Division Overview

Our Vision

We will be the leaders in the care of children with digestive diseases.

Our Mission

• Care: We will deliver exceptional, safe, and affordable care.
• Research: We will catalyze high-impact research in digestive diseases.
• Education: We will train the future leaders of the field.

Our Values

• We are respectful
• We are honest
• We speak the truth
• We value diversity
• We work as a team

Innovation in Clinical Care

The location of the division on the eighth and ninth floors of the Clinical Sciences Building, where clinical, research, and training projects permit integration to provide the most innovative, evidence- and expert-based care for children with all forms of digestive disease. Delivery of direct patient care occurs in the Outpatient Gastroenterology Clinic and in inpatient units for gastroenterology (A4S) and for hepatology and liver transplantation (A4N). Our team also provides timely consultation to all clinical services at Cincinnati Children’s Hospital, where we work as a multi-disciplinary team to improve the care of the children we serve. The scope of care starts with the most common digestive problems and extends to the most rare and complex disorders that require ever-improving technologies to aid in diagnosis and to design new therapies. Some of our specialized services include liver and intestinal transplantation, intestinal rehabilitation, total pancreatectomy and islet cell autotransplantation, inflammatory and complex esophageal and intestinal disorders, and others (described below).

Our medical and nurse specialists also provide care in satellite clinics with the goal to bring gastroenterology expertise to our communities and improve patient experience. We hold daily clinics at the Cincinnati Children’s Hospital Liberty Campus focusing on gastroenterology, an increasing number of subspecialty clinics (example: NASH clinic and Neurogastroenterology / Motility clinic), and gastrointestinal endoscopies. Other satellite gastroenterology clinics are available in the Cincinnati Children’s Hospital facilities in Mason, Green Township, Anderson, Northern Kentucky, and Portsmouth. Our experts also partner with other programs via TeleHealth or other forms of professional-to-professional digital consultations in Kalamazoo (MI), Lexington (KY), Akron (OH), and in Park View (IN).

Innovation and Research

The division is a scientific hub for digestive disease research for Cincinnati Children's and the University of Cincinnati College of Medicine. We founded our research programs on the premises that defects in development, genetics, and immunology play key roles in determining the phenotypes of digestive diseases in children. We aim to discover the biological underpinnings of digestive diseases that begin in childhood. To this end, physician-scientists and researchers receive funding from the National Institutes of Health and industry to use novel model systems in the laboratory and to perform clinical trials. Our commitment is to increase the tempo of translation of new discoveries to the clinics so that the investments from our hospital and our society can translate into actionable items in the clinic and improve the outcome of children with digestive diseases. The listings below are a review of our broad research portfolio by the individual Centers of Excellence.

Innovation in Education

Our training program receives funding from a T32 grant for over 15 years. Most of our graduates are on academic positions and hold several positions as division chiefs in the U.S. Our commitment is to integrating the clinical and research programs into an arena of opportunities for advanced training in the field of gastroenterology and related subspecialties. Our training programs include:

• Fellowship Program in Gastroenterology, Hepatology and Nutrition
• Advanced fellowship training in Hepatology and Liver Transplantation, Neurogastroenterology / Motility, Nutrition, and IBD
• Short-term clinical observation / clerkships for U.S. and international trainees
• Research training for international scientists

Below, we present summaries and accomplishments by individual Centers of Excellence.

Digestive Health Center: A Catalyst for Research on Digestive Disease

Members:

Jorge Bezerra, MD, Director
Lee (Ted) Denson, MD, Associate Director
Heidi Kwalkarf, PhD, Associate Director
Cynthia Wetzel, PhD, Center Manager

The Digestive Health Center (DHC) is one of only 18 Silvio O. Conte Digestive Diseases Research Core Centers funded by the National Institutes of Health in the U.S., and the only one dedicated to pediatric digestive diseases. Aaron Zorn, PhD, from the Division of Developmental Biology, serves as an associate director. The center seeks to improve child health through better diagnosis, treatments and outcomes that will emerge from highly innovative work in our three key research themes: 1) Mechanisms of liver disease; 2) Digestive disease and immunity; and 3) Stem cell and organoid modeling of digestive disease. Three scientific cores link these themes to provide investigators with timely access to state-of-the-art technologies: Integrative Morphology, Gene Analysis, and Stem Cell / Organoid and Genome Editing Cores. An additional clinical component facilitates patient-based research. With 68 investigators, the DHC supports faculty from 17 divisions within the Department of Pediatrics and eight other departments within the University of Cincinnati, College of Medicine. This group of investigators has a research portfolio funded by $36.6 million in digestive disease research and published 351 papers during the past 12 months, of which 164 are on digestive disease research. To strengthen pediatric digestive disease and the career development of junior investigators, the DHC funds highly promising pilot and feasibility projects and sponsors a dynamic enrichment program of scientific seminars, workshops, and annual symposium. The DHC Pilot and Feasibility Program invested $2.58 million among 59 early-stage investigators since 2007. These investigators have since attracted $81.7 million in extramural grant funding.

In addition to the accomplishments described above, the following DHC investigators received national and international recognition for their clinical, research, and educational accomplishments this past year:

• Bezerra is president of the American Association for the Study of Liver Diseases in 2020 and is the chairman of the Board of Scientific Councils for NIDDK Intramural Research.
• Kalkwarf is standing member of the National Institutes of Health Neurological, Aging and Musculoskeletal Epidemiology Study Section for Scientific Review.
• Takanori Takebe, MD, received an election to the American Society for Clinical Investigation and is the new recipient of the NIH Director’s New Innovator Award.

