Acute liver failure Board review - PowerPoint Presentation

1. Acute liver failureBoard reviewJulie MenardCornell University

2. Liver FunctionRecognition and detoxification of xenobiotics and endogenous wastesElimination of toxinsManufacturing of substancesStorage of metabolic productsMetabolic activationMetabolic eliminationCVT 14 chapter 131 : drug associated liver disease

3. Definition1970 Trey and Davidson Severe liver injury w onset of encephalopathy within 8 weeks of symptoms appearance and without pre-existing liver disease1986 Bernuau: Time from icterus to HEFulminant: 0-2 weeksSubfulminant: 2-12 weeks1993 O’Grady: Time from icterus to HEHyperacute: 0-1 weekAcute: 1-4 weekSubacute: 4-12 week

4. EtiologyEtiologydogcatInfectious agentcanine adenovirus-1Acidophil cell hepatitis virusCanine herpes virusGram positive septicemiaGram negative septicemiaSalmonella spp.Clostridia spp.BartonellosisLeptospirosisLiver abcessTularemiaHepatozoonosisRickettsia RickettsiiHistoplasmosisCoccidiomycosisBlastomycosisLeishmaniasisToxoplasmosisDirofilaria ImmitisEhrlichia CanisFeline infectious peritonitisClostridiosisliver abscessHistoplasmosisCryptococcosisToxoplasmosisLiver Flukes

5. EtiologyEtiologyDogsCatsDrugsAcetaminophenAspirinPhenobarbitalPhenytoinCarprofenTetracyclineMacrolidesTrimethoprim-sulfaGriseofulvinthiacetarsamideKetoconazole, ItraconazoleHalothaneacetaminophenAspirindiazepamhalothanegriseofulvinketoconazoleitraconazolemethimazolemethotrexatePhenobarbitalphenytoin

6. EtiologydogcatChemical agents and toxinsXylitolindustrial solventplants (sago palm)envenomationheavy metalsmushroomsalfatoxinsblue green algae cycad seedscarbon tetrachloridedimethynitrosamineZinc phosphidesame as dogTraumatic, thermal, hypoxicDiaphragmatic herniaShockliver torsionheat strokemassive ischemiasame as for dogs

7. EtiologyDogsCatsMiscellaneousChronic hepatitis, CirrhosisIdiopathicCopper storage diseaseleptospirosis inducedIdiosyncratic drug reaction lobular dissecting hepatitisGranulomatous hepatitisHepatic amyloidosis (Shar Pei)Hepatic neoplasia (primary or metastatic disease)Portosystemic shuntingportal venous hypoplasia/ microvascular dysplasia (YST and Cairn T)Feline hepatic lipidosisinflammatory bowel diseasepancreatitischolangitischolangiohepatitissepticemiaendotoxemiahemolytic anemianeoplasia (lymphoma, mastocytosis)Mestasisamyloidosis (abyssinian, Oriental and siamese cats)

8. Drug reaction: mechanismMost pharmacological active substance: lipophyllicEnhancement or elimination: need to be transformed to hydrophyllicLiver metabolism:Phase IPhase IISmooth endoplasmic reticulum of the liver

9. Phase IUsually precedes phase II (not always)Activation or inactivation of the drugOxidationReductionHydrolysisCyclization or decyclizationCytochrome P450 mono-oxygenase (CYP), NADH and O2

10. Phase IIConjugation reaction MethylationSulphanationAcetylationGlucorinidationMost often detoxification in nature

11. PathophysiologyCytotoxic:direct injury to hepatocyte caused by virus, drugs and their toxic metabolites or toxinsCytopathicImmune mediated response to hepatocytes that express abnormal cell surface antigens (idiosyncratic drug reaction)Both

12. Tissue ischemia/ hypoxiaCytoprotective cofactor depletionFree radical oxidative injuryImmunogenic injuryMembrane peroxidation Phospholipase injuryIntracellular toxin production P 450 cytochromes interacting w macromoleculesCholestatic injuryCell membrane injuryToxins binding to cells proteinsEndotoxin initiated injuryMicrobial, viral, parasite initiated injury

