Chapter 417. Disorders of the Exocrine Pancreas

In the fourth week of gestation, the human pancreas develops as two outpouchings of the duodenal endoderm (Figure 381-3 and eFig. 417.1).1-3 The larger dorsal bud develops into the tail, body, and a portion of the head of the pancreas. The ventral bud fuses with the dorsal bud at about the 17th week of gestation to create the remainder of the head of the pancreas and the uncinate process. Each bud possesses its own ductal system; variations in fusion, which occurs in 15% of the population, lead to developmental anomalies. The dorsal duct forms the distal portion of the duct of Wirsung and the ventral portion forms the accessory duct of Santorini, which empties independently in about 15% of the population. Defective fusion of the two pancreatic primordia leads to a number of anatomic anomalies of the pancreatic ductal system (see also Chapter 381). Anomalies in this developmental process can have clinical implications.

Pancreas Divisum

Pancreatic divisum, which arises from incomplete fusion of the dorsal and ventral pancreatic ductal systems, occurs in 5% of the population.4,5 In pancreas divisum the major portion of the gland is drained by the minor duct of Santorini. When there is partial obstruction, recurrent pancreatitis may occur. Pancreatic divisum is diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) or by magnetic resonance cholangiopancreatography (MRCP). Endotherapy is the treatment of choice.

Common Pancreaticobiliary Junction

The presence of a common channel, with the pancreaticobiliary junction outside the duodenal wall, is associated with pancreatitis and implicated in the pathogenesis of choledochal cysts. The diagnosis can now be made noninvasively by magnetic resonance cholangiopancreatography.

Annular Pancreas

Annular pancreas, which arises from incomplete rotation of the ventral bud, can produce symptoms at any age. Presentation in infancy usually is characterized by high obstruction following polyhydramnios in utero. A “double bubble” appearance on plain-film abdominal radiographs is typically seen (see Chapter 389). In older children, partial obstruction may give rise to recurrent vomiting. The treatment of choice is duodenojejunostomy. Division of the pancreatic ring is not attempted, because a duodenal diaphragm or duodenal stenosis frequently accompanies annular pancreas. Annular pancreas may be associated with Down syndrome, intestinal atresia, imperforate anus, pancreatitis, and malrotation. Genetic causes of annular pancreas and other pancreatic disorders are found in Table 417-1.

Ectopic Pancreatic Tissue

Ectopic pancreatic tissue, lacking any continuity with the main body of the pancreas, occurs in 3% of the population. Most (70%) pancreatic ectopia are found in the upper gastrointestinal tract. On endoscopy they are irregular, umbilicated nodules 2 to 4 mm in diameter (pancreatic rest). In most instances, this anomaly is an incidental finding, but it rarely may cause pain, gastrointestinal (GI) bleeding, or obstruction.

Complete Agenesis of the Pancreas

Complete agenesis of the pancreas is rare and usually results in severe intrauterine growth retardation and death shortly after birth. Varying degrees of pancreatic hypoplasia, resulting from defects in embryonic development occur. Clinical manifestations vary according to the degree of loss of the exocrine and endocrine pancreatic tissue; there may be no symptoms or variable effects of endocrine and exocrine deficiency.

The acinus is the functional unit of the exocrine pancreas. Acinar cells are arrayed in a semicircle around a lumen. Ducts that drain the acini are lined by centroacinar and ductular cells. This arrangement allows the secretions of the various cell types to mix. The acinar cell synthesizes, stores, and secretes more than 20 enzymes (see Chapter 381 and eTable 381.1). These enzymes are stored in zymogen granules, some in inactive forms. The stimuli for exocrine pancreatic secretion are neural and hormonal. Acetylcholine mediates the cephalic phase; cholecystokinin (CCK) mediates the intestinal phase. CCK is released from the duodenal mucosa by luminal amino acids and fatty acids. Feedback regulation of pancreatic secretion is mediated by pancreatic proteases in the duodenum. Secretion of CCK is inhibited by the digestion of a trypsin-sensitive, CCK-releasing peptide released in the lumen of the small intestine or by a monitor peptide released in pancreatic fluid. Centroacinar and duct cells secrete water and bicarbonate. Bicarbonate secretion is under feedback control and is regulated by duodenal intraluminal pH. The stimulus for bicarbonate production is secretin in concert with CCK. Secretin cells are abundant in the duodenum.

