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PHL - 5.06 PAT - 5.06 Liver and Gallbladder physiology & pathology Dr. Hurnik BMS 150 Week 12 Outline Liver & Gallbladder physiology Liver anatomy, vasculature, & histology Liver microarchitecture Liver function Biotransformation Biliru...

PHL - 5.06 PAT - 5.06 Liver and Gallbladder physiology & pathology Dr. Hurnik BMS 150 Week 12 Outline Liver & Gallbladder physiology Liver anatomy, vasculature, & histology Liver microarchitecture Liver function Biotransformation Bilirubin conjugation Storage & synthesis of nutrients Bile production Gallbladder anatomy & histology Gallbladder function Bile concentration Liver & Gallbladder pathology Cirrhosis Cholelithiasis Jaundice Learning outcomes Coming soon Liver - introduction Big organ – about 1.2 - 1.5 kg 2-5% of body weight (adult) Has a special place in the circulatory system Receives portal blood that drains the stomach, small intestine, large intestine, pancreas, and spleen Play an important role in immunology: Kupffer cells of the liver represent up to 80% of the mononuclear phagocyte system Anatomy and Physiology (Betts et al). Figure 23.24 Liver – Anatomy: lobes Four lobes: Right lobe Left lobe Quadrate lobe Located inferiorly Caudate lobe Located posteriorly non-palpable Moore et al et. al., Moore’s Clinically Oriented Anatomy (7th ed). Fig 2.64, p. 269  Liver – Anatomy: Ligaments Important ligaments: Coronary ligaments anchors the liver to the diaphragm § Falciform ligament separates right an left lobe § Round ligament found on free border of falciform ligament separates quadrate and left lobe Aka ligamentum teres Connects the liver to the umbilicus Remnant of the left umbilical vein Moore et al et. al., Moore’s Clinically Oriented Anatomy (7th ed). Fig 2.64, p. 269 Liver – Anatomy: Ligaments Important ligaments continued: Ligamentum venosum Separates the caudate & left lobe Fibrous remnants of ductus venosus from fetal circulation Gallbladder separates Quadrate & (R) lobe Moore et al et. al., Moore’s Clinically Oriented Anatomy (7th ed). Fig 2.65, p. 270 Liver – Vasculature: The liver receives blood from 2 sources: § Oxygenated blood from the hepatic artery § Deoxygenated, nutrient-rich blood from the hepatic portal vein § Both enter Porta hepatis: Opening for 3 main things entering liver: § Hepatic artery § Portal vein § Common hepatic duct Moore et al et. al., Moore’s Clinically Oriented Anatomy (7th ed). Fig 2.65, p. 270 Liver - Histology Three main components: § Hepatocytes § Bile canaliculi/cholangiocytes § Hepatic sinusoids § Other Hepatic stellate cell/Ito cell Kupffer cells Liver – Histology: Hepatocytes Hepatocytes § Major functional cells of liver Specialized epithelial cells 80% of the volume of the liver § Arranged into hepatic laminae “Plates” of hepatocytes (1 cell thick), bordered by endothelial-lined vascular spaces (hepatic sinusoids) Highly branched structures Grooves in the cell membrane of neighboring hepatocytes provide space of bile canaliculi Retrieved from: https://commons.wikimedia.org/wiki/File:Hepatic_structure2.svg  Hepatocytes & Vasculature Hepatocytes are arranged into lobules § Hepatic Lobules surround a central vein and are cornered by portal triad Central Vein § Drains hepatic sinusoids § Empties into hepatic vein Portal Triad: § Bile duct § Arteriole branch of hepatic artery Portal Triad § Venule branch of portal vein Anatomy and Physiology (Betts et al). Figure 23.25 Liver – Histology: Bile canaliculi & Cholangiocytes Bile canaliculi & Cholangiocytes § Bile canaliculi Small ducts found between hepatic laminae that collect bile § Cholangiocytes line bile ductules & ducts Cholangiocytes Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.4 Liver – Histology: Hepatic sinusoids Hepatic sinusoids § Capillary system specific to the liver Fenestrated discontinuous endothelium § Hepatocytes are separated from sinusoids by the space of Disse § Hepatic sinusoids are an area where blood from the portal vein and hepatic artery mix Converge and drain into central vein Retrieved from: https://commons.wikimedia.org/wiki/File:Hepatic _structure2.svg Liver – Histology: Hepatic stellate cell Hepatic stellate cell/Ito cell § Found in space of Disse; normally in a quiescent state § Major cell type involved in liver fibrosis Cells become active when there is damage Secrete collagen and extracellular matrix in response to damage à Scar tissue formation More to come in pathology section § Cell has several long protrusions that wrap around sinusoids § Store lipid droplets in cell body containing Vitamin A retinol esters Also known as lipocytes for this reason  Liver – Histology: Kupffer cells Kupffers cells: § Resident macrophage of the liver Derived from circulating monocytes § Function: Phagocytose old RBC’s, Hemoglobin, particulate matter, cellular debris, microorganisms Retrieved from: https://commons.wikimedia.org/wiki/File:Hepatic _structure2.svg Liver – Histology: microarchitecture Hepatocytes, bile duct system and hepatic sinusoids can be organized into functional units called hepatic acinus: § Approximate oval mass that includes portions of 2 neighboring hepatic lobules Short axis defined by branches of portal triad Long axis