Embryology and Anatomy
The pancreas originates during week 4 of gestation as dual evaginations from the foregut endoderm. The dorsal pancreatic bud gives rise to the body and tail of the pancreas, its minor duct (Santorini) and papilla, and the continuation of the major duct (Wirsung) into the body and tail. The ventral pancreatic bud arises from the biliary diverticulum and swings around the dorsal aspect of the duodenal anlage during gut rotation to give rise to the head of the pancreas as well as the proximal portion of the Wirsung duct ( Fig. 45.1 ).
Pancreatic embryology. (A) Stomach (a), gallbladder (b), and ventral (c) and dorsal (d) pancreatic buds develop separately at embryologic week four. The pancreas develops as an evagination of the developing foregut. The dorsal bud evaginates directly off the duodenal anlage. (B) The ventral bud evaginates from the biliary bud and then swings around to the left, with gut rotation occurring simultaneously. (C) The main pancreatic duct of Wirsung and the minor accessory duct of Santorini are shown.
The two pancreatic buds fuse to form one pancreas at approximately 7 weeks’ gestation, although it appears that complete fusion of the two ducts to form the main pancreatic duct is delayed until the perinatal period. The endocrine component of the pancreas, the islets of Langerhans, starts to differentiate before evagination of the pancreatic buds from the wall of the foregut. The islets comprise 10% of the pancreas during early embryonic and fetal life, but this contribution decreases to less than 1% in adulthood. Pancreatic acini begin to form at 12 weeks’ gestation and begin to accumulate organelles and zymogen granules at this stage, but they do not secrete appreciable amounts of enzyme until birth.
The pancreas is retroperitoneal and is light pink in color in children. The acini can be seen under low-power loupe magnification, as can the septa dividing the lobulations. The head of the pancreas lies in the C-loop of the duodenum while the uncinate process, emanating from the posteromedial portion of the head, projects under the superior mesenteric artery (SMA) and vein. The neck of the pancreas is defined as that portion of the pancreas anterior to these vessels. The body and tail, to the left of these vessels, angle sharply toward the hilum of the spleen. The main pancreatic duct courses along the posterior aspect of the gland and curves downward in the head to run alongside the common bile duct, which runs either in a groove posterior to the pancreas or within the substance of the posterior gland. The main pancreatic duct and common bile duct may fuse to form a common channel before entry into the duodenum.
The pancreas is convex, and its midportion is reflected over the anterior surface of the upper lumbar vertebrae and aorta. Its lateral aspects fall posteriorly toward each kidney. The arterial supply of the pancreas is from the celiac and SMA arteries, which form the pancreaticoduodenal arcade. The pancreas also has anastomoses from the splenic artery.
Congenital Anomalies
Pancreas divisum is an anomaly of the pancreas present in 10% of the population and is thought to result from failure of the dorsal duct to fuse with the ventral duct. It is the most common congenital anomaly of the pancreas. In pancreas divisum, most exocrine pancreatic secretions, including those from the entire body and tail, must drain through the small minor duct of Santorini. Endoscopic retrograde cholangiopancreatography (ERCP) is regarded as the most definitive and reliable diagnostic method for revealing pancreas divisum. In the past, ERCP was not feasible in neonates. Since 2009, with the development of a smaller duodenoscope with an outer diameter of 7.5 mm and a 2 mm working channel, , there have been reports of safe and effective ERCP in neonates as young as 3 days old. ERCP may cause a mild pancreatitis or postsphincterotomy bleeding if interventions are performed during the procedure. , The overall complication rate of ERCP is <5% in large series, with high success rates in the hands of experience endoscopists. , Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive and accurate method in the diagnosis of pancreas divisum. The clinical relevance of pancreas divisum remains controversial. A relative obstruction to pancreatic exocrine secretory flow through the duct of Santorini and minor papilla could result in pancreatitis in a small number of patients with pancreas divisum. This can be treated with ERCP, sphincterotomy, and stent placement.
