Page 9 – Practical Gastro

Nutritional Considerations for Hypermobile Ehlers-Danlos Syndrome

May 2024 • Volume XLVIII, Issue 5

Cheryl Iny Harris,

Dacre R.T. Knight,

Lisa A. Mejia,Laurie Bilyeu

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While the hallmarks of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum
disorders (HSD) are pain, joint instability, and injuries to soft tissues, most patients with hEDS and
HSD have a myriad of manifestations within the gastrointestinal tract that affect dietary tolerance
and quality of life. These include irritable bowel syndrome, functional dyspepsia, gastroparesis,
constipation, and celiac disease. Other common comorbidities include postural orthostatic tachycardia
syndrome and mast cell activation disorders, which may impact fluid and electrolyte balance, food
intolerances, and contribute to anxiety around food. Nutritional supplements are commonly used,
though research is needed to clarify their potential role in hEDS/HSD management. Patients with hEDS/
HSD benefit from the support of a multidisciplinary healthcare team. This review discusses nutritional
implications and provides practical recommendations to address the manifestations of hEDS/HSD.

Introduction

Ehlers-Danlos syndromes (EDS) encompass a group of 14 heritable connective tissue disorders.¹ The most prevalent form of EDS is hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) with hEDS/HSD appearing to be female-predominant inherited disorders.² All types of EDS except hEDS/ HSD have identified genetic markers. HSD is also known as joint hypermobility syndrome (JHS), an older term that still appears in research. Key characteristics of hEDS/HSD are pain, fatigue, joint instability, and its consequential injuries to soft tissues.3 Patients with HSD share most of the features of hEDS, with similar symptoms, disease severity, and treatment strategies.³ Clinical features are widespread, affecting neurologic, cardiovascular, gastrointestinal, and urogynaecological systems.

The largest prevalence study is from Wales, UK, indicating 1:500 (2%) of the general population received a formal diagnosis of hEDS or JHS.⁴ Both hEDS/HSD are currently underdiagnosed, with diagnosis typically taking 10+ years.⁵ According to an EDS worldwide survey, 97% of people with EDS report that prior to diagnosis, their healthcare team attributed their symptoms to psychological causes.⁶ Studies suggest the actual prevalence of hEDS/ HSD is closer to 3% of the general population.^4,7

Management of hEDS/HSD involves relieving symptoms and ensuring sufficient nutrient intake. This review focuses on gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), functional dyspepsia (FD), gastroparesis, celiac disease, and other nutrition-related disorders, such as temporomandibular joint (TMJ) dysfunction, eating disorders (EDs), autonomic disorders such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation disorder (MCAD).⁸ Practical applications will be emphasized (see Table 1).

Gastrointestinal Manifestations of hEDS/HSD

Gastrointestinal disorders are among the most common manifestations of hEDS/HSD, with studies reporting ~90% of patients experience symptoms of diseases of gut-brain interaction (DGBIs).⁸ GI symptoms may include dysphagia, reflux, postprandial fullness, bloating, abdominal pain, nausea, vomiting, diarrhea, and constipation. Patients often attribute symptoms to eating, which can generate food fears and changes in appetite that impact nutritional intake and contribute to disordered eating patterns.⁸

Irritable Bowel Syndrome

Research suggests that up to 62% of people with hEDS/HSD are diagnosed with a subtype of IBS (IBS-diarrhea, IBS-constipation, IBS-mixed, IBS-undefined).⁹ Using the ROME IV criteria, IBS is characterized by the presence of recurrent abdominal pain one day a week or more for at least 3 months and the presence of at least two symptoms related to defecation, a change in stool frequency and/or form. Visceral hypersensitivity, central sensitization, autonomic dysfunction, mast cell activation, and/or biopsychosocial factors may also contribute to symptoms of IBS. Symptomatic patients often seek nutrition guidance initially; however, organic disease must be ruled out first if there is unintentional weight loss, anemia, elevated inflammatory markers, or signs of a potential GI bleed.

A first-line approach for IBS management is to implement the NICE (National Institutes for Health and Care Excellence) guidelines, which include:^10,11

eating regular, small meals

eating slowly

hydrating adequately

avoiding excessive caffeine, alcohol, or carbonation

avoiding more than 3 portions of fruit or juice daily

avoiding polyols for people with loose stools

reducing fatty foods

limiting insoluble high fiber foods

Research is limited on the efficacy of the NICE guidelines; however, they are often the initial strategy because of the relative ease of implementation.

If symptoms do not improve, a secondary approach is the low FODMAP diet (LFD) (fermentable oligo, di, monosaccharides, and polyols). The LFD involves a 2–6 week guided elimination diet of osmotically active short-chain carbohydrates, followed by a structured reintroduction phase to learn potential triggers while adding in high FODMAPs, and finally, a personalization phase to maintain intake of FODMAPs that are tolerated well.^10,11 Studies show the LFD reduces GI symptoms, such as bloating, abdominal pain, and diarrhea, in 57-82% of people with IBS.¹⁰ An LFD should only be undertaken with the guidance of a trained Registered Dietitian Nutritionist (RDN).

In a study of 165 patients diagnosed with both IBS and JHS, and controls with IBS only, all subjects followed the LFD.¹² Patients with JHS had greater decreases in abdominal pain and bloating. The patients who had both JHS and IBS-C showed the largest improvement on an LFD compared to IBS-C controls.¹² Further studies are needed to confirm these results and understand the biological mechanism for decreased pain in patients with JHS.

Irritable Bowel Syndrome	Start with the National Institutes for Health and Care Excellence (NICE) guidelines If the NICE guidelines are not successful in alleviating symptoms, consider the low FODMAP diet with the elimination, reintroduction, and personalization phases
Functional Dyspepsia	Consider a trial limiting fatty or spicy foods, wheat, caffeine, and alcohol Consider a Mediterranean Diet pattern to reduce intake of animal protein and increase intake of fruits and vegetables Consider a trial of the low FODMAP diet Have small meals throughout the day Eat slowly and chew well
Gastroparesis	Incorporate a small particle size diet with a focus on blending, mashing, or mincing foods Adjust fiber intake if necessary Increase movement after meals if possible Have small meals throughout the day Consume foods with fat as tolerated. Fat is sometimes tolerated best in liquid form.
Constipation	Eat two kiwifruit a day Increase intake of soluble fiber which binds water (e.g., oats, flax) with increased fluid intake Add foods with natural sorbitol content (e.g., prunes, dried apricots) For IBS-C, consider a short-term trial of the NICE guidelines or the low FODMAP diet
Celiac Disease	Adopt a lifelong gluten-free diet Monitor for nutrient deficiencies
Temporomandibular Disorders	Switch to pureed foods or soft textures if needed Cut food into smaller pieces to ease chewing
Postural Orthostatic Tachycardia Syndrome	Increase fluid consumption to 2-3 liters daily and increase salt up to 6-10 grams unless contraindicated Consider a lower glycemic diet if appropriate Monitor symptoms and tailor specific recommendations based on the patient’s needs
Mast Cell Activation Disorders	An experienced RDN should evaluate a diet journal for potential MC triggers Consider a low histamine diet elimination and reintroduction if indicated

Table 1. Diet Recommendations for Manifestations of hEDS/HSD

Functional Dyspepsia

The hallmarks of functional dyspepsia (FD) include decreased appetite, postprandial distress, early satiety, nausea, belching, and epigastric pain.¹³ Studies found that between 37-86% of patients with hEDS/HSD experience FD symptoms.¹³ FD often impairs dietary intake. Limited research supports small, frequent, regular meals, eating slowly, and chewing well. There is potential benefit to limiting fatty or spicy foods, wheat, caffeine or alcohol.¹⁴ Lower adherence to the Mediterranean diet pattern has been associated with worsening of symptoms in FD, thus there may be utility to adopting the Mediterranean diet, which reduces intake of animal protein and increases intake of fruits and vegetables. Also, implementing the LFD has been shown to reduce symptoms.¹⁴

Gastroparesis

Common gastroparesis symptoms include changes in appetite, nausea, vomiting, early satiety, and unintentional weight loss. A large case-control study compared hospitalized patients with and without EDS and found patients with EDS exhibited a 12.26 higher odds ratio of a concurrent diagnosis of gastroparesis.¹⁵ These results are supported by another study which found 52% of patients with GI symptoms and JHS were diagnosed with gastroparesis.¹⁶ Nutrition interventions to manage gastroparesis include smaller meals, modification of fiber intake, and post-prandial

movement as tolerated to enhance motility. A small particle size diet, or altering food consistency by blending, processing or mashing food may help expand dietary tolerance (e.g., smoothies, mashed potatoes).¹⁷

Constipation

Constipation is common; a recent study found 73% of patients with hEDS/HSD had constipation versus 16% of controls.³ The underlying etiology of constipation in hEDS/HSD is multifactorial and includes DGBIs, delayed motility, small intestinal methane overgrowth, pelvic floor dyssynergia, medication induced constipation, and rectal hyposensitivity.^8,18 Treatment should be individualized, and dietary adjustments may include eating two kiwifruit daily, gradually increasing higher fiber foods, like oats, prunes, or flaxseed, or adding soluble fiber supplements, such as psyllium husk or partially hydrolyzed guar gum.^11,19 Excess fiber intake can potentially aggravate constipation, especially without concurrent adequate water intake. Patients with comorbid rectal hyposensitivity may benefit from biofeedback, which has been studied in hEDS/ HSD.¹⁸

Celiac Disease

One small study found that 16% of people with hEDS/HSD also had celiac disease.⁸ A large case control study determined the rate of celiac disease was 5.5 times higher in people with EDS than the average hospitalized patient.¹⁵ Swedish patients with EDS/JHS had an odds ratio of 2.3 of a subsequent celiac diagnosis.²⁰ A study in children with joint hypermobility (excessively lax joints, without associated pathology) found an odds ratio of 10.9% for positive celiac serology.²¹ Further studies are needed; however, celiac testing is prudent for patients with symptoms or a family history.

People diagnosed with celiac disease need to follow a lifelong, strict gluten-free diet and benefit from consultation with an RDN. Newly diagnosed patients tend to be low in vitamins A, D, E, B12, copper, zinc, folate, and iron, and anyone following a gluten-free diet may be deficient in B vitamins, folate, iron, and calcium due to lack of enrichment and fortification of gluten-free products.²² Nutrient levels should be monitored, with diet modifications and/or supplementation as indicated.

Other Nutrition-Related Manifestations of hEDS/HSD

A range of conditions, including TMJ, POTS, MCAD, and EDs, are frequently found in people with hEDS/HSD. These conditions contribute to the patient’s symptom burden and add an additional layer of complexity to eating.

Temporomandibular Joint Disorders

While the literature is limited, 40-100% of people with EDS report headache and jaw pain.²³ A recent case-control study found that TMJ symptoms, including myofascial pain, headache, jaw pain, and disc displacement occurred more in people with hEDS than controls.²³ Dislocations or subluxations may make chewing difficult and compromise nutritional status. Pain with oral care may exacerbate dental problems. Patients with TMJ and hEDS/HSD should be referred to an RDN to ensure adequate oral intake and appropriate food consistencies, and to knowledgeable dentists and physical therapists (PTs) as needed.

Postural Orthostatic Tachycardia Syndrome

POTS is a form of dysautonomia affecting approximately 30% of people with hEDS/HSD.⁷ It is characterized by an increase in heart rate of 30 beats per minute (bpm) in adults (40 bpm for adolescents) in the first 10 minutes when moving from a recumbent to a standing position. Patients must have symptoms of orthostatic intolerance, such as palpitations, concentration difficulties, abnormal fatigue, presyncope, or headache for 3 or more months without another explanation.²⁴

Nutrition changes are the cornerstones of treatment for POTS, although medication is often needed. POTS involves hypovolemia; treatment expands blood volume via increased fluids, salt, exercise, and decreased fluid pooling with compression garments.²⁴ Over 90% of people with POTS experience GI symptoms. Most symptoms improve when sitting or recumbent; bloating, constipation and diarrhea generally do not.^7,25 People with concurrent hEDS/HSD and POTS may experience a higher burden of GI symptoms compared to those with hEDS/HSD without POTS.²⁵

Recommendations should be tailored based on physician guidance and co-morbid illnesses, such as cardiac diseases.^26,27 Unless contraindicated, the initial recommendations are 6 grams of salt and 2-3 liters of fluid.²⁷ Patients can gradually increase salt intake up to 10 grams, with close monitoring of symptoms, and adjustments based on clinical response.²⁴ Alcohol, caffeine, and dehydration typically worsen symptoms.²⁶

Two small studies investigated dietary interventions in people with POTS. In one study, 20 females with POTS (8 also had hEDS) experienced significant improvements in orthostatic and GI symptoms with a 4-week, self-reported gluten-free diet.28 Another case-control study examined 12 women with POTS who had a history of orthostatic symptoms with high glycemic foods; information on comorbid conditions such as hEDS/HSD was not provided. The study participants experienced a significant increase in tachycardia after consuming 75 grams of glucose, compared to the 13 controls.²⁹ This preliminary research suggests a gluten-free and/or a low glycemic diet deserve further study. They may be worth exploring for motivated patients who have been screened for celiac disease and are not at risk of an ED.

Mast Cell Activation Disorders

Mast cells (MCs) are white blood cells found in the mucosa and throughout connective tissue and skin. MC diseases include clonal diseases, which are rare and associated with genetic mutations, and non-clonal MCADs, which include mast cell activation syndrome (MCAS).³⁰ Typically, MCs respond to pathogens; however, in MCADs, MCs may respond to benign stimuli, such as temperature, food, chemicals, medications, physical exertion, stress, etc. and degranulate, causing an inflammatory cascade by releasing histamine, heparin, prostaglandins, and other mediators. MCAD symptoms affect multiple organ systems: gastrointestinal, neurologic, cardiovascular, dermatologic, and respiratory. Symptoms range from mild to anaphylaxis.³⁰

Ehlers-Danlos Syndromes
Ehlers-Danlos Society: ehlers-danlos.com
Ehlers-Danlos Syndrome (EDS) GP Toolkit: gptoolkit.ehlers-danlos.org
Ehlers-Danlos Support UK: ehlers-danlos.org
Hypermobility Syndrome Association (HMSA): hypermobility.org
SEDS Connective: sedsconnective.org
hEDS/HSD Diagnostic Checklist: ehlers-danlos.com/heds-diagnostic-checklist
EDS Diet & Nutrition: ehlers-danlos.com/international-consortium-working-groups

Physical Therapy
Clarkson University Technologia/Leslie Russek PT, DPT, PhD: webspace.clarkson.edu/~lrussek/research.html
Jeannie di Bon, PT: youtube.com/c/JeannieDiBonHypermobility

Other
Dysautonomia International: dysautonomiainternational.org
The Mast Cell Disease Society: tmsforacure.org

The only well-researched treatment for MCADs is avoidance of known MC triggers, especially in the case of anaphylaxis, and MC stabilizing medications, such as cromolyn sodium, ketotifen, or histamine blocking medications.³⁰

Controversy exists over diagnostic algorithms for MCADs; however, overall, studies estimate a 24-31% overlap between MCADs and hEDS.31 MCADs have potential nutritional implications, including risks for bone loss and food restriction. A low histamine diet (LHD) is commonly

recommended, despite a lack of research.³² Aged and fermented foods are higher in histamine, but there is no universally accepted list of low histamine foods, and no experimental studies examining the clinical impact of an LHD in people with MCAD. One survey of self-reported experiences on an undefined LHD had 51.1% reporting improvement, 19.1% reporting no change and 29.8% of people who were unsure.³³An experienced RDN should work with patients to identify patterns of foods triggering MC reactions, and advocate for the widest range of foods tolerated.³⁴

Eating Disorders

Patients with GI disorders are at increased risk for developing ED and patterns of disordered eating. There is a bi-directional relationship where GI symptoms can lead to food restriction and restriction exacerbates GI symptoms. Avoidant-restrictive food intake disorder (ARFID) is an ED unrelated to weight involving fear of symptoms from eating, such as choking, pain, or nausea.³⁵ In a 2023 study, 37.9% of people with hEDS/HSD had a positive ARFID screen using the Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS).36 A positive screen was associated with changing diets, skipping meals, eliminating foods, and seeking or receiving nutritional support, such as enteral feeding.³⁶

Patients should be screened to identify an ED, although the NIAS has not been validated for people with GI disorders.³⁷ An experienced ED specialist can discern the difference between necessary vigilance due to pain, disease management or disordered eating. A multi-disciplinary approach is necessary, including an RDN, psychological support, and medical interventions when appropriate.

