Embryology, Anatomy, and Physiology

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Chapter 339 Embryology, Anatomy, and Physiology

Steven L. Werlin

The human pancreas develops from the ventral and dorsal domains of the primitive duodenal endoderm beginning at about the 5th wk of gestation (see Fig. 339-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). The larger dorsal anlage, which develops into the tail, body, and part of the head of the pancreas, grows directly from the duodenum. The smaller ventral anlage develops as 1 or 2 buds from the primitive liver and eventually forms the major portion of the head of the pancreas. At about the 17th wk of gestation, the dorsal and ventral anlagen fuse as the buds develop and the gut rotates. The ventral duct forms the proximal portion of the major pancreatic duct of Wirsung, which opens into the ampulla of Vater. The dorsal duct forms the distal portion of the duct of Wirsung and the accessory duct of Santorini, which empties independently in ∼5% of people. Variations in fusion might account for pancreatic developmental anomalies. Pancreatic agenesis has been associated with a base pair deletion in the ipf1 HOX gene, PDX1, and possibly in the PTF1A and FS123TER genes. Other recessive genes involved in pancreatic organogenesis include the IHH, SHH or sonic hedgehog gene, SMAD2, and transforming growth factor (TGF)-1β genes.

Figure 339-1 Development of the exocrine pancreas. A, Gestational age 6 wk. B, Gestational age 7-8 wk. The ventral pancreas has rotated but has not yet fused with the dorsal pancreas. C, The ventral and dorsal pancreatic ductal systems have fused.

(From Werlin SL: The exocrine pancreas. In Kelly VC, editor: Practice of pediatrics, vol 3, Hagerstown, MD, 1980, Harper and Row.)

The pancreas lies transversely in the upper abdomen between the duodenum and the spleen in the retroperitoneum (Fig. 339-2). The head, which rests on the vena cava and renal vein, is adherent to the C loop of the duodenum and surrounds the distal common bile duct. The tail of the pancreas reaches to the left splenic hilum and passes above the left kidney. The lesser sac separates the tail of the pancreas from the stomach.

Figure 339-2 Anterior view of the pancreas: relationship to neighboring structures.

From Werlin SL: The exocrine pancreas. In: Kelly VC, editor: Practice of pediatrics, vol 3, Hagerstown, MD, 1980, Harper and Row.)

By the 13th wk of gestation, exocrine and endocrine cells can be identified. Primitive acini containing immature zymogen granules are found by the 16th wk. Mature zymogen granules containing amylase, trypsinogen, chymotrypsinogen, and lipase are present at the 20th wk. Centroacinar and duct cells, which are responsible for water, electrolyte, and bicarbonate secretion, are also found by the 20th wk. The final 3-dimensional structure of the pancreas consists of a complex series of branching ducts surrounded by grapelike clusters of epithelial cells. Cells containing glucagon are present at the 8th wk. Islets of Langerhans appear between the 12th and 16th wks.

339.1 Anatomic Abnormalities

Steven L. Werlin

Complete or partial pancreatic agenesis is a rare condition. Complete agenesis is associated with severe neonatal diabetes and usually death at an early age (Chapter 583).

Partial or dorsal pancreatic agenesis is often asymptomatic but may be associated with diabetes, congenital heart disease, polysplenia, and recurrent pancreatitis. Pancreatic agenesis is also associated with malabsorption.

An annular pancreas results from incomplete rotation of the left (ventral) pancreatic anlage, which may be due to recessive mutations in the IHH or SHH genes. Patients usually present in infancy with symptoms of complete or partial bowel obstruction or in the 4th or 5th decade. There is often a history of maternal polyhydramnios. Other congenital anomalies such as Down syndrome, tracheoesophageal fistula, intestinal atresia, imperforate anus, malrotation and cardio-renal abnormalities, and pancreatitis may be associated with annular pancreas. Some children present with chronic vomiting, pancreatitis, or biliary colic. The treatment of choice is duodenojejunostomy. Division of the pancreatic ring is not attempted, because a duodenal diaphragm or duodenal stenosis often accompanies annular pancreas.

Ectopic pancreatic rests in the stomach or small intestine occur in ∼3% of the population. Most cases (70%) are found in the upper intestinal tract. Recognized on barium contrast studies by their typical umbilicated appearance, they are rarely of clinical importance. On endoscopy, they are irregular, yellow nodules 2-4 mm in diameter. A pancreatic rest may rarely be the lead point of an intussusception, produce hemorrhage, or cause bowel obstruction.

