Clinical Manifestations

More than 80% of children with acute pancreatitis complain of abdominal pain. However, only 30% of pediatric patients have epigastric pain, as usually described by adults. In children, other sites of focal tenderness or diffuse pain include the right upper quadrant of the abdomen, the periumbilical area, the entire abdomen, and, less commonly, the right lower quadrant of the abdomen. The onset of pain usually is rapid and increases to a maximal intensity in a few hours, but occasionally the onset may be slow and gradual. Most often the pain is sharp and excruciating. Only one-third of children complain of pain that radiates to other areas, including the back, lower part of the abdomen, upper abdominal quadrants, and anterior chest wall. In school-aged children, the pain often intensifies after meals.

Two-thirds of children with acute pancreatitis have vomiting. Children younger than 5 years occasionally experience vomiting without abdominal tenderness. Fever is present in only 30% of children with pancreatitis, but temperatures greater than 38.5°C (101.3°F) are observed occasionally. Children may present with only the symptom of cough, and pleural effusions are found on radiography.

On physical examination, children are classically found lying quietly on their sides with their knees flexed. They usually have epigastric tenderness to palpation and decreased or absent bowel sounds. Abdominal distention is found in 30% of children with pancreatitis and occurs more commonly in preschool-aged children. Rebound tenderness, guarding of the epigastrium, jaundice, an abdominal mass, or ascites occasionally is detected. Rarely ecchymoses of the flanks (Grey Turner sign) or the umbilical area (Cullen sign) can be identified but usually only when life-threatening hemorrhagic pancreatitis is present. In severe pancreatitis, children may present with evidence of shock and multiple-organ failure.

Chronic pancreatitis occurs when irreversible damage in the pancreatic architecture causes abnormalities in the function of the pancreas. Children with chronic pancreatitis often have lengthy or recurrent bouts of abdominal pain and vomiting.

Laboratory Diagnosis

The single most common useful laboratory test for the clinical diagnosis of pancreatitis in children is measurement of the serum amylase concentration, but the level correlates poorly with the severity of the disease. In most studies of childhood pancreatitis, the diagnosis is confirmed when the serum amylase level is greater than three times the normal level for the particular laboratory completing the test. The serum concentration rises quickly within hours after symptoms develop. High serum amylase concentrations can be observed, however, in numerous other illnesses, including acute cholecystitis, intestinal obstruction, perforations of abdominal organs, appendicitis, salpingitis, ruptured ectopic pregnancy, and salivary gland disease. The serum amylase concentration can return to normal in 24 to 72 hours after the onset of symptoms; thus the diagnosis of pancreatitis can be missed. In this situation, the urine amylase concentration can remain elevated for at least 1 week.

Serum amylase concentrations occasionally are not elevated during the course of pancreatitis in children. Marked hyperlipidemia may interfere with the laboratory measurement of amylase. Serum lipase is useful in these situations; however, high serum concentrations often are not detected until 24 hours after the beginning of the illness. Because lipase is produced only in the pancreas and intestinal cells, measurement of its serum concentration helps distinguish children with high serum amylase concentrations of pancreatic as opposed to salivary origin. Some children with pancreatitis have high amylase levels without an elevation of serum lipase. Laboratory findings in children with severe and/or necrotizing pancreatitis may include leukocytosis with increased immature polymorphonuclear leukocytes, an elevated erythrocyte sedimentation rate, and elevated C-reactive protein level. In children with fulminant hemorrhagic pancreatitis, anemia develops quickly. Other associated findings include hyperglycemia, hypertriglyceridemia, hypoalbuminemia, and hypocalcemia. Scoring systems for children have been devised to predict severe pancreatitis, but these are extrapolated from adult studies or are difficult to use in clinical practice. Procalcitonin or d -dimer plasma levels may be useful in predicting severe pancreatitis and later complications. Elevated aminotransferase and alkaline phosphatase levels generally are observed only when the episode of pancreatitis is caused by biliary obstruction, such as in gallstone-related disease.

The radiographic features of childhood pancreatitis also are nonspecific. Radiographs of the abdomen may show localized ileus of the jejunum in the midepigastric or left upper quadrant region adjacent to the pancreas (sentinel loop), a distended transverse colon without visualization of the descending colon because of adjacent pancreatic inflammation (colon cutoff sign), duodenal distention with air-fluid levels, or loss of the left psoas shadow. Occasionally chest radiography reveals an elevated left hemidiaphragm or pleural effusion.

