Lesson 8 Hepatic - Liver Anatomy and Physiology PDF

# Liver Anatomy and Physiology ## Focus - Have a solid understanding of anatomy and physiology to understand anesthetic implications - Know some testing and function - Know some pathophysiology - **DO NOT** study liver transplant ## Liver Gross Anatomy - Divided into 4 lobes = left, right, quadr...

# Liver Anatomy and Physiology ## Focus - Have a solid understanding of anatomy and physiology to understand anesthetic implications - Know some testing and function - Know some pathophysiology - **DO NOT** study liver transplant ## Liver Gross Anatomy - Divided into 4 lobes = left, right, quadrate, caudate - Left and right lobes are divided by the falciform ligament - Liver is the second largest organ in the body - Skin is first - Enclosed within Glisson's capsule ## Couinard Classification - Division of liver into 8 independent functional units - Surgical classification - Each unit has its own vascular supply ## Hepatic Blood Flow - Receives 25% of cardiac output from the hepatic artery and portal vein ### Hepatic Artery - Supplies less of the total blood supply to the liver (20%) than the portal vein, but better oxygenated blood - Average pressure is 90 mmHg - Comes off of the celiac artery ### Portal Vein - Blood draining from the gastrointestinal tract that is rich in nutrients and bacteria - Average pressure is 8-10 mmHg - Supplies most of blood to the liver (75%), but less oxygenated ### Hepatic Vein - Pressure is 4 mmHg - Not a steep gradient between portal vein and hepatic vein - Total hepatic blood flow = portal vein + hepatic artery - Hepatic artery supplies about 50% of total $O_2$ and portal vein has 50% of total $O_2$ to the liver - **How is this different from other organs in our body in terms of oxygenated blood supply?** ## Hepatic Blood Flow Determination - 800-1200 ml of blood flow per minute - Hepatic blood flow is determined by hepatic perfusion pressure (HPP) and splanchnic vascular resistance - HPP = hepatic perfusion pressure = mean arterial pressure minus hepatic vein pressure or portal vein pressure minus hepatic vein pressure - Splanchnic vessels are innervated by the sympathetic nervous system - Sympathetic nervous system stimulation increases splanchnic vascular resistance resulting in decreased hepatic blood flow - Hepatic blood flow is reduced by pain, hypoxia, catecholamines, volatile anesthetics, regional anesthesia, surgical site, positive pressure ventilation, excess fluid administration ## Hepatic Artery Buffer Response (HABR) - Hepatic artery tone adjusts to changes in portal blood flow up to 100% increase - Response is mediated by adenosine - Decreased portal vein blood flow leads to low pH, low $O_2$, or hypercapnia → increased adenosine → hepatic artery vasodilates - Portal vein does *not* compensate for changes in hepatic artery supply - Volatile anesthetics and cirrhosis interfere with this response ## Hepatocyte - Make up 80% of liver mass - Store glycogen, vitamin B12, and iron - Participate in lipid turnover and transport - Synthesize plasma proteins (albumin, prothrombin, fibrinogen) - Metabolize and detoxify fat - Turnover of steroid hormones - Regulate cholesterol - Secrete bile ## Myeloid Cells - Kupffer cells play a critical role in detoxification and act as phagocytic macrophages - Located in portal and lobular liver sinusoids - Dendritic cells promote tolerance to phagocytized particles - Hepatic myeloid-derived suppressor cells suppress the immune response in the liver ## Hepatic Stellate Cells - Reside in the space of Disse - Store vitamin A and regulate sinusoidal circulation - Can proliferate in liver injury leading to hepatic inflammation and fibrosis ## Liver Sinusoidal Endothelial Cells - Permeable barrier that helps regulate hepatic vascular tone - Separates blood cells from hepatocytes/hepatic stellate cells - **Understand how shunting occurs and why it leads to ascites given the different pressure in various vessels?