Pancreatitis

Abstract

After reading this article, readers should be able to:Pancreatitis is an inflammatory process of the pancreas presenting as a spectrum of clinical disease. Acute pancreatitis (AP) is a reversible process, but it may progress to acute recurrent pancreatitis (ARP). This increases the risk of developing chronic pancreatitis (CP), which carries higher morbidity due to irreversible pancreatic duct strictures, exocrine pancreatic insufficiency, insulin-dependent diabetes mellitus, and chronic pain. Pancreatitis is occurring at an increasing rate in children, which is troubling given the paucity of research in pediatric patients. Historically, management recommendations for pediatric pancreatitis have evolved based on consensus conferences and research in the adult population. In 2018, consensus guidelines for the management of AP were published for both pediatrics (1)(2)(3) and adult medicine. (4)Per the INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE), the 3 categories of pancreatitis are AP, ARP, and CP.AP in pediatric patients requires at least 2 of the following 3 criteria: 1) abdominal pain suggestive of AP, such as acute onset and epigastric in origin; 2) serum amylase and/or lipase levels at least 3 times the upper limit of normal; and 3) imaging findings consistent with AP. (5) ARP is defined by at least 2 acute attacks within a year, with interval resolution of pain or normalization of serum pancreatic enzyme levels, or by more than 3 lifetime episodes without evidence of CP. (5)(6) CP requires the presence of exocrine or endocrine insufficiency and histologic and morphologic changes that are irreversible, including fibrosis, islet cell loss, inflammatory cell infiltrates, and intraductal calculi. (5)The incidence of pediatric AP has increased in the past 2 decades, (7) ranging from 0.78 to 13.2 pediatric cases per 100,000 annually in the United Kingdom (8) and the United States, (9) respectively. This increase in incidence is multifactorial, having been linked to heightened awareness, appropriate biochemical testing, increasing multisystem disorders, and the rising prevalence of obesity. (10)(11)The damage associated with pancreatitis occurs after inflammatory cytokine-mediated induction of systemic inflammatory response syndrome (SIRS). (12) Specifically, the initial trigger results in excessive intracellular calcium signals in a few pancreatic acinar cells (Fig 1). (13) This intracellular hypercalcemia prematurely activates intra-acinar pancreatic trypsinogen to trypsin, which then activates other digestive proenzymes and together mediates acinar cell injury via autodigestion. (14) This process is exacerbated by inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, IL-6, and IL-8. Histamine, kallikrein, and bradykinin also contribute to the progression and severity of illness by liberating additional proteases and amplifying the SIRS cycle that causes damage to acinar cells. Oxygen free radicals are thought to be involved in the direct attack of unsaturated phospholipids of the cell membrane, leading to accumulation of lipid degradation products (eg, malonaldehyde and 4-hydroxynonenol) and resulting in increased membrane permeability, protease intracellular leakage, and Ca2+ influx. (15)Protective mechanisms such as autodegradation of trypsin and inhibition of trypsin by pancreatic secretory trypsin inhibitor, alpha-1 antitrypsin, and α2-macroglobulin can negate the initial triggering events. Other defense mechanisms, such as the compensatory anti-inflammatory response syndrome, can offset SIRS via the production of anti-inflammatory cytokines, including IL-4, IL-10, and IL-1ra. (14)(16) However, when the balance shifts toward SIRS, pancreatic necrosis and/or multiple organ failure ensues.The causes of AP in children can be broadly categorized into biliary disorders, systemic conditions, infections, trauma, medications, structural abnormalities, metabolic diseases, genetic mutations, autoimmune disorders, and idiopathic etiologies (Table 1). Furthermore, any of these conditions could lead to ARP or CP.Gallstones, microlithiasis, sludge, and pancreaticobiliary anomalies are common etiologies of pancreatitis in the pediatric population, accounting for 3% to 30% of cases. (19) In particular, pancreatitis should be suspected if the presentation includes transaminitis and/or direct hyperbilirubinemia. Pancreaticobiliary anomalies increase the risk of pancreatitis, such as pancreas divisum, (19)(20) choledochocyst, or, rarely, Caroli disease, which is characterized by cystic dilation of hepatic bile ducts.Approximately 13% to 34% of pancreatitis cases are reported as idiopathic. However, this statistic continues to decrease as genetic data for previously diagnosed idiopathic cases