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Management of Hepatic Encephalopathy , today

Management of Hepatic Encephalopathy , today. Changes suggested by clinical experience Cosimo Colletta. Belgirate, 22 giugno 2019. Disclosure. C auses of portal hypertension: prehepatic, intrahepatic, and posthepatic. Approach to the diagnosis of portal hypertension

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Management of Hepatic Encephalopathy , today

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  1. Management of HepaticEncephalopathy, today Changessuggested by clinicalexperience Cosimo Colletta Belgirate, 22 giugno 2019

  2. Disclosure

  3. Causes of portal hypertension: prehepatic, intrahepatic, and posthepatic Approach to the diagnosis of portalhypertension Christopher Koh, M.D. and Theo Heller, M.D. Clinical Liver Disease, Vol. 1, No. 5, November 2012

  4. Portal hypertensionHVPG > 5 mm Hg Clinicalsyndromecharacterized by • splenomegaly, • ascites, • gastrointestinalvarices, • encephalopathy

  5. How isportalhypertensionmanifested in cirrhosis? • Increasedsplanchnic arterial flow and, accordingly, increasedsplanchnicvenousinflowinto the liver. • Increasedsplanchnic arterial flow isexplainedpartly by decreasedperipheralvascularresistance and increasedcardiac output. Putative splanchnicvasodilatorsinclude nitricoxide

  6. Normale Normale Cirrosi Cirrosi

  7. Cardiac index according to portal Pressure

  8. Risksassociated with increased HVPG

  9. The diagnosis of portalhypertension

  10. Ascites • 5% to 10% of patients with compensatedcirrhosis/year. • The mainstay of ascitesformationisrenalsodiumretention. • Reducedeffectivevolaemiais a maindeterminant of thesealterations, butrenalfunctionabnormalitiesinduced by systemicinflammationalso play a role. • Portal hypertensionalsocontributes by actingas a compartmentalisingfactor of the expandedextracellularfluid volume. • The appearance of ascitesheralds a poorprognosis, as the five-yearsurvivaldropsfrom about 80% in compensatedpatients to about 30% in patients with ascites.

  11. Whatis the role of ultrasonography?

  12. Recommendations • A diagnosticparacentesis • Neutrophilcount and culture of asciticfluid culture should be performed to exclude SBP. A neutrophilcountabove 250 cells/ isrequired to diagnose SBP. • Ascitictotalproteinconcentrationshould be performed to identifypatientsathigherrisk of developing SBP. • The SAAGshould be calculatedwhen the cause of ascitesisnotimmediatelyevident, and/or whenconditionsotherthancirrhosis are suspected. • Cytologyshould be performed to differentiatemalignancy-relatedascites.

  13. Recommendations • A moderate restriction of sodiumintake(4.6-6.9 g of salt) isrecommended in patients with moderate, uncomplicatedascites. Thisisgenerallyequivalent to a no addedsaltdiet with avoidance of pre-preparedmeals. • Diets with a verylowsodiumcontentshould be avoided, astheyfavourdiuretic-inducedcomplications and can endanger a patient’snutritional status. • Prolonged bed restcannot be recommended.

  14. Recommendations • Patients with the first episode of grade 2 ascitesshouldreceive an anti-mineralocorticoiddrug alone, startingat 100 mg/day. • In patientswho do notrespond, asdefined by a body weightreduction of lessthan 2 kg/week, or in patientswhodevelophyperkalemia, furosemide should be added. • Patients with long-standing ascitesshould be treated with a combination of an anti-mineralocorticoiddrug and furosemide. • Duringdiuretictherapy a maximum weightloss of 0.5 kg/day in patientswithoutoedema and 1 kg/day in patients with oedemaisrecommended. • Once asciteshasresolved, the dose of diureticsshould be reduced.

  15. Recommendations

  16. Recommendations

  17. Drugscontraindicated in patients with ascites • Non-steroidal anti-inflammatory: high risk of sodiumretention, hyponatraemia, and AKI. • ACE inhibitors, angiotensin II antagonists, a1-adrenergic receptorblockers: increasedrisk of renalimpairment. • Aminoglycosides: asthey are associated with an increasedrisk of AKI. • In patients with ascites and preservedrenalfunction, the use of contrast mediadoesnotappear to be associated with an increasedrisk of renalimpairment. There are insufficient data in patients with renalfailure.

  18. When are NSAIDscontraindicated in the treatment of cirrhosis? • Nonsteroidal anti-inflammatorydrugs (NSAIDs) inhibitprostaglandinsynthesis. Theymaypotentiaterenalvasoconstriction, with a resultingdrop in glomerularfiltration. Thus, the use of NSAIDsiscontraindicated in patients with decompensatedcirrhosis. • Nephrotoxicmedications, includingaminoglycosideantibiotics, should be avoided in patients with cirrhosis. Patients with earlyhepatorenalsyndromemay be salvaged by aggressive expansion of intravascular volume with albumin and freshfrozen plasma and by avoidance of diuretics. The use of renal-dose dopamine isnoteffective.

  19. The treatment of choice for the management of patients with grade 3 ascitesisrepresented by LVP • LVP is the first-line therapy in patients with large ascites. • LVP should be followed with plasma volume expansion to prevent PPCD. • Plasma volume expansionshould be performed by infusingalbumin (8 g/L of ascitesremoved). • After LVP, patientsshouldreceive the minimum dose of diureticsnecessary to prevent re-accumulation of ascites. • Whenneeded, LVP shouldalso be performed in patients with AKI or SBP.