Ectopic pancreatic rests are frequently encountered along foregut derivatives such as stomach, duodenum, jejunum, and colon, but are also infrequently located in the thorax and other sites. , These lesions are found in approximately 2% of autopsy series and represent the most common anomaly of the gastric antrum. Moreover, they may cause gastric outlet obstruction. Their origin is unknown but may be the result of aberrant epithelial–mesenchymal interactions that lead to the transdifferentiation of embryonic epithelium into pancreatic epithelium. Several studies have implicated defects in hedgehog signaling and notch signaling as the cause of ectopic pancreatic rests. Ectopic rests are typically asymptomatic and are encountered incidentally at laparotomy or during endoscopy. They can be identified as pancreatic tissue visually because the surface has the same granular acinar appearance as the normal pancreas. These ectopic pancreatic rests commonly do not become inflamed, possibly because they contain numerous small drainage ducts that usually do not obstruct; however, they can occasionally cause intestinal obstruction or bleeding. When encountered at laparotomy, ectopic rests should probably be excised, unless the excision would entail significant risk of complications.
An annular pancreas is thought to result from faulty rotation of the ventral pancreatic bud in its course around the posterior aspect of the duodenal anlage. The duodenum is encircled and can be obstructed by normal pancreatic tissue. Abnormal expression patterns of endodermal hedgehog may be responsible for the formation of annular and ectopic pancreas. Duodenal atresia and stenosis, intestinal malrotation, and trisomy 21 can often be found in combination with an annular pancreas. Duodenal obstruction leads to bilious vomiting. Radiographic studies may reveal the classic “double bubble” sign. Management consists of bypass of the obstructing lesion with a duodenoduodenostomy. The pancreatic ring may cause the distal duodenum to be fixed in the retroperitoneum preventing mobilization and requiring duodenojejunostomy or, less commonly, gastrojejunostomy for bypass. Resection or division of the annular pancreas should not be performed due to the variable and complex ductal drainage system. Occasionally, patients with complex ductal anatomy may require reoperation for pancreatobiliary anomalies not apparent at the time of the initial operation. Since the early 2000s, there has been a rise in laparoscopic repair of congenital duodenal obstruction from annular pancreas, duodenal atresia, or duodenal web. , Retrospective series have demonstrated that laparoscopic repair compared to open is associated with slightly longer operative times that tend to improve with more experience. , Laparoscopic repair did not increase the anastomotic leak rate and may be associated with a decreased hospital length of stay and a decreased time to full oral intake. , Multiple techniques have been used for anastomotic construction including handsewn, use of nitinol clips, and use of the smaller 5.8 mm endo-stapler developed for pediatric surgery. , , Relative contraindications to the laparoscopic approach include patient weight <2 kg and severe, uncorrected congenital cardiac anomalies. Given the association with trisomy 21, preoperative echocardiogram before duodenal bypass should be considered.
Cystic fibrosis (CF) is an autosomal recessive condition, seen primarily in Caucasians, and occurs in about 1 of 2500 births. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes a protein expressed on the apical membrane of exocrine epithelial cells. CF results in significant pancreatic insufficiency. The pancreatic secretions generally have a reduced amount of bicarbonate, a lower pH, and a lower overall fluid volume. The inspissated secretions cause blockage of the ducts with dilatation. This may lead to acinar cell degeneration, acute and chronic pancreatitis, and pancreatic fibrosis. The result is impaired digestion of fats and proteins from loss of these digestive enzymes, requiring supplementation with oral pancrelipase. The recent development of CFTR modulator drugs for CF, known as highly effective modulator therapy (HEMT), has ushered in a new era for patients with CF. The impact of HEMT on pancreatic insufficiency from CF is currently unknown. There has been a report of an infant homozygous for delF508 CF mutation who did not develop pancreatic insufficiency as the mother was taking HEMT throughout pregnancy and during breastfeeding. There are major barriers to drug availability for the pediatric patient, due to prohibitive costs and lack of FDA approval in patients younger than 12 years old. See Chapter 30 on Meconium Disease for more information about CF.
Pancreatitis
Acute Pancreatitis
Acute pancreatitis is an acute inflammation of the pancreas, varying in severity from mild abdominal pain to fulminant necrotizing pancreatitis and death ( Fig. 45.2 ). Acute pancreatitis has an incidence between 3.6 and 13.2 cases per 100,000 children. When episodes of acute inflammation completely resolve and then recur, it is termed acute recurrent pancreatitis. It is thought that complete interval resolution of morphology and function occurs between episodes, unlike in cases of chronic pancreatitis.
This specimen is from a case of acute necrotizing pancreatitis displaying diffuse stippled necrosis of the pancreatic parenchyma and peripancreatic fat.
