The Pancreas
[Congenital anomalies]
PANCREATITIS
Mechanisms that normally protect the pancreas from self-digestion
o Enzymes secreted as inactive proenzymes (zymogens)
o Activation of proenzymes in the small intestine, not the pancreas
Enterokinase (duodenal enteropeptidase) activates trypsin in the small
intestine activates zymogens
o Acinar and ductal cells secrete trypsin inhibitors (serine protease inhibitor Kazal type 1)
Pancreatitis: deranges protective mechanisms pancreas autodigestion
ACUTE PANCREATITIS
Inappropriate activation of pancreatic enzymes reversible pancreatic parenchymal injury and
tissue destruction, and acute inflammation reaction
Intrapancreatic trypsin activation
o Prophospholipase activation fat cells degradation
o Proelastase activation damage of elastic fibers of blood vessels rupture
o Prekallikrein activation
o Coagulation factor XII activation clotting (thrombosis) and complement system
Mechanisms of pathogenesis
o Pancreatic duct obstruction
Mainly gallstones and biliary sludge
Periampullary neoplasms (pancreatic cancer), choledochoceles (congenital cystic
dilation of common bile duct), parasites (Ascaris lumbricoides and Clonorchis
sinensis), pancreas divisum
Obstruction increase intrapancreatic ductal pressure enzyme-rich fluid
accumulation in interstitium, contains lipase (normally secreted in active form)
local fat necrosis signals from necrotic adipocytes inflammatory
mediators release from periacinar myofibroblasts and leukocytes
inflammation and edema impaired blood flow acinar cells ischemia
o Primary acinar cell injury
Caused by
Oxidative stress free radical generation membrane lipid oxidation
and transcription factors activation (AP1 and NF-kB)
Increased calcium influx autoinhibition no more trypsin
inactivation and cleavage trypsinogen to trypsin
o Defective intracellular transport of proenzymes within acinar cells
Defect transport of digestive proenzymes and lysosomal hydrolases together
(normally separate) proenzymes activation lysosomes disruption and
enzymes release
Alcohol consumption
o Causes secretion of protein-rich pancreatic fluid protein plugs deposition small
pancreatic ducts obstruction
, o Causes oxidative stress on acinar cells free radicals generation, lysosomes and
zymogens granules fusion, and mitochondrial damage ( increase intracellular calcium)
Other causes: metabolic disorders (hypertriglyceridemia, hypercalcemia, hyperparathyroidism),
genetics, medications (estrogens, furosemide), infections (mumps)
Hereditary factors: cause recurrent attacks of severe acute pancreatitis in childhood chronic
pancreatitis
o Mutations increased and sustained trypsin activity
o Genes: PRSS1 (trypsinogen gene gain-of-function, autosomal dominant), SPINK1 (trypsin
inhibitor loss-of-function, autosomal recessive), and CFTR (causes decrease bicarbonate
secretion by pancreatic ductal cells protein plugging and duct obstruction)
o Increased risk of pancreatic cancer
Basic alterations
o Microvascular leak and edema
o Fat necrosis
o Acute inflammation
o Pancreatic parenchyma destruction
o Blood vessels destruction and interstitial hemorrhage
Acute interstitial pancreatitis
o Milder form
o Mild inflammation, interstitial edema, focal areas of fat necrosis in pancreas and
peripancreatic fat (released fatty acids + calcium insoluble salts: blue granules in cells)
Acute necrotizing pancreatitis
o More severe form
o Necrosis of acinar and ductal cells, and islets of Langerhans
o Vascular injury hemorrhage
o Macroscopically: red-black (hemorrhage) with interspersed foci of yellow-white (fat
necrosis)
o Fat necrosis in pancreas, omentum and mesentery of the bowel, and outside the
abdominal cavity (subcutaneous fat)
o Peritoneal cavity contains serous, turbid, brown-tinged fluid with globules of fat
Hemorrhagic pancreatitis
o Most severe form
o Extensive parenchymal necrosis
o Hemorrhage within the gland
Symptoms:
o Abdominal pain in the upper back and left shoulder
o Elevated serum amylase in first 24 hours
o Elevated serum lipase in 72 – 96 hours
o Glycosuria, hypocalcemia (calcium soap precipitation in necrotic adipocytes)
o Enlarges pancreas on CT scan
Full-blown acute pancreatitis
o Medical emergency
o Sudden onset of an “acute abdomen”
o Systemic inflammatory response: leukocytosis, DIC, edema, and ARDS shock
Treatment: total restriction of oral intake, with supportive IV fluids and analgesia
Complications: ARDS and acute renal failure, sterile pancreatic abscess and pancreatic
pseudocyst, infection with enteric gram (-) bacteria