13. PathophysiologyDamage to hepatocyte cell membraneDecrease mitochondrial energy functionLeakage of enzymes Retention of irritative waste: bile acidsInitiation of apoptosisInflammatory cascade w cytokineFormation free radicalsLIVER NECROSIS

14. ConsequencesHemodynamic instabilityHepatic encephalopathyCerebral edemaCoagulopathyRenal failureSepsisMetabolic disturbancesDEATH…

15. Hemodynamic instabilityHigh cardiac output + decreased systemic vascular resistanceMarked splanchnic and systemic arteriolar vasodilation -> hepatic arterial blood flow and portal flow decreasedHyperdynamic circulationLow arterio-venous O2 content ≠Tissue hypoxia

16. Hepatic encephalopathy Pathophysiology poorly understood1893: Nencki and Pavlov: meat intoxication syndrome:Increase ammonia levels after a meal associated w behavioral disturbances in dogs w surgical PSS1991: Direct evidence ammonia in HE NH3 uptake into brain in HE vs. healthy

17. Pathophysiology HEAccumulation non metabolized NH3Production of false neurotransmittersActivation GABA-benzodiazepine receptors by ligands from endogenous originAltered cerebral metabolismDisturbed Na K ATP ase activityZinc deficiency of zinc dependant enz of urea cycleManganese deposition of basal ganglia

18. Ammonia- NH3Central role in HEOrigin: Colonic urease-producing bacteriaEnterocytes SI (glutamine breakdown)Liver: metabolizes ammonia to ureaKidney: Produce and excrete NH3Muscles: detoxifies during hyper NH3 NH3  Glutamine

19. NH3EnterocytesBacteria urase +NH3  UREAAstrocyteNH3  GlutamineGlutamine NH3

20. Pathophysiology of NH3 in HEAstrocyte: site of NH3 detoxificationNH3 converts to glutamine “Ammonia-glutamine- brain edema hypothesis”Accumulation of glutamine in astrocyteOsmotic stressSwollen astrocytes

21. Astrocyte swellingActivation extracellular protein kinaseIncrease intracellular calciumUpregulation benzo receptorsEndosomal activation (Ion channel and aa transport)NeurosteroidsIncrease inhibitory GABA neurotransmitter activity Deposition glycogen andinhibition glycogenolysis

22. Role of NH3 in HEDecrease excitatory neurotransmitterDown regulating NMDA receptorsBlocks chloride extrusion: inhibitory neurotransmitter is ineffectiveCerebral energy failureNeuronal oxidative stress Impaired mitochondrial function

23. Other factors

24. TryptophanTryptophan:GlutamineTryptophanSerotoninquinolateInhibitoryexcitatoryBBBvasculaturecerebral parenchyma

25. Other moleculesAmino acid imbalance: Branch > aromatic = production false neurotransmittersDeficiency arginine and citrulineHypoglycemiaHypoxemiaEndotoxemiaHypotension

26. SummaryToxinsMechanisms suggested AmmoniaIncrease brain tryptophan and glutaminebrain edemadecreases ATP availabilityIncreases excitatibilityIncreases glycolysisDecreases microsomal Na, K ATP ase in brainGlutaminealters blood brain barrier aa transportAromatic amino acidsDecreases dopa neutrotransmitter synthesisAlters neurorecptorsIncreases production of false neurotransmittersShort fatty acidsDecreases microsomal Na, K ATPase in brainUncouple oxidative phosphorylationImpairs oxygen utilisationDisplaces tryptophan from albuminIncreases free tryptophan

27. False neurotransmitterMechanism suggestedTyrosine -> octopamineImpairs norepinephrine actionPhenylalanine -> phenylethylamineImpairs norepinephrine actionMethionine -> mercaptansSynergistic with ammonia and short chain fatty acids Decreases ammonia detoxification in brain urea cylcleGIT derived Decreases microsomal Na, K APTase TryptophanDirectly neurotoxicincreases serotonin and quionlatePhenol (from phenylalanine and tyrosine)Synergistic w other toxinsDecreases cellular enzymesNeurotoxic and hepatotoxicBile acidsmembrane cytolytic effects, alter cell membrane permeabilityimpairs cellular metabolism due to cytotoxicityGABANeuronal inhibitionIncreases BBB permeability to GABAEndogenous benzodiazepinesNeuronal inhibitionhyperpolarize neuronal membrane