emerge. (21)The reported case association between AP and systemic illness ranges from 3.5% to 48%. (22) Commonly described systemic conditions associated with an increased risk include sepsis, shock, hemolytic uremic syndrome, systemic lupus erythematosus, juvenile idiopathic arthritis, celiac disease, and inflammatory bowel disease, especially with the association of primary sclerosing cholangitis. (23) Cystic fibrosis, leading to inspissated bile and pancreatic fluids in pancreaticobiliary ducts, may present with pancreatitis. Vasculitides such as polyarteritis nodosum, Henoch-Schonlein purpura, and Kawasaki disease have also been linked to pancreatitis.Drug-induced pancreatitis is due to different mechanisms depending on the medication, including immunologic reactions (eg, 6-mercaptopurine, amino salicylates), accumulation of toxic metabolites, ischemia (eg, diuretics), intravascular thrombosis (eg, estrogen), and increased viscosity of a pancreatic juice (eg, glucocorticoids). (8)(18)Trauma should always be considered as an etiology for AP. Examples of trauma associated with pancreatitis include blunt injury, child abuse, and instrumentation of the pancreaticobiliary junction and pancreatic ducts via endoscopic retrograde cholangiopancreatography (ERCP).Many infections have been associated with pancreatitis, including viruses such as mumps, measles, coxsackievirus, echovirus, influenza, hepatitis A, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster virus. Bacterial etiologies for pancreatitis include Mycoplasma pneumoniae, Salmonella, and gram-negative bacteria.Several metabolic diseases are associated with AP. A few etiologies include diabetic ketoacidosis, hyperlipidemia, organic acidemias such as methylmalonic academia, hypercalcemia, and alpha-1 antitrypsin deficiency. (17) Prolonged total parenteral nutrition (TPN) may not only predispose children to AP but also trigger acute episodes in patients with CP.With advancements in gene sequencing, genetic variants associated with pancreatitis are becoming increasingly important factors for understanding the pathophysiology of pediatric pancreatitis. (24) Studies have identified mutations in genes involved in premature intrapancreatic activation of trypsin (CFTR, PRSS1, PRSS2, SPINK1, CTRC, CTSB, KRT8, CASR), in calcium signaling and zymogen exocytosis (ATP2C2, STIM, TRPV6, DMBT1, TRP), in pancreatic secretion and ion homeostasis (CLPS, F2RL1, SLC4A2, RAP27B, CPB1, SLC4A4, SLC26A3, TMPRSS15, UBR1, SBDS), and in the autophagy pathway (HSP90AA1, LAMP2, MAP1LC3B). Other newly discovered potential pancreatitis susceptibility genes include CPA1, (25) CLDN2, (26) and CEL. (27) Although up to 34 gene mutations have been associated with ARP and CP, mutations of CFTR and PRSS1 occur at the highest rate in idiopathic ARP and CP, respectively. (21)(28)(29)(30) As specific mutations predispose an individual to ARP and CP, genetic testing is recommended for recurrent AP and/or an isolated AP event in the setting of family history of AP or CP. Initial screenings should focus on the most common pathogenic variants, which include PRSS1, SPINK1, CTRC, CPA1, CFTR, and the CEL hybrid. Genetic findings aid in long-term prognosis, especially since hereditary pancreatitis associated with PRSS1 mutations have been linked to increased risk of pancreatic adenocarcinoma. (31)Autoimmune pancreatitis (AIP), a rare cause of pediatric pancreatitis, is defined by pancreatic parenchymal changes that are clinically responsive to corticosteroids. (32) AIP occurs as either type 1 or type 2. Type 1 is associated with elevated immunoglobulin G4 levels, diffuse narrowing of the main pancreatic duct, segmental enlargement of the pancreas, and/or strictures of the lower bile duct. (33) However, normal immunoglobulin G4 levels do not rule out AIP. Type 2 is more common in children and is associated with inflammatory bowel disease and other autoimmune processes. (34)The pancreas may be predisposed to pancreatitis due to congenital anatomical abnormalities such as pancreaticobiliary junction malunion, which creates an environment causing poor flow of the pancreatic fluids in the abnormal duct. Annular pancreas is a congenital anomaly that may increase the risk of pancreatitis. Pancreas divisum and sphincter of Oddi dysfunction can result in inadequate pancreatic secretion drainage, resulting in pancreatitis.In pediatrics, 68% to 95% of patients with AP present with abdominal pain, (14)(35) 62% to 89% are localized to the epigastric region, and 1.6% to 5.6% have associated radiating back pain. (36)(37) In contrast, infants and toddlers present more commonly with irritability and vomiting. (22) The pain associated with pancreatitis stems from multiple mechanisms, including stimulation of visceral pancreatic and