** ## Functions of the Liver - **Filtration and storage of blood** - Moderates hypotensive response to hemorrhage and hypovolemia - Liver is expandable and can store up to 1 L of blood – liver has ability to autotransfuse blood - Forms about 50% of body's lymph ## Metabolism of Carbohydrates - **Glycogenesis** = converting glucose to glycogen - **Glycogenolysis** = breakdown of glycogen for glucose - **Lipogenesis** = converting excess glucose into fat - **Gluconeogenesis** = converting lactate, glycerol, and amino acids to glucose; also converting galactose and fructose to glucose = creating glucose from non-carbohydrate sources ## Protein Metabolism in the Liver - **Deamination of amino acids/proteins to form carbs or fat.** Ammonia is a byproduct of this reaction. - **Formation of urea for removal of ammonia.** - **Ammonia level DOES NOT correlate with severity of encephalopathy** - it is toxic in small doses - Liver produces albumin, angiotensinogen, thrombopoietin, and plasma cholinesterase ## Liver Produces All Plasma Proteins Except - Gamma globulin, factors III, IV, and VIII - In liver failure/injury, the plasma proteins made by the liver will be low and the other plasma proteins will be high to compensate - **Vitamin K is required for synthesis of prothrombin (factor II) and factor VII, IX, and X.** ## Amino Acid Synthesis - Albumin accounts for >50% of total plasma proteins - Many medications are bound to albumin - Albumin helps maintain intravascular fluid volume - Half life of albumin is ~23 days → if patient has signs of liver dysfunction and a normal albumin, it is likely an acute problem. ## Fat Metabolism in the Liver - Liver produces bile, which is needed for digestion of fat and cholesterol production. - Oxidation of fatty acids to CoA as an energy source - Synthesis of cholesterol, phospholipids, and most lipoproteins - Synthesis of fat from proteins and carbohydrates to be stored in adipose tissues. ## Drug Metabolism - Biotransformation of drugs into inactive H2O soluble substances that can be excreted in urine or bile. - **Phase 1 reactions** are mediated by hepatic CP450 enzymes - Consist of oxidation, reduction, and hydrolysis. - Convert lipophilic drugs to water soluble molecules. - **Phase 2 reactions** are conjugation reactions. - Consist of glucuronidation, acylation, sulfate, and glycine. - Combine water soluble molecule with something else so it can be excreted. - **Intrinsic metabolic clearance** = fraction of drug that is metabolized/extracted on a single pass through the liver. - **First pass effect** occurs with PO and buccal drugs that have to pass through the Gl tract and subsequently the liver to be metabolized. - High clearance drugs are readily cleared and dependent on hepatic blood flow for clearance. - Low clearance drugs are not readily cleared and are independent on hepatic blood flow. ## Synthesis and Metabolism of Hormones - Liver synthesizes angiotensinogen, thrombopoietin, 25-hydroxyvitamin D (calcitriol precursor). - Liver regulates thyroxine, estrogen, cortisol, aldosterone. - Liver works both synthesis and metabolism of key hormones to include endocrinologic hormones. ## Elimination of Foreign And Chemical Toxins - Kupffer cells act as macrophages and filter so that <1% of bacteria from gut gets through the circulation. - Liver also generates 50% of body's lymph. ## Hgb Breakdown - Bilirubin is the major end-product of hemoglobin degradation that gets excreted by the liver. - Heme gets converted to bilirubin - Bilirubin excreted into bile duct ## Formation of Bile - Bile is produced by hepatocytes. - Bile facilitates excretion of toxins and absorption of dietary fats. - Bile used to excrete endogenous compounds and exogenous compounds. - Bile flows from liver lobules → common bile duct → duodenum through the ampulla of Vater. ## Storage of Vitamins And Iron - Fat soluble vitamins = A, D, E, and K. - Vitamin A (10-month supply) - Vitamin B12 (> 1 year supply) - Vitamin D (3-month supply) - **Vitamin K necessary for synthesis of Factors II, VII, IX and X.