Approximately half the cases of acute pancreatitis in childhood are idiopathic. Trauma such as from bicycle handlebar injuries make up the largest proportion of identifiable causes. Biliary problems such as those associated with gallstones and anomalies of the biliary tract make up the next largest group. It is possible that hereditary pancreatitis is less common than represented because cases of hereditary pancreatitis are more likely to be reported than other forms of childhood pancreatitis. Examples of drugs causing pancreatitis (Slide 58) include valproic acid and sulfasalazine. As illustrated in the "other" group, many otherconditions can be associated with pancreatitis.
Hereditary pancreatitis should be suspected in every child with childhood pancreatitis, especially those that have a history of recurrent episodes of severe abdominal pain. The first attacks cannot be differentiated from idiopathic acute pancreatitis. The diagnosis should be suspected if pancreatic calcification is noted in the first few attacks. Approximately 82 kindreds with 375 separate cases of hereditary pancreatitis have been reported in the literature. Although hereditary pancreatitis follows an autosomal dominant pattern of inheritance, variable clinical penetrance may make this pattern difficult to elicit. A survey of family members may show an increased incidence of pancreatic carcinoma even in subjects who have never had pancreatitis. Although some kindreds have been described with aminoaciduria, most families do not demonstrate this feature. Management is similar to that of acute, recurrent, and chronic pancreatitis.
Pediatrics in Review
Pancreatitis in Childhood
Pancreatitis in children is a disease characterized by inflammation of the pancreas in the clinical setting of epigastric abdominal pain and usually is accompanied by elevated levels of pancreatic enzymes, amylase, and lipase. Pancreatitis can be categorized as acute, chronic, necrotic, hemorrhagic, and hereditary. The types are distinguished most frequently according to clinical and radiologic criteria; material obtained from the organ rarely is analyzed histologically.
Acute pancreatitis is a self-limited disorder causing nausea, vomiting, anorexia, abdominal pain, and marked elevations in enzymes. Bouts of acute pancreatitis may recur, but normal pancreatic function and morphology usually are restored between attacks. If the inflammatory process is progressive, morphologic changes may occur in the gland, leading to chronic pancreatitis, often with debilitating pain and possible irreversible loss of both exocrine and endocrine function. Protein ductal plugs may calcify in the gland, leading to chronic calcific pancreatitis, which indicates advanced disease. Relatively high mortality occurs in necrotizing hemorrhagic pancreatitis, where the inflamed gland can become infected secondarily with bacteria and sepsis can occur, often in association with subsequent multiorgan failure. Hereditary pancreatitis is an autosomal dominant condition that is characterized by recurrent attacks of pancreatitis, usually presenting during childhood within affected families.
It is difficult to estimate the true incidence and prevalence of pancreatitis in children because most of the literature reports individual cases or small clusters of patients. Although pancreatitis is not seen as commonly in children as in adults, it most likely is underdiagnosed and requires a high index of suspicion on the part of the clinician. Acute pancreatitis is believed to be the most common pancreatic disorder in children, with cystic fibrosis second in prevalence.
Although the majority of adult cases of acute pancreatitis can be attributed to either alcohol or gallstone disease, the causes of acute pancreatitis in childhood are more numerous and include trauma, infection, medications, anatomic variants, and systemic and metabolic disorders. Gallstone pancreatitis is relatively common in adolescent females. Despite the varied causes, the clinical characteristics of acute pancreatitis follow a similar pattern. The severity of the disease and long-term complications may differ, depending on the cause. The primary initiating event, whether traumatic, infectious, or metabolic, is damage to the pancreatic acinar cell by the premature activation of digestive enzymes within the cell. The damaged acinar cell then attracts inflammatory cells and activates platelets and the complement system, which leads to the release of cytokines (such as tumor necrosis factor-alpha, interleukin-1, nitric oxide, and platelet activating factor), free radicals, and other vasoactive substances. These substances damage the gland directly, causing pancreatic edema, ischemia, necrosis, and eventual loss of glandular tissue. Systemically, often within hours of the initial insult, fever, hypotension, tachycardia, hypoxia, and capillary leak syndrome may occur in severe cases. The direct links between these chains of events are not well understood, but current research is targeting this inflammatory cascade for therapy that may be beneficial in all types of pancreatitis, regardless of the inciting event.