somatic peritoneal pain receptors by inflammatory cytokines. (38) Elevated pressures in the pancreatic system leading to ischemia and activation of primary sensory neurons are other mechanisms for abdominal pain during pancreatitis. (39)Although amylase and/or lipase levels are used to diagnose pancreatitis, an elevated serum lipase level is more sensitive than amylase level for diagnosis. (6)(14) Serum amylase and lipase levels are elevated in 50% to 85% and 77% to 100% of pediatric patients, respectively. (19)(22)(35)(37)(40) Serum amylase levels rise within 6 to 12 hours and fall within 3 to 5 days. The differential diagnosis for hyperamylasemia includes salivary gland conditions, intestinal etiologies such as obstruction, peptic ulcers, appendicitis, celiac disease, gastroenteritis, and eating disorders. Conversely, an elevated serum lipase level can be seen as early as day 1 of illness, persists for 14 days, and is pancreatic specific. Serum triglyceride and calcium levels should be measured with the first episode of AP to rule out hypertriglyceridemia or hypercalcemia as potential etiologies. (1)The diagnostic features of AP on imaging studies include evidence of biliary obstruction, parenchymal changes, and peripancreatic fluid collections. Controlled trials on the use of imaging tools have yet to be performed in children. (1) Transabdominal ultrasonography (TUS) is the recommended initial imaging study for suspected AP, with an effectiveness rate of 56% to 84% in pediatric patients with AP. (41) TUS is advantageous because it lacks ionizing radiation, is effective for the identification of gallstones and pancreatic fluid collections, and comparatively costs less than other modalities.Although not yet widely used in children due to its availability, endoscopic ultrasonography (EUS) is an effective tool to recognize biliary pancreatitis or pseudocysts in children greater than 5 years old. (42) In a study looking at 11,000 pediatric EUS procedures, indications, and outcomes, the authors underscored that EUS indications in children are comparable with those in adults. Furthermore, the findings significantly contributed to the diagnosis and treatment of pediatric pancreaticobiliary disease. (43)Magnetic resonance cholangiopancreatography (MRCP) is the imaging method of choice for diagnostic evaluation of the pancreaticobiliary system in children and is recommended by the INSPPIRE consensus when TUS is suggestive of AIP (32) or in pediatric ARP and CP. (5) It carries less risk than ERCP and is highly sensitive in detecting congenital ductal abnormalities, choledocholithiasis, strictures, pancreas divisum, and pancreatic and biliary tumors. (44)(45) Figures 2 and 3 present MRCP images from an 11-year-old with CP due to PRSS1 mutation demonstrating pancreatic duct stricture with intermittent dilation, so-called beading, of the duct.Contrast-enhanced abdominal computed tomography is not first-line imaging due to radiation exposure but is best suited for situations of diagnostic uncertainty and clinical deterioration, such as necrosis and bleeding in clinically severe AP. The optimal timing for detecting inflammatory changes surrounding the pancreas by computed tomography is at least 72 to 96 hours after initial AP presentation. (46)ERCP is available in some pediatric centers and may be combined with EUS where available. (47)(48) ERCP should be used only for therapeutic purposes due to the risks associated with ERCP, such as bleeding, perforation, and pancreatitis. In particular, the risk of pancreatitis after ERCP was reported to be 9.7%. (47)(48)Aggressive fluid resuscitation is a mainstay in the acute management of AP. It addresses hypovolemia, increases pancreatic perfusion, improves microcirculation, and reduces the risk of necrosis. Both normal saline and lactated Ringer solution (LR) have been studied. In an adult study, compared with normal saline, LR was shown to significantly decrease the incidence of SIRS (49) and the development of post-ERCP pancreatitis. (50) However, another study found no difference between LR and normal saline when looking at mortality and duration of hospital stay. (51) Current recommendations are for initiation of therapy with dextrose-containing crystalloids (1) or LR (2) at 1.5 to 2 times maintenance within 24 hours (Table 2). (47) Notably, pediatric studies have demonstrated an association between aggressive fluid administration and fewer ICU admissions, shortened hospital stays, and higher rates of clinical recovery. (52)(53)There is no specific pain management guideline for pediatric AP or quality data on differences between analgesics. Acetaminophen and ibuprofen are the first-line agents for mild pain, and opioids are indicated for severe pain. Although opioids increase the sphincter of