Reprinted from Iyer S, Drake A, West R, et al. Case report of acute necrotizing pancreatitis associated with combination treatment of sitagliptin and exenatide. Endocr Pract . 2012;18:e10–e13, with permission from the American Association of Clinical Endocrinologists.
The causes of acute pancreatitis include trauma, biliary tract stone disease, choledochal cyst, ductal developmental anomalies, drugs, metabolic derangements, and infections. Most commonly, the cause is not apparent—idiopathic pancreatitis. As the pancreas is fixed against the lumbar spine, trauma to the upper abdomen can fracture the pancreas or injure the major duct at that point ( Fig. 45.3 ). Biliary stone disease, increasing in frequency in children, may lead to pancreatitis from transient pancreatic duct obstruction. ERCP is safe and effective in children and is the preferred method for stone retrieval. Drugs that are thought to induce pancreatitis include asparaginase and valproic acid. Systemic illnesses and metabolic conditions, such as CF, Reye syndrome, Kawasaki disease, hyperlipidemias, and hypercalcemia, as well as viral infections (e.g., coxsackievirus and rotavirus) and generalized bacterial sepsis, can also cause pancreatitis.
This abdominal contrast-enhanced CT shows a complete transection ( arrow ) of the body of the pancreas following a bicycle handlebar injury to the epigastrium. The patient underwent laparoscopic distal pancreatectomy and recovered uneventfully.
Choledochal cysts produce pancreatitis by pancreatic duct compression or bile reflux resulting from a long common biliary–pancreatic duct within the head of the pancreas. Other rare ductal anomalies may result in obstruction and recurring bouts of pancreatitis. Pancreatitis in patients with a choledochal cyst is associated with fusiform dilation of the cyst and dilation of the common channel, compared to patients without pancreatitis.
Although acute pancreatitis has many etiologies, they all appear to share a common pathway of nonphysiologic calcium signaling in the pancreas, followed by the premature activation of acinar proenzymes. These enzymes, especially trypsin, lead to acinar cell injury and cytokine release. The cytokines, along with vascular dissemination of activated enzymes, free radical formation, and release of vasoactive substances, such as kallikreins and histamine, mediate extrapancreatic inflammation.
Diagnostic criteria for acute pancreatitis include at least two of the following: acute abdominal pain (especially in the epigastric region), serum amylase or lipase more than three times the upper limit of normal, and imaging findings characteristic or compatible with acute pancreatitis. The abdomen is diffusely tender, often with signs of peritonitis, and distention occurs with a paucity of bowel sounds. In severe cases of necrotizing or hemorrhagic pancreatitis, hemorrhage may spread away from the pancreas along tissue planes, appearing as ecchymosis either in the flanks (Gray Turner sign) or at the umbilicus (Cullen sign) ( Fig. 45.4 ). These ecchymoses generally take 1–2 days to develop.
Positive Cullen sign, with periumbilical ecchymosis, in a patient with hemorrhagic pancreatitis.
Elevated amylase or lipase levels are helpful in the diagnosis, although a normal serum amylase level does not exclude pancreatitis. Hyperamylasemia may also be caused by salivary inflammation/trauma, intestinal disease (such as perforation, ischemia, necrosis, or inflammation), and macroamylasemia. Lipase can be falsely elevated in pancreatic cancer, macrolipasemia, renal insufficiency, cholecystitis, esophagitis, intestinal perforation, and hypertriglyceridemia. The degree of enzyme elevation does not correlate with disease severity. ,
Imaging the abdomen is important as part of the evaluation of the patient with abdominal pain. In the patient with pancreatitis, plain abdominal radiographs may reveal an isolated loop of intestine in the vicinity of the inflamed pancreas, termed a sentinel loop. Pancreatic calcifications suggest chronic pancreatitis. Plain chest radiographs should be performed in all patients with acute pancreatitis to look for evidence of pleural effusion and pulmonary edema.
Abdominal ultrasound (US) is useful in the evaluation of the patient with pancreatitis but has limited applications. It is well established in the evaluation of biliary stone disease as the etiology for pancreatitis and can detect choledochal cysts and pancreatic pseudocysts as well. Advanced techniques such as contrast-enhanced US and US elastography have also been shown to be useful in the diagnosis of pancreatitis and its complications, but their availability is limited to a few experienced centers.
