BMS150 Liver and Gallbladder Physiology & Pathology PDF

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