  20. What are possible complications of massive ascites in cirrhosis?

  21. Whatis the role of paracentesis in the evaluation of ascites in cirrhosis? • Paracentesisisessential in determiningwhetherascitesiscaused by portalhypertension. Ascitesstudiesalso are used to rule out infection and malignancy. • Paracentesisalsoshould be performedwhen SBP issuggested by the presence of abdominalpain, fever, leukocytosis, or worseninghepaticencephalopathy. • Paracentesisshould be performed in allpatients with cirrhosiswhohaveascitesat the time of hospitalization, given the significantpossibility of asymptomatic SBP.

  22. Whatisspontaneousbacterialperitonitis (SBP) in cirrhosis? • SBP isobserved in 15-26% of patientshospitalized with ascites. The syndromearisesmostcommonly in patientswhoselow-proteinascites (< 1 g/dL) containslowlevels of complement, resulting in decreasedopsonicactivity. • SBP appears to be caused by the translocation of gastrointestinal (GI) tractbacteriaacross the gutwall and also by the hematogenous spread of bacteria. • The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiellaspecies, and other gram-negative entericorganisms.

  23. How isspontaneousbacterialperitonitis (SBP) diagnosed?

  24. What are the treatment options for spontaneousbacterialperitonitis (SBP)? • The mostcommonlyusedregimen in the treatment of SBP is a 5-day course of cefotaxime at 1-2g intravenouslyevery 8 hours. • Alternatives include oralofloxacin and other IV antibiotics with activityagainst gram-negative entericorganisms. • Manyauthoritiesadviserepeatparacentesis in 48-72 hours to document a decrease in the ascites PMN count to lessthan 250 cells/mm3

  25. Whatis the frequency of recurrence of spontaneousbacterialperitonitis (SBP) in cirrhosis?

  26. Whatis the role of norfloxacin for in the treatment of cirrhosis? • Therapy with norfloxacinat 400 mg orallytwice per day for 7 days can reduce seriousbacterialinfection in patients with cirrhosiswhohave GI bleeding. • Onestudynotedthat the 37% incidence of seriousbacterialinfectionwasreduced to 10% when treatment with norfloxacinwasinstituted. • Furthermore, it can be arguedthatallpatients with low-proteinascitesshouldundergoprophylactictherapy (eg, with norfloxacin 400 mg daily PO) at the time of hospital admission, given the high incidence of hospital-acquired SBP.

  27. How is rupture of umbilical hernia prevented in cirrhosis?

  28. HRS • The absence of renalparenchymaldamage, hasneverbeenproven. • The absence of significant proteinuria and/or haematuria do notrule out renallesions, particularlytubularand interstitiallesions. • The new theoryisthat the increasedcirculatinglevels of pro-inflammatorycytokinesmayexercise a directrelevantrole in the development of HRS. • An interplay of inflammation and microvasculardysfunctionisresponsible for the amplification of the signalthatPAMPs and DAMPsexert on proximalepithelialtubularcells. • The consequentincreases of sodiumchloride delivery to the macula densa triggersfurtherintrarenalactivation of the RAAS and thuslowers GFR. • Finally, cholestasismayfurtherimpairrenalfunction.

  29. PVT in Patients with Cirrhosis

  30. PVT in Patients with Cirrhosis • The prevalence of PVT is < 1% in patients with compensatedcirrhosis, 8%-25% in candidates for liver transplantation. In patients with cirrhosis, portalvenousobstructioniscommonlyrelated to invasion by hepatocellular carcinoma. • Even in patients with wellcompensatedcirrhosis, an underlyingprothromboticconditionisdifficult to detect. • However, in cirrhoticpatients with PVT, moleculartesting shows an increasedprevalence of the factor V Leiden, MTHFR, and prothrombin gene mutations, the latterbeingparticularly common.

  31. FDA recommendation for DOACsusage in liver disease according to Child-Pugh class

  32. Direct OralAnticoagulants (DOACs) in Patients with Liver Cirrhosis • Dabigatran: 1.5% to 3% of patientshave more than 3-fold rise in aminotransferase. Rare cases of jaundice and clinicallyapparent liver injurysecondary to Dabigatranhavebeenreported. • Rivaroxaban. 1.5% to 3% of patientstreated with Rivaroxabanhave more than 3-fold rise in aminotransferase, a rate thatissimilar to that of Warfarin and lowerthanthat of LMWH. • Rivaroxabanhasbeenrelated to severalinstances of acute liver injury with jaundice. • Apixaban. 1% to 2% of patientstreated with Apixabanhave more than 3-fold rise in aminotransferasemainly in hepatocellular pattern; this rate issimilar or lowerthanrates with Warfarin. • Apixabanrequires no dose adjustment in patients with CTP A cirrhosis.

  33. DOACs versus TraditionalAnticoagulation in Patients with Liver Cirrhosis • Oneobservationalstudy on patients with cirrhosiscompared 20 patients on DOACs to 19 patients on conventionalanticoagulationtherapy over a 3-year period. • Amongpatients on DOACstherapy, 11 receivedