device to the previously collected control data on patients who received the standard-of-care diverting ostomy procedure.
Hôpital Saint-Antoine (AP-HP), Sorbonne Université, Paris, France, under the direction of Prof. Jérémie Lefevre, successfully enrolled the SAFE-3CV study’s first patient. Prof. Lefevre has extensive experience with the Colovac® device as a co-leader of recent studies conducted in the U.S., Europe, and Asia, where Colovac® has demonstrated favorable safety and efficacy as an alternative to ostomy. Based on these prior studies, in August 2025, Colovac® was granted European Union marketing approval under the new Medical Device Regulation (EU MDR 2017/745, Medical Devices, Annex IX Chapter I).
“The current standard-of-care, the use of a diverting stoma, places a significant burden on the patient in terms of associated physical complications, lifestyle compromises, and an extended recovery period,” said Prof. Lefevre. “We welcome Colovac’s potential to offer a less-invasive alternative to a stoma, and we are excited to generate additional evidence behind this innovation.”
As the current standard of care for the surgical treatment of rectal cancer, a diverting ostomy is applied prophylactically to most patients today undergoing a low anterior resection (LAR) and a low anastomosis. The ostomy temporarily diverts the stool away from the healing anastomosis to the outside of the body and into an ostomy bag. In most cases, the ostomy is needed only until the anastomosis has healed, and can then be reversed, typically after 2-6 months. The eventual reversal of the ostomy requires another operation, with a second hospital stay, recovery period and associated complications. In some cases, the ostomy may not be reversed and becomes permanent. In addition to the potential surgical complications associated with ostomy procedures, patients may experience a negative impact on their quality of life due to social isolation, reduced physical activity and/or intimacy issues.
Colovac® is designed to eliminate the need for a temporary stoma in most patients. It aims to improve patient recovery and quality of life by eliminating stoma-related complications, including permanent stoma, and eliminating the physical and emotional burden associated with stoma management and care.
“We are proud to partner with world-class clinicians like Prof. Lefevre and Dr. Sylla to build upon SafeHeal’s already impressive body of evidence, as we drive toward FDA marketing approval of Colovac,” said Chris Richardson, President & CEO of SafeHeal®. “We look forward to making the clinical and economic benefits of this technology available to U.S. patients and providers in the very near future.”
Successful completion of the SAFE-3CV study is the final step in the path to U.S. Food and Drug Administration (FDA) approval and U.S. commercialization of the Colovac® device. The FDA has already granted the product Breakthrough Device designation. Breakthrough Device designation is granted to novel products and provides expedited review of innovative technologies that can improve the lives of people with life-threatening or irreversibly debilitating diseases or conditions.
ABOUT SAFEHEAL®
SafeHeal SAS, headquartered in Paris, France, and its wholly owned U.S. subsidiary, SafeHeal Inc., is a medical device company developing Colovac®, a device intended as an alternative to diverting ostomy in patients undergoing colorectal surgery. Colovac® is a flexible endoluminal bypass sheath designed to reduce the contact of fecal content at the anastomotic site following colorectal surgery. The device is placed endoluminally and remains in place for approximately 10 days, until the body’s natural healing and tissue repair processes are complete, after which it is removed during an endoscopic procedure without the need for a second surgical intervention.
Colovac® enables patients to resume their normal life without the stigma and complications associated with an ostomy procedure. In the U.S., Colovac® is limited by Federal law to investigational use and not currently available for sale.
Most hepatic hemangiomas in infants are benign and are typically divided into two groups: 1) focal hepatic hemangiomas which are congenital and limited in size and 2) infantile hepatic hemangiomas which are diffuse in nature. The authors of this study evaluated the clinical course of infantile hepatic hemangiomas over time. The study used a patient database which included all patients diagnosed with congenital hepatic hemangiomas from 2004 to 2022. Data for the study included initial age at presentation, presence of anemia or thrombocytopenia, and an analysis of all radiographic images involving the hepatic hemangiomas over time.
A total of 96 infants in the patient database with hepatic congenital hemangiomas were studied. An equal number of male and female infants were present, and the patient group had a median gestational age of 37 weeks. Anemia was present in 48% of infants, and thrombocytopenia was present in 57% of infants. There was a significant statistical relationship between increasing infantile hepatic hemangioma size and risk of anemia and thrombocytopenia. Only 11% of infants had cutaneous hemangiomas, and no patient developed hypothyroidism in relation to their hepatic hemangioma.
Congenital hepatic hemangiomas were detected prenatally in approximately one third of infants in which ultrasound imaging detected lesions between 18 to 37 weeks gestation. Such initial prenatal lesions were noted to be single and hypervascular. Often these lesions continued to grow in the prenatal period with 24% of patients developing arterial or venous shunting.
In patients who had serial hepatic hemangioma imaging (47 patients), a residual hemangioma volume of 43% was present at 12 months while a residual volume of 16% was present at 24 months. Medical intervention did not change the rate of hemangioma involution. Biopsy specimens were available for 16 patients, and 13 of these biopsy specimens demonstrated a rapidly involuting congenital hemangioma. The other three patients had either partially involuting congenital hemangiomas or non-involuting congenital hemangiomas.
In patients who had data available, 46% of patients with congenital hepatic hemangiomas underwent medical therapy for which the most common therapies were corticosteroids (34%) and propranolol (31%). A total of nine patients underwent procedural therapy which included embolization, surgical resection, embolization /surgical resection, and embolization/liver transplantation. Extra-hepatic complications associated with this disorder included cardiomegaly (31%), heart failure (23%), and respiratory failure (23%). Although cardiac dysfunction was not significantly associated with hemangioma size, there was a significant correlation between hemangioma size and risk of respiratory failure. The mortality rate in this study was 4% because of hemorrhagic shock, sepsis, or complications of prematurity.
This study provides insight into the natural history of congenital hepatic hemangiomas. Most infants seem to tolerate this disorder with involution of hemangiomas over time. However, some infants with congenital hepatic hemangiomas can have lift-threatening consequences which should be considered early in the care of such children.
Ostertag-Hill C, Fevurly R, Kulungowski A, Christison-Lagay E, McGuire A, Rialon K, Duggan E, Murillo R, Zurakowski D, Staffa S, Alomari A, Kozakewich H, Al-Ibraheemi A, Fishman S, Dickie B. The natural history of congenital hepatic hemangiomas. Journal of Pediatrics 2025; doi: 10.1016/j.jpeds.2025.114523. Online ahead of print.
Infant Colic and Atopy
Infant colic is characterized by excessive crying and irritability and is a common cause of clinic visits to both general pediatricians and pediatric gastroenterologists. Proposed causes of colic have included functional, neurological, allergic, migraine-related, or potential dysbiosis components. The authors of this study previously determined that risk factors such as prematurity, low birth weight, first born status, and maternal factors (atopy, severe nausea during pregnancy, and postpartum depression) may lead to infant colic. These risk factors led the authors to study if infant colic is associated with an increased long-term risk of atopy or respiratory symptoms as these children become older.
Data for this study was obtained from Project Viva which evaluates the long-term health of mother-infant pairs in eastern Massachusetts. Mothers were recruited between 1999 and 2002 before their 22nd week of pregnancy. Research visits to obtain clinical information were performed at the second and third trimester of pregnancy as well as several time points including: just after delivery or during infancy, toddler years, early childhood, middle childhood, early adolescence, and middle adolescence. A total of 1249 infants had data available for potential colic and excessive crying symptoms. These infants also had long-term data for the following symptoms: allergic rhinitis, reactive airway disease, and respiratory infections. Maternal information included education history, smoking history, marital status, income, number of prior births, use of oral antibiotics during pregnancy, and atopy of the mother and her partner. Infant data consisted of sex, mode of delivery, and infant feeding method.
Infant colic was present in 320 infants (26%) and excessive crying was present in 118 infants (9%). Infants with colic were statistically more likely to be of white ethnicity, have a history of prematurity, be born to a nulliparous mother, and be born to a mother with a history of atopy. The presence of eczema at all childhood time points was increased in patients who had a history of colic or excessive crying compared to children with no history of such symptoms, but this increase was not statistically significant except at follow up during middle childhood (median 7.7 years). Children with allergic rhinitis had an increased risk of colic during infancy, but the increase was only significant during the follow-up periods of early childhood (median 3.1 years) and middle childhood. Children with excessive crying as infants also were noted to have an increased risk of allergic rhinitis as they became older, but the risk was not statistically significant. Children in the age range of middle childhood and middle adolescence (median 17.5 years) had a higher risk of reactive airway disease if they had colic as infants although no such relationship was seen between colic and reactive airway disease in the other age ranges as well as with excessive crying and all age ranges. Respiratory infections in the age range of the toddler years (median 2.1 years), early childhood, and middle adolescence had a higher relative risk of respiratory infections if they had colic as infants although no such effect was seen between colic and the other age ranges as well as with excessive crying during infancy and all age ranges. Children with a history of colic were more likely to have more than one atopic disorder long term compared to children with no history of colic although no such effect was present in children with a history of excessive crying during infancy.
This study suggests that infant colic symptoms may be a marker of future atopic disease. Perhaps colic is associated with infant atopic symptoms which become more obvious as children become older.
Switkowski K, Oken E, Simonin E, Nadeau K, Rifas-Shiman S, Lightdale J. Associations of infant colic and excessive crying with atopic outcomes in childhood and adolescence. Journal of Pediatrics 2025; 283: 114623
Ondansetron Use in the Setting of Pediatric Gastroenteritis
Acute gastroenteritis (AGE) is a frequent reason that children present to the emergency department (ED). Besides utilization of intravenous fluid, ondansetron can reduce both nausea and emesis symptoms while such children are being seen in the ED. The authors of this study evaluated the utility of ondansetron continuing into the outpatient setting for children initially presenting to the ED with AGE.
This study was a double-blind, placebo-controlled randomized study that occurred at six pediatric EDs in Canada. Children from 6 months to less than 18 years of age were enrolled in the study if that had AGE defined as at least 3 emesis episodes in the 24 hours prior to study enrollment, emesis or diarrhea at least 72 hours before enrollment, and emesis 6 hours before enrollment. All enrolled patients received ondansetron in the ED. These study patients were randomized with patients receiving ondansetron or placebo for a total of 6 doses at time of ED discharge. Besides collecting basic patient data, patient AGE severity was defined by using a modified Vesikari scale (range 0 – 20) in which a higher score on the scale was associated with more severe AGE.
The study occurred over an approximately 5-year period, and 517 patients received ondansetron while 512 patients received placebo. Baseline characteristics were the same between the two groups. Post enrollment scores of children with AGE demonstrated that Vesikari scores of 9 or higher were lower in the ondansetron group compared to the placebo group (unadjusted risk difference, −7.4 percentage points, 95% confidence interval, −11.2 to −3.7). A linear regression model demonstrated less AGE symptoms for patients using ondansetron after leaving the ED (adjusted odds ratio, 0.50, 95% confidence interval 0.40 to 0.60 and risk difference, −6.6 percentage points, 95% confidence interval, −10.9 to −2.3). A multivariable analysis demonstrated that patients taking ondansetron had a decreased risk of having a Vesikari score of 9 or higher (adjusted odds ratio, 0.46, 95% confidence interval, 0.27 to 0.78). Although both study groups had equal numbers of patients who had emesis during the study, the patients who received ondansetron had significantly a smaller number of emesis episodes. Interestingly, the percentage of children who had unscheduled medical visits within 7 days after study enrollment as well as the percentage of children who required intravenous fluid within 7 days after study enrollment was not statistically significant between groups.
This study demonstrates that sending pediatric patients home with a limited number of ondansetron doses after being seen in the ED for AGE may be beneficial in reducing gastrointestinal symptoms. The authors of the study noted that no patient developed symptoms of QT prolongation after being sent home on ondansetron, and it is always prudent to send children home with only limited amounts of this medication to prevent this side effect.
Freedman S, Williamson-Urquhart S, Plint A, Dixon A, Beer D, Joubert G, Pechlivanoglou P, Finkelstein Y, Heath A, Zhang J, Wallace A, Offringa M, Klassen T, and the Pediatric Emergency Research Canada Innovative Clinical Trials Study Group. The New England Journal of Medicine 2025; 393: 255-266.
Autoimmune Hepatitis Treatment Outcomes in Children
Autoimmune hepatitis (AIH) in children is a progressive and destructive autoimmune disease of the liver which can be fatal. Treatment of pediatric AIH often consists of two regimens: 1) prednisolone with possible addition of azathioprine or 2) tacrolimus (a calcineurin inhibitor). The authors of this study compared the efficacy of these two treatments.
This retrospective study occurred using data from 5 European medical centers in which children with AIH were studied over a 13-year period (2005-2018). Children included in the study were younger than 18 years of age, had liver biopsies obtained within 6 months of therapy, and had at least 2 years of follow-up care. Initial patient data and follow-up data at 3, 6, and 12 months on therapy were analyzed. Four medical centers utilized prednisolone starting at 1-2 mg/kg/day with azathioprine at 1-2 mg/kg/day either added or not added after 14 days of AIH diagnosis. Prednisolone weaning was guided by the treating physician. The fifth medical center used tacrolimus at a dose starting at 0.025-0.050 mg/kg/day in order to obtain a tacrolimus trough of 3-6 ng/mL with the addition of prednisolone (10-20mg daily) at the discretion of the treating physician. Chart review occurred to evaluate for the presence of other medical disorders, AIH parameters (autoantibodies, liver biopsy results), and the presence of any imaging (ultrasound or magnetic resonance cholangiopancreatography (MRCP)).
A total of 157 children with AIH were included in the study, and all children still had their native liver one year after diagnosis. Therapeutic options consisted of prednisolone with possible azathioprine in 111 patients and tacrolimus therapy with possible prednisolone occurring in 46 children. The children treated with prednisolone and possible azathioprine were statistically more likely to have other autoimmune diseases and higher platelet counts. The children treated with tacrolimus and possible prednisolone were statistically more likely to higher Metavir fibrosis scores, have higher bilirubin levels, and have more esophageal varices at diagnosis. A total of 12 children (six patients in each group) had a diagnosis of acute liver failure with an INR greater or equal to 2, and such patients all had eventual response to therapy.
Liver histology confirmed AIH in 112 children, and 41 of these children had biliary involvement. Seven of the 41 children with biliary involvement did not have associated autoimmune sclerosing cholangitis. MRCP testing occurred in 105 children (67%) within the first year of therapy. Statistically more children undergoing therapy with prednisolone and possible azathioprine underwent MRCP. MRCP diagnosed autoimmune sclerosing cholangitis in 42 children with 23 patients having combined large and small duct disease.
Autoantibody testing was positive in 148 patients (94%) and elevated IgG serum levels were present in 125 patients (85%). The most common autoantibody detected was anti-smooth muscle actin antibody occurring in 117 patients. Most patients had high rates of advanced fibrosis/cirrhosis as noted by a Metavir score of 3 or 4 in 46% of patients, and advanced fibrosis/cirrhosis was significantly higher in the patient group treated with tacrolimus and possible prednisolone.
Only one child in the entire patient group did not experience lowering serum alanine aminotransferase (ALT) levels by 6 months of therapy. ALT normalization took a statistically longer time in the patient group receiving tacrolimus with possible prednisolone compared to the prednisolone group with possible azathioprine use at both 3 months (26.8% versus 58% normalization) and 6 months (46.2% versus 68.8% normalization). However, there was no significant difference in normalization at 12 months between the two treatment groups. Serum IgG levels took longer to normalize in patients receiving tacrolimus with possible prednisolone compared to the prednisolone group with possible azathioprine use at 3 months, 6 months, and 12 months although the normalization time was not consistently statistically significant at 3 months and 12 months. No significant difference in Z-scores for height and weight was present between the two treatment groups during the study. The number of children eventually not requiring prednisolone was higher in the group receiving tacrolimus compared to the prednisolone group with possible azathioprine use. However, this finding makes sense as the latter group received prednisolone initially.
This study suggests that starting tacrolimus for pediatric patients with AIH may be preferable as less steroid use may be needed. This study is retrospective only, and large multi-national prospective studies in the treatment of pediatric AIH are very much needed.
Jorgensen M, Almaas R, Kharrazi G, Urbonas V, Kvistgaard H, Wollen E, Andreassen B, Casswall T, Fischler B. Various regimens for autoimmune hepatitis in northern European children show equivalent outcomes at 1 year: a retrospective study. Journal of Pediatrics 2025; 284: 114635
GI Outcomes After Pediatric Malrotation Repair
Intestinal malrotation in children is a surgical emergency if a resultant intestinal volvulus occurs. The Ladd procedure is a surgical technique to prevent complications from a potential volvulus. However, it is unclear what gastrointestinal (GI) symptoms occur long term in pediatric patients with malrotation after the Ladd procedure. The authors of this study attempted to answer this question using the TriNetX Research Network which contains de-identified patient data from electronic medical records as well as other sources. Using a database of 130 million patients, this retrospective matched cohort study compared pediatric patients with a history of malrotation repair to a control group of general pediatric patients. Patients were matched by sex, race, age, and ethnicity. GI symptoms were determined using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. Patients were evaluated at 1 to 5 years post-surgery and 3 to 5 years post-surgery.
A total of 354 patients with a history of intestinal malrotation status post repair were matched to 354 control patients. There was no significant difference in patient demographics across the two groups. At both 1 to 5 post surgery or years 3 to 5 post surgery, patients with a history of intestinal malrotation repair were statistically more likely to have GI symptoms of constipation, diarrhea, abdominal pain, gastroesophageal reflux disease, nausea, and emesis.
This study suggests that GI symptoms may be persistent in patients even after malrotation surgical repair, and these results seem to differ with prior research showing that GI symptoms generally resolve after a Ladd procedure. Perhaps this patient group has an increase in functional GI symptoms in the setting malrotation repair. More research is now needed to determine if this patient group is at a higher risk of mucosal GI disease long term which could include celiac disease, erosive esophagitis, gastritis, and other related disorders.
Corcoran K, Martinez S, Tsikis S, Al-Mamun M, Intestinal Malrotation Clinical Group. Long-term gastrointestinal outcomes in pediatric intestinal malrotation patients following operative treatment. Journal of Pediatric Gastroenterology and Nutrition 2025; online ahead of print (DOI: 10.1002/jpn3.70204)
Electrohydraulic lithotripsy (EHL) has emerged as a vital adjunct to endoscopic retrograde cholangiopancreatography (ERCP), providing an effective means of fragmenting large, impacted, or otherwise difficult-to-extract stones within the pancreatic and biliary ducts. This review integrates current evidence and technical considerations, with emphasis on clinical application by outlining the indications for EHL, strategies to optimize procedural safety, and its role in relation to mechanical lithotripsy, laser lithotripsy, and extracorporeal shock wave lithotripsy (ESWL).
Background
Electrohydraulic lithotripsy (EHL) is a critical adjunct to endoscopic retrograde cholangiopancreatography (ERCP) for the fragmentation of large, impacted, or otherwise difficult-to-remove pancreatic and biliary stones.,,,, The technology generates microsecond-duration spark discharges at the probe tip that create cavitation bubbles, which collapse into high-pressure shock waves capable of fracturing mineralized concretions under direct vision., Over the past decade, integration of EHL with digital single-operator cholangioscopy has led to improved ductal clearance rates with acceptable adverse event rates in patients with difficult stones.,
Indications for EHLBiliary Stones
For most common bile duct (CBD) stones, standard ERCP techniques such as sphincterotomy with balloon or basket extraction, and, in selected cases, endoscopic papillary large-balloon dilation (EPLBD), achieve ductal clearance in a single session.1,2 A subset of stones remains difficult to manage. EHL should be considered for stones ≥15–20 mm, those impacted proximal to a biliary stricture, intrahepatic calculi not amenable to standard techniques, and in patients where conventional extraction methods have proven unsuccessful.,,,,,,,, (Figure 1) When performed under direct cholangioscopic visualization, EHL allows precise fragmentation of stone surfaces and is particularly valuable in cases where conventional or mechanical lithotripsy has limited efficacy.3,6 Meta-analyses of cholangioscopy-guided lithotripsy consistently demonstrate technical success and ductal clearance rates of ≥85–95%, with adverse event (AE) rates in the range of 8-10%, especially when performed under direct digital visualization.3,4 The most frequently reported AEs include cholangitis, post-procedural fever, and, less commonly, pancreatitis; most are mild and manageable with supportive care.3,4 The evidence suggests that EHL may be most effective when introduced earlier in the treatment course, rather than being deferred until after several unsuccessful ERCP attempts.12 Pooled data from Jin et al. and Amaral et al. similarly demonstrated ductal clearance consistently exceeding 90% with acceptable adverse event rates ranging between 8-12%.11,13 Recent systematic review by Manti et al. reported pooled ductal clearance rates of 90–94% with adverse event rates between 6–10%, confirming the efficacy of EHL in difficult biliary stones.
Pancreatic Duct Stones
In chronic calcific pancreatitis with obstructing main pancreatic duct stones, extracorporeal shock wave lithotripsy (ESWL) combined with ERCP continues to serve as the cornerstone of therapeutic management if stones cannot be removed via pancreatic sphincterotomy and balloon or basket extraction. Pancreatoscopy with intraductal lithotripsy (using either EHL or laser) has emerged as an effective second-line or alternative strategy, particularly in cases refractory to ESWL or when stones are concentrated in the head/neck adjacent to strictures.,,, (Figure 2) These locations are particularly amenable to intraductal therapy, as direct visualization permits targeted fragmentation of impacted stones, while adjunctive maneuvers such as stricture dilation and temporary stenting facilitate fragment clearance and ductal drainage.21,22,23,24
Systematic reviews have demonstrated high technical success rates and significant improvements in pain outcomes with this approach, with most adverse events related to mild post-ERCP pancreatitis.23,24 Multicenter data from Gutierrez et al. demonstrated clearance rates > 95 % with low adverse event rates (< 5 %), confirming the safety and efficacy of digital cholangioscopy-guided lithotripsy in complex biliary stone disease.8 These findings support the use of pancreatoscopy with intraductal lithotripsy as a salvage therapy following failed ESWL and as a potential first-line option in patients whose anatomy or clinical profile favors direct intraductal intervention.21,22,23,24
Set-up and Technique
Access and Visualization
For biliary stones, digital single-operator cholangioscopy performed in the context of ERCP offers a stable platform for targeted lithotripsy and subsequent stone retrieval. Adequate irrigation is essential to maintain a clear visual field, as rapid accumulation of debris can obscure visualization and potentially increase intraductal pressure.5,6
For pancreatic stones, pancreatoscopy with intraductal lithotripsy requires careful advancement of the pancreatoscope to the level of the target stone to ensure stable positioning and safe energy delivery. This may include passage of the pancreatoscope across strictures, which may be technically challenging.22 In many cases, pre-dilation and temporary stent placement are required to facilitate passage of the scope through strictures to reach offending stones before EHL can even commence.3,22
Probe Selection and Energy Settings
Modern electrohydraulic lithotripsy (EHL) probes (1.9–2.5 Fr) are compatible with the working channel of digital single-operator cholangioscopy platforms, which can be applied for both biliary and pancreatic duct interventions. The commercially available electrohydraulic lithotripsy (EHL) probes used in gastrointestinal (GI) endoscopy are typically 1.9 French (F) and 3 French (F) in size, with vendors including Boston Scientific Autolith Touch Biliary EHL system and Walz Elektronik (Germany). These probes are designed for use through the working channel of cholangioscopes or pancreatoscopes during ERCP or direct peroral cholangioscopy and are compatible with both single-operator and mother-baby endoscopic systems.27 Direct peroral cholangioscopy using multibending ultra slim endoscopes has further expanded therapeutic access to difficult bile duct stones. The 1.9F probe is most commonly used due to its compatibility with the narrow working channels of digital cholangioscopes (e.g., SpyGlass DS), while the 2.5F probe is used in larger-caliber scopes or for intraoperative applications.27 Some suggest that power and frequency should be set at low-to-moderate levels, with stepwise escalation only as needed to gradually fragment the stone while limiting the risk of injury to the ductal wall, but in practice settings are left to the discretion of the operator.27 Safe use requires frequent probe repositioning and delivery of short, focused bursts to the stone surface rather than the surrounding mucosa.5,6
EHL probes have a limited life span, which is proportional to the potency chosen during the procedure. The American Society for Gastrointestinal Endoscopy, in its most recent guideline, does not specify an exact number of shocks or procedures per probe, but clinical studies referenced in the guideline and in the broader literature support the practical approach of monitoring probe function and replacing the probe when performance declines and/or failure occurs.
Irrigation Strategy
Continuous irrigation is necessary to dissipate heat, clear debris, and effectively transmit shock waves to target stones.26 Liberal intermittent suction is recommended by some authors to reduce intraductal pressure, as high-pressure irrigation may increase the risk of cholangitis and post-procedural fever. Evidence regarding prophylactic antibiotics is inconclusive, with large studies showing limited overall benefit, although in general they are given to patients. Nevertheless, prophylaxis is indicated in specific contexts, including obstructed systems, primary sclerosing cholangitis, and procedures requiring prolonged intraductal manipulation.32
Fragment Clearance
Following stone fragmentation, meticulous duct clearance is performed using balloons and retrieval baskets, while endoscopic papillary large balloon dilation (EPLBD) may be employed to expedite fragment removal when appropriate.16,17 Cholangioscopy facilitates identification of residual stones or stone fragments that may have been overlooked on occlusion cholangiography; therefore, a final direct inspection is often performed prior to confirming complete ductal clearance.15
Outcomes and Comparative Effectiveness
Cholangioscopy-guided EHL vs conventional ERCP in Biliary Stone Management
Randomized trials demonstrate that cholangioscopy‑guided lithotripsy improves single‑session clearance and reduces the need for crossover to other rescue modalities (e.g., mechanical lithotripsy, repeat ERCP, or surgical intervention).18 This advantage derives from direct intraductal visualization, which allows targeted fragmentation of difficult stones while minimizing the need for multiple procedures.3 Several meta-analyses support these findings, showing high technical success rates and acceptable adverse event profiles when EHL is used earlier in the treatment course.3,13 Korrapati et al. similarly reported ductal clearance rate of 88%, with an adverse event rate of 7%.4
Comparative Role of Mechanical, Laser, and Electrohydraulic Lithotripsy
Mechanical lithotripsy works by capturing the stone with a basket and fracturing it, which often allows immediate extraction.2 In contrast, EHL and laser lithotripsy use energy-based fragmentation to break stones into smaller pieces that typically require balloon or basket extraction for clearance.2 Mechanical lithotripsy remains the most established rescue modality for large or impacted bile duct stones, valued for its technical simplicity, low cost, and widespread availability. Mechanical lithotripsy achieves clearance in more than 85% of cases involving stones ≤15–20 mm. In contrast, success rates decline markedly when stones are very large, heavily calcified, or located intrahepatically, where basket capture may be difficult and/or incomplete.18
Laser lithotripsy has emerged as a highly effective alternative, particularly when combined with digital single-operator cholangioscopy.10,12 It achieves high ductal clearance through precise photothermal fragmentation under direct visualization, with excellent fragmentation efficiency; pooled data suggest that in some series it may outperform EHL.10,12 Its drawbacks include high equipment costs, requirement for specialized staff training, need for laser certification, and limited availability in many centers.
EHL occupies an intermediate position when compared to laser lithotripsy: it is broadly accessible, compatible with existing single-operator cholangioscopy platforms, and consistently achieves ductal clearance with low adverse event rates.8,10 Veld et al. found comparable safety between EHL and laser, with fragmentation efficiency numerically favoring laser, while overall clearance remained high for both technologies.10 Amaral et al. directly compared EHL with laser lithotripsy and confirmed both to be safe, with no significant difference in AE profile.11
Pancreatoscopy with Intraductal Lithotripsy vs. ESWL
Pancreatoscopy with intraductal lithotripsy has demonstrated high technical and clinical success in patients with pancreatic duct stones, resulting in significant pain relief, with AE rates comparable to other ERCP-based therapies such as balloon or basket extraction, mechanical lithotripsy, and stenting.22 Comparative studies suggest that pancreatoscopy with intraductal lithotripsy may serve as a reasonable alternative to ESWL-first strategies, particularly when stone location, ductal strictures, or other anatomic factors favor direct intraductal therapy.22,23 Careful multidisciplinary case selection and the use of staged stenting remain important to optimize safety and outcomes.21,23 Staged stenting refers to the sequential placement of one or more temporary pancreatic duct stents, often upsized over multiple procedures, to facilitate ductal decompression, maintain drainage, and reduce the risk of procedure-related complications before or after intraductal lithotripsy. Systematic reviews by Huang et al. reported technical success rates of 90%.24 Van der Weil et al. noted more than 50 % decrease in pain score or reduction in opioid usage at 6 months of follow-up.22 Meta-analysis by Guzmán-Calderón et al. also demonstrated a pooled technical success rate of 91% and overall adverse event rates of approximately 12%, the majority of which were mild and self-limited.
Adverse Events Related to Cholangioscopy-Guided Lithotripsy
Meta-analyses of cholangioscopy-guided lithotripsy report overall AE rates of approximately 7%, most often transient fever or cholangitis, with the majority classified as mild.19 For pancreatoscopy with intraductal lithotripsy, pooled analyses show overall AE rates of 12%, again largely mild and self-limited, with post-ERCP pancreatitis (PEP) the most common event.22,23 Severe adverse events are uncommon but have been described, including cholangitis with sepsis (2-4%) and perforation (1%).4,
Troubleshooting and Special Scenarios
Impacted Proximal/Hilar Stones and Intrahepatic Bile Duct Stones
Impacted proximal/hilar and intrahepatic stones are particularly challenging because conventional balloon or basket extraction is often unsuccessful, owing to their location and the limited maneuverability of the balloon and extraction basket.9 In such cases, the strategy involves using a lithotripsy probe to debulk the central portion of the stone first, creating space for subsequent peripheral fragmentation.9 Prior and recent studies confirm the feasibility of EHL for intrahepatic stones, although multiple staged sessions may be required to achieve complete clearance.9
Cystic-duct Stones and Mirizzi Syndrome
Cystic-duct stones and Mirizzi syndrome are technically demanding scenarios where conventional ERCP often fails because of the angulated cystic-duct takeoff and stone impaction. Mirizzi syndrome is defined as extrinsic compression of the common hepatic duct by an impacted stone in the cystic duct or gallbladder. Patients with Mirizzi syndrome may also have cholecysto-choledocho fistulas, complicating matters significantly. Cholangioscopy-guided EHL provides a valuable alternative to surgical intervention, enabling targeted fragmentation and clearance of stones in patients who might otherwise require cholecystectomy or complex biliary reconstruction.40 Pawa et al. reported 21 patients with cystic-duct stones managed with cholangioscopy-guided EHL, achieving 87% clearance with adverse events in 7%, limited to mild post-ERCP pancreatitis and transient fever.40 Despite these successes, repeat sessions are frequently required.40 Adjunctive balloon or basket extraction is necessary for fragment clearance after lithotripsy.16,17 Temporary stenting has also been described as an important adjunct to maintain drainage and reduce the risk of recurrent obstruction between procedures.21,22,23,24
Altered Anatomy or Enteroscopy-Assisted ERCP
EHL can be performed during device-assisted ERCP in patients with surgically altered anatomy, including those with Roux-en-Y gastric bypass, Billroth II gastrectomy, or hepaticojejunostomy. In these settings, an enteroscope is often required to access the biliary-enteric anastomosis or the papilla, but the long length and narrow working channel of the enteroscope impose technical limitations that can restrict accessory use and fragment retrieval.42
Pancreatic Duct Strictures
Pre-dilation of high-grade strictures and staged pancreatic duct stenting can facilitate pancreatoscope passage and fragment clearance in patients with pancreatic duct stones upstream of pancreatic duct strictures.23 This strategy often involves sequential stent exchanges with gradual upsizing to “remodel” the stricture, decompress the duct, and permit easier reintroduction of the pancreatoscope during subsequent sessions.36 Temporary stenting also helps reduce the risk of procedure-related pancreatitis by maintaining drainage between interventions.36 In the head and neck of the pancreas, where the duct is more tortuous and mucosal surfaces are thin, short and controlled EHL bursts with continuous irrigation are strongly recommended to optimize visualization and minimize the risk of thermal or mechanical injury.31 Careful irrigation control is particularly important in these regions, as excessive fluid infusion can elevate intraductal pressure and increase the risk of post-ERCP pancreatitis.31
Conclusions
Electrohydraulic lithotripsy (EHL) is an effective option for the management of difficult biliary and pancreatic duct stones. Evidence supports its role both as a rescue therapy and as an early option when conventional ERCP is unlikely to achieve clearance. Cholangioscopy-guided EHL achieves high success rates with mostly mild, manageable adverse events. Pancreatoscopy with intraductal lithotripsy is a useful option for pancreatic stones, offering an alternative to ESWL in patients refractory to standard treatment strategies. EHL occupies a middle ground among intraductal therapies. It is more effective than mechanical lithotripsy in complex scenarios, less costly, more widely available than laser, and broadly compatible with existing endoscopic platforms. Its safety and efficacy depend on careful techniques, including direct visualization, controlled irrigation, conservative energy use, and staged procedure when needed. EHL offers a reliable and accessible option for complex stone disease, with ongoing studies continuing to clarify its role within advanced endoscopic practice.
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biliary therapy in the era of bariatric surgery. Frontline
Gastroenterol. 2021 Feb 24;13(2):133-139. doi: 10.1136/
flgastro-2020-101755. PMID: 35295751; PMCID:
PMC8862446.
Adler
Colorectal cancer remains the third most common cancer and second most common cause of cancer deaths, often from metastatic disease.1-6 While liver metastases are most common, other sites of metastases include lung, peritoneum, ovary, and brain.1-6 We report the presentation of cutaneous skin metastases in a patient with history of recent renal transplant.
Clinical Scenario
A 68-year-old man who had undergone kidney transplant two years prior presented to clinic with weeks of constipation, decreased flatus, and malaise. Ongoing abdominal pain and bloating led to poor oral intake and a 15-pound weight loss over three months. On physical exam, his abdomen was distended and tender on the right side. He was noted to have multiple firm, nontender, pink papules in the right lower quadrant (Figure 1). The patient reported that the papules had been present for several months. He was admitted to the hospital and underwent a noncontrasted CT of his chest, abdomen, and pelvis. This scan demonstrated pulmonary nodules, retroperitoneal lymphadenopathy, dilated small bowel, and narrowing of the ascending colon with decompressed distal colon (Figure 2). Carcinoembryonic antigen (CEA) was 398 ng/ml (normal = 0-5.4 ng/ml). No masses in the liver were identified.
A presumptive diagnosis of obstructing colon cancer was made, and the abdominal skin nodules were biopsied. Histopathologic examination showed an adenocarcinoma consistent with metastasis from a colonic primary (Figure 3). Due to pain, obstruction, and concern for potential perforation in the setting of malnutrition, he underwent a palliative resection with end ileostomy. Pathology for this tumor revealed poorly differentiated, mucinous adenocarcinoma with multiple positive lymph nodes. Final stage was pT4b pN2a pM1a. The tumor was found to be MLH1/PMS2 deficient by immunohistochemistry and molecular testing revealed a BRAF V600E mutation. The patient decided to focus on comfort driven measures and did not receive adjuvant chemotherapy and immunotherapy. He succumbed to the disease four months after diagnosis.
Clinical Pearls
Prior to being listed for kidney transplant, patients undergo extensive medical evaluation to ensure fitness for the operation and immunosuppression.7 These include cancer screening tests, such as colonoscopy and dermatological skin exam.7 This patient had undergone colonoscopy at a referring institution four years prior to this presentation, two years before his transplant. Findings at his colonoscopy included five polyps, measuring 0.3-1 cm, from his ascending, transverse, and descending colon. Pathology of each polyp was consistent with tubular adenoma. At the time, it was recommended to repeat screening colonoscopy in three years, but that was never completed.
This case highlights the increased rates of cancer in transplant patients due to immunosuppression, the varied metastatic patterns of colon cancer, and the importance of timely screening and surveillance colonoscopies as well as their false negative rate.
Immunosuppression prevents transplanted organ rejection but also increases risk of malignancy in the transplant recipient.7 The two major ways this occurs is by decreasing immune surveillance and increasing susceptibility to viruses such as BK polyomavirus, cytomegalovirus (CMV), human papillomavirus (HPV) and Epstein Barr virus (EBV) which are associated with cancer development.7 Cell lines including T-lymphocytes, naïve B-lymphocytes and natural killer cells (NK cells) are reduced which in turn reduces the recognition of dysregulated cellular replication and viral reproductions.7 While the rate of cancer rises with age, the risk elevation is not proportional to age. Younger transplant patients have a three to five times greater relative risk of developing a malignancy than older transplants since they are immunosuppressed; this contributes to their increased risk of cancer compared to the general population.7 Regardless, colorectal cancer rates are still elevated by 1.5-to-3-fold.7 Therefore, there needs to be a high index of suspicion for cancer in transplant recipients, and screening guidelines must reflect that.
Colonoscopy remains the gold standard for colorectal cancer. However, around 1% of colorectal cancers occur within the interval between colonoscopies.1 Currently, the most cited reason for post-colonoscopy colorectal cancer is a missed lesion, representing up to 57% of cases.1 It is suggested that a quarter of colonoscopies have missed adenomas or precancerous lesions.1 Wallace et al. demonstrated this in their evaluation of artificial intelligence (AI) enhanced screening colonoscopies followed by a short interval repeat colonoscopy (frequently same day) with 15-32% adenoma miss rate in AI and non-AI screening colonoscopies.1
Around 20-35% of patients with colorectal cancer present with metastatic disease at diagnosis.4,5 Cutaneous metastases in CRC are uncommon, occurring in 4-5% of cases.2,3 They are often associated with BRAF V600E mutations.3 Cutaneous metastases are an independent predictor of poor survival, with around two-thirds of patients dying within six months of diagnosis.2,3
Immunotherapy has shifted the treatment paradigm of high microsatellite instability (MSI-H) colorectal cancers and has significantly improved progression-free survival.5 MSI-H, found in up to 20% of colon cancers, is due to a deficiency in mismatch repair (MMR) proteins and subsequent unrepaired alterations in DNA sequences.5 While this patient had an MLH1/PMS2 deficiency that may have responded to immunotherapy, he was not offered it due to his renal transplant. In transplant patients, immunotherapy risks triggering graft rejection. Furthermore, its efficacy in the setting of maintenance immunosuppression may be reduced.8 As this patient did not wish to risk allograft rejection and need for hemodialysis, he transitioned to hospice care.
References
References
1. Wallace MB, Sharma P, Bhandari P, et al. Impact of Artificial Intelligence on Miss Rate of Colorectal Neoplasia. Gastroenterology. Jul 2022;163(1):295-304 e5. doi:10.1053/j.gastro.2022.03.007
2. Bittencourt MJS, Imbiriba AA, Oliveira OA, Santos J. Cutaneous metastasis of colorectal cancer. An Bras Dermatol. Nov/Dec 2018;93(6):884-886. doi:10.1590/abd1806-4841.20187610
3. Zhou S, Tang W, Wang Q, et al. A Case Report: Cutaneous Metastasis of Advanced Rectal Cancer with BRAF Mutation. Onco Targets Ther. 2021;14:989-993. doi:10.2147/OTT.S287064
4. Xia W, Geng Y, Hu W. Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer. Cancers (Basel). Nov 29 2023;15(23)doi:10.3390/cancers15235641
5. Hou W, Yi C, Zhu H. Predictive biomarkers of colon cancer immunotherapy: Present and future. Front Immunol. 2022;13:1032314. doi:10.3389/fimmu.2022.1032314
6. Aakif M, Balfe P, Elfaedy O, et al. Study on colorectal cancer presentation, treatment and follow-up. Int J Colorectal Dis. Jul 2016;31(7):1361-3. doi:10.1007/s00384-015-2479-0
7. Au E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat Rev Nephrol. Aug 2018;14(8):508-520. doi:10.1038/s41581-018-0022-6
8. Padala SA, Patel SK, Vakiti A, et al. Pembrolizumab-induced severe rejection and graft intolerance syndrome resulting in renal allograft nephrectomy. J Oncol Pharm Pract. Mar 2021;27(2):470-476. doi:10.1177/1078155220934160
Functional dyspepsia (FD) is a common disorder of the gut-brain interaction characterized by bothersome symptoms including postprandial fullness, early satiation, epigastric pain, and epigastric burning, without structural disease. Despite its frequency, the exact prevalence of FD remains poorly understood. There is a significant overlap of FD with other common gastrointestinal disorders, including irritable bowel syndrome (IBS), gastroparesis (GP), and gastroesophageal reflux disease (GERD). This review aims to explore the most studied dietary interventions for managing FD symptoms, including the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet, gluten-free diet (GFD), and traditional dietary advice (TDA). Furthermore, this review will discuss the efficacy of alternative nutrition therapies including STW-5, caraway oil, artichoke leaf extract, and ginger. To support clinical practice, this review will also provide clinical pearls and practical tools designed to enhance symptom management and optimize patient care for those living with FD.