Although normal pancreatic function is required for digestion, maldigestion occurs only after considerable reduction in pancreatic function; lipase and colipase secretion must be decreased by 90% to 98% before fat maldigestion occurs.

A variety of tests have been developed for the evaluation of exocrine pancreatic function, however all clinically available tests have one or more major deficiencies. Direct tests assess the secretory capacity of the pancreas, by collecting secreted enzymes from the duodenal lumen, by duodenal tube or endoscope, following stimulation of pancreatic secretion with intravenously administered exogenous hormones, cholecystokinin and/or secretin or by a test meal.6,7 Direct testing is the most sensitive method but is invasive, difficult to perform, not standardized and available only at specialized centers. Indirect tests are insensitive and nonspecific. Those that test absorption (eg, stool microscopy, fecal fat) do not differentiate between intestinal and pancreatic disease. Fat absorption is best determined by quantifying fat intake and measuring fecal fat losses over 72 hours. In normal individuals, fat losses are less than 7% of intake (< 15% during infancy). Fecal elastase highly correlates with direct tests of pancreatic function and fat absorption.8Breath tests are based on the principle that metabolites of digestion may be exhaled during respiration. They utilize a variety of ingested substrates including starch and food enriched with 13CO2. Starch is dependent on pancreatic amylase for digestion. In the presence of pancreatic insufficiency, undigested starch is broken down by colonic bacteria, releasing hydrogen, which is absorbed and exhaled in the breath. Breath tests, for pancreatic function, are not widely used or standardized for use in children. The currently available blood tests are not useful for the diagnosis or monitoring of exocrine pancreatic function. Specific serum assays such as pancreatic isoamylase and immunoreactive trypsinogen (IRT) can be helpful in the diagnosis of cystic fibrosis by newborn screening (high IRT) or Shwachman syndrome (low IRT, low isoamylase), but are not widely available.

The exocrine pancreas is functionally immature at birth. Although protease function is adequate, lipase and amylase secretion in the infant approximates 5% to 10% of adult values. Pancreatic immaturity does not appear to be of major clinical importance, since there are alternative mechanisms of fat digestion (breast milk and gastric lipase) and carbohydrate digestion (mucosal glucoamylase and salivary amylase). Pancreatic dysfunction can be hereditary or acquired.9

Congenital Exocrine Pancreatic Dysfunction

Cystic Fibrosis (CF)

Cystic fibrosis (CF), the most common cause of disturbed pancreatic function among children, is discussed elsewhere (Chapter 514). Approximately 85% of patients have pancreatic insufficiency. Regardless of their pancreatic status, all patients have impaired pancreatic fluid secretion. Patients with CF and pancreatic sufficiency typically experience milder symptoms and have superior survival than those with pancreatic insufficiency. Pancreatic function can be related to specific mutations. For example, patients homozygous for δF508 have a high likelihood of having pancreatic insufficiency. Treatment of the pancreatic insufficiency leads to improvement in absorption, better growth, and normalized stools. Pancreatic function can be monitored in children with CF with serial measurements of fecal elastase. Children with pancreatic sufficiency are at risk for the development of recurrent or chronic pancreatitis. Certain mutations in the CF gene are associated pancreatic sufficiency, which appears to place the patient at increased risk for episodes of pancreatitis and chronic pancreatitis.10

The Schwachman Diamond Syndrome (SDS)

Schwachman Diamond syndrome (SDS) is the second most common cause of exocrine pancreatic dysfunction in childhood (see also Chapter 432).11 Clinical findings include malabsorption; short stature with normal linear growth velocity; skeletal changes, including thoracic dystrophy, clinodactyly, and metaphyseal dysplasia; bone marrow changes, including neutropenia (intermittent or persistent), which is virtually universal; and, less commonly, anemia, thrombocytopenia, and pancytopenia. Almost a third of patients, predominantly boys, develop myeloproliferative malignancies. Recurrent infections, due to neutropenia and neutrophil dysfunction can result in life threatening bacterial infections. Pancreatic dysfunction usually is less severe than in cystic fibrosis. Most patients present with signs and symptoms of malabsorption. The pancreatic lesion is that of acinar cell hypoplasia with intact function of the pancreatic ducts.

Johanson-Blizzard Syndrome

Johanson-Blizzard syndrome is a rare cause of pancreatic acinar hypoplasia which includes agenesis of the alae nasi, hair anomalies, deafness, hypothyroidism, genitourinary defects, and delayed development (Table 417-1).12 Absence of bone marrow and skeletal abnormalities differentiates it from SDS.

