Keywords

Introduction

Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems [1]. From a pathological point of view, the findings of acute pancreatitis range from microscopic interstitial edema and fat necrosis of the pancreatic parenchyma to macroscopic areas of pancreatic and peripancreatic necrosis and hemorrhage [1]. From a clinical point of view, the disease is accompanied by upper abdominal pain with variable abdominal symptoms, ranging from mild tenderness to rebound; it is also often accompanied by vomiting, fever, tachycardia, leukocytosis and the presence of elevated pancreatic enzymes in the blood and/or urine [1]. Clinically, two forms of acute pancreatitis are recognized: the mild form associated with minimal organ dysfunction and uneventful recovery, and the severe form associated with organ failure and/or local complications, such as necrosis, walled-off pancreatic necrosis, and pseudocysts [1].

Acute pancreatitis, especially if severe, can lead to several potential local complications. Pancreatic necrosis is a focal or diffuse area of non-viable parenchyma, which typically is associated with peripancreatic steatonecrosis. Computed tomography (CT) with intravenous contrast bolus is currently the best diagnostic method (accuracy 80–90 %). The necrosis may become infected in 10–30 % of cases. The distinction between sterile and infected pancreatic necrosis is important because the therapeutic approach (mainly medical therapy in sterile pancreatic necrosis and surgical in the infected type) and prognosis (mortality rate about three times higher in infected pancreatic necrosis) differ considerably. The diagnostic gold standard for suspected infection of pancreatic necrosis is represented by microbial cultures of material from percutaneous needle aspiration. Acute fluid collection is a localized effusion in or near the pancreas, without a fibrotic wall. It tends to appear early and regresses spontaneously in most cases. It is not considered a sign of disease severity unless it becomes infected.

Pseudocysts are collections of pancreatic juice enclosed by a non-epithelial wall. The maturation of a pseudocyst after acute pancreatitis requires at least 4 weeks after the onset of the disease. A post-acute pancreatitis pseudocyst is also an acute fluid collection persisting more than 4 weeks and surrounded by a well-defined wall. Finally, a walled-off pancreatic necrosis is an intra-abdominal collection of pus (usually near the pancreas), appearing after an attack of acute pancreatitis or after pancreatic trauma. Pus predominates and there is only a small amount of necrotic tissue, distinguishing it from infected pancreatic necrosis. A pseudocyst containing pus is also correctly defined as walled-off pancreatic necrosis [2].

Epidemiology

Acute pancreatitis is a rare disease in children; unfortunately, there are no epidemiological data on the incidence of the disease in childhood. Early published series reported five to ten patients per year at major children’s hospitals and pediatric referral centers [3], even if an increasing number of children with this disease have been seen in large teaching hospitals where a number ranging from 30 to more than 100 children per year may be treated [3, 4]. No ethnic groups seem to be overexpressed [4]. As regards gender, the male:female ratio ranges from 0.7:1 to 2:3 [5]. The mean age at onset varies from 8 to 14 years; all ages, from under 1–18 years of age, seem to be involved [3, 6, 7]. The median duration of hospitalization per episode ranges from 8 to 13 days [3, 6].

Pathophysiology

Three phases characterize the pathophysiology of acute pancreatitis, as shown in Fig. 3.1. The concept that the cause of the pathophysiological changes in acute pancreatitis lay in the autodigestion of the pancreas mediated by the pancreatic enzymes is still generally accepted [8], and the intra-cellular activation of trypsin seems to play a key role in initiating acute pancreatitis. Furthermore, this event induces a variety of local and systemic responses, mainly mediated by the production of cytokines.