What is Functional Dyspepsia?
Dyspepsia is a Greek term: dys- (meaning “bad” or “impaired”) and pepsis (meaning “digestion”).1 Although dyspeptic symptoms can be associated with an underlying organic pathology—such as peptic ulcer disease, gastroesophageal reflux disease, or malignancy — more than 75% cases have no organic cause and are therefore labeled as functional dyspepsia (FD).2
According to the Rome IV criteria, FD encompasses chronic or recurrent upper abdominal symptoms, including postprandial fullness, early satiation, epigastric pain, or burning, in the absence of structural disease that could explain these complaints.³ The Rome IV criteria further subdivide FD into two clinically meaningful subtypes—Postprandial Distress Syndrome (PDS) and Epigastric Pain Syndrome (EPS)—which reflect differences in symptom patterns, timing in relation to meals, and severity (See Table 1). While patients may exhibit overlapping features, identifying the subtype can guide management strategies.
Furthermore, symptoms of FD that extend beyond the ROME IV criteria tend to be specific to each subtype (See Table 2). Patients may not experience all the listed symptoms, but clear patterns differentiate EPS from PDS when assessed in this context.
Background and Statistics
Although FD is a common disorder of the gut-brain interaction (DGBI), little is known about its prevalence.4 A global systematic review and meta-analysis of 256,915 participants from 40 countries (1990–2022) found functional dyspepsia (FD) affected 7–12% of people.5The Rome criteria for diagnosing functional dyspepsia have become increasingly rigorous as subclassifications have evolved, making prevalence under Rome IV lower than under previous Rome iterations. Dyspepsia is more common in women, smokers, in developing countries vs. developed countries, and those taking non-steroidal anti-inflammatory drugs.5,6 Dyspepsia is estimated to cost the United States healthcare service over $18 billion per annum and societal costs are likely to be double this with 2–5% of patients taking time off work because of symptoms.7-8
Table 1. ROME IV Criteria for Functional Dyspepsia and Subtypes3
Functional Dyspepsia includes one or more of the following symptoms:
In the absence of structural disease that is likely to explain the symptoms. Symptoms must be chronic or recurrent, with onset at least six months prior to diagnosis and persistence for the previous three months.
Functional Dyspepsia is further classified into two subtypes: Postprandial Distress Syndrome (PDS) and Epigastric Pain Syndrome (EPS).3 PDS diagnosis must include one or both of the following for at least three days per week: 1. Bothersome postprandial fullness (i.e., severe enough to impact usual activities) 2. Bothersome early satiation (i.e., severe enough to prevent finishing a meal of usual size)
EPS diagnosis must include one or both of the following at least 1 day per week: 3. Bothersome epigastric pain (i.e., severe enough to impact usual activities) 4. Bothersome epigastric burning (i.e., severe enough to impact usual activities)
Possible Overlap between Functional Dyspepsia and Other Gastrointestinal Disorders
Various research studies have been conducted over the years to explore the overlap among FD and other gastrointestinal disorders, including gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and gastroparesis (GP).
Gastroesophageal Reflux Disease
FD and GERD often present with overlapping symptoms including upper abdominal bloating, epigastric pain, regurgitation, and heartburn.9-10 A systematic review and meta-analysis examined the overlap between FD and GERD and found that 41.15% of patients with GERD also experienced FD symptoms. Similarly, 31.32% of patients with FD also experienced GERD-like symptoms.9 Research has shown that there is similarity in pathophysiological mechanisms as well. A well-known mechanism in FD, impaired gastric accommodation, has been associated with more frequent transient lower esophageal sphincter relaxation (TLESRs) episodes.9 Additionally, both impaired gastric accommodation and TLESRs can increase stomach pressure, promoting acid reflux.10 Other potential overlapping pathways include esophageal acid exposure, delayed gastric emptying, and visceral hypersensitivity.9
Irritable Bowel Syndrome
In a multicenter, 12-month longitudinal study involving 807 individuals diagnosed with IBS according to the Rome IV criteria, 208 participants (25.8%) had coexisting PDS, 60 (7.4%) had EPS, and 178 (22.1%) had both PDS and EPS.11 Participants with IBS and PDS, as well as those with both PDS and EPS, reported a significantly greater impact on daily activities, defined as interference ≥ 50% of the time, compared to those with IBS alone (73.8% for IBS and PDS, 72.7% for IBS, PDS, and EPS, vs. 50.5% for IBS alone; p < 0.001). Patients with overlapping PDS and EPS were more likely to see their physician about their symptoms and underwent a higher number of IBS treatments compared to those with IBS alone.
Table 2. Other Symptoms of Postprandial Distress Syndrome and Epigastric Pain Syndrome
Other Symptoms of PDS
Other Symptoms of EPS
Postprandial epigastric pain or burning
Pain may be induced by ingestion of a meal, relieved by ingestion of a meal, or may occur while fasting
Postprandial epigastric bloating
Epigastric bloating
Postprandial belching
Excessive belching
Postprandial nausea
Nausea
Gastroparesis
GP is a neuromuscular disorder that is classified by delayed gastric emptying, with more than 60% of food remaining in the stomach at 2 hours and/or more than 10% at 4 hours.12 Recent studies have shown that delayed gastric stomach emptying is also present in 25-37% of patients with FD.12 Bloating, postprandial fullness, early satiety, and epigastric pain are symptoms commonly experienced by both patients with FD and GP; however, nausea and vomiting are hallmarks for GP alone.13 Pasricha et al.conducted a prospective study of 944 patients for 48 weeks to study the relationship between FD and GP.14 Out of the total patients, 720 (76%) were diagnosed with GP and 224 (24%) with FD. By 48 weeks, 41% of patients had a revised diagnosis: 42% of those initially diagnosed with GP were reclassified as FD, whereas 37% with FD initially were now diagnosed with GP.This diagnostic shift reflects the clinical overlap between these two disorders and the hypothesis that gastric emptying studies alone may not be an accurate marker for distinguishing between the two.
Self-Reported Dietary Triggers
In a study of over 200 patients with FD, an increase in all FD symptoms occurred within 15 minutes of eating a meal in 79% of patients, showing that diet is a significant contributor to symptoms.15 Studies on self-reported food and lifestyle triggers show that fatty foods, acidic foods, spicy foods, wheat products, watermelon, and fruit juices are the most common reported.16 However, some studies suggest that spicy foods may actually improve symptoms. In a small randomized controlled trial of 30 individuals with functional dyspepsia, red pepper powder significantly improved overall symptom scores, including reductions in epigastric pain, fullness, and nausea compared to placebo.17 In a cross-sectional survey of 121 patients with FD, 55% listed FODMAPs as the most reported trigger which included wheat, fruit juices, and watermelon.18
Current Evidence from Studied Diet Interventions
There have been several dietary approaches explored for the treatment of FD including the traditional dietary advice (TDA), gluten-free diet (GFD), and the low FODMAP diet (LFD), though evidence at this time is limited.
Traditional Dietary Advice
The recommendations under TDA include eating small, frequent meals, avoiding perceived dietary triggers such as alcohol, caffeine, chocolate, spicy or acidic foods, and high-fat foods, consuming food slowly and chewing thoroughly, and not eating 3 hours before bed. Recent research has explored the relationship between symptom exacerbation and some of the foods listed above, including high-fat food and spicy foods. High-fat foods have been shown to delay gastric emptying, impair gastric motility, and increase post-meal fullness in patients with FD.19
Capsaicin, the chemical compound found in higher concentrations in chili peppers, has been shown to lead to more symptoms in individuals with FD when compared to healthy controls or placebo.19 Capsaicin activates the transient receptor potential vanilloid-1 (TRPV1) receptors, leading to a burning sensation. Capsaicin can also result in chemical hypersensitivity, which can trigger upper gastrointestinal symptoms in individuals with FD.20 The genetic variation of the TRPV1 gene, G315 polymorphism, is inversely correlated with FD, though research has shown that gene variations were unable to predict the severity of FD symptoms based on questionnaires.
Gluten-Free Diet
Hosseinian et al. conducted a systematic review including information on the impact of gluten on FD symptoms across 27 studies, with a meta-analysis on 5 RCTs.21 The meta-analysis showed that there was a statistically significant increase in the severity of epigastric pain (weight mean difference (WMD) = 0.46; 95% CI), bloating (WMD = 0.67; 95% CI), and early satiety (WMD = 0.91; 95% CI) following gluten-consumption of 0.5-32 gram per day.21 These findings suggest relief of FD symptoms associated with avoiding or reducing gluten. Refractory functional dyspepsia (RFD) is defined by symptoms that continue despite medical interventions or Helicobacter pylori (H. pylori) eradication.
The presence of non-celiac gluten sensitivity (NCGS) in 77 patients with RFD was investigated in a randomized, double-blind, placebo-controlled trial.22 Each patient followed the GFD for 6 weeks, in which 27 patients (35%) showed symptom improvement. Of the 27 patients that were then assigned to a gluten or placebo challenge, 5 patients (6.4% of the total sample) reported intestinal and/or extra intestinal symptoms after gluten exposure. The most common symptoms reported included postprandial fullness (100%), epigastric pain/burning (80%), fatigue (80%), headache (80%), and musculoskeletal pain (60%). Patients were monitored for three months following the study and three additional patients reported symptom recurrence with gluten consumption. Due to the overlap seen between NCGS and FD, the GFD may be an effective dietary recommendation in symptom management for a subset of patients with FD in which there is a clinical concern for NCGS.22
Low Fodmap Diet
In a single-blind prospective study, Goyal et al.evaluated the efficacy of the LFD and TDA.23 During the study, the Short-Form Nepean Dyspepsia Index (SF-NDI) was used to measure symptomatology in 105 patients with FD (54 assigned to LFD, 51 assigned to TDA), with each subject completing either one of the two diets for 4 weeks (phase I). The participants following the LFD were then advised to follow the reintroduction phase of the LFD for 4-12 weeks (phase II). The baseline SF-NDI scores improved significantly with both diets (LFD: 66.7% improvement [36/54]; TDA: 56.9% improvement [29/51]; p = 0.32). Patients with bloating and PDS had significantly greater improvements with the LFD versus TDA at 4 and 12 weeks (p = 0.04), despite improvements in overall symptomatology in both diets.23 While not statistically significant, there was a trend towards improvement in EPS patients with TDA.
