The Liver as an Organ PDF

The Liver as an Organ Lecture Outline I. Gross Anatomy of the Liver II. Physiologic Anatomy of the Liver III. Bile and the Gallbladder IV. Blood Flow and Vascular Resistance V. Metabolic Functions of the Liver VI. Pathophysiology 1 The Liver as an Organ Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11....

The Liver as an Organ Lecture Outline I. Gross Anatomy of the Liver II. Physiologic Anatomy of the Liver III. Bile and the Gallbladder IV. Blood Flow and Vascular Resistance V. Metabolic Functions of the Liver VI. Pathophysiology 1 The Liver as an Organ Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Explain the gross anatomy of the liver Describe the dual blood supply of the liver Explain the hepatic arterial buffer response Compare the architecture of the liver lobule and acinus Explain the functional implications of the zones of a liver acinus Describe the bile acid pool Identify terminology related to gallbladder disease Explain bilirubin production and the development of jaundice Understand the reservoir function of the liver Identify implications of the low vascular resistance of hepatic blood flow Explain cirrhosis and changes to hepatic vascular resistance Understand portal hypertension and portosystemic anastomoses and shunts Describe the liver’s metabolic function Explain ammonia homeostasis and hepatic encephalopathy List other metabolic functions of the liver Identify pathologic consequences of liver disease List anesthesia implications of liver disease 2 References Assigned reading from your text: Hall Chapter 71 Miller (8th ed.) Chapter 22 3 I. Gross Anatomy of the Liver 4 The Liver ❑ The liver is LARGE: Largest internal organ Largest gland –produces bile Largest producer of lymph ❑ Liver can regenerate Hepatocytes function as stem cells Removal of up to 70% Regeneration in 7 days Hepatocytes quiescent after original size attained Liver diseases impair regeneration 5 Anatomical Lobes Of The Liver ❑ Located in the right upper quadrant In the peritoneal space Below the right diaphragm Occupies the right dome of the diaphragm Extends to the apex of the left dome Is protected by the lower thoracic cage 7th to the 11th rib (right midaxillary line) 6 Surface Anatomy of the Liver ❑ Right- largest lobe Two accessory lobes of the anatomic right lobe Caudate lobe is posterior/superior Quadrate lobe is anterior/inferior ❑ Left lobe smaller 7 The Liver Moves with Respiration Figure 5.62 Surface anatomy of the liver. The liver’s location, extent, relationship to the thoracic cage, and range of movements with change of position and diaphragmatic excursion are demonstrated. 8 Morison’s Pouch ❑ The hepatorenal recess- Morison or Morison’s pouch A potential space between the liver and right kidney- can fill with blood or fluid Posterosuperior extension of the subhepatic space Lies between the right visceral surface of the liver and the right kidney/suprarenal gland 9 Dual Blood Supply ❑ Receives 27% of total cardiac output High blood flow & low vascular resistance ❑ The liver has a dual vascular supply Supply 1350 ml/min into liver sinusoids Hepatic artery - 300 ml/min: Branch of celiac trunk 25% blood supply- mostly stromal 50% oxygen supply Autoregulates Hepatic portal vein - 1050 ml/min: Formed by the confluence of the superior mesenteric vein and splenic vein 75% blood supply- mostly parenchymal 50% oxygen supply Does not autoregulate 10 Comparison of Hepatic Portal Vein and Hepatic Artery ❑ Hepatic portal vein Receives venous flow from visceral organs Has a low PO2 Contains all the absorbed substances from the intestines except chylomicrons that entered the lacteals Portal vein eventually subdivides to yield branches at the periphery of a liver lobule ❑ Hepatic artery Supplies hepatic cells with nutrients Has a high PO2 11 Hepatic Arterial Buffer Response ❑ Important intrinsic mechanism When portal venous flow decreases, adenosine accumulates The hepatic artery compensates if portal vein supply diminished Can double hepatic arterial blood flow Severe splanchnic hypoperfusion can abolish 12 II. Physiologic Anatomy of the Liver 13 Basic Structure Of A Liver Lobule ❑ The liver lobule is a cylindrical structure: ~2 mm diameter and several mm long Composed mainly of