Supplement Use in hEDS/HSD

Supplements are widely used; however, research on utility for hEDS/HSD is lacking. Supplements should be discussed with patients reporting use or expressing interest. There are currently no evidence-based recommendations for dietary supplementation to treat hEDS/HSD, nor supplements that will benefit all patients. Supplementation regimens should be based on nutrition assessments of individual patients. Research specific to hEDS/ HSD is needed, particularly on the supplements mentioned below.

Antioxidants

Mantle et al. proposed a 12-nutrient and antioxidant protocol intended to address various forms of EDS in 2004.³⁸ No trials have been published on this. Three studies explored supplement use, and 61- 81% of patients with hEDS/HSD report taking supplements.^36,39,40 Patients frequently reported using vitamins C, D and magnesium in all studies and B vitamins and multivitamins in two studies.^39,40

Collagen

Abnormal synthesis and processing of collagen proteins and the extracellular matrix (ECM) are recognized in EDS, with some of the specific proteins and genetic variants identified.⁴¹ The collagen or ECM variants associated with hEDS/ HSD have not yet been identified.² Collagen synthesis always requires adequate dietary intake of amino acids and cofactors. However, no data suggests excess collagen from any source or type provides additional benefit for hEDS/HSD.

Folate

A recent review postulates that hEDS/HSD might be due to a common polymorphism known as a methylenetetrahydrofolate reductase (MTHFR) deficiency that prevents the proper usage of vitamin B9, or folate. The solution would be providing the supplemental 5-methyltetrahydrofolate and/ or decreasing folic acid supplementation.⁴² The authors allude to trials of folate supplementation in patients with hEDS/HSD but did not share the number of patients, the dose used, or if they confirmed that those patients had MTHFR mutations, or the wider context of interactions with the methionine cycle. There are no published trials in patients with hEDS/HSD. Further research is warranted, and more information is needed before practice guidelines can be developed.

CONCLUSION

Patients with hEDS/HSD experience a wide range of manifestations that impact nutrient intake, digestion, and food tolerance and will benefit from specialized nutrition guidance and having access to resources (See Table 2). Common comorbidities, such as DGBIs, other GI disorders, EDs, MCAD, and POTS add additional layers of complexity. Each patient with hEDS/HSD will need a plan tailored to their individual circumstances. Supplement usage is common, and clinicians should query about usage and evaluate its appropriateness. Clinicians should anticipate that patients will benefit from coordinated support from a multi-disciplinary team including RDNs.

References

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The Basics of Liver Transplantation for the Primary Care Provider and the General Gastroenterologist

May 2024 • Volume XLVIII, Issue 5

Phoenix Fung,

Michael Babich

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Liver transplant remains a well-established treatment that can drastically improve the survival and quality of life for patients with end-stage liver disease and certain hepatic malignancies. It is crucial for the primary care provider (PCP) and/or general gastroenterologist to understand the basics of liver transplantation as they play an important role in the management of patients with liver disease. Timely identification and referral to a transplant center is key. We are providing the PCP with an overview of liver transplantation indications, evaluation process, and management factors to consider prior to transplant. We want to highlight the importance of identification of potential liver transplant candidates who may benefit from early referral as well as provide information on evolving trends and advances in the liver transplant process. By raising liver transplantation knowledge, we can improve patient outcomes, facilitate timely referral, and ensure comprehensive care for patients throughout the transplantation process.

Introduction

Despite the advances in the management of chronic liver disease, liver transplantation remains a definitive life sustaining treatment for patients with severe acute or advanced chronic liver disease despite best medical therapy. It is important for the provider to be aware of the basics of the liver transplant process as they are often the gatekeepers to help screen patients requiring referral for liver transplantation. The process of liver transplantation is often both complex and multifaceted requiring a multidisciplinary approach between multiple healthcare professionals, including the PCP. This article aims to educate providers who treat patients with liver disease with an overview of the indications for liver transplantation, the evaluation process, and the pre-transplant management of patients during the waiting list period. Learning the principles of liver transplantation and management of patients with chronic liver disease can facilitate improved outcomes of patients. In addition, this paper serves to provide basic clinical updates within the last decade on liver transplantation for practitioners who manage cirrhosis.

Liver Transplant Statistics

The first successful human liver transplant was performed in 1963 by Dr. Thomas Starzl. Since then, over 200,000 liver transplants have been performed in the United States (US) in the past 35 years. According to the Organ Procurement and Transplantation Network (OPTN), the liver is the second most transplanted organ. Between 2019-2022, the average number of liver transplants per year in the US was between 7,000-8,000 for deceased donors and 400-500 for living donors. Despite the COVID-19 pandemic, 8,906 liver transplants were performed in the United States in 2020, which was more than in any previous year.¹The average wait time for liver transplant can range widely, from a few days to up to 5 years depending on the urgency. As of April 2023, there were approximately 10,000 patients listed for liver transplant. Liver transplant recipients had a five-year survival rate of >70%, compared to 15% for patients receiving medical therapy alone, emphasizing the life-saving impact of transplantation.²

Chronic non cholestatic liver disorders
Chronic hepatitis C
Chronic hepatitis B
Autoimmune hepatitis
Alcohol-related liver disease
Cholestatic liver disorders
Primary biliary cirrhosis
Primary sclerosing cholangitis
Biliary atresia
Alagille syndrome
Nonsyndromic paucity
of the intrahepatic bile ducts
Cystic fibrosis
Progressive familial intrahepatic cholestasis
Metabolic disorders causing cirrhosis
Alpha-1-antitrypsin deficiency
Wilson disease
Nonalcoholic steatohepatitis
and cryptogenic cirrhosis
Hereditary hemochromatosis
Tyrosinemia
Glycogen storage disease type IV
Neonatal hemochromatosis
Metabolic disorders causing severe
extrahepatic morbidity
Familial amyloid polyneuropathy
Primary Hyperoxaluria
Urea cycle defects
Disorders of branched chain amino acids
Hepatocellular carcinoma
Hepatoblastoma
Fibrolamellar hepatocellular carcinoma
Hemangioendothelioma
Fulminant hepatic failure
Budd-Chiari syndrome
Metastatic neuroendocrine tumors
Polycystic disease
Retransplantation

Alcohol associated liver disease was the leading indication for transplant in 2020. Other common categories for adult liver transplantation are hepatitis C virus infection, hepatocellular carcinoma (HCC), acute liver failure, and non-alcoholic steatohepatitis (NASH) according to the 2019 OPTN.³

Research has revealed disparities in liver transplant access and outcomes based on ethnicity. A study published in the American Journal of Transplantation found that Hispanic and African American patients faced a higher risk of waitlist mortality and lower chances of receiving a liver transplant compared to Caucasian patients.⁴ A significant gender disparity also exists in the donor pool. In the United States, approximately 62% of deceased liver donors are male, while only 38% are female.

Timing of Referral for Liver Transplant Evaluation

Who is a Candidate for Liver Transplantation?

Patients with severe acute or advanced chronic liver disease for which medical therapy has reached maximization should be evaluated for liver transplantation.⁵ The main population that the PCP should focus on referring for liver transplantation are patients with decompensated cirrhosis, cirrhotic patients with MELD (Model for End Stage Liver Disease) score ≥ 15, and patients with significant quality of life issues secondary to their end stage liver disease. Hepatic decompensation develops due to progressive portal hypertension from cirrhosis, with varying presentations, such as hepatic encephalopathy, ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension. Patients who develop hepatic decompensation in the form of variceal bleeding, hepatic encephalopathy, or ascites have significantly reduced survival compared to cirrhotic patients who are well-compensated. The median survival of persons with compensated cirrhosis is 9-12 years compared to 2 years in persons with decompensated forms of liver disease. In a patient with compensated cirrhosis, the rate of decompensation is 5-7% per year.⁶ Providers should be screening for hepatic decompensations in a routine and systematic fashion.

The PCP should be aware of the definition of fulminant or acute liver failure and recognize the need for expedited inpatient evaluation in a liver transplantation center. Fulminant liver failure is the rapid hepatic deterioration with development of hepatic encephalopathy and coagulopathy in patients who do not have underlying liver disease. If the adult patient has fulminant liver failure, and anticipated life expectancy of less than 7 days without liver transplant, in an intensive care unit, and acute onset of hepatic encephalopathy with one of the following criteria: (1) ventilator dependence (2) required dialysis or (3) INR >2, then the patient qualifies for Status 1A. When listed as Status 1A, the OPTN prioritizes the search for first available liver donors by expanding the criteria from regional to national. For the purposes of this paper, we would like to focus on recognition of indications for liver transplant referral for patients with chronic liver disease in the outpatient setting.

There are clinical considerations to help determine successful liver transplant candidacy. Oftentimes, the patient has to be sick enough, where transplant would increase survival odds, but not too ill where they would not be expected to survive the operation and the immediate postoperative period. Patients must be able to demonstrate the insight and willingness to comply with a complex medical regimen required post-transplantation, particularly the need to take chronic immunosuppressive medications to prevent allograft rejection and prophylactic antibiotics/antivirals to prevent infection. Patients cannot have other severe comorbid conditions that could potentially compromise the graft or patient survival. These evaluations will occur in the transplant center through a comprehensive multidisciplinary team approach.

Understanding the Basics

Classification of Liver Disease Severity

The Child-Turcotte-Pugh Score and the MELD-3.0 scoring system help classify the liver disease severity and need for liver transplantation evaluation. The Child-Turcotte classification system was developed in 1964 to risk-stratify patients undergoing shunt surgery for portal hypertensive decompression. In 1972, Pugh modified the Child-Turcotte system, and it became known as the Child-Turcotte-Pugh (CTP) score. Components of the CTP score include the serum total bilirubin, serum albumin, INR, presence/quantity of ascites, and presence/grade of encephalopathy. CTP score has been shown to accurately predict surgical outcomes in patients with cirrhosis and portal hypertension. In addition, clinicians have widely used this tool to assess the risk of short-term mortality in cirrhotic patients. Overall, the 30-day post operative mortality following abdominal surgery of a cirrhotic patient with CTP score A is 10%, CTP score B is 30% and CTP score C is 76–82%. One year survival is 45% in CTP score C, compared to 95% and 80% in CTP score A and CTP score B, respectively.⁷ Patients with CTP-C scores are the sickest, and special attention should be focused on this group.

Model of End Stage Liver Disease (MELD) Score is another prognostic scoring system which estimates the survival probability of a patient with end-stage liver disease. It is calculated using the serum bilirubin, serum creatinine, and INR. United Network for Organ Sharing (UNOS) manages the United States transplant allocation system and uses the MELD score for organ recipient priority. In 2002, the MELD score was adopted by UNOS for deceased liver organ allocation. The MELD scores range from 6 to 40, which correspond to 3-month survival odds of 90% and 7%, respectively. In January 2016, the MELD score was further modified to incorporate serum sodium to create the MELD-Na equation as hyponatremia in cirrhosis is a marker of increased liver transplant waitlist mortality.⁸ Further adaptations of the MELD score have been utilized to reduce wait time death of patients on the transplant list and make listing more equitable. In July 2023, the MELD 3.0 score was implemented to reduce liver transplant wait list mortality by accounting for female sex, serum albumin, and a lowered serum creatinine cut-off from 4.0 mg/dL to 3.0 mg/dL. The new scoring system addresses the disparity that females have had consistently lower transplant rates historically.⁹

The PCP should use prognostic score systems of CTP score and MELD-3.0 score to risk stratify cirrhotic patients. Patients with decompensated cirrhosis or MELD-3.0 ≥ 15 are recommended to be referred to a liver transplant center for evaluation due to their high risk of morbidity and mortality.

Indications for Liver Transplant Evaluation

Liver transplantation can restore quality of life and prolong patient survival. Progressive advancements in care of liver transplant patients show favorable short and long term outcomes. Graft survival is 91.2% at 1 year, 76.5% at 5 years, and 56.4% at 10 years.¹⁰ The main indications for liver transplantation are decompensated liver disease, acute liver failure, primary unresectable hepatic malignancy, inherited metabolic liver disease, and retransplantation. Chart 1 provides an inclusive list of indications for liver transplantation.

The Evolving Liver Transplantation Population

The most recent American Association of the Study of Liver Disease (AASLD) Guidelines has modified nomenclature to change “alcoholic” to “alcohol-associated” cirrhosis to help reduce the stigma associated with the disease faced by patients and family members.¹¹ Alcohol-associated liver disease is the most common indication for liver transplant in the United States at present. Alcohol-associated liver disease has surpassed hepatitis C as the leading indication for liver transplant in the United States in the last several years. Since the introduction of well tolerated direct acting antivirals with substantial rates of hepatitis C eradication, there is a reduction in the need for liver transplantation and development of hepatocellular carcinoma in this subset of patients.¹²

Alcohol-associated liver disease and metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as non-alcoholic steatohepatitis (NASH) are projected to be the leading indications for liver transplantation in the near-future.¹³ Obesity and metabolic syndrome are risk factors for development of metabolic dysfunction associated liver disease (MASLD), which can progress to MASH and cirrhosis. The rate of obesity has doubled in the last 30 years worldwide, with the growth rate within the United States being one of the highest. Patients added to the transplant wait list with NASH as an indication increased by 170% between 2004 and 2013.¹⁴ It is predicted that MASH will be the leading indication for liver transplant in the U.S. over the next 10 to 20 years.¹⁵ Up to 25% of patients with MASH will progress to cirrhosis with increased risk of hepatocellular carcinoma development, therefore early diagnosis and management may curb the need for liver transplantation. Patients with MASH-induced cirrhosis can be a challenging population to manage due to comorbid conditions such as severe cardiovascular disease, which can preclude transplantability. Metabolic clinics for weight loss and early referral for bariatric surgery may be an option to help reduce MASLD-associated fibrosis but is not recommended in decompensated liver disease. Potential pharmacologic treatments for MASH are being studied. Resmetirom, an oral liver-directed thyroid hormone receptor beta–selective agonist, has been recently FDA approved for patients with stage 2-3 fibrosis secondary to MASH, which has been shown to be helpful in hepatic fibrosis regression.¹⁶

Alcohol-induced hepatitis is one of the most severe manifestations of alcohol-associated liver disease, with high morbidity and mortality. Liver transplantation may be considered as a last option for patients with alcohol-induced hepatitis when medical treatment has failed or is contraindicated. Many liver transplant centers require six months of alcohol abstinence prior to evaluation for liver transplantation. Due to the risk of significant morbidity and mortality without transplantation during that 6-month period, predictors have been studied in the US and Europe to identify a subset of patients with low risk of recidivism. Select patients with severe alcohol-induced hepatitis who fail to respond to medical therapy should be considered for liver transplant.¹⁷ The most favorable factors associated with low risk of recidivism include: alcohol induced hepatitis as initial hepatic decompensating event, good social support, insight to severity of disease, absence of severe psychiatric disorders, recent life stressor, prolonged duration of abstinence prior to transplantation, stable employment, and a covenant to adhere to life-long alcohol abstinence.¹⁸ Although there are similar favorable one and three years survival outcomes in patients transplanted for alcohol induced hepatitis compared to other indications for liver transplant, the cumulative incidence of persistent alcohol use post-transplant was 10% in the first year and 17% by the third year, with increasing alcohol use associated with increased mortality over time, based on recent studies.¹⁹ Further longitudinal studies need to be performed to elucidate the generalizability of these outcomes.

