Digestive Health Center: A catalyst for research on digestive disease

The Digestive Health Center (DHC), directed by Dr. Jorge Bezerra, MD, and managed by Dr. Cynthia Wetzel, PhD, 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 diseases. Drs. Lee Denson, MD; Heidi Kalkwarf, PhD, RD; and Aaron Zorn, PhD, from the Division of Developmental Biology serve as associate directors. The center seeks to improve diagnosis, treatments and outcomes of children with digestive diseases. It does so by enabling investigators to have timely access to state-of-the-art technologies at three scientific Cores: Integrative Morphology, Gene Analysis, and Pluripotent Stem Cell and Organoid Cores. With 84 investigators, the Digestive Health Center (DHC) contributes to the research goals of faculty from 20 divisions within the UC Department of Pediatrics and seven other departments within the University of Cincinnati, College of Medicine, with a total extramural grant portfolio of $32.6 million in digestive disease research. The DHC Pilot and Feasibility Program has invested $1.94 million among 45 early stage investigators since 2007. These investigators have since attracted $51.54 million in extramural grant funding. In addition to an outstanding record of publications with 196 digestive disease related articles during the past 12 months, the following center investigators received national and international recognition for their clinical, research, and educational accomplishments:

  • Jorge Bezerra, MD, Senior Councilor of the American Association for Studies of Liver Diseases and Member of the Board of Scientific Councilors for National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research
  • Lee Denson, MD, received the Sherman Prize for Excellence in Crohn’s and Colitis from the Bruce and Cynthia Sherman Charitable Foundation
  • James Heubi, MD, President of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
  • Heidi Kalkwarf, PhD, RD, Standing Member of the National Institutes of Health Neurological, Aging and Musculoskeletal Epidemiology Study Section for Scientific Review
  • Takanori Takebe, MD, received the prestigious Presidential Award from the Japan Agency for Medical Research and Development

Digestive Health Center: A catalyst for research on digestive disease

The Digestive Health Center (DHC), directed by Dr. Jorge Bezerra, MD, and managed by Dr. Cynthia Wetzel, PhD, 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 diseases. Drs. Lee Denson, MD; Heidi Kalkwarf, PhD, RD; and Aaron Zorn, PhD, from the Division of Developmental Biology serve as associate directors. The center seeks to improve diagnosis, treatments and outcomes of children with digestive diseases. It does so by enabling investigators to have timely access to state-of-the-art technologies at three scientific Cores: Integrative Morphology, Gene Analysis, and Pluripotent Stem Cell and Organoid Cores. With 84 investigators, the Digestive Health Center (DHC) contributes to the research goals of faculty from 20 divisions within the UC Department of Pediatrics and seven other departments within the University of Cincinnati, College of Medicine, with a total extramural grant portfolio of $32.6 million in digestive disease research. The DHC Pilot and Feasibility Program has invested $1.94 million among 45 early stage investigators since 2007. These investigators have since attracted $51.54 million in extramural grant funding. In addition to an outstanding record of publications with 196 digestive disease related articles during the past 12 months, the following center investigators received national and international recognition for their clinical, research, and educational accomplishments:

  • Jorge Bezerra, MD, Senior Councilor of the American Association for Studies of Liver Diseases and Member of the Board of Scientific Councilors for National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research
  • Lee Denson, MD, received the Sherman Prize for Excellence in Crohn’s and Colitis from the Bruce and Cynthia Sherman Charitable Foundation
  • James Heubi, MD, President of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
  • Heidi Kalkwarf, PhD, RD, Standing Member of the National Institutes of Health Neurological, Aging and Musculoskeletal Epidemiology Study Section for Scientific Review
  • Takanori Takebe, MD, received the prestigious Presidential Award from the Japan Agency for Medical Research and Development

Advanced Nutrition

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 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.

Dr. Conrad Cole, MD, MPH, MSc, continues to have collaboration/consulting role in projects in Ghana and Nigeria focused on micronutrient deficiencies (zinc and iron) in undernutrition, diarrheal diseases and sickle cell disease.

Dr. Lee Denson, MD, continues collaboration with investigators at the University of Virginia and the Aga Khan University in Pakistan on patient-based studies to define the pathogenesis of environmental enteropathy in affected children. 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.