** - Iron - Excess iron binds with apoferritin and is stored in liver as ferritin. ## Formation of Clotting Factors - Except factors III, IV, and VIII that are all produced outside of the liver. - Hepatocytes contain apoferritin (which combines reversibly with iron) - Liver is the site for synthesis of all procoagulant and anticoagulant factors - Factor VIII elevated in the setting of liver disease - Liver is also the site for clearance of activated factors - **Know factor 7 has the shortest half-life** - Evaluate factor 7 via PT blood test ## Each Liver Lobule is an Anatomic and Functional Unit of the Liver - Consists of a portal triad, plate of hepatocytes, and a central vein - **Portal triad** = branch of hepatic artery, branch of portal vein, and bile ducts - **Acinus** = functional unit of the liver - **Zone 1 - Periportal** - Well-oxygenated hepatocytes - Very nutrient-rich - Responsible for oxidative activities - **Zone 2 - Midzone** - **Zone 3** - Hepatocytes furthest from blood supply - Penetrating vessels - Most susceptible to ischemic injury because they are the furthest from blood supply - Responsible for glycolysis, lipogenesis, detoxification, and biotransformation of drugs occur ## Bile Synthesis, Function and Drainage - Facilitates excretion of toxins & absorption of dietary fats. - Also used to excrete endogenous compounds (bile acids, bilirubin, phospholipids, cholesterol, steroid hormones) and exogenous compounds (drugs, toxins) - Bile flows from liver lobules → common bile duct →sphincter of Oddi → ampulla of Vater to the duodenum. - **Sphincter of Oddi** is a muscular valve that controls flow of bile and pancreatic juices into the small intestine via the ampulla of Vater. ## Blood Flow in/around Liver Lobules - Space of Disse lies between sinusoidal capillaries and hepatocytes. ## Liver Function Tests - Do not measure specific liver function. - Abnormalities are late in hepatic disease due to the segmental nature of the liver that provides redundancy – one segment can do the work of others - Reflect hepatocellular injury, more than liver function. - LFTs can help define pathophysiology with clinical assessment. - **Hepatic synthetic function**: - Serum albumin, PT, INR, serum cholesterol, plasma pseudocholinesterase - **Hepatic protein synthesis**: serum albumin, prothrombin time, INR - **Hepatic excretory function/clearance**: direct bilirubin - **Cholestatic or infiltrative conditions**: alkaline phosphatase - **Hepatic cellular integrity**: AST, ALT, LDH, GST - **Hepatic detoxification function**: ammonia ## Aminotransferases are enzymes involved in gluconeogenesis = ALT and AST - **ALT primarily found in liver and most specific marker of liver injury.** - **AST found in liver and non-hepatic tissue** - ALT and AST can be normal in end-stage liver disease because there are no cells left to be injured. - Mild elevations occur with any hepatocyte injury. - Large elevations are indicative of hepatic necrosis, fulminant viral hepatitis, drug-induced liver injury, shock liver. - Ratio of AST/ALT = 2 indicates alcoholic liver disease ## LDH = Lactate Dehydrogenase - Non-specific marker of hepatic injury. - Extreme elevations seen with ischemia or drug-induced hepatotoxicity (e.g. Tylenol OD) - Tylenol OD is the most common cause of acute liver failure. - Extrahepatic disorders can increase LDH (e.g. hemolysis, rhabdo, tumor necrosis, renal infarction, MI) ## GST = Gluthathione-S-Transferase. - Sensitive for liver injury and short half life. ## Alkaline Phosphatase (AP): - Mild elevations may be normal - Non-specific (found in extra-hepatic tissues) - Values 2-4x normal seen in cholestatic disease - Can indicate intrahepatic or extrahepatic biliary obstruction ## Serum Bilirubin: - Indicates excretory function of the liver. - Normal total bilirubin is < 1.5 mg/dL. - Jaundice is usually evident if total bilirubin is >3. ## Conjugated (Direct) Bilirubin - Water soluble – liver is unable to excrete → secretion or obstruction problems ## Unconjugated (Indirect) Bilirubin - Lipid soluble - Heme catabolism - reticuloendothelial system - Differential diagnosis of bilirubin ## Serum Albumin: - Used to evaluate chronic liver disease and hepatocellular function (protein synthesis). - Poor specificity (low levels seen with malnutrition, renal losses, 3rd spacing). ## Prothrombin Time: - Measures the activity of fibrinogen, prothrombin, and factors V, VII, and X. - Normal 11-14s. ## INR: - Prolonged INR usually indicates liver dysfunction. - Effect on coagulation depends on balance between coagulation and anticoagulation factors. - Alkaline phosphate and bilirubin elevations expected in obstructive liver/gallbladder disorders. ## Hepatocellular (Parenchymal) Liver Disease - **Chronic** - Causes = chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease - Our population has gotten fatter so increased incidence of nonalcoholic fatty liver disease. - **Acute** - Causes = drug toxicity, infection, alcoholic hepatitis, pregnancy. ## Biliary Disease - Causes = biliary obstruction, cholestatic disease, primary biliary cholangitis, primary sclerosing cholangitis ## Drug Related Causes of Liver Injury - **Acetaminophen** - **Halothane** causes ALF (acute liver failure)/hepatic necrosis - Halothane metabolized 20% hepatically - Active metabolite is the cause of ALF - Can occur with Enflurane (2%) > Iso (0.2%) > Des (0.01%) - **Anabolic steroids** - **NSAIDs** - **Amiodarone** - **ΤΡΝ** ## Pregnancy Related Liver Disease - Causes = hyperemesis gravidarum, intrahepatic cholestasis, pre-eclampsia - HELLP syndrome = hemolysis, elevated liver enzymes, low platelet count - Platelet count affects regional technique - AFLP = acute fatty liver disease of pregnancy ## Hepatitis - **Acute** - Injury due to viral infection, drug reaction, or exposure to hepatotoxin - Causes = alcohol, acetaminophen, mushrooms - **Chronic** - Lasting 6+ months - Lab values do not correlate with severity of disease - Liver biopsy assists in classification into one of 3 types = Chronic Persistent Hepatitis, Chronic Lobular Hepatitis, Chronic Active Hepatitis ## Types of Viral Hepatitis: - Type A - Transmitted fecal-oral - Type B - Transmitted percutaneous or sexual - Type C - Percutaneous route - Turns into chronic hepatitis 70-85% - No vaccine available - Type D - Transmitted percutaneous or sexual - Requires type B coinfection - Type E - Transmitted fecal-oral route - Associated with travel to endemic area ## Cirrhosis = End-Result of Chronic Liver Disease - Lobules are replaced with fibrosis and regenerative nodules. - Disrupts blood flow through the liver leading to shunt formation, portal hypertension, esophageal varices, ascites, Hepatorenal syndrome, pulmonary hypertension. - Increased resistance of blood flow through the fibrotic areas. - End with a hyperdynamic circulation = increase cardiac output and low systemic vascular resistance. - **Reason for increased cardiac output is due to low systemic vascular resistance** - Treatment = use nonselective beta blockers to increase splanchnic vasoconstriction to lower portal pressure. ## Portal HTN - Increased resistance to blood flow thru the liver leads to portal hypertension (+5 mmHg) - Considered severe if hepatic venous pressure gradient (HVPG) >10-12 mm Hg ## Hemostasis - Disrupted balance between bleeding and clotting ## Cirrhotic Cardiomyopathy: - Hyperdynamic circulation characterized by high cardiac output, low blood pressure, and low systemic vascular resistance. - Increased overall fluid volume with decreased circulating volume - Prolonged QT ## Hepatorenal Syndrome (HRS) - Prerenal disease characterized by sodium and water retention - Increased prostaglandin levels to help maintain renal perfusion - Increased sensitivity to nephrotoxic drugs e.g. aminoglycosides, ACEIs, ARBs ## Hepatopulmonary Syndrome - Triad of liver dysfunction, unexplained hypoxemia, intrapulmonary vascular dilation ## Postpulmonary HTN = Pulmonary HTN in a Patient With Portal HTN ## Hepatic Hydrothorax - Ascites fluid passes from peritoneal cavity to the pleural space ## Hepatic Encephalopathy - Result of accumulated neurotoxins directly affecting the brain (e.g. ammonia and others) - Symptoms = altered mental status, hyper-reflexiveness, nystagmus, decerebrate posturing. - Mortality is related to infection. - Treatment = paracentesis and slow correction of hyponatremia. - **Why do we slowly correct hyponatremia?