The various etiologies of pancreatitis are too numerous to be discussed in detail for this review (table1), which is limited to some of the more common causes and those in which recent advances in research have been made. Numerous drugs have been reported to be associated with pancreatitis. However, most of them have a proposed and unproved pathophysiology and do not have an established causal relationship (Table 2).
Infections from a variety of organisms, including bacteria, viruses, and parasites, account for a significant number of cases of pancreatitis worldwide. The Escherichia coli strain that produces verotoxin and is associated with hemolytic-uremic syndrome, as well as varicella and influenza B that have been associated with Reye syndrome in the past, all have been implicated in causing acute pancreatitis in children. In developing areas, parasites such as Ascaris and Clonorchis may migrate into the biliary tree, causing obstructive jaundice, pancreatitis, and portal hypertension, and ultimately can lead to liver failure. In patients who have viral infections, such as human immunodeficiency virus, an elevated serum amylase level may be associated with parotid inflammation rather than pancreatitis. With such infections, determining serum amylase isoenzymes may be clinically useful.
Trauma is a significant and possibly the most common cause of acute pancreatitis in children in the United States. Blunt traumatic pancreatitis often results from motor vehicle and bicycle handlebar accidents. Findings on a physical examination that are consistent with trauma in the absence of a reliable history should raise the suspicion for child abuse. There usually are other associated intra-abdominal injuries in cases of significant blunt abdominal trauma. Duodenal hematoma or bowel rupture is not uncommon. In the absence of complete duct transection, nonoperative management is believed to be safe, and there usually are no long-term complications.
Congenital defects in the formation of the pancreas are rare, but can lead to chronic pancreatitis if not corrected. The most common anatomic variant, pancreatic divisum, occurs when the dorsal and ventral pancreatic ducts fail to fuse during a critical time in fetal development. As a result of this failure, pancreatic flow is directed primarily to the dorsal duct. This is believed to lead to relapsing pancreatitis, which eventually may require endoscopic or surgical treatment. However, some believe that pancreatic divisum is a normal anatomic variant and a rare cause of pancreatitis.
Cystic fibrosis, an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is thought to be the most common inherited disease involving the exocrine pancreas. CFTR is located on the apical membrane of the epithelial cells that line the pancreatic ducts, and it promotes dilution and alkalinization of the "juice" as it flows through the ducts. Up to 2% of individuals who have cystic fibrosis experience pancreatitis as a result of pancreatic ductal plugging due to mutant CFTR. There appears to be a strong correlation between specific CFTR mutations and idiopathic chronic pancreatitis, even in the absence of lung disease. Ongoing research is seeking to define the role of CFTR further in pancreatitis and other diseases of the pancreas.
In the United States, the most common cause of chronic relapsing pancreatitis in childhood is believed to be hereditary pancreatitis. The gene defects in the two types of hereditary pancreatitis, which were reported in 1996, may shed some light on the pathophysiology of the nonhereditary forms of acute and chronic pancreatitis. Clinically similar, both types are autosomal dominant, with 80% penetrance. The majority of affected patients report symptoms before the age of 15 years, many before the age of 5 years. Type I hereditary pancreatitis involves a mutation in the gene that codes for cationic trypsinogen on chromosome 7q35; type II hereditary pancreatitis involves a different mutation in the same gene. Both mutations are believed to allow trypsinogen to become activated to trypsin within the pancreas instead of within the duodenum. This, in turn, may lead to uncontrolled activation of the other pancreatic enzymes within the gland's acinar cells, leading to autodigestion, inflammation, and resultant pancreatitis. Attacks of acute pancreatitis are only intermittent, perhaps because this uncontrolled activation only occurs when trypsinogen exceeds the inhibitory capacity of the "secondary brake" of the pancreas, pancreatic secretory trypsin inhibitor. Affected patients are at increased risk for pancreatic pseudocysts, exocrine and endocrine failure, and pancreatic adenocarcinoma.
Pancreatitis has been a reported complication in children who have received heart, kidney, liver, pancreas, and bone marrow transplants. It can be life-threatening following liver transplantation and is associated with retransplantation, emergency transplantation, and infectious peritonitis. As with autoimmune and collagen-vascular diseases, it is difficult to distinguish the contribution that medications play in this scenario versus the transplant or primary disease process.
