Pancreatic Problems in Infants and Children

Annular Pancreas

In the fetus the caudal portion of the developing foregut develops into the proximal duodenum, as well as the dorsal and ventral pancreatic buds. At 5 weeks of gestation, rightward rotation begins to bring the ventral pancreatic bud to the right of the duodenum, where it comes to join the dorsal pancreatic bud to give rise to the head of the pancreas ( Fig. 103.1 ). The lumen of the duodenum becomes transiently obliterated with proliferation of the lining cells during the same period of development. By the eighth week of gestation, rotation of the pancreas is complete and recanalization of the duodenum has occurred. Thus it is easy to understand that any perturbation influencing the rotation of pancreatic tissue may also impact recanalization of the duodenum. Therefore annular pancreas is occasionally associated with various degrees of intrinsic duodenal stenosis and atresia. However, in most cases, annular pancreas is associated with external compression of the duodenum resulting in partial or complete obstruction.

Annular pancreas generally presents in the newborn period, with 75% of cases presenting in the first week of life, but it has been reported in an 11-year-old and may be encountered incidentally in adults. It has been suggested that a large percentage of patients with annular pancreas remain asymptomatic; however, it is impossible to know because the denominator is unknown. Prenatal ultrasound may detect polyhydramnios or may diagnose duodenal obstruction directly in 30% of patients ( Fig. 103.2 ). At birth, infants have a scaphoid abdomen. Radiographs showing the “double bubble” sign, classically attributed to duodenal atresia, may be seen in more than 88% of patients ( Fig. 103.3 ). Emesis may be bilious (up to 50%) or more commonly nonbilious (>90%), depending on whether the obstruction is above or below the ampulla of Vater.

Associated congenital anomalies occur in approximately 70% of patients (32% chromosomal and 38% other malformations) and should be looked for prior to, and during, operation for annular pancreas. These may include nonsurgical anomalies, such as Down syndrome, and operative conditions, including esophageal atresia, malrotation, Meckel diverticulum, and imperforate anus. In addition, 4% of patients with annular pancreas may have a second duodenal obstruction related to stenosis or web usually noticed intraoperatively as a dilated duodenum distal to the annular pancreas. Congenital cardiac defects must be assessed with preoperative echocardiogram.

At operation, a transverse right upper quadrant skin incision is used. In the newborn the proximal, obstructed, duodenal bulb may be markedly dilated, with the rim of annular pancreas visible just caudal to it. Repair is by duodenoduodenostomy, done in diamond-shaped fashion by making a transverse incision in the proximal duodenum and a perpendicular longitudinal incision in the distal duodenum ( Fig. 103.4 ). The two ends may then be “fish mouthed” or “diamond shaped” together using a single layer of interrupted, absorbable, monofilament suture. If duodenoduodenostomy is precluded by excess tension or a poorly developed distal duodenum, then duodenojejunostomy should be performed. Advances in minimally invasive surgery techniques have allowed attempts at laparoscopic duodenal repair. Laparoscopic duodenoduodenostomy has proven safe with excellent short-term outcomes when completed by pediatric surgeons with advanced laparoscopic skills, with complication rates similar to open duodenoduodenostomy. Thus annular pancreas, which Merrill and Raffensperger in 1976 deemed an “eminently curable lesion,” is cured without ever touching the pancreas itself.

Occasionally after correction for annular pancreas, a patient may experience recurrent abdominal pain that may be related to biliary anomalies, such as pancreatic divisum or pancreaticobiliary maljunction. These anomalies can be detected by ERCP or magnetic resonance cholangiopancreatography (MRCP) and may require surgical intervention for recurrent or chronic pancreatitis.

Congenital Hyperinsulinism

CHI is characterized by dysregulated insulin secretion that results in persistent mild to severe hypoglycemia. The various forms of CHI represent a group of clinically, genetically, and morphologically heterogeneous disorders. CHI occurs at a frequency of 1 in 30,000 to 50,000 live births. There has been significant ambiguity surrounding the pathophysiology of CHI. Early recognition of CHI is critical because, if untreated, profound hypoglycemia may lead to brain damage. The clinical manifestations of CHI include babies who are jittery, floppy, or lethargic; seizures are common, and near-death events may occur. Diagnosis requires the presence of inappropriately elevated insulin in the setting of hypoglycemia (<2.5 mmol/L, 45 mg/dL), along with the need for continuous glucose infusion (>15 mg/kg/min) to maintain normoglycemia. The presence of low ketone bodies, low free fatty acid, and an increase in blood glucose after glucagon administration may additionally be used as diagnostic criteria.