Advanced Nutrition

Members:

Antoinette Adjowa Amevor, MD
Conrad Cole, MD, MPH, MSc
Lee (Ted) Denson, MD
James E. Heubi, MD
Heidi Kalkwarf, RD, PhD
Samuel Kocoshis, MD
Marialena Mouzaki, MD, MSc, Director
Stavra Xanthakos, MD, MS

Our mission is to optimize nutritional status of children exposed to chronic medical conditions and environmental hardships through surveillance of patients at risk, and identification and implementation of best treatment practices. We seek to improve the prevention and treatment of childhood diarrhea, obesity and undernutrition by implementing best practices and creating new knowledge through bench-to-bedside research collaborations between Cincinnati Children’s Hospital Medical Center and global partners.

Mouzaki is investigating the presence and pathophysiology of sarcopenia seen in the context of liver diseases such as non-alcoholic fatty liver disease (NAFLD) in collaboration with Xanthakos along with Andrew Trout, MD, and Jonathan Dillman, MD, MSc, both from the Department of Radiology. He is also investigating autoimmune liver diseases in collaboration with Amevor and Alexander Miethke, MD, from the Division of Gastroenterology, Hepatology and Nutrition. Furthermore, Mouzaki, in collaboration with Sarah Orkin, MD, an early career investigator, is studying the role of food insecurity in pediatric NAFLD.

Mouzaki developed a novel study investigating the impact of pregnancy on the development of fetal hepatic steatosis, as well as the role of early life factors such as diet and weight gain, on the natural history of early onset NAFLD.

Xanthakos completed study visits for her NIH-funded study and is currently analyzing the liver-related and metabolic outcomes of adolescents who completed either intensive lifestyle interventions or weight loss surgery, including the role of dietary changes.

Kalkwarf is investigating the long-term effects of bariatric surgery performed in adolescence on bone density and nutritional status. Kalkwarf and Heubi are completing a study investigating trajectories of bone mineral accrual in young children and the influences of dietary intake, growth, and body composition. This data will establish normal ranges for bone density based on age and enable detection of bone deficits in children with chronic medical conditions.

Denson continues collaboration with investigators at the University of Virginia and three international sites on patient-based studies to define the pathogenesis of environmental enteropathy in affected children. A high-impact journal published single-center results of this study. He is also leading the first multi-center RCT of the prebiotic 2’-fucosyllactose nutritional supplement in children and young adults with Crohn’s disease and ulcerative colitis.

Cole continues to have collaboration / consulting role in projects in Ghana and Sierra Leone focusing on micronutrient deficiencies (zinc and iron) in undernutrition, diarrheal diseases and development of endoscopy skills and services. Cole and Kocoshis are Center investigators in clinical trials and patient-based research involving patients with intestinal failure.

Cincinnati Center for Eosinophilic Disorders

Members:

Phil Putnam, MD, GI Director
Vince Mukkada, MD, GI Associate Director
Scott Bolton, MD

The Cincinnati Center for Eosinophilic Disorders (CCED) is an established multidisciplinary referral center for evaluation and treatment of eosinophilic gastrointestinal disorders (EGID) in children and adults. Physicians representing the Divisions of Gastroenterology, Hepatology and Nutrition, Allergy and Immunology, and Pathology provide comprehensive clinical services supported by experienced nurses, dieticians, a psychologist and social worker. Over 70% of our patients agree to participate in clinical and basic science research studies. Our clinical research includes important studies of both dietary and pharmacologic management of eosinophilic disorders and we are continuing to focus on identifying less invasive means of diagnosis and disease monitoring. Putnam, Bolton, and Mukkada collaborate with other leading investigators in the CCED in studies of genetic and immunologic factors underlying the development of eosinophilic inflammation in the gut, and in evaluating the effectiveness of biological agents (including anti-IL-4 receptor binding antibodies, anti-IL5 receptor binding antibodies, and anti-Siglec8 antibodies) and topical glucocorticoids in the management of eosinophilic disease. The CCED team continues (with the support of the Thrasher Foundation) to investigate eosinophil progenitor (EoP) as a potential noninvasive biomarker, which is an essential step toward simpler disease monitoring over time, with the potential of reduced discomfort, costs, and side effects.

Recent research includes prominent roles for a number of CCED investigators including Sandy Durrani, MD, and Marc Rothenberg, MD, PhD, from the Division of Allergy and Immunology, Margaret Collins, MD, from the Division of Pathology, and Mukkada, such as a number of recently published clinical trials of novel therapeutics in EGID, including a phase 3 trial on the use of oral viscous budesonide in eosinophilic esophagitis and phase 2 trials of an anti-Siglec 8 antibody in eosinophilic gastritis and duodenitis and the anti-IL4 receptor antibody dupilumab in eosinophilic esophagitis. These trials and several others we are currently participating in (including phase 2 trials of an anti-IL5 receptor antibody in EoE and EG, an anti-Siglec 8 antibody in EoE, the anti IL-4 receptor antibody in EG, and phase 3 trials of the anti-IL4 receptor antibody in EoE, the anti-Siglec 8 antibody in EG/ED, an anti-IL13 antibody in EoE, and the anti-IL5 receptor antibody in EG) raise the hopes that we will soon have FDA approved therapies for these diseases, and that the CCED will continue to be at the leading edge of research into new therapeutics. In a collaborative effort across the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), we recently published manuscripts describing the disassociation between symptoms and histology in patients who have undergone esophageal dilation as well as our efforts to identify a core set of outcomes measures in our trials in EGIDs. We also recently published our experience in identifying novel risk genes for eosinophilic esophagitis.