by 2 imaginary curved lines which connect the 2 central veins to the short axis § Hepatocytes are arranges in 3 zones around short axis Zone 1 – most O2 Zone 2 Zone 3 – least O2 Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.3 Liver – Histology: Hepatocytes FYI – microarchitecture of the liver has also been described in the following models: Preferred structural & functional unit of the liver is considered the Hepatic Acinus described on the previous slide Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.3 Liver – Histology: microarchitecture Hepatocyte function differs based on zone within hepatic acinus For example: § Periportal hepatocytes in zone 1 specialize in oxidative metabolism § Pericentral hepatocytes in zone 3 specialize in biotransformation of drugs Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.3 Liver functions The liver plays many important roles: § Biotransformation & degradation § Bilirubin conjugation § Storage & synthesis of nutrients § Bile production Liver function – biotransformation & degradation One of the major functions of the liver is to metabolize, detoxify, and inactivate both endogenous compounds and exogenous compounds § Process lipophilic chemicals into polar, water-soluble metabolites Why? § Liver will then either excrete them into bile OR return them into circulation The liver functions to convert important hormones and vitamins into their more active forms: § Eg. Initial hydroxylation of Vitamin D § Deiodination of T4 to T3 Liver function – biotransformation & degradation An enormous variety of compounds are brought into hepatocytes from portal and systemic circulation § 4 major steps: 1. Hepatocyte imports the compounds from blood across it’s basolateral membrane § Basolateral membrane = closest to sinusoid 2. Hepatocyte transport material within the cell 3. Hepatocyte may chemically modify/ degrade products intracellularly § Can occur in lysosomes or via biotransformation reactions 4. Hepatocyte excretes the molecule into bile across its apical membrane Medical Physiology (Boron and Boulpaepl). § Apical membrane = canalicular 3rd ed. Figure 46.5 Biotransformation & degradation - Step 1 A Na-K pump at the basolateral membrane provide energy for transporting a wide variety of solutes Medical Physiology (Boron and into the hepatocyte via channels and Boulpaepl). 3rd ed. Figure 46.5 transporters § Maintains a low intracellular Na+ concentration, thus diffusion of Na+ into the cell (ie down its concentration gradient) is used to fuel a number of active transporters: Eg. Na-H exchanger, Na/HCO3 cotransporter, Na+-driven amino acid transporter Na/taurocholate co-transporting polypeptide (NTCP) – responsible for uptake of bile  Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.5 Biotransformation & degradation - Step 1 cont. There are also several Na-independent transporters: § Organic anion-transporting polypeptides (OATPs) – responsible for uptake of a variety of endogenous & exogenous amphipathic compounds Eg. Bile acids, bilirubin, ecosanoids, prostaglandins, statin drugs, methotrexate, etc. § Organic cation transporter (OCT) – responsible for update of a variety of lipophilic organic cations Eg. Acyclovir, lipodcain, epinephrine, norepinephrine, histamine  Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.5 Biotransformation & degradation - Step 3 Divided into two phases: § Phase I – oxidation or reduction reactions typically catalyzed by P-450 cytochromes enzymes (aka CYP450) Can include hydroxylation, dealkylation, dehalogenation, etc. Ultimately, however, 1 atom of oxygen is inserted into the substrate, making it a more polar compound Some drugs and herbs can alter the function of P-450 cytochrome enzymes § Hypericum perforatum is an inducer of many CYP450 enzymes What do you think this means? RH ROH RO-Conjugate Phase I Phase II  Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.5 Biotransformation & degradation - Step 3 cont. Divided into two phases: § Phase II – conjugation A highly hydrophilic compound is added § What does this help with? Typically involve addition of glucuronate, sulfate, or glutathione § Uridine diphosphate gluconosyntransferase (UGT) add glucuronic acid Found in smooth ER § FYI - Sulfotransferases & Glutathione-S-transferases catalyze sulfation & addition of glutathione respectively Found in cytosol RH ROH RO-Conjugate Phase I Phase II  Details FYI – for illustration of ABC transporters Biotransformation & degradation - Step 4 Conjugated compound is transported out of the hepatocyte Also called phase III § Secreted into bile across canalicular membrane or into the blood via sinusoidal membrane § Requires transporters on either membrane: ATP-binding Casette (ABC) – can be found on canalicular and sinusoidal membranes § Transports a wide variety of conjugated drugs & bilirubin either into bile or blood Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.5 Liver function – bilirubin conjugation Senescent erythrocytes are phagocytosed by macrophages & heme will be degraded into bilirubin & released into the blood § Unconjugated bilirubin will be carried to the liver bound to albumin In the liver bilirubin will be conjugated § 1-2 residues of glucuronic acid are added § Catalyzed by _________ Bilirubin glucuronide will be excreted into bile Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 18.26, p. 852 Liver function – bilirubin conjugation Bacteria in the terminal ileum and colon converts some of the conjugated bilirubin back into bilirubin § The this bilirubin will be converted to urobilinogen Some will then be converted to stercobilin § Stercobilin = main pigment of feces Some will be reabsorbed into the blood and will be filtered by the kidney § Given urine it’s yellow colour Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 18.26, p. 852 Liver function – Storage & synthesis of nutrients After absorption, nutrients are brought to the liver via the hepatic portal vein § Depending on metabolic requirements, these substrates can be: Stored in hepatocytes, Released unbound into circulation Bound to a carrier molecules and released into circulation Liver function – Storage & synthesis of nutrients The liver can also synthesize many substances essential to body metabolism § Highly regulated § Can we name some? § Also: albumin, coagulation factors, plasma proteins § Lipoprotein synthesis will be discussed on Friday Liver function – Bile production Bile production by the liver serves two functions: § 1. Elimination of exogenous and endogenous waste products Eg. Bilirubin & cholesterol § 2. Promotes digestion and absorption of lipids from the intestines Covered last week  Liver function – Bile production Bile is synthesized initial from cholesterol in the liver § Yielding primary bile acids § These bile acids will be conjugated prior to being secreted into bile (yielding bile salts) In the terminal ileum and colon bile can be dehydroxylated by bacteria and reabsorbed § This process is called _____________ § These secondary bile salts will also be conjugated prior to be re- secreted into bile Medical Physiology Reactions FYI – (Boron and Boulpaepl). 3rd ed. Figure 46.9 for visualization only Liver function – Bile production Other components of Bile: § Phospholipids § IgA – inhibit bacterial growth in bile § Excretory waste products Cholesterol Bile pigments – bilirubin Lipophilic drugs & metabolites Oxidized glutathione Trace minerals Liver function – Bile production Bile flows pathway § Hepatocyte à bile canaliculi § à bile ductules § à bile ducts (Right & left) § à common hepatic duct § à cystic duct § à common bile duct § à duodenum Bile composition will be modified significantly as it travels along intra & extrahepatic bile ducts & will be concentrated in the gallbladder. Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.4 Gallbladder Anatomy Small, pear shaped organ on inferior aspect of liver § ~10 cm in length and 4 cm in cross section § Can hold about 30-50mL of liquid in adults Absorptive surface is enhanced with numerous prominent folds § Important for bile concentration Continuous with the cystic duct § Cystic duct histology is continuous with the gallbladder Same surface columnar epithelium, lamina propria, muscularis, serosa Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.4 Gallbladder - Histology Mucosa § Epithelium: simple columnar § Lamina propria Loose CT with lots of elastic and collagen fibers Thin muscularis § Muscle fibers oriented in several directions Serosa § Simple squamous epithelium Gallbladder Function Function: § Storage of bile that is secreted continuously by hepatocytes until it’s needed in the duodenum § Bile concentration Reabsorption of Na, Cl & water Medical Physiology (Boron and Boulpaepl). 3rd ed. Figure 46.12 Occurs during inter-digestive period Gallbladder Function - emptying Review § When food digestion begins in upper GI tract, the gallbladder begins to empty (especially with fatty foods) Emptying occurs with rhythmical contractions of gallbladder wall Also requires simultaneous relaxation of the sphincter of Oddi § Regulation: CCK most potent Acetylcholine-secreting nerve fibers from vagus and ENS also contribute Liver & gallbladder pathology We will cover select pathologies of the liver & gallbladder: § Cirrhosis § Cholelithiasis & cholecystitis § Jaundice Cancers to be covered later in the term Cirrhosis - intro Definition: § Diffuse remodeling of the liver into parenchymal nodules surrounded by fibrous bands and variable degree of vascular shunting Etiologies § Leading causes of cirrhosis Chronic hepatitis B, chronic hepatitis C, Nonalcoholic fatty liver disease Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Alcoholic liver disease Fig 18.5, p. 828  Cirrhosis - pathogenesis Stellate cells become activated & differentiate into highly fibrogenic myofibroblasts § Activated by inflammatory cytokines (eg. TNF-alpha), interactions with extracellular matrix, toxins, reactive oxygen species § Differentiation stimulated by signals transmitted by platelet-derived growth factor –Beta (PDGF-B) receptor & cytokines (TGF-Beta, IL- 17) Retrieved from: https://commons.wi kimedia.org/wiki/Fil e:Hepatic_structure 2.svg Cirrhosis – pathogenesis & pathophysiology Activated stellate cells deposit extracellular matrix § Often in space of Disse Concurrent loss of sinusoidal endothelial cells Areas of hepatocyte loss are converted into dense fibrous septa Surviving hepatocytes form Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 18.6, p. 829 regenerative nodules in an Thick bands of collagen separate attempt to restore liver rounded cirrhotic nodules parenchyma Cirrhosis – clinical features, progression, & complications Symptoms § Many are asymptomatic until most advanced stages of disease § Symptoms are often non-specific: Anorexia, weight loss, weakness Progression § Reversal is possible, but will often progress to liver failure Complications § Progression to liver failure resulting in jaundice, nausea/vomiting, encephalopathy and coagulation defects § Common causes of death: hepatic encephalopathy, bleeding from esophageal varices, bacterial infections, and hepatocellular carcinoma Cholelithiasis - intro Aka gallstones § Most common biliary tract disease Affects 10-20% od adult populations in high income countries § Two main types: Cholesterol stones § Crystalline cholesterol monohydrate Pigment stones § Bilirubin calcium salts Risk factors – differ slightly between types § Major risk factors for gallstones include: Age & sex – more common in females & in individuals of middle to older age Environmental factors – estrogen exposure Obesity & rapid weight loss Cholelithiasis - pathogenesis Pathogenesis of cholesterol stones § Cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation) à cholesterol can no longer remain dispersed and nucleates into solid cholesterol monohydrate crystals § Cholesterol gallstone formation involves: Bile supersaturated with cholesterol Hypomotility of the gallbladder Cholesterol nucleation in the bile is accelerated Hypersecretion of mucus in the gallbladder traps the nucleated crystals, leading to their aggregation into stones Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 18.58, p. 874 Cholelithiasis - pathogenesis Complex mixtures of insoluble calcium salts of unconjugated bilirubin + inorganic calcium salts Pathogenesis of pigment stones is associated with: § Excessive bilirubin production (eg. chronic hemolytic anemia) § Ileal disease (reduction of bile acids) § Infection of the gallbladder (bacteria deconjugates bile) Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 18.60, p. 874 Cholelithiasis Clinical features § Biliary pain Can be excruciating and constant or “colicky” (spasmodic), Caused by biliary obstruction (right upper quadrant or epigastric pain that may radiate to the right scapula, tends to last 1 – 5 hours, ebb, and then repeat) Inflammation of gallbladder (cholecystitis) in association with stones also generates pain Cholelithiasis Complications: § Progression into acute cholecystitis Acute inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct (cholangitis) One of the most common indications for abdominal surgery & reason for emergency cholecystectomy Symptoms: § Begins with progressive right upper quadrant or epigastric pain, § frequently associated with mild fever, anorexia, tachycardia, sweating, nausea, and vomiting § Occasionally a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction § Increased risk for carcinoma of the gallbladder Jaundice Elevated bilirubin results in jaundice and icterus § Jaundice – yellow discolouration of the skin § Icterus – yellow discolouration of the sclera Etiology – can be divided into: § Pre-hepatic causes § Intra-hepatic causes § Post-hepatic causes Jaundice Pre-hepatic causes § Excessive extrahepatic production of bilirubin Hemolytic anemias, resportion of blood from internal hemorrhage, ineffective erythropoeisis Intra-hepatic causes § Reduced hepatocyte uptake § Impaired conjugation Genetic deficiency of UGTIAI activity (Gilbert syndrome) § Decreased hepatocellular excretion Deficiency of canalicular membrane transporters Hepatocellular disease (eg. Cirrhosis) Post-hepatic causes § Impaired bile flow Duct obstruction Liver – Anatomy: review Which ligaments attach the liver to the diaphragm? _________ Ligament separate the (R) & (L) lobe. _________Ligament separates the (L) lobe and caudate lobe _________Ligament separates the (L) lobe and quadrate lobe _________(organ) separates Quadrate & (R) lobe References Moore et al. Moore’s Clinically Oriented Anatomy (7th ed). Kumar et. al., Robbins and Cotran. Pathologic Basis of Disease (9th ed). Boron and Boulpeap. Medical Physiology (3rd ed). Betts et al. Anatomy and Physiology. OpenStax Canadian Pharmacist Association. (2017). Compendium of Therapeutic Choices Images: https://commons.wikimedia.org/wiki/File:Hepatic_structure2.svg Pancreas Part II - Diseases of the Pancreas BMS 150 Week 13 Acute pancreatitis Basics: Severity ranges from life-threatening to a self-limited illness that causes mild-moderate abdominal pain ▪ Acute, reversible pancreatic injury associated with inflammation Reasonably common – incidence of 10-20/100,000 ▪ Major risk factors are excessive alcohol intake and cholelithiasis 80% of acute pancreatitis is due to these two risk factors ▪ 5% of those with gallstones will have an episode  Etiologic Factors in Acute Pancreatitis Metabolic Acute pancreatitis - Alcoholism - Hyperlipoproteinemia - Hypercalcemia Etiologies - Drugs (e.g. azathioprine) Particularly notable are the Genetic genetic causes – why might it - Mutations in the cationic be a bad idea to