Mutations in six genes have been associated with CHI: the sulfonylurea receptor 1 (SUR-1; encoded by ABCC8 ) ; potassium inward rectifying channel (Kir6.2; encoded by KCNJ11 ) ; glucokinase (GK; encoded by GCK ) ; glutamate dehydrogenase (GDH; encoded by GLUD1 ) ; short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD; encoded by HADH ), and ectopic expression on β-cell plasma membrane of SLC16A1 (encodes monocarboxylate transporter 1 [MCT1]). Genetic testing is available through commercial laboratories for four of the six genes known to be associated with CHI (ABCC8 , KCNJ11 , GCK , GLUD1) .

SUR-1 and Kir6.2 combine to form the β-cell plasma membrane K _ATP channel. Inactivating mutations in the K _ATP channel result in membrane depolarization and calcium influx into the β cell, resulting in constitutive insulin secretion. This is the most common and severe form of CHI. There are three subtypes of K _ATP -CHI, recessively inherited K _ATP -CHI, dominantly inherited K _ATP -CHI, and focal K _ATP -CHI.

GDH CHI is the second most common form of CHI. It is also known as the hyperinsulinism and hyperammonemia (HI/HA) syndrome. GDH-CHI presents with recurrent episodes of hypoglycemia that are less severe than in K _ATP -CHI and can be precipitated by a protein-rich meal. These patients do not typically present with hypoglycemia at birth but are frequently diagnosed after several months of age. The hypoglycemia in patients with GDH-CHI is easily controlled with diazoxide.

CHI can also occur in the setting of perinatal stress, resulting in prolonged neonatal hypoglycemia. Transient CHI is seen in the infants of diabetic mothers that develops after birth and resolves spontaneously within the first 3 to 4 weeks of life, but perinatal stress–induced CHI can persist up to a year. The mechanism is unknown; however, transient CHI has been associated with shorter gestational age and low birth weight. Transient CHI is believed to be caused by mainly nongenetic factors, whereas persistent CHI likely has genetic etiology. These infants usually respond well to diazoxide; however, via comprehensive analysis, the responsible genes can be identified in only 53% of diazoxide-responsive CHI patients. Mimickers of CHI include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann syndrome, Sotos syndrome, Kabuki syndrome, Costello syndrome, Usher-CHI syndrome, mosaic Turner syndrome, and congenital disorders of glycosylation.

The ability to distinguish focal and diffuse CHI is of paramount importance, in that focal CHI is curable by partial pancreatectomy. Interventional radiology studies, such as transhepatic portal venous insulin sampling and selective pancreatic arterial calcium stimulation, have been used to localize focal lesions. More recently, positron emission tomography (PET) scans with F-dihydroxyphenylalanine (DOPA) have been shown to accurately discriminate focal CHI from diffuse CHI. PET-CT may offer even better localization because the ¹⁸ F-DOPA PET scan detects focal lesions as small as 5 mm. Supplemental imaging modalities, such as computed tomography (CT), ultrasound, and intraoperative ultrasound, have not yet been validated in the literature for this problem in infancy; however, PET-MRI appears promising. In diffuse CHI, β cells throughout the pancreas are functionally abnormal and have characteristic enlarged nuclei in approximately 2% to 5% of cells ( Fig. 103.5 ). Focal CHI lesions are usually less than 1 cm in diameter and are characterized by the presence of a confluent proliferation of islet cell clusters (focal adenomatosis).

The goal of treatment in infants with CHI is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels greater than 700 mg/L (70 mg/dL). First-line pharmacologic therapy in patients with CHI is diazoxide, a K _ATP channel agonist. Because a functional K _ATP channel is required for diazoxide to exert an effect, patients with recessive focal or diffuse K _ATP -CHI do not respond to therapy with diazoxide. Patients with GDH-CHI, SCHAD-CHI, and perinatal stress–induced hyperinsulinism typically respond well to diazoxide. Second-line medical therapy for infants unresponsive to diazoxide is octreotide. Patients with K _ATP channel CHI can be maintained on long-term treatment until spontaneous remission at 2 to 5 years of age.

