Still no optimal treatments for pediatric AP

Nov. 12, 2016

Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by upper abdominal pain, elevated levels of pancreatic enzymes (at least three times the upper limit of normal) and inflammatory changes on pancreatic imaging. Two of the three factors must be present for a diagnosis of AP, according to guidelines from the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE). Although AP is a rare disorder, it has been increasing in incidence for the last two decades, most likely due to better recognition and testing in children.

AP seems to be triggered by the premature activation of proteolytic enzymes and the subsequent release of cytokines, leading to an inflammatory response. Gallstones and chronic alcohol use are precipitating factors in the majority of adults, but the etiologies in children are more diverse. Many pediatric AP cases result from congenital anomalies such as annular pancreas or pancreas divisum, abdominal trauma related to sports injuries, accidents or abuse, or genetic mutations, especially in the serine protease 1 (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1) and cystic fibrosis transmembrane conductance regulator (CFTR) genes.

A cross-sectional study published in JAMA Pediatrics in 2016 looked at 301 children with either acute recurrent pancreatitis (ARP) or chronic pancreatitis who were enrolled in an INSPPIRE study between 2012 and 2015. At least one mutation in pancreatitis-related genes was found in nearly half the patients with ARP and in 73 percent of those with chronic pancreatitis. CFTR mutations, which can cause pancreatitis without associated cystic fibrosis, were the most common mutations in ARP.

"When a child has recurrent AP, we recommend a hereditary pancreatitis panel, which includes full gene sequencing of PRSS1, CFTR, chymotrypsin C (CTRC) and SPINK1," explains Mark G. Bartlett, M.D., a pediatric gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota.

Other risk factors for pediatric AP include gallstones, undetermined viruses and reactions to certain drugs, especially valproic acid, L-asparaginase, prednisone and 6-mercaptopurine, although no clear mechanism has been identified for the development of medication-induced disease.

AP therapies

Most adult and pediatric patients have a mild form of AP that resolves in a few days. Others develop moderately severe disease characterized by local complications or organ failure lasting less than 48 hours. And some patients have severe disease with persistent organ failure. Local or infectious complications or persistent organ failure are leading causes of morbidity and mortality in both children and adults with severe disease.

For uncomplicated AP, supportive care with aggressive hydration is the cornerstone of therapy. Several studies, including a 2009 Mayo Clinic study published in Pancreatology, have shown that patients who receive less than one-third of their total resuscitation fluid volume in the first 24 hours of presenting to the emergency department are at greater risk of persistent organ failure and mortality than those who are initially treated more aggressively.

"AP can become very severe, with reduced blood flow to the pancreas and the release of inflammatory cytokines leading to further pancreatic damage and necrosis," Dr. Bartlett says. "Patients with infected necrosis who don't respond to antibiotics may need minimally invasive pancreatic debridement. Only about 20 percent of patients develop necrotizing disease, but there is no prognostic scoring system for pediatric AP and therefore no way to know which kids will develop severe disease. Healthy young children generally tend to do better than adults overall, however."

Early feeding is also an integral part of AP management. "There is a push to feed people sooner," Dr. Bartlett says. "We used to have patients NPO for two weeks, but now as soon as the acute wave passes, we start feeding by mouth or nasogastric tube. This helps maintain the gut barrier function, inhibits the translocation of bacteria that can lead to infectious complications and lowers the inflammatory response. A number of studies have shown better outcomes when there is early feeding into the stomach, even with higher fat diets."

Pain management

Abdominal pain is the most common presenting symptom of AP and the one that is the most challenging to manage; in the past, the vast majority of children, like adults, were treated with morphine and related opioids.

"The chronic pain associated with AP is a huge ordeal for kids," Dr. Bartlett says. "Once a child has an attack, there are likely to be recurrent attacks, so these children are often in the hospital on chronic pain medications. There are also clusters of families with familial pancreatitis where the adults and children are both addicted to pain pills. Unfortunately, we just don't have curative treatments to offer these children and families right now."

The one exception, he says, is total pancreatectomy with islet cell autotransplantation (TP-IAT), which was pioneered by the University of Minnesota in the 1970s. Surgeons there have performed about 100 TP-IAT procedures in children, who often do better than adults —the procedure is successful in about 60 percent of pediatric cases.

"If you can treat kids before they develop chronic pain syndrome, TP-IAT can be really successful. Children who had horrible pain between the ages of 2 and 7 can become normal kids playing soccer," Dr. Bartlett says. "But a 15-year-old who has a 10-year history of chronic pain — even if the source of pain is gone — is likely to have a chronic opioid addiction that needs to be managed by gastrointestinal pain specialists."

It's frustrating, he says, that there are no good treatments for chronic pancreatitis short of a radical surgical procedure. But he points out that children seen at Mayo Clinic for AP are at a distinct advantage because of the strong collaboration between adult and pediatric gastroenterologists.

"We have access to specialists in adult ERCP and endoscopic ultrasound — two important diagnostic modalities for AP — that are not commonly performed by pediatric gastroenterologists," he says. "Endoscopic ultrasound is particularly valuable because it allows biopsies to be taken under direct visualization when needed. We have children who come here from other centers precisely because of the collaboration we have with adult pancreas specialists. This collaboration also allows us to be involved in research studies that require endoscopic ultrasound and other advanced technologies."

Looking ahead, preliminary studies investigating the role of prostaglandins in inflammation are underway with some hope for future interventions for both adult and pediatric AP. For now, though, treatment options remain limited. "This is a lifelong disease that often starts in childhood, and it's a shame we don't have better treatments for it," Dr. Bartlett says.

For more information

Kumar S, et al. Risk factors associated with pediatric acute recurrent and chronic pancreatitis: Lessons from INSPPIRE. JAMA Pediatrics. 2016;170:562.

Gardner TB, et al. Faster rate of initial fluid resuscitation in severe acute pancreatitis diminishes in-hospital mortality. Pancreatology. 2009;9:770.

Abu-El-Haija M, et al. Early enteral nutrition in children with acute pancreatitis. Journal of Pediatric Gastroenterology and Nutrition. 2016;62:453.