28. Classification of HEhttp://www.youtube.com/watch?v=zxdz_m5gcpU&NR=1Grade III- IV: subclinical seizure Improved w phenytoin and  cerebral edema in 2000 england. 2004 study showed no benefit

29. Cerebral edemaPresent in 70-80% of grade IV HE30 % humans cerebellar herniation

30. Pathophysiology cerebral edemaMultifactorialAstrocyte swellingVasogenic, cytotoxic, intertitial edemaDamaged BBB barrier:  permeabilityLoss of CBF regulation and hypoperfusionLocal increase in lactate concentration

31. CoagulopathyAbrupt and profound decrease in synthesis of coagulation proteinsConsumption of clotting factors and plateletsThrombocytopeniaQualitative platelet defect ( adhesion and aggregation)Deficiencies in anticoagulant: Protein C and S, AT

32. Renal failure- HumansCommon in humans = hepatorenal syndromeReported in small animalsPathophysiologyRelative hypovolemiaMicrocirculatory disturbancesAcute tubular necrosisComplicating sepsisDirect nephrotoxicity

33. SepsisImpaired reticuloendothelium functionDecreased opsonisationImpaired neutrophil chemotaxismImpaired neutrophil and Kuppfer cell phagocytic functionDecrease complement levelBacterial translocationInvasive procedures

34. SepsisPresent in 80% cases50% gram positive: Staph and StrepColiformes1/3 patients: afebrile and normal WBCFungal infection in 30%

35. Pulmonary abnormalities33% humans: pulmonary edemaAltered permeability pulmonary vesselsVasodilationARDS+/- Hypoalbuminemia

36. Portal hypertensionUsually secondary to cirrhosisIn acute liver failureMassive sinusoidal collapse -> blockade against intrahepatic circulationAscitesPoor prognostic indicator

37. CholestasisEarly or late in FHFBiliary hyperplasia secondary to massive injuryIncrease in ALPHyperbilirubinemia develops several days after

38. Metabolic derangementsHypoglycemia:Impairement of glycogen storageReduced glycogenisisReduced hepatic synthesis of insulin like growth factor 1 -> increase protein degradation in muscles

39. Metabolic derangementsHypokalemiaInadequate K+ intakeIncrease loss: V+, D+, potassium wasting diureticsWorsens HE: decreases NH3 renal excretionHyponatriemiaimpaired excretion of free waterFailure of Na K ATP ase pump: accumulation Na w/i the cells

40. Metabolic derangementsHypophosphatemiaRespiratory alkalosis: Phosphate moves into intracellular space Ventilatory failureNausea and diarrheaDecrease HCO3- excretionImpaired myocardial functionRBC fragility and left shift O2 dissociation curveDecrease leukocyte activity Decrease platelet survivalWorsens HEInsulin resistance

41. Metabolic derangementsLactic acidosisTissue hypoxiaAltered tissue oxygen extractionDecrease liver function, unable to metabolize Respiratory alkalosisHypoventilation in final stage

42. Clinical signsSeverity and duration of impairement of:SyntheticBiotransformationEndotoxin scavenging effectsSystemic effects of toxins released from necrotic liverExtend and rate of regeneration

43. Clinical signsAnorexiaDepressionVomitingPolydyspsiaLow BUN: defective renal medullary gradientDecrease release and/ or responsiveness of collecting duct to ADHHematochezia/ melenaHematemisis

44. Physical examinationDehydrationShockCranial abdominal painHepatomegalyIcterus

45. Clinical pathology- CBCTarget cellsAcanthocytesAnisocytosisNon regenerative anemia > regenerative anemiaThrombocytopeniaLeukocytosis or leukopenia

46. Clinical pathology- ChemistryALT and AST:Increase within hours of the insultPeak after 3 daysGradual decreaseAST/ ALT ratio:If AST> ALT mitochondrial damage

47. Clinical pathology- ChemistryALT: acts like an acute phase proteinIncrease after day 2Will remain elevated until resolution of the intrahepatic cholestasis, cholangiohepatitis, and hepatic regeneration GGT: elevatedCats: early detection of parynchemal inflammation and cholestasisALP> GGT hepatic lipidosis

48. Clinical pathology-ChemistryBilirubinIncrease early in disease when hepatic necrosis around portal triadLate in disease when hepatic necrosis periacinarRemains elevated until return of sinusoidal blood flow

49. Clinical pathology- dogs

50. Clinical pathology-cats

51. Clinical pathologyAlbumin70 % loss of functional hepatic tissueNegative acute phase protein25% of the protein produced by the liverGlucose75% loss of functional hepatic tissueDepletion of the glycogen stores Impaired gluconeogenesis

52. Clinical pathologyCholesterol Up to 50% synthetized in the liverIf altered cholesterol elimination could be normal or elevated despite decrease synthesisBUNProduced from NH3 Urea cycle

53. Clinical pathologyFunctional testingNH3 tolerance test: more specificBile acids: not feasible icterusBSP and ICG: Anion indicator dyes: earliest indication

54. Clinical pathology- CoagulationProlongation of PT and PTTDecrease in fibrinogenDecrease in factor V and factor VIIDecrease in PlasminogenDecrease in Protein C? Platelets have adhesion and aggregation deficiencies

55. Coagulation - humansDegree of prolongation of PT : relates to severity of liver damageFactor 7: Vit K dependant Shortest ½ lifeFailure to improve 25% after IV vit K: little hepatic reserveFactor 5: Non vit KShortest ½ life?Most sensitive index for impaired synthesisFactor 8/5 ratio > 30 poor prognosis

56. CytologyPoor correlation w histologyWill diagnosis infiltrative diseaseHistology needed for firm diagnosis

57. HistologyUltrasound guided –poor correlation w sx biopsyKey holeLaparoscopyLaparotomyTransjugular –humansRisk of bleeding

58. HistologyPortal triadHepatic vein

59. HistologyPeriportal or zone 1 lesionsToxins:SynthalineOther:IBDPancreatitis

60. HistologyMidzonal or zone 2 lesionDrugs:Berylium, paraquat

61. HistologyPeriacinar or centrolobular or zone 3 lesionsHypoxemiaHypoperfusionworsened by anemia and hypoxemiaAcetaminophen

62. HistologyParacentral lesion involving the entire aciniDiazepamMenbendazole

63. TreatmentGeneral treatment principlesAdress underlying cause if knownReduce and prevent inflammationReduce and prevent oxidative damageProvide adequate nutritionReduce and prevent fibrosisReduce and prevent copper accumulation

64. Fluid therapyResuscitationGuided by PE, HR, MAP, CVP..Supplementation with potassiumAvoid Lactate Ringer’s SolutionDecrease hepatic ability to metabolize lactate to HCO3-

65. Metabolic derangementsMonitor glucoseSupplement if necessaryCentral vein if high supplementationPhosphateAvoid hypophasphatemia

66. If in need of blood transfusion..Prefer fresh whole blood > Pack red blood cellsMinimizes exposure to: NH3PyrogensMicroorganisms

67. CoagulopathyFresh frozen plasmaHemorrhagic diathesisGive in preparation of invasive procedure Vitamin K1Subcuteneous injection0.5 mg/kg q 12-24 hrs for 3 days or as long as PT is prolonged

68. AntibioticsPrevent bacterial translocationGood hepatic penetrationBroad spectrum anbitioticReduce urease producing bacteriasAntifungalsHumans use of clotrimazole and amphotericin B

69. Gastro intestinal bleedingProphylatic use of sucralfate > antiacidsPredisposes to gastric bacterial overgrowthPredisposes to nosocomial pneumoniaAntiacidsProton pump inhibitorProstaglandin analogueH2 blockers (cimetidine> famotidine)