cellular plates radiating from a central vein Between adjacent cells, bile canaliculi empty into bile ducts ❑ Portal triads exist in interlobular septa: Portal veins (venules) flow into hepatic sinusoids Hepatic arterioles supply septal tissues & sinusoids Bile ducts direct bile to the hepatic ducts ❑ Liver sinusoids serve as blood capillaries Are lined by 2 cell types – Endothelial cells have large pores (~ 1 um) Allow passage of proteins – Kupffer cells are resident macrophages- line sinusoids Reticuloendothelial cells that phagocytize bacteria Colon bacteria found in blood before portal vein ❑ Spaces of Disse connect with lymphatic vessels Receive plasma proteins synthesized in hepatocytes Large quantities of lymph (50%) formed in liver 14 Lymph Flow ❑ Liver produces half the body’s lymph Hepatic sinusoids are permeable Allow passage of fluid and proteins into Spaces of Disse Protein content slightly less than plasma (80-90%) ❑ Ascites occurs when pressure in the hepatic vein rises At 3-7 mmHg above normal Fluid transudation into abdominal cavity from liver and portal capillaries through outer surface liver capsule directly into abdominal cavity At 10-15 mmHg above normal Lymph flow increases 20 x normal- Ascites results 15 Hepatic Architecture ❑ Liver is organized both anatomically into lobules and functionally into acini There are ~ 50-100k lobules/acini per liver Lobule Basic anatomic unit Hexagonal arrangement Central vein at center has low pO2 Drains venous blood from portal vein Acinus Functional microvascular unit Parenchyma around terminal vessels Hepatic arteriole/portal venule at center- high pO2 Supplies oxygenated blood to hepatocytes 16 Directional Flow In A Lobule ❑ Draining into the lobule: Hepatic artery and portal vein supply the lobule then drain into central vein Liver sinusoids serve as blood capillaries ❑ Draining away from the central vein: Bile canaliculi drain bile from hepatic cells and deliver it to interlobular bile ductules Bile ductules coalesce into left and right hepatic ducts Left and right hepatic ductules coalesce into the hepatic duct proper Excess fluid in the spaces of Disse removed by lymphatics 17 Boron Figure 46-3. Hepatocytes can be thought of as being arranged as A. classic hepatic lobules, B. portal lobules, or C. acinar units 18 Zones Of A Liver Acinus ❑ ❑ Zones describe regions of an acinus – Zone 1- Periportal Contains portal venule and hepatic arteriole Oxygen-rich blood at center – Zone 2- Midzone Moderately well-oxygenated – Zone 3- Pericentral Already perfused zones 1&2 Oxygen-poor blood; furthest from arteriole Implications of Zones – Zones 1&2 has the highest concentration of mitochondria Major site of oxidative metabolism and glycogen synthesis Ureagenesis for urea cycle and bile acid produced here – Zone 3 is the major site of CYP 450 proteins Major site of glycolysis, ketogenesis, and detoxification reactions Ischemic injury decreases the liver’s capacity to excrete many drugs 19 Relationship of Lobule to an Acinus Figure 14–2 A: Detailed structure of the liver lobule. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.) B: Relationship of lobule to acinus. (CV, central vein; PS, portal space [or triad].) (Redrawn, with permission, from Leeson CR. Histology, 2nd ed. Saunders, 1970.) C: Hepatic acinus. (HV, hepatic venule.) (Reproduced, with permission, from Gumucio JJ. Hepatic transport. In: Kelley WN (ed): Textbook of Medicine. Lippincott, 1989.) 20 Flow of Blood and Bile in the Liver Moore Figure 5.69 Flow of blood and bile in the liver. A. This view of a small part of a liver lobule illustrates the components of the interlobular portal triad and the positioning of the sinusoids and bile canaliculi. The enlarged view of the surface of a block of parenchyma removed from the liver in (B) shows the hexagonal pattern of lobes and the place of (A) within that pattern. B. Extrahepatic bile passages, gallbladder, and pancreatic ducts are demonstrated. C. The bile duct and pancreatic duct enter the hepatopancreatic ampulla, which opens into the descending part of the duodenum. 