Oddi tone, clinical studies do not correlate this with poor outcomes. A Cochrane review assessing the efficacy and safety of opioid use found that it is appropriate in the treatment of pain related to AP and that its use may decrease the need for supplementary analgesia. (54) However, a retrospective review of 211 pediatric patients with AP at the Boston Children’s Hospital Emergency Department found that opioid analgesia was more frequently prescribed than nonopioid alternatives, time to analgesia was shorter in opioid-receiving patients, and they required more doses of analgesics. (55)Procaine, a local anesthetic that is administered systemically, has been considered for basic analgesia for AP. One controlled trial showed the effectiveness of systemic administration of procaine in pancreatitis, with accelerated postoperative recovery, improved cognitive function, and overall shortened hospital stay. (56) Epidural anesthesia, used as a sympathetic nerve block that redistributes blood flow to nonperfused pancreatic regions, has shown improved pancreatic perfusion, decreased AP pain, and the need for necrosectomy. (57)Guidelines for pediatrics have been extrapolated from adult data and consensus from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee. (2)(3) Enteral feeding within 24 to 48 hours of pancreatitis onset is recommended. Multiple studies support early feeding with a regular diet in mild AP because early feeding can reduce the length of stay. (2)(3) Remaining nil per os or on a clear liquid diet does not improve abdominal pain. If a patient cannot tolerate an oral diet, nasogastric or nasojejunal enteral formula feeding is recommended. Initiation of feedings is not dependent on the severity of pancreatitis, and studies have not demonstrated a difference between nasogastric and nasojejunal feedings. Likewise, polymeric formula is appropriate first-line nutrition. TPN is reserved for when enteral nutrition cannot be tolerated, such as pancreatic fistulae, perforated pancreatic duct, ileus, or abdominal compartment syndrome. The risks of central line infections secondary to bacterial translocation increase with TPN in the setting of AP. (1)Prophylactic antibiotics are not recommended in AP, even in the presence of severe AP or existing necrosis, because most are sterile. Indications for antibiotics include systemic infectious complications, cholangitis, and suspected infected pancreatic necrosis. In the setting of persistent systemic inflammatory response beyond the first week of symptom onset, ultrasonography-guided fine-needle aspiration could differentiate infected and sterile pancreatic necroses. Imipenem, meropenem, fluoroquinolones, and metronidazole exhibit effective tissue penetration and bactericidal properties for infected pancreatic necrosis and prevention of septic complications. (58)(59) Antibiotics ideally are used in conjunction with surgical or is indicated in the setting of choledocholithiasis, biliary duct causing biliary pancreatitis, cholangitis, and biliary or pancreatic duct (Fig performed with ERCP in pediatric patients include biliary or pancreatic stricture dilation, and of One study showed that therapeutic ERCP is frequently used in children with ARP or CP because both are associated with pancreaticobiliary ERCP should be within 24 hours in patients with severe cholangitis. fluid and pseudocysts are common of AP, occurring in and of children with AP, respectively. EUS is used for to pancreatic include the development of pancreatic necrosis, and A is a of pancreatic fluid by The to and can be by or resulting in pancreatic if compensatory anti-inflammatory response syndrome is excessive in the inflammatory inhibition of production can lead to increased susceptibility to sepsis, infectious necrosis, and pancreatic systemic are can be in pancreatitis, and may include system shock, bleeding, intestinal obstruction, and In and may including acute syndrome, acute intravascular and is a to of AP after the initial factors a in the development of ARP and CP. risk to AP, include genetic mutations, disorders, and autoimmune (Table genetic mutations CFTR, SPINK1, or in of children with pancreatitis, which is defined as occurring 6 years of a of such mutations was in years and with ARP or CP. differences in such as autoimmune diseases, metabolic diseases, or as more etiologies for ARP in children. is an irreversible inflammatory process that results in morphologic changes, such as and or exocrine or endocrine pancreas as a of (5) CP is most diagnosed clinically with the aid of and imaging studies than by Genetic etiologies are common for pediatric CP, recurrent or obstruction, trauma, chronic such as and systemic diseases such as AIP are etiologies. 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