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Story of Discovery: Pancreatitis in Children

A painful, chronic disease is hard enough for an adult to manage, but when a child faces such a disease, it proves even more difficult. Pancreatitis is one of these conditions, placing a significant burden on children and their families—physically, emotionally, and financially, as well as in terms of overall quality of life. For a child with pancreatitis, every aspect of their life is affected, including the ability to eat, be active, and go to school. Treatments are currently limited to supportive therapy for pain management and surgical procedures. Although relatively rare, pancreatitis in children is more common than was previously thought, and it can progress in a surprisingly short timeframe.

Over the years, NIDDK-supported research has made important strides toward better understanding pancreatitis in children and contributing to efforts to improve its diagnosis, treatment, and, ultimately, prevention.

HOW PANCREATITIS AFFECTS CHILDREN

Pancreatitis is an inflammation of the pancreas, an organ located behind the stomach. The pancreas performs many important functions, including the secretion of insulin and other key hormones, as well as production of a fluid containing precursor forms of enzymes and bicarbonate that flows through ducts into the intestine, where the enzymes become activated and aid digestion of food. In pancreatitis, the digestive enzymes become activated too early—while still inside the pancreas. This causes inflammation and damage to the organ, leading to the symptoms of pancreatitis— the main one being abdominal pain that is often severe, as well as nausea and vomiting.

The disease can occur in three forms: acute, acute recurrent (two or more acute episodes), and chronic. Acute pancreatitis can progress to the chronic form, which carries with it an increased risk of pancreatic cancer. Once considered an uncommon disease in children, the incidence of pediatric acute pancreatitis has increased over the last 10 to 20 years and currently affects approximately 1 in 10,000 children. Chronic pediatric pancreatitis, in which children have diagnostic or functional evidence of irreversible pancreatic damage, is estimated to have an incidence of approximately 2 per 100,000 children per year.

Both acute recurrent and chronic forms of pediatric pancreatitis place a significant burden on children and their caregivers. Risk factors for pancreatitis differ for children compared to adults. In children, the main risk factors are inherited genetic variants, followed next by obstructed ducts caused by congenital abnormalities or gallstones. In adults, risk factors include genetics and gallstones, but environmental factors such as alcohol and tobacco use are the most predominant. Although diabetes is another risk factor for pancreatitis, it is not as common in children as adults. An insufficient production of pancreatic enzymes is found in both children and adults with pancreatitis. Emergency room visits and hospitalizations are common in children and adults with the disease, as are missed days of school or work. Pain, whether it comes in discrete episodes or is constant, is frequently difficult to treat, leading to lost school time for children and increased utilization of health care and high medical costs. There are currently no drugs that effectively halt progression of this potentially debilitating disease or that reverse the disease process. Treatment options to manage the severe, often unremitting pain typically accompanying chronic pancreatitis include opioids, which carry the risk of addiction. If traditional pain management fails, a child with pancreatitis may need a surgical procedure called a total pancreatectomy-islet autotransplantation (TP-IAT), in which the pancreas is surgically removed and its insulin-producing islet cells, which regulate blood glucose (sugar), are collected and infused into the liver, where the cells implant and function. (See the chapter on Diabetes, Endocrinology, and Metabolic Diseases for a profile on an individual who underwent TP-IAT for pancreatitis.) This current state of knowledge of and care for children with pancreatitis is based, in part, on groundbreaking advances from studies conducted over the past several years with NIDDK support, including the following examples.

EARLY CLUES TO PANCREATITIS DEVELOPMENT

A hereditary form of chronic pancreatitis, which affected multiple family members over generations, was first recognized in 1952, only a few years after the NIDDK was established. However, the discovery of the first genetic mutation associated with this disease would occur more than 40 years later. In 1996, NIDDK-supported scientists reported that a mutation in a gene called PRSS1 was associated with hereditary pancreatitis; this gene codes for the protein trypsinogen, an inactive precursor of the digestive enzyme trypsin. This study and others identified a number of genetic variants associated with pancreatitis in the trypsinogen gene, in more genes that affect trypsinogen/trypsin, and in genes with additional functions. These discoveries were made possible by the availability of information on human gene sequences through such efforts as the NIH’s Human Genome Project.

Around the same time of these discoveries by individual investigators, in 1996 the NIDDK funded the beginnings of the first large clinical cohort study of pancreatic disease in the United States, called the North American Pancreatic Study (NAPS) Group. Additionally, the NIDDK provided some support for a later study in European families on clinical and genetic characteristics of hereditary pancreatitis that associated different PRSS1 mutations with age of symptom onset and disease progression, and showed a median age of 10 years for the onset of first symptoms of the disease in families with one of the mutations. These studies, together with a subsequent larger cohort study in adults called the North American Pancreatitis Study 2, or “NAPS2,” advanced knowledge of the numerous genetic and environmental factors playing a role in pancreatitis, including the first genome-wide association study of pancreatitis in 2012, which identified new genetic regions associated with the disease.