Abdominal computed tomography (CT) provides much better resolution of the pancreas than US. Its primary role is in the detection of early and late complications, such as pancreatic necrosis, pseudocysts, and fluid collections, and should be reserved for patients with more severe pathology or recurrent symptomatology with an equivocal US. If necessary, CT can be combined with interventional procedures to drain fluid collections.
MRCP is a newer, noninvasive technique for evaluating the biliary tree and pancreatic duct ( Fig. 45.5 ). It is the initial imaging study of choice for the evaluation of pancreatic ductal anatomy in children with recurrent or unexplained pancreatitis. Studies comparing MRCP and ERCP show high concordance in diagnoses. Its disadvantages are that it does not allow for therapeutic intervention (though it may direct the type of intervention necessary), its poor spatial resolution limits the visualization of ducts in smaller children, and it usually requires anesthesia in the pediatric age group. ,
Pancreatic duct stenosis following acute pancreatitis. (a) Presecretin MR image shows discontinuity of the main duct at the level of the pancreatic neck (white arrowhead), an adjacent high-signal-intensity fluid collection (black arrowhead), and diffuse ascites (arrow). (b) MR image obtained 7 minutes after secretin injection shows stenosis of the main pancreatic duct in the pancreatic neck (white arrowhead) and diffuse ascites (arrow). The fluid collection adjacent to the pancreatic neck (black arrowhead) appears brighter than on the presecretin image, a feature suggestive of a connection to the duct. (c) ERCP image helps confirm the presence of stenosis (white arrowhead) and absence of disconnection of the duct. The fluid collection (black arrowhead) is filled with injected contrast material, which indicates disruption of the duct. The patient underwent percutaneous placement of a pancreatic stent (not shown) and did not need open surgery.
The most frequent indication for ERCP in children is in the diagnosis or treatment of acute, recurrent, or chronic pancreatitis. A large single-institution retrospective study found a low rate of post-ERCP complications and a high therapeutic success rate. In that study, ERCP was shown to be particularly useful in the diagnosis of recurrent pancreatitis, though in only 60% of patients was an organic etiology found. Gallstone pancreatitis associated with common bile duct obstruction or cholangitis is the most frequent indication for ERCP in acute pancreatitis. Sphincter of Oddi manometry was particularly useful in establishing a diagnosis when no anatomic abnormalities were present.
The mainstays of therapy for pancreatitis are pain control, intravenous fluid resuscitation, pancreatic rest, and monitoring for complications. Fluid resuscitation and maintenance should be guided toward a goal urine output of 2 mL/kg/h measured by an indwelling urinary catheter. Because of circulating cytokines, activated digestive enzymes, and other proinflammatory molecules, extracellular fluid losses can be enormous. Constant monitoring is necessary to avoid the development of severe hypovolemia. Patients with severe acute pancreatitis may require nasogastric decompression. Most patients receive histamine-2 (H 2 ) receptor antagonists to reduce exposure of the duodenal secretin-producing cells to gastric acid, a potent stimulator of pancreatic secretion. This therapeutic regimen is logical but empiric because no studies have shown improvement in outcomes with these interventions. The effectiveness of somatostatin in the treatment of pancreatitis is equivocal and probably serves more to mitigate complications of pancreatitis rather than to treat the disease itself. Further studies are needed to clearly define its role in both adults and children.
Nutrition is critically important in patients with pancreatitis. In the past, pancreatic rest with fasting was thought to prevent disease progression and pain. Since 2010, there has been a paradigm shift in the nutritional management of patients with pancreatitis given findings that ATP depletion and catabolism plays a key role in the acute phase of pancreatitis. Enteral nutrition (EN) has become the preferred method over total parenteral nutrition (TPN) if tolerated. Patients who cannot tolerate oral nutrition should be treated with EN via a nasogastric or nasojejunal tube. In severe pancreatitis, EN whether oral or via nasal tube should be avoided prior to resuscitation given the risk of inducing intestinal injury from mesenteric ischemia. Compared with TPN, EN has been shown to decrease length of stay, reduce the need for surgery, and reduce the risk of infection. When restarting a diet, conservatively determined by resolution of symptoms, there appears to be no difference between clear liquids and solid food as the initial meal. Unfortunately, these data come almost exclusively from the adult population as pediatric trials are lacking. ,
Adequate analgesia is critical to minimizing the physiologic stress that develops from pain. Although meperidine (Demerol) was once advocated because morphine was thought to cause spasm of the Sphincter of Oddi, no clinical trials have shown superiority of meperidine over other narcotic analgesics. However, large doses of meperidine are associated with the risk of seizure, euphoria, and drug interactions, suggesting other narcotics such as morphine and fentanyl may be safer alternatives. The diagnosis of pancreatitis must be certain prior to initiating treatment with high doses of narcotics as these may mask signs of serious nonpancreatic pathology, such as intestinal or gastric perforations.
