Pancreas

The pancreas is a glandular organ located in the retroperitoneum between the duodenal curvature and the splenic hilum. It has both exocrine and endocrine functions and is anatomically classified into four parts: the head, neck, body, and tail. Because it is embryologically derived from the foregut, the pancreas receives arterial supply from the celiac trunk and its branches. The veins of the pancreas drain into the portal vein and the lymphatics eventually drain into the celiac, superior mesenteric, and splenic lymph nodes. The pancreas receives both sympathetic and parasympathetic innervation via the celiac ganglia. Histologically, the pancreas has two functional structures: the exocrine acinar glands and the endocrine pancreatic islets. The exocrine glands produce digestive enzymes, which are secreted into the duodenum, and the endocrine islets produce blood glucose-regulating hormones such as insulin and glucagon, which are secreted into the blood.

Overview

• Characteristics
  • Glandular organ
  • Length: 12–15 cm
  • Weight: approx. 80 g
• Location
  • In the abdominal cavity, between the duodenal curvature and the splenic hilum
  • Secondary retroperitoneal organ
  • Caudal to the omental bursa
  • At vertebral level L1/L2
• Function
  • Endocrine: produces somatostatin, glucagon, and insulin
  • Exocrine
    • Produces digestive enzymes that aid the absorption of macronutrients
    • Produces bicarbonate, which neutralizes chyme

Anatomical subdivisions of the pancreas ^[1][2]

• Head
  • Located within the C-shaped duodenal curvature
  • Contains the pancreatic duct and distal common bile duct
  • Uncinate process of pancreas: an extension of the pancreatic head that is located posterior to the superior mesenteric vessels (the remainder of the pancreas is not)
• Neck: lies anterior to the portal vein
• Body: lies anterior to the aorta and extends to the left kidney
• Tail
  • Lies in the splenorenal ligament and extends to the splenic hilum
  • The distal segment is intraperitoneal.

The uncinate process is posterior to the superior mesenteric vessels. The head, body, and tail of the pancreas lie anterior to the superior mesenteric vessels.

Pancreatic ducts ^[1][2]

• Pancreatic duct (duct of Wirsung): extends from the tail to the head of the pancreas
  • Ventral pancreatic duct: drains the ventral bud of the developing pancreas; merges with the dorsal pancreatic duct to form the main pancreatic duct
  • Dorsal pancreatic duct: drains the dorsal bud of the developing pancreas; merges with the ventral pancreatic duct to form the main pancreatic duct
  • Joins with the common bile duct → together they form the hepatopancreatic ampulla (ampulla of Vater) → empties into the major duodenal papilla
  • Hepatopancreatic sphincter (sphincter of Oddi): controls the secretion of bile and pancreatic fluid into the duodenum
• Accessory pancreatic duct (duct of Santorini): begins in the head and drains the pancreatic head and body → empties at the minor duodenal papilla

Tumors in the pancreatic head often cause bile duct obstruction and can manifest with painless jaundice (Courvoisier sign).

Gallstones that block the ampulla of Vater can result in both pancreatitis and cholangitis (double duct sign).

Vasculature, lymphatics, and innervation of the pancreas ^[1][2]

• Arteries
  • Head and neck
    • Superior pancreaticoduodenal branches (from the gastroduodenal artery)
    • Inferior pancreaticoduodenal branches (from the superior mesenteric artery)
  • Body and tail: branches of the splenic artery (itself a branch of the celiac trunk)
• Veins
  • Head and neck: pancreatic veins → superior mesenteric vein → portal vein
  • Body and tail: pancreatic veins → splenic vein → portal vein
• Lymphatics: celiac, superior mesenteric, and splenic lymph nodes → paraaortic lymph nodes
• Innervation: celiac ganglia
  • Sympathetic fibers from T6–12
  • Parasympathetic fibers from the vagus nerve

Exocrine pancreas ^[1]