The effectiveness of the LFD was compared to standard dietary advice (SDA), like the recommendations under TDA, in an observational study.24 Of the 59 patients with FD, 40 followed the LFD and 19 were assigned to SDA. The Structured Assessment of Gastrointestinal Symptoms (SAGIS) was used to collect data on epigastric and overall gastrointestinal symptoms. The results showed a greater reduction in epigastric scores in the LFD compared to SDA (p = 0.032). Additionally, there were greater reductions in postprandial pain, excessive belching, and bloating in the LFD (p < 0.05). When looking at overall gastrointestinal symptoms, there was statistically significant improvement in the LFD group compared with the standard dietary advice (p = 0.026).
Preliminary results seen in an abstract from the University of Leuven showed that 62% of 25 patients with FD experienced a statistically significant improvement in symptoms following a 6-week low FODMAP diet. Improvements were observed in both overall and individual symptom scores, including upper abdominal bloating, early satiety, and postprandial fullness. Following the 6-week intervention, patients followed a blinded reintroduction phase, which revealed variability in the specific FODMAPs that triggered symptom recurrence. Mannitol and galacto-oligosaccharides triggered symptom recurrence in 29% of the patients, followed by fructans (21%), sorbitol (14%), fructose (14%) and lactose (12%).25 It is important to note that fructans are found in many gluten-containing grains. Researchers who have studied the GFD in FD have noted that it is not clear whether fructans or gluten is the culprit for triggering dyspeptic symptoms.21
Complementary and Alternative Therapies
According to American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) guidelines, the quality of evidence supporting complementary and alternative nutrition therapies for FD management is of poor quality.26 The available evidence on the therapeutic benefits of caraway oil, STW5, artichoke leaf extract, and ginger in management of FD will be reviewed.
Caraway Oil
Caraway oil has been hypothesized to increase gastric accommodation, and L-menthol is an antispasmodic whose action includes modulation of gastric sensory nerves, thereby promoting smooth muscle relaxation. The combination of these agents may exert a prokinetic effect and reduce visceral hypersensitivity. A meta-analysis and systematic review of five randomized controlled trials involving 578 patients showed that the combination of caraway oil and L-menthol resulted in statistically significant improvement in overall FD symptoms, specifically with a reduction in epigastric pain. While these results are promising, limitations identified from this study include a short treatment duration of only four weeks, an insufficient sample size to be able to evaluate publication bias adequately, and potential differences in patient diagnosis due to the lack of using validated criteria among all studies.27It should be noted that peppermint is not appropriate for all patients, including those with hiatal hernia, GERD, gallbladder disorders, and those that are pregnant and lactating.28,29
STW-5
Efficacy of STW-5, a nine-herb preparation, was tested in an 8-week double-blind, placebo-controlled RCT of 315 patients with FD. In the treatment group, the therapeutic effect was seen as early as within 2 weeks, with symptom improvement of 57%, which increased to 86% by week 4. However, the number of responders in the placebo group was similar to the STW-5 group, respectively 72.2% versus 78.3%. Overall, in comparison to the placebo group, the GIS score improved significantly in the STW-5 group during the course of treatment (p < 0.05).30 Furthermore, a meta-analysis of three RCTs demonstrated that STW-5 provided a statistically significant benefit over placebo in reducing postprandial fullness, early satiety, and epigastric pain.31 It should be noted that case reports of liver injury with use of this product have been reported and close monitoring with a medical professional is recommended if considering use of STW-5.32
Artichoke Leaf
Artichoke (Cynara scolymus) leaf extract (ALE), long used for dyspepsia, has been shown to have lipid-lowering, antioxidant, and antispasmodic effects. The effectiveness of ALE in managing FD was evaluated in a six-week, double-blind, placebo-controlled study involving 247 patients with FD. Participants received either ALE preparation or a placebo, and the effectiveness of ALE was assessed using a four-point patient-rated scale of overall symptom change. Dyspeptic symptoms and quality of life were also evaluated using the Nepean Dyspepsia Index (NPI). After six weeks, the ALE group showed significantly greater symptom improvement than placebo (p < 0.01), with notable reductions in early satiety, flatulence, and fullness compared to placebo (all p < 0.05), and enhanced quality of life scores (p < 0.01).33 However, evidence is too limited at this time to make clinical recommendations.
More recently, the effectiveness of ALE in the management of FD has been evaluated in combination with ginger (Zingiber officinalis). In addition to its well-known anti-nausea and antiemetic effects, ginger has also been shown to enhance gastric motility. The efficacy of a combination of ALE and ginger was explored in a 4-week, double-blind, placebo-controlled trial including 126 adults diagnosed with FD. Participants took two capsules daily; 65 received the supplement containing ginger and ALE, while 61 received the placebo. After two weeks, there were significant improvements in FD symptoms in the supplementation group compared to the placebo group (p = 0.017). These results remained consistent at the 4-week mark. Specifically, there were significantly greater improvements in nausea, epigastric fullness, epigastric pain, and bloating in the supplementation group when compared to the placebo (p < 0.001, p < 0.001, p < 0.002, p = 0.017, respectively).34
Ginger
Ginger alone also has been studied in the context of stomach emptying, with results showing that 3 pills daily equaling 1200mg could increase gastric emptying and stimulate antral contractions, though its impact on FD symptoms is conflicting.35-36 In all but one of the studies, there were no adverse events noted. In the oldest of the studies, adverse events were classified as gastrointestinal, identified as mild to moderate and resolved on their own by the end of the study.
Practical Applications
When selecting dietary or complementary interventions for FD, tailoring recommendations to the patient’s specific symptom profile can improve effectiveness. The following points highlight how current evidence can guide clinical decision-making:
Patients experiencing bloating and PDS may benefit more from an LFD than a TDA.
Individuals with postprandial pain, excessive belching, and bloating are the most likely to experience meaningful symptom relief from an LFD.
Given the overlap between NCGS and FD, a GFD may help manage symptoms in patients for whom NCGS is a clinical concern.
Although evidence is not statistically significant, patients with EPS may notice some improvement with a TDA.
Caraway oil, based on limited data, may reduce FD symptoms—particularly epigastric pain.
STW-5 may help alleviate postprandial fullness, early satiety, and epigastric pain; however, it may not be appropriate for all patients and has been linked to possible liver-related adverse effects.
Ginger and artichoke extracts may provide relief for FD symptoms; however, current evidence is limited and insufficient to support routine clinical use.
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Gastrointestinal bleeding (GIB) is associated with significant morbidity and mortality. Despite improved endoscopic practices for GIB, approximately 8-15% of patients fail primary endoscopic therapy, which includes injection, thermal, and mechanical therapy. These techniques require precise localization of the bleeding source and may not be as effective in patients with lesions that are difficult to access, have tumor-associated bleeding, or broad based bleeding sources. Additionally, a high level of endoscopic expertise is required for these modalities which may not be available at smaller hospitals.
Recently, topical endoscopic hemostatic agents were introduced to treat GIB. These agents have had promising results as salvage therapy or even as primary therapy without requiring precise localization or extensive technical expertise.3, There are five approved agents (Table 1): hemostatic agent TC-325 (HemosprayTM, Cook Medical Inc, Winston-Salem, North Carolina, US), synthetic self-assembling peptide agent (PuraStatTM, 3D-Matrix, Europe Ltd., France), EndoclotTM (Endoclot Plus Inc., Santa Clara, California, US) polysaccharide hemostatic system (PHS), biocompatible natural polymer UI-EWD (NexpowderTM, NextBiomedical Co., Incheon, South Korea) and erythrocyte protein network (Ankaferd Blood StopperTM, ABS, Ankaferd Health Products Ltd., Turkey).
Table 1. Summary of Topical Endoscopic Hemostatic Agents
Agent/Trade Name
Composition
Mechanism of Action
Approved Application
TC-325 (HemosprayTM)
Granular mineral-based
Absorbs water and activates the clotting cascade to form a mechanical tamponade
Prophylaxis post-intervention, Peptic ulcer disease, malignant tumors, and post-interventional bleeding
Ankaferd Blood StopperTM
Erythrocyte protein network
Encapsulated protein network provides focal points for erythrocyte aggregation
Only approved in Turkey: non-variceal upper GIB (Case reports: peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding)
Topical endoscopic hemostatic agents are intended to control active non-variceal GIB (NVGIB) by delivering a substance over the bleeding site through a catheter via the endoscope working channel. The main advantage of topical agents is that less precision is required when applying the agent to the bleeding site. This allows for treatment of lesions that may be difficult to access or refractory to standard therapy. Although recent studies have shown that hemostatic agents were effective in NVGIB, there had been reports of high re-bleeding rates.5 Topical agents can also be used prophylactically to reduce the risk of bleeding following polypectomy, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD). These agents can also be used to treat or reduce the risk of sphincterotomy bleeding during endoscopic retrograde cholangiopancreatography (ERCP).
This manuscript aims to discuss the efficacy, safety, advantages, and disadvantages of the FDA-approved topical endoscopic hemostatic agents.
Hemostatic agent TC-325/Hemospray
Hemostatic agent TC-325 is a metabolically inert, nontoxic, granular mineral-based inorganic powder that when in contact with blood will induce hemostasis by absorbing water and activating the clotting cascade. As a result, a mechanical tamponade and adhesive barrier form over the bleeding site. Hemospray is deployed through the endoscope-integrated catheter in short bursts when a compressed carbon dioxide propellant is activated by the device’s trigger.
