Hepatic Physiology

Hepatic PhysiologyNow would be the time to make sure you have coffee in hand.ObjectivesUnderstand hepatic anatomy and physiologyUnderstand livers role in metabolismReview liver functions testsDescribe the effects of anesthesia on the liver

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

Hopefully, she will provide cookies.

Largest Organ in the Body

Lobule: The Anatomic UnitCentrilobular vein surrounded by cylinder of hepatocytesPortal triads surround lobuleHepatic arterioleBile ductPortal venule

Acinus: The Functional UnitDefined by blood supplyPortal Tract at the centerCentrilobular veins at peripheryZone 1: Near portal tractwell-oxygenatedZone 3: Near veinsusceptible to injury

Liver Recevies 25-30% Cardiac OutputNormal hepatic blood flow 1500cc/min25-30% from hepatic artery70-75% from portal veinOxygenation requirements supplied by both45-50% from hepatic artery50-55% from portal veinLiver can act as a reservoirNormally 450 ccCan hold up to 1 Liter in cases of CHFPortal Vein flow not regulatedsusceptible to systemic hypotensionHepatic FunctionsBlood-cleansing

Metabolism of carbohydrates, fats, proteins, and drugs

Synthesis of proteins, enzymes, clotting factors

Blood-CleansingKupffer cells line sinusoids

Part of monocyte-macrophage system

Involved in phagocytosis, antigen processing, and release of mediators

Removes bacteria and endotoxin leaving portal circulation

Who is ready for some biochemistry?

Carbohydrate MetabolismMain organ for storage and release of glucoseGlycogenesis converts glucose to glycogenBig Meal Increased insulin glycogenesisGlycogenolysis breaks down glycogen to glucoseInitiated by starvation, stress, or sympathetic activation Epi or Glucagon glyconeolysisGlycogen stores depleted after 24 hours

More Simplistically

Fat MetabolismIf 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 fuelNeurons only utilize glucose except during starvation ketone bodiesFatty acids converted to Acetyl-CoA which then entersMore FatThe Citric Acid Cycle!ATP producedAcetyl CoA :converts to ketone bodiesUtilized in cholesterol and phospholipid production

Protein MetabolismWithout the livers 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 synthesizedWhat is the cause of hepatic encephalopathy?Answer: Ammonia accumulation

Urea Cycle converts ammonia and CO2 to Urea excretion by kidney

Synthetic FunctionsAll plasma proteins except immunoglobulins

Coagulation factorsUnfortunately will talk more about this

Bile formationAbsorption of fat soluble vitaminsWhat makes up the MELD Score?

What about Child-Pugh-Turcotte?

What do they mean?

Putting it all together

Drug MetabolismMost drugs undergo hepatic biotransformationTwo (or three) pathwaysPhase I: modification of active groups by cytochrome P-450 or mixed-function oxidasesPhase II: conjugation of metabolites to water-soluble substrates elimination via urine or bilePhase III (Baby Miller): energy dependent excretion into bileMetabolism of certain drugs dependent on hepatic bloodflow LidocaineMorphineVerapamilLabetalolPropranololCytochrome P-450Key point of drug interactions

Inducers of note: barbituates, ketamine, ethanol, phenytoin, rifampin, omeprazole, isoniazidInduction increases action increased metabolismPatient exhibits increased tolerance to medications

Inhibitors of note: anti-retrovirals, cimetidine, chloramphenicol, fluconazole, bupropionInhibition decreases action decreased clearanceProlonged duration of actionLiver Function TestsAST (SGOT)ALT (SGPT)Alk PhosAlbuminProthrombin TimeBilirubinINR

AST, ALT, Alk Phos measure hepatocellular integrityAlbumin, PT, INR measure synthetic functionReviewBilirubinT bili (N 3Direct (conjugated) may reflect hepatocellular dysfunction, cholestasis, or biliary obstructionIndirect (unconjugated) seen with hemolysis or defects in bilirubin conjugationDirect bilirubin is toxic to cellsAlkaline PhosphataseProduced by liver, bone, small bowel, kidneys, and placentaMajority derived from boneHigh levels indicate intrahepatic cholestasis or biliary obstruction

ALTPrimarily in liverASTPresent in liver, heart, skeletal muscle, kidneysAST elevating to greater extent EtOHAlbuminNormal 3.5-5.5Half-life 2-3 weeks sevo > iso)Isoflurane causes direct arterial vasodilationNeuraxial techniques decrease via lowering arterial BPGeneral 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, VasopressinSurgical stress affects metabolismLevels of catecholamines, glucagon, and cortisol increase

Results inGlycogenolysis HyperglycemiaNegative nitrogen balance

Stress response can be blunted by regional techniques, deep general anesthesia, or sympathetic blockadeAnesthesia alters drug metabolismHalothane directly inhibits metabolismPhenytoinWarfarinKetamine

Decreased hepatic blood flow decreases metabolism of other drugsFentanyl, verapamil, propranololOpioids can clench the Sphincter (of Oddi)All opioids potentially cause spasm and increase biliary pressure

Fentanyl > morphine > meperidine

Relieved by naloxone or glucagon Mild postoperative liver dysfunction not uncommonMay 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 resorption of hematomaHalothane is always the answerHalothane Hepatitis also seen with methoxyflurane, enflurane, and isofluraneRange from asymptomatic increase in LFTs (1:5) to fulminant hepatic necrosis (1:35,000)

Risk factors includeMiddle ageObesityFemale speciesRepeat exposure to halothane (> if within 28 days)

Diagnosis of exclusionEliminate pre-existing diseaseViral hepatitis, CMV, herpes, etcSo apparently coagulation is not covered anywhere elseI hate my life

Three processesVascular spasmPlatelet plug (primary hemostasis)Coagulation (secondary hemostasis)

Primary hemostasis

Secondary Hemostasis

Rapid fireProlonged bleeding in liver disease? Vitamin K deficiencyImpaired hepatic synthesisSplenic sequestration of platelets

Normal PT, PTT, prolonged bleeding time?Platelet disorderQuantitative thrombocytopeniaQualitative Normal platelet countRapid fireMost common inherited bleeding disorder?von Willebrands (1:800)Most heterozygousonly apparent during major bleedingTreatmentDDAVP is mildCryoprecipitate or factor VIII if no responseHemophilia AFactor VIII deficiency X-linked (1:10,000 males)Prolonged aPTT, normal PTSymptomatic if < 5% activity, raise level to 50% prior to surgeryHemophilia B (Christmas disease)Factor IXX-linked (1:100,000 males)

Still goingVitamin K dependent factors?II, VII, IX, X

Heparin mode of action?Promotes Antithrombin III

Whats different about LMWHs?Inhibits Xa preferentiallyFinallyCutest kid?

Questions?