As pancreatitis progresses in severity, patients need to be monitored closely for signs of multisystem organ failure. Pleural effusions, pulmonary edema, and tense abdominal distention may lead to hypoxia requiring intubation and acute respiratory distress syndrome. Hypocalcemia, hypomagnesemia, anemia from hemorrhage, hyperglycemia, renal failure, and late sepsis can also be seen in these patients. Disagreement exists regarding the use of prophylactic antibiotics in severe cases of pancreatitis. The most recent adult data suggest a trend toward decreased mortality and infection with prophylactic antibiotics, but this study failed to reach statistical significance. Imipenem is the antibiotic therapy of choice when necessary.
Operative exploration is usually not necessary in acute pancreatitis. However, exploration is needed in patients with infected necrotic pancreatitis or sometimes with a pancreatic abscess. Infected pancreatic necrosis increases mortality significantly. Diagnosis is typically by CT pancreatography, with confirmation of infection by fine-needle aspiration, clinical deterioration, or positive cultures. The latest adult data suggest that infected necrosis or peripancreatic abscesses are best treated in a stepwise manner from least to most invasive. Percutaneous drainage should be followed by surgical necrosectomy only if the patient fails to improve. Delayed operative therapy has been shown to improve mortality compared with primary necrosectomy. ,
Pancreatic pseudocyst is a complication of trauma or pancreatitis that forms after injury to the pancreatic ductal system. The extravasated pancreatic enzymes and digested tissue are contained by the formation of a cavity composed from a fibroblastic reaction and inflammation that lacks an epithelial lining. The acute pseudocyst has an irregular wall on CT scan, is tender, and usually develops shortly after an episode of acute pancreatitis or trauma ( Fig. 45.6 ). Chronic pseudocysts are usually spherical with a thick wall and are commonly seen in patients with chronic pancreatitis. The distinction is important because half of acute pseudocysts resolve without treatment, while chronic pseudocysts rarely spontaneously resolve. An acute pseudocyst matures and forms a thick fibrous wall in 4–6 weeks, allowing for drainage. Those smaller than 5 cm in diameter usually spontaneously regress. When compared with those in adults, pseudocysts in children tend to resolve more frequently with medical therapy alone. There are anecdotal reports of pseudocyst resolution in children after treatment with long-acting somatostatin analogs.
CT scan of an acute pseudocyst in a patient after a severe motor vehicle accident. The wall ( arrows ) is irregular with nonloculated fluid inside.
Pancreatic pseudocysts that persist or are symptomatic require either a drainage procedure or excision. There is no absolute size criteria for intervention in children and the decision to pursue invasive procedures for pancreatic pseudocyst should be predominantly guided by the patient’s clinical presentation. Initial management may involve ERCP with stent placement to prevent progressive enlargement. Ultimately, the patient may require endoscopic cystgastrostomy (E-CG). E-CG is well established in adults and has been reported to be safe and efficacious in children as well. This should be performed only at centers with sufficient experience with these techniques. Other options for definitive management include surgical cystgastrostomy or cystojejunostomy ( Fig. 45.7 ).
This adolescent sustained blunt trauma from a motor vehicle accident that resulted in a pancreatic pseudocyst several weeks later. After 6 weeks, laparoscopic cyst gastrostomy was performed. (A) The stomach has been opened. (B) A needle is introduced into the pseudocyst through the posterior wall of the stomach. (C) The common wall between the pseudocyst and stomach has been excised and is opened widely for adequate drainage of the pseudocyst. (D) The resulting gastrotomy has been closed with an endoscopic stapler. The patient recovered uneventfully and has not developed any postoperative problems.
The three major complications of pancreatic pseudocysts are hemorrhage, rupture, and infection. Hemorrhage is the most serious complication and usually results from pressure and erosion of the cyst into a nearby visceral vessel. These patients require emergency angiography with embolization. Rupture or infection of a pseudocyst is uncommon. In both cases, external drainage is indicated. Percutaneous drainage is the preferred approach for an infected pseudocyst because these cysts typically have thin, weak walls that are not amenable to internal drainage. Internal drainage is preferred for noninfected cysts as external drainage can lead to a chronic fistula.
