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Hepatic Physiology

Hepatic Physiology. Now would be the time to make sure you have coffee in hand. Objectives. Understand hepatic anatomy and physiology Understand liver’s role in metabolism Review liver functions tests Describe the effects of anesthesia on the liver. March 14, 2013.

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Hepatic Physiology

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  1. Hepatic Physiology Now would be the time to make sure you have coffee in hand.

  2. Objectives Understand hepatic anatomy and physiology Understand liver’s role in metabolism Review liver functions tests Describe the effects of anesthesia on the liver

  3. March 14, 2013 Dr. Lindsay Higgins will be presenting Chapter 34: Anesthesia for Patients with Liver Disease Hopefully, she will provide cookies.

  4. Largest Organ in the Body

  5. Lobule: The Anatomic Unit • Centrilobular vein surrounded by cylinder of hepatocytes • Portal triads surround lobule • Hepatic arteriole • Bile duct • Portal venule

  6. Acinus: The Functional Unit • Defined by blood supply • Portal Tract at the center • Centrilobular veins at periphery • Zone 1: Near portal tract—well-oxygenated • Zone 3: Near vein—susceptible to injury

  7. Liver Recevies 25-30% Cardiac Output • Normal hepatic blood flow 1500cc/min • 25-30% from hepatic artery • 70-75% from portal vein • Oxygenation requirements supplied by both • 45-50% from hepatic artery • 50-55% from portal vein • Liver can act as a reservoir • Normally 450 cc • Can hold up to 1 Liter in cases of CHF • Portal Vein flow not regulated—susceptible to systemic hypotension

  8. Hepatic Functions Blood-cleansing Metabolism of carbohydrates, fats, proteins, and drugs Synthesis of proteins, enzymes, clotting factors

  9. Blood-Cleansing • Kupffer cells line sinusoids • Part of monocyte-macrophage system • Involved in phagocytosis, antigen processing, and release of mediators • Removes bacteria and endotoxin leaving portal circulation

  10. Who is ready for some biochemistry?

  11. Carbohydrate Metabolism • Main organ for storage and release of glucose • Glycogenesis converts glucose to glycogen • Big Meal  Increased insulin  glycogenesis • Glycogenolysis breaks down glycogen to glucose • Initiated by starvation, stress, or sympathetic activation •  Epi or  Glucagon  glyconeolysis • Glycogen stores depleted after 24 hours

  12. More Simplistically

  13. Fat Metabolism • If carbohydrate stores are saturated, carbs converted to triglycerides. • Fatty acids can be used immediately or stored for winter. • Of note, RBCs only use glucose for fuel • Neurons only utilize glucose except during starvation  ketone bodies • Fatty acids converted to Acetyl-CoA which then enters…

  14. More Fat • The Citric Acid Cycle! • ATP produced • Acetyl CoA : • converts to ketone bodies • Utilized in cholesterol and phospholipid production

  15. Protein Metabolism Without the liver’s role in protein metabolism death would occur within several days Deamination of excess amino acids  carbohydrates and fats All plasma proteins except immunoglobulins synthesized in the liver Nonessential amino acids synthesized

  16. What is the cause of hepatic encephalopathy? • Answer: Ammonia accumulation • Urea Cycle converts ammonia and CO2 to Urea  excretion by kidney

  17. Synthetic Functions • All plasma proteins except immunoglobulins • Coagulation factors • Unfortunately will talk more about this • Bile formation • Absorption of fat soluble vitamins

  18. What makes up the MELD Score?

  19. What about Child-Pugh-Turcotte?

  20. What do they mean?

  21. Putting it all together

  22. Drug Metabolism Lidocaine Morphine Verapamil Labetalol Propranolol • Most drugs undergo hepatic biotransformation • Two (or three) pathways • Phase I: modification of active groups by cytochrome P-450 or mixed-function oxidases • Phase II: conjugation of metabolites to water-soluble substrates  elimination via urine or bile • Phase III (Baby Miller): energy dependent excretion into bile • Metabolism of certain drugs dependent on hepatic bloodflow

  23. Cytochrome P-450 • Key point of drug interactions • Inducers of note: barbituates, ketamine, ethanol, phenytoin, rifampin, omeprazole, isoniazid • Induction increases action increased metabolism • Patient exhibits increased tolerance to medications • Inhibitors of note: anti-retrovirals, cimetidine, chloramphenicol, fluconazole, bupropion • Inhibition decreases action  decreased clearance • Prolonged duration of action

