Acute pancreatitis, the most common pancreatic disorder in childhood,^1,2 is a costly and increasingly recognized disease. Studies from the United States, Mexico, and Australia have reported an increasing incidence of pediatric acute pancreatitis over the past two decades, though the reasons for such increases remain unclear.^3-9 In the United States, approximately 11,000 children are diagnosed with acute pancreatitis each year, providing a total fiscal burden of more than $200 million/year. The burden, however, is not limited to cost, as pediatric acute pancreatitis is associated with significant morbidity and mortality, with reported mortality rates ranging from 0% to as high as 11%. The incidence of acute pancreatitis is 2 to 13 new cases annually per 100,000 children.^4,7,10

ETIOLOGY

Acute pancreatitis is a reversible process characterized by the presence of interstitial edema, infiltration by acute inflammatory cells, and varying degrees of necrosis, apoptosis and hemorrhage.^4,11 There are many causes of acute pancreatitis (Table 82-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated.

While gallstones and alcohol consumption cause most cases in adults, the etiologies in children are more diverse (Table 82-1). The most common causes of acute pancreatitis in children are medications; biliary, idiopathic, and systemic causes; and trauma, followed by infectious, metabolic, and hereditary causes.^4,8,12,13

Medications cause almost 30% of cases of acute pancreatitis in children (Table 82-2)⁴. The most common medications include valproic acid, L-asparaginase, prednisone, 5-ASA derivatives (e.g. sulfasalazine) and 6-mercaptopurine¹⁴; however, true causality is difficult to establish because many patients receive concomitant medications (such as 6-mercaptopurine) for systemic illnesses that in and of themselves may predispose to pancreatitis (i.e. inflammatory bowel disease).

Biliary tract disease refers to the presence of gallstones or sludge in the gallbladder. Thirty percent of biliary causes are attributed to sludge, as opposed to formed gallstones,^2-4,6,8 in children. In most cases of pediatric biliary pancreatitis, children will have abnormal liver enzymes, particularly transaminase elevation and sometimes mild total hyperbilirubinemia.^1,3,5,7-9

Pancreatitis associated with multisystem disease accounts for approximately one-third of the cases in pediatric patients. The most common associated systemic diseases include sepsis, shock with and without sepsis, hemolytic-uremic syndrome, and systemic lupus erythematous.^4,6,7 While rare, Kawasaki disease has also been reported as a cause of acute pancreatitis.^4,10,11 Trauma, while previously thought to be a leading cause of acute pancreatitis in children, was reported as a precipitating cause in 10% to 40% of patients in case series.⁴ Most commonly reported examples of trauma include blunt injury related to motor vehicle collisions, sports injuries, accidental falls, and child abuse.^4,8,12,13 Despite better imaging modalities and increased awareness, up to one-third of cases of pancreatitis still have unknown etiology (i.e. idiopathic).

Less common causes of acute pancreatitis in children include infectious, metabolic, and hereditary causes. Viral etiologies, especially enteroviruses, tend to predominate with regard to infectious etiologies (Table 82-1); however, causation by any specific pathogen can be difficult to prove. Symptoms of infection and pancreatitis may occur at the same time and be independent events, or an infectious episode may serve as a nonspecific trigger in a host with an underlying predisposition to pancreatitis. The most common metabolic causes of acute pancreatitis in children include diabetic ketoacidosis, followed by hypertriglyceridemia and hypercalcemia.^4,14 Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g. drugs, alcohol) that causes an abrupt increase in serum triglycerides can precipitate acute pancreatitis. Most cases of hypercalcemia related pancreatitis are due to hyperparathyroidism.¹⁵

Congenital anomalies such as pancreatic divisum, abnormal junction of the common bile duct and main pancreatic duct (common channel syndrome), choledochal cysts, and annular pancreas increase the risk for acute pancreatitis. Pancreas divisum, which is present in approximately 15% of the population, occurs when the dorsal and ventral pancreatic buds fuse incompletely during embryonic development (7th week of gestation). Despite its proposed obstructive mechanism leading to acute pancreatitis, clinical causality remains controversial.¹⁶

The pathophysiology of acute pancreatitis remains obscure. Autodigestion is a currently accepted pathogenic theory, whereby pancreatitis results when proteolytic enzymes (e.g. trypsinogen, chymotrypsinogen, proelastase, and additional lipolytic enzymes) are activated in the pancreas acinar cell rather than the intestinal lumen.¹⁷