21 III. Bile and the Gallbladder 22 Bile ❑ Bile consists of organic molecules in an alkaline solution, produced by the liver, stored and concentrated in the gallbladder ❑ Has three functions: – Assimilation of dietary lipid 50% dietary lipid appears in feces if bile is excluded from the small intestine Bile emulsifies and solubilizes fats into micelles for absorption – Excretion of hydrophobic molecules – Neutralizes gastric acid- it is an alkaline solution ❑ Hepatocytes secrete bile into the canaliculi – Canaliculi coalesce into hepatic ducts prior to the common hepatic duct – Cystic duct transmits bile to gallbladder where it is concentrated- has a volume of 20-50 ml 23 Bile Acid Pool ❑ Bile acids undergo enterohepatic circulation multiple times per meal/day Pool is insufficient to digest lipids and requires recycling Enterohepatic circulation can be intentionally disrupted as a treatment for high blood cholesterol by ingesting bile-binding resins (cholestyramine) which cause fecal bile acid excretion and reduce the pool of circulating bile acids. – Hepatic synthesis of new bile acids requires an increased supply of cholesterol – Increases uptake of low-density lipoproteins- desired therapeutic effect of reducing plasma LDLs FIGURE 14–3 A: Mechanism of bile acid secretion. About 90% of these compounds derive from bile acids absorbed in the intestinal epithelium and recirculated to the liver. The remainder are synthesized in the liver by conjugating cholic acid with the amino acids glycine and taurine. This process occurs in the smooth endoplasmic reticulum (SER). B: Protein synthesis and carbohydrate storage in the liver. Protein synthesis occurs in the rough endoplasmic reticulum, which explains why liver cell lesions or starvation leads to a decrease in the amounts of albumin, fibrinogen, and prothrombin in a patient’s blood. In several diseases, glycogen degradation is depressed, with an abnormal intracellular accumulation of this compound. (RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum.) (Redrawn, with permission, from Junqueira LC et al. Basic Histology, 10th ed. McGraw-Hill, 2003.) 24 Gallbladder Diseases ❑ Two types of gallstones (cholelithiasis) include: Cholesterol gallstones- most common- due to excess cholesterol Pigment gallstones- in patients with hemolytic disease with excess bilirubin excretion ❑ Different areas are involved in gallbladder diseases Cholecystitis is a blockage of the cystic duct with associated infection of the gallbladder Choledocholithiasis is a blockage of the common bile duct Ascending cholangitis is a blockage of the common bile duct with associated infection of the bile ducts Gallstone pancreatitis occurs with a blockage of the ampulla of Vater 25 Bilirubin Production ❑ Bile pigments bilirubin production When RBC membranes rupture after ~ 120 days, hemoglobin phagocytized by macrophages Heme ring opened, pyrrole nuclei form biliverdin which is quickly reduced to free bilirubin aka unconjugated bilirubin which is gradually released from the macrophages into the plasma Combined with albumin- is transported through blood and interstitial fluids Within hours is released from albumin and conjugated with glucuronic acid and other substances The reticuloendothelial system Then can be excreted from the hepatocytes by active transport processes into bile canaliculi and intestines Glucuronides of the bile pigments bilirubin and biliverdin are responsible for the color of bile Normally yellow Intestines convert conjugated bilirubin to urobilinogen 26 Pathophysiology- Jaundice ❑ Jaundice (icterus) When free or conjugated bilirubin accumulates in blood– The skin, mucous membranes and sclera turn yellow ❑ Hyperbilirubinemia may be due to: Excess production of bilirubin (hemolytic anemia) – Rapid release of bilirubin into blood – Jaundice due to unconjugated bilirubin bound to albumin Obstruction of bile ducts – by gallstones or cancer – Obstruction causes overflow of bile into spaces of Disse then blood – Normally, most bilirubin in plasma is unconjugated – Jaundice due to obstruction is caused by conjugated bilirubin Hepatitis – Jaundice due to hepatocellular damage increases conjugated bilirubin in plasma 27 IV. Blood Flow and Vascular Resistance 28 Blood Reservoir ❑ The liver serves as a blood reservoir due to its volume and innervation Normally, the liver contains ~ 450 ml blood (10% body’s total blood volume) The liver is innervated by the