MELD Exception Points

OPTN prioritizes organ allocation based on medical necessity using the MELD-3.0 score, with higher scores given higher priority access to the donated organs. MELD exception points are granted in certain liver diseases when the severity of the liver disease is not reflected by the calculated MELD score. Typically, the morbidity and mortality is higher in this population subset and the patient is “sicker than the MELD” score. These indications include hepatocellular carcinoma, hilar cholangiocarcinoma, primary hyperoxaluria, metabolic disorders of the urea cycle, hepatopulmonary syndrome, portopulmonary hypertension, cystic fibrosis, and familial amyloid polyneuropathy. If the patient meets specific inclusion criteria, they are OPTN waitlisted with a MELD score equivalent to the median MELD at transplant within the surrounding transplant centers minus 3 points (MMaT-3). The median MELD is calculated from within 150 nautical miles surrounding each donor hospital in the country and is applied to the exception point score for any transplant candidate receiving liver offers from that donor hospital. Patients with primary hyperoxaluria and metabolic diseases, such as urea cycle disorders or organic acidemia, meeting criteria receive MELD exception equivalent to the MMaT.^20,21

Hepatocellular Carcinoma

Hepatocellular carcinoma in a cirrhotic patient is an important indication for liver transplant. A landmark trial by Mazzaferro showed a 4-year post-liver transplant survival benefit of 75% with recurrence-free survival of 83% when the liver cancer was confined to the “Milan criteria”.²² Hepatocellular carcinoma within “Milan criteria” includes one lesion ≤ 5 cm, or three lesions < 3 cm without metastasis. Hepatocellular carcinoma is diagnosed based on cross sectional CT or MRI with confirmation of tumor dimensions by a radiologist in an OPTN approved transplant center. These patients are eligible for MELD exception points if they meet criteria. HCC can be treated with locoregional therapy while awaiting transplantation. Hepatocellular carcinoma that is beyond the Milan criteria limits can be attempted to be down-staged by loco-regional treatment so as to be brought within Milan criteria, and then can be reconsidered for transplantation without sacrificing post-transplant survival.²³

Cholangiocarcinoma

Cholangiocarcinoma is a bile duct cancer with increased risk of development in patients with underlying primary sclerosing cholangitis (PSC). In general, intrahepatic cholangiocarcinoma is a relative contraindication to liver transplant due to the aggressive nature of the malignancy with poor post-transplant survival. For patients undergoing curative surgical resection, there are high rates of recurrence up to 60-70%. Five-year survival for patients with resectable disease is 20-40%.²⁴Patients with hilar cholangiocarcinoma are likely not candidates for resection due to the anatomical location of tumor being in the area of the hepatic duct and its bifurcation. The Mayo Clinic has created a highly selective protocol using neoadjuvant chemotherapy prior to liver transplant for early stage unresectable, non-metastatic perihilar cholangiocarcinoma. The five-year survival after liver transplant is 73%, based on their protocol.²⁵ For consideration of liver transplant for perihilar cholangiocarcinoma, UNOS requires the transplant institution to have an approved written treatment protocol, and grants MELD exception points if the patient is suitable.

HRS – New Nomenclature

Hepatorenal syndrome (HRS) is defined as renal failure in a person with cirrhosis in the absence of intrinsic renal disease. Previous nomenclature of Type 1 HRS is now termed HRS-acute kidney injury (HRS-AKI). Patients with HRS-AKI have a rapid deterioration in renal function with very high morbidity and mortality. AKI is defined as an increase in serum creatinine ≥ 0.3 mg/dL from baseline within 48 hours or a ≥ 50% increase in serum creatinine within the last 7 days.²⁶ After ruling out intrinsic renal disease and post-renal obstruction as a cause, and after failing to improve with 48 hours of intravascular volume repletion, this entity would be considered HRS-AKI. Patients with HRS-AKI should have an expedited referral for liver transplantation. HRS-AKI is usually reversible after liver transplantation. HRS Type 2, now termed HRS-chronic kidney disease (HRS-CKD), is a more gradual impairment in renal function that is less severe than type 1 HRS and is seen typically in patients with refractory ascites, which are resistant to diuretics. The definition of HRS-CKD requires the patient to meet HRS criteria and have eGFR < 60 ml/min per 1.73 m2 for ≥ 3 months, in absence of other structural causes. Select patients with chronic kidney disease and liver disease should be considered for combined liver-kidney transplantation.

Contraindications for Liver Transplantation

An important concept of liver transplantation is to recognize contraindications to liver transplantation. Universal absolute contraindications include severe cardiopulmonary disease, active extrahepatic malignancy, metastatic hepatocellular carcinoma, uncontrolled sepsis, brain death, AIDS, active alcohol or illicit substance abuse, persistent noncompliance or lack of social support, and anastomotic barriers to liver transplantation.²⁷ Many transplant centers require a minimum alcohol abstinence of 6 months with substance dependence program attendance. Literature suggests the risk of recidivism is lower in patients who complete at least 6 months of sobriety compared to those with shorter periods.²⁸ The recommendation remains controversial, as other studies suggest the length of pre-transplantation abstinence is a relatively poor predictor of post-transplantation abstinence.²⁹ An exception to the “six-month rule” may be considered when patients are being transplanted for alcohol-induced hepatitis in a center with a protocol for this situation. Conversely, hepatic function may improve with alcohol abstinence in patients with alcohol-induced cirrhosis to the extent a transplant is less urgent.³⁰

Relative Contraindications

Physiologic, not chronologic, age should be considered in a patient undergoing liver transplant evaluation. There has been an increasing median age of patients being evaluated and waitlisted for transplantation. Registrants for UNOS liver transplant waitlist aged ≥ 65 years increased from 8% in 2002 to 17% in 2014.³¹ Post transplant survival for patients over age 65, compared to younger cohorts, was overall lower in earlier studies.^32,33 More recent studies do not indicate higher rates of mortality or lower graft survival in young compared to elderly liver recipients in early transplant outcomes, however increased malignancy rates are seen in older patients.³⁴

It is also feasible that being transplanted at an older age is associated with increased morbidity and mortality due to natural shorter life expectancy in older patients. A detailed evaluation to assess for functional and nutritional status, as well as medical comorbidities including cardiopulmonary status and malignancy, is highly recommended. In the absence of significant comorbidities, age > 70 years is not a contraindication for liver transplant.

Patients will need curative treatment for isolated primary extrahepatic malignancy with oncologic clearance prior to liver transplant. Typically, there is a waiting period to ensure absence of tumor recurrence after definitive treatment prior to transplant listing. There is heightened concern for risk of tumor recurrence for patients with prior malignancy who are on long-standing immunosuppression after transplant. The Israel Penn database is a collection of patients who developed malignancy after organ transplants. Based on the Israel Penn data, malignancies which have a low risk of recurrence are incidental renal tumors, lymphoma, testicular, cervical, and thyroid cancers. Malignancies with intermediate risk of recurrence are uterine, Wilms’ tumor, colon cancer, prostate, and breast cancer. Tumors associated with a high risk of recurrence include bladder cancer, sarcoma, melanoma, symptomatic renal cancer, and myelomas.³⁵ A judicious individualized, multidisciplinary approach by the transplant team is used to decide on optimal candidates and timing of listing.

Although AIDS is a contraindication for transplant, HIV patients are eligible for transplantation in the presence of adequate immune function with CD4 >100/µL with undetectable viral load at the time of liver transplant. Co-management with an infectious disease specialist is recommended.⁵

Class III obesity (body mass index (BMI) ≥ 40) is a relative transplant contraindication. It is associated with coronary artery disease, hyperlipidemia, diabetes mellitus, renal dysfunction, and obstructive sleep apnea.⁵ Obesity increases the risk of perioperative complications and length of post-operative hospital stay and reduces long term survival. Primary graft non function, immediate, 1-year, and 2-year mortality were significantly higher in the morbidly obese group. Five-year mortality was significantly higher both in the severely and morbidly obese subjects, mostly due to cardiovascular events.³⁶ Weight loss is recommended prior to transplant in patients with class III obesity. While patients with severe obesity and/or metabolic-associated fatty liver disease can be considered for bariatric surgery, this is contraindicated in decompensated liver disease due to risk of worsening hepatic dysfunction with surgery. Studies investigating the performance of gastric sleeve placement simultaneously with liver transplant, to assist with weight management, demonstrate safety and may be helpful in long term total body weight loss.³⁷

Patients with severe ascites can be seen as “overweight”, but this should not be confused for obesity as oftentimes that patient has co-existing anasarca and sarcopenia. The presence of ascites is associated with an increased risk of postoperative morbidity and mortality post-transplant. A study performed by Leonard et al. showed that correction of BMI for ascites volume placed 11-20% of the studied patients who received a liver transplant into a lower BMI classification. It was calculated that each liter of ascites removed during the transplant was associated with a 7% increased relative risk of mortality.³⁸ Special care should be utilized to prevent further malnutrition, as patients with ascites will still require high protein diets as cirrhosis is a catabolic state.

Underweight patients also pose a concern, as patients at both extremes of BMI have significantly higher wait list mortality and worse liver transplant outcomes as compared with those with normal BMI (18.5 to <25). Underweight patients (BMI < 18.5) have higher risk of hemorrhagic complications and cerebrovascular events. Overweight patients (BMI > 40) have a higher risk of infectious complications and cancer events. Given this disparity, innovative means are required to target high risk groups.³⁹ A comprehensive nutrition assessment and dietary management should be utilized in patients who are at extremes of BMI to help minimize complications.

Understanding the General
Liver Transplant Evaluation Process

Patients should be referred to a liver transplant center if there is decompensated liver disease or MELD-3.0 ≥ 15. The PCP should be familiar with their local transplant centers. Oftentimes, there will be local outreach clinics if the nearest center is distant. The patient should understand that a referral does not mean they will be automatically listed for a liver transplant. Generally, the multidisciplinary transplant team consists of the transplant hepatologist and surgeon, nurse coordinator, financial coordinator, social worker, psychiatrist, dietician, physical therapist, anesthesiologist, and pharmacist, all of whom will interact with the patient. During the initial evaluation, the transplant process will be discussed with the patient, and individual evaluations performed. The patient’s motivation and insight to comply with medication therapy and long term follow up, social support, functional and nutritional status, and substance abstinence duration are assessed. The hepatologist ensures medical management has been maximized and appropriate treatments are up to date. The transplant surgeon evaluates surgical contraindications for liver transplant, as well as suitability for living donor evaluation if applicable. Standard blood tests, including blood type, screening for liver disease, and determining the infection status of HBV, HCV, EBV, CMV, VZV, RPR, and HIV are performed. Status of tuberculosis exposure is typically performed with interferon-gamma release assay (i.e., Quantiferon gold) or tuberculin skin testing. Cardiopulmonary testing may include echocardiogram, cardiac stress test, heart catheterization as needed, and pulmonary function testing. These are used to screen for significant valvular disease, heart failure, coronary artery disease, significant respiratory diseases, hepatopulmonary syndrome, and portopulmonary hypertension. Testing is based on individualized risk. Cross sectional abdominal imaging with CT or MRI are performed to rule out intra- and extra-hepatic malignancy, especially hepatocellular carcinoma, and anatomic contraindications. Standard preventative care measurements such as age- and indication-appropriate malignancy screening with mammogram, colonoscopy, low dose contrast CT chest, and pap smear are reviewed. Screening for osteoporosis with DEXA scan and vitamin D levels are incorporated into the process. Dental exam should be completed to assess for necessary extractions prior to transplant. After an extensive evaluation is completed and the patient/family comprehends the aspects of the transplant process, the multidisciplinary team discusses whether the patient should be waitlisted for organ transplant.

Understanding Liver Donation

Deceased Donor vs. Living Donor

Transplanted livers may be received from a living or a deceased donor. Almost 20% of patients on the US waiting list die or become too sick for the transplant. Deceased liver donation remains the primary source of organs for liver transplantation. However, the scarcity of deceased donor organs has led to the utilization of living donors to expand the donor pool to provide timely transplants for recipients. Deceased liver donors are typically individuals who have experienced irreversible brain damage or cardiac arrest and are declared legally brain dead. These donors are often individuals who have registered as organ donors or have consented to donation through their families. The process involves meticulous matching of the donor liver with a suitable recipient based on factors such as blood type, body size, and urgency of need. Organs from deceased donors are carefully preserved and transported to the recipient’s transplant center.

Living donor liver transplantation (LDLT) occurs when an individual readily volunteers to donate a portion of their liver to someone in need. This is possible because of the liver’s incredible ability to regenerate. Candidates being considered for living donor transplantation will need to meet evaluation criteria set forth by the transplant center. The decision to accept a liver donor is determined by a multidisciplinary team in a transplant center.

