Figure 14.1 Schematic of inflammatory cascade in AP.

Mild disease is limited to the pancreas and results in only peripancreatic inflammation and oedema. In more severe cases, extensive pancreatic tissue necrosis, thrombosis of intrapancreatic vessels and intraparenchymal haemorrhage can be seen, which precipitates a systemic inflammatory response syndrome (SIRS) and extrapancreatic involvement. This state is often associated with a diffuse capillary-leak phenomenon, resulting in significant fluid loss in the extravascular space and intravascular volume depletion. Excessive SIRS or a superimposed infection may then lead to multiple organ dysfunction syndrome (MODS), manifesting as acute respiratory distress syndrome, acute renal failure or acute hepatic decompensation [4,5].

14.4  AETIOLOGY

In adults, pancreatitis is most commonly caused by alcohol abuse and biliary tract disease, but in children, its aetiology is much more diverse (Table 14.1). The five most common causes of AP in children are trauma, idiopathic, systemic disease, biliary disease and medications. Less common aetiologies are listed in Table 14.1. Alcohol, not surprisingly, is rarely reported as a cause in children [5].

Table 14.1 Aetiology of AP in children

Note:  Reference is given in parentheses. MVA, motor vehicle accident; NAI, nonaccidental injury; DKA, diabetic ketoacidosis.

The most common cause of paediatric pancreatitis overall is probably trauma (10%–40%), and in turn, this is usually caused by blunt abdominal injury secondary to motor vehicle accidents, bicycle handlebar injuries, sports injuries and accidental falls [2,5]. Child abuse should also be considered in younger children who have an unclear mechanism of injury or may be unwilling to give an accurate history. Sometimes, pancreatitis may result from latrogenic injury due to surgical or endoscopic manipulation of the pancreatic duct.

The second most common cause of pancreatitis is idiopathic (13%–34%). Despite medical advancements and increased awareness of the myriad causes of pancreatitis in children, there has been little reduction in those deemed idiopathic over the past two decades [5].

There has been a steady increase in that due to associated systemic disease. Currently, it is estimated that up to 30% of cases in children are associated with diseases such as sepsis, shock, haemolytic uremic syndrome or systemic lupus erythematosus [3,6]. This overall increase in incidence is multifactorial, and it has been attributed to greater physician recognition of the risk of pancreatitis during systemic illnesses and, consequently, a lower clinical threshold to evaluate pancreatic enzyme levels in critically ill children with abdominal pain.

Biliary disease is probably the major ‘surgical’ cause of AP in children (10%–30%). The aetiology includes a broad range of pathology and may be subdivided into functional nonanatomic causes and congenital anomalies. Nonanatomic causes typically present acutely and are secondary to mechanical obstruction of the biliary tree from gallstones, microlithiasis or perhaps from sphincter of Oddi dysfunction. Gallstones are the most common cause of biliary pancreatitis in children and are often formed from haemolytic disorders such as spherocytosis, α-thalassaemia and sickle cell disease.

Congenital pancreaticobiliary anomalies may have a more chronic presentation with a history of recurrent abdominal pain. The most common is a choledochal malformation (see Chapters 7 and 8), while other less common variants are choledochoceles, intraluminal duodenal diverticula, annular pancreas, pancreas divisum and pancreaticobiliary malunion [5,7]. Although perhaps only 10% of cases are due to such anomalies, there have been great improvements in diagnosis with early recourse to magnetic resonance cholangiopancreatography (MRCP) and the increasing availability of endoscopic retrograde cholangiopancreatography (ERCP) in this age group.

In large children’s hospitals with an active oncology practice, the most common cause of AP is related to drugs, specifically L-asparaginase,^* prednisone and 6-mercaptopurine [5]. Epileptic children on valproic acid or sodium valproate^* acid are also prone to AP. There is limited understanding of the specific mechanisms for medication-induced pancreatitis; therefore, diagnosis requires a high clinical suspicion when other causes are excluded.