The ability to diagnose pancreatitis in children has been improved greatly by ultrasonography. The echodensity of the pancreas is normally equal to or greater than that of the left lobe of the liver. During acute pancreatitis, edema causes the gland to enlarge and become less dense than the liver. These two findings can aid in establishing the diagnosis of pancreatitis, and complications such as abscesses and pseudocysts can be identified. Also, ultrasonography may delineate dilations of the pancreatic ducts due to obstruction or ductal stones. Visualization of the pancreas by ultrasonography may be obscured because of overlying bowel gas. In such cases, computed tomography (CT) is useful in detecting pancreatic size and density.

CT of the pancreas should be performed in complicated cases of pancreatitis after a few days of treatment to determine the severity of disease and extent of pancreatic necrosis. It is especially useful when surgery is being considered for drainage of abscesses and pseudocysts.

Endoscopic retrograde cholangiopancreatography (ERCP) is used in children with pancreatitis to treat gallstones, strictures, or Ascaris infection. Because of ongoing improvement in image quality, magnetic resonance cholangiopancreatography (MRCP) is being increasingly used as a noninvasive technique for evaluating children with chronic or recurrent pancreatitis, with results similar to those from ERCP.

Causes

A cause for childhood pancreatitis can be determined in more than 90% of cases if diagnostic evaluation is thorough, especially in children younger than 6 years. The frequency of each specific cause depends on the patient population of the particular medical center. The most common noninfectious causes of pancreatitis in children include trauma, medications, obstructive diseases, vasculitis, autoimmune diseases, and genetic and metabolic diseases.

Physicians with expertise in the management of infectious diseases are becoming more aware of drug-induced pancreatitis because many antimicrobial agents can cause pancreatic inflammation. Pentamidine isethionate has been used in the treatment of Pneumocystis jejuni pneumonia, African trypanosomiasis, and leishmaniasis. It may cause hypoglycemia because of toxicity to pancreatic islet cells and is associated with severe and occasionally fatal episodes of pancreatitis. In children, aerosolized pentamidine prophylaxis for P. jejuni pneumonia also has been associated with severe cases of pancreatitis in patients with acquired immunodeficiency syndrome (AIDS). Similarly, pentavalent antimonial agents such as sodium stibogluconate and meglumine antimonite, used for the treatment of visceral leishmaniasis, can induce pancreatic inflammation.

Sulfonamides, including trimethoprim-sulfamethoxazole, have been implicated occasionally as a cause of acute pancreatitis in adults. Symptoms have recurred when patients have been reexposed to the medication. The abdominal pain often is accompanied by a hypersensitivity-type rash. Tetracycline- and doxycycline-induced pancreatitis have been described in children with and without overt liver disease. In addition, clarithromycin, erythromycin, rifampin, roxithromycin, linezolid, dapsone, nitrofurantoin, isoniazid, tigecycline, and metronidazole have been added to the list of agents that can cause pancreatitis in previously healthy individuals when given in routine doses or when high amounts are consumed. Although uncommonly used in children, quinolone antibiotics, such as gatifloxacin and ciprofloxacin, have been associated with hepatotoxicity and acute pancreatitis. An adolescent who was receiving ceftriaxone also developed pancreatitis secondary to obstruction of the biliary tract from gallstones.

Pancreatitis has been a major dose-limiting toxic effect of the human immunodeficiency virus (HIV)-inhibiting nucleoside analogue reverse transcriptase inhibitor (NRTI) class of medications because of mitochondrial toxicity, especially dideoxyinosine andstavudine. Most episodes of pancreatitis associated with dideoxyinosine occur when the dose is 360 mg/m ² per day or greater, and usually the pancreatic inflammation resolves when the medication is discontinued. Concomitant administration of pentamidine or another NRTI, such as ribavirin, used in the treatment of hepatitis C infection may increase the risk for developing pancreatitis. In pediatric patients with AIDS, serum amylase concentrations often are elevated in patients without pancreatic symptoms, whereas children with pancreatitis can have normal serum amylase concentrations. The serum lipase concentration is useful in evaluating HIV-infected children for possible pancreatic inflammation. Increased liver aminotransferase or lipase concentrations before the administration of an NRTI may be helpful in predicting those children in whom pancreatitis will develop. In all children with symptoms consistent with pancreatitis, NRTIs should be withheld pending the results of a lipase assay, and they should be discontinued if the concentration is elevated. Similarly, they should be discontinued for 1 week after treatment with pentamidine. Because of increased awareness of NRTI toxicity, the incidence rate of pancreatitis in HIV-infected children in the highly active antiretroviral therapy (HAART) era appears to be decreasing.