• > 90% of the pancreas
• Produces digestive enzymes that are secreted into the gastrointestinal tract (see ”Exocrine pancreas” below)
• Composed of serous glandular tissue that is separated into lobules by collagenous septae
• Pancreatic acini
  • Units of secretory acinar cells surrounding a small lumen
  • Secrete proenzymes (e.g., trypsinogen, chymotrypsinogen) into intercalated ducts → ducts eventually merge to form the pancreatic duct → duct carries the enzymes out of the pancreas and to the duodenum
  • Centroacinar cells: pale cells in the center of the acini, which secrete bicarbonate ions into the pancreatic fluid
  • Electron micrographs of acinar cells show:
    • Basophilic rough endoplasmic reticulum at the basal pole
    • Eosinophilic proenzyme granules at the apical pole

Histologically, the exocrine pancreas closely resembles the salivary glands. However, unlike the salivary glands, the pancreatic exocrine glands lack myoepithelial cells in the acini and do not possess striated ducts. Additionally, centroacinar cells are unique to the pancreas.

Endocrine pancreas ^[1]

• Produces different hormones that are primarily involved in the regulation of blood glucose levels (see “Endocrine pancreas” below)
• Composed of islets of Langerhans embedded within the exocrine pancreas
  • Islet cell types are dispersed throughout the pancreas.
    • Alpha cells produce glucagon.
    • Beta cells produce insulin.
    • Delta cells produce somatostatin.
    • Epsilon cells produce ghrelin.
    • Pancreatic polypeptide cells (formerly gamma cells) produce pancreatic polypeptide (PP).

Beta cells, which are located on the INSide of islets of Langerhans, produce INSulin.

Pancreatic ducts ^[1]

• Smaller ducts have cuboidal epithelium.
• Larger interlobular ducts have columnar epithelium.
• Most pancreatic malignancies are adenocarcinomas that originate in the ductal epithelium. ^[1]

Exocrine secretions

The pancreatic fluid is isotonic. It contains the following:

• Digestive pancreatic enzymes
  • Pancreatic proteases: digestion of proteins
    • Secreted as inactive proenzymes (zymogens) by pancreatic acinar cells into the pancreatic duct
    • Trypsin and chymotrypsin
      • Proenzymes: trypsinogen and chymotrypsinogen
      • Activated in the duodenum: Trypsinogen is activated to trypsin by enterokinases, which are located at the brush border of the duodenal and jejunal mucosa.
      • Once activated, trypsin activates chymotrypsinogen to form chymotrypsin and, furthermore, converts additional trypsinogen molecules to trypsin (positive feedback loop).
    • Elastase (activated by trypsin)
      • Digestion of elastin fibers
      • Activated by trypsin
    • Carboxypeptidase: activated by trypsin
  • Pancreatic amylase (secreted in active form): digestion of carbohydrates
  • Pancreatic lipase: digestion of lipids
  • Phospholipase A: digestion of phospholipids
  • Nucleases: digestion of RNA/DNA
• Electrolytes (Na⁺, K⁺, Cl^-, HCO₃^-): Concentration of Cl^- and HCO₃^- increases with the rate of pancreatic juice secretion
• Water

Cystic fibrosis is caused by a defective chloride channel that impairs pancreatic water and electrolyte secretion. This results in obstruction of the pancreatic ducts, with subsequent maldigestion and malabsorption.

Feedback mechanisms

• Stimulation
  • Cholecystokinin (CCK): from enteroendocrine cells of the duodenum
  • Secretin: from enteroendocrine cells of the duodenum
• Inhibition: somatostatin

Acute pancreatitis leads to activation of the pancreatic enzymes within the pancreatic ducts, which also leads to subsequent autodigestion of pancreatic tissue.

Elevations in serum lipase and amylase can be seen in acute pancreatitis.