Pearson Pancreatic and Bone Marrow Syndrome

Pearson syndrome is a rare condition, associated with macrocytic anemia with varying degrees of neutropenia and thrombocytopenia.3 Erythroid and myeloid precursors contain peculiar vacuolization and hemosiderosis. Both acinar and ductal functions are decreased. Unlike Schwachman Diamond syndrome, there is pancreatic cell atrophy with fibrosis.

Isolated Enzyme Deficiencies

Rare isolated deficiencies of trypsinogen, lipase, colipase, and combined colipase-lipase have been reported but are poorly documented. Patients with enterokinase deficiency may appear to have pancreatic insufficiency because of symptoms of malnutrition, diarrhea, protein malabsorption, and hypoproteinemia.

Acquired Pancreatic Exocrine Dysfunction

Exocrine pancreatic disturbance may result from enteropathy, including celiac disease and postinfectious enteropathy, chronic pancreatitis, or surgical excision. Enteropathy may cause pancreatic insufficiency due to a lack of endocrine stimulation of the exocrine pancreas. Chronic pancreatitis causes pancreatic insufficiency because of progressive accumulated damage. Surgical excision may result in pancreatic insufficiency, but more than 95% of the pancreas must be excised before pancreatic insufficiency occurs. Excision may be required for hyperinsulinemic hypoglycemia of infancy, pancreatic tumors, chronic pancreatitis, or following severe trauma to the pancreas.

Management of Pancreatic Insufficiency

Treatment of pancreatic exocrine insufficiency is with pancreatic enzymes given with meals (see Chapter 514). Pancreatic enzymes, particularly lipase, are rapidly denatured by gastric acid and pepsin. Since pancreatic bicarbonate output is often reduced, low intestinal pH also reduces enzyme activity. Microencapsulated, pH-resistant enzyme preparations now available provide protection from the acidic environment of the stomach. Dissolution of the protective coating occurs only when microspheres are exposed to a pH above 5.5 to 6.0. Therapy is improved in some patients by inhibiting gastric acid secretion, thereby increasing duodenal pH. Daily requirements of enzymes vary considerably from patient to patient. Most patients require lipase, 1000 to 2000 IU/kg/meal. Despite pancreatic enzyme supplementation, some patients have persistent fat malabsorption, requiring supplemental fat soluble vitamins. Enteric-coated preparations given in excessive quantities (⩾ 5000 IU/kg/dose) to children with cystic fibrosis have been implicated as a cause of colonic fibrosis and stricture formation.

Acute pancreatitis is now recognized to be more frequent in childhood than was previously believed. Major North American Children’s Hospitals report more than 50 cases per year.13 Following mechanical, biochemical, or inflammatory damage, an autodigestive process is induced by activation of Lysolecithin and phospholipase, both extremely toxic, are activated. Active enzymes are released locally and systemically. Following an insult, release of cytokines and subsequent depletion of antioxidants leads to pancreatitis and the further activation of pancreatic proenzymes. In severe attacks, circulatory shock as well as renal and pulmonary failure occurs. Acute pancreatitis may occur in a single episode or recur. In milder forms, there is considerable interstitial edema, but in severe cases, there are extensive peri- and intrapancreatic fat necrosis, parenchymal necrosis, and hemorrhage. Animal models suggest that vascular dysfunction may play a major role in determining the severity of an episode of acute pancreatitis.

Pathophysiology

The most common causes of pancreatitis include trauma, systemic disease, choledocholithiasis and drugs, particularly valproic acid, mercaptopurines and L-aspariginase (Table 417-2).13,14 Pancreatitis is idiopathic in 8% to 25% of cases. Traumatic cases commonly are associated with blunt abdominal injury. With the advent of endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) congenital and acquired anomalies of the pancreaticobiliary ducts are more frequently identified.

In children under 3 years of age causes of acute pancreatitis are similar but an association with multisystem disease (34%), hemolytic uremic syndrome and systemic infection (18%) is more common, whereas biliary disease (10%) and trauma (10%) are less common.15

Clinical Features and Diagnostic Evaluation

Clinical findings may include severe abdominal pain, nausea and vomiting. Abdominal findings are consistent with paralytic ileus.16 Tenderness, with guarding or rebound, often is localized to the epigastrium. Abdominal distension may be present. Ascites and fever are less frequent findings. Other nonspecific physical findings in severe pancreatitis include pleural effusion, respiratory distress, coma, renal failure, and circulatory collapse.

Acute pancreatitis is usually diagnosed by measurement of serum lipase activity, which is typically elevated more than 3 times the upper level of normal. Serum lipase is more specific than amylase for acute pancreatitis and should be determined when pancreatitis is suspected.16,17 The serum lipase typically remains elevated 8 to 14 days longer than serum amylase. The serum amylase level is typically elevated for up to 4 days. A variety of other conditions may also cause hyperlipasemia or hyperamylasemia without pancreatitis (Table 417-3). Initially, serum lipase levels are normal in 10% to 15% of patients. Other laboratory abnormalities that may be present include hemoconcentration, coagulopathy, leukocytosis, hyperglycemia, glucosuria, hypocalcemia, elevated gamma glutamyl transpeptidase, and hyperbilirubinemia.

Imaging techniques are helpful adjunctive diagnostic tests. A plain-film radiograph of the abdomen helps to exclude other abdominal catastrophes, and a chest radiograph will identify secondary pulmonary complications. Ultrasonography (US) may demonstrate increased pancreatic size, reduced density, or dilated ducts. Ultrasonography also will identify gallstones and choledochal cysts. Computed tomography should be reserved for complex cases or those in whom US yields equivocal results. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) are invaluable for identifying pancreaticobiliary ductal anomalies.16,18,19 ERCP also is useful if surgical intervention is being contemplated, traumatic pancreatic duct laceration is suspected, or if there is associated evidence of bile duct dilation and cholestasis indicating likely obstruction by a gallstone. MRCP has replaced ERCP in many centers when endotherapy is not expected to be required.19 The role of endoscopic ultrasound is not yet clear in children but has shown to be useful for evaluation of recurrent pancreatitis in adults.20

Treatment and Complications

The clinical course of acute pancreatitis varies from mild in most patients, to severe, fatal disease. Patients with mild disease are treated with hydration and analgesics. A nasogastric tube is used only when severe vomiting is present. Most patients recover within 4 to 7 days. Oral feeding may be resumed as soon as vomiting has resolved. Although there is little supporting data, a low fat diet is recommended. Analgesia is given as required. A surgical or endoscopic approach may be necessary following trauma.

Those with a fulminant, rapidly progressive, and sometimes fatal course, require management in a critical-care setting. Patients should be observed for complications such as sepsis, hypocalcemia due to lipid saponification, shock, respiratory distress, and infection. Careful monitoring and management of intravascular volume, urinary output, electrolytes, acid–base balance, glucose, and calcium are essential. In cases with paralytic ileus and vomiting, bowel decompression with nasogastric suction is helpful. Analgesia is achieved with narcotics when necessary. Proton pump inhibitors are used to inhibit acid secretion. Since patients receiving enteral nutrition have fewer complications and possibly a shorter hospital stay than those receiving parenteral nutrition, nutrition is provided orally, when tolerated, and if not, through a nasogastric or nasojejunal tube.21,22 In some patients, adequate nutrition cannot be delivered enterally and parenteral nutrition may be required. The use of prophylactic antibiotics is controversial. Radiologic or surgical drainage of fluid collections, such as pseudocysts and abscesses, may be necessary. Clinical outcome depends on the cause of the pancreatitis and secondary complications.

Chronic pancreatitis is relatively rare in childhood. It usually is characterized by recurring or unremitting pain, but some patients experience no pain and may present clinically for the first time with symptoms of pancreatic failure and/or diabetes mellitus. Pathologic changes generally are irreversible and progressive, with focal or diffuse destruction of the pancreatic parenchyma, fibrotic replacement, ductal scarring, and plugging with or without calculi.

Hereditary Pancreatitis

Hereditary pancreatitis is the most common childhood form of chronic pancreatitis in developed countries.23-25 Mutations of the PRSS1 gene allow trypsin autoactivation within acinar cells, which in turn causes recurrent episodes of pancreatitis through activation of other intracellular enzymes. The onset of pancreatitis occurs during the first two decades of life in 80% of patients, with a mean age at onset of 11 years. Recurrent attacks of pancreatitis, associated with severe abdominal pain, recur at intervals of months to years. Episodes of pancreatitis usually are of mild to moderate severity. The frequency and severity of the episodes of pancreatitis may decrease with age. Severe pain requiring endoscopic or surgical intervention to palliate pain or relieve ductal obstruction often occurs. Pancreatic insufficiency occurs in up to 50% of patients, and diabetes mellitus in up to 25%. The lifetime risk of pancreatic adenocarcinoma is greater than 50%.