Along with the assignment of an Independent Living Donor Advocate (ILDA) by the recovery hospital, the evaluation and selection of an adult liver donor involves a comprehensive assessment of their medical and psychosocial health status to determine eligibility. The ILDA, either an individual or a team, must be qualified and understand the full transplant protocol of the recovery hospital, function independently of the recipient’s team, advocate for the donor, and ensure that the donor has received all information required to make an informed decision. The living donor must undergo psychosocial testing with a team of psychiatrists and psychologists prior to organ recovery to ensure that there are no detrimental psychosocial issues (including high risk behaviors, mental health issues, substance use disorders, etc.) that precludes organ donation or would affect long term recovery. This team also must determine that the donor is free of coercion, can make informed decisions, and understands the long and short term psychological and medical risks.⁴⁰ Advantages of living donor liver transplantation (LDLT) include reduced wait time for the recipient, use of a graft with minimal ischemic time, and sufficient time to plan for an elective surgery. The evaluation process is otherwise similar to deceased donor.⁴¹

Surgical techniques for living donor liver transplantation involve the partial resection of the donor’s liver, either the right or left lobe, which can regenerate to near-normal size and function in both the donor and recipient within a few months. With regards to outcomes, graft failure occurs in 5.9% (6 months), 7.9% (1 year), 14.7% (3 year), 20.7% (5 year), and 40.6% (10 year) of deceased donor recipients. There is a slightly lower graft failure rate for living donor recipients: 4.9% (6 months), 7.4% (1 year), 12.2% (3 year), 23.7% (5 year), and 36.7% (10 year). It is notable that overall recipient mortality has continued to improve over the last decade.⁴²

Given the current allocation policies in the United States, patients with MELD scores <15 on the waiting list rarely receive a liver in a timely fashion. Patients with low MELD scores must rely on either living donors or expanded-criteria deceased donors if they are to receive a transplant. In the landmark Adult-to-Adult Living Donor Liver Transplantation Cohort (A2ALL) study, the survival benefit of an LDLT was demonstrated at MELD-Na scores less than 15.⁴³

An ideal patient for LDLT would be one with a low MELD score but decreased quality of life due to underlying end stage liver disease. Life altering manifestations from end stage liver disease, such as refractory hepatic encephalopathy, ascites/hepatic hydrothorax, sexual dysfunction, sarcopenia, and pruritus can occur, and are not reflected in the MELD 3.0 score. A study performed in the United States by Jackson et al. showed significant survival benefit of LDLT in patients with end-stage liver disease, even at MELD-Na scores as low as 11. For patients with low MELD scores and significant quality of life issues from liver disease, LDLT is a good alternative to waiting for a deceased donor as it will significantly increase survival compared with remaining on the waitlist.⁴⁴

Although the number of living donor transplants performed annually has increased slowly over the years, it still accounts for only about 5% of liver transplants in the United States.⁴⁵ Of the 8,906 liver transplants performed in the US in 2020, 7,979 (89%) patients received organs from a deceased donor and 425 (11%) from a living donor.⁴⁶

Medical Management of Patients
Awaiting Liver Transplantation

The matching of a donor and recipient is prioritized based on recipient MELD score per UNOS and compatible ABO blood type. As such, the waitlist time for liver transplant is variable. For patients with low MELD scores, waitlist time can be years, between listing and getting called for their transplant. It is therefore essential to continue management of the cirrhotic patient during this time period to help reverse or delay the need for transplant. The management of the cirrhotic patient can be complex. It is recommended to communicate with the transplant team for major medical decisions, however “day to day” management of portal hypertension, HCC surveillance, counseling on substance dependence and tobacco cessation, weight loss counseling for obese patients, screening for malnutrition and monitoring of functional status, vaccination for Hepatitis A and B, and preventative measures such as ensuring PAP smear, mammogram, colonoscopy and DEXA scan are up to date can be performed by the PCP. Early referral for liver transplant is recommended for patients with alcohol-related liver disease to facilitate prompt treatment for substance addiction.

PCPs should recognize that non-transplant peri-operative risk is substantially increased in patients with decompensated cirrhosis, especially CTP class C. PCPs should consult with the transplant hepatologist/transplant team prior to any, particularly abdominal, surgery to weigh the risks and benefits, as surgery can increase morbidity and mortality. In addition, patients should be counseled on eating a high protein diet to counteract sarcopenia and development of hepatic encephalopathy. Typically, the recommended protein intake is 1.2 to 1.5 g/kg per day, based on ideal body weight, with protein included with each meal and snack. A protein-based bedtime snack can reduce the incidence of sarcopenia.⁴⁷

Summary

In conclusion, it cannot be overstated that liver transplantation is a life-saving procedure for patients with acute or chronic end-stage liver disease. The evaluation process involves a comprehensive assessment of a patient’s medical history, comorbidities, and psychosocial factors that play a key role in identification of suitable candidates for this life saving procedure. The decision to undergo liver transplantation is complex and requires a collaborative approach involving multiple healthcare professionals. As a PCP, the understanding of key aspects of the evaluation process is crucial for recognizing patients who may benefit from liver transplantation and ensuring their timely referral to transplant centers. Candidates for liver transplant referral include, but are not limited to, patients with acute liver failure, decompensated liver disease, primary unresectable hepatic malignancy, inherited metabolic liver disease, and MELD score ≥ 15. The role of the primary care provider does not end with timely referral to transplant centers, but also involves being knowledgeable about pre-transplant management, including optimizing patient health, managing complications, and providing appropriate long term follow up. PCPs can make a significant difference in improving patient quality of life and long-term survival rates by actively participating in the care of patients with chronic liver disease. By collaborating closely with transplant teams and staying updated on the indications, evaluation criteria, and potential contraindications, PCPs can enhance patient outcomes and contribute to the overall success of liver transplantation.

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Endoscopic Therapy for Refractory Benign Esophageal Strictures

May 2024 • Volume XLVIII, Issue 5

Douglas G. Adler,

Zheyuan Jenny Wang

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The management of refractory benign esophageal strictures (RBES) presents a formidable clinical challenge, necessitating frequent interventions to ameliorate symptoms and enhance the quality of life for affected individuals. Among the array of available endoscopic therapeutic modalities for RBES, esophageal dilation stands out as the primary treatment approach, with both balloon dilators and bougies demonstrating high rates of technical success and satisfactory clinical resolution. Despite its efficacy, approximately 30-40% of strictures recur following dilation, prompting exploration into adjunctive therapies such as steroid injections, incisional therapy, stent placement, and the application of mitomycin C. Triamcinolone injections have emerged as an option, reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, the literature reports conflicting findings regarding their efficacy, underscoring the need for further investigation. Similarly, stent placement, including the use of self-expanding metal stents (SEMS) and lumen-apposing metal stents (LAMS), offers viable alternatives, albeit with concerns regarding migration rates and adverse events. Furthermore, self-dilation, while rarely employed, presents a patient-centered approach that can be both safe and effective when appropriately implemented. Despite these advancements, several knowledge gaps persist, necessitating further research to refine treatment strategies, optimize clinical outcomes, and enhance the overall management of RBES. This literature review aims to synthesize existing evidence, identify areas of agreement and disagreement, and delineate avenues for future investigation to address these critical gaps in understanding and practice.

Dilation

Esophageal dilation remains the primary treatment for RBES as patients with RBES often require multiple dilations.^,, Most strictures are successfully treated with endoscopic dilation, however approximately 30-40% recur. There are several methods of performing esophageal dilation. These vary by the type of dilator used and the way it is passed through the esophagus to the level of the stricture itself. Generally, dilation can be categorized as either balloon or mechanical (bougie-type). Balloon dilators can be passed through-the-scope (TTS) or over a guidewire. Placement can be verified by direct visualization via endoscopy, and/or via fluoroscopy.^1,4 TTS balloons come in a variety of sizes and are in widespread use. (Figure 1) The most common type of bougies in current use are Savary-Gilliard (SG) or Maloney dilators. Modern bougies, made of polyvinyl chloride, are generally passed over a wire, frequently with additional fluoroscopic guidance, across a stricture where they exert radial and longitudinal pressure on the stricture. It should be noted that using balloon dilation is technically easier, but the cost is higher as balloons are one time use devices. SG and Maloney dilators are not disposable and can be used repeatedly and are more cost effective over time.⁴ There is no statistical difference between the balloon dilation and SG dilators in terms of clinical resolution of esophageal strictures.^, Repeated dilation treatment by balloons and bougies was found to have an overall clinical success rate of 70.9% in a 2019 retrospective analysis.⁷Another study found successful dilation, defined as the ability to expand the esophageal lumen to accommodate a 42F (14 mm wide) catheter, was attained in 93.5% of patients undergoing endoscopic dilation.¹⁰

Among the adverse events associated with dilation for benign esophageal strictures are perforation, bleeding, bacteremia, and (rarely) esophageal fistula. The perforation rate has been reported between 0.1 – 0.4%, which no clear evidence of different perforation rates for mechanical versus balloon dilators.¹Significant bleeding and bacteremia are rare adverse events. Furthermore, data suggests no significant difference in adverse event rates between the use of balloon dilators and other methods, underscoring the safety and efficacy of both approaches in clinical practice.⁸ Numerous individuals encounter challenges with traditional interventions such as balloons and bougies in managing refractory strictures, necessitating the exploration of additional and alternative therapeutic modalities.

Steroid Injection

Triamcinolone, a long-acting and semi-viscous corticosteroid agent, has been utilized as an adjunctive therapy to enhance the efficacy of dilation in the treatment of refractory strictures, or as standalone therapy. Most investigators utilize triamcinolone acetate or acetonide at concentrations of 10 mg/mL, although higher concentrations of 40 mg/mL have also been employed. The volume of injection has varied across studies, ranging from 0.5 mL to 2.8 mL. Additionally, betamethasone and dexamethasone preparations have been utilized, with no discernible differences in outcomes reported among different steroid formulations.

Triamcinolone injections are indicated for refractory strictures where conventional dilation techniques have proven ineffective. The precise mechanism of action of triamcinolone in stricture management remains unclear. However, studies suggest that corticosteroids decrease the fibrotic healing that appears to occur after dilation.⁹ Triamcinolone injections have shown potential results in reducing stricture recurrence rates and improving dysphagia scores, particularly in patients with refractory anastomotic strictures.^9, Meta-analysis has not demonstrated consistent improvement in dysphagia scores among patients receiving steroid injections, but the interpretation of these findings is limited due to the high heterogeneity of the data. Studies have reported a significant decrease in the Periodic Dilation Index (PDI), which is defined as the number of dilations required/duration of time in months, among patients receiving intralesional steroid injections alongside dilation therapy.¹¹ Triamcinolone may prove beneficial in managing RBES, potentially reducing the frequency of necessary dilations. There is currently no standardized protocol for the number of triamcinolone injection sessions. The optimal dosing regimen and injection technique may vary based on the specific characteristics of the stricture and individual patient factors.⁹ The literature presents conflicting results regarding the efficacy of triamcinolone injection in the management of patients with RBES. Pereira-Lima et al. reported a significant increase in the number of dysphagia-free patients after 6 months and an improvement in dysphagia scores in a double-blind randomized study consisting of 19 patients. In contrast, the double-blind study of 60 patients conducted by Hirdes et al. failed to replicate these results.

While endoscopic triamcinolone injections are generally well-tolerated, adverse events may include intramural infection, yeast esophagitis, and perforation. Due to the low number of adverse events, statistical analysis was not possible in a 2018 meta-analysis that analyzed the effect of intralesional steroid injections in addition to endoscopic dilation of benign refractory esophageal strictures.¹¹

Incisional Therapy

Incisional therapy represents an additional option for patients with RBES. This therapeutic approach entails the use of electrocautery or mechanical devices to directly incise or cauterize the fibrotic stricture itself. The fundamental principle underlying this modality mirrors that of dilation, involving the disruption or displacement of circumferential fibrotic tissue and collagen fibers to facilitate the restoration of a satisfactory lumen diameter and prevent reformation of scar tissue.

Needle knife incision is the most commonly employed technique. This technique employs a needle-knife catheter, widely used for ERCP, to perform electrosurgical incisions in a radial manner around the stricture. (Figure 2) The determination of the length and quantity of incisions is tailored to each specific stricture. Typically, an average of 4-12 radial incisions is required for ideal treatment.¹³ Optimal outcomes are typically observed with short-segment strictures measuring less than 1 cm such as Schatzki rings or anastomotic strictures. With long segment strictures, complete removal of the stricture rim may not always be feasible. In a prospective outcome study, 87.5% of patients had neither subjective dysphagia nor endoscopic recurrence at a 24 month follow up after incisional therapy.

Potential adverse events associated with incisional therapy include pain, bleeding, and perforation. The perforation or hemorrhage rate associated with balloon or bougie dilation ranges from 0.1% to 0.4%,¹ while the perforation rate with endoscopic incision therapy falls within the range of 0% to 3.5%, with no reported evidence of significant bleeding.¹³

Stents

Self-Expanding Metal Stents

Endoscopic stent placement has emerged as mainstay of treatment for managing RBES. It is widely recognized as a safe procedure and is frequently used as a first-line therapy option. Stents commonly employed in therapy include partially covered self-expanding metal stents (PCSEMS), fully covered self-expanding mental stents (FCSEMS), LAMS, and biodegradable stents (where they are commercially available). Stents are deployed under endoscopic and/or fluoroscopic guidance, depending on the patient and the type of stent used, with placement confirmation via endoscopy. Alternatively, direct visualization can guide stent placement without fluoroscopic assistance.

SEMS were introduced into clinical practice approximately three decades ago. PCSEMS and FCSEMS have both been evaluated for treatment of RBES. Presently, temporary placement of SEMS is commonplace in the management of RBES. (Figure 3) It has been recommended by one study that FCSEMS should be left in place for up to 12 weeks to minimize the risk of hyperplastic tissue and stent embedment, but in practice many patients require longer stent indwell times and treatment should be individualized. Both PCSEMS and FCSEMS were found to have a high technical success rate and short-term clinical efficacy. There was no statistical difference between PCSEMS and FCSEMS. Adverse events linked to PCSEMS encompass stent migration and tissue ingrowth. Conversely, FCSEMS primarily presents stent migration as the main adverse event. Stent migration persists as a significant concern and represents a primary factor prompting re-intervention with SEMS.

Migration rates were observed to be 17.6% for PCSEMS post-placement and 17.4% for FCSEMS, as reported in a 2015 retrospective case review.¹⁸ A different 2016 multicenter study reported stent migration in 44.4% of patients with SEMS. Additionally, a literature review published in 2017 documented stent migration in 11.9% of patients treated with SEMS, while 20.3% experienced tissue in-growth or overgrowth. Another multicenter study conducted in 2016 reported a notable stent migration rate of 44.4% among patients receiving SEMS. It should be stressed that stent migration is not always an adverse event per se. If the stricture responds to stenting, and the lumen opens up appropriately, there may no longer be a stenosis there to help anchor the stent in place.

Biodegradable stents have emerged as a potential solution to address adverse events associated with SEMS and self-expandable polymer stents (SEPS), although these devices are not currently available in the United States. Two main types of biodegradable stents have been developed: knitted poly-L-lactic acid monofilaments, although no longer available, and the SX-ELLA BDS composed of semicrystalline biodegradable polymer known as polydioxanone. These stents offer constant radial force over a period of 4-5 weeks, allowing sufficient time for treating underlying esophageal diseases, while their progressive hydrolysis-mediated self-degradation prevents tissue overgrowth.²² Notably, their complete dissolution within 11-12 weeks obviates the need for endoscopic removal. Adverse events such as bleeding and chest pain have been reported. It is worth noting that BDS are associated with a higher incidence of major adverse events (28.6%) compared to FCSEMS and SEPS (10.6% and 14.3% respectively).²² Further prospective randomized trials are warranted to compare the clinical effectiveness of BDSs with FCSEMS. These trials should aim to determine the optimal duration of stent placement, evaluate the value of repeat stenting over extended periods, and assess the cost-effectiveness alongside patient satisfaction. A 2012 prospective multicenter study comparing FCSEMS, SEPS, and BDS revealed no significant differences in the clinical success of all three stent types. However, BDSs and FCSEMS demonstrated superiority over SEPS in several variables, including the dysphagia-free period, long-term improvement, and the number of reinterventions required.¹⁶ It should be noted that SEPS are no longer in clinical use.