We continue to involve our trainees in cutting edge research in eosinophilic disease. Recent graduates published manuscripts examining the potential role of estrogen receptors in the pathogenesis of EoE and identifying the effect of EoE and its treatment on bone health in our local patient population. They also looked at a novel characterization of very early onset EoE compared to a control group of patients who present as adolescents, the development and characteristics of EGID in patients who have undergone liver or small bowel transplants, and a report of our experience with benralizumab in patients with EoE.

With support from the National Institutes of Health to Rothenberg, the CCED leads a consortium of organizations with a common goal to conduct clinical research into eosinophilic disorders and to train investigators in how to conduct clinical research. We are now in our first five-year renewal of the consortium’s work. This Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) is a collaboration of clinician investigators, translational scientists, physicians, patients, families and patient advocacy groups and is part of the Rare Disease Clinical Research Network (RDCRN). Work from this collaborative group has to date focused on studies of the natural history of eosinophilic disease, particularly the comparatively rare types including eosinophilic gastritis and eosinophilic colitis, as well as a number of studies looking at treatments including determining the disease response to less-restrictive diet therapy in adult patients with EoE, a project examining the use of the angiotensin receptor blocker losartan in the treatment of EoE, and another assessing the role of elemental diet therapy for eosinophilic gastritis. We are now starting a trial of the anti-IL4 receptor antibody dupilumab in the treatment of eosinophilic gastritis and will be starting a new round of pilot projects shortly. Extending our work with a new focus on diversity, equality and inclusion, encompassing not only a renewed focus on making our research efforts relevant and inclusive for all including underserved populations, but also in a renewed focus on training a diverse group of clinicians and investigators with interests in this work is exciting for us. J. Pablo Abonia, MD, from the Division of Allergy and Immunology, and Mukkada have prominent roles in the new Diversity Committee within CEGIR.

Clinically, Bolton and Mukkada are leading our efforts to begin performing non-sedated transnasal endoscopy in the office setting, which should provide both cost and safety advantages to eligible patients, with the first patients scheduled to start in late summer. We, like all of our colleagues and patients, have been deeply affected by the ongoing COVID-19 crisis and contributed to our improved understanding of effects of the pandemic in chronic disease by participating in an international registry of patients with EGIDs who have contracted coronavirus (SECURE-EoE/EGID). We have deep involvement in our local efforts to safely provide effective care via telemedicine and in our process to full reopening of in-person visits and elective endoscopic procedures, and have been advocating strongly for our chronic patients to receive a vaccination against this new disease.

IBD - The Schubert-Martin Inflammatory Bowel Disease Center

Members:

Lee “Ted” Denson, MD, Director
Phillip Minar, MD, Medical Director
Jasbir Dhaliwal, MD
Jennifer Hellmann, MD
Kaitlin Whaley, MD

The Division of Gastroenterology, Hepatology and Nutrition and the IBD Center sees more than 1,000 patients with IBD each year. Over 100 new patients receive a diagnosis annually and close to 80 second-opinion patients see physicians at the Schubert-Martin Inflammatory Bowel Disease (IBD) Center from more than 20 states and abroad. These numbers reflect a steady increase in total patient volume over the last five years.

The center is an integral and leading participant in collaborative consortia like the ImproveCareNow (ICN) Quality Improvement Network and the Crohn’s and Colitis Foundation’s PRO-KIDS Clinical Research Network. This role reflects in superior outcomes for our patients, with 84% of IBD patients within the center being in remission, 65% in sustained remission, and 87% expressing a high level of confidence in disease management. A focus of quality improvement has been the development of care algorithms for biologic therapy. Implementation of these is quite effective, with 98% of patients having drug levels measured, and 88% achieving target drug levels. We embraced telehealth to maintain care and these outcomes for our IBD population during the COVID-19 pandemic. We share these processes and outcome measures transparently on the center’s website, and with other ICN centers. Our Annual IBD Family Education Day, co-hosted by the local chapter of the Crohn’s and Colitis Foundation continues to be one of the largest educational events of its kind in the country.

Physicians within the center continue to develop and lead basic, translational and clinical research to identify key etiopathogenic mechanisms for inflammatory bowel diseases, minimally invasive biomarkers for predication of disease flares and remission, tools to optimize effective use of biologic therapies, and test novel therapies with immune and microbial targets. A study published in Nature led by Theresa Alenghat, VMD, PhD, in the Division of Immunobiology, with Denson as collaborator, defined mechanisms by which specific dietary factors and associated microbial metabolites may promote healing in IBD via an epigenetic mechanism. A study published in Clinical Pharmacology and Therapeutics led by Minar described the development of an electronic health record-embedded dashboard to guide precision biologic therapy dosing in children with Crohn's Disease. He is now leading a clinical trial to test the impact of this model for personalized drug dosing, and will support biologic therapy dosing for the multi-center CAMEO NIH U01 led by Denson. Hellman reported results of a quality improvement project which successfully optimized infliximab drug levels in our IBD population in Pediatric Quality and Safety. Dhaliwal utilized the Canadian Children IBD Network to define outcomes with a newer biologic therapy, ustekinumab, in children with UC refractory to infliximab, in Alimentary Pharmacology and Therapeutics. Collaborators within the institution include the James M. Anderson Center for Health Systems Excellence, the Center for Adherence and Self-Management, Divisions of Behavioral Medicine and Clinical Psychology, Pediatric Surgery, Allergy and Immunology, Adolescent and Transition Medicine, Immunobiology, and the Department of Radiology continue to make significant contributions to finding a cure as well as improving outcomes and self-management skills for children suffering from IBD.