Hereditary and sporadic cases of recurrent or chronic pancreatitis may also be due to mutations in the serine protease inhibitor Kazal type 1 (SPINK1) and CF (CFTR) genes (Table 417-1).23-25SPINK1 functions as a trypsin inhibitor within the acinar cell. When SPINK1 function is decreased or absent intracellular trypsin activity may be inadequately controlled. Patients with CFTR mutations associated with pancreatic sufficiency have an increased risk of recurrent pancreatitis.26 These patients may have atypical forms of cystic fibrosis without pulmonary disease. Some patients are compound heterozygotes while others have been shown to have only a single mutation.

Juvenile Tropical Chronic Pancreatitis (Tcp)

Tropical pancreatitis (TCP) is the most prevalent form of chronic pancreatitis in developing countries abutting the equator. The highest prevalence throughout the world is in the state of Kerala in India. TCP has now been associated with mutations in the SPINK gene in 50% of cases, the CASR (calcium sensing receptor) gene and the chymotyrpsin C gene.28,29 It presents during late childhood or early adulthood, with abdominal pain and irreversible pancreatic insufficiency. Diabetes mellitus follows within 10 years.30 The pancreatic ducts are obstructed with inspissated secretions, which later calcify.

Autoimmune Pancreatitis

Autoimmune pancreatitis is a rare disorder and the incidence in children and adolescents is unknown. Diagnosis of autoimmune pancreatitis is made by a combination of radiologic, serologic, and histopathologic items: (1) radiologic imaging showing narrowing of the main pancreatic duct and enlargement of the pancreas, which are characteristic of the disease; (2) laboratory data showing abnormally elevated levels of serum gamma-globulin, IgG or IgG4, or the presence of autoantibodies; (3) histopathologic examination of the pancreas demonstrating marked fibrosis and prominent infiltration of lymphocytes and plasma cells, which is called lymphoplasmacytic sclerosing pancreatitis (LPSP). For a diagnosis of autoimmune pancreatitis, criterion 1 must be present, together with criterion 2 and/or criterion 3. Treatment is with corticosteroids and immunosuppression.31

Management of Chronic Pancreatitis

Treatment of acute episodes of pain is the same as that recommended for acute pancreatitis. Recurrent episodes of severe pain may result in anorexia, weight loss, and growth failure. The risk of narcotic addiction is a major concern. Between episodes a low-fat diet and abstinence from alcohol are recommended. Alternative but unproven approaches include inhibition of gastric acid secretion and feedback inhibition of pancreatic secretions by regular administration of oral pancreatic enzyme supplements.

Distal strictures can be dilated and stones removed by endoscopic retrograde cholangiopancreatography (ERCP). Endotherapy may provide prolonged pain relief. In adult patients with unremitting pain celiac plexus blockade may be helpful.32Consultation with a psychologist or pain team is essential. In patients with uncontrolled pain associated with obstruction a drainage procedure such as a subtotal pancreatectomy or a lateral pancreatojejunostomy should be considered. Prior knowledge of the pancreatic ductal anatomy by ERCP or magnetic resonance cholangiopancreatography (MRCP) is important.

Endocrine and exocrine tumors of the pancreas are uncommon in children. Gastrinoma is discussed in Chapter 414. Hyperinsulinemic hyperglycemia of infancy, formerly called nesidioblastosis, may cause severe refractory hypoglycemia in the newborn, requiring subtotal or total pancreatectomy, which may lead to malabsorbtion due to pancreatic insufficiency (See Chapter 545).33 Patients with multiple endocrine neoplasia type 1 syndrome develop small pancreatic adenoma that may be diagnosed due to persistent elevations in plasma pancreatic enzyme measurements, or on CT scan or ultrasound. Malignancy of the pancreas is rare in children with this syndrome (see Chapter 537).

The most common nonendocrine tumors are pancreatoblastomas, pancreatic adenocarcinomas, cystadenomas, and rhabdomyosarcomas. Pancreatoblastomas are embryonal tumors that secrete α-fetoprotein and may contain both endocrine and exocrine elements. Presurgical chemotherapy should be considered for lesions not primarily resectable. Carcinoma of the exocrine pancreas is very rare in childhood. The Frantz tumor is a papillary cystic tumor that is found in girls and young women. Presenting symptoms are usually abdominal pain, mass, or jaundice. The treatment of choice is total surgical removal.