Fig. 3.1
figure 1

Pathophysiological and clinical phases of acute pancreatitis

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Trypsin is synthesized as an inactive proenzyme called trypsinogen in the endoplasmatic reticulum and is then transported to the Golgi system where the protein is sorted, together with other pancreatic enzymes, into core particles. In acute pancreatitis, according to the co-localization theory, trypsin activation occurs within cytosolic vacuoles containing both digestive enzymes and lysosomal enzymes. One of the lysosomal enzymes, cathepsin B, seems to be able to transform trypsinogen into trypsin by removing the TAP region from trypsinogen [9], as demonstrated by the detection of immunoreactivity against trypsinogen activation peptide (TAP) in vacuoles positive for lysosomal markers [10, 11]. Another possible mechanism in the activation of trypsinogen involves intracellular calcium. In fact, it has been demonstrated that premature trypsin activation takes place in the apical cells in response to supramaximal cholecystokinin stimulation, and that this activation is dependent on the spatial and temporal distribution of Ca2+ release within the same subcellular compartment [12].

Finally, as protective mechanisms against active trypsin and other proteinases, there are several inhibitors secreted by the pancreas, such as the pancreatic secretory trypsin inhibitor; when the balance between proteases-antiproteases is optimal, the pancreatitis does not progress but, when the balance is in favor of the activated trypsin, the pancreatitis progresses to the necrotizing form of the disease.

The destruction of the pancreatic parenchyma following acute pancreatitis quickly induces an inflammatory reaction at the site of the injury. The initial cellular response involves the infiltration of polymorphonuclear leukocytes into the perivascular regions of the pancreas. Within a few hours, macrophages and lymphocytes accumulate and phagocyte-derived oxygen radicals participate in a primary injury to the pancreatic capillary endothelial cells. The increased microvascular permeability facilitates margination and extravascular migration of additional neutrophils and monocytes amplifying the inflammatory process. Following an experimental insult, there is rapid expression of tumor necrosis factor-alfa (TNF-alfa) and interleukin-1 (IL-1) [13]; these two substances are primary inducers of pro-inflammatory interleukin 6 and 8 (IL-6 and IL-8) production and are known to initiate and propagate many consequences including fever, hypotension, acidosis and acute respiratory distress syndrome (ARDS). Finally, in severe forms of acute pancreatitis, there is also a reduced production of anti-inflammatory cytokines, such as interleukin-10 (IL-10) a chemokine capable of blocking the action of the pro-inflammatory cytokines [14].

Etiology

The possible causes associated with an attack of acute pancreatitis are reported in Table 3.1. Acute pancreatitis in children is often found after abdominal trauma in (15 % of the cases), followed by biliary or pancreatic malformation (13 %), drugs (10 %), biliary stones (9 %), viral of bacterial infections (7 %), systemic illnesses (7 %) and metabolic diseases (5 %). A variety of medications have been hypothesized to be causative agents of acute pancreatitis, such as anticonvulsant agents [15], asparaginase [16], and mercaptopurine [17]. The mechanism for drug-induced pancreatitis is not fully understood; disruption of the cellular metabolism by drugs or their metabolites may be the initial trigger point. However, in more than 20 % of the cases, no clear etiological factors can be detected; thus, many young patients have an idiopathic form of pancreatitis.

Table 3.1 Study period, gender, age at onset of pancreatitis, etiology, severity, recurrences and mortality of acute pancreatitis in ten studies
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Genetics

Genetic evaluation constitutes a diagnostic challenge, especially in patients with recurrent attacks of acute pancreatitis or in those with an unknown etiology of the disease. The hereditary pancreatitis locus was narrowed to the long arm of chromosome 7, and the gene responsible was identified no more than 10 years ago [18]. The mutation was identified in the third exon of the gene which transcribes cationic trypsinogen (Protease-Serine-1 gene, PRSS-1), and it is the result of an arginine to histidine substitution (R122H “classic” mutation). Subsequently, other family members with a similar phenotype who tested negative for this mutation were found positive for other less frequent mutations, namely the N91I and the A16V mutation [19]. The suggested pathomechanism of hereditary pancreatitis is related to the block of intracellular trypsin autolysis which prevents pancreatic autodigestion; the PSSR-1 mutation eliminates the initial hydrolysis site, thus preventing the destruction of the trypsin prematurely activated in the pancreas and, in turn, leading to generalized zymogen activation, autodigestion and pancreatitis [20]. The median age of symptom onset of hereditary pancreatitis is 12 years of age with no difference between patients presenting different PSSR-1 mutations [19]; the median number of attacks was two per year, and nearly 30 % of these patients had surgery at a median age of 24 years (about 15 years after the onset of symptoms). Hereditary pancreatitis should be investigated in families with at least two first-degree relatives, or three or more second-degree relatives, over two or more generations, having acute relapsing pancreatitis and/or chronic pancreatitis for which there were no causative or precipitating factors. In the U.S., it is estimated that at least 1,000 individuals are affected by hereditary pancreatitis [20].