Interdisciplinary Feeding Team

Members:

Scott Pentiuk, MD
Vince Mukkada, MD
Candace Hochstrasser, APRN
Lisa Witte, APRN

The Interdisciplinary Feeding Team (IFT) provides comprehensive evaluation for children with swallowing / feeding disorders. This multidisciplinary team includes experts from the Divisions of Gastroenterology, Hepatology and Nutrition, Otolaryngology, Speech-Language Therapy, Occupational Therapy, Social Services. The IFT had over 1340 patient visits and 375+ new patients in Fiscal Year 2021. In addition to comprehensive consultation and care, the IFT offers unique multidisciplinary outpatient treatment sessions and child-adult relationship enhancement training for families. IFT added telemedicine options both for outpatient appointments and therapies. Ongoing research projects by IFT investigators include the development and use of the pureed by G-tube diet and methods to evaluate children with swallowing dysfunction.

Intestinal Rehabilitation and Intestinal Transplantation Programs

Members

Conrad Cole, MD, MPH, MSc, Medical Director, Intestinal Rehabilitation Center
Samuel Kocoshis, MD, Medical Director, Intestinal Transplantation Program
Stephanie Oliveira, MD
Antoinette Adjowa Walker, MD

These two programs continue to expand their clinical profiles and facilitate the translational and clinical research conducted by both programs. Our circumspect, thoughtful approach to intestinal rehabilitation has obviated the need for intestinal transplantation for many of the patients referred for transplantation as less than one in five patients referred for intestinal transplantation get transplanted. Our mission is to provide the best possible care for children with intestinal failure though innovation. Outcomes for both intestinal rehabilitation and intestinal transplantation are excellent. Our central line associated blood stream infection rate of 1.1/1000 catheter days is among the best in North America. We are working on identifying alternate measures and lock therapy to prevent CLABSI as the cost of ethanol lock therapy is impacting the use of ethanol locks in our patient population. We were the lead center for the expanded multicenter pediatric clinical trial funded by Shire / Takeda Pharmaceuticals for the recently approved Teduglutide (Gattex®) with Kocoshis (lead investigator) and Cole (co- investigator). Additional studies include the evaluation of the impact of quality of life of the family on the outcome of children with intestinal failure. We continue to address micronutrient deficiencies in our population including those of iodine and iron in an effort to develop novel therapeutic options for children with intestinal failure. We continue to monitor these modalities and are actively working on identifying the shortest duration of exclusive parental nutrition that associates with the development of specific micronutrient deficiencies. Michael Helmrath, MD, continues to lead the surgical program in using unique surgical procedures associated with better outcomes in these patients. The Helmrath lab studies the biology of intestinal stem cells as a key to unravel the mechanism involved during the disease process.

Our intestinal transplantation team shows excellent results over the past several years, demonstrating a one-year survival of approximately 90% for our patients undergoing either combined liver / small bowel transplant and isolated small bowel transplant. They also stratified risk for exfoliative rejection by presence or absence preformed or de novo donor specific antibodies (DSA). Patients with a positive DSA receive two to three times higher antithymocyte induction doses. Yet another potentially valuable observation is that patients who develop early-onset exfoliative rejection have a one-thousand-fold increase in peripheral lymphocyte counts during the three days prior to histologic features of exfoliative rejection. Recognizing this, enabled us to utilize aggressive immunosuppressive strategies prior to the onset of exfoliation. Preliminary data suggest that these strategies impact patient survival insofar as all five of our most recently transplanted patients have survived from nine months to three years. An even more exciting project is the Helmrath’s “Core Project” whereby organoids containing recipient epithelium delivered to allograft bowel already developed exfoliation. The expectation is for the acceptance of the organoids and that they will reconstitute an intact allograft epithelium that requires little or no immunosuppression.

Liver Care Center

Members:

Jorge A. Bezerra, MD, Director
William F. Balistreri, MD
Akihiro Asai, MD, PhD
Kathleen Campbell, MD
Chandrashekhar Gandhi, PhD
James Heubi, MD
Stacey Huppert, PhD
Alexander Miethke, MD, Associate Director
Anna Peters, MD, PhD
Pranav Shivakumar, PhD
Takanori Takebe, PhD
Amy Taylor, MD
Chunyue Yin, PhD

The Pediatric Liver Care Center provides comprehensive care for children with liver diseases and serves a national and international referral population via a comprehensive evaluation of all medical and surgical aspects of liver diseases. The evaluation includes a full spectrum of metabolic analysis, autoimmune and inflammatory processes, and gene sequencing techniques to diagnose mutations that cause clinical phenotypes. The multidisciplinary nature of the comprehensive care makes the center a “one-stop-shop” in which the timely consultation with hepatologists, surgeons, pathologists, radiologists, and nutritionists with expertise in pediatric liver disease optimizes patient care. It also catalyzes patient-based research to narrow the knowledge gap and solve clinical challenges with the ultimate goal to improve outcomes.