Lumen-apposing metal stents (LAMS)

LAMS were initially designed for the management of pancreatic fluid collections, chosen for their anti-migratory property attributed to their saddle-shaped design. Over time, their clinical applications have expanded greatly beyond their initial indications, owing to several benefits such as offering multiple different diameters, short stent lengths, and facilitating simple stepwise deployment, which enhances technical success. These devices can be used effectively to treat short-segment RBES. (Figure 4) Comparative effectiveness studies have demonstrated that LAMS procedures are both feasible and safe, yielding good clinical outcomes. Technical and clinical success rates have been reported at 98.6% and 79.7%, respectively.²³ Notably, the migration rate with LAMS stands at 10.6%, significantly lower than that observed with SEMS.²⁴ Moreover, LAMS have exhibited superior clinical outcomes compared to FCSEMS and BDS. However, adverse events associated with LAMS include perforation, discomfort prompting early removal, stent migration, bleeding, and stricture reformation.

In a 2020 multicenter study comparing 15 mm and 20 mm stents, stent migration (15.6%) was the most common adverse event with 15 mm LAMS, but pain (14.3%) was the most common adverse event with 20 mm LAMS. Moving forward, future research endeavors aim to provide more extensive data on long-term outcomes and explore the utility of LAMS in managing refractory strictures, thereby guiding device refinement, and enhancing clinical practice.

Mitomycin C

Mitomycin C, a chemotherapeutic agent primarily employed in the treatment of malignancies such as esophageal, anal, breast, and bladder cancer, possesses pharmacological properties that make it a potential candidate for scar modulation.³ In the context of esophageal strictures, mitomycin C is administered either topically at the site of the stricture or injected directly into the stricture following dilation. The typical dosing regimen involves diluting 0.4 mg/mL of mitomycin C in 1 mL of saline, which is then divided into aliquots of 0.5 mL each. These aliquots are injected into the four quadrants of the narrowest part of the stricture.³ Despite its potential benefits, the administration of mitomycin C is not without risks, as adverse events such as intense pain, necrosis, and ulceration have been reported. However, while no longer widely practiced, there is published literature reporting the use of this agent in patients with corrosive esophageal strictures refractory to repeated endoscopic dilation.

Self-Dilation

Self-dilation represents a patient-centered approach to the management of strictures, aiming to empower patients with the ability to actively participate in their own care. Self-dilation is offered to patients with esophageal strictures refractory to other treatments such as endoscopic dilation, incisional therapy, or stent placement.²⁸ Techniques for safe and effective self-dilation typically involve educating patients either in the clinic or during their hospital stay, if admitted, within 48 hours following endoscopic dilation. Patients are instructed to begin self-dilation with a Maloney dilator that is either the same size or one size smaller than the dilator used during their typical endoscopic dilation procedure. Patient selection criteria include those with recurrent strictures after dilation, many of which are proximal, and individuals who have failed previous treatments such as Savary or balloon dilation, or those who have undergone dilation combined with intralesional steroid injections or incisional therapy.^, Despite the potential benefits, patients may exhibit reluctance to engage in self-dilation due to concerns regarding pain or perforation. Nevertheless, self-dilation offers a safe, effective, and cost-efficient treatment option for appropriately selected patients with refractory strictures. In a 2013 small retrospective study, esophageal self-dilation was successful in treatment of 90% of patients. Another 2018 retrospective study showed comparable results, with a technical success rate of 94% and median number of endoscopic dilation procedures dropping from 17 over a median period of 9 months to 1.5 procedures after initiation of self-dilation. Further research is needed to refine patient selection criteria and optimize the implementation of self-dilation protocols in clinical practice.

Conclusion

The management of RBES continues to pose a significant clinical challenge, often requiring repeated interventions to alleviate symptoms and improve quality of life for affected individuals. The array of endoscopic therapeutic modalities available for RBES includes dilation, steroid injections, incisional therapy, stent placement, and the use of mitomycin C. While each approach offers distinct advantages and potential drawbacks, several key agreements and disagreements have emerged from the existing body of literature. Endoscopic dilation, whether performed with balloon dilators or bougies, remains the primary treatment modality for RBES, demonstrating high rates of technical success and an acceptable rate of clinical resolution. Triamcinolone injections have shown promise in reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, conflicting findings regarding the efficacy of triamcinolone injection underscore the need for further research to elucidate its true effectiveness. Discrepancies in reported stent migration rates highlight the necessity for standardized protocols and further investigation into optimal stent selection and placement techniques. Self-dilation is rarely undertaken although when appropriately implemented this approach offers a safe, effective, and cost-efficient treatment option for selected patients with refractory strictures. Overall, while significant progress has been made in the endoscopic management of RBES, several knowledge gaps persist, warranting additional research to refine treatment strategies and optimize clinical outcomes in this challenging patient population.

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Kiwifruit in the Clinic: Nutritional Insights and Evidence-based Applications for Constipation

April 2024 • Volume XLVIII, Issue 4

Jason Nasser,

Barbara Hollander,

Bianca W. Chang

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Chronic constipation is a common presenting concern in primary care and gastroenterology clinics. Multiple factors can contribute to constipation, including dietary habits, physical activity, dehydration, medication side effects, systemic diseases, and pelvic floor dysfunction. While many new medications have been developed, patients are often interested in conservative and natural remedies to medical illnesses. Rich in fiber and protease enzymes, in addition to a plethora of micronutrients, kiwifruits hold a unique ability to retain water and bulk feces. By virtue of unique proteolytic enzymes, they can further aid in digestion and promote food transit. Recent studies underscore the efficacy of consuming two kiwifruits daily in addressing functional constipation and constipation-predominant irritable bowel syndrome symptoms through alleviating constipation as well as abdominal pain, bloating, and dyspepsia. This article will review the evidence in support of kiwifruit use for constipation management as well as provide suggestions for sustainable incorporation into the diet.

Introduction

Chronic constipation is a common gastrointestinal disorder, affecting 8-12% of adults in the U.S.; its prevalence increases with age and is twice as common among women.¹ In clinical practice, constipation is most simplistically and pragmatically defined as unsatisfactory defecation in the setting of reduced stool frequency, hardened stool consistency, and/or difficulty with stool evacuation. Patients can further report straining, prolonged time spent on the toilet, a sensation of incomplete emptying, or the requirement of manual maneuvers to remove stool. It is often associated with other gastrointestinal symptoms, including abdominal discomfort, pain, bloating, and distention. When such symptoms persist for more than a month, constipation is considered chronic. Kiwifruit offers patients a natural alternative in the management of constipation, abdominal pain, and dyspepsia with randomized controlled trials supporting its efficacy.

Why does chronic constipation happen?

The pathophysiology of constipation is multifactorial, and it is paramount to evaluate for identifiable causes and risk factors. While some risk factors are unmodifiable, such as older age and female sex, many risk factors can be reversed, including low dietary fiber intake, dehydration, physical inactivity, and medication adverse effects.

A common etiology of constipation that is often associated with a delay in diagnosis is the spectrum of evacuation disorders. These include structural disorders that create a mechanical obstruction, such as enteroceles, rectoceles or rectal intussusception, and those associated with the dissipation of the defecatory force, such as in descending perineum syndrome and rectal prolapse. Functional evacuation disorders, namely dyssynergic defecation, may manifest as paradoxical involuntary contraction or non-relaxation of the anal sphincter and puborectalis muscle during defection and/or inadequate abdomino-rectal propulsive force generation. Given the prevalence of dyssynergic defecation, estimated in some studies to affect nearly 20% of patients with chronic constipation, it is recommended to perform anorectal manometry early in the course of evaluation, especially if the patient exhibits symptoms suggestive of an evacuation disorder.² This is further supported by the efficacy of biofeedback therapy, which can be upwards of 70%.³ Aside from defecatory dysfunction, chronic constipation subtypes include functional constipation and constipation-predominant irritable bowel syndrome, as well as slow transit constipation and normal transit constipation.

Constipation can also be secondary to medications and systemic diseases, as shown in Table 1. It is worth noting that constipation can precede the identification of the underlying disorders’ primordial symptoms, particularly in scleroderma, Parkinson’s, and neuropathy.

How is chronic constipation managed?

In managing constipation, the initial approach often hinges on dietary modifications, promotion of physical activity, and over-the-counter fiber supplementation.⁴ Although general guidance emphasizes increasing fiber through dietary staples like whole grains, fruits, and vegetables, few natural foods have been tested in clinical trials to validate their individual benefits for constipation management. Nevertheless, the spotlight is gradually shifting towards functional foods. These are foods that are recognized to provide health advantages beyond basic nutrition, with examples including aloe, rhubarb, figs, prunes, and kiwifruit.⁵

The typical management of constipation typically follows the order of:

Lifestyle modifications, including dietary changes, increased physical activity, and hydration

Laxatives:

Bulk-forming laxatives (such as psyllium and methylcellulose, the latter being a non-fermentable, synthetic fiber)

Osmotic laxatives (such as polyethylene glycol and milk of magnesia)

Stimulant laxatives (such as bisacodyl and senna, whose long-term use is avoided)

Prescription medications:

Chloride channel activators (lubiprostone)

Guanylate cyclase-C agonists (linaclotide and plecanatide)

Sodium/hydrogen exchange inhibitors (tenapanor)

5-HT4 serotonin receptor agonists (prucalopride)

Ingested vibrating capsules.

Peripherally acting mu-opioid receptor antagonists (or PAMORAs; methylnaltrexone and naloxegol) for patients with opioid-induced constipation

While lifestyle modifications are often taken for granted, certain dietary modifications, like the addition of kiwifruit, are often underutilized and can be introduced into the management of constipation at any point in the course of treatment.

How does kiwifruit help constipation?

Kiwifruit is available in two main varieties: green and gold. The green kiwifruit (Actinidia deliciosa, cultivar Hayward) and the gold kiwifruit (Actinidia chinensis, cultivar Zesy002) are the two most widely consumed varieties. Over the past few years, they have gained traction as a dietary intervention for various gastrointestinal concerns, particularly constipation. This food’s nutritional profile has many potential mechanisms explaining its laxative benefits, in addition to being generally regarded as a nutrient-dense, low-calorie fruit considering its high fiber, water, and micronutrient content, as highlighted in Table 2.

Fiber and water content – One green kiwifruit of around 80g contains 2.4g of fiber while a similar gold kiwifruit contains 1.1g of fiber.⁶ As a reference, the USDA 2020-2025 dietary guidelines for Americans recommends 14g of fiber per 1000 calories. Americans should thus, on average, consume between 25-30g of fiber per day. Two green kiwifruits per day provide around 20% of the daily recommended intake of fiber. The fiber content of kiwifruit is approximately one-third soluble fiber, mainly composed of pectic polysaccharides which are fermentable fibers; and two-thirds insoluble fiber mainly composed of cellulose and hemicellulose which are non-fermentable and fermentable fibers. The insoluble fiber content is thought to stimulate water secretion and thereby improve stool transit time, while the soluble fiber binds to water, creating a gel that helps to soften and bulk the stool.⁷ Kiwifruit’s fiber content is particularly unique in its capacity to swell, passively increasing its volume in water, and in its elevated water retention capacity, distinguishing it from other high-fiber fruits like apple and even psyllium husk.⁸

Simple Carbohydrate content – Green kiwifruit contains approximately 7g of sugars, split evenly between glucose and fructose, while the sweeter-tasting gold kiwifruit contains 10g of sugars with a similar distribution of glucose and fructose.⁹ Given the absence of polyols and oligosaccharides, kiwifruit is an appropriate addition to a low fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. This stands in contrast to other fruits recommended for constipation such as prunes, which are high in sorbitol and may lead to bloating, diarrhea, and discomfort in patients unable to digest sorbitol. A small study showed that ingestion of 2 kiwifruit was not associated with increases in hydrogen or methane levels on breath testing, consistent with this notion.¹⁰

Protein and amino acids -While kiwifruit is not a high-protein food, with under 1g protein per fruit, the proteins and amino acids contained within it are significant.⁹ Actinidin, the primary protein in kiwifruit, is a protease enzyme that can aid digestion. Remarkably, actinidin remains stable against pepsin degradation and displays broad proteolytic action, especially in the acidic environment of gastric pH.¹¹ It has been shown to quickly digest ingested proteins, with evidence of improving gastric emptying time.^12,13 While the protein concentrations of most kiwifruit cultivars are comparable, there is a marked variation in their enzymatic activity.¹³ Specifically, the green kiwifruit actinidin’s proteolytic activity is much greater (about eight times greater) than that of the SunGold™ kiwifruit.^11,13 Gold kiwifruit varieties other than the SunGold™ variety have little to no actinidin.¹³ Beyond actinidin, kiwifruit houses other proteins and derivatives like kiwellin, kissper, and thaumatin-like protein, which have also been shown to exhibit anti-inflammatory, anti-bacterial, and anti-fungal activities.¹⁴ Interestingly, the kiwifruit’s kissper protein exhibits ion channel-like, pore-forming properties, suggesting that modulation of the intestinal membrane permeability may be one of the mechanisms for alleviating constipation.¹⁵

Micronutrients – While they may not contribute to its laxative effect, the kiwifruit is an excellent source of vitamins, particularly vitamin C, vitamin E, and folate. It is also rich in other antioxidants, such as phenolics and carotenoids, including lutein, violaxanthin, and β-carotene.⁶ Furthermore, it is a significant source of potassium, containing around 6 mEq of potassium per kiwifruit.⁶

Evidence Supporting Kiwifruit for Constipation

Historically, knowledge of kiwifruit’s gastrointestinal benefit can be traced back to the Tang Dynasty (circa 600 AD).⁶ A pioneering human study in 2001 offered evidence on this matter, revealing that kiwifruit improved bowel movement frequency, consistency, volume, and ease of defecation among healthy elderly participants.¹⁶ Subsequent studies have echoed these positive findings, particularly among patients with functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C), the latter being characterized by abdominal pain. In these studies, participants typically consumed 2-3 kiwifruits daily from either the green or gold variety, though some trials explored the impact of powdered kiwifruit extract.

In a recent 2023 international multicenter, randomized crossover study of patients with FC and IBS-C, the consumption of two peeled green kiwifruit per day (providing 6g of fiber) as compared to 7.5g of psyllium fiber was associated with an increase in the number of complete spontaneous bowel movements (CSBM), at an increase of 1.5 CSBM per week for FC and 1.7 CSBM per week for IBS-C.¹⁷ On the other hand, psyllium was associated with a non-significant increase of 0.7 CSBM per week for FC and a significant increase of 1.3 CSBM for IBS-C. Comparing the improvement with kiwifruit to that with psyllium showed kiwifruit to be superior (overall increase in CSBM of 1.7 vs. 0.9, p=0.038).¹⁷ There was also a statistically significant improvement in stool consistency and straining for both kiwifruit and psyllium, again showing kiwifruit to be superior.¹⁷ Another similarly designed study from New Zealand was published in 2022, comparing two gold kiwifruits to 7.5g of psyllium fiber.¹⁸ Findings revealed comparable efficacy between the interventions with an increase of approximately 1 CSBM weekly for gold kiwifruit and around 1.5 weekly for the psyllium (p=0.63 in comparing interventions).¹⁸ Chey et al., found that two green kiwifruit daily were associated with a mean increase of 1 CSBM weekly.¹⁹ In contrast, 12g psyllium provided an increase of 1.7 CSBM weekly and prunes offered 2.¹⁹ Beyond the number of bowel movements, kiwifruit intake also improved stool consistency, reduced straining, and mitigated the sensation of incomplete evacuation.¹⁹ Of note, for those with constipation, an improvement of over 1 CSBM weekly constitutes a clinically meaningful amelioration.

