3.6 Complications of CP in Children
3.6.1 Exocrine Pancreatic Insufficiency（EPI）
In children with long-standing CP，EPI may develop when a large portion of pancreatic acini are permanently damaged（＞95%）.In adults，exocrine pancreatic insufficiency occurs in 50-80%of patients in a median time of 5.6-13.1 years（Ammann et al.1984；Layer et al.1994）.In the INSPPIRE cohort，34%of children were exocrine pancreatic insufficient at the time of diagnosis（Schwarzenberg et al.2015）.It should be noted that EPI may develop in other forms of exocrine pancreatic disease in children（CF，Shwachman-Diamond syndrome，etc）.There is not a perfect exocrine pancreatic function test that could accurately measure acinar and/or ductal functions of the pancreas.Below is a brief review of currently available tests.
Pancreatic stimulation test（PFT）.In this test，pancreatic fluid is collected as it is secreted into the duodenum and measured for volume，pancreatic enzymes and electrolytes before and after stimulation with cholecystokinin and/or secretin（Schibli et al.2006）.Although it is considered“gold standard”to quantify the exocrine pancreatic function，PFTs are not widely performed due to their invasive nature.The collection of the duodenal fluid via the endoscope（endoscopic pancreatic function test or ePFT）has been proposed as an alternative and is currently performed by few pediatric centers using various protocols.This approach has the potential to underestimate the pancreatic secretory capacity and classify patients as pancreatic insufficient erroneously（Schibli et al.2006）.
72-hour fecal fat collection.This test relies on the exocrine pancreas losing greater than 95%of its enzyme secretory output and development of steatorrhea（DiMagno et al.1973）.Steatorrhea can be measured by a 72-h stool collection and calculation of coefficient of fat absorption［CFA:（grams of fat ingested-grams of fat excreted）/（grams of fat ingested）× 100］.In children younger than 6 months of age，a fecal fat greater than 15%of fat intake is considered abnormal；this value is 7%for children over 6 months of age.It is not a specific test for EPI as it can be abnormal in other diseases causing fat malabsorption.
Fecal elastase-1（FE1）.This widely available ELISA-based stool test is the preferred method to diagnose EPI.A value of less than 100 µg/g is considered diagnostic.Intermediate values of fecal elastase（100-200 µg/g）may be due to loss of pancreatic function，but not severe enough to cause clinical EPI.The sensitivity of FE1 to diagnose moderate and severe EPI is approximately 100%.In patients with mild loss of pancreatic function，the test sensitivity is～25%with a specificity of 96%（Daftary et al.2006）.Therefore，FE1 is notreliable to determine mild or borderline loss of exocrine pancreatic function.FE1 may be falsely low when the stool is diluted in cases of diarrhea（i.e.infectious diarrhea，severe enteropathies，short gut，collected from an ileostomy）.
Secretin-MRCP.s-MRCP findings（changes in pancreatic duct caliber，anteroposterior diameter of the pancreas，signal intensity ratio between pancreas and spleen on T1-weighted and arterialvenous enhancement ratios and duodenal filling）show correlation with other exocrine pancreatic tests including ePFT（Balci et al.2010）and fecal elastase（Manfredi et al.2012）.This test has not been validated in children.
Treatment of EPI.Pancreatic enzymes are only recommended for the treatment of CP and EPI in children，as their role in controlling pain in CP has not been established.Pancreatic enzyme replacement therapy（PERT）is based on number of lipase units administered per meal.Children＜4 years of age require 1000 lipase units/kg per meal；500 lipase units/kg per meal are used for those＞4 years of age and 25,000-40,000 units/meal are used for adults.For snacks half the dose is recommended.The daily dose for most patients is less than 10,000 units of lipase/kg per day or 6000 units of lipase/kg per meal to prevent fibrosing colonopathy.For children who cannot swallow capsules，delayed release capsules containing enteric coated microspheres or microtablets may be opened and the contents sprinkled on soft food that does not require chewing and has a low pH（applesauce，gelatins，pureed apricot，banana or sweet potatoes）.Foods having a pH greater than 7.3，such as milk，custard or ice cream should be avoided as a vehicle for the sprinkled enzymes because the protective enteric coating can dissolve in these foods，leaving the enzymes vulnerable to inactivation by gastric acid.Pancrealipase tablets or capsules should not be crushed or chewed.Concurrent administration with H2 antagonists or proton pump inhibitors may enhance enzyme efficacy.
