Pathology and pathogenesis of acute and chronic pancreatitis Dr. Mamlook Elmagraby

Objectives of the lecture: Upon completion of this lecture, students should be able to: Recognize the predisposing factors of pancreatitis Understand the pathogenesis of acute and chronic pancreatitis Describe the different types of pancreatitis

Acute Pancreatitis

Acute Pancreatitis Pancreatitis is inflammation in the pancreas associated with injury to the exocrine parenchyma Acute pancreatitis is reversible pancreatic parenchymal injury associated with inflammation The clinical manifestations range in severity from a mild to a life-threatening process Biliary tract disease and alcoholism account for approximately 80% of acute pancreatitis cases

Hyperlipoproteinemia Hypercalcemia Drugs (e.g., azathioprine) METABOLIC Alcoholism Hyperlipoproteinemia Hypercalcemia Drugs (e.g., azathioprine) GENETIC Cationic trypsinogen (PRSS1) gene Trypsin inhibitor (SPINK1) gene MECHANICAL    Gallstones Trauma Iatrogenic injury VASCULAR Shock Atheroembolism Vasculitis INFECTIOUS Mumps Etiologic Factors in Acute Pancreatitis

Acute Pancreatitis Morphology The basic alterations are: Acute inflammation Microvascular leakage causing edema Necrosis of fat by lipolytic enzymes Proteolytic destruction of pancreatic parenchyma Destruction of blood vessels and interstitial hemorrhage The extent of these alterations depends on the duration and severity of the process

Acute Pancreatitis In the milder form, there are: Mild inflammation Interstitial edema Focal areas of fat necrosis In the more severe form: The acinar, ductal, the islets of Langerhans cells are necrotic Areas of red-black hemorrhage interspersed with foci of yellow- white, chalky fat necrosis A serous, turbid, brown-tinged fluid in the peritoneal cavity In the most severe form (hemorrhagic pancreatitis) : Extensive parenchymal necrosis accompanied by massive hemorrhage within the substance of the gland can occur

Acute pancreatitis. The pancreas has been sectioned longitudinally to reveal dark areas of hemorrhage in the head of the pancreas and a focal area of pale fat necrosis in the peripancreatic fat (upper left) 

Acute pancreatitis. The microscopic field shows a region of fat necrosis on the right and focal pancreatic parenchymal necrosis (center) 

Acute Pancreatitis Clinical Features Abdominal pain is the cardinal manifestation of acute pancreatitis Suspected acute pancreatitis is diagnosed by: ↑ plasma levels of amylase and lipase The exclusion of other causes of abdominal pain Severe acute pancreatitis is a medical emergency Direct visualization of the enlarged inflamed pancreas by radiography is useful

Acute Pancreatitis The systemic features of severe disease can be due to release of toxic enzymes, cytokines, other mediators into the circulation Explosive activation of the systemic inflammatory response → leukocytosis, hemolysis, DIC, ARDS and diffuse fat necrosis Shock with acute renal tubular necrosis may occur Most individuals with acute pancreatitis recover completely 5% with severe acute pancreatitis die from shock

Acute Pancreatitis Sequelae can include: a pancreatic pseudocyst The necrotic debris becomes infected

Chronic Pancreatitis

It is as inflammation of the pancreas with: irreversible destruction of exocrine parenchyma Fibrosis the destruction of endocrine parenchyma (late stages) The cause of chronic pancreatitis include: long-term alcohol abuse Long-standing obstruction of the pancreatic duct Tropical pancreatitis Hereditary pancreatitis CFTR gene mutations

Chronic Pancreatitis It is as inflammation of the pancreas with: irreversible destruction of exocrine parenchyma Fibrosis the destruction of endocrine parenchyma (late stages) The cause of chronic pancreatitis include: long-term alcohol abuse Long-standing obstruction of the pancreatic duct Tropical pancreatitis Hereditary pancreatitis CFTR gene mutations

Chronic Pancreatitis Pathogenesis The events that lead to the development of the disease include: Ductal obstruction by concretions Toxic effects Oxidative stress Several chemokines have been identified in chronic pancreatitis (IL-8, MCP, TGF-β, PDGF) The profibrogenic chemokines tend to predominate in chronic pancreatitis

Comparison of the mediators in acute and chronic pancreatitis. In acute pancreatitis acinar injury results in release of proteolytic enzymes, leading to a cascade of events including activation of the clotting cascade, acute and chronic inflammation, vascular injury, and edema. In most patients, complete resolution of the acute injury occurs with restoration of acinar cell mass. In chronic pancreatitis, repeated episodes of acinar cell injury lead to the production of profibrogenic cytokines such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF), resulting in the proliferation of myofibroblasts, the secretion of collagen, and remodeling of the extracellular matrix (ECM). Repeated injury produces irreversible loss of acinar cell mass, fibrosis, and pancreatic insufficiency

Chronic Pancreatitis Morphology Grossly, the gland is hard, sometimes with dilated ducts and visible calcified concretions Chronic pancreatitis is characterized by: parenchymal fibrosis reduced number and size of acini dilation of the pancreatic ducts which may contain protein plugs in their lumens atrophied or hyperplastic or metaplastic ductal epithelium a chronic inflammatory infiltrate around lobules and ducts relative sparing of the islets of Langerhans

Chronic pancreatitis. A, Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right), with a sprinkling of chronic inflammatory cells and acinar tissue. B, A higher power view demonstrating dilated ducts with inspissated eosinophilic ductal concretions in a person with alcoholic chronic pancreatitis

Chronic Pancreatitis Clinical Features Chronic pancreatitis may present in many different forms: repeated attacks of abdominal pain persistent abdominal and back pain pancreatic insufficiency diabetes mellitus The long-term outlook for individuals with chronic pancreatitis is poor

Chronic Pancreatitis Patients with hereditary pancreatitis have a 40% lifetime risk of developing pancreatic cancer Pancreatic pseudocysts develop in about 10% of patients