Drs. Heidi Kalkwarf, PhD, RD, and Christine Heubi, MD, are investigating trajectories of bone mineral accrual in young children and the influences of dietary intake, growth, and body composition. These data will establish normal ranges for bone density based on age and enable detection of bone deficits in children with chronic medical conditions.

Drs. Kalkwarf and Stavra Xanthakos, MD, MS, are investigating deficits in bone density among adolescents with non-alcoholic fatty liver disease (NAFLD), and are also researching deficiencies of iron, vitamin B12 and calcium in adolescents who have undergone bariatric surgery.

Dr. Stephanie Oliveira, MD, CNSC, investigates the role of inflammation on vitamin D metabolism and along with Drs. Cole and Samuel Kocoshis, MD, participates in research involving patients with intestinal failure.

Dr. Marialena Mouzaki, MD, MSc, is investigating the intestinal microbiota and the bile acid homeostasis of patients with NAFLD. Dr. Mouzaki collaborates with Yale New Haven Children’s Hospital to determine the optimal approach to screening patients with suspected NAFLD and is also investigating the natural history and comorbidities of patients with NAFLD.

Cincinnati Center for Eosinophilic Disorders

The Cincinnati Center for Eosinophilic Disorders (CCED) is an established multidisciplinary referral center for evaluation and treatment of eosinophilic gastrointestinal disorders in children and adults. Physicians representing the Divisions of Gastroenterology, Hepatology and Nutrition; Allergy and Immunology; and Pathology and Laboratory Medicine 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 has included important studies of both dietary and pharmacologic management of eosinophilic disorders.

Drs. Philip Putnam, MD, and Vincent Mukkada, MD, collaborate with other leading investigators in the CCED in studies of genetic and immunologic factors responsible for eosinophilic inflammation in the gut, and in evaluating the effectiveness of biological agents (including anti-IL-13 humanized antibodies, anti-IL5 receptor binding antibodies, and anti-Siglec8 antibodies) and topical glucocorticoids in the management of eosinophilic disease. The CCED team was the first to investigate eosinophil progenitor (EoP) levels in patients with Eosinophilic Esophagitis (EoE), leading to the identification of a potential new 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 the transcriptomic study of proton pump inhibitor(PPI)-responsive esophageal eosinophilia, providing convincing evidence that PPI-REE is an EoE sub-entity with significant molecular overlap with EoE in which PPI therapy reverses nearly the entire allergic inflammatory transcriptome. In a collaborative effort led by Dr. Margaret Collins, MD, from the Division of Pathology and Laboratory Medicine, we recently published our experience developing a novel histologic scoring system using multiple microscopic changes seen in EoE patients which outperforms the current histologic gold standard. In addition, the CCED (With Dr. Marc Rothenberg, MD, PhD, as Principal Investigator) continued work as the central site for a Patient Centered Outcomes Research Institute contract for a multicenter trial examining the efficacy of minimally restrictive empiric diets in the management of pediatric eosinophilic esophagitis. The data from this study is showing the effectiveness of only removing one food (milk) for the treatment of EoE. A genome wide association study (GWAS) further clarified the genes responsible for making the esophagus a target for eosinophilic inflammation; in particular, this effort has led to the identification of calpain-14 as a causative pathway in promoting epithelial changes that occur in EoE, and raised the possibility of enzymatic blockade of this pathway as a possible therapeutic strategy. Research findings have highlighted the role of IL-13 in eosinophilic esophagitis pathogenesis, and the preliminary positive effects of antibodies against IL-13 in human patients with EoE. This has led to a number of therapeutic trials in which the CCED is an active participant.

A novel study continues to expand our understanding of eosinophilic gastritis, using techniques employed previously for studying the esophagus, including elucidation of the transcriptome and the identification of promising non-invasive biomarkers. Recent studies have identified loss an esophageal protease inhibitor (SPINK7) as an upstream event that triggers EoE-associated pathological processes, and that anti-protease replacement therapy, starting with alpha-1-antitrypsin, an already available FDA-approved drug, may be an effective treatment strategy. We have extended the work on eosinophilic progenitor cells as a noninvasive biomarker in EoE by following patients longitudinally to see whether the EoP reflects changes in therapy.