Physicians, surgeons and scientists in the center are performing exciting research with the goals of understanding the mechanisms of liver development, advancing tissue engineering, discovering the causes and pathogenesis of pediatric liver disease, and designing new therapies to block progression of liver injury. This work receives funding by independent grants from the National Institutes of Health, foundations, and industry. It aims to close the knowledge gap in the field with a focus on translating new discoveries into improved clinical care.

Our faculty published over 20 original scientific reports last year, as shown below as a brief summary of key findings:

• Modeling the human bile acid transport and synthesis using iPSCs harboring mutations in the bile salt export protein (Asai, published in Stem Cell Reports)
• Studies of the prevalence of colorectal dysplasia and cancer in pediatric-onset ulcerative colitis associated with PSC (Miethke, published in Clinical Gastro and Hepatology), and an analysis of the use of oral vancomycin and UDCA in children with PSC (Miethke, published in Hepatology)
• Polygenic basis of hepatotoxicity and high-fidelity drug screen using iPSC-derived mini liver organoids modeling of drug-induced liver injury (Takebe, published in Nature Medicine and Gastroenterology), and single-cell transcriptomics of endoderm-mesoderm diversification during organogenesis (Takebe, published in Nature Communications)
• Clinical best practice guidance for Hepatology and Liver Transplantation during the COVID-19 pandemic (Bezerra, published in Hepatology) and modeling outcomes of biliary atresia (Bezerra, published in Hepatology Communications)
• Natural course of pediatric portal hypertension (Campbell, published in Hepatology Communications) and health literacy and its association with adherence in pediatric liver transplant recipients Campbell, published in Pediatric Transplantation)
• Role of the Augmenter of Liver Regeneration in susceptibility to NASH and fibrosis (Gandhi, published in Hepatology) and the role of cMyb and related circuits in modulating hepatic stellate cell activation (Gandhi in Hepatology)

We have several lines of ongoing and new clinical and translational investigation addressing mechanisms of disease and new treatments. Examples includes Bezerra and Balistreri’s clinical trial assessing the efficacy of Tenofovir in children with chronic hepatitis B infection. Miethke is leading studies investigating the efficacy of an ASBTi for children with PFIC. Asai is using CRISPR-editing to introduce patient-specific mutation in pluripotent stem cells, generate inducible hepatocytes, and study mechanisms of cholestasis. In the Center for Autoimmune Liver Disease, Miethke leads a multi-disciplinary team studying radiological, biomarker, and genetic underpinnings of autoimmune liver disease, with a focus on studies of primary sclerosing cholangitis. Taylor is investigating family networks to understand the needs of children with autoimmune hepatitis and sclerosing cholangitis to improve clinical outcome and foster participation in clinical trials. Miethke will be a co-principal investigator in new prospective observational and interventional studies for children with primary sclerosing cholangitis as part of the NIH-funded Childhood Liver Research Network. Breaking new ground for transplantation science, Peters is applying single cell sequencing to study the cellular mechanisms underlying late-onset acute cellular rejection for liver-transplanted children.

In the laboratory, Huppert is studying mechanisms of cellular plasticity in the liver, with exciting work investigating re-programming mechanisms to regenerate the biliary epithelium. Gandhi is pursuing studies defining the role of augmenter of liver regeneration in pathogenesis of NASH, and the cellular crosstalk among sinusoidal endothelial cells, hepatic stellate cells and inflammatory cells that regulates fibrogenesis. Using zebrafish models, Yin is uncovering molecular mechanisms of cell injury and biliary secretion that drive pathogenic mechanisms of cholestatic syndromes.

Neurogastroenterology and Motility

Members:

Ajay Kaul, MD, Professor and Director, NGM Center
Khalil El-Chammas, MD, MS, Associate Professor, Medical Director of MDMC Program, Director of Advanced Motility Fellowship Program
Neha Santucci, MD, Assistant Professor, Lead for FGID Program
Kahleb Graham, MD, Assistant Professor
Sherief Mansi, MD, Assistant Professor

Despite the pandemic, the Neurogastroenterology and Motility Disorders (NGM) Center, continues to experience unprecedented growth, with 1656 outpatient encounters (83% more than prior fiscal year), performing 425 manometry procedures, over 150 impedance studies, 21 endoflip studies, 11 transrectal ultrasound, and seven gastric electric stimulation devices placed. We added a fourth faculty Graham to the center with a focus on functional GI disorders (FGID). Over the past year, the center received about 40 new referrals / second opinions per month, primarily from patients outside of our primary service area. Patients came from 30 states for evaluation at the center. El-Chammas, as medical director of the collaborative Multidisciplinary Motility Clinic (MDMC) with the Colorectal Center, was instrumental in successfully managing the unprecedented growth of the program. The MDMC program saw children with complex motility disorders from the region and across the nation. Santucci, with her expertise in FGID, led an effort to develop a novel program for managing children with pain related FGID. Since its inception in 2019, and with the addition of Graham, the program experienced significant growth with a total of 362 clinic visits for IB stim device placement alone. Santucci and Graham developed a FGID registry with a goal to deliver improved care as well as community support tools to assist general pediatricians in the diagnosis and management of FGID. They are also members of the Cincinnati Children's advisory team to design a combined medical and psychiatric unit for children with complex FGID. With his advanced motility training and expertise, Mansi, the latest addition to the faculty team, will significantly impact our productivity. Our team made a significant contribution to the evolving neuromodulation program by placing percutaneous electric nerve field stimulation devices in a record 59 patients with FGID, working with our CRC colleagues in managing patients with sacral nerve stimulators (SNS) for intractable constipation, and, more recently, gastric electric stimulation (GES) in patients with severe gastroparesis. We continue to improve our diagnostic armamentarium and treatment modalities incorporating latest, advanced technology and knowledge.