Interferon-α, which is used in the treatment of chronic hepatitis, has been associated with the development of pancreatitis. The antifungal agents liposomal amphotericin B, micafungin, and itraconazole rarely cause pancreatic toxicity.

Infectious Causes

Infections caused by various microorganisms have been shown by culture, histologic examination, or antibody titer rise during the course of acute pancreatitis ( Box 52.1 ). A true causal relationship usually is not shown. Although not all of the following infectious agents have been shown to be associated with childhood pancreatitis, they must be considered as possible etiologic agents because adult patients with infectious pancreatitis have been described. Compared with previous decades, infectious agents are being encountered less as a cause of acute pancreatitis, most likely because of mumps vaccination.

Parasite Infestations and Infections

Ascaris lumbricoides can migrate in the intestines to the ampulla of Vater and subsequently to the pancreatic duct or common bile duct. Obstruction of the biliary or pancreatic duct can cause acute pancreatitis. Ascariasis is diagnosed when adult roundworms are identified in the duodenum by radiographs of the upper gastrointestinal tract ( Fig. 52.1 ) or more commonly by ultrasonography or ERCP. Often a history of seeing worms in the feces can be elicited. Other roundworms including hookworms and Strongyloides stercoralis can cause obstruction and acute pancreatitis. The flukes Clonorchis sinensis and Fasciola hepatica and the cestode Taenia saginata similarly can migrate to the pancreatic and biliary drainage systems and cause pancreatitis. Rarely hepatic hydatid cysts caused by Echinococcus can obstruct biliary drainage and cause pancreatic inflammation. Wuchereria bancrofti occasionally has been found to cause chronic pancreatitis. Parasitic infestations should be considered as a cause of pancreatitis, particularly in immigrant children and patients who have traveled to developing nations.

An ascaris close to the ampulla of Vater, with the body and tail lying in the second and third parts of the duodenum. The patient was a 9-year-old girl with acute pancreatitis.

The protozoan Cryptosporidium parvum has been identified in the bile of an AIDS patient with elevated serum amylase levels and right upper quadrant abdominal pain. ERCP demonstrated biliary and pancreatic ductal disease, and no other opportunistic pathogens were isolated. Cryptosporidia also have been observed in the interlobular pancreatic ducts of experimentally infected immunocompromised mice. Whether cryptosporidial infection causes pancreatitis in immunocompetent patients is unknown; however, a previously healthy adolescent developed pancreatitis after having cryptosporidial diarrhea. Toxoplasma gondii cysts have been found in the postmortem pancreatic tissue of patients with AIDS. Rarely pancreatitis occurs during acute episodes of malaria. Other systemic manifestations of malaria that often are present include high fever, hepatitis, intestinal malabsorption, encephalitis, and pulmonary insufficiency.

Pathogenesis

When trypsinogen is activated prematurely to trypsin within the pancreatic acinar cells, autodigestion occurs within the pancreas, causing edema. The microcirculation may be compromised, leading to ischemia, hemorrhage, or necrosis. An inflammatory response develops, which may be mild, as occurs in episodes of infectious pancreatitis, or may be more severe with hemorrhagic necrosis. Major mediators of an intense immune response include chemoattractant chemokines and their upregulated receptors; cytokines including tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-33; and platelet-activating factor. Mast cells may also play an active role in the proinflammatory process. If an imbalance of the proinflammatory response occurs within the pancreas, a systemic inflammatory response including shock may occur, leading to high morbidity and mortality. Also sepsis may occur because of extensive necrotic tissue within the pancreas and translocation of microorganisms from the intestines.