IBD the Schubert-Martin Inflammatory Bowel Disease Center

The Division of Gastroenterology, Hepatology and Nutrition and the Schubert-Martin Inflammatory Bowel Disease / IBD Center sees more than 800 patients with IBD. Over 100 new patients are diagnosed annually and close to 80 second-opinion patients are seen by the physicians of the Schubert-Martin Pediatric IBD Center from more than 20 states and abroad. These numbers reflect a significant increase in total patient volume over the last five years.

The Center is an integral and leading participant in collaborative consortia like the ImproveCareNow Quality Improvement Network and the Crohn’s and Colitis Foundation’s PRO-KIDS Clinical Research Network. This role reflects superior outcomes for our patients with more than 85% of IBD patients within the center being in remission, 65% in sustained remission, and 84% having a good quality of life. These outcome measures are shared transparently on the center’s website. 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. A rejuvenated and energized Parent Advisory Board partners with center providers to identify priority areas for improvement, education, increased awareness and community involvement with an active Facebook page.

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 prediction of disease flares and remission, development of mobile phone apps for patient engagement and self-management, and transition of patients to adult providers. We reported in Gastroenterology results of a study which defined clinical and genomic correlates of neutrophil reactive oxygen species (ROS) production in children with Crohn's Disease. We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases and tested for association with neutrophil gene expression and antimicrobial function. We identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production and bacterial killing by neutrophils from the patients. We reported in the Inflammatory Bowel Diseases journal a study to validate the neutrophil CD64 blood biomarker to detect mucosal inflammation in pediatric Crohn's Disease. In a large Crohn's disease cohort, we found that neutrophil CD64 index and soluble CD64 were significantly elevated during active gastrointestinal inflammation. The clinic now uses the CD64 biomarker as a treatment target for our IBD patients. Collaborators within the institution from the James M. Anderson Center for Health System Excellence, the Division of Behavioral Medicine and Clinical Psychology, the Center for Adherence and Self-Management, Pediatric Surgery, Divisions of Allergy and Immunology, Adolescent and Transition Medicine, and Radiology continue to make significant contributions to finding a cure as well as improving outcomes and self-management skills for children suffering from IBD. These efforts were recognized with the Cincinnati Children’s Clinical Team award in 2017.

Interdisciplinary Feeding Team

Under the Pediatric Gastroenterology leadership of Drs. Scott Pentiuk, MD, MEd; Vince Mukkada, MD; and Stephanie Oliveira, 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 Pathology; Physical Therapy, Occupational Therapy; and Social Services. The IFT evaluated over 1,400 patient visits and 400 new patients in Fiscal Year 2017. In addition to comprehensive consultation and care, the IFT offers unique multidisciplinary outpatient treatment sessions and child adult relationship enhancement training for families. Ongoing research projects by IFT investigators include the use and development of the pureed by G-tube diet, methods to evaluate children with swallowing dysfunction, and quality improvement projects to decrease patient wait times.

Intestinal Rehabilitation and Intestinal Transplantation Programs  

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 obviates 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 1.3/1000 catheter days is among the best in North America. We are the lead center for the expanded multicenter pediatric clinical trial funded by Shire Pharmaceuticals for Teduglutide (Gattex®) with Dr. Samuel Kocoshis as the lead investigator. Additional studies include the use of fish-oil derived lipid (Omegaven®) to prevent chronic liver disease associated with the use of parenteral nutrition, and the impact of the quality of life of the family on the outcome of children on chronic parenteral nutrition. Dr. Conrad Cole, in collaboration with Dr. Nana-Hawa Yayah Jones, MD, with the Division of Endocrinology, identified a high prevalence of iodine deficiency in patients on total parenteral nutrition and have developed ongoing evaluation and novel therapeutic options for these patients. In collaboration with our colleagues in the Division of Infectious Diseases (Dr. David Haslam, MD, and Heidi Anderson), we are evaluating the interaction of diet and antimicrobials on intestinal microbiome and how this impacts adaptation. Our small bowel transplant surgical team, led by Dr. Nathan is studying microbiome changes in stool and allograft intestinal tissue following intestinal transplantation, to correlate them with diminution of the Treg population in tissue and blood during intestinal allograft rejection. Additionally, our intestinal transplantation team, noting much better survival with combined liver/intestinal transplantation than with isolated intestinal transplantation, has (as a quality improvement measure) stratified risk for exfoliative rejection by presence or absence of allograft liver in the graft or by presence or absence of preformed or de novo donor specific antibodies (DSA). Patients with a positive DSA receive two-three times higher induction doses. The impact of these strategies is being analyzed with regard to overall survival, length of ICU stay and length of overall hospital stay.