The Impact of Kiwifruit on Symptoms Associated with Constipation

A 2022 systematic review delved into kiwifruit’s benefits in gastrointestinal symptoms other than constipation.²⁰ They found that there was good evidence supporting a positive influence of kiwifruit, particularly green kiwifruit, on abdominal discomfort and pain (good evidence, medium-high quality), abdominal distention and bloating (medium evidence, medium quality), disrupted swallowing and reflux (good evidence, high quality), and indigestion or dyspepsia (good evidence, high quality).²⁰ The evidence supporting gold kiwifruit in this context was weaker, with low evidence for abdominal discomfort/pain and disrupted swallowing/reflux, no evidence for abdominal distention/bloating, and good evidence only for indigestion/dyspepsia.

Evidence Regarding Kiwifruit Extracts

Despite the evidence showing the benefit of kiwifruit for constipation, studies investigating the effect of kiwifruit supplements (often freeze-dried powders) have not shown similar benefits. ²¹ It is likely that components of the fresh fruit are crucial to derive its benefits. However, the single positive randomized controlled trial that demonstrated evidence supporting kiwifruit supplements used Kivia powder containing Zyactinase^TM at a dose of 5.5g per day, compared to other studies which used 0.6g to 1g of other kiwifruit extracts.^21,22 This study found improvements in the frequency and consistency of bowel movements as well improvements in abdominal discomfort, flatulence, and urgency.²² As such, the benefit appears to be related to dosage and extract formulation, similar to how the benefit of fresh kiwifruit is related to the quantity and strain of the ingested fruit.

How to Apply Research Results in the Clinic

In clinical settings, we recommend presenting kiwifruit as a potential treatment option, especially for patients with mild symptoms and those reluctant to take medications. Patients can be counseled to eat two to three kiwifruits per day, ideally of the green Hayward variety, as the evidence is strongest for this cultivar. The gold cultivar may be offered as well if the green variety is not palatable, but the supportive evidence is weaker. There is some evidence that consuming the kiwifruit flesh with its skin may enhance the beneficial effects on gastrointestinal symptoms, although most studies were performed on peeled kiwifruit.²³ Therefore, we suggest deferring the choice to the patient given the unappetizing texture of the skin. While there is no evidence regarding the timing of consuming the fruits, it is likely that consuming the fruit near meals may be beneficial given their potential digestive benefits.

From Clinic to Bowl –
How to Make it Sustainable

Kiwifruit is generally palatable and well-received. In a 2021 study by Chey et al., only 7% of those assigned to consume kiwifruit for constipation reported dissatisfaction, in comparison to 17% for prunes and 38% for psyllium.¹⁹ While kiwifruit can easily be enjoyed on its own, strategies to avoid taste fatigue can include the creative methods of incorporated kiwifruit into the diet as described in Table 3. It is also worth noting that while most studies specify that fruits were ingested whole, there is no evidence to suggest that blending kiwifruit is detrimental. Juicing, on the other hand, is not recommended as the juice extraction process removes most of the fruit’s fiber content. Similarly, baking kiwifruit is not ideal as the heat is likely to denature the enzymes, detracting from its benefits.²⁴

Conclusion

The management of chronic constipation can be challenging. Given the compelling evidence, kiwifruits should be added to the healthcare provider’s therapeutic toolkit. A daily intake of two green kiwifruits offers a promising option for constipation management through enhancing stool frequency, consistency, and ease of evacuation. Kiwifruits are further likely to benefit associated symptoms of abdominal pain, bloating, indigestion, and reflux. While their palatability is generally well-received, it can be pivotal to proactively discuss the potential for taste fatigue with patients to improve sustained treatment adherence. Two kiwifruits a day may truly keep the gastroenterologist away.

References

Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis. Am J Gastroenterol. 2011;106(9):1582-1591.

2.
Tanner S, Chaudhry A, Goraya N, et al. Prevalence and Clinical Characteristics of Dyssynergic Defecation and Slow Transit Constipation in Patients with Chronic Constipation. J Clin Med. 2021;10(9):2027.

3.
Lee HJ, Boo S-, Jung KW, et al. Long-term efficacy of biofeedback therapy in patients with dyssynergic defecation: results of a median 44 months follow-up. Neurogastroenterol Motil. 2015;27(6):787-795.

4.
Chang L, Chey WD, Imdad A, et al. American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation. Gastroenterology. 2023;164(7):1086-1106.

5.
Singh P, Tuck C, Gibson PR, Chey WD. The Role of Food in the Treatment of Bowel Disorders: Focus on Irritable Bowel Syndrome and Functional Constipation. Am J Gastroenterol. 2022;117(6):947-957.

6.
Richardson DP, Ansell J, Drummond LN. The nutritional and health attributes of kiwifruit: a review. Eur J Nutr. 2018;57(8):2659-2676.

7.
Bellini M, Tonarelli S, Barracca F, et al. Chronic Constipation: Is a Nutritional Approach Reasonable? Nutrients. 2021;13(10):3386.

8.
Sims IM, Monro JA. Fiber: Composition, Structures, and Functional Properties. Vol 68.; 2013.

9.
Sivakumaran S, Huffman L, Sivakumaran S, Drummond L. The nutritional composition of Zespri® SunGold Kiwifruit and Zespri® Sweet Green Kiwifruit. Food chemistry.2018;238:195-202.

10.
Chen AGY, Offereins MSL, Mulder CJ, Frampton CM, Gearry RB. A Pilot Study of the Effect of Green Kiwifruit on Human Intestinal Fermentation Measured by Hydrogen and Methane Breath Testing. J Med Food. 2018;21(12):1295-1298.

11.
Grozdanovic MM, Ostojic S, Aleksic I, Andjelkovic U, Petersen A, Gavrovic-Jankulovic M. Active actinidin retains function upon gastro-intestinal digestion and is more thermostable than the E-64-inhibited counterpart. J Sci Food Agric. 2014;94(14):3046-3052.

12.
Montoya CA, Rutherford SM, Olson TD, et al. Actinidin from kiwifruit ( Actinidia deliciosa cv. Hayward) increases the digestion and rate of gastric emptying of meat proteins in the growing pig. Br J Nutr. 2014;111(6):957-967.

13.
Kaur L, Mao B, Bailly J, Oladeji O, Blatchford P, McNabb WC. Actinidin in Green and SunGold Kiwifruit Improves Digestion of Alternative Proteins—An In Vitro Investigation. Foods. 2022;11(18):2739.

14.
Bayer SB, Gearry RB, Drummond LN. Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. Crit Rev Food Sci Nutr. 2018;58(14):2432-2452.

15.
Ciardiello MA, Meleleo D, Saviano G, et al. Kissper, a kiwi fruit peptide with channel-like activity: Structural and functional features. J Pept Sci. 2008;14(6):742-754.

16.
Rush EC, Patel M, Plank LD, Ferguson LR. Kiwifruit promotes laxation in the elderly. Asia Pac J Clin Nutr. 2002;11(2):164-168.

17.
Gearry R, Fukudo S, Barbara G, et al. Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial. Am J Gastroenterol. 2023;118(6):1058-1068.

18.
Bayer SB, Heenan P, Frampton C, et al. Two Gold Kiwifruit Daily for Effective Treatment of Constipation in Adults—A Randomized Clinical Trial. Nutrients. 2022;14(19):4146.

19.
Chey SW, Chey WD, Jackson K, Eswaran S. Exploratory Comparative Effectiveness Trial of Green Kiwifruit, Psyllium, or Prunes in US Patients With Chronic Constipation. Am J Gastroenterol. 2021;116(6):1304-1312.

20.
Bayer SB, Frampton CM, Gearry RB, Barbara G. Habitual Green Kiwifruit Consumption Is Associated with a Reduction in Upper Gastrointestinal Symptoms: A Systematic Scoping Review. Adv Nutr. 2022;13(3):846-856.

21.
van der Schoot A, Creedon A, Whelan K, Dimidi E. The effect of food, vitamin, or mineral supplements on chronic constipation in adults: A systematic review and meta-analysis of randomized controlled trials. Neurogastroenterol Motil. 2023;35(11):e14613.

22.
Udani JK, Bloom DW. Effects of kivia powder on Gut health in patients with occasional constipation: a randomized, double-blind, placebo-controlled study. Nutr J.2013;12(1):78.

23.
Eady SL, Wallace AJ, Hedderley DI, Bentley-Hewitt KL, Butts CA. The Effects on Immune Function and Digestive Health of Consuming the Skin and Flesh of Zespri® SunGold Kiwifruit (Actinidia Chinensis var. Chinensis ‘Zesy002’) in Healthy and IBS-Constipated Individuals. Nutrients.2020;12(5):1453.

24.
Zhu X, Kaur L, Boland M. Thermal inactivation of actinidin as affected by meat matrix. Meat Sci.2018;145:238-244.

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MAUNA KEA TECHNOLOGIES PARTNERS WITH METRODORA TO CREATE FIRST U.S. CENTER OF EXCELLENCE FOR THE USE OF CELLVIZIO® TO IDENTIFY AND TREAT FOOD INTOLERANCE IN ADULTS

MAUNA KEA TECHNOLOGIES PARTNERS WITH METRODORA TO CREATE FIRST U.S. CENTER OF EXCELLENCE FOR THE USE OF CELLVIZIO^®TO IDENTIFY AND TREAT FOOD INTOLERANCE IN ADULTS

Cellvizio Food Intolerance Test (C-FIT) delivers real-time, in vivo visibility to accurately identify food intolerance in patients suffering from Irritable Bowel Syndrome (IBS)

Metrodora will serve as Center of Excellence for patient care and physician training to enable broad access to this breakthrough procedure

Paris, Boston and Salt Lake City, March 6, 2024 – Mauna Kea Technologies (Euronext Growth: ALMKT), inventor of Cellvizio^®, the multidisciplinary probe and needle-based confocal laser endomicroscopy (p/nCLE) platform, and Metrodora Institute, a leading multispecialty healthcare institute, today announced the formation of a new partnership. This collaboration aims to establish Metrodora Institute as the first U.S. Center of Excellence that will serve as the model of patient care and physician training on the use of Cellvizio for identifying and treating food intolerances in patients suffering from Irritable Bowel Syndrome (IBS). The Cellvizio Food Intolerance Test (C-FIT) offers a groundbreaking approach to diagnosing food intolerances, providing a real-time visualization of the intestinal barrier during a food challenge.

In the United States, about 10-15%[1] of the general adult population suffers from IBS, a condition reportedly linked to atypical food intolerance in the majority of cases, characterized by a group of symptoms including abdominal pain, bloating, and changes in bowel habits (diarrhea, constipation, or both). This condition significantly affects the quality of life of those affected who often face a protracted and distressing journey of medical consultation that could last 2 to 3 years on average with no guaranteed path to identifying the underlying cause of their symptoms.

“This partnership is perfectly aligned with our strategic ambition and represents a significant step forward in expanding the use of Cellvizio in the food intolerance markets. The Cellvizio U.S. Center of Excellence at the Metrodora Institute serves as a key driver in increasing awareness among the medical and patient communities about C-FIT, positioning it as a benchmark method for food intolerance detection”, said Sacha Loiseau, Ph.D., Founder, Chairman and Chief Executive Officer of Mauna Kea Technologies. “There is an urgent, unmet need for the immense pool of IBS patients who endure debilitating daily complications. It is crucial to swiftly extend the C-FIT procedure to as broad an audience as possible.”

Metrodora was established in 2021 as a multidisciplinary care and research center for people with neuroimmune disorders, including neurogastrointestinal disorders. Metrodora’s state-of-the-art ambulatory surgery center in Salt Lake City, Utah, offers advanced diagnostic and therapeutic procedures to evaluate and treat a range of complex and routine conditions.

“We couldn’t be more excited about being named the first U.S. Center of Excellence for implementing and serving as a healthcare model for the C-FIT procedure,” said John Wirthlin, CEO, Metrodora Institute. “Many patients live with undiagnosed food intolerances, simply because existing testing methods cannot identify the underlying issues. Our vision is that Metrodora Institute will adopt novel technologies like Cellvizio to improve the lives of the patients we serve.”

About Mauna Kea Technologies

Mauna Kea Technologies is a global medical device company that manufactures and sells Cellvizio^®, the real-time in vivo cellular imaging platform. This technology uniquely delivers in vivo cellular visualization which enables physicians to monitor the progression of disease over time, assess point-in-time reactions as they happen in real time, classify indeterminate areas of concern, and guide surgical interventions. The Cellvizio^® platform is used globally across a wide range of medical specialties and is making a transformative change in the way physicians diagnose and treat patients.

[1]

Hungin APS, Tack J, Mearin F, Whorwell PJ, Dennis E, Barghoui V. Irritable bowel syndrome (IBS): prevalence and impact in the USA – the truth about IBS (T-IBS) survey. Am J Gastroenterol. 2002; 97:242. (Poster #460)

For more information, visit:

maunakeatech.com

2024 Sherman Prize
Now Accepting Nominations

Honoring Excellence in Crohn’s and Colitis

BOCA RATON, Florida, March 11, 2024 – The Bruce and Cynthia Sherman Charitable Foundation announced today that the Sherman Prize is now accepting nominations for 2024. Now in its ninth year, the Sherman Prize, which recognizes and rewards those who have gone above and beyond in the fight to overcome Crohn’s disease and ulcerative colitis, also known as the inflammatory bowel diseases (IBD), has honored the outstanding achievements of 24 extraordinary IBD professionals.

“The Sherman Prize is the highest recognition of the talent and achievements in the field of IBD today,” said Dr. Maria T. Abreu, 2024 Selection Committee Chair and 2019 Sherman Prize Recipient. “Honoring the innovators who have devoted their careers to helping those who suffer from Crohn’s disease and ulcerative colitis elevates their work and inspires others to excel, which is why the Sherman Prize is so meaningful. This is a great opportunity for our colleagues to nominate outstanding individuals who are pushing the boundaries of treatment and care.”

All nominees are evaluated by the Sherman Prize Selection Committee. In 2024, Chair, Dr. Abreu is joined by:

Dr. Jessica Allegretti, Brigham and Women’s Hospital, 2020 Sherman Prize Emerging Leader Prize recipient.

Dr. Stephen Hanauer, Northwestern University Feinberg School of Medicine.

Dr. James Lewis, University of Pennsylvania, 2016 Sherman Prize recipient.

Dr. Uma Mahadevan, University of California San Francisco, 2022 Sherman Prize recipient.

Bruce Sherman said, “Since we launched the Sherman Prize in 2016, my wife Cynthia and I have been proud to honor the visionaries who share a deep commitment to addressing the unmet challenges of Crohn’s and colitis and lead the scientific research that not only improves the quality of life for people with IBD today but lays the foundation for greater discoveries in the future. We hope that by rewarding these achievements, the Sherman Prize may inspire excellence in others.”