The decision to operate is based on a laboratory evaluation consistent with CHI, medical responsiveness, genetic testing, and imaging. Operation is necessary in more than two-thirds of cases. The decision to operate should hinge on the demonstration of focality or, in the case of diffuse disease, on the failure of medical management. Treatment of the focal form of CHI is by partial pancreatectomy. Cretolle et al. have reported cure in 44 of 45 patients undergoing partial pancreatectomy following localization, and most, although not all, were found to appropriately correlate with preoperative venous localization. The authors approached lesions of the midportion of the pancreas by means of middle pancreatectomy with preservation of the head, along with Roux-en-Y jejunal loop to the transected portion of the pancreatic tail. Forty-four patients in the series had normal postoperative glucose and glucose tolerance tests, as well as hemoglobin A1c, and all patients were without exocrine dysfunction, with a reported mean follow-up of 3.7 years. Curative laparoscopic enucleation of focal lesions has been reported by others.

Infants with diffuse disease will normally require a near-total pancreatectomy (95% to 98%) to control the CHI and might require additional therapy with diazoxide, octreotide, and/or frequent feedings to maintain euglycemia. In the diffuse form of CHI, there is diffuse hyperfunction of pancreatic β cells with enlargement of their nuclei, but neither the β-cell proliferation rate nor the overall β-cell mass is increased. Diagnosis may also be made by pancreatic venous sampling or by the observation on frozen section of diffuse enlargement of nuclei seen in all specimens. In this case, near-total pancreatectomy is required. Classic anatomic benchmarks, such as removing all pancreatic tissue up to the superior mesenteric vein, should be taken with caution in light of a pediatric autopsy study by Reyes et al., who demonstrated that distal pancreatectomy taken past the mesenteric vessels, up to the left border of the pancreaticoduodenal vessels in the head of the pancreas, accounted for removal of only an average of 71% of the pancreas by weight, with a highly variable range of 43% to 96%. The approach of Fékété et al. is to perform near-total pancreatectomy, leaving only a “small lump of pancreatic tissue in the concavity of the duodenal genu superius, with choledochal dissection.” Long-term complications reported following near-total pancreatectomy have included growth disturbance, glucose intolerance or overt diabetes, and variceal bleeding due to splenic vein thrombosis, the latter presenting as late as 18 years postoperatively. Reports of long-term pancreatic exocrine deficiency are hard to find. Regeneration of the pancreas following near-total pancreatectomy in infancy has been documented. Patients with CHI requiring surgical therapy have a higher incidence of neurodevelopmental problems compared with patients responsive to medical therapy. The risk of developing diabetes has been attributed to pancreatectomy ; however, it has also been observed in patients who did not have surgery. In a series of 114 patients with CHI, the incidence of diabetes was as high as 27% after pancreatectomy, and 71% in patients requiring multiple surgical resections.

Pancreas Divisum

Pancreas divisum is a congenital anomaly, but it may or may not manifest itself at any time during life. During fetal development, as the pancreas forms from the rotation and fusion of the ventral pancreatic anlage and the dorsal pancreatic anlage, the ventral duct of Wirsung and the dorsal duct of Santorini ordinarily join. Failure of fusion of the two ducts results in a spectrum of anomalies known as pancreas divisum ( Fig. 103.6 ). In the most common variant the duct of Wirsung drains the uncinate process and variable amounts of the head of the pancreas through the major papilla, while the smaller duct of Santorini drains the majority of the pancreas through a more cephalad accessory papilla. Stenosis of one or both ducts may contribute to the development of pancreatitis.

Pancreas divisum is associated with 25% of patients with recurrent pancreatitis. In contrast, a group of patients with primary biliary disease who had ERCP manifested a 3.6% incidence of pancreas divisum. Necropsy series show a 5% to 10% incidence in the general population. A more recent pediatric study corroborates that of 52 children with relapsing or chronic pancreatitis, 10 had variants of pancreas divisum. The association with chronic or recurrent pancreatitis is unproven but suspected, and, if true, likely is multifactorial in mechanism.