Liver Diseases

The Pediatric Liver Care Center provides comprehensive care for children with liver diseases. Staffed by eight pediatric hepatologists, four hepatobiliary surgeons and two specialty nurses, the program 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, 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. Starting with laboratory investigation, Dr. Stacey Huppert, PhD, reported the ability of hepatocytes to transdifferentiate into biliary epithelial cells using genetically targeted mice (published in Nature); Dr. Takanori Takebe, MD, showed that inducible pluripotent stem cells can give rise to different cell lineages that self-aggregate to form human liver buds (published in Cell Reports); and Dr. Chandrashekhar Gandhi, MSc, PhD, found a pro-fibrogenic program linked to the activation of hepatic stellate cells (published in the Journal of Hepatology).

In translational studies, Dr. Chunyue Yin, PhD, used CRISPR/Cas technology to introduce severe mutations in the gene encoding the bile salt export pump (abcb11) in zebrafish, reproduced the human liver disease, and identified potential therapeutic strategy to improve bile flow (published in Hepatology). Studying mice carrying a mutation of another canalicular transporter (Mdr3, encoded by the Abcb4 gene), Dr. Alexander Miethke, MD, found that lipid homeostasis is linked to inflammation and biliary injury (published in Hepatology), while Dr. Jorge Bezerra, MD, identified the cytokine receptor Cxcr2 (related to IL-8 signaling) and the intestinal microbiome as key determinants of biliary epithelial injury in an experimental model of biliary atresia (published in PLoS-ONE). From a broad proteomic analysis of serum from babies with biliary atresia, Dr. Bezerra also discovered MMP-7 as a remarkably distinctive biomarker of the disease, with direct implications for the potential improvement in diagnostic algorithms used in clinical practice (published in Science Translational Medicine). Using a systems biology approach, Dr. Bezerra reported that a molecular signature containing the RAGE-AGE pathway shares the biliary atresia, primary sclerosing cholangitis, and primary biliary cholangitis, and triggers cholangiocyte proliferation and fibrogenic activation (published in Hepatology). Other exciting laboratory work by Dr. Takebe explores the use of organoids to restore metabolic liver disease, and Dr. Akihiro Asai, MD, PhD, is modeling cholestatic liver diseases to discover pathogenic mechanisms of disease and identify new treatment strategies.

Several lines of important clinical investigation are opening new diagnostic and treatment options for children with liver disease. Examples includes Dr. William Balistreri’s work reporting the efficacy of Ledipasvir-Sofosbuvir in treating children with HCV infection (published in Hepatology), and Dr. James Heubi, MD, showing the efficacy and safety of cholic acid in treating children with bile acid defects and Zellweger spectrum disorders (published in Journal of Pediatric Gastroenterology and Nutrition). Ongoing studies by Dr. Balistreri and Dr. Bezerra are determining the efficacy of Tenofovir in children with chronic hepatitis B infection, and the efficacy of other direct acting antivirals to completely eradicate hepatitis C virus during childhood. Drs. Miethke and Amy Taylor, MD, are studying radiological, biomarker, and genetic underpinnings of autoimmune liver disease, with a focus on studies of primary sclerosing cholangitis.

Neurogastroenterology and Motility Disorders Center

Under the leadership of Dr. Ajay Kaul, MD, the Neurogastroenterology and Motility Disorders Program has continued to experience growth, with 941 outpatient encounters and 542 manometry procedures (35% increase from prior year) and the addition of a third faculty, Dr. Neha Santucci, MD, MBBS. Over the past year, we received about 40 new referrals per month, primarily from patients outside of our primary service area. Patients came from 31 states and 14 from outside the country. In addition, the team in collaboration with the Colorectal Center started an interdisciplinary clinic in July 2014 to evaluate and treat children with complex colorectal and motility disorders such as Hirschprung disease, anorectal malformations and severe idiopathic chronic constipation with a goal to improve patient outcomes through standardization of practice and clinical research. This year alone we saw 102 patients from across the nation and overseas in our combined multi-disciplinary motility clinic. Due to unprecedented growth of the program, the combines multi-disciplinary motility clinic appointed Dr. Khalil El-Chammas, MD, MS, as the Medical Director.