A strong association between mutations in a gene encoding the serine protease inhibitor-Kazal type 1 (SPINK1); also known as pancreatic secretory trypsin inhibitor (PSTI) and idiopathic pancreatitis has also been reported. The human gene has four exons and is located on chromosome 5 [21]. SPINK1 inhibits approximately 20 % of the total trypsin activity within the pancreas, thus providing an important defense against prematurely activated trypsinogen [22]. Whether an N34S mutation should be considered a causative factor of pancreatitis per se or simply a disease modifier is uncertain [23–25].

The most commonly inherited disease of the pancreas is cystic fibrosis, inherited as an autosomal recessive illness [26]. The cystic fibrosis transmembrane conductance regulator-gene (CFTR-gene) is located on chromosome 7q3.1, existing as a single copy in the human genome, and encoding a 170,000 molecular-weight glycoprotein. A deletion of three base pairs of the CFTR-gene, resulting in the loss of phenylalanine residue (ΔF508 mutation), has been shown to be responsible for the disease in approximately 70 % of patients [27, 28]. Many other mutations have been reported, and more than 800 disease-causing lesions have been identified in the CFTR-gene [29]. The suggested underlying pathogenetic mechanism involves a defect in the regulation of the apical membrane-chloride channels of epithelial cells, resulting in highly viscous secretions having an inability to maintain luminal hydration. From the clinical standpoint, cystic fibrosis is the only hereditary disease in which pancreatic involvement can be expressed by both exocrine insufficiency (without pancreatic inflammatory disease) and pancreatitis [30]. Symptoms of acute relapsing pancreatitis develop in approximately 2 % of patients with cystic fibrosis diagnosed on clinical grounds and they occur in adolescence or adulthood, but only in patients with pancreatic sufficiency.

Diagnosis

The diagnosis of acute pancreatitis still depends on clinical suspicion and requires confirmatory laboratory and imaging studies [3, 4, 6, 7]. The most common clinical symptoms and signs are abdominal pain in almost all patients, followed by vomiting and abdominal tenderness with abdominal distension [5]. Other less common clinical signs include fever, tachycardia, hypotension, jaundice and abdominal signs, such as guarding, rebound tenderness and decreased bowel sounds [5]. The determination of amylase and lipase levels remains the most commonly used laboratory tests. Although serum levels of lipase and amylase over three times the upper reference limit suggest pancreatitis, the level of elevation is not diagnostic. Both enzymes can be elevated in conditions unrelated to pancreatitis (e.g., salivary diseases, uremic syndrome, ketoacidosis, macroamylasemia, macrolipasemia), and both can be normal in the presence of imaging evidence of acute pancreatitis. CT images of the pancreas are useful not only in confirming the presence of acute inflammation of the pancreas, but also in identifying the complications of acute pancreatitis and in diagnosing a possible biliary origin of the disease. It is reasonable to avoid a CT scan early in the course of pancreatitis because the presence of necrosis requires up to 48 h to be visualized [31]. In the near future, findings similar to those obtained with a CT scan may be obtained using magnetic resonance (MR) [32]. An ultrasound examination can demonstrate the presence of gallstones, biliary sludge, dilated common and intrahepatic ducts, and choledochal cysts.