Infectious causes are uncommon, occurring in <10% of cases. Children typically present with fever, respiratory tract symptoms or a viral prodrome. Mumps is the most frequent infectious aetiology that has been attributed to pancreatitis in children. Other infectious agents reported in children include hepatitis A, rotavirus [8], varicella, adenovirus, coxsackievirus, mycoplasma pneumonia and Moraxella catarrhalis^† [9].

Metabolic causes are uncommon (2%–7%), with diabetic ketoacidosis the most common, followed by hypertriglyceridaemia and hypercalcaemia. Children with these disorders are more likely to have recurrent episodes of AP if their underlying disease is uncontrolled. Treatment is dependent on the underlying disease process.

Genetic causes are seen in 5%–8% of children. The most important is referred to as hereditary pancreatitis, which is usually described as an autosomal dominant disease with incomplete penetrance (see Chapter 15). There are a number of defined mutations (e.g. cationic trypsinogen gene [PRSS1], serine protease inhibitor Kazal-1 gene [SPINK1] and cystic fibrosis transmembrane conductance regulator [CFTR] gene). PRSS1 is associated with a single-point mutation in the third exon of PRSS1, resulting in a gain-of-function mutation and subsequent enhanced intrapancreatic trypsinogen activation. SPINK1 is a potent protease inhibitor that inactivates intrapancreatic trypsin activity. Mutations in this gene result in loss of function for trypsin inhibition and are thought to predispose patients to pancreatic autodigestion and AP. Sultan et al. identified 23 of 29 (79%) who had mutations in one or more of these genes in a genetic survey of children with recurrent AP and chronic pancreatitis from Wisconsin [10]. Pancreatitis, both acute and chronic, is more common in children with cystic fibrosis, typically caused by mutations in the CFTR gene. This is thought to be precipitated by viscid pancreatic secretions that result in pancreatic ductal obstruction. While hereditary causes are rare, widespread access to genetic testing has resulted in a higher proportion being detected, and such testing is certainly encouraged in those regarded as ‘idiopathic’ [5,10].

In very rare instances, pancreatitis may occur during the antenatal period. These infants demonstrate pancreatic insufficiency, generally very low serum trypsinogen and near total exocrine pancreatic atrophy at birth. This condition is referred to as Shwachman–Diamond syndrome,^‡ and it is an autosomal recessive disorder that has been mapped to the centromeric region of chromosome 7 [11].

14.5  DIAGNOSIS

Evaluation of AP includes a thorough clinical history, physical exam, select laboratory tests and occasionally diagnostic imaging. Initial presenting symptoms are often nonspecific and may depend on the patient’s age or level of development. The classic symptoms are abdominal pain, nausea, vomiting and anorexia. The quality of pain may be described as sharp, sudden or constant, and it is typically located in the epigastrium. Pain may also occur in the other abdominal quadrants; typical radiation through to the back seems to be uncommonly elicited. Dietary investigation may elicit food as a trigger that worsens pain and vomiting.

On physical examination, there may be fever, tachycardia or even hypotension. A child is usually irritable with a distended tender abdomen. Pain relief may be elicited when the knees are drawn up to a flexed trunk. In severe cases of haemorrhagic pancreatitis, the Grey-Turner^§ sign (blue discolouration of the flanks) or Cullen^¶ sign (blue discolouration around the umbilicus) may be noted.

Serum amylase and lipase levels should be diagnostic in AP (defined as three times the upper limit of normal range). Amylase generally rises within a few hours of onset of symptoms and normalises within 3–5 days. Although amylase is an isoenzyme that may be released during episodes of pancreatic injury, hyperamylasaemia may also occur in diseases of the salivary glands, renal dysfunction or other extrapancreatic abdominal diseases associated with inflammation, including acute appendicitis and intestinal obstruction [12].

Serum lipase levels are more specific for pancreatitis and have a longer half-life (7–14 h) than amylase (2 h) [13]. Lipase increases within 4–8 h of symptoms and normalises within 8–14 days. Utilising both serum amylase and lipase results together has a clinical sensitivity for the diagnosis of pancreatitis of up to 94% when levels are at least three times the upper limit of normal [2,12]. However, the degree of elevation of amylase and lipase does not necessarily correlate with severity of pancreatic disease.