  24. Liver Function Tests • AST (SGOT) • ALT (SGPT) • AlkPhos • Albumin • Prothrombin Time • Bilirubin • INR • AST, ALT, AlkPhos measure hepatocellular integrity • Albumin, PT, INR measure synthetic function

  25. Review • Bilirubin • T bili (N <1.5) reflects production and biliary excretion…jaundice at >3 • Direct (conjugated) may reflect hepatocellular dysfunction, cholestasis, or biliary obstruction • Indirect (unconjugated) seen with hemolysis or defects in bilirubin conjugation • Direct bilirubin is toxic to cells • Alkaline Phosphatase • Produced by liver, bone, small bowel, kidneys, and placenta • Majority derived from bone • High levels indicate intrahepatic cholestasis or biliary obstruction

  26. ALT • Primarily in liver • AST • Present in liver, heart, skeletal muscle, kidneys • AST elevating to greater extent  EtOH • Albumin • Normal 3.5-5.5 • Half-life 2-3 weeks • <2.5  chronic liver disease, acute stress, or severe malnutrition

  27. PT • Measures activity of fibrinogen, prothrobin, and factors V, VII, X • Half-life 4-6 hours • Normal 11-14 seconds • Prolongation of 3-4 s ~ INR of 1.5 • Reflects • Severe liver disease • Vitamin K deficiency

  28. Finally, effects of anesthesia

  29. Anesthesia reduces hepatic blood flow • Both general and regional anesthsia • Volatiles reduce portal flow (Halothane > sevo > iso) • Isoflurane causes direct arterial vasodilation • Neuraxial techniques decrease via lowering arterial BP • General anesthesia decreases via lowering BP, reducing cardiac output, and reducing sympathetic stimulation • Positive pressure ventilation decrease blood flow through decrease in venous return • Hypoxemia reduces flow • Beta-Blockers, Alpha-1 agonists, H2 Blockers, Vasopressin

  30. Surgical stress affects metabolism • Levels of catecholamines, glucagon, and cortisol increase • Results in • Glycogenolysis Hyperglycemia • Negative nitrogen balance • Stress response can be blunted by regional techniques, deep general anesthesia, or sympathetic blockade

  31. Anesthesia alters drug metabolism • Halothane directly inhibits metabolism • Phenytoin • Warfarin • Ketamine • Decreased hepatic blood flow decreases metabolism of other drugs • Fentanyl, verapamil, propranolol

  32. Opioids can clench the Sphincter (of Oddi) All opioids potentially cause spasm and increase biliary pressure Fentanyl > morphine > meperidine Relieved by naloxone or glucagon

  33. Mild postoperative liver dysfunction not uncommon May be due to reduction in blood flow, sympathetic stimulation, or surgery its self Elevation of LFTs postoperatively usually secondary to surgery or pre-existing disease Most common cause of post-operative jaundice is resorptionof hematoma

  34. Halothane is always the answer • Halothane Hepatitis • also seen with methoxyflurane, enflurane, and isoflurane • Range from asymptomatic increase in LFTs (1:5) to fulminant hepatic necrosis (1:35,000) • Risk factors include • Middle age • Obesity • Female species • Repeat exposure to halothane (> if within 28 days) • Diagnosis of exclusion • Eliminate pre-existing disease • Viral hepatitis, CMV, herpes, etc

  35. So apparently coagulation is not covered anywhere else • I hate my life • Three processes • Vascular spasm • Platelet plug (primary hemostasis) • Coagulation (secondary hemostasis)

  36. Primary hemostasis

  37. Secondary Hemostasis

  38. Rapid fire • Prolonged bleeding in liver disease? • Vitamin K deficiency • Impaired hepatic synthesis • Splenic sequestration of platelets • Normal PT, PTT, prolonged bleeding time? • Platelet disorder • Quantitative  thrombocytopenia • Qualitative  Normal platelet count

  39. Rapid fire • Most common inherited bleeding disorder? • von Willebrand’s (1:800) • Most heterozygousonly apparent during major bleeding • Treatment • DDAVP is mild • Cryoprecipitate or factor VIII if no response • Hemophilia A • Factor VIII deficiency • X-linked (1:10,000 males) • Prolonged aPTT, normal PT • Symptomatic if < 5% activity, raise level to 50% prior to surgery • Hemophilia B (Christmas disease) • Factor IX • X-linked (1:100,000 males)

  40. Still going… • Vitamin K dependent factors? • II, VII, IX, X • Heparin mode of action? • Promotes Antithrombin III • What’s different about LMWHs? • Inhibits Xa preferentially

  41. Finally Cutest kid?

  42. Questions?

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