hepatic plexus composed of branches of the: Vagus nerves Splanchnic (postganglionic sympathetic fibers) The hepatic plexus runs alongside afferent hepatic vessels and bile ducts SNS tone affects splanchnic reservoir Decreased tone increases volume; increased tone decreases hepatic volume When volume is expanded, the liver can accommodate additional volume (.5-1.0 L) When needed, SNS stimulation can translocate blood into central circulation 29 Hepatic Adrenoceptors and Vascular Resistance ❑ Adrenoceptors Hepatic arteries have ⍺1, ⍺2, and β2 adrenergic receptors Portal vein has only alpha receptors Any increase in SNS outflow will produce hepatic arterial vasoconstriction ❑ Hepatic vascular resistance is Low Resistance to blood flow in normal liver sinusoids is low Pressure in the portal vein= 9 mmHg Pressure in the hepatic vein leading into the vena cava ~ 0 ❑ Anesthesia affects hepatic blood flow 30 Cirrhosis ❑ Cirrhosis of the liver greatly increases resistance to blood flow Chronic inflammation of the liver causes: – Fibrosis (scar tissue formation) replaces parenchymal cells – Bands of scar tissue have a “pebble” appearance – Both inflammation and fatty infiltration compress sinusoids and impede blood flow – Disturbed hepatic architecture disrupts portal blood flow and causes portal hypertension 31 Etiology of Cirrhosis ❑ Cirrhosis most commonly caused by: Chronic alcohol abuse- chronic daily consumption or binge drinking (> 5 drinks in 2 hours) – – – Nonalcoholic steatohepatitis (NASH) – Usually related to obesity and type II diabetes High fructose consumption; liver is the only organ that can metabolize fructose NAFLD is the leading cause of liver disease in US Viral hepatitis – Excess fat accumulation in the liver and subsequent inflammation Nonalcoholic fatty liver disease (NAFLD) is less severe form of fat accumulation/inflammation – – – Alcohol withdrawal begins in 6-8 hours Delirium tremens (DTs) -global confusion and autonomic hyperactivity-begin in 2-4 days Deficient in thiamine- Wernicke’s encephalopathy Hepatitis – Viral etiology; A, B, C, D (with B) ; E is uncommon in the US Other secondary causes: toxins, infection, obstruction of bile ducts ❑ Substantial cirrhosis may be present with few or no laboratory abnormalities 32 Portal Hypertension ❑ Impedance to flow through the portal system results in portal hypertension – – Acute can result in excess loss of fluid from capillaries into lumen of intestines and death in a few hours Chronic development better tolerated ❑ Portal hypertension has the following clinical consequences: Ascites- abnormal accumulation of fluid in the abdominal cavity – – Excess plasma “sweats” through the capsule Blockage of portal blood flow causes transudation of fluid through serosa Congestive splenomegaly Hepatic encephalopathy – toxins in the blood are not removed by the diseased liver – Decreased hepatic clearance→ increased ammonia→ cerebral edema→ increased ICP Portosystemic shunts are formed at the portosystemic anastomoses 33 Portosystemic Anastomoses and Shunts ❑ Portal system of veins lacks valves 4 major veins- inferior/superior mesenteric, splenic, portal Blood will bypass the liver via these anastomoses to return to the SVC,IVC, & azygos Portosystemic anastomoses are lifesaving Engorged veins result at the anastomoses ❑ Portosystemic shunts may form at the: Distal esophagus – esophageal varices Rectum – hemorrhoids Anterior abdominal wall- caput medusa Retroperitoneal (internal) 34 ❑ Esophageal varices – high risk of bleeding Careful instrumenting the pharynx of liver patients ❑ Caput medusa surround the umbilicus 35 V. Metabolic Functions of the Liver 36 Hepatic Carbohydrate Metabolism ❑ The liver is both a source and a “sink” for glucose and is a key effector of blood glucose concentration Substrates are transported from the intestine to the liver in portal blood to: – Store large amounts glycogen from consumed glucose Pathways include glycogen synthesis, fatty acid synthesis, glycolysis, and the tricarboxylic acid cycle – Convert galactose and fructose to glucose – Produce glucose through gluconeogenesis and glycogenolysis Glucose buffer function – The liver maintains blood glucose post-prandially by removing excess blood glucose – Replenishes when