In addition to the exemplary clinical services provided, the center is very productive in academic pursuits. Exploring new research opportunities, the center has involvement in multicenter trials on the use of percutaneous electrical nerve field stimulation (PENFS) in FGID, the characterization of high-resolution colon manometry studies, and the use of Mirtazapine in functional abdominal pain, amongst others. The team also received the Procter Scholar and Heubi Investigator Award / grants to study sleep mechanisms in children with FGID and the effect of neuromodulation respectively. The team is working on other cutting-edge studies to assess PENFS outcomes in combination with behavioral intervention as well as other disorders like eosinophilic esophagitis, chronic pancreatitis and inflammatory bowel disease. Our advanced fellowship program in pediatric NGM (one of few in the nation) has three fellows graduate and then join as faculty at the Children’s Hospital of Pittsburgh (University of Pittsburgh Medical Center), Children’s Mercy Hospital (University of Missouri-Kansas City), and Cincinnati Children’s Hospital Medical Center. We are currently training our fourth advanced motility fellow and our first international graduate from Israel. Due to the COVID-19 pandemic, our team members did not host the annual National Workshop on Pediatric Manometry Training for physicians and nurses in 2020 and 2021. However, to continue to share knowledge and advances with the pediatric GI community, we collaborated with the sponsors to start a series of educational (10) webinars on related topics during this time. Members of the center presented at regional, national, and international virtual meetings and conferences, featured speakers on podcasts, received young investigator awards and had several publications in peer-reviewed journals, and contributed book chapters during this pandemic year.

Pancreas Care Center

Members:

Maisam Abu-El-Haija, MD, MS, Medical Director
Tom K. Lin, MD, Associate Director, Endoscopy Director
David Vitale, MD

Our vision is to be the leader in delivering world class healthcare to children with pancreatic disease, through comprehensive multidisciplinary management that puts patient outcomes at the forefront of our overarching goals. We implement chronic care algorithms that enhance the care coordination and apply state of the art research methodology to lead our innovation in patient care.

The program, which leads providers in surgery, endocrinology, pain team and psychology teams members, currently follows more than 600 patients coming from over 30 states. Patients seek the Pancreatic Care Center (PCC) for various pancreatic disorders including pancreatitis, exocrine pancreatic insufficiency, congenital anomalies of the pancreas, and pancreatic tumors. Our center offers comprehensive treatment options including endoscopic retrograde cholangiopancreatographies (ERCPs), endoscopic ultrasounds (EUS), and total pancreatectomy with iselt cell autotransplantation (TPIAT).

Since its inception in fiscal year 2013, the program assembled a multidisciplinary care team to evaluate and treat complex pancreatic disorders and established a REDCap database for pancreatitis patient registry. This is a robust registry and biorepository for pancreatic surgical patients for future research initiatives. In 2020, in collaboration with the endocrine team we built a diabetes registry for post TPIAT patients to better track our patients insulin requirements in real-time. The existing databases design is to allow generation of data that drives healthcare outcomes positively.

The PCC performed its first TPIAT operation in fiscal year 2015, and performed 22 operations in FY21, which makes the total TPIATs and subtotal pancreatectomies with IAT performed at 93 operations since our program’s inception. There were 580 gastroenterology pancreas clinic visits in fiscal year 2021 which includes 109 new pancreas patients visits. Included in the new visits were 37 patients seen for new TPIAT evaluations. The PCC advanced endoscopists, Lin and Vitale performed 192 ERCPs and 70 EUS in fiscal year 2021.

Our scientific highlights for this past year include cutting edge research on the role of imaging in staging pancreatic disease in children and predicting islet yield pre- TPIAT, published in the Journal of Pancreatology (PMID33339723). Our work in the acute pancreatitis arena have shown that drugs are the leading known cause of acute pancreatitis in childhood (PMID:32800650). Our unique TPIAT program generated important clinical studies on the role of continuous glucose monitoring devices in the care of subjects following TPIAT (PMID: 33925523 and 34064129). We also published on the cost effectiveness of early surgical intervention and its impact on healthcare and resource utilization in the American Journal of Surgery (PMID: 33541688). The PCC is proud to collaborate with the islet laboratory under the leadership of Balamurugan Appakalai, PhD, for the last year, where they are planning the next set of experiments to conduct islet cell isolation and islet cell biology and physiology related studies.

Abu-El-Haija receives funding from a K23 NIDDK grant for predicting severity and improving the outcomes of acute pancreatitis, and currently the grant is in the fourth year of funding. Our center is participating in NIH-funded multi-center studies (first two studies listed below) that will help advance the care of children with pancreatic disorders, amongst other grants submitted and awaiting review.