Abdominal imaging is useful to confirm the diagnosis of AP when any doubts exist after clinical and biochemical evaluation. Plain abdominal radiographs of the abdomen, although not diagnostic, are useful to rule out other causes of acute abdominal pain, such as intestinal perforation. Findings that may be suggestive of AP include ileus with colonic dilatation, a ‘sentinel loop’ of dilated small bowel or obscure psoas margins.

Calcification may be seen in chronic pancreatitis, and is indicative of either actual intraductal stones or parenchymal lesions. Ultrasound is the radiological study of choice in children with acute abdominal pain for pancreatitis. Sonographic evaluation of the pancreas can assess for size, texture and ductal diameter. Additionally, other intra-abdominal abnormalities, such as appendicitis, cholelithiasis, pseudocysts, abscesses and ascites, may be visualised. Computed tomography (CT) has more than 90% sensitivity and specificity for diagnosis of AP, but it should probably be reserved for children who fail to improve after 48–78 h of therapy, in order to assess for local complications of pancreatitis, or in cases of acute abdominal trauma [12].

ERCP is rarely necessary in children with AP, but it may be indicated in selected cases due to structural or biliary causes, or if recurrent with an elusive aetiology. This study may be performed in children, even in infants as small as 4 kg, and allows detailed mapping of the pancreatic and biliary anatomy to exclude pancreaticobiliary malformations, biliary strictures or mechanical obstruction from gallstones. If anatomical variation is of significant concern, ERCP is the study of choice for the diagnosis of pancreas divisum and anomalous pancreaticobiliary duct junction. Although ERCP is an invasive procedure, it has the benefit of being both diagnostic and therapeutic at the time of investigation. Available endoscopic treatment options include pancreatic ductal clearance, sphincterotomy and stent placement. Amylase and lipase should be reassessed post-ERCP because pancreatic ductal manipulation can exacerbate pancreatitis. This modality has a complication rate of <10% [7].

A noninvasive, radiation-free alternative is MRCP. MRCP can provide a comprehensive morphologic assessment of the biliary and pancreatic ducts and has been shown to be useful in identifying and ruling out pancreaticobiliary tract abnormalities in children. It has 100% accuracy in evaluation of choledochal malformation, although it is much less reliable in the detection of an abnormal pancreaticobiliary junction (40%–80%) [14]. Additionally, MRCP is also useful for detecting choledocholithiasis as small as 3 mm in size.

Several scoring systems are available to gauge the severity of pancreatitis in children (Table 14.2). The Ranson^* [15] and modified Glasgow scores [16] are most frequently utilised and validated in the adult population to assess prognosis within the first 48 h, but they can be applied in paediatric pancreatitis. Unfortunately, certain criteria, such as age of >55 years or fluid deficit of >6 L, are not pertinent in children [17]. Recognising the significant clinical differences of pancreatitis in children and adults, Debanto et al. developed a new paediatric acute pancreatitis severity (PAPS) scoring system with eight variables, four to be scored at the time of admission and four by 48 h [18]. Another severity score is the computed tomographic severity index (CTSI), or Balthazar score [19]. This system is based on the radiologic appearance of the pancreas, including pancreatic enlargement, peripancreatic inflammation, pancreatic fluid collection and extent of necrosis.

Calcification may be seen in chronic pancreatitis, and is indicative of either actual intraductal stones or parenchymal lesions. Ultrasound is the radiological study of choice in children with acute abdominal pain for pancreatitis. Sonographic evaluation of the pancreas can assess for size, texture and ductal diameter. Additionally, other intra-abdominal abnormalities, such as appendicitis, cholelithiasis, pseudocysts, abscesses and ascites, may be visualised. Computed tomography (CT) has more than 90% sensitivity and specificity for diagnosis of AP, but it should probably be reserved for children who fail to improve after 48–78 h of therapy, in order to assess for local complications of pancreatitis, or in cases of acute abdominal trauma [12].

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