INSPPIRE-D TO ADVANCE KNOWLEDGE OF PEDIATRIC PANCREATITIS

In 2009, a group of international investigators came together to form the first multi-center group dedicated to studying pancreatitis in children, which would come to be called the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE) Consortium, established with support from the NIDDK. The Consortium’s focus was the characterization of acute recurrent and chronic forms of pediatric pancreatitis, in terms of their global distribution, causes, disease processes, and outcomes at 14 sites throughout the United States, Canada, Israel, and Australia. This multi-center approach, assembling the largest cohort of children with pancreatitis to date, was necessary to have sufficient numbers of participants for studying the relatively rare disease of pediatric pancreatitis.

The work of the INSPPIRE investigators, together with study participants, proved extremely productive, yielding multiple research advances and publications. For example, one study presented a fuller picture of the significant burden placed on children with chronic pancreatitis by quantifying their experiences of severe, often constant pain, resulting in hospitalizations and missed school days. Another study revealed the steep economic cost of acute recurrent and chronic pancreatitis in children, due to repeated hospitalizations, tests, procedures, and medications. Other findings focused on better characterizing the genetic risk factors often at work in these forms of pediatric pancreatitis and how they influence disease onset and progression.

Following the success of the original INSPPIRE study group, and based on recommendations stemming from NIH workshops on pancreatitis research held in 2012 and 2013, the NIDDK and the National Cancer Institute co-sponsored the formation of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer in 2015. The INSPPIRE group became part of this larger Consortium as “INSPPIRE 2,” featuring an even larger and more diverse population of study participants.

Within the last few years, INSPPIRE 2 and the broader Consortium have made major contributions relevant to pediatric pancreatitis. Consortium studies of adult pancreatitis established standards for imaging procedures used to diagnose and assess disease severity as part of pancreatitis care. One analysis performed by the INSPPIRE 2 investigators better characterized risk factors and disease progression in children with pancreatitis, showing both commonalities and differences with adult patients. Other INSPPIRE 2 findings included the observation of the surprisingly short timeframe for children with acute recurrent pancreatitis to develop chronic pancreatitis, occurring over 2 to 4 years, with more rapid progression in those who were diagnosed later in childhood and who carried PRSS1 genetic variants associated with the disease. Another study conducted by an NIDDK grantee associated with the INSPPIRE program found that several genetic risk variants are likely to play a significant role in progression to acute recurrent and chronic disease after the first attack of pancreatitis in children. NIDDK-supported researchers also found that carriers of these pancreatitis-associated risk variants are at higher risk for developing pancreatic cancer later in life. These studies, reported in 2018 and 2019, could help researchers and clinicians develop better approaches to diagnose and treat children with pancreatitis.

FUTURE DIRECTIONS IN PEDIATRIC PANCREATITIS RESEARCH

The NIDDK has been continuing its support for the “inspiring” work of the INSPPIRE 2 investigators and study participants, as well as others studying pancreatitis in children. In the future, INSPPIRE 2 researchers will continue the long-term cohort study to probe deeper into remaining questions, such as better understanding risk factors involved in pancreatic disease progression, determining how chronic pancreatitis first develops, defining pancreatic enzyme insufficiency (a lack of digestive enzymes that hinders proper digestion of food), and improving treatment options. For example, one study is testing the first drug-free approach for pediatric pancreatitis—a web-based cognitive behavioral therapy intervention to manage pain without opioid exposure and improve quality of life in adolescents with chronic pancreatitis. Other ongoing INSPPIRE 2 investigator studies of pediatric pancreatitis are monitoring rates across sites, identifying the earliest diagnostic imaging evidence of disease, defining metabolic and skeletal complications, understanding why chronic pancreatitis more commonly affects girls, and understanding the contribution of drug-induced pancreatic diseases. The NIDDK also continues to support investigator-initiated research in this area, such as the recent development of the first pre-clinical mouse model to faithfully mimic human chronic pancreatitis—made possible through genetic alterations in the trypsinogen gene of mice— that can be used to inform the development of new treatments.

While providing ongoing support for research on pediatric pancreatitis, the NIDDK regularly sponsors scientific workshops that bring together leaders in the research community to discuss how to advance pancreatitis research. Past workshops have focused on research opportunities relating to such themes as research challenges in chronic pancreatitis, biomarkers of pancreatic disease, and optimizing use of the TP¬IAT procedure. In 2018, the NIDDK, with additional support from the National Pancreas Foundation, sponsored a workshop focused on ways to accelerate the development of new treatments for pancreatitis. The workshop’s recommendations were shared widely with the scientific community through multiple publications in the scientific literature. Most recently, in 2019, the NIDDK sponsored a workshop on how precision medicine-related methods and technologies can be applied to new and more personalized ways to diagnose and manage pancreatitis and other forms of pancreatic disease. These workshop recommendations and additional sources of external stakeholder input will continue to inform the NIDDK’s efforts to reduce the burden of pediatric pancreatitis through research.

Sellers ZM, et al. Gastroenterol 155: 469–478, 2018.

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