Outcome

As in adults, acute pancreatitis in children can be life-threatening. In children, death occurs in about 5 % of the cases ranging from 0 to 27 % of all pancreatitis cases [3, 6]. As reported in Table 3.1, the percentage of severe pancreatitis in children is about 15 %; this figure is similar to that reported in adult patients [33]. The early causes of death are shock and respiratory failure, whereas late life-threatening complications of pancreatitis are generally associated with infected pancreatic necrosis due to colonic bacteria translocation.

About one-fifth of children may experience recurrent attacks of acute pancreatitis [6, 34] ranging from 7.4 to 32.7 % and, in most cases (about 50 %), the etiology of the disease is unknown. This figure is similar to that reported in the adult population [35]; of course, the causes of recurrent acute pancreatitis in adults are quite different (about 60 % of adult patients are alcoholics whereas only 10 % of adults had unrecognized causes). In the era of genetic tests, it has been reported that mutations of CFTR, SPINK1, and PRSS1 genes can be found up to 40 % of children with recurrent acute pancreatitis [36].

Assessment of Severity

The clinical course and the outcome differ significantly between mild and severe cases; the physician must make a rapid assessment of the patient’s condition and evaluate the risk of a severe clinical course. Several scoring systems have been developed to assist the physician in this decision; in adults; a scoring system has been developed and validated in children [7] (Table 3.2). However, other authors demonstrated that this score was useful in excluding severe pancreatitis (positive predictive value 26 %, negative predictive value 96 %) in a retrospective study on 135 patients with acute pancreatitis [37]. In addition, it seems that clinicians caring for children with acute illness of the pancreas do not generally apply the multiple score systems in clinical practice [6]. The determination of a unique index of severity, such as C-reactive protein (CRP) determination may be an alternative tool; in fact, this marker of inflammation at a level greater than 150 mg/dL is able to distinguish the mild from the severe forms of childhood pancreatitis in a fashion similar to that found in adults [6]. Another possibility is to determine the IL-6 in the serum; this cytokine is able to detect the severity of acute pancreatitis in adults earlier than CRP [38].

Table 3.2 Clinical and laboratory criteria for identifying the severity in acute pancreatitis in children. This score is evaluated as the number of criteria satisfied; the presence of three or more criteria indicates a severe attack of acute pancreatitis
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Treatment

Objectives and Methods of Conservative Treatment

The primary objectives to be achieved in the treatment of acute pancreatitis are essentially: (1) pain control, (2) electrolyte support and energy intake, (3) removal of the causal agent, when possible, (4) attenuation of inflammatory and autolytic processes at the glandular level (“specific” therapy) and (5) prevention and eventual treatment of the local and systemic complications of the necrotizing forms. For mild forms of the disease, in most cases, the first three steps are sufficient for clinical resolution. In severe forms, the therapeutic engagement is more complex and patients may, with reasonable frequency, require periods of hospitalization in intensive care units. The therapeutic approach to severe acute pancreatitis is reported in Fig. 3.2.

Fig. 3.2
figure 2

Therapeutic approach to severe acute pancreatitis

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The control of pain must be swift and effective [39]. Supportive therapy is mandatory because it counterbalances the loss of fluids and hypercatabolism. The maintenance of cardiovascular, renal and respiratory parameters can, in many cases, prevent the onset of multisystem complications. Pancreatic hypoperfusion, secondary to the inadequate maintenance of plasma volume, is indeed able to trigger and increase the phenomena of pancreatic necrosis. Patients with mild forms, for which oral refeeding is expected within 4–6 days of hospitalization, do not need an aggressive nutritional approach [39]. In contrast, in the severe forms, total parenteral nutrition (TPN) must be used, which must take into account any metabolic imbalances (such as acidosis or alkalosis, hyperglycemia, hypocalcemia, hypokalemia and hypomagenesemia) and cardiovascular complications in its formulation [39]. Recently, enteral nutrition using a jejunal feeding tube has been used with good results in patients with severe acute pancreatitis instead of TPN. The pathophysiological assumption is that the TPN does not provide all essential nutrients (e.g. glutamine) and does not protect intestinal mucosa trophicity, and this phenomenon, in turn, can increase intestinal permeability to toxins and bacterial translocation.

