Exocrine Pancreas 1 and 2. Lecture.pdf

Exocrine Pancreas 1 and 2 DEPARTMENT OF ANATOMICAL PATHOLOGY 2022 Learning objectives 1. Know the four of congenital abnormalities of the pancreas 2. Know the causes, morphology , pathogenesis and complications of acute and chronic pancreatitis 3. Know the non-neoplastic and neoplastic pa...

Exocrine Pancreas 1 and 2 DEPARTMENT OF ANATOMICAL PATHOLOGY 2022 Learning objectives 1. Know the four of congenital abnormalities of the pancreas 2. Know the causes, morphology , pathogenesis and complications of acute and chronic pancreatitis 3. Know the non-neoplastic and neoplastic pancreatic cysts 4. Know the causes, pathogenesis and morphology of pancreatic carcinoma  Anatomy Retroperitoneal organ Extends : C-loop of the duodenum → hilum of the spleen Separated: head, neck, body and tail 20cm in length  Anatomy Pancreatic duct system Main pancreatic duct (duct of Wirsung) drains into duodenum at papilla of Vater Accessory pancreatic duct (duct of Santorini) drains into duodenum through minor papilla Main pancreatic duct joins common bile duct – forms ampulla of Vater Ductal architecture differs significantly amongst people Physiology Exocrine portion produces digestive enzymes, constitutes 80-85% of organ Endocrine portion composed of islets of Langerhans; secrete insulin, glucagon and somatostatin, constitutes 1-2% of organ Physiology Exocrine pancreas secretes 1 – 2 litres of alkaline fluid per day Fluid contains approximately 20 enzymes – proteases, lipases, elastases, amylases Epithelium lining duct of pancreas secretes bicarbonate to make secretions alkaline Histology Exocrine pancreas composed of acinar cells, which produce enzymes needed for digestion Series of ductules & ducts convey secretions to duodenum Acinar cells o pyrimidally shaped epithelial cells o radially orientated around a central lumen o contain zymogen granules rich in digestive enzymes Congenital Anomalies Normal development Arises from fusion of dorsal and ventral outpouchings of the foregut. Dorsal primordium: body, tail, superior/anterior aspect of head of pancreas, accessory duct of Santorini Ventral primordium: posterior/inferior part of the head pancreas and drains through the main pancreatic duct into the into papilla of Vater. Agenesis Very rare Pancreas totally absent Associated with other severe malformations, incompatible with life Pancreas Divisum Most common congenital anomaly of pancreas Caused by failure of fusion of fetal duct systems of dorsal and ventral pancreatic primordia Bulk of pancreas drains through dorsal pancreatic duct and minor papilla Head of pancreas drains through major papilla Pancreas Divisum Relative stenosis caused by bulk of pancreatic secretions passing through minor papilla predisposes → chronic pancreatitis Annular Pancreas Band-like ring of normal pancreatic tissue Completely encircles second portion of duodenum Often associated with other congenital anomalies May present early in life or in adults Signs and symptoms of duodenal obstruction Ectopic Pancreas Accessory pancreatic tissue Aberrantly situated pancreatic tissue Favoured sites – stomach and duodenum Jejunum, Meckel diverticula and ileum Embryologic rests – few mm to cm in size, located in submucosa Micro : normal-appearing pancreatic acini, glands and islets of Langerhans Ectopic Pancreas Pain – localised inflammation or mucosal bleeding 2% islet cell neoplasms arise from ectopic pancreatic tissue Pathogenesis – not established Pancreatitis Acute Pancreatitis Acute Pancreatitis Reversible pancreatic parenchymal injury associated with inflammation Relatively common Causes Metabolic Alcoholism Hyperlipoproteinemia Hypercalcaemia Drugs e.g.: azathioprine Genetic Mutations in genes encoding trypsin, trypsin regulators, or proteins that regulate calcium metabolism Mechanical Gallstones Trauma Iatrogenic injury: Operative injury, endoscopic procedures with dye injections Vascular Shock Atheroembolism Vasculitis Infections Mumps Pathology - Gross o Severe blood-stained ascites o Evidence of acute peritonitis – fibrinous o Fat necrosis in omentum, mesentery & peritoneal wall White flakes with a haemorrhagic