have mutations trypsinogen (PRSS1) and trypsin in trypsinogen and trypsinogen inhibitor (SPINK1) genes inhibitors? Mechanical Helps understand the - Gallstones pathology of more common - Trauma causes of acute pancreatitis - Iatrogenic Injury (operative/ endoscopic procedures with dye) A huge list of drugs – around 80 Vascular – have been shown to incite - Shock acute pancreatitis; thankfully, - Atheroembolism it’s a rare adverse effect - Vasculitis Infectious - Mumps Acute pancreatitis What is the role of trypsinogen activation in acute pancreatitis? ▪ It’s a digestive enzyme (trypsin) capable of activating other zymogens Reasonable to hypothesize that this leads to a straightforward autodigestion of the pancreas However, genetic knock-out studies that remove trypsinogen from transgenic mice demonstrate local and systemic inflammation that are very similar to chronic pancreatitis ▪ This suggests it may be important in activation of acute pancreatitis BUT there are other factors and/or mechanisms are involved Acute pancreatitis Pathophysiology ▪ Alcohol ingestion: Leads to excessive protein in pancreatic secretions, “plugs” the ducts Direct toxic effects on acinar cells Causes contraction of the sphincter of Oddi ▪ Biliary tract obstruction: Pancreatic secretions are stuck in the ducts, due to a gallstone or sludge blocking outflow Common factor = blockage of ducts Acute pancreatitis Duct blockage and acinar cell injury result in profound pancreatic damage Acute pancreatitis Pathophysiology More than just auto-digestion: ▪ Injured tissues, periacinar myofibroblasts, and leukocytes release proinflammatory cytokines including IL-1β, IL-6, tumor necrosis factor, platelet-activating factor, and substance P Inflammation and edema increase ▪ Activation of complement and clotting cascades, as well as elevated interstitial pressures lead to impairment of blood flow ▪ Can result in a systemic inflammatory response, resulting in leukocytosis, hemolysis, disseminated intravascular coagulation (DIC), acute respiratory distress syndrome  Acute pancreatitis Pathological features: 1. Microvascular leakage causing edema Mild injury 2. Digestion of fat by lipolytic enzymes 3. Acute inflammation 4. Proteolytic destruction of pancreatic parenchyma 5. Destruction of blood vessels and subsequent interstitial hemorrhage Severe injury, hemorrhage and third-spacing of fluid Fat necrosis can be seen in any stage – smaller areas in mild injury, larger areas in more severe injur Free pancreatic lipases cleave triglycerides in the abdominal cavity → fatty acids that combine with extracellular calcium (known as saponification) Saponification can be severe enough to cause hypocalcemia (bad prognostic factor) Acute pancreatitis Clinical features: ▪ Abdominal pain is the cardinal manifestation of acute pancreatitis Constant, intense and often referred to the upper back or shoulder Severity varies (moderate to quite severe) Anorexia, nausea, and vomiting frequently accompany the pain ▪ Systemic effects of severe acute pancreatitis (systemic inflammation, hemorrhage, and fluid loss into abdomen) result in a medical emergency Patients can rapidly proceed to shock and kidney failure Acute pancreatitis Complications: ▪ Pseudocysts ▪ Chronic pancreatitis ▪ Infection of fluid collections and/or necrotic debris by bacteria ▪ Hemorrhage, shock (ARDs and kidney failure can complicate shock) ▪ 5% with severe acute pancreatitis die from shock during the first week of illness Chronic pancreatitis Inflammation of the pancreas with irreversible destruction of exocrine parenchyma, fibrosis, and, in the late stages, the destruction of endocrine parenchyma ▪ Usually caused by repeated bouts of acute pancreatitis ▪ Usually caused by long-term alcohol abuse Don’t usually keep a gallbladder in if you keep getting pancreatitis from stones… Less common causes include cystic fibrosis and hereditary pancreatic disease, as well as other causes of obstruction (tumours, pancreatis divisum) Chronic pancreatitis Pathophysiology: ▪ Thought to be related to multiple episodes of acute pancreatitis ▪ Ductal obstruction by concretions – due to increased protein concentrations in the pancreatic juice, forms plugs that can become calcified ▪ Alcohol has a toxic effect on pancreatic acinar cells Oxidative stress on pancreatic cells (from alcohol abuse) may result in the activation of pancreatic enzymes and damage Chronic pancreatitis Chronic pancreatitis Pathology: ▪ Parenchymal fibrosis ▪ Reduced number and size of acini Islets of Langerhans usually remain spared, until end- stage disease ▪ Variable dilation of the pancreatic ducts ▪ Chronic inflammatory infiltrate around lobules and ducts The interlobular and intralobular ducts are frequently dilated and contain protein plugs in their lumens Chronic pancreatitis Clinical findings: ▪ Repeated attacks of mild or moderately severe abdominal pain or back pain The disease may be entirely silent until pancreatic insufficiency and diabetes mellitus develop ▪ 50% mortality after 25 years, usually linked to development of malabsorption and diabetes Pseudocysts Localized collections of necrotic-hemorrhagic material rich in pancreatic enzymes ▪ No epithelial lining (hence the prefix “pseudo”) and account for approximately 75% of cysts in the pancreas (rest being neoplastic cysts) ▪ Usually arise after an episode of acute pancreatitis or in the setting of chronic alcoholic pancreatitis Can also be caused by traumatic injury to the pancreas  Pseudocysts Pathogenesis: ▪ Usually, solitary ▪ Locations: Within the pancreas Lesser omentum Retroperitoneum between the stomach and transverse colon or between the stomach and liver Rarely subdiaphragmatic ▪ Formed by the walling off of fat necrosis with fibrous tissue ▪ Usually are composed of central necrotic-hemorrhagic material rich in pancreatic enzymes surrounded by non- epithelial-lined fibrous walls of granulation Can range in size from 2 to 30 cm in diameter Pseudocysts Pseudocysts Clinical features ▪ Symptoms are those of the underlying illness, usually (i.e. chronic pancreatitis) ▪ Can become complicated by secondary infection or perforation Can cause peritonitis if they rupture Larger pseudocysts can compress adjacent structures, thus causing symptoms References Junquiera’s Basic Histology: Text and Atlas (13th edition) – pg. 326-329 Guyton’s Medical Physiology – pg. 780-783 Moore’s Clinically-Oriented Anatomy, pages 265 - 268 Robbin’s and Cotran’s Pathologic Basis of Disease, Chapter 19 Pancreas Part I - Anatomy, Histology and Physiology Part II – Common Pathologies of the Pancreas BMS 150 Week 13 Overview Anatomy and histology of the pancreas Exocrine functions of the pancreas Digestive enzymes Bicarbonate Regulation of pancreatic secretions Pancreas: Anatomy Four Parts: Head and uncinate process Neck Body Tail Ducts: Main pancreatic duct joins the common bile duct at the hepatopancreatic ampulla (Ampulla of Vater) Accessory pancreatic duct drains to the minor duodenal papilla (less important) Transverse plane – L1 25 cm long, 5cm wide, 1-2 cm thick Retro-peritoneal structure Possesses a thin capsule Septa from the capsule divide it into lobes and lobules Pancreatic Arterial Supply Arterial Supply: Head: Pancreaticoduodenal branches of the gastroduodenal artery Superior mesenteric artery Neck, Body, Tail Branches of splenic artery (celiac trunk) supply neck, body and tail Venous Supply: Splenic vein & superior mesenteric vein Moore’s Clinically- Oriented Anatomy Fig. 2.59  Exocrine Pancreas – Histology The exocrine functions of the pancreas are carried out by the acini Compound tubulo-acinar gland system ▪ produces 1200 ml of bicarbonate-rich fluid containing digestive enzymes per day 40-50 acinar cells form a spherical acinus ▪ Most of the cells making up the acinus = acinar cells (pyramidal-shaped columnar epithelial cells) ▪ Acinar cells surround centroacinar cells – the centro-acinar cells line the lumen of the acinus Beginning of the intercalated ducts Intercalated ducts branch from the lumen of the acinus and merge into interlobular ducts Exocrine Pancreas - Histology General function of acinar cells: ▪ Secretion of inactive pancreatic enzymes (zymogens) ▪ Rich RER, lots of granules (filled with zymogens) ▪ CCK major stimulator General function of centroacinar cells: ▪ Secretion of HCO3-rich fluid ▪ Secretin major stimulator Exocrine Pancreas Centroacinar cells and intercalated duct cells can both secrete bicarbonate in response to secretin major contributors to bicarbonate-rich secretions  Secretion of Bicarbonate Ions CO2 diffuses from blood to interior of cell and combines with H2O to form H2CO3 (carbonic anhydrase) which dissociates into HCO3- and H+ HCO3- is actively transported into duct Na+ follows HCO3- into the duct – drawn into the duct via the negative charge of HCO3- ▪ H+ exchanged for Na+ at the basolateral surface of ductule cells Movement of HCO3- and Na+ into ducts creates osmotic pressure causing osmosis of H2O into duct  Phases of Pancreatic Secretion Cephalic ▪ Same nervous signals from brain that cause secretion in stomach also cause acetylcholine release by vagal nerve endings in pancreas ▪ 20% of pancreatic secretion Gastric phase ▪ Nervous stimulation of enzyme secretion (5-10%) Intestinal Phase ▪ After chyme leaves stomach and enters small intestine = lots of pancreatic secretion due to secretin and CCK release → more fluid Cephalic and gastric phase Intestinal phase  Regulation of pancreatic secretion Both neural and hormonal control ▪ cephalic and gastric phases are mostly regulated through nervous system ▪ Intestinal phase is mostly under hormonal control Hormone Source Stimulus Stomach Pancreas Gall Bladder Motility and Secretion Secretin S cells lining Acid Inhibits Stimulates fluid None duodenum entering secretion duodenum (HCO3-) CCK I Cells lining Fat and Inhibits Stimulates - Contraction of duodenum amino acids emptying enzyme the gall bladder entering secretion - Relaxation of the sphincter of duodenum Oddi Regulation of pancreatic secretion Secretin (review) ▪ Released from S cells in mucosa of duodenum and jejunum when acidic chyme (pH 4.5 – 5) reaches the small intestine ▪ Released into bloodstream, causes pancreas to secrete large quantities of bicarbonate-rich fluid ▪ Creates appropriate pH for action of pancreatic enzymes (7.0 to 8.0) Regulation of pancreatic secretion Cholecystokinin (review) ▪ Released from I cells in mucosa of duodenum