Pancreas divisum, which occurs in 5-15% of the population, is the most common pancreatic developmental anomaly. As the result of failure of the dorsal and ventral pancreatic anlagen to fuse, the tail, body, and part of the head of the pancreas drain through the small accessory duct of Santorini rather than the main duct of Wirsung. This anomaly may be associated with recurrent pancreatitis if there is relative obstruction of the outflow of the ventral pancreas. Diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) or by magnetic resonance cholangiopancreatography (MRCP). The treatment of choice of recurrent pancreatitis associated with pancreas divisum is endoscopic insertion of an endoprosthetic stent. If the episodes stop occurring, surgical sphincterotomy is indicated.

Choledochal cysts are dilatations of the biliary tract and usually cause biliary tract symptoms, such as jaundice, pain, and fever. On occasion, the presentation may be pancreatitis. The diagnosis is usually made with ultrasonography, CT or biliary scanning, or MRCP. Similarly, a choledochocele, an intraduodenal choledochal cyst, manifests with pancreatitis. The diagnosis can be difficult and require MRCP, ERCP, or endoscopic ultrasound.

A number of rare conditions, such as Ivemark and Johanson-Blizzard syndromes include pancreatic dysgenesis or dysfunction among their features. Many of these syndromes include renal and hepatic dysgenesis along with the pancreatic anomalies.

Cano D, Hebrok M, Zenker M. Pancreatic development and disease. Gastroenterology. 2007;132:745-762.

Howard ER. Congenital abnormalities. In: Howard ER, Stringer MD, Colombani PM, editors. Surgery of the liver and bile ducts in children. ed 2. London: Arnold; 2002:493-502.

Klein SD, Affronti JP. Pancreas divisum, an evidence-based review: part I, pathophysiology. Gastrointest Endosc. 2004;60:9-25.

Klein SD, Affronti JP. Pancreas divisum, an evidence-based review: part II, patient selection and treatment. Gastrointest Endosc. 2004;60:585-589.

339.2 Physiology

Steven L. Werlin

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 >20 enzymes, which are stored in zymogen granules, some in inactive forms. The relative concentration of the various enzymes in pancreatic juice is affected and perhaps controlled by the diet, probably by regulating the synthesis of specific messenger RNA. The main enzymes involved in digestion include amylase, which splits starch into maltose, isomaltose, maltotriose; dextrins; and trypsin and chymotrypsin, endopeptidases secreted by the pancreas as inactive proenzymes. Trypsinogen is activated in the gut lumen by enterokinase, a brush border enzyme. Trypsin can then activate trypsinogen, chymotrypsinogen, and procarboxypeptidase into their respective active forms. Pancreatic lipase requires colipase, a coenzyme also found in pancreatic fluid, for activity. Lipase liberates fatty acids from the 1 and 3 positions of triglycerides, leaving a monoglyceride.

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 90-98% before fat maldigestion occurs.

Although amylase and lipase are present in the pancreas early in gestation, secretion of both amylase and lipase is low in the infant. Adult levels of these enzymes are not reached in the duodenum until late in the 1st yr of life. Digestion of the starch found in many infant formulas depends in part on the low levels of salivary amylase that reach the duodenum. This explains the diarrhea that may be seen in infants who are fed formulas high in glucose polymers or starch. Neonatal secretion of trypsinogen and chymotrypsinogen is at ~70% of the level found in the 1 yr old infant. The low levels of amylase and lipase in duodenal contents of infants may be partially compensated by salivary amylase and lingual lipase. This explains the relative starch and fat intolerance of premature infants.

Christian M, Edwards C, Weaver LT. Starch digestion in infancy. J Pediatr Gastroenterol Nutr. 1999;29:116-124.

Werlin S, Mayer AN. Development of the exocrine pancreas. In Polin RA, Fox WW, Abman SH, editors: Fetal and neonatal physiology, ed 4, Philadelphia: WB Saunders, 2010.

Werlin S, Mayer AN. Development of the exocrine pancreas. In Polin RA, Fox WW, Abman SH, editors: Fetal and neonatal physiology, ed 4, Philadelphia: WB Saunders, 2010.

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