Hemospray has been shown to be successful in controlling bleeding from peptic ulcer disease, variceal GIB, and lower GIB as both monotherapy and as an adjunctive therapy to conventional therapy.8,9,10,11 (Figures 1 and 2) Sung et al. and Kwek et al. reported hemostasis in 90% of patients with monotherapy and 100% of patients as an adjunctive therapy., In another study, Ibrahim et al. reported 100% hemostasis in nine patients treated with monotherapy. In regards to lower GIB, Hemospray was effective in achieving hemostasis for spurting post-polypectomy bleeding that did not respond to clipping. Additionally, in a systematic review and meta-analysis by Facciorusso et al., the immediate hemostasis rate for Hemospray monotherapy in 8 studies with 175 patients was 96.2% (95% CI 93.5-99.7%). Bleeding from gastrointestinal tumor may sometimes be diffuse and lack a specific target suitable for endoscopic hemostasis. In these cases, Hemospray is a good option to provide short-term hemostasis. In a large multicenter study conducted by Pittayanon et al., they found that hemostasis was achieved with Hemospray in 98% of cases.
However, the downside of Hemospray monotherapy is that studies show high rebleeding rates at 7 days typically ranging between 15-49%.12,,, Facciorusso et al. found that there was a 9.8% (95% CI 3.8-15.8%) pooled 7-day rebleeding rate and a 12.3% (95% CI 6.0-18.7%) pooled 30-day rebleeding rate. A study by Cahyadi et al. found even higher rebleeding rates at 3 days (43.1%) and at 7 days (49.0%). This is likely due to the fact that while Hemospray induces coagulation, it generally does not treat the underlying cause of a bleed. Recent guidelines published in the Annals of Internal Medicine recommend that Hemospray be used only as a temporizing measure when primary endoscopy therapy fails and should not be used as a monotherapy due to the high re-bleeding rates.
Hemospray can often limit endoscopic visualization after deployment, and when it is used before other hemostatic agents, there may be a risk of obscuring the boundaries of a lesion (making it more difficult to implement other hemostatic options if they are needed). As Hemospray is sprayed, the cloud of powder can temporarily fill the endoscopic field of view and if the endoscope’s tip is too close to the site of application, the powder can adhere directly to the lens. To avoid this, we recommend releasing the powder in short 1- to 2- second bursts and maintaining the endoscope’s tip at least 1-2 cm away from the lesion.
PuraStat
PuraStat is a biocompatible synthetic peptide gel consisting of a repeating sequence of the amino acids Arginine, Alanine, and Aspartic Acid. Once Purastat gel comes in contact with blood, the peptide solution is neutralized to form a 3-dimensional nano-fiber hydrogel scaffold of beta-sheets. This structure, similar to the extracellular matrix, forms a physical barrier over the bleeding vessel or bleeding site to achieve hemostasis.
PuraStat is currently intended for prophylaxis of bleeding secondary to therapeutic endoscopic procedures such as endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR), although it has been used in a wide variety of contexts. (Figures 3 and 4) Prior studies have shown that post-ESD, there was a smaller mean number of any secondary temporizing measures required when PuraStat was used initially compared to the control group without PuraStat (1.0±1.4 vs 4.9±5.2, p<0.001), demonstrating the efficacy of PuraStat in managing intraoperative bleeding. , In a study by Uraoka et al., only 1 out of 51 included patients had post-ESD bleeding after being treated with PuraStat. However, Gomi et al. 2024, in a more recent and larger study of 101 patients, did not find that PuraStat was associated with improved rates of post-ESD bleeding, highlighting the need for further research in this area.
The efficacy of PuraStat in managing post-sphincterotomy bleeds has also been studied. Ogura et al. found that 98% of patients achieved complete cessation of bleeding with PuraStat monotherapy. Kishore et al. found that 96.5% (95% CI: 92.3-100) of patients achieved complete cessation of bleeding with PuraStat monotherapy, with a rebleeding rate of 3.10% (95% CI: 0.50-5.60).
Furthermore, in a recent meta-analysis, three studies showed PuraStat to be effective in both primary and rescue hemostasis for bleeds caused by peptic ulcer disease, large polyps, tumors, and capillary lesions. 20,,, For primary hemostasis, the pooled immediate hemostasis rate was 87% (95% CI 75%-94%) and the pooled rebleeding rate within 30 days was 10% (95% CI: 6%-16%).20,26,27,28 In Bianchi et al.’s study, 111 patients were included with an initial hemostatic success rate of 94% (95% CI 88-99%). When used as a secondary hemostatic product, PuraStat had a hemostatic success rate of 75% (95% CI 59-91%). The rebleeding rates at 3 and 7 days were 9% and 15% after primary use and 13% and 19% after secondary use, respectively. The overall rebleeding rate at 30 days was 16%.20
In comparison with Hemospray, PuraStat is a transparent hemostatic agent that does not compromise endoscopic visualization after deployment. This makes it possible to check post-therapy bleeding status and continue further interventions, if needed. It is already prepared for the endoscopist in a single prefilled, ready-to-use syringe and deployed through the endoscopic catheter. Given that PuraStat is a gel, it is also highly versatile and can be used in narrow spaces where the bleeding site is difficult to reach with a hemoclip or a thermal probe.
However, similar to Hemospray, the downside of PuraStat is it has a high rebleeding rate of 10%-15% at 7 days if used as monotherapy.20, 26 This is a drawback of hemostatic agents in general given they can only bind to sites with active bleeding for 12-24 hours. However, one recent retrospective study showed there was no statistical significant differences in rebleeding (p=0.64) or mortality (p=0.69) when comparing initial PuraStat use and the standard care (i.e. injection, hemoclips, etc.).
Endoclot
Endoclot is a starch-derived compound consisting of biocompatible absorbable hemostatic polysaccharide that when in contact with blood, will rapidly absorb water. This causes a high concentration of clotting factors, red blood cells, and platelets to accumulate at the bleeding site accelerating the hemostasis process.3 Afterwards, the polysaccharide will form a gelled, adhesive matrix providing a mechanical barrier to seal and potentially protect the wound site from further bleeding.
Endoclot is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, esophageal ulcers and esophagitis, as well as post-interventional bleeding. ,,,, In a recent meta-analysis of 5 studies and 398 patients, the immediate hemostasis rate for any GIB after Endoclot monotherapy was 86% (95% CI: 80%-90%), with a rebleeding risk within 30 days of 10% (95% CI 6%-16%).26 In a recent multicenter analysis of 43 patients by Hagel et al., the immediate hemostasis rate was 81.8% when Endoclot was used as a salvage therapy. In one study, among patients with tumor bleeding, there was a 0% rebleeding rate after treatment with Endoclot as monotherapy.35
Furthermore, Endoclot is delivered differently compared to other hemostatic agents. Hemospray is delivered at high pressure with a carbon dioxide cartridge which can be advantageous in situations with high pressure bleeding. However, the high-pressure application from the carbon dioxide can potentially cause tissue injury as well. Two studies have shown perforation in their patient cohort after Hemospray application due to high-pressure carbon dioxide application.35, In contrast, the pressure at which Endoclot is sprayed is much lower making it more suitable for localized bleeding lesions and has lower risks of causing tissue injury.
The main disadvantage of Endoclot, similarly to other hemostatic agents, is the risk of rebleeding due to low binding times of the adhesive matrix to the bleeding site. Limited studies report the advantages and disadvantages of Endoclot compared to other forms of hemostatic agents. Beg et al. reported on the use of Endoclot by novice operators. In their study, assisting nurses who had no specific training using Endoclot had success and ease of use when it was applied.32
Nexpowder
Nexpowder is a biocompatible natural polymer composed of oxidized dextran and succinic anhydride that gets converted to adhesive hydrogel when in contact with water. It then forms a mechanical barrier at bleeding site(s) to promote hemostasis.39 It is deployed by insoluble air propellant and uses a pre-installed battery as its power source, allowing air pressure generated from the air pump in the delivery system’s spray body to provide a force to move the powder into the delivery catheter.39 The advantage of Nexpowder is that it does not require active bleeding to work which allows it to have a potential role in prophylaxis post-procedural. However, most studies show promising results for Nexpowder as a role in primary hemostasis or prophylaxis post-intervention as well.,,
Nexpowder is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, and post-interventional bleeding.40,41,42 It can also be used as prophylaxis post-intervention.40,42 In a recent meta-analysis of 3 studies and 114 patients, the immediate hemostasis rate for any GIB after Nexpowder monotherapy was 96% (95% CI: 91%-99%), with a rebleeding risk within 30 days of 8% (95% CI 3%-20%).26 Shin et al. found that there was immediate hemostasis in 100% (n=23) of their patient cohort when using Nexpowder monotherapy for active bleeds secondary to luminal malignant tumors. However, there was a high rate of rebleeding within 1 month in 26.1% and 22.5% of their patients when using Nexpowder as monotherapy and salvage therapy, respectively.42 All three studies used Nexpowder post-intervention as a prophylaxis for acute bleeding.40,41,42
One advantage of Nexpowder is it has a lower rebleeding rate within 30 days (8%) compared to other hemostatic agents (subgroup differences: p < 0.01).26 In a study conducted by Park et al., they found that only 2 out of 54 patients (3.7%) had rebleeding within 30 days after using Nexpowder as a monotherapy.41 In another study, Park et al. used a second-look endoscopy after 24 hours of applying the Nexpowder as a monotherapy and saw that the hydrogel from Nexpowder was still attached to the bleeding site in 69% of their patients 24 hours later.40 Shin et al. found that the when using Nexpowder as a monotherapy, the hydrogel was reported to be present at 70.2% of sprayed bleeding sites using second-look endoscopy at 24 hours.