3.6.2 Pancreatogenic Diabetes Mellitus（T3cDM）
Diabetes mellitus can also occur in 40-70%of adults with CP with a median time to onset of 11.9-26.3 years（Ammann et al.1984；Layer et al.1994）.The diabetes occurs in～5%of patients with hereditary pancreatitis by 10 years after the onset of symptoms，and 18%by 20 years（Howes et al.2004）.This form of diabetes is called type 3c or pancreatogenic diabetes and is the result of partial or complete loss of insulin secretion.In the INSPPIRE cohort，1%of children already had diabetes at the time of enrollment（Schwarzenberg et al.2015）.Although there are no consensus definition and diagnostic criteria for T3DM，a deficient pancreatic polypeptide response to nutrients in the setting of CP and EPI and no evidence for type 1 or 2 diabetes mellitus have been proposed as discriminating factors.The exact mechanism of pancreatic diabetes is unknown，but patients have evidence of islet dysfunction and altered glucose metabolism（Lundberg et al.2016）.Endocrine pancreatic insufficiency can be diagnosed via 2006 WHO criteria for the diagnosis of diabetes mellitus（fasting glucose≥7.0 mmol/L（126 mg/dL）or plasma glucose≥11.1 mmol/L（200 mg/dL）2 h after glucose load 1.75 g/kg children（to maximum 75 g glucose load）（Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1997）.Children should routinely be followed and monitored for the development of EPI and diabetes.Screening tests for early diagnosis of T3cDM are not established but may involve fasting blood glucose，oral glucose tolerance test and mixed meal glucose tolerance test.It is also not known how frequently children with CP should be monitored for EPI and T3cDM.The experience with the treatment of pancreatogenic diabetes comes mostly from total pancreatectomy with islet cell autotransplantation（TPIAT）studies and involves insulin therapy（Bellin et al.2008，2012，2013）.(https://www.daowen.com)
3.6.3 Pain and Impaired Quality of Life
In the INSPPIRE cohort，substantial disease burden was associated with pediatric CP：～80%reported abdominal pain within the previous year and one-third were taking narcotic analgesics（Schwarzenberg et al.2015）.Hospitalizations，emergency department visits and school absences were common.Overall，burden of pain is significant in children with ARP to CP contributing significantly to impaired quality of life，as well as higher level of fatigue（Pohl et al.2012）.
Medical therapies.The experience with the medical therapy of pain in pediatric CP is limited.Nonsteroidal anti-inflammatory drugs and acetaminophen should be the first-line agents for pain control.The addictive profile of narcotics and their gastrointestinal side effects should be considered when initiating the therapy.Tramadol and Gabapentin have shown efficacy in controlling pain in adults with CP，but there are no pediatric studies（Olesen et al.2011）.
Endoscopic Interventions.In adults with uncomplicated CP，endoscopic therapy may be useful in treating chronic pain（Cahen et al.2005，2007）.The main goal is to alleviate a pancreatic duct obstruction in the presence of ductal stone or stricture，placement of a stent in the main pancreatic duct or pancreatic portion of the bile duct（Cremer et al.1991；Ponchon et al.1995）.In adults with CP，endoscopic stenting of bile duct strictures may result in high response rates（Costamagna et al.2001；Draganov et al.2002）.
ERCP can be done successfully in over 90%of children（Issa et al.2007）and therapeutic ERCP is frequently utilized in children with ARP or CP.In a small pediatric study，children were evaluated with ERCP for recurrent acute and chronic pancreatitis；in 52%of patients ERCP altered the therapy（Graham et al.1998）.In another pediatric study，the majority of children with pancreas divisum and CP had resolution of symptoms and did not require surgery following placement of a pancreatic duct stent（Bhasin et al.2013）.In the INSPPIRE cohort，～40%of children undergo therapeutic ERCP during the course of their illness and their response to therapy is currently being evaluated.
Surgical Therapies.Surgical techniques include drainage operations that aim to decompress dilated ducts or resections of strictures and removal of pancreatic stones（Andersen and Frey 2010）.In the majority of cases，a Puestow-type procedure（longitudinal pancreatojejunostomy that involves opening the pancreatic duct throughout the body and tail of the gland）is used.The timing and choice of interventions are not welldefined for pediatric CP，but a recent study recommended a step-wise approach for children with hereditary pancreatitis with early endoscopic interventions；surgical drainage procedures reserved in case therapeutic ERCP was unsuccessful（Kargl et al.2015）.In general，drainage procedures are not encouraged if the patient will undergo TPIAT in the future，because this procedure has been reported to decrease the islet yield from the pancreas（Bellin et al.2011；Kobayashi et al.2010）.TPIAT is increasingly being proposed as a treatment for pediatric CP.Currently，there are no consensus guidelines for TPIAT eligibility.Children with intractable abdominal pain due to CP who have failed other therapies are proposed as candidates for this operation.The decision for TPIAT requires a multidisciplinary team including pediatric gastroenterologists，pediatric surgeons，pediatric endocrinologists，psychologists，and anesthesiologists.The child's physical and emotional status in coping with and managing diabetes must be assessed.Within a year of this operation，50-80%of patients from a single center have become narcotic independent on follow-up（Bellin et al.2008，2011；Chinnakotla et al.2014a，b；Sutherland et al.2012；Wilson et al.2013）.The pain improvement was largely sustained at 10-year follow-up，whereby 10-20%of patients continued to take narcotics（Chinnakotla et al.2014a，b）.Similar to the narcotic independence，insulin independence was also generally sustained over the 10-year follow-up in the majority of children（～40%）（Chinnakotla et al.2014a）.Both children and adults demonstrate significant improvement in physical and mental health after TPIAT（Bellin et al.2011；Chinnakotla et al.2014b；Walsh et al.2012；Wilson et al.2013）.
Conclusion
Pediatric chronic pancreatitis continues to be a challenging disease.It is relatively uncommon and poorly characterized.Although there have been pediatric focused reports recently，little is known about its epidemiology，natural history，prognostic factors and response to therapies.Current studies suggest that pediatric CP has unique features with a high prevalence of genetic risk factors and few confounding environmental factors，thus distinguishing it from adult pancreatitis populations.Future studies should focus on early identification of pediatric CP，better understanding of its natural history and prognostic factors and better therapeutic strategies to improve pain and quality of life.