Among new advances, we expanded our motility program to the Liberty campus, are setting up a mind-gut interaction disorders program and are adding new technology, including EndoFLIP, transrectal ultrasound and Smartpill to our investigative armamentarium. Dr. Santucci has expertise in functional GI disorders and will develop a pain-related functional GI disorders program. Exploring new research opportunities, the Program has been involved in multicenter trials to investigate the efficacy of Linaclotide in children with functional constipation and irritable bowel syndrome with constipation, the use of the extra-auricular device in functional gastrointestinal disorders, the characterization of high resolution colon manometry studies and the use of Mirtazapine in functional abdominal pain.

We started an advanced fellowship in motility disorders and trained our first fellow this year who has graduated and will be joining as faculty at the University of Pittsburgh. We have a clinical observer from Thailand who is spending a year with us on an educational scholarship from her country. This year the team presented at the third Annual Workshop on Motility Disorders for physicians and nurses from across the nation.

Pancreas Care Center

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, led by Drs. Maisam Abu-El-Haija, MD, Medical Director; Jaimie Nathan, MD, Surgical Director; Tom Lin, MD, Associate Director and Endoscopy Director; and Deborah Elder, MD, Endocrinology Director, in collaboration with pain team and psychology, currently follows more than 380 patients with various pancreatic disorders including pancreatitis, exocrine pancreatic insufficiency, congenital anomalies of the pancreas, and pancreatic tumors. Since its inception in FY13, the program has completed a survey of Cincinnati Children’s providers to better understand the variation in management of acute pancreatitis, assembled a multidisciplinary care team to evaluate and treat complex pancreatic disorders, established a REDCap database for patient registry, and instituted an evidence-based order set for the management of acute pancreatitis which has led to decreased length of hospital stay and intensive care admissions. Our treatment modalities became a guideline nationally as published this year in the Journal of Pediatric Gastroenterology and Nutrition (Abu-El-Haija et al, under the NASPGHAN umbrella PMID: 29280782).

We began offering Total Pancreatectomy with Islet Autotransplantation (TPIAT) operations in FY15, and by end of FY18, our center had performed 31 TPIATs and two subtotal pancreatectomies with IAT for treatment of unremitting pain due to chronic pancreatitis. Under the leadership of Dr. Lin, we continue our active advanced endoscopy program and we performed 102 ERCPs in FY18. There were 389 gastroenterology pancreas clinic visits for FY18.

Our scientific highlights for this past year include cutting edge research findings on the imaging modalities that assess pancreatic function and volume in normal controls and diseased pancreatic patients published in Pediatric Radiology and the American Journal of Gastroenterology. Our consortiums collaborations resulted in our center leading studies in pancreas divisum involvement in the progression of acute and chronic pancreatitis published in the Journal of Clinical Gastroenterology, we also led studies that described patterns of autoimmune pancreatitis in children and the pathways to diagnosis. Our clinical and translational studies from the acute pancreatitis registry generated a novel predictive tool for severe pancreatitis, and a clinical tool to diagnose gallstone pancreatitis on admission, an entity not well studied in a prospective fashion from before published in Pancreatology. Our unique program for total pancreatectomy islet autotransplantation generated important clinical studies for the use of continuous glucose monitoring for transplanted islets function published in Pediatric Transplantation and basic science research discovery for growing pancreatic ductal and islet cells organoids from human cells. The latter two aspects will allow discovery for improving islet yield transplanted and cellular function studies on the islets and pancreatic ducts such as the role of CFTR modulators and correctors in halting chronic pancreatitis progression.

We have ongoing studies in pancreatitis severity biomarkers as well as molecular genetic studies for which Dr. Abu-El-Haija is currently awaiting the notice of award for a K23 application from the NIDDK. Our center is participating in NIH-funded multi-center studies (first two studies listed below) that help advance the care of children with pancreatic disorders. Amongst others that are submitted and awaiting reviews including the development of pancreatic ducal organoids and islet organoids grants. PCC team extramural funding during FY18:

1. NIH U01 Abu-El-Haija (Site PI) - 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 out of 19 national and international centers.