Surgical treatment of recurrent pancreatitis in the setting of pancreas divisum with ductal stenosis includes transduodenal sphincteroplasty of the minor papilla draining the stenotic accessory duct of Santorini, as well as sphincteroplasty of the major papilla. The sphincteroplasties are done by insinuating a probe into the papilla and sharply dividing anterior to the probe, in gradual fashion. During the course of this sharp division, which serves to splay open the sphincter, interrupted 6-0 or 7-0 synthetic, monofilament, absorbable sutures are sequentially placed from ductal mucosa to surrounding duodenal mucosa. No stent is left. The duodenotomy, opened longitudinally, is closed transversely. Secretin (1 U/kg) given during the operation may assist in the localization of the papilla.

However, this treatment does not ensure resolution of the patient's symptoms. In one study of six patients, all patients had preoperative evidence of pancreas divisum with ductal obstruction by ERCP. Of the six, only one had a long-term excellent result. Another required ERCP and stenting 3 years later. Two of the six patients continued to have attacks of abdominal pain. Two others went on to have Puestow procedures, with achievement of long-term improvement. Clearly, for some patients with recurrent or chronic pancreatitis and pancreas divisum, sphincteroplasty alone may not address the whole problem, and pancreaticoenteric anastomosis may be required.

Acute and Chronic Pancreatitis

The most common pathologic entity affecting the pancreas in children is acute pancreatitis. Approximately a third of pancreatitis episodes are recurrent. In stark contrast with cases of pancreatitis in adults, where the most frequent causes are alcohol and gallstones, in children the etiology is much more diverse and includes biliary stones, familial, drug ingestion, hypercalcemia, trauma, hypertriglyceridemia, and pancreatic anomalies such as divisum. Multi­institutional and single-center studies have indicated an increase in the incidence of acute pancreatitis in children over a 26 year period from 1993--2009. The increase is noted to be multifactorial, with one of the most likely culprits being the obesity epidemic, which is a significant independent risk factor for acute biliary pancreatitis. There are approximately 3.6 to 13.2 cases of acute pancreatitis per 100,000 pediatric individuals, which approaches the incidence in adults. There is also substantial morbidity associated with pancreatitis, with one-quarter developing a severe complication, such as necrotizing pancreatitis, portal vein thrombosis, and diabetes, with mortality rates reaching 4% to 10% ( Fig. 103.7 ).

Medical management of chronic pancreatitis revolves around the use of total parenteral nutrition (TPN), somatostatin, pain management, pancreatic enzyme replacement, and endoscopic sphincterotomy and stenting. When these fail, surgical therapy is indicated. There are three pancreaticoenteric procedures described for the surgical management of chronic pancreatitis in children: the Frey, Puestow, and Duval procedures.

The Frey procedure involves opening the main pancreatic duct throughout its length in the neck, body, and tail of the gland, after which the head is “cored out” in continuity with the opened duct. A longitudinal anastomosis is then constructed between the gland and a Roux-en-Y limb of intestine. A retrospective study demonstrated improvements in symptoms and in quality of life in seven of nine patients (average age: 13 years) who underwent the Frey procedure. The Puestow procedure may also be used in children. DuBay et al. described 12 cases of hereditary pancreatitis treated by modified Puestow. The patients ranged from 2 to 16 years of age, and all had dilated ducts. They used a two-layer, side-to-side anastomosis between the opened pancreatic duct and a retrocolic, Roux-en-Y jejunal limb. These authors found significantly decreased rates of hospitalizations after 1 and 3 years and a significant gain in percentage of ideal body weight after 3 years. All but 1 of the 12 patients rated their own outcome as good or excellent. Crombleholme et al. also reported favorable results using the Puestow (with splenectomy) or modified Puestow (without splenectomy) procedure in a group of 10 children with chronic pancreatitis of varying etiologies. The authors found improvement or resolution of pain in all patients, with a mean follow-up of 4 years (range: 7 months to 20 years). The Duval procedure (distal pancreatectomy with Roux-en-Y pancreaticojejunostomy) may also be indicated in some patients. Weber and Keller reviewed 16 patients who had this procedure as the primary operation, and an additional 2 patients who were converted to Duvals following failure of prior Puestow procedures. Half had familial pancreatitis. Of the 18 patients, 13 were weaned entirely off pain medications and required no further hospitalizations, with a mean follow-up of 7.5 years. No claim can be made as to the relative superiority of one operative approach over the other.