The early removal of the causative agent makes it paramount to reach a sufficiently precise etiologic diagnosis and early intervention. The removal of a biliary obstruction using endoscopic techniques has now entered into the routine treatment of these patients [31]. The use of systemic antibiotics for the prevention of pancreatic infections is one of the cornerstones of the conservative treatment of the severe forms of acute pancreatitis. Several studies have shown a significant reduction in the incidence of pancreatic and extrapancreatic infections in patients treated with imipenem-cilastatin [40]; this measure does not reduce the mortality of patients with severe acute pancreatitis.

Objectives and Indication of Surgical Treatment

The infection of pancreatic necrosis in the course of acute pancreatitis is a very serious medical condition, and its presence is associated with a marked increase in risk of death; it develops in percentages varying from 15 to 70 % of all patients with acute necrotizing pancreatitis and accounts for more than 80 % of deaths from acute pancreatitis. The risk of infection increases with the extent of necrosis and the days after the initiation of acute pancreatitis, reaching a peak incidence (70 %) after 3 weeks [41]. In most cases, the infection is caused by Gram-negative bacteria of enteric origin, and about two-thirds of the infections are caused by a single microbiological agent. In some cases, fungi can be found [42]. From a clinical point of view, acute pancreatitis with sterile necrosis can be difficult to distinguish from a form with infected necrosis, because both can give fever, leukocytosis and abdominal pain. However, this distinction is very important since mortality in patients with infected necrosis who did not undergo early surgery is high. Computer tomography or ultrasound-guided percutaneous suction of the necrotic material and/or peripancreatic fluid collections, with a fresh microscopic examination and bacterial culture, is safe and accurate (sensitivity and specificity exceeding 95 %). It must be used, even repetitively, usually from the second week of illness, in patients whose clinical condition worsens or does not tend to improve, despite the removal of any causative agent and the implementation of a vigorous supportive treatment. Debridement is the surgical treatment of choice for infected necrosis and the only therapeutic doubt concerns which type of intervention to be performed (necrosectomy with drainage-washing or an open packing technique). Recently, other treatment options, such as percutaneous, endoscopic or minimally invasive surgery have been proposed [43–45]. These methods require highly experienced operators.

The treatment of patients with sterile pancreatic necrosis remains controversial and it should be reserved for selected cases, such as those patients in whom repeated attempts at oral re-feeding after 5–6 weeks of therapy are associated with abdominal pain, nausea, vomiting or the recurrence of pancreatitis. At this stage of the disease, however, necrosis is more demarcated and surgery is easier. In other cases, supportive care associated with prophylactic antibiotic treatment should be the primary treatment [46–50]. It is, therefore, very important that a cholecystectomy be carried out in due time (possibly during the same hospitalization for mild forms, usually at a distance of 3–4 weeks for severe forms) in the case of gallstones in order to prevent the recurrence of acute episodes [31].

Refeeding in the Mild Form of Acute Pancreatitis

The recommendation is to initiate refeeding when pain disappears, using a low-fat solid diet; in fact, in mild acute pancreatitis, immediate oral feeding is feasible and safe and may accelerate recovery without adverse gastrointestinal events [51]. There is also the need to know the exocrine pancreatic function in patients who have experienced an acute episode of pancreatitis in order to cure possible maldigestion [52].

Conclusion

The following points should be kept in mind in the case of acute pancreatitis: (1) in a child with unexplained abdominal pain, we must think about acute pancreatitis, (2) the severity and the etiology of the disease should be rapidly assessed, (3) the pain must be alleviated, and fluids and electrolytes should be administered immediately. After the acute pancreatitis is resolved, genetic tests should be carried out in cases of patients having a disease of unknown origin.