2. NIH R01 Nathan (Site PI) - Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT. Our center is the highest enrolling center for pediatric TPIAT nationally in this consortium.

We also have widely marketed our launched Pancreas Gene Panel developed in collaboration with the Molecular Genetics Laboratory, and it is now a clinically available test that evaluates 10 known genes causing inheritable pancreatitis using Next Generation Sequencing technology. Since the launch in November 2016, we performed steadily about 10 tests/month using the Pancreas Gene Panel. In addition, the PCC members are actively involved in the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), as Dr. Abu-El-Haija is the vice chair of the pancreas committee, and a course director for the National Pancreas Foundation (NPF) annual meeting. Dr. Lin is an active member in the NASPGHAN ERCP special interest group. Dr. Nathan is part of the NASPGHAN Pancreas Committee as well. The PCC at Cincinnati Children's is one of only a few pediatric centers that are an NPF-approved center of excellence for pancreatic care in the nation and is a destination sought out by patients from around the nation based on its reputation for excellence in patient care and its commitment to innovative research.

Liver Transplant Center

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 have performed more the 675 liver transplants since the program began in 1986. Our patient and graft survival rates are at or above the national average at one and three years post-transplant.

In addition to providing care for the most common pediatric liver disorders leading to transplantations we are able to 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 Hospital Medical Center Liver Transplant Team has performed more pediatric liver transplants for hepatic tumors than any other program in the United States. In addition to providing outstanding patient care, the Pediatric Liver Transplant Program is a leader in multicenter clinical and translational research studies and national quality improvement efforts. These include: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH), the Studies in Pediatric Liver Transplantation (SPLIT) quality improvement community and clinical registry, and the Medication Adherence in Liver Transplant (MALT) study group, and multiple local projects and initiatives. For instance, we developed collaborations with the Center for Transplant Immunology (CTIMM) to molecularly define transplant rejection responses to ultimately personalize immunosuppression therapies.

Steatohepatitis Center

Understanding and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (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, the most common cause of liver disease in the United States and increasingly in most of the developed world. NAFLD affects one in 10 children and one in three adults in the United States. About 1/4 to 1/3 of patients with NAFLD can develop a more severe progressive form of disease called nonalcoholic steatohepatitis that can progress to severe fibrosis. NASH-related cirrhosis has become one of the leading causes of liver transplant in adults, especially among younger adults. Thus, 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 Diabetes Center, 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 661 patient visits in fiscal year 2018. Given the high prevalence of this disease, our program now offers clinics at our Burnet, Liberty and Anderson locations, with four faculty members, including Drs. Ana Catalina Arce-Clachar, MD; Kristin Bramlage, MD; Marialena Mouzaki and Stavra Xanthakos (Director). Because patients of Hispanic ethnicity carry a high burden of NAFLD and may face additional barriers to accessing healthier lifestyles, we now offer a clinic staffed by Dr. Arce-Clachar, who is bilingual in Spanish and English, to improve communication.

Our program also seeks to develop more broadly effective prevention and intervention strategies for NAFLD. 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, with a new trial due to start in the fourth quarter of 2018. In fiscal year 2018, we also joined TARGET-NASH, 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. Additional research highlights in 2018 included investigating performance of alanine amino transferase levels and fibrosis prediction scores, as well as the accuracy of non-invasive magnetic resonance imaging modalities, in monitoring NAFLD severity and outcomes in children with NAFLD. The CCSC has an ongoing NIH-funded clinical trial comparing the effectiveness of comprehensive lifestyle intervention to bariatric surgery in treating NASH in severely obese adolescents. Outcomes of NAFLD among participants in the Teen-Longitudinal Assessment of Bariatric Surgery cohort were also presented in June 2018 at the American Diabetes Association annual meeting. The work by the CCSC investigators has been published in Alimentary Pharmacology and Therapeutics, Gastroenterology, Obesity, New England Journal of Medicine, Nature, JAMA Pediatrics, Journal of Pediatrics, Nature Reviews Gastro Hepatology, and others.