Despite multiple etiologies, inflammation in pancreatitis appears to be the result of a common pathway.⁴ Current dogma suggests that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Aberrant nonphysiological calcium signals within acinar cells are generated first, followed by premature activation of the intraacinar pancreatic proenzymes, or zymogens.¹⁸ Acinar cell injury is believed to be the consequence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction.¹⁷ Production of cytokines such as tumor necrosis factor-α leads to varying degrees of extrapancreatic inflammation and the final phase, in which the ensuing inflammatory cascade leads to fulminant pancreatitis. Here the active enzymes and cytokines digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal necrosis. Cellular injury and death result in the release of vasoactive substances and histamines that produce local and distal vasodilation, increased vascular permeability, and edema with effects on other organs. Most notable is the development of the systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multi-organ failure that may occur as a result of this cascade. While rare in children, progression to this final phase results in significant morbidity and mortality.

AUTOPROTECTION OF THE PANCREAS

Autodigestion of the pancreas and associated pancreatitis is prevented by several innate protective mechanisms: (1) the packaging of pancreatic proteases in a precursor (proenzyme) form, (2) intracellular calcium homeostasis, (3) acid–base balance, and (4) the synthesis of endogenous trypsin or protease inhibitors; i.e. pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor of Kazal type 1 (SPINK1).

Trypsin activity that might be generated in the acinar cell is reduced by two mechanisms— the trypsin inhibitors (SPINK1) and trypsin-degrading proteases, such as chymotrypsin C (CTRC). Mutations of the proteins involved in these pathways increase the risk of developing pancreatitis since the abnormal proteins are not able to control prematurely activated trypsin within the acinar cell.¹⁹

GENETIC SUSCEPTIBILITY

Multiple genetic factors can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis, recurrent pancreatitis, and chronic pancreatitis. These factors are related to control of trypsin activity within the acinar cell. There are five identified genes, variants of which are associated with increased susceptibility to pancreatitis: (1) cationic trypsinogen mutations (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1), (3) the cystic fibrosis transmembrane conductance regulator (CFTR), (4) the chymotrypsin gene (CTRC), and (5) the calcium sensing receptor (CASR).¹⁹

APPROACH TO THE PATIENT

In children, abdominal pain is the major presenting symptom in 80% to 95% of cases.⁴ Pain is most commonly localized to the epigastrium; however, 20% of patients report diffuse pain, and 10% or less describe the “classical” radiation to the back. Rarely, patients may present complaining only of back pain. In non-verbal children, unusual irritability may be the only clue that the patient is in pain.⁶ The pain and/or irritability are often worsened by eating and may be more intense when the patient is supine. Patients may obtain some relief by sitting with the trunk flexed and knees drawn up.

The next most common presenting symptom in children is nausea or vomiting, occurring up to 80% of patients.⁴ Other findings may include fever, jaundice, ascites, or chest pain (the latter due to a pleural effusion). If an abdominal mass can be palpated, consider the possibility of a pseudocyst.

Infants and toddlers may differ in their presentation when compared to children older than 3 years of age. Abdominal distension and fever may be more likely than abdominal pain and nausea.⁶

In episodes of severe pancreatitis, the systemic inflammatory response syndrome may ensue. Patients can present in multi-organ failure manifested as shock, coagulopathy, hemorrhage, ARDS, renal failure, and secondary infections.

Physical examination frequently reveals a distressed patient. Tachycardia is often present and may be associated with hypotension. Compensated shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space, (2) increased formation and release of kinin peptides which cause vasodilation and increased vascular permeability, and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation.¹⁷ Jaundice may occur and is usually due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct or passage of a biliary stone or sludge. Patients may demonstrate pulmonary findings such as tachypnea, basilar rales, atelectasis, possibly due to the presence of a (usually left-sided) pleural effusion. Abdominal tenderness and rigidity are present to a variable degree but may be hard to illicit depending on the patient’s body habitus. Abdominal distension may also be seen. Cutaneous manifestations termed Grey-Turner’s or Cullen’s sign, secondary to ecchymoses in the flanks or periumbilicus respectively due to hemorrhagic pancreatitis, is rare.¹² Rarely, a palpable mass may be appreciated in the upper abdomen later in the course of the disease (i.e. 4–6 weeks) suggestive of a pseudocyst.

The differential diagnosis for abdominal pain in children is very broad and also age specific. Since pancreatitis can present at any age (although it is rare in infants and toddlers), clinical suspicion is required and there should be a low threshold to obtain appropriate laboratory studies (see below). Elevations of serum amylase and lipase are the most common biochemical abnormalities in pancreatitis. However, it is important to be aware they are not 100% specific to acute pancreatitis, as there are other pediatric conditions that can be associated with elevated amylase or lipase (Table 82-3).