Ascites in children can follow pancreatic trauma or pancreatic surgery. Free fluid results from the uncontained leakage from a major pancreatic ductal injury. When suspected, CT, ERCP, or MRCP should be performed to assess for a ductal injury. Nonoperative management initially consists of bowel rest with hyperalimentation and the use of long-acting somatostatin analogs. In many cases, the ascites resolves spontaneously with this treatment. The recent literature is full of controversy regarding optimal management for pancreatic trauma with a ductal injury. More complications, a longer time to goal feeds, and a higher rate of pseudocyst formation were found with nonoperative management in two recent retrospective reviews. , However, other recent studies support nonoperative management of pancreatic trauma in children, even in the presence of a ductal injury. When operative treatment is needed, depending on the nature and site of the injury, drainage alone may be sufficient. Distal ductal injuries can be treated with distal pancreatic resection, and recent experience has shown that the laparoscopic approach is safe and feasible. Proximal injuries require a Roux-en-Y jejunal onlay anastomosis to preserve pancreatic tissue. Pseudocyst formation is common in this patient population. ,
A pancreatic fistula can develop postoperatively or from nonoperative management. Most low-output fistulas close spontaneously but can drain for several months. Long-acting somatostatin analogs decrease fistula output and accelerate the rate of closure, but do not appear to induce closure of fistulas that would not otherwise have closed. Managing a pancreatic fistula centers around maintaining nutrition, with hyperalimentation necessary if enteral feeding increases fistula output, and ensuring the fistula tract does not become obstructed. Operative intervention with a Roux-en-Y jejunostomy anastomosed to the fistula site is usually curative if the fistula fails conservative management. See Chapter 15 on Abdominal and Renal Trauma for more information regarding management of the injured pancreas.
Chronic Pancreatitis
Chronic pancreatitis is distinguished from acute pancreatitis by the irreversibility of the changes associated with the inflammation. Chronic pancreatitis remains a substantial clinical problem, afflicting roughly 140,000 individuals in the United States alone. , The disease entails several clinical problems: (1) severe and intractable pain typically requiring narcotics; (2) malabsorption due to loss of pancreatic digestive enzymes from the exocrine pancreas, requiring chronic enzyme replacement for life; (3) life-threatening complications such as pancreatic pseudocyst, pancreatic ascites, biliary obstruction, etc.; (4) a 13-fold increased risk of pancreatic cancer ; and (5) the development of insulinopenia and overt diabetes mellitus in over half of patients (and probably most patients if they live long enough). Diabetes is likely due to the proximity of the endocrine pancreas to the inflamed exocrine pancreas.
Chronic pancreatitis can be classified as either calcifying or noncalcifying. The calcifying form, most common in hereditary or idiopathic pancreatitis, is more prevalent than the obstructive form in children and is associated with intraductal pancreatic stones, pseudocysts, and more aggressive scar formation. The obstructive type of chronic pancreatitis, which is associated with an anatomic or functional obstruction, is generally less severe with less scarring than calcifying pancreatitis. Single institutional experiences vary as to distributions in etiology, though the predominant causes are hereditary/genetic, obstructive, or idiopathic. ,
The discovery of a genetic basis for certain forms of chronic pancreatitis represents a breakthrough in our understanding of its pathogenesis. Current thinking is that familial pancreatitis results from a combination of environmental triggers, genetic susceptibility, and an inappropriate immune response leading to chronic inflammation and fibrosis. Hereditary pancreatitis, the most common genetic cause of pancreatitis, can result from abnormalities in the cationic trypsinogen gene PRSS1 . This autosomal dominant condition most commonly results from one of two mutations that either prevent degradation of prematurely activated trypsin or make trypsin resistant to inactivation. Penetrance in this condition is approximately 80%. Other gene mutations implicated in chronic pancreatitis are SPINK1 and CFTR . Genetic testing is recommended for children with recurrent, idiopathic pancreatitis, with or without a family history of pancreatitis. Notably, patients with hereditary pancreatitis have a markedly increased risk of pancreatic cancer after age 50 years.