border o Pancreas – oedematous, haemorrhagic & (depending on severity) necrotic The pancreas is swollen and does not show the typical tan, lobulated architecture. Instead, it has areas of hemorrhagic necrosis that appear as blotchy black-red areas (mid-right). Pathology - Microscopy Depends on severity o Mild  Periductal necrosis  Acute inflammatory cell infiltrate within & around ducts  Variable amounts of oedema o Severe (additional)  Acinar necrosis  Parenchymal haemorrhage There is a region of fat necrosis on the right and focal pancreatic parenchymal necrosis (centre) The neutrophilic infiltrates of acute pancreatitis can be seen here with early fat necrosis At low power, the extent of the necrosis with acute pancreatitis is seen here. The mid-lower portion of the picture also demonstrates haemorrhage that is typical of this process. At high magnification, acute inflammation with necrosis and hemorrhage is seen with residual pancreatic acini in a case of acute hemorrhagic pancreatitis. The fat necrosis consists of steatocytes that have lost their nuclei and whose cytoplasm has a granular pink appearance. Some hemorrhage is seen at the left in this case. Pathogenesis Main event Autodigestion of pancreas by inappropriately activated pancreatic enzymes Trypsin synthesised in an inactive proenzyme form If trypsin inappropriately activated – activates other proenzymes , prophospholipase & proelastase → degrade fat cells & damage elastic fibres of blood vessels Trypsin also converts prekalikrein to its activated form → kinin system Pathogenesis Activation of Factor XII → clotting & complement systems Inflammation & small-vessel thromboses (which may lead to congestion & rupture of already weakened vessels) are amplified Thus inappropriate trypsinogen activation is an important triggering event Pathogenesis Mechanisms of activation of pancreatic enzymes : 1. Pancreatic duct obstruction Gallstones or biliary sludge impacted in region of ampulla of Vater can raise intrapancreatic ductal pressure & lead to accumlation of enzyme-rich fluid in interstitium Lipase (secreted in active form) causes local fat necrosis Pathogenesis Injured tissues release cytokines Initiating local inflammation and interstitial oedema through a leaky microvasculature Oedema may further compromise local blood flow causing vascular insufficiency & ischaemic injury to acinar cells Pathogenesis 2. Primary acinar cell injury Viruses – mumps Drugs Direct trauma Following ischaemia or shock 3. Defective intracellular transport of proenzymes within acinar cells Mechanism not clearly understood in human acute pancreatitis Pathogenesis Alcohol consumption may cause pancreatitis by several mechanisms : Chronic alcohol ingestion results in secretion of protein-rich pancreatic fluid leads to deposition of inspissated protein plugs & obstruction of small pancreatic ducts Also transiently ↑ pancreatic exocrine secretion & contraction of sphincter of Oddi Has direct toxic effects on acinar cells Clinical Aspects Abdominal pain o Constant & intense o Referred to upper back Anorexia, nausea, vomiting - frequent Full blown acute pancreatitis – medical emergency o Acute abdomen o Leukocytosis o Hemolysis o DIC – disseminated intravascular coagulation o ARDS – acute respiratory distress syndroma o Diffuse fat necrosis o Vascular collapse : Shock and acute renal tubular necrosis Clinical Aspects Lab findings : o Marked elevation of serum amylase levels during first 24 hours o Followed within 72-96 hours by a rising serum lipase level o Glycosuria o Hypocalcaemia Diagnosis : Increased plasma amylase & lipase levels Radiographical visualisation of enlarged inflamed pancreas exclusion of other causes of abdominal pain Management & Prognosis “Rest” pancreas Total restriction of oral intake Supportive therapy – IV fluids & analgesia Most patients recover fully; 5% with severe pancreatitis die from shock Complications Local : o Pancreatic abscess (superinfection by GIT organisms) o Pancreatic pseudocyst o Duodenal obstruction Complications Systemic : o Shock & its complications (shock lung, acute tubular necrosis) o Peritonitis (initially chemical, may become