** ## Varices - End result of portal HTN - Treat with beta-blockers to decrease portal pressure and endoscopic ligation. ## Chronic Cholestatic Disease - Impaired bile flow increases biliary pressure and backflow into liver resulting in hepatocyte destruction. - If bacteria in bile -> ascending cholangitis, hepatic abscess, sepsis, and acute kidney injury can occur - Deficiencies in Vitamin K-dependent clotting factors (II, VII, IX, X) - Hypercoagulability - Extrahepatic causes = obstruction - Labs = Elevated serum AP and GT; may have elevated bilirubin. Check AMA titers to rule out Primary Biliary Cholangitis - Treatment = endoscopic retrograde pancreatography (ERCP) ## Primary Biliary Cholangitis - Autoimmune mediated destruction of bile duct cells – won't be tested on this! ## Primary Sclerosing Cholangitis - Won't be tested on this! ## Hepatocellular Carcinoma - Most common primary liver malignancy and 3rd most common cause of death globally. - Treatment = surgical resection, liver transplant, ablation, chemoembolization ## Nonalcoholic Fatty Liver Disease (NAFLD) - Ranges in severity from steatosis (fat deposits on liver) to hepatocellular necrosis (NASH/steatohepatitis) - Associated with metabolic syndrome - Most common cause of elevated liver enzymes in adults - Treatment = weight loss or bariatric surgery ## Anesthetic Implications - Signs to look for during preop assessment = jaundice, bleeding abnormalities, spider angiomas - great number - Spider angiomas are associated with varices and hepatopulmonary syndrome. - Avoid routine screening LFTs. Test if indicated by physical exam/history. - **Preop LFTs:** - Elevated ALT and AST in asymptomatic patient? Proceed if <2x normal and normal alk phos, bilirubin, INR. - Transaminases > 2x normal □ Workup prior to elective surgery (US, CT, liver biopsy). - Both transaminases and INR abnormal □ Workup prior to elective surgery (US, CT, liver biopsy). - Elevated alk phos and elevated transaminases □ Suspect biliary disease and workup indicated. - **Altered Pharmacokinetics** - Altered protein binding – low albumin so reduced protein to bind resulting in more free drug. - Altered Volume of distribution with ascites and increased total body weight. - Reduced metabolism. - Potentiation of anticoagulants due to decreased production of clotting factors. - So what? Smaller doses of meds at longer intervals. - **Induction of GA** - Increased aspiration risk, rapid desaturation and hypoxemia. - Increased susceptibility to CNS depressants. - **Precedex:** - Liver metabolism primarily. - Decreased clearance and prolonged half-life - **Midazolam:** - Reduced clearance prolongs elimination half-life. - Avoid procede and midazolam/any drugs that are primarily cleared hepatically. - Goal platelet >50k - Opioids - fentanyl is best choice due to its short duration, remifentanil can be used as well but caution for hyperalgesia. - All volatiles decrease cardiac output which can ultimately decrease hepatic blood flow. - **Neuraxial Techniques:** - May have reduced responsiveness to pressors and catecholamines. - May be contraindicated in thrombocytopenia. - Avoid high neuraxial block. - Peripheral nerve blocks are not associated with hepatic blood flow or liver function. - **Alcoholism And Anesthesia** - Acute alcohol symptoms = tachycardia that progresses to seizures. - **Porphyria:** - Rare genetic aberrations in heme production.