and jejunum when partially digested proteins and long-chain fatty acids are present in the lumen ▪ Travels through the bloodstream to the pancreas ▪ Stimulates secretion of more pancreatic digestive enzymes by acinar cells  Pancreatic Secretions 2 secretions combine and then flow through long pancreatic duct ▪ Joins the common bile duct to release secretions into the ampulla of Vater ▪ Empties into duodenum through the major duodenal papilla ▪ Major duodenal papilla is surrounded by sphincter of Oddi  FYI – actions of pancreatic proteolytic enzymes Proteolytic Source; Inactive Activated by Action Products Enzyme Form Pepsin Stomach (chief cells); Low pH Cleaves between aromatic and Large Pepsinogen (stomach acid) hydrophobic a.a.s peptides good at collagen digestion (10-15% of protein digestion) Trypsin Pancreas (acinar Entero-kinase Cleaves bonds next to lysine or small cells); Trypsinogen (brush border arginine peptides enzyme in duodenum) Chymo- Pancreas (chymo- Trypsin (in cleaves next to: phenylalanine, small trypsin trypsinogen) duodenum) tyrosine, tryptophan, peptides methionine, asparagine, histidine elastase Pancreas (pro- Trypsin (in cleaves elastin small elastase) duodenum) peptides Carboxy- Pancreas (pro- Trypsin (in cleaves COOH terminal end of single a.a.s peptidase carboxypeptidase) duodenum) peptides A&B A: non-polar and aromatic a.a.s B: basic a.a.s  Pancreatic proteolytic enzymes Review: Endopeptidases: ▪ through hydrolysis, cleave peptide bonds at certain amino acids Example: pepsin cleaves between aromatic and hydrophobic amino acids Endopeptidases include pepsin, trypsin, chymotrypsin, elastase Exopeptidases: ▪ through hydrolysis, cleave peptide bonds at the carboxyterminus Exopeptidases include carboxypeptidases (A + B)  Pancreatic Secretions – controlling trypsin Trypsin inhibitor – prevents pancreatic auto-digestion ▪ Secreted from acinar cells, prevents activation of trypsin inside secretory cell and in ducts of pancreas ▪ Packaged together with other pancreatic enzymes in zymogen granules Trypsin, when it “runs out” of proteins to break down in the duodenum, then hydrolyzes itself in a form of negative feedback ▪ Genetic defects involving either of these processes increase the risk of pancreatitis (more in path later) Pancreatic secretions Review: Pancreatic amylase: ▪ Hydrolyzes alpha 1-4 linkages in amylose (starch) Pancreatic lipase and colipase: ▪ Pancreatic lipase needs fat emulsification (bile salts) as well as colipase in order to cleave triglycerides into 2- monoglyceride and FFAs Can be absorbed by the enterocyte Phospholipase A2 ▪ activated by trypsin, digests phospholipids (FYI – glycerophospholipids) References Junquiera’s Basic Histology: Text and Atlas (13th edition) – pg. 326-329 Guyton’s Medical Physiology – pg. 780-783 Moore’s Clinically-Oriented Anatomy, pages 265 - 268 Robbin’s and Cotran’s Pathologic Basis of Disease, Chapter 19 Large Intestine E-Learning: Anatomy, Histology and Physiology Dr. Maria Shapoval BMS 150 Week 14 Overview Anatomy and histology of the large intestine Physiology of the large intestine Diseases of the large intestine Irritable Bowel Syndrome (IBS) Inflammatory Bowel Disease (IBD) UC Crohn’s Diverticular Disease and Hemorrhoids Learning Objectives Identify the major anatomical components of the large intestine, rectum and anal canal Identify the main vessels supplying the large intestine and their respective structures Identify the sympathetic and parasympathetic nerves innervating the large intestine Compare the histology of large intestine to the typical histological findings in other parts of the digestive tract Relate the role of mucin to the function of the large intestine Compare gastroileal and gastrocolic reflexes Describe the mechanism of defecation and inhibition of defecation Describe the epidemiology, main clinical feature and pathogenesis of the common pathologies of the large intestines, including: Learning Objectives Describe the epidemiology, main clinical feature and pathogenesis of the common pathologies of the large intestines, including: Irritable bowel syndrome Inflammatory bowel disease Diverticular diseases Hemorrhoids Large Intestine – Big Picture Functions to convert undigested material into feces by removing water and adding mucus Store and transport feces Largest microbial presence Produce Vitamin K and Biotin Slower motility to allow for water and solute absorption Large Intestine: Anatomy LI begins at ileocecal valve and ends at the anus Cecum – widest part of colon and most prone to perforation Ascending colon transitions to transverse colon at the hepatic flexure, and the splenic flexure marks the transition to descending colon Sigmoid colon – narrowest part of LI and most mobile Generally located within left lower quadrant, but parts can actually migrate to the right side Vulnerable to volvulus; intestinal loop twists around itself causing bowel obstruction Rectum 12-15 cm long Denonvilliers’ fascia/ rectovaginal fascia runs anterior to rectum and separates it from prostate and seminal vesicles or vagina Rectocele can develop if fascia defective Lateral ligament support the lower portion of the rectum and provide scaffold for blood vessels and nerves