Signs and Symptoms
The classic symptoms of pancreatitis in children are abdominal pain, nausea, vomiting, and anorexia. The quality of the pain may be sharp and sudden or constant. It may be located in the epigastrium or right upper quadrant or even in the periumbilical area, back, or lower chest. Eating usually triggers a worsening of the pain and vomiting. The emesis may be bilious. A family history of pancreatitis should prompt the clinician to ask about symptoms of hereditary and systemic/metabolic disorders, such as diarrhea, vasculitis, joint pain, rashes, and pulmonary disease.
A careful physical examination may provide more clues for differentiating pancreatitis from other, more common causes of acute abdominal pain in the child. Fever, if present, is usually low grade, but tachycardia and hypotension may be present early in the course of the illness. The child may be icteric, with a distended abdomen, decreased bowel sounds, and diffuse or localized tenderness and guarding on palpation. He or she may experience some pain relief when the knees are drawn up to a flexed trunk. In the case of severe hemorrhagic or necrotizing disease, Grey Turner sign (blue discoloration of the flanks) or Cullen sign (blue discoloration around the umbilicus) may be noted. In advanced disease, ascites, a mass (pseudocyst), or pulmonary findings may be appreciated. The physician always should be alert to additional physical evidence of child abuse.
A complete blood count with differential count, chemistry panel, amylase, and lipase usually differentiate pancreatitis from other, more common causes of abdominal pain. Leukocytosis with bandemia, hemoconcentration, hyperglycemia, hypocalcemia, and elevated alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin are frequent findings. Hypoxemia with hypoalbuminemia, hypocalcemia, and azotemia with elevated glucose and lactate dehydrogenase levels reflect more progressive disease and hemorrhagic pancreatic damage.
Although it has a relatively low sensitivity and specificity (75% to 92% and 20% to 60%, respectively), the serum amylase level remains the test used most frequently to confirm acute pancreatitis. By making the cut-off three to six times the upper limit of normal, specificity increases for pancreatitis, but at the expense of sensitivity. In addition, as shown in (Table 3), hyperamylasemia may result from many diseases of nonpancreatic origin, and normal amylase levels may be seen in cases of pancreatitis. Measurement of the isoamylase levels to differentiate between enzymes of pancreatic and salivary origins is more discriminatory. Serum activity of amylase begins to increase 2 to 12 hours after the pancreatic insult and peaks at 12 to 72 hours after the onset of symptoms.
Serum lipase levels have a reported clinical sensitivity of 86% to 100% and clinical specificity of 50% to 99%. By increasing the cut-off level to greater than three times the upper limit of normal, sensitivity can by increased to 100% and specificity to 99%. Lipase levels remain elevated for a longer period of time in the plasma than do amylase levels, beginning to increase within 4 to 8 hours after symptoms, peaking at 24 hours, and decreasing over 8 to 14 days. It should be noted, however, that the degree of elevation of amylase and lipase in the plasma does not reflect the severity of the pancreatic disease. By using serum amylase and lipase determinations together, clinical sensitivity for the diagnosis of pancreatitis increases to 94%.
Plasma immunoreactive cationic trypsin, pancreatic elastase I, and phospholipase A2 are serum enzymes that show higher sensitivities than amylase and lipase and correlate with disease severity. Unfortunately, they are not readily available in most centers.
The diagnosis of chronic pancreatitis depends on the assessment of pancreatic function and clinical and radiographic findings. Noninvasive tests of pancreatic function reflect decreased enzymes in the blood or stool or increased amounts of malabsorbed food products. These tests include measuring serum pancreatic enzymes (amylase, lipase, isoamylase, and immunoreactive trypsinogen) and fecal assays for fat and pancreatic enzymes. However, due to the poor negative predictive value of these tests, chronic pancreatitis cannot be excluded confidently. These tests also may be falsely positive in the presence of intestinal bacterial overgrowth or other mucosal diseases of the small bowel. A recent study examining the usefulness of measuring fecal pancreatic elastase I versus the secretin-pancreozymin test in children who had cystic fibrosis and healthy controls reported a sensitivity of 100% and a specificity of 96% and may offer a valid noninvasive test to detect pancreatic insufficiency.