PCC team main extramural funding during fiscal year 2020:

1. NIH U01 Abu-El-Haija (site principal investigator) - CPDPC INSPPIRE International Study Group to Study Pediatric Acute Recurrent and Chronic Pancreatitis: In Search for a Cure. Cincinnati Children's is the highest recruiting center for four years in a row out of 21 national and international centers.

2. NIH R01 Abu-El-Haija (site principal investigator ) - Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT. Our center is the highest enrolling center for pediatric TPIAT nationally in this consortium.

3. NIH P30 award, Abu-El-Haija (co investigator)- Personalized Cystic Fibrosis Therapy and Research Center, Core title: Personalized Model System.

We widely marketed our pancreas gene panel we developed and launched in collaboration with the Molecular Genetics Laboratory. It is now a clinically available test for genes known to cause pancreatitis using next generation sequencing technology. Since the launch in November 2016, we steadily perform ~10 tests/month using the pancreas gene panel. In fiscal year 2021, 13 external sites utilized our laboratory for pancreatic genetic testing.

Nationally, PCC members have active involvement in the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). Abu-El-Haija is the current chair of the pancreas committee and a course director for the National Pancreas Foundation (NPF) annual meeting. Abu-El-Haija is on the American Gastroenterology Association Pancreas Selection Committee, the president-elect for the Collaborative Alliance for Pancreatic Education and Research (CAPER), and is on the planning committees of NASPGHAN and CAPER national meetings. Vitale is an active member in the NASPGHAN endoscopy committee. Lin and Vitale are active members in the NASPGHAN ERCP Special Interest Group. The PCC at Cincinnati Children's is one of only a select few pediatric centers that are an NPF-approved Center of Excellence for pancreatic care in the nation and is a referral destination sought out by patients and physicians from around the nation based on its reputation for excellence in patient care and its commitment to innovative research.

Pediatric Liver Transplantation

Members:

Alexander Miethke, MD, Medical Director
Akihiro Asai, MD
William Balistreri, MD
Jorge A. Bezerra, MD
Kathleen Campbell, MD
James Heubi, MD
Anna Peters, MD, PhD
Michael Rogers, MD
Amy Taylor, MD

The mission of the Pediatric Liver Transplant Program is to advance the care of liver transplant recipients by providing unparalleled clinical care, addressing gaps in knowledge through patient-based and basic laboratory research, improving health care delivery system through continuous quality improvement, and serving as advocates for organ donation and allocation in our community and country. As one of the largest pediatric liver transplant programs in the country, we performed 780 liver transplants since the program began in 1986.

We performed 37 liver transplants in pediatric recipients or young adults in the year 2020, which makes Cincinnati one of the busiest pediatric liver transplant programs in the nation. Transplants are either in isolation or in combination with small intestine, heart, or kidney. Our patient and graft survival rates are at or above the national average, and we are performing living donor liver transplantation from related or altruistic donors. In addition to providing care for the most common pediatric liver disorders leading to transplantations, we leverage institutional strengths to provide care and the best outcome available to a number of patients with rare diseases and extremely complex needs. This includes children with advanced liver tumors. Since 2007, the Cincinnati Children's liver transplant team performed 56 liver transplants for pediatric patients with hepatic tumors, more than any other program in the United States.

Chronic liver disease and transplantation impact other organs especially the kidneys and hearts. In collaboration with the nephrology service, we provide innovative renal replacement therapies including MARS before transplant or during the surgery, protect renal function following transplant through multi-disciplinary care coordination, and for those in need we perform simultaneous liver-kidney transplants. We performed five combined heart-liver transplants for patients with congenital heart disease and chronic liver failure from failing Fontan physiology.

In addition to providing outstanding patient care, the Liver Transplant program is a leader in multicenter clinical and translational research studies and national quality improvement efforts. These include: studies in pediatric liver transplantation (SPLIT) quality improvement community and clinical registry and multiple local projects. For instance, we developed a quality improvement program to identify barriers for medication non-compliance to design individualized mitigation strategies in our adolescent patients with support of the James M. Anderson Center for Health Systems Excellence. In collaboration with the Center for Transplant Immunology (CTIMM), Peters uses single-cell sequencing technology to molecularly define transplant rejection responses to better understand the biological processes underpinning late-onset acute cellular rejection and ultimately personalize immunosuppression therapies. Following successful liver-heart transplantation for a patient with dyskeratosis congenita, we are now supporting a multi-center effort to study liver disease phenotype and solid organ transplant outcomes in this rare bone marrow failure syndrome.

At the program level, our multi-disciplinary teams are undertaking various QI initiatives and innovative approaches to improve patient outcomes. These include live vaccines for post-transplant patients, and a new remote home monitoring program for our freshly transplanted patients. We formed a working group of hepatologists, surgeons, interventional cardiologist, and hematologists to optimize surgical techniques to decrease the rate of hepatic venous outflow obstruction, to establish non-invasive imaging protocols for more accurate diagnosis of this complication, and to refine protocols for endovascular intervention and oral anticoagulation.