Nominations may be submitted at ShermanPrize.org through May 24. The 2024 Prize recipients will be announced in the Fall and honored at the Prize presentations during the Advances in IBD (AIBD) conference in Orlando, Florida, December 10.

About the Sherman Prize

In 2016, Bruce and Cynthia Sherman established the Sherman Prize to provide national recognition and financial prizes to pioneering IBD professionals who exemplify excellence in Crohn’s disease and ulcerative colitis. Since its inception, the Sherman Prize has honored 24 IBD practitioners from diverse specialties.

Two $100,000 Sherman Prizes are awarded annually to IBD clinicians, surgeons, researchers and/or academics, recognizing exceptional and pioneering contributions that transform the care of people with IBD. Sherman Prize recipients are accomplished experts changing the paradigm in IBD and inspiring future innovators through their achievements.

A $25,000 Sherman Emerging Leader Prize is awarded to an IBD clinician, surgeon, researcher, academic, or physician assistant, who, while early in his or her career, has contributed to an advancement and shows great promise for significant future contributions.

Selection decisions are made by the Board of Directors, following an extensive review and evaluation by the Prize Selection Committee, which is comprised of five of the nation’s preeminent IBD specialists.

For eligibility guidelines and to nominate an individual doing exceptional work on behalf of people with IBD, please visit:

ShermanPrize.org

Pancreatic Duct Leaks

April 2024 • Volume XLVIII, Issue 4

Nicole D. Ferrante,

Monica Saumoy

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INTRODUCTION

Pancreatic duct (PD) leaks can occur in the setting of acute or chronic pancreatitis, trauma, or pancreatic resection. Their clinical manifestations vary widely depending on the underlying etiology and the site and extent of PD disruption. Sequelae of PD leaks include peripancreatic and pancreatic fluid collections (PFCs), as well as internal and external pancreatic fistulas. Small PD leaks may resolve with conservative management alone, but other therapeutic options include endoscopic, radiologic, surgical, and combined approaches necessitating a multidisciplinary care team. The role of endoscopic retrograde cholangiopancreatography (ERCP) is primarily to provide a therapeutic intervention to PD leaks and their sequelae. Over time, the role of endoscopic therapy for PD leaks has expanded with comparable effectiveness to surgical and radiologic approaches. Currently, the mainstay of endoscopic therapy involves transpapillary pancreatic duct stenting to bridge the site of PD disruption. In this article, we review the pathophysiology, epidemiology, clinical manifestations, diagnosis, and approach to endoscopic management of PD leaks. (See Figure 1.)

PATHOPHYSIOLOGY AND CLASSIFICATION

PD leaks result from disruption of the pancreatic ductal system, which can be seen in the setting of acute or chronic pancreatitis, abdominal trauma, and as a complication of pancreatic resection or peripancreatic surgery. (See Figure 2.) Activation of proteolytic enzymes, pancreatic autodigestion, and the production of proinflammatory cytokines are felt to play key roles in the pathogenesis of acute pancreatitis.¹ While the exact mechanism is unknown, pancreatic duct disruption is likely a secondary effect of pancreatic inflammation in patients without trauma or prior instrumentation. Disruption of the PD results in the leakage of pancreatic fluid, which may contribute to autodigestion of pancreatic parenchyma.¹ PD leaks can also occur in the setting of chronic pancreatitis either because of superimposed acute pancreatitis or increased intraductal pressure from obstructing PD stones or strictures. Lastly, PD leaks can occur as a result of direct injury to the PD from abdominal trauma, pancreatic resection, or inadvertent pancreatic injury during abdominal surgery. The American Association for the Surgery of Trauma grading system grades pancreatic injury based on the location of PD injury and degree of ductal involvement.² Postoperative pancreatic fistulae are defined and graded based on the 2016 International Study Group of Pancreatic Fistula consensus definitions.³

Persistent leakage of pancreatic fluid can erode into neighboring structures and spaces resulting in the formation of PFCs and pancreatic fistula. The classification of PFCs has changed over time and is currently based on the time that they develop in relation to pancreatitis onset and the presence of necrosis.⁴ Pancreatic fistula are abnormal connections between the pancreatic ductal epithelium and another epithelial surface. Fistula are traditionally classified as internal or external, as well as anatomically based on the site of involvement. Internal pancreatic fistula can result from pancreatic fluid erosion into the peritoneal space (pancreaticoperitoneal fistula), pleural space (pancreaticopleural fistula), mediastinum (pancreaticomediastinal fistula), pericardial space (pancreaticopericardial fistula), bronchial tree (pancreaticobronchial fistula), biliary tract (pancreaticobiliary fistula), stomach (pancreaticogastric fistula) and nearby small or large bowel (pancreaticoenteric or pancreaticocolonic fistula). External pancreatic fistula, or pancreaticocutaneous fistulas, result from communication between the pancreas and the skin, and are most commonly iatrogenic secondary to drains placed via interventional radiology or surgery.

EPIDEMIOLOGY

PD disruption and its sequelae are most commonly seen in the setting of severe acute pancreatitis, though the true incidence of PD leaks is unknown as small leaks may be clinically silent.^5–7 Disconnected pancreatic duct syndrome (DPDS) represents the most severe form of PD disruption with complete transection of the main PD resulting in a portion of the pancreas (usually the tail) becoming isolated from the remainder of the pancreas.^8,9 It is most commonly seen in the setting of necrotizing pancreatitis with up to 10-30% of patients developing DPDS, though the true incidence is not known.^5,6

PD leaks can also occur post-operatively after pancreatic resection or inadvertent pancreatic injury during surgery of nearby organs such as the spleen, left kidney, colon, and left adrenal gland. (See Figure 3.) In the setting of pancreatic resection, PD leaks can complicate up to 5-29% of cases depending on the health of the underlying pancreatic tissue, extent of pancreatic resection, and main PD diameter.^10–13

Lastly, PD leaks can be seen in the setting of pancreatic injury from abdominal trauma. The incidence of pancreatic injury is up to 5% after blunt abdominal trauma and up to 30% after penetrating abdominal trauma, with the most common complication being pancreatic fistula.^14–19

CLINICAL MANIFESTATIONS

The clinical manifestations of PD leaks vary widely and are driven by the underlying etiology, the site of the PD leak, the extent of PD disruption, rate of secretion of pancreatic fluid, and the presence of pancreatic fistula.²⁰ (See Figure 4.) In acute pancreatitis, the initial presentation is largely driven by the etiology and severity of the pancreatitis, whereas the sequelae of PD disruption play a greater role as the clinical course evolves. Generally, low-grade leaks can be asymptomatic, precipitate pancreatitis, or evolve to become pseudocysts whereas severe leaks and their sequelae are more likely to be symptomatic. Depending on the size, location, and presence of superinfection, PFCs may present as nonspecific gastrointestinal symptoms, sepsis/septic shock, gastric outlet obstruction, or biliary obstruction. DPDS typically presents as a refractory PFC or pancreatic fistula, as the isolated portion of the pancreas continues to secrete pancreatic fluid that is unable to be secreted appropriately into the GI tract.

The clinical manifestations of pancreatic fistula are highly variable depending on the distant site of communication. Pancreaticocutaneous fistulas are usually the most obvious, as they present with visible leakage of pancreatic fluid from the skin with or without skin excoriation. Pancreaticoperitoneal fistulas result in pancreatic ascites with varying degrees of abdominal symptoms and can be complicated by peritonitis. Pancreaticoenteric fistulas can present with gastrointestinal (GI) bleeding, diarrhea, or malabsorption. Thoracopancreatic fistulas can result in cough, dyspnea, chest pain, dysphagia, mediastinitis, and pneumonia depending on the site of involvement. Because pancreatic fluid is high in bicarbonate and protein, PD leaks can cause a metabolic acidosis, dehydration, and malnutrition, especially in the setting of high-grade leaks.

DIAGNOSIS

Accurate identification and characterization of PD disruption is important in guiding the approach to management. Currently, there are no consensus guidelines for the diagnosis of PD leaks. ERCP is traditionally considered the gold standard for confirming the presence, severity, and site of PD disruption, which is defined by contrast extravasation from the pancreatic ductal system. (See Figures 5-7.) The potential for ERCP to cause pancreatitis and superinfection, and the improvement in noninvasive imaging modalities, has resulted in ERCP being primarily reserved for cases where endotherapy is warranted in the setting of a diagnostic evaluation.²¹ Generally, the diagnostic approach is determined by the clinical presentation.

In the setting of acute pancreatitis, contrast-enhanced computerized tomography (CT) is often obtained as part of the initial diagnostic workup. Clinical worsening should prompt repeat CT imaging to evaluate for the development of PFCs and pancreatic necrosis. Identification of a PFC suggests that a PD leak is present, and its location may suggest the site of PD disruption. (See Figure 8.) Serial imaging demonstrating a persistent or enlarging PFC further supports the presence of an ongoing PD leak, which can be confirmed with magnetic resonance cholangiopancreatography (MRCP), secretin-enhanced MRCP (S-MRCP), or ERCP. In the setting of DPDS, S-MRCP has high sensitivity for identifying the site of ductal disruption and may additionally visualize the disconnected portion of the pancreas.²² In the setting of chronic pancreatitis, CT is often used in the initial diagnosis of chronic pancreatitis and to evaluate for calcified PD stones, PD strictures, and sequelae of PD leaks in the case of symptom progression.²³

Similarly, internal pancreatic fistula can be suggested by findings on cross-sectional imaging and, in the case of pancreatic ascites and pancreaticopleural fistulas, can be confirmed by the presence of a high fluid amylase in the peritoneal and pleural fluid, respectively. (See Figure 9.) The diagnosis of external pancreatic fistula and post-operative PD injury is often more straightforward, as they typically present as persistent fluid output from a percutaneous or surgical drain. Fluid analysis demonstrating a fluid amylase that is >3x upper limit of normal (ULN) supports the diagnosis, and a fistulogram is rarely necessary for diagnostic purposes.³

Occasionally, sequelae of PD disruption may present in the absence of a clear inciting event. If a patient presents with a PFC in the absence of preceding pancreatitis, a general approach involves obtaining cross-sectional imaging (CT or MRI) with or without EUS for fluid analysis to rule out a neoplasm.

MANAGEMENT

PD leaks and their sequelae can result in fluid and electrolyte imbalance, malnutrition, and sepsis; thus, conservative medical therapy plays a key role in management and may result in resolution of low-volume PD leaks. A multi-disciplinary approach is essential to identify patients that might benefit from endoscopic, radiologic, surgical, or multimodal therapy.

Overview of Endoscopic Therapy

ERCP can be used to effectively treat PD leaks and their sequelae. The presence of a PD leak is not a strict indication for endotherapy, as low-grade leaks may resolve with conservative management alone; thus, a key step is to identify patients that would benefit from an endoscopic approach to management. Still, in practice, most patients with PD leaks come to endotherapy at some point in their clinical course. Important considerations include whether there is evidence of an ongoing PD leak, PFC, or necrosis.

Relative indications for endotherapy of presumed or definite PD leaks and their sequelae include:

Persistent or worsening PD leak despite conservative management

Symptomatic PFC

Superinfected PFC

The mainstay of endoscopic therapy for PD leaks and their sequelae involves transpapillary pancreatic duct stenting to bridge the site of PD disruption and/or transmural drainage of associated PFCs. If a leak cannot be crossed with endoscopic transluminal stenting, which usually occurs in the setting of DPDS, surgery or interventional radiology approaches may be indicated. (See Figure 10.)

Transpapillary Drainage

Transpapillary drainage involves an ERCP with insertion of a PD stent that bridges the site of PD disruption. (See Figures 11-13.) Bridging the site of PD disruption with a PD stent promotes physiological flow of pancreatic fluid into the duodenum rather than through the site of PD disruption and correlates with successful outcomes.^24,25 Additionally, PD stents can be used to bypass areas of ductal obstruction due to PD stones and strictures. The stent diameter depends on the PD diameter and should not exceed the diameter of the upstream PD.²⁶ While pancreatic sphincterotomy is not required for stent insertion, it can be used to facilitate stone extraction and PD stricture dilation and is often performed if the need for repeated PD access is anticipated in the future. Optimal stent duration/indwell time is unclear and depends on the etiology of the PD leak and operator preference. In cases where the upstream portion of the PD is unable to be accessed, a shorter stent can be placed, with a plan to re-attempt ERCP to bridge the leak at a later date. In most case series, PD stents were left in place for 4-8 weeks with shorter durations being associated with an increased risk of recurrence or failure and longer durations being associated with stent occlusion and ductal changes in a previously otherwise normal PDs, but this has not been universally reported.^{24,25,27–29} Importantly, many patients need, and tolerate, long PD stent indwell times without any evidence of duct injury. Lastly, transpapillary drainage can be used to drain PFCs that communicate directly with the main PD. This technique involves placing the distal aspect of the stent directly into the PFC and is supported by case-series that have demonstrated its effectiveness, though it is not the preferred route of drainage.^30,31 (See Figure 14.) Even if the PD does not clearly communicate with the PFC, a PD stent can still help to prevent backfilling of the PFC and can promote resolution.

Transmural Drainage

Transmural drainage directs PFC contents into the stomach or duodenum, which decompresses the PFC and promotes healing of the PD leak. This technique involves transmural puncture of a mature PFC through the gastric wall (cystgastrostomy) or duodenal wall (cystenterostomy) and placement of one or more stents to allow for drainage of the contents into the GI tract. (See Figure 15) Transmural drainage is performed during esophagogastroduodenoscopy (EGD) with or without EUS guidance, although in current practice the use of EUS is almost universal. EUS allows for the identification of blood vessels and solid debris and is the preferred approach, especially in the absence of an obvious area of extrinsic compression.^32,33 Effective drainage of liquefied PFCs has been reported with the placement of double-pigtail plastic stents, biliary SEMS, or lumen apposing metal stent (LAMS).^34–41 Currently, there are no consensus guidelines for stent selection and duration and, thus, this is left at the discretion of the endoscopist. Typically, cross-sectional imaging is performed 4-8 weeks later to confirm PFC resolution followed by stent removal 6-8 weeks after radiographic resolution of the PFC.²¹ If percutaneous drains were also placed, they are typically removed before the transmural drains to minimize the risk of developing external PF. If the PFC contains solid necrotic material, this can also be debrided endoscopically via direct endoscopic necrosectomy (DEN).

Pancreatic Leak from Acute Pancreatitis

In the setting of acute pancreatitis, PFCs are classified according to the time they develop in relation to onset of pancreatitis and the presence of necrosis.⁴ Briefly, acute PFCs are seen earlier in the course of pancreatitis, lack a definable wall, and are either predominantly fluid-filled (acute PFCs) or contain some component of solid necrotic debris (acute necrotic collections).⁴ Most acute collections resolve spontaneously but if drainage is necessary, endoscopic drainage is often not recommended in the absence of a definable outer wall. Occasionally, acute collections evolve into pancreatic pseudocysts or WON which contain a well-defined wall.⁴ Distinguishing between pseudocysts and WON is important, as this will inform therapeutic management.