Obstructive pancreatitis is most often due to an anatomic or functional obstruction of the pancreatic duct. The most common anatomic causes are pancreas divisum followed by choledochal cysts. Uncertainty exists as to why a minority of patients with pancreas divisum develop chronic pancreatitis while most do not. The literature suggests that potential causes are the anatomic variant, structural narrowing of the minor papilla, sphincter of Oddi dysfunction, or the relatively high association with CFTR mutations. Many patients with ductal dilatation and anatomic or functional obstruction clearly improve with endoscopic sphincterotomy and/or stents. Pancreatic dyskinesia, though not well studied in children, may be improved by endoscopic sphincterotomy and sometimes temporary stent placement. For those in whom endoscopic treatment is not feasible or fails, individualized surgical treatment is reasonable based on the patient’s ductal anatomy, level of obstruction, and severity of pancreatic fibrosis.
Chronic pancreatitis can manifest with a characteristic pain, diminished pancreatic function, and radiographic abnormalities. Increased stool fat, diabetes, and steatorrhea are signs of pancreatic insufficiency. On a CT scan the pancreas frequently has microcalcifications throughout the parenchyma and calcified stones in the duct ( Fig. 45.8 ). Additionally, pancreatic pseudocysts or inflammation may be seen on the CT scan. ERCP and MRCP can evaluate the ductal anatomy and identify anatomic causes of chronic pancreatitis. Only ERCP provides a means for evaluating sphincter pressure measurements for functional obstruction.
CT scan of a pancreas with chronic calcifying pancreatitis. A dilated duct can be seen within the pancreas, further supporting the diagnosis of chronic pancreatitis. Calcified stones ( arrows ) can be seen in the dilated duct.
Therapy for chronic pancreatitis is directed toward palliation of symptoms. Initial management for acute exacerbations is pain control and hydration. Steatorrhea indicates the need for pancreatic enzyme replacement. In general, these patients respond better to small, frequent meals. The diabetes that results from chronic pancreatitis tends to be unusually brittle, with a propensity for severe hypoglycemic episodes after even low doses of insulin. This hypersensitivity to insulin may be due to the loss of entire islets, which includes the glucagon-producing alpha cells that normally oppose the glucose-lowering effect of insulin.
In patients with chronic pancreatitis who have severe, intractable pain, ERCP or MRCP may help locate correctable problems such as large stones or a stricture with distal duct dilatation. Surgical options in chronic pancreatitis include sphincteroplasty, excision of localized pancreatitis, subtotal pancreatectomy, lateral pancreaticojejunostomy (modified Puestow procedure), and the duodenum or pylorus-preserving Whipple. Individualization of the operative approach and maximization of pancreatic ductal drainage are key components. Patients failing conservative surgical management may require a more definitive procedure to achieve symptomatic relief. Although the operative results in patients with hereditary pancreatitis are generally disappointing, evidence suggests that complicated patients treated with a modified Puestow procedure may experience an improved quality of life (QOL), with subsequent improvement in pancreatic function and nutritional status ( Fig. 45.9 ). Unlike adults with hereditary pancreatitis, some reversal of the steatorrhea may be seen in children.
Modified Puestow procedure. The pancreatic duct is opened longitudinally and a side-to-side anastomosis to a Roux loop of jejunum is performed.
Functional Pancreatic Disorders
The causes of persistent hypoglycemia in children vary greatly with age. In newborns and young infants, the major causes are (1) congenital hyperinsulinism of infancy, previously called nesidioblastosis; (2) a lack of substrate for gluconeogenesis (e.g., glycogen storage disease); and (3) inadequate gluconeogenic hormones (e.g., hypothyroidism or growth hormone deficiency). In children with the onset of hypoglycemia after 1 year of age, the causes are different, with insulinoma being the most common.
Congenital Hyperinsulinism
Nesidioblastosis, the original term for what is now called congenital hyperinsulinism of infancy (CHI), comes from the Greek nesidio , meaning “island,” and blast , meaning “new formation.” Nesidioblasts were originally thought to be progenitor cells in the wall of the pancreatic ducts, which overproliferate in patients with this condition. With the advent of genetic analysis, this pathogenesis is now known to be incorrect.