secondarily infected by bacteria – secondary bacterial peritonitis can result in shock) o Fat necrosis Chronic Pancreatitis Chronic Pancreatitis Inflammation of pancreas with irreversible destruction of exocrine parenchyma, fibrosis, and, in late stages, destruction of endocrine parenchyma Distinction between acute & chronic pancreatitis – irreversible impairment in pancreatic function in chronic pancreatitis Incidence - middle-aged males Causes Chronic alcoholism (commonest) Long-standing pancreatic duct obstruction Genetic disease Metabolic – cystic fibrosis gene mutations Autoimmune IgG4 Idiopathic Pathology Macroscopically : o Firm or hard with loss of normal lobular architecture o White to pale grey – excessive amounts of fibrous tissue o Dilatation of pancreatic ducts with calculi Pathology Microscopically : o Parenchymal fibrosis o Reduced number & size of acini, relative sparing of islets of Langerhans o Islets become embedded in fibrous tissue, eventually disappear in late stages o - Insular pancreas Pathology o Dilation of pancreatic ducts & contain protein plugs in lumens o Chronic inflammation – around lobules & ducts o Areas of calcification Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right) with a scattering of chronic inflammatory cells and acinar tissue A dilate duct with inspissated eosinophilic ductal concretions This image demonstrates scattered chronic inflammatory cells in a collagenous stroma with a few remaining islets of Langerhans The pancreatic parenchyma has been nearly replaced by pink collagenous connective tissue. About all that remains are islets of Langerhans. Pathogenesis Not well understood Proposed that acute pancreatitis initiates a sequence of perilobular fibrosis, duct distortion & altered pancreatic sectretions Over time & with multiple episodes – loss of pancreatic parenchyma & fibrosis Pathogenesis 1. Ductal obstruction by calcified plugs / concretions o Some agents responsible for causing chronic pancreatitis - ↑ protein concentrations in pancreatic juice o These proteins form ductal plugs o These plugs – prominent in alcoholic chronic pancreatitis o Ductal plugs calcify, forming calculi that further obstructs pancreatic ducts & contributes to development of chronic pancreatitis Pathogenesis 2. Toxic-effects o Toxins, including alcohol & its metabolites, exert a direct toxic effect on acinar cells 3. Oxidative stress o Alcohol-induced oxidative stress generates free radicals in acinar cells o May promote fusion of lysosomes & zymogen granules, acinar cell necrosis, inflammation & fibrosis Clinical Aspects May present in many different forms : Repeated attacks of moderately severe abdominal pain, recurrent attacks of mild pain or persistent abdominal & back pain Disease may be entirely silent until pancreatic insufficiency & Diabetes Mellitus develop Recurrent attacks of jaundice or vague attacks of indigestion may hint at pancreatic disease; Attacks may be preciptated by Alcohol abuse Overeating (increases demand) Use of opiates or other drugs that increase tone of sphincter of Oddi Clinical Aspects Diagnosis – requires a high degree of suspicion Attack of abdominal pain – mild fever & mild-to-moderate elevations of serum amylase (disease present for a long time – destruction of acinar cells may preclude such diagnostic clues) Gallstone-induced obstruction – jaundice or elevations in serum alkaline phosphatase Clinical Aspects CT Scan & MRI – calcifications within pancreas (even X-ray) Weight loss & hypoalbuminaemic oedema – provide clues Complications Severe pancreatic exocrine insufficiency Chronic malabsorption Diabetes Mellitus Severe chronic pain Pancreatic pseudocysts Prognosis Not an immediately life-threatening condition but long-term outlook is poor – with a 20- to 25- year mortality rate of 50% A lot of causes? "I VINDICATE AIDS": Iatrogenic Vascular Infectious Neoplastic Degenerative Inflammatory, immune Congenital Autoimmune Traumatic Endocrine, metabolic Allergic Idiopathic Drugs – prescription, illicit, traditional Social – environment, occupational, abuse Don’t forget: CNS (incl peripheral, autonomic nervous system)  Causes of epigastric pain?