70. NutritionEnteral route > parenteralLow protein diet?Vegetal protein > animalIncrease fiber: increase transitControversies in cirrhotic patients w low protein diet vs normalSimilar protein synthesisHigher protein breakdown in low protein group

71. SeizuresControversialAvoid benzodiazepines, barbituatesTreat with propofol?Prophylactic treatment of subclinical seizures in grade 2 HE w phenytoin: No benefit

72. Renal replacement therapyPrefer CVVHD to hemodialysisAvoids fluids shifts

73. N-acetylcysteineCystein donorEnters hepatocytesStimulate GSH synthesisEnhance glutathione S transferase activityPromotes detoxification of certain hepatotoxinsDirect antioxydant (HOCl, O2-, H2O2)

74. N acetylcysteineMedical applicationsEnhance RBC GSH in hypoxic patientsImprove/ preserve hepatocyte membrane fluidity and antioxydant in biliary tree occlusionEnhance hepatic detoxification of toxinsAugments NADP and GSH reduction and reductive detoxification of xenobioticsProtective effect in Ischemia reperfusion injury

75. N acetylcysteineBenefit treatment ofAcetaminophenImprove hemodynamic stabilityDecrease incidence MOFImprove survivalMost benefical given w/I 12 hrs Beneficial up to 36 hrsHeavy metals

76. N-acylcysteineTreatment of HE:Improved O2 deliveryImproved global tissue consumptionImproved CBF and cerebral O2 consumptionFHF and NAC:Decrease incidence of renal dialysisBeneficial regional effect on hepatosplanchnic circulation

77. N-acetylcysteineGiven IVNon-pyrogenic filter (0.25μm)10% solution diluted 1:2 w salineAdminister over 20-30 minInitial: 140 mg/kg followed by 70 mg/kg q 8 hrs

78. S-AdenosylmethionineMethionineDietSAMe S-adenosylmethionineMAT 1 + ATPCysteineTRANSSULFURATIONDETOXIFICATIONGLUTATHIONETAURINESULPHATESMETHYLATIONAMINOPROPYLATIONPOLYAMINESStimulates hepatocellular regenerationNecessary for DNA replicationMay inhibit toxin induced proteasesAmeliorates necrotizing effects of some toxins

79. S-AdenosylmethionineMethionineDietSAMe S-adenosylmethionineMAT 1 + ATPCysteineTRANSSULFURATIONDETOXIFICATIONGLUTATHIONETAURINESULPHATESMETHYLATIONAMINOPROPYLATIONPOLYAMINESStimulates hepatocellular regenerationNecessary for DNA replicationMay inhibit toxin induced proteasesAmeliorates necrotizing effects of some toxinsIncreased in ALFRole in HELIMITED IN ALF

80. SAMeShown to influence Gene expressionApoptotic cascadeCell response to cytokinesMembrane integrityMitochondrial functionRedox status

81. SAMeHepatoprotection Toxins AcetaminphenBile acids hepatitisEHBDOIRI

82. SAMeSide effects:NauseaDecreased appetite post pill ingestionAnxietyVomiting post pill cats20 mg/kg SID Fasted animalPeak plasma: 1-4 hrs dogs2-8 hrs cats

83. Vitamin ETocopherol and tocotrienolLipophyllic requires bile and pancreatic juice for GI absorptionPrevents lipid perodixationNeeds Vit C to regenerateMeta-analysis humans: increased mortality when dose> 150 u/ d10 IU/kg per day

84. Milk thistleSilymarinAntioxydant and free radical scavengerDecreases lipid peroxidationAntifibrotic effectsAnti inflammatory effectsDecreases NF-κβnuclear DNA bindingImmunomodulatory effectsIncrease gene transcription/ translationAccelerates hepatocellular regenerationInduced synthesis of ursodeoxychloic acid

85. Milk ThistleShown benefit in hepatoxinAcetaminophen Carbon tetrachlorideRadiotionIron AmanitaAflatoxin B1EthanolThioacetamideMicrocystin (cyanobacteria)CysplatinMethotreaxte20-50 mg/kg q 24 h