needed Gluconeogenesis, glycogenolysis add glucose to blood Glycogen synthesis, glycolysis, oxidative metabolism, and fat synthesis all consume blood glucose ❑ In liver failure- hypoglycemia common; hyperglycemia can also result Insulin cleared by liver- in liver failure, this exacerbates hypoglycemia 37 Hepatic Lipid Metabolism ❑ Oxidizes fatty acids to supply energy – – – During fat metabolism, chylomicrons and fatty acids are taken up by the liver Beta-oxidation more efficient in liver than other tissues- liver responsible for a majority of fat metabolism The liver uses fatty acids for energy metabolism via beta oxidation and ketone synthesis Is the site of keto acid production ❑ Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins – – Major sources of cholesterol are dietary and de novo synthesis in the liver Liver manufactures 80% of cholesterol synthesized in body from acetyl Co-A Major elimination pathway for cholesterol is in bile 80% cholesterol synthesized in liver is converted to bile salts Remainder cholesterol and phospholipids transported in lipoproteins by the blood – Cell membranes, cellular structures, etc ❑ Synthesis of fat from proteins and carbohydrates – Then transported as lipoproteins to adipose tissue for storage 38 Protein Metabolism ❑ The liver is involved in protein metabolism and synthesis: Deamination of amino acids – Hepatocytes metabolize amino acids to glutamine and ammonia via transamination and oxidative deamination – Then forms urea for the removal of ammonia from body fluids The liver produces all plasma proteins except immunoglobulins – Antibodies made in plasma cells Liver proteins include: Transport proteins – Albumin main regulator of oncotic pressure » Accounts for 15% liver’s protein production » Albumin is a reservoir for acidic drugs – Alpha-1 acid glycoprotein is a reservoir for basic drugs Procoagulants Hormones Cytokines Chemokines Plasma cholinesterase - aka pseudocholinesterase or butyrylcholinesterase 39 Interconverts various amino acids and synthesizes other compounds from amino acids Ammonia Homeostasis ❑ Liver is critical for ammonia handling – – – – When amine groups are removed from amino acids, hepatocytes convert them to NH3 Excess ammonia is toxic to the CNS (cross BBB) Converts circulating ammonia to urea via the urea cycle Urea is released into the blood and is excreted by the kidneys Individuals with liver disease who are incapable of forming urea can develop increased plasma levels of NH3 that can lead to hepatic encephalopathy Left untreated- can progress to coma and death 40 Other Metabolic Functions Of The Liver ❑ The liver is a storage site for vitamins A,D,E, and K – – Mostly stores Vit A Also B12 ❑ The liver forms blood substances used in coagulation: – – Fibrinogen, prothrombin, factor VII (all except III, VIII and von Willebrand factor) Vitamin K is required for the formation of prothrombin (II) and factors VII, IX, and X Vitamin K absorption dependent on the presence of bile in the gut ❑ The liver detoxifies or excretes drugs, hormones and other substances: – Removal of bioactivity of organic molecules, including steroids and hyodrophobic drugs Phase I biotransformation involves CYP 450 enzymes Phase II biotransformation involves conjugation to generate products that are more soluble for excretion Conjugation involves the addition of glucuronate, sulfate, or glutathione – In liver failure- accumulation of estrogen may cause gynecomastia, testicular atrophy, and spider hemangiomas ❑ Liver Kupffer cells are the largest group of fixed macrophages in the body – Ingest pathogens entering the blood via the GI tract 41 VI. Pathophysiology 42 Other Pathophysiologic Consequences Of Liver Disease ❑ Hyperdynamic Circulation- Advanced disease Low SVR and low BP→ increased CO Increased RAAS→ increased blood volume Increased peripheral shunting→ increased SvO2 Anatomic shunting → Abnormal vessels such as spider angiomas Increased SNS and RAAS; ANS reflex dysfunction ❑ Hepatopulmonary syndrome: Restriction- decreased compliance and atelectasis Respiratory alkalosis→ compensatory hyperventilation r/t hypoxia Abnormal intrapulmonary vasodilation→ congestion Right-sided heart failure if PVR increases ❑ Renal hypoperfusion: Decreased GFR→ increased RAAS→ Na+ and H2O retention Hepatorenal Syndrome→ Liver failure precipitates decreased GFR→ liver transplant needed 43 Hematologic Perturbations Of Liver Disease ❑ Hematologic changes Decreased clotting factor production- may lead to bleeding or clotting inappropriately Prolonged PT and INR balanced by decreased anticoagulant factors Adequate thrombin production requires an adequate number of functioning platelets Usual causes of excessive bleeding in chronic liver disease: Severe thrombocytopenia Endothelial dysfunction Portal hypertension Renal failure Sepsis Combination hypercoagulation and thrombosis as well as increased risk of bleeding 44 Liver Function Tests ❑ LFTs can be classified into two categories: – Hepatocellular damage AST and ALT – Hepatic synthetic function ❑ Liver abnormalities can be divided into two classes based on lab tests: – Parenchymal disorders result in generalized hepatocellular dysfunction Fibrosis Cirrhosis – Mechanical biliary obstructive disorders result in hepatocellular damage 45 Tests of Hepatic Synthesis ❑ Tests of synthetic functions: – Cholesterol – Pseudocholinesterase Reduced pseudocholinesterase production increases duration of succinylcholine – PT Prothrombin directly determines the amount of clotting factors available Only ~25% clotting factors required for normal coagulation Prolonged PT (esp after Vit K administration) → severe disease – Albumin (half-life is 21 days) → not a measure of acute disease 46 Tests of Hepatocellular Damage ❑ Tests of hepatocyte damage Transaminases – Aspartate Aminotransferase (AST) aka serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) are cytosolic enzymes released as a result of cell damage Serum bilirubin- jaundice occurs when total bilirubin elevated Serum alkaline phosphatase – Biliary obstruction increases alkaline phosphatase synthesized and in plasma Ammonia-significant elevations reflect disruption of hepatic urea synthesis 47 Anesthesia Considerations ❑ Suspect a relative hypovolemia and portal hypertension Assess for high CO and low peripheral vascular resistance May have increased sensitivity to highly protein bound drugs (sedatives) Lower plasma proteins may affect volume of distribution Suspect esophageal varices Anticipate depressed response to inotropes and vasopressors GA and RA can decrease liver blood flow by 30-50% ❑ Impaired hepatic function Be aware of hepatotoxic drugs: Tylenol, sulfonamides, tetracycline, penicillin, amiodarone. Decreased pseudocholinesterase Decreased hepatic clearance of meds Elevated liver enzymes probably due to underlying liver disease or the procedure Expect higher than normal blood loss 48 1. A 34- yo man with a history of sickle cell disease is admitted with upper right quadrant abdominal pain, nausea, and vomiting. His hematocrit is 30 and ultrasound shows gallstones. What is the most likely composition of his gallstones? A. Bile pigments B. Calcium carbonate C. Calcium oxalate D. Cholesterol 2. The ammonia released during deamination of amino acids is removed from the blood almost entirely by the conversion into which substance? A. Ammonium B. Carbon dioxide C. Ornithine D. Urea 3. An expirement using hepatocytes tests means to effectively support regeneration of liver cells. Hepatocyte viability is best documented by an increase in which function of these cells in vitro? A. Ethanol output B. Albumin output C. Oxygen output D. Carbon dioxide uptake 4. Erythrocytes are constantly dying and being replaced. Heme from the hemoglobin is converted to what substance before being eliminated from the body? A. Bilirubin B. Cholesterol C. Cholic acid D. Globin E. Glucuronic acid 5. Which of the following cell types protects against sepsis secondary to translocation of intestinal bacteria? A. Cholangiocyte B. Kupffer cell C. Hepatocyte D. Gallbladder epithelial cell 6. A 60-year-old man comes to his physician complaining of a progressive increase in his girth despite attempts to diet. He is also jaundiced and complains of nausea and malaise. When a large needle is inserted into his abdomen, several liters of tan fluid drain out. An increase in which of the following is not involved in this fluid accumulation? A. Portal pressure B. Hepatic collagen C. Plasma albumin E. Plasma transudation 49