Options for the endoscopic management of pseudocysts include transpapillary drainage, transmural drainage, or a combination of the two.²¹ The approach depends on the collection’s size, proximity to the gastric or duodenal wall, and communication with the main PD. Smaller pseudocysts (≤ 6cm) that communicate with the main PD can be effectively managed with transpapillary drainage alone.^42,43 Outcomes have otherwise been variable due to heterogeneity in PFC nomenclature and varying patient populations. More recently, evidence has emerged regarding the lack of additional benefit with transpapillary drainage among individuals with successful transmural drainage of PFCs.^44,45 Transmural drainage has become increasingly popular over time, with SEMS and especially LAMS being widely utilized with excellent reported outcomes.^39,40 Percutaneous drainage can also be performed but is associated with pancreaticocutaneous fistulae (which can become chronic); thus, it is typically reserved for PFCs that are either immature or not amenable to transmural drainage because of their location.²¹ In regards to timing, endoscopists may choose to perform an ERCP and place a PD stent if there is an active PD leak either at the time of transmural drainage or later in the patient’s course, as transmural drainage alone may result in healing of the leak.⁴⁴

Whereas pseudocysts are predominantly fluid filled, WON contains solid debris which cannot be effectively drained with a transpapillary approach. The preferred approach to endoscopic management is transmural drainage and necrosectomy with a “step-up” approach to potentially include percutaneous drainage and/or surgical debridement, although this last step is rarely required.

Pancreatic Leak from Chronic Pancreatitis

In the setting of chronic pancreatitis, PD disruption can occur from either an episode of acute on chronic pancreatitis, or ductal obstruction secondary to PD stones or strictures. The most common indication for endotherapy in chronic pancreatitis is to alleviate abdominal pain that is felt secondary to PD obstruction and to treat PD leaks, and is supported by international consensus guidelines.⁴⁶ Similar to PD leaks from acute pancreatitis, PD stents can bridge the site of PD disruption and bypass areas of obstruction, thus restoring endoluminal flow of pancreatic duct secretions.

External Pancreatic Fistula

External pancreatic fistula are most commonly iatrogenic due to surgery or percutaneous drainage of PFCs, and are rarely due to penetrating abdominal trauma. Endoscopic therapy is typically reserved for persistent pancreaticocutaneous fistulae despite initial attempts at conservative management, as the majority of low-volume leaks will close with conservative therapy. Conservative management includes enteral feeding, which has been shown to improve fistula closure rates.⁴⁷ The use of somatostatin analogs for prevention and treatment of pancreatic fistula has been extensively studied with mixed results; thus, it is typically reserved for patients with high-output fistulas in the absence of contraindications.^48,49 If fistula output fails to decrease with conservative management, MRCP or S-MRCP should be performed prior to evaluate for DPDS. In the absence of DPDS, transpapillary stent placement can be performed to facilitate closure of external PF and is supported by case series.^50–55 In addition, case series have described combined endoscopic and percutaneous rendezvous approaches to internalizing external fistulae but this should only be attempted at expert centers.⁵⁶ Surgery is rarely necessary and typically reserved for inaccessible superinfected PFCs, bleeding from pseudoaneurysms, failure of endoscopic methods, and clinical instability.

Internal Pancreatic Fistula

As previously discussed, internal pancreatic fistulae can communicate with the peritoneum, pleural space, bowel, biliary tree, or other thoracomediastinal spaces. The approach to therapy depends on the type of fistula and whether or not there is an associated pseudocyst. Pancreatic ascites and high-amylase pleural effusions were initially managed with conservative management consisting of bowel rest, diuretics, octreotide, and large-volume paracenteses and thoracenteses with suboptimal success and recurrence.^57–59 Transpapillary stenting has proven to be effective in multiple case series, so long as the site of PD disruption can be bridged with the stent.^27,60–64 In the presence of a concomitant pseudocyst, transmural drainage alone may result in resolution of pancreatic ascites and pleural effusions.⁶⁵ Surgical options include partial pancreatectomy, enteropancreatic anastomosis, or Roux-en-Y cystojejunostomy if concomitant pseudocysts are present, but is associated with up to 10% mortality and 15% recurrence rates.^12,57,66,67

Pancreatic fistulization into the bowel can also occur. While pancreaticoenteric fistulas in the upper GI tract appear to be effectively managed with conservative therapy, pancreaticocolonic fistulas are associated with higher mortality rates due to associated sepsis and/or GI bleeding.^68,69 For stable patients, endoscopic therapy can be considered, as case series have reported acceptable rates of success with transpapillary stent placement and transmural drainage of associated PFCs.^70,71 Of note, specialized centers have described the use of transcolonic necrosectomy, SEMS placement, and over-the-scope clip closure of pancreatoenteric fistulas but this should only be attempted at expert centers.^72–74 Surgical management, which often includes diverting ileostomy or colostomy, should be considered in patients who fail endoscopic therapy or develop clinical instability or GI bleeding.

Lastly, pancreatobiliary fistulae are a rare complication of PD leaks, which may result in cholestasis or cholangitis/sepsis. Similar to the above, case reports and case series have reported successful outcomes with different combinations of transmural drainage of associated PFCs, transpapillary PD stent placement, and biliary stent placement in the presence of cholestasis or cholangitis.^75,76 Based on limited case series, an endoscopic approach appears to be safe and effective, with surgical biliary reconstruction reserved for patients who fail endoscopic therapy.

Disconnected Pancreatic Duct Syndrome

DPDS most commonly manifests as a PFC or pancreaticocutaneous fistula that is refractory to conservative management. The management of DPDS is complex and has not been standardized. Traditionally, it involves distal pancreatectomy or internal drainage via Roux-en-Y pancreaticojejunostomy with the disconnected segment.⁸ More recently, there has been interest in endoscopic and multimodal approaches.⁷⁷ For DPDS-associated PFCs, percutaneous drainage alone carries the risk of pancreaticocutaneous fistula formation. Alternatively, transmural drainage allows for enteral drainage of the upstream pancreatic secretions that are unable to drain transpapillary. In these instances, transmural drains are often left in place indefinitely with favorable outcomes.^8,78,79 Lastly, interventional radiology-guided percutaneous embolization of the disconnected portion of the PD with cyanoacrylate or other agents has been described in case series.⁸⁰ Currently, there is no consensus regarding optimal nonsurgical management in these patients due to a lack of robust comparative studies. Important limitations of previous studies are the inclusion of patients with partial duct disruption, which may skew the findings in favor of endoscopic therapy, and varying definitions of DPDS and endoscopic success. In a recent systematic review, endoscopic transmural drainage was found to be superior to transpapillary drainage with comparable success rates of >80% when compared to surgical management, analogous to previous systematic reviews and meta-analyses.^81–83 Should endoscopic therapy be attempted, it is important to consider a step-up approach for patients who fail minimally invasive treatment.

Traumatic PD Leaks

Traumatic PD leaks can present similarly to PD leaks from other etiologies. The role of ERCP in traumatic PD leaks has not been established. As with other clinical scenarios, ERCP is useful when the suspicion of PD disruption is high and endotherapy can be performed. Case series have described the utility of early ERCP to assess PD anatomy, which may influence immediate surgical management.^84,85 If the PD leak is identified at a later presentation, they typically present as smoldering pancreatitis or a PFC, the management of which is described above.

CONCLUSION

It is important to be able to identify PD leaks and understand the indications and contraindications for endotherapy. While small PD leaks may resolve with conservative management alone, larger leaks often require additional therapy for which the options include endoscopic, radiologic, surgical, and combined approaches. The majority of PD leaks can be managed effectively without surgery, but a multidisciplinary approach to therapy is recommended to identify patients that require step-up therapy. The mainstay of endoscopic therapy for PD leaks and their sequelae involves transpapillary pancreatic duct stenting to bridge the site of PD disruption and/or transmural drainage of associated PFCs. Importantly, current evidence for the management of PD leaks is limited to case series, retrospective observational studies, and expert opinion; therefore, prospective studies are needed to inform clinical practice guidelines.

ACKNOWLEDGEMENTS

We would like to thank Drs. Ricardo Morgenstern, Kashyap Panganamamula, Nuzhat Ahmad, and Galen Leung for providing images.

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76. Carrere, C. et al. Biliopancreatic fistulas complicating pancreatic pseudocysts: a report of three cases demonstrated by endoscopic retrograde cholangiopancreatography. Endoscopy 33, 91–94 (2001).

77. Pawa, R. et al. Long-term Transmural Drainage of Pancreatic Fluid Collections with Double Pigtail Stents Following Lumen-Apposing Metal Stent Placement Improves Recurrence-free Survival in Disconnected Pancreatic Duct Syndrome. Dig Endosc (2022) doi:10.1111/den.14266.

78. Bang, J. Y. et al. Impact of Disconnected Pancreatic Duct Syndrome on the Endoscopic Management of Pancreatic Fluid Collections. Annals of Surgery 267, 561–568 (2018).

79. Rana, S. S., Shah, J., Sharma, R. K. & Gupta, R. Clinical and morphological consequences of permanent indwelling transmural plastic stents in disconnected pancreatic duct syndrome. Endosc Ultrasound 9, 130–137 (2020).

80. Findeiss, L. K., Brandabur, J., Traverso, L. W. & Robinson, D. H. Percutaneous embolization of the pancreatic duct with cyanoacrylate tissue adhesive in disconnected duct syndrome. J Vasc Interv Radiol 14, 107–111 (2003).

81. Chong, E. et al. Endoscopic transmural drainage is associated with improved outcomes in disconnected pancreatic duct syndrome: a systematic review and meta-analysis. BMC Gastroenterol 21, 87 (2021).

82. Pandanaboyana, S. et al. Endoscopic Transmural Drainage is Associated With Improved Outcomes in Disconnected Pancreatic Duct Syndrome: A Systematic Review and Meta-analysis. https://www.researchsquare.com/article/rs-60493/v1 (2020) doi:10.21203/rs.3.rs-60493/v1.

83. van Dijk, S. M. et al. Treatment of disrupted and disconnected pancreatic duct in necrotizing pancreatitis: A systematic review and meta-analysis. Pancreatology 19, 905–915 (2019).

84. Rogers, S. J., Cello, J. P. & Schecter, W. P. Endoscopic retrograde cholangiopancreatography in patients with pancreatic trauma. J Trauma 68, 538–544 (2010).

85. Thomson, D. A., Krige, J. E. J., Thomson, S. R. & Bornman, P. C. The role of endoscopic retrograde pancreatography in pancreatic trauma: a critical appraisal of 48 patients treated at a tertiary institution. J Trauma Acute Care Surg 76, 1362–1366 (2014).

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Nutrition Reviews in Gastroenterology, SERIES #11

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

March 2024 • Volume XLVIII, Issue 3

Berkeley N. Limketkai,

Preetha Iyengar

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

Introduction

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

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

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

Mechanism of Action

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

Metabolism and Bioavailability

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

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

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

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

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

Ulcerative Colitis

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

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

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

Safety

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

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

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

Table 2. Recommendations for Curcumin Use in Ulcerative Colitis

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

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

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

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

Practical Applications

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

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

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

Conclusion

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

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

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30. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas P. Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers. Planta Med. 1998;64(04):353-356.

31. Jamwal R. Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers. Journal of Integrative Medicine. 2018;16(6):367-374.

32. Lang A, Salomon N, Wu JCY, et al. Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Clinical Gastroenterology and Hepatology. 2015;13(8):1444-1449.e1.

33. Sadeghi N, Mansoori A, Shayesteh A, Hashemi SJ. The effect of curcumin supplementation on clinical outcomes and inflammatory markers in patients with ulcerative colitis. Phytotherapy Research. 2020;34(5):1123-1133.

34. Masoodi M, Mahdiabadi MA, Mokhtare M, et al. The efficacy of curcuminoids in improvement of ulcerative colitis symptoms and patients’ self-reported well-being: A randomized double-blind controlled trial. J of Cellular Biochemistry. 2018;119(11):9552-9559.

35. Kedia S, Bhatia V, Thareja S, et al. Low dose oral curcumin is not effective in induction of remission in mild to moderate ulcerative colitis: Results from a randomized double blind placebo controlled trial. WJGPT. 2017;8(2):147.

36. Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis — A randomized, placebo-controlled, pilot study. Journal of Crohn’s and Colitis. 2014;8(3):208-214.

37. Hanai H, Iida T, Takeuchi K, et al. Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial. Clinical Gastroenterology and Hepatology. 2006;4(12):1502-1506.

38. Suskind DL, Wahbeh G, Burpee T, Cohen M, Christie D, Weber W. Tolerability of Curcumin in Pediatric Inflammatory Bowel Disease: A Forced-Dose Titration Study. Journal of Pediatric Gastroenterology & Nutrition. 2013;56(3):277-279.

39. Williams CT. Herbal Supplements. Nursing Clinics of North America. 2021;56(1):1-21.

40. Center for Food Safety and Applied Nutrition. Small Entity Compliance Guide: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. Published December 2010. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/small-entity-compliance-guide-current-good-manufacturing-practice-manufacturing-packaging-labeling

41. Cooperman T. Turmeric and Curcumin Supplements and Spices Review. ConsumerLab.com. Published June 15, 2023. Accessed December 11, 2023. https://www.consumerlab.com/reviews/turmeric-curcumin-supplements-spice-review/turmeric/?search=Curcumin

42. Natural Medicines Comprehensive Database. Accessed October 29, 2023. https://naturalmedicines.therapeuticresearch.com/

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

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

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

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

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

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

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

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

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

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

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

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Medical Bulletin Board

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

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

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

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

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

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

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

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

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

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

About the Dupixent Pediatric Eosinophilic Esophagitis Trial

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

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

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

About Dupixent

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

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

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

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

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

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

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

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

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

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

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

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

About NETTER-2

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

About Lutathera^®

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

Novartis and Radioligand Therapy (RLT)

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

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

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

Disclaimer

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

About Novartis

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

Reimagine medicine with us:

Visit us at:

novartis.com

NEWS FROM THE AMERICAN
COLLEGE OF SURGEONS

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

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

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

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

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

How much is colorectal cancer
increasing in younger adults?

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

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

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

Why is colorectal cancer increasing among young people?

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

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

What can people do to prevent colorectal cancer?

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

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

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

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

the disease due to other health factors.

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

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

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

Additional resources:

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

facs.org/colorectalcancer/

References

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

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

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Dispatches from the GUILD Conference, Series #57

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

March 2024 • Volume XLVIII, Issue 3

Edward V. Loftus Jr.

Read Article

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

INTRODUCTION

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

PATHOGENESIS OF ATHEROSCLEROSIS IN INFLAMMATORY DISORDERS

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

CARDIOVASCULAR RISK: SCOPE OF THE PROBLEM

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

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

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

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

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

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

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

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

THROMBOEMBOLISM RISK

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

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

RISK WITH SPECIFIC MEDICATIONS

Janus Kinase Inhibitors

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

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

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

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

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

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

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

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

Anti-Interleukin Antibodies

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

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

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

Sphingosine-1-Phosphate Receptor Modulators

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

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

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

CONCLUSIONS

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

References

References
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From the Pediatric Literature

Zonulin and Pediatric Celiac Disease

March 2024 • Volume XLVIII, Issue 3

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

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

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

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

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

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

Infant Symptoms are Often Misdiagnosed as GERD

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

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

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

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

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

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

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