The "gold standard" for establishing pancreatic insufficiency involves direct testing of pancreatic function by administering intravenous cholecystokinin or secretin and measuring output of bicarbonate and pancreatic enzymes in pancreatic ductal secretions. If performed correctly, the sensitivity and specificity for this procedure range from 90% to 100% in the diagnosis of chronic pancreatitis. However, these tests require oroduodenal or endoscopic intubation, accurate placement of a duodenal catheter, and complete recovery of all duodenal secretions. Because these studies are difficult to perform and interpret, they usually are available only at tertiary centers.
Although ultrasonography is the radiologic study of choice in pancreatitis, a simple radiograph of the kidneys, ureters, and bladder (KUB) may suggest the diagnosis. Findings of ileus, with colonic dilatation, a sentinel loop of dilated small bowel, obscured psoas margins, or a radiolucent "halo" around the left kidney, are suggestive of the disease. In chronic pancreatitis, calcifications may be seen in the area of the pancreatic parenchyma or ductal system. Changes in pancreatic size, contour, and echotexture are appreciated best with ultrasonography, as is the presence of dilated ducts, pseudocysts, abscesses, ascites, and associated gallstone disease. Computed tomography often is used to help manage the complications of pancreatitis, such as providing guidance in the aspiration and drainage of an abscess, phlegmon, or pseudocyst or prior to surgical intervention.
Recurrent attacks of acute pancreatitis and chronic pancreatitis of unknown etiology require a detailed delineation of the pancreatic and biliary anatomy to rule out anatomic malformations, biliary strictures, and cholelithiasis. Cholangiopancreatography may be accomplished by endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) intraoperatively or via a percutaneous cholangiogram. ERCP is considered the study of choice to diagnose pancreas divisum and anomalous pancreaticobiliary duct junction. It has the added benefit of being a therapeutic modality, allowing sphincterotomy, stent placement, and stone removal, which can be performed at the time of diagnostic evaluation. These procedures should be undertaken at centers that have significant experience both in performing the studies and in managing childhood pancreatitis.
If an anatomic variant is suspected and ERCP is not possible, the next appropriate step is transduodenal exploration with intraoperative pancreatography. Surgical sphincteroplasty can be performed if minor or major papillae stenosis is found. MRCP has proven useful in determining the presence of pancreaticobiliary disease, the level of biliary obstruction, and the presence of malignancy and bile duct calculi. This procedure may prove useful in the patient who is unable to tolerate general anesthesia for ERCP or for an open laparotomy. Percutaneous cholangiography requires a skilled interventional radiologist and may be used when dilated bile ducts are present or through a biliary drain placed postoperatively (such as with postpancreatic debridement or postorthotopic liver transplant).
The treatment of pancreatitis is primarily supportive, providing adequate hydration, pain relief, and "pancreatic rest" by decreasing the cephalic, gastric, and intestinal phases of pancreatic secretion. In the case of severe pancreatitis, the child is made nil per os, and nasogastric suction may be necessary to manage persistent vomiting or ileus. Parenteral nutrition should be initiated if the patient is expected to be without enteral feedings for more than 3 days to prevent protein catabolism. Antibiotics are indicated when there are clinical signs of sepsis, necrotic pancreatitis, or multiorgan system failure. Histamine2 receptor antagonists may help prevent stress ulceration by reducing duodenal acidification.
It may be difficult to relieve pain completely, and opiates have been reported to worsen symptoms by increasing spasm of the sphincter of Oddi. Of all the pure opiate agonists, meperidine is the analgesic of choice by most clinicians for acute pancreatitis because it produces the least increase in enterobiliary pressure. We have used hydromorphone hydrochloride in many children who had severe acute pancreatitis, as well as in chronic pancreatitis, with excellent pain control. Chronic pancreatitis that leads to exocrine or endocrine insufficiency may require pancreatic enzyme replacement, insulin, or an elemental or low-fat diet to optimize nutritional status once enteral feedings are reinitiated.
The major cause of mortality in patients who have acute pancreatitis is septic complications, believed to arise from bacteria that have translocated from the small or large intestine via the mesenteric lymph nodes and lymphatics. This can lead to pancreatic abscess, infected pseudocyst, or pancreatic necrosis. These infections necessitate surgical intervention, but whether sterile necrosis requires operative management is still controversial. Evidence of infection within an area of necrosis can be obtained via fine-needle aspiration, with either ultrasonographic or CT guidance, for Gram stain and culture. The most common organisms recovered are Escherichia coli, Klebsiella sp, and other gram-negative enteric rods.