86. Milk thistle - hepatoprotectiveAnti- inflammatory effectsCell and mitochondrial membrane protectionBlockade of cell membrane transporters or receptorsAltered xenobiotics metabolismsAugmented toxic adduct elimination

87. Treatment of HE- ALFRapid onset and progression of HEAlmost always complicated by cerebral edemaGoal: Limit development of cerebral edemaMechanical ventilationParalysis and fentanylHead elevationMannitol

88. Acute HE treatmentHypothermia (international trial in progress) systemic production amnd decrease cerebral uptake of NH3Adverse effects coag disturbancesimpairement of hepatic regenerationincrease risk of infectionNacetylcysteineImproves cerebral blood flowImproves cerebral metabolic rate for oxygenProstaglandin I2Improves metabolic rate for oxygen

89. Reduction of production and absorption of NH3Restricting dietary protein intakeVegetable protein > animalNon absorbable disaccharidesLactulose- LactitolCathartic effectReduces luminal pHHostile environment for urease bacteriaReduces net NH3 absorptionNet mouvement NH3 from blood into lumen

90. Reduction production and absorption of NH3AntibioticsMetronidazoleNeomycinOtotoxicity and nephrotoxicityRifamixinShould we combine both therapies?Additive effects

91. Reduction of production and absorption of NH3Populating colonic lumen non urease producing bacterias Lactobacillus acidophilus may be beneficial w other treatmentsEnterococcus Faecium pulse therapyAs effective as lactulose even in the non treatment weeks

92. Increase metabolism of NH3 in tissuesMusclesConversion site NH3 -> GlutamineOrnithine + NH3 -> ureaAspartate + NH3 -> GlutamineOrnithine aspartate: significant  NH3Zinc dependant enzymes2/5 enzymes in urea cycleZinc supplementation: controversial results

93. Reduction false neurotransmittersIncrease supplementation branch aa > aromatic aaNo benefit in randomized clincial trial in decreasing mortality, grade of HE or bothDecrease dopaminergic neurotransmitterNo benefit in treatment w levodopa or bromocriptine

94. Inhibition of GABA-benzodiazepine receptorsEndogenous benzodiazepine like ligandsFlumazenilIncomplete improvement in the grade of HESome patients had received exogenous benzodiazepineNeed more studies

95. Correction manganese deposition at basal gangliaHyperdensity in T1 weighted MRI imagesNo studies done to evaluate treatment of chelation in HE patients

96. Future directionsHumans: Orthotopic liver transplant1 year survival rate > 80 % post transplantImmunosupressiveDonor compatibilityHepatocyte injectionBioartifical liverExtracorporeal liver

97. PrognosisSurvival:40%-80%Depends on Age (young and old= BAD)Severity liver diseaseDegree liver necrosisNumber and nature of complicationsDuration of illness

98. PrognosisGrade HEGrade 2: mortality rate 30%Grade 4: mortality rate 80%

99. Prognostic factors- transplant criteriasKing’s College criteriaAcetaminophenArterial pH < 7.3 post adequate volume resuscitationHE grade > 3 + PT > 100 sec (= INR > 6.5) + serum creat > 300μmol/LNon AcetaminophenPT > 100 sec (regardless or HE grade) Unfavorable causeAge < 10 yo > 40 yoBiilurubin > 300 μmol/LINR > 6.5 or PT > 50 secORAny grade of HE AND any 3 of: OR

100. Prognostic factors- transplantation criteriaClichy-Villejuif criteriaPatient less than 30 years oldEncephalopathy grade 3 or > AND factor V < 20 % Patient more than 30 years oldEncephalopathy grade 3 or > AND factor V > 30%

101. Other prognostic factorsLiver biopsy> 70% necrosis associated > 90% mortality rate w/o transplantationSerum Alpha-fetoproteinSerial increase from day 1 to 3: correlation w successful outcomeSerum Gc-GlobulinDecreased level associated with death or transplant

102. references

103. Questions