Treatment

Despite increasing recognition of cases of childhood pancreatitis, no major pharmacologic advances have been made in the treatment of the disease since the mid-1970s. Animal data have shown that medications such as glucagon, aprotinin, 5-fluorouracil, somatostatin, probiotics, and vitamin-based antioxidants may be useful in the treatment of pancreatitis, but human benefit is lacking. Clinical trials in adults and children using high-dose octreotide or gabexate mesilate have shown no or only modest benefit.

The continuing main objectives of treatment are to relieve abdominal pain and treat aggressively systemic manifestations, such as shock, electrolyte abnormalities, and anemia. Meperidine continues to be the medication most commonly used for controlling pain. Meta-analyses in adults and series of pediatric patients have shown that feeding with a low-fat elemental diet decreases the complication rate of patients with acute pancreatitis and now is considered the treatment of choice over total parenteral nutrition. Intravenous fluids and colloids are used during the acute episode to maintain intravascular volume. During the entire course of acute pancreatitis, the hematologic and biochemical parameters of the child must be monitored closely.

If the episode of pancreatitis is drug induced, use of the medication should be curtailed immediately. Often the symptoms recur if the medication is restarted. Pancreatitis caused by M. pneumoniae or that involve bacteria should be treated with proper antimicrobial agents. Obstructions to pancreatic flow (e.g., gallstones, roundworms, congenital abnormalities) may have to be excised or altered either by surgery or endoscopy. Overall the mortality rate of acute pancreatitis in children today is 5%, with a mean duration of hospital stay at 13 days.

Complications

During the acute episode of pancreatitis, the systemic inflammatory response syndrome may develop, leading to renal, hematologic, central nervous system, pulmonary, and cardiovascular complications. In 12% of children with pancreatitis, an inflammatory mass develops in the first weeks after the onset of illness; however, these masses more commonly occur after trauma. Continued or increasing abdominal pain, nausea, or vomiting often accompanies the development of a phlegmon, abscess, or pseudocyst. An inflammatory phlegmon usually develops into a thin-walled pseudocyst of the lesser sac but may become secondarily infected and induce the formation of an abscess. Patients in whom an inflammatory mass develops must be monitored closely with frequent physical examinations and serial CT studies. In children with pseudocysts, acute abdominal pain accompanied by hypotension often signifies bleeding into the pseudocyst or rupture of the pseudocyst into the peritoneum. Slowly leaking pseudocysts may cause pancreatic ascites. Pseudocysts should be treated conservatively but have to be resected surgically, drained externally, or drained by endoscopy when complications occur. Approximately 77% of pseudocysts in children resolve spontaneously and require no surgical intervention.

The development of fever and leukocytosis during the course of pancreatitis should suggest an infected pseudocyst, pancreatic abscess, or sepsis. In adults, infectious complications account for 80% of deaths associated with acute pancreatitis. Isolates from pancreatic abscesses and necrotic pancreatic tissue have yielded intestinal flora, including anaerobes, in more than 90% of cases, but Candida spp. are being isolated more frequently in many medical centers. Candida skin colonization appears to best predict subsequent pancreatic tissue infection in critically ill patients. Rarely Streptococcus pneumoniae can be isolated from infected pancreatic tissues of adults with chronic pancreatitis. Carbapenems, such as imipenem and meropenem, are used commonly to treat adult patients with suppurative complications of pancreatitis because these antibiotics penetrate well into pancreatic tissues and have activity against intestinal flora. Performing percutaneous catheter drainage under CT guidance may reduce the mortality rate associated with treating pancreatic abscesses. Rarely fistulas from pseudocysts or abscesses to other abdominal organs may develop.

The role of prophylactic antibiotics in preventing the suppurative complications of acute pancreatitis remains controversial despite three decades of debate. Most recent meta-analyses on the subject conclude that prophylactic antibiotics do not prevent pancreatic necrotic tissue from being infected and do not prevent death, although a poorly powered 2010 Cochrane review suggests that imipenem may reduce the number of pancreatic infections. Infections, when they do occur after the administration of prophylactic antimicrobial agents, often are caused by multiresistant bacteria or by fungi.

Osteolytic lesions resembling osteomyelitis may develop weeks to months after an acute episode of pancreatitis. Elevated systemic levels of lipase activity possibly may cause intramedullary fat necrosis in the bone. Usually the lesions are asymptomatic and resolve spontaneously without therapy.