Mutations in seven genes are currently known to cause CHI, though roughly half of cases are caused by genetic malformations not yet understood. Initially discovered was the loss-of-function mutations in the SUR1 and Kir6.2 components of the ATP-sensitive potassium channel (KATP) found in the cell membrane of the pancreatic β-cell. These mutations either impair the ability of Mg-adenosine diphosphate (ADP) to stimulate channel activity or affect the expression of the KATP channels at the surface membrane, resulting in continuous depolarization of the β-cell membrane and dysregulated insulin secretion. Heterozygous gain-of-function mutations in GULD1 , the mitochondrial gene encoding glutamate dehydrogenase, leads to CHI caused by the insensitivity of the enzyme to inhibition by guanosine-5′-triphosphate. This gain-of-function mutation results in a milder form of CHI, which may be diagnosed later in childhood, and is associated with hyperammonemia and occasionally epilepsy. Heterozygous loss-of-function mutations in HNF4A , an islet transcription factor gene, are also associated with CHI through unknown mechanisms. Rarer are cases of CHI caused by mutations in glucokinase (GCK), hydroxyacyl-coenzyme A dehydrogenase (HADH), and the solute carrier SLC16A1.
CHI occurs in a focal and diffuse type, the differentiation of which is critical for operative management. However, unfortunately the clinical presentation is identical. Patients with SUR1 mutations often have the focal type. The focal type is actually a focal adenomatous hyperplasia, different from an adenoma. Histologically, it is seen as a confluence of hyperplastic but otherwise normal-appearing islets. There is little insulin present within the lesion due to excess secretion, while uninvolved islets outside are small with high insulin content. The diffuse type is macroscopically normal, but careful evaluation of the islets reveals enlarged β-cells with abnormally large nuclei, a large Golgi apparatus, and weak insulin staining due to hypersecretion.
CHI patients typically develop hypoglycemia shortly after birth, though it may manifest at a later age. Infants with CHI are often macrosomic. Symptoms may be subtle, such as lethargy and irritability, or severe with apnea, seizures, and coma. Simultaneous insulin and glucose measurements show a high ratio of insulin to glucose, recalling that insulin levels may be normal but inappropriate in the presence of hypoglycemia. These patients differ from insulinoma patients, who usually have high absolute insulin levels. Another powerful indicator of CHI is a glucose requirement greater than 8 mg/kg/min. Owing to the much higher incidence of insulinoma, patients older than 1 year at the onset of hypoglycemia should be evaluated for both conditions.
Stabilization of the CHI patient includes frequent intermittent or continuous feeding, with the addition of intravenous glucose as needed. Central venous access is advised because adequate venous access is lifesaving and high concentrations of intravenous glucose may be necessary. Maintaining normoglycemia is critical to prevent potentially disabling hypoglycemic brain injury. Intramuscular glucagon can be used as a temporizing measure until definitive venous access is obtained.
Treatment of CHI begins with medical management. Diazoxide remains a mainstay of therapy. Diazoxide binds the SUR1 component of the KATP channel and maintains it in a persistently open state, preventing insulin secretion. Patients with diazoxide-sensitive CHI who can tolerate fasting can be managed medically until they outgrow their condition. Those unresponsive to diazoxide should be managed with frequent feedings, glucose infusions, and somatostatin analogs. Somatostatin analogs inhibit pancreatic insulin secretion and can be administered subcutaneously, either intermittently or continuously by a pump. Somatostatin analogs are associated with gallstones and biliary sludge and have been implicated in cases of necrotizing enterocolitis. Medical failure to control hypoglycemia necessitates surgical intervention.
Distinguishing diffuse versus focal CHI is critical for operative planning. The development of a fluoro-18- l -dihydroxyphenylalanine (18F-DOPA) positron emission tomography-CT (PET-CT) scanner has replaced pancreatic venous sampling as the optimal method for delineating focal versus diffuse disease, with a sensitivity of 94% and specificity of 100% ( Fig. 45.10 ). Intraoperative US can provide additional anatomic detail to help avoid injury to the biliary tree. For the focal type, resection of the hypermetabolic focus is curative. Focal lesions in the head may require duodenum-preserving pancreatic head resection and distal pancreaticojejunostomy with excision of distal lesions via spleen-preserving distal pancreatectomy. In patients with diffuse disease, a near-total pancreatectomy is needed, leaving only a rim of pancreatic tissue along the common bile duct ( Fig. 45.11 ). The laparoscopic approach for both procedures has been reported, but data are limited. , Operative complications include bile duct injury, pancreatic insufficiency, and the need for repeat pancreatic resection due to persistent hypoglycemia.