Main endocrine cell types and hormones produced

Insulin synthesis and regulation

• Insulin synthesis ^[3][4]
  1. Insulin gene transcription and translation in the rER of pancreatic β-cells → preproinsulin (precursor protein)
  2. Signal proteases remove the signal peptide of preproinsulin → proinsulin
  3. Protein folding and formation of one disulfide bridge in the α-chain and two disulfide bridges between the α-chain and β-chain
  4. Proinsulin is transported to the Golgi apparatus → packaged in membrane-bound secretory granules with proprotein convertases
  5. Proinsulin is cleaved by proteases → mature insulin and C-peptide
  6. Secretion of insulin and C-peptide via exocytosis
• Regulation: The secretion of insulin is chiefly regulated by the levels of serum blood glucose. ^[4]
  • Insulin secretory pathway: GLUT2-mediated transfer of glucose into the pancreatic β cells → ↑ glucose metabolism → ↑ ATP production → closure of ATP-sensitive potassium channels → cell membrane depolarization → opening of voltage-gated calcium channels → ↑ intracellular calcium levels → ↑ insulin secretion
  • Insulin release stimulants ^[5][6]
    • Glucose (because of incretin secretion following food ingestion, oral administration stimulates more insulin release than IV glucose)
    • β₂ agonists
    • Free fatty acids ^[7]
    • Amino acids ^[8]
    • Incretins (e.g., GLP-1 and GIP) ^[9]
  • Insulin release inhibitors ^[6]
    • α₂agonists
    • Epinephrine
    • Cortisol
    • Glucagon
    • Somatostatin ^[10]
• Clearance: via liver and kidney

C-peptide is released by the β-cells in an equimolar proportion to insulin but is not present in exogenous insulin. It can, therefore, be used to differentiate between endogenous (e.g., insulinoma, sulfonylurea use) and exogenous hyperinsulinism.

Oral glucose results in a greater increase in insulin levels than IV administration.

• Origin: derived from the foregut (endoderm)
• Steps
  1. The endoderm forms ventral and dorsal pancreatic buds.
     • Ventral pancreatic bud: main pancreatic duct, uncinate process, lower part of pancreatic head
     • Dorsal pancreatic bud: rest of pancreatic head, neck, body, tail, and accessory pancreatic duct
  2. Foregut rotation: ventral pancreatic bud fuses with the dorsal pancreatic bud
  3. Secondary retroperitonealization
  4. The pancreas comes to rest under the lesser sac (omental bursa).
• Impaired development ^[11][12]
  • Annular pancreas: failure of the ventral pancreatic bud rotation → fusion of the ventral and dorsal buds → formation of a pancreatic ring around the second part of the duodenum → duodenal compression (preampullary or postampullary)
    • Associated with Down syndrome
    • Clinical features
      • Antenatal: polyhydramnios
      • Postnatal: feeding difficulties, nonbilious or bilious vomiting, abdominal distention
      • Adults: abdominal postprandial distention, epigastric pain, nonbilious or bilious vomiting
    • Imaging findings: double bubble sign on x-ray (if duodenal stenosis is present)
  • Pancreas divisum: failure of the ventral and dorsal buds to fuse by the 8^th week of gestation results in separate drainage of the dorsal and ventral pancreatic ducts via minor and major duodenal papillae respectively
    • Most common congenital defect of the pancreas
    • Clinical features: usually asymptomatic but may cause chronic abdominal pain or pancreatitis in some cases
• See also “Embryology of the gastrointestinal tract.”

Exocrine pancreas

• Cystic fibrosis
• Acute pancreatitis
• Chronic pancreatitis
• Pancreatic cancer
• Gallstone pancreatitis
• Cholangitis
• Mumps
• Pancreatic pseudocyst

Endocrine pancreas

• Diabetes mellitus
• Pancreatic neuroendocrine tumors
  • Insulinoma
  • Gastrinoma (Zollinger-Ellison syndrome)
  • Glucagonoma
  • Somatostatinoma
  • VIPoma
• MEN 1 syndrome
• Hemochromatosis

Embryology of the pancreas

• Annular pancreas
• Pancreas divisum