Ankaferd Bloodstopper
Ankaferd Bloodstopper (ABS) is a hemostatic agent only approved in Turkey and Bosnia-Herzegovina and composed of a mixture of plants, including Thymus vulgaris, Glycrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. The mechanism of action of ABS is it rapidly forms an encapsulated protein network that provides multiple focal points for erythrocyte and leukocyte aggregation, including fibrinogen, which, in turn, induces protein aggregation., ABS is a topical powder application that is sprayed via a catheter through the working channel of the endoscope. ABS is currently approved in Turkey and Bosnia-Herzegovina for upper and lower GIB that is only refractory to conventional hemostatic measures.3
There has been a relative paucity of studies analyzing the effectiveness and safety of ABS monotherapy and salvage therapy. No safety concerns have been reported to date. A case series of 27 patients with active, non-variceal GIB showed an immediate hemostasis rate of 73% when ABS was used as a monotherapy and 100% when used in combination with standard therapy.46 Rebleeding within 48 hours was seen in 15.8% of patients with ABS monotherapy and 33.3% with ABS salvage therapy. There are multiple case reports of the success of immediate hemostasis using ABS monotherapy in patients with peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding.,,,,,,,
Conclusion
Topical hemostatic agents have been shown to be effective in hemostasis for gastrointestinal bleeding, especially when used in combination with conventional methods or as salvage therapy. Limited studies have demonstrated high primary hemostasis rates in both upper and lower GIB when used as monotherapy but with some risk of rebleeding. Topical hemostatic agents are simple to use and do not require a high level of endoscopic expertise to employ.
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39 Bang B, Lee E, Maeng J, Kim K, Hwang JH, Hyon SH, Hyon W,
Lee DH. Efficacy of a novel endoscopically deliverable muco-adhesive
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YW, Lee DH. Efficacy of a novel hemostatic adhesive powder in
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42 Shin J, Cha B, Park JS, Ko W, Kwon KS, Lee JW, Kim HK, Shin
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Bacterial Translocation and Biliary Atresia in Infants
Biliary atresia (BA) is a fibro-obliterative disease process of unknown etiology affecting the biliary tract in infants. BA eventually leads to cirrhosis and is the leading cause of liver transplantation in infants. Since changes in the intestinal microbiome are associated with chronic liver disease in adults, the authors of this study looked for similar issues occurring in infants with BA. Research previously done by this group has demonstrated increased alpha-diversity of pathogenic intestinal bacteria with an associated decrease in potential beneficial bacteria in children with BA who had underwent hepatoportoenterostomy (the “Kasai procedure” (KP)) and had worse surgical outcomes. This current study evaluated gut bacterial translocation and intestinal barrier function in children with BA.
Infants with BA were recruited in a prospective manner and were assessed at 6 weeks, 12 weeks, and 24 weeks post-KP. Prior to KP, all infants had standard blook work and demographics obtained. They also underwent liver biopsies to assess for fibrosis. After KP, standard blood work for liver disease as well as hepatic elastography studies were obtained. Additionally, blood and stool specimens were obtained to assess for intestinal barrier function and evidence of bacterial translocation.
A total of 55 infants with BA were recruited for the study for which 33 infants had no jaundice at 6 months after KP while the rest of the patient group continued to have jaundice. Patient demographics were similar between the two groups. Liver transplantation occurred in 24 of the 55 infants by 2 years of age for which 91% of those infants requiring liver transplantation had no clearance of jaundice by 6 months after KP. At least one episode of cholangitis occurred with 26 of the 55 infants by 6 months after KP for which 64% of these specific infants were still jaundiced at 6 months after KP.
A comparison occurred between patients who were cleared of jaundice after KP and those that did not clear jaundice after KP. Although markers for intestinal barrier function and bacterial translocation were similar between the two patient groups prior to KP, differences were noted very soon after KP. At 6 weeks post KP, intercellular adhesion molecule 1 (ICAM-1), interleukin-4 (IL-4), and claudin-3 were significantly elevated in the patient group with continuing jaundice after KP. By 12 weeks post KP, ICAM-1, IL-8, IL-1ß, and claudin-3 were significantly elevated in the patient group with continuing jaundice after KP. By 24 weeks post KP, ICAM-1, IL-2, IL-6, IL-8, IL-1ß, tumor necrosis factor alpha (TNF-ɑ), and vascular cell adhesion molecule 1 (VCAM-1) were significantly elevated in the patient group with continuing jaundice after KP.
Univariate analysis done at 6 weeks post KP demonstrated that elevated levels of total bilirubin, serum aspartate aminotransferase (AST), ICAM-1, and claudin-3 were significantly associated with persistent jaundice. A multivariate analysis demonstrated that elevated levels of ICAM-1 and claudin-3 were significantly associated with jaundice at 24 weeks post KP. VCAM-1, ICAM-1, TNF-ɑ, lipopolysaccharide (LPS), and intestinal fatty acid binding protein (IFABP) all increased significantly from before KP to 24 weeks post KP in patients who remained jaundiced. A significant correlation of total bilirubin levels after KP was found with ICAM-1 levels at 6 weeks post KP; with ICAM-1, IL-8, IL-1ß levels at 12 weeks post KP; and with ICAM-1, IL-8, IL-1ß, IL-6, IL-2, and VCAM-1 levels at 12 weeks post KP.
In terms of fibrosis correlation, only ICAM-1 was significantly associated with an elevated AST-to-platelet ratio prior to KP although liver histology prior to KP was not associated with ICAM-1 levels. ICAM-1 and VCAM-1 were significantly associated with an elevated AST-to-platelet ratio and liver stiffness measured by elastography at 6 weeks post KP. IL-1ß, TNF-ɑ, IL-8, IL-4, and IL-2 were significantly associated with an elevated AST-to-platelet ratio at 12 weeks post KP. Only ICAM-1 was associated with an elevated liver stiffness measurement as measured by elastography at 24 weeks post KP. D-lactate (used to demonstrate bacterial translocation) was significantly associated with hepatic fibrosis only at 12 weeks post KP.
In terms of markers of bacterial translocation and inflammation, lipopolysaccharide binding protein (LBP) levels were significantly correlated with IL-6 and TNF-ɑ at 6 weeks post KP; were significantly correlated with D-lactate and ICAM-1 at 12 weeks post KP; and were significantly correlated with IL-6 and IL-17 at 24 weeks post KP. Using 16S rRNA amplicon sequencing, the most common bacteria identified in fecal specimens at all time points post KP included Enterococcus, Clostridium, Fusobacterium,and 10 other bacterial species. Finally, elevated fecal calprotectin levels were significantly associated with severity of jaundice in infants at 24 weeks post KP.
This study demonstrates that gut inflammation and potential bacterial translocation into the bloodstream of infants with BA who undergo KP may be associated with worse surgical outcomes. The authors point out that claudin-3, which is a biomarker for tight junction integrity, may be an effective screening tool to determine potential outcomes after KP in children with BA.
Jain V, Nulty J, Alexander E, Buford C, Davenport M, Chokshi S, Riva A, Dalby M, Verma A, Hall L, Yuksel M, Dhawah A. Claudin-3, Lipopolysaccharide Binding Protein, and Jaundice Clearance in Infants with Biliary Atresia. Journal of Pediatrics 2025; 286: 114703.
Using H. pylori Antibiotic Sensitivity to Drive Treatment in Children
Helicobacter pylori (H. pylori) is a gram-negative bacteria associated with gastric infections worldwide. Besides causing gastritis and peptic ulcer disease, a chronic infection by this bacterium can lead to gastric adenocarcinoma and MALT lymphoma. Antibiotic therapy is essential for curing this infection, and it would be especially important to identify a correct antibiotic regimen as H. pylori is associated with a high rate of antibiotic resistance. The authors of this study evaluated the efficacy of susceptibility-guided treatment (SGT) compared to empirical therapy (ET) for H. pylori.
This retrospective study occurred at a single tertiary care children’s hospital in the United States. All included patients had a history of a biopsy-proven initial H. pylori infection and had received antibiotic treatment. All patients were treated for H. pylori using the 2016 Joint ESPGHAN / NASPGHAN guidelines for treatment of H. pylori in children (see https://www.naspghan.org/files/Joint_ESPGHAN_NASPGHAN_Guidelines_for_the.33.pdf).
All patients treated either by ET or by SGT underwent testing for H. pylori eradication by either fecal antigen screening or by repeat esophagogastroduodenoscopy (EGD) with biopsy.
A total of 238 patients were diagnosed with an initial H. pylori infection over a 5-year period (2019 to 2024). After excluding patients who had received no therapy, had no H. pylori culture sent, or had a culture with no bacterial growth, a total of 218 patients were left for which 95 patients underwent ET and 123 patients underwent SGT. Mean patient age was 13.6 ± 4.8 years, and 50.9% of patients were male. The most common endoscopic finding was gastritis in 92.7% of patients with 100% of patients having gastritis on histology. Antibiotic resistance was present in 45.5% of H. pylori cultures with the most common single antibiotic resistance being clarithromycin at 26.8%. The most common dual antibiotic resistance was clarithromycin and metronidazole at 10.6%. No cultures demonstrated resistance to tetracycline. The most common treatment for H. pylori in the study was clarithromycin-based triple therapy which was used in 41.3% of patients. Subsequent eradication was achieved in 80.7% of patients.
Age, sex, and ethnicity were not associated with antibiotic treatment failure in patients treated with either ET or SGT. However, patients categorized as “white” had significantly higher eradication rates. Treatment failure rates were significantly higher in those infections associated with amoxicillin resistance as well as in infections associated with clarithromycin-metronidazole dual resistance. Amoxicillin use was significantly associated with eradication while a history of prior amoxicillin, clarithromycin, and metronidazole use were significantly associated with treatment failure.
Eradication was significantly higher in those patients treated using SGT (89.4%) compared to ET (70.2%). Univariate analysis demonstrated that patients who received amoxicillin during therapy, received clarithromycin during therapy, received metronidazole during therapy, or had received any of these three antibiotics in the past were significantly less likely to achieve eradication with no other factors reaching significance. Multivariate analysis demonstrated that amoxicillin use was the sole factor associated with H. pylori eradication.
This study clearly demonstrates that H. pylori eradication was superior when using SGT. Amoxicillin bacterial resistance and prior use of antibiotics seemed to be a significant issue in preventing eradication in this patient population. Obtaining H. pylori cultures to drive directed antibiotic therapy is recommended and should be more widely available.
Chan C, Bousvaros A, Goldsmith J, Liu E, Bonilla S. Antimicrobial Susceptibility-Guided Treatment is Superior to Empiric Therapy for Helicobacter pylori Infection in Children. Journal of Pediatric Gastroenterology and Nutrition. 2025; 81: 1133-1141.
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Christina M. Minami
Douglas G. Adler
Neha D. Shah
Elizabeth Wall
Vatsal Khanna
Sophia Scattaglia
Nancee Jaffe
Magnus Chun