Steatohepatitis Center

Members:

Stavra Xanthakos, MD, MS, Director
Marialena Mouzaki, MD, MSc, Associate Director
Catalina Arce-Clachar, MD
Kristin Bramlage, MD

Understanding and treating NAFLD and NASH: The Cincinnati Steatohepatitis Center (CCSC) is a multidisciplinary program that provides care to a growing population of children and adolescents with nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease worldwide. NAFLD affects one in ten children and one in three adults in the United States; up to 1/3 of these affected persons can develop a more severe form called nonalcoholic steatohepatitis (NASH) that can progress to severe fibrosis. NASH-related cirrhosis has become one of the leading causes of liver transplant in adults, especially younger adults. Early identification and intervention is critical to prevent progression to end-stage liver disease.

Because NAFLD and NASH are closely associated with obesity, cardiovascular disease, prediabetes and diabetes, the CCSC collaborates with the Center for Better Health and Nutrition, the Sleep Center, the Hypertension Clinic, the Lipid Clinic, the Type2 Diabetes Comprehensive Care Clinic and the Surgical Weight Loss Program for Teens to help identify and manage comorbid conditions and help patients achieve a healthier weight, the current first-line treatment. Our program completed over 922 patient visits in fiscal year 2020, in spite of the limitations imposed by the COVID-19 pandemic. We offer multidisciplinary clinics at our base, Liberty and Anderson locations, with four faculty members from the Division of Gastroenterology, Hepatology and Nutrition including Arce-Clachar, Bramlage, Mouzaki, and Xanthakos; Sanita Ley, PhD, from the Division of Behavioral Medicine and Clinical Psychology; and our team of experienced nurses and registered dietitians. Because patients of Hispanic ethnicity are at higher risk of NAFLD and may face additional barriers to accessing healthier lifestyles, we offer a clinic staffed by Arce-Clachar, who is bilingual in Spanish and English, to improve communication. In fiscal year 2021, we initiated telehealth offerings to expand patient care during the ongoing global pandemic. Additional clinical innovations in fiscal year 2021, led by Vitale in the Division of Gastroenterology, Hepatology and Nutrition introducing ultrasound-guided endoscopic liver biopsies, combined with endoscopic esophagogastroduodenoscopy.

Our active clinical and translational research program seeks to develop more broadly effective prevention and intervention strategies for NAFLD. For over 10 years, we are a leading pediatric site in the NIDDK-funded NASH Clinical Research Network (NASH-CRN), a multi-center consortium investigating the natural history and determinants of NASH in adults and children and conducting trials of novel therapies. In 2021, we initiated phase III of an ongoing observational cohort study, with the aim of determining natural history of children with NAFLD as they advance into young adulthood. In addition, we continue to be part of TARGET-NASH (since 2018), a multi-center observational cohort study that will examine natural history and comparative effectiveness of diverse treatments in populations under-represented in phase II and phase III clinical trials. We actively investigated novel noninvasive biomarkers for the diagnosis and staging of NAFLD, to reduce need for liver biopsies, including imaging methods (in collaboration with Trout and Dillman in the Department of Radiology) and cutaneous biomarkers (led by Mouzaki in collaboration with Kenneth Setchell, PhD). We recently completed an R01-funded study examining outcomes of adolescents with NAFLD who underwent either intensive lifestyle intervention vs. sleeve gastrectomy (principal investigator: Xanthakos). Xanthakos also collaborates with Shah, from the Division of Endocrinology, and Helmrath, from the Division of Pediatric General and Thoracic Surgery in investigating the impact of NAFLD on outcomes of youth with type 2 diabetes enrolled in an ongoing multi-center R01 examining outcomes after medical vs surgical treatment. In the past year, we initiated exciting new studies investigating the early onset of NAFLD in infants and preschool children (Mouzaki, Senad Divanovic, PhD, and Gandhi) and the contribution of early-life endocrine disrupting chemical exposures in the development of NAFLD in childhood (Xanthakos, in collaboration with the HOME Study at Cincinnati Children, MPIs: Kimberly Yolton, PhD, Kim Cecil, PhD, and Joseph Braun, PhD, MSPH, RN). In addition, Orkin, who joined our Division of Gastroenterology, Hepatology and Nutrition faculty in 2020, recently received a Diversity and Health Disparities Award to expand her analyses of social determinants of health to a multicenter cohort of children with NAFLD (collaborators: Beck, Richard Cole Brokamp, PhD). Finally, we continue to collaborate with innovative scientists across Cincinnati Children's, who are discovering novel mechanisms contributing to development of NAFLD, including Divanovic, Gandhi, Helmrath and Takebe (CuSTOM program).

Published research highlights in fiscal year 2021 include a multicenter analysis that found that alternate etiologies of liver disease in 900 children with suspected NAFLD were rare (Yodoshi T, et al. Pediatrics, 2021). We demonstrated that a diet high in fat and fructose induces early hepatic mitochondrial aging in murine model of NASH (Bramlage K, et al. J Pediatr Gastroenterol Nutr. 2021). Finally, we reported that one third of children with NAFLD enrolled in placebo arms of NASH Clinical Research Network trials had continued histologic progression of liver disease severity and high incidence of type 2 diabetes, despite receiving standard of care lifestyle counseling (Xanthakos, et al. Gastroenterology, 2020).

The published work by CCSC investigators is in Alimentary Pharmacology and Therapeutics, Gastroenterology, Hepatology, Clinical Gastroenterology and Hepatology, Obesity, New England Journal of Medicine, Nature, JAMA Pediatrics, Journal of Pediatrics, Journal of Pediatric Gastroenterology and Nutrition, Nature Reviews Gastro Hepatology, Pediatric Obesity and others.