Antibiotics and intensive care unit management usually provide adequate support for the patient who has sterile necrosis, but persistent ileus, bowel perforation, portal vein thrombosis, and multisystem organ failure are indications for urgent surgical intervention. Infected pancreatic necrosis is an absolute surgical indication, requiring necrosectomy (surgical debridement). Debridement of the pancreatic and peripancreatic parenchyma is thought to stop the progression of the necrotizing process and resultant multiorgan failure. Debridement, rather than partial or total pancreatic resection, is preferred because it preserves the exocrine and endocrine function of the gland. Multiple reoperations or continuous lavage with catheters left in the retroperitoneum may be necessary. Complications after necrosectomy include sepsis, hemorrhage, wound infection, and fistulas of the intestine, pancreas, and biliary system.
The chances of surviving an acute attack of severe pancreatitis are related to associated complications, which may affect virtually all organ systems, including pulmonary, cardiovascular, hematologic, gastrointestinal, renal, metabolic, and central nervous system (Table 4). Most cases of acute pancreatitis in children, which are uncomplicated and rarely progress to chronic pancreatitis, persist for only 5 to 7 days. The primary morbidity and mortality arise from septic shock, adult respiratory distress syndrome and respiratory failure, renal failure, and inflammatory masses of the pancreas. Criteria to predict the outcome from acute pancreatitis have been developed for adults (APACHE-II, Ranson), but they may not be as reliable in young children. Studies have shown a mortality rate of 5% to 17.5% from an initially mild presentation of acute pancreatitis and 80% to 100% from hemorrhagic pancreatitis or severe multisystem disorders. Exocrine and endocrine insufficiency are common after necrotizing pancreatitis, and the degree of dysfunction correlates with the extent of parenchymal necrosis.
The general clinician needs to have a high index of suspicion for pancreatitis when a child presents with the nonspecific symptoms of nausea, vomiting, and localized upper abdominal pain. A thorough history and physical examination that emphasizes recent infections, medications used, recent trauma, and underlying medical conditions may make the diagnosis clearer. Using serum enzyme testing alone (amylase and lipase) to diagnose both acute and chronic pancreatitis remains a challenge because although clinical sensitivity has improved, clinical specificity remains suboptimal. Ultrasonography is the first radiographic study of choice in the child who has pancreatitis to look for evidence of congenital anomalies, biliary ductal dilatation, cholelithiasis, and infection. More detailed imaging of the pancreatic and biliary system should be performed in recurrent acute pancreatitis and chronic pancreatitis. Unlike the adult disease, in which the majority of cases are due to alcoholism or gallstone disease, pancreatitis in the child may be due to infection, trauma, abnormal anatomy, or hereditary or systemic diseases and the medications used to treat them. Nearly 25% of cases of childhood pancreatitis may remain idiopathic. Gallstone pancreatitis is not infrequent in teenagers. A family history of the disease should prompt the clinician to look for evidence of inherited biochemical or anatomic abnormalities.
Treatment is basically supportive in an effort to decrease the cephalic, gastric, and intestinal phases of pancreatic stimulation. Despite the varied etiologies, the course of acute pancreatitis in the child usually is limited, with complications being rare. However, the complications of this disease can involve virtually every organ system, and major morbidity and mortality can result despite aggressive supportive care. For severe cases or when complications occur, ERCP and pancreatic surgical and nonoperative radiologic intervention should be undertaken at a center that has significant expertise in caring for children who have pancreatic disorders.
Quiz also available online at www.pedsinreview.org.
6. Hereditary pancreatitis is characterized by recurrent attacks of pancreatitis beginning in childhood. Inheritance is best described as:
7. A 14-year-old girl who has severe bulimia presents with abdominal pain with guarding, distention, decreased bowel sounds, and low-grade fever. As part of your evaluation, you obtain a serum amylase activity level, which is three times the upper limit of normal for your laboratory. Your next step in interpreting this result would be to measure:
8. The result of your further laboratory evaluation increases your suspicion of pancreatitis. The radiologic study of choice is:
9. Among the following, the surgical treatment of choice for infected pancreatic necrosis is:
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