[Congenital anomalies]
PANCREATITIS
Mechanisms that normally protect the pancreas from self-digestion
o Enzymes secreted as inactive proenzymes (zymogens)
o Activation of proenzymes in the small intestine, not the pancreas
Enterokinase (duodenal enteropeptidase) activates trypsin in the small
intestine activates zymogens
o Acinar and ductal cells secrete trypsin inhibitors (serine protease inhibitor Kazal type 1)
Pancreatitis: deranges protective mechanisms pancreas autodigestion
ACUTE PANCREATITIS
Inappropriate activation of pancreatic enzymes reversible pancreatic parenchymal injury and
tissue destruction, and acute inflammation reaction
Intrapancreatic trypsin activation
o Prophospholipase activation fat cells degradation
o Proelastase activation damage of elastic fibers of blood vessels rupture
o Prekallikrein activation
o Coagulation factor XII activation clotting (thrombosis) and complement system
Mechanisms of pathogenesis
o Pancreatic duct obstruction
Mainly gallstones and biliary sludge
Periampullary neoplasms (pancreatic cancer), choledochoceles (congenital cystic
dilation of common bile duct), parasites (Ascaris lumbricoides and Clonorchis
sinensis), pancreas divisum
Obstruction increase intrapancreatic ductal pressure enzyme-rich fluid
accumulation in interstitium, contains lipase (normally secreted in active form)
local fat necrosis signals from necrotic adipocytes inflammatory
mediators release from periacinar myofibroblasts and leukocytes
inflammation and edema impaired blood flow acinar cells ischemia
o Primary acinar cell injury
Caused by
Oxidative stress free radical generation membrane lipid oxidation
and transcription factors activation (AP1 and NF-kB)
Increased calcium influx autoinhibition no more trypsin
inactivation and cleavage trypsinogen to trypsin
o Defective intracellular transport of proenzymes within acinar cells
Defect transport of digestive proenzymes and lysosomal hydrolases together
(normally separate) proenzymes activation lysosomes disruption and
enzymes release
Alcohol consumption
o Causes secretion of protein-rich pancreatic fluid protein plugs deposition small
pancreatic ducts obstruction
, o Causes oxidative stress on acinar cells free radicals generation, lysosomes and
zymogens granules fusion, and mitochondrial damage ( increase intracellular calcium)
Other causes: metabolic disorders (hypertriglyceridemia, hypercalcemia, hyperparathyroidism),
genetics, medications (estrogens, furosemide), infections (mumps)
Hereditary factors: cause recurrent attacks of severe acute pancreatitis in childhood chronic
pancreatitis
o Mutations increased and sustained trypsin activity
o Genes: PRSS1 (trypsinogen gene gain-of-function, autosomal dominant), SPINK1 (trypsin
inhibitor loss-of-function, autosomal recessive), and CFTR (causes decrease bicarbonate
secretion by pancreatic ductal cells protein plugging and duct obstruction)
o Increased risk of pancreatic cancer
Basic alterations
o Microvascular leak and edema
o Fat necrosis
o Acute inflammation
o Pancreatic parenchyma destruction
o Blood vessels destruction and interstitial hemorrhage
Acute interstitial pancreatitis
o Milder form
o Mild inflammation, interstitial edema, focal areas of fat necrosis in pancreas and
peripancreatic fat (released fatty acids + calcium insoluble salts: blue granules in cells)
Acute necrotizing pancreatitis
o More severe form
o Necrosis of acinar and ductal cells, and islets of Langerhans
o Vascular injury hemorrhage
o Macroscopically: red-black (hemorrhage) with interspersed foci of yellow-white (fat
necrosis)
o Fat necrosis in pancreas, omentum and mesentery of the bowel, and outside the
abdominal cavity (subcutaneous fat)
o Peritoneal cavity contains serous, turbid, brown-tinged fluid with globules of fat
Hemorrhagic pancreatitis
o Most severe form
o Extensive parenchymal necrosis
o Hemorrhage within the gland
Symptoms:
o Abdominal pain in the upper back and left shoulder
o Elevated serum amylase in first 24 hours
o Elevated serum lipase in 72 – 96 hours
o Glycosuria, hypocalcemia (calcium soap precipitation in necrotic adipocytes)
o Enlarges pancreas on CT scan
Full-blown acute pancreatitis
o Medical emergency
o Sudden onset of an “acute abdomen”
o Systemic inflammatory response: leukocytosis, DIC, edema, and ARDS shock
Treatment: total restriction of oral intake, with supportive IV fluids and analgesia
Complications: ARDS and acute renal failure, sterile pancreatic abscess and pancreatic
pseudocyst, infection with enteric gram (-) bacteria