Innervated by parasympathetic NS; pelvic splanchnic nerves Supplied by branches of the inferior mesenteric artery/vein (superior rectal a/v.), internal iliac artery/vein (middle rectal a./v) and internal pudendal artery/vein (inferior rectal a./v) Anal Canal 4 cm in length; connects rectum to anal opening Mucosa transitions from simple columnar epithelium to stratified squamous epithelium Submucosa: Hemorrhoidal plexuses Sebaceous glands and apocrine sweat glands Internal anal sphincter – involuntary; circular layer of smooth muscle External anal sphincter – voluntary; skeletal muscle Vasculature of the LI Superior Mesenteric Artery: Ileocolic artery Terminal ileum Proximal ascending colon Right colic artery Ascending colon Middle colic artery Transverse colon Inferior Mesenteric Artery: Left colic artery Descending colon Sigmoid branches Sigmoid colon Superior rectal artery Proximal rectum Venous Supply – same terminology as the arteries Innervation of the LI Sympathetic NS Sympathetic nerves arise from T6-T12 and L1-L3 Parasympathetic NS Vagus nerve Ascending and transverse colon S2-S4 nerve roots – pelvic splanchnic nerves Descending and sigmoid colon Large Intestine: Histology Mucosa No folds (only rectum – rectal columns of Morgagni) or villi Absorptive colonocytes do have irregular microvilli and appear to be dedicated to fluid absorption Simple columnar epithelium with lots of goblet cells Many deep crypts/ intestinal glands Lamina propria with lots of lymphoid cells and nodules (some extend into submucosa) Submucosa Lower rectum – hemorrhoidal plexus of veins; no valves – high likelihood of varicosity (aka hemorrhoids) Large Intestine: Histology Muscularis Externa Teniae coli – 3 thick longitudinal bands of smooth muscle in the outer layer with thin layer of sm between the bands Inner layer is the same as SI Serosa Appendices epiploicae – teardrop-shaped adipose-filled outpockets within the serosa throughout the colon Adventitia – surrounds rectum Digestion, Absorption, and Secretion Digestion accomplished exclusively by microbiota and breakdown products such as SCFA are used to feed the enterocytes Minimal absorption beyond water, Na+ and other minerals Vitamin K, biotin – produced by microbiota Secretes mucin proteins which attract water and create a layer of mucus on epithelial cells Lubricate and prevent intestines from sticking together Support innate immune function – acts as barrier Motility 3 types of movement: segmentation, peristalsis and mass action contraction: Simultaneous contraction of smooth muscle over large areas of LI with the goal of moving feces into rectum Hirschsprung Disease – aganglionic megacolon is a congenital disorder where ganglions are absent in myenteric and submucosal plexuses in distal colon resulting in lack of peristalsis and defecation rate of 1 every 3 weeks Gastroileal reflex Food leaving the stomach allows the cecum to relax which allows the ileocecal valve to relax and chyme to pass from SI to LI Gastrocolic reflex Large waves of peristalsis are stimulated by presence of food in the stomach after a meal Fluid Homeostasis Absorbs up to 5 L of water per day 1-2L of chyme enters LI and after 90% of fluid is absorbed only 200 mL of feces remains Water absorption is primarily driven by absorption of Na+, which differs across ascending and descending colons with greater absorption capacity in the ascending compared to descending and sigmoid colons Fluid Homeostasis There are multiple mechanisms for Na+ absorption: Electrogenic Na+ absorption based on electrochemical gradient for influx, and Na+/K+ ATPase on basolateral side Electroneutral NaCl absorption; Na+ is exchanged with H+ while Cl- is exchanged for HCO3- SCFA coupled Na+ absorption Na+ AND water absorption by colonic crypts Defecation The presence of feces causes distention of the rectum which initiates a reflex contraction of the rectal muscles and communicates to the CNS a desire to defecate Voluntary defecation Internal anal sphincter (smooth muscle) involuntarily relaxes in response to inhibitory signals from sacral parasympathetic NS and distention When not relaxing, sphincter is tonically active (promoted by sympathetic NS) Parasympathetic nerves also relax puborectalis muscle which causes the rectoanal angle to straighten External anal sphincter (skeletal muscle) can voluntarily relax and expulsion of feces may occur unaided if enough pressure has been reached (lots of distention) OR supported by contraction of abdominal muscles (aka straining/ Valsalva maneuver) Innervated by pudendal nerve Defecation The presence of feces causes distention of the rectum which initiates a reflex contraction of the rectal muscles and communicates to the CNS a desire to defecate Inhibition of defecation (aka – maintaining fecal continence) is achieved by the following 3 components: Both sphincters are tonically active Puborectalis muscle maintains contraction Angle between rectum and anus is 90 degrees Large Intestine Diseases of the Large Intestine BMS 150 Week 14 Irritable Bowel Syndrome (IBS) Most common Functional Gastrointestinal disorders (FGID) Epidemiology 9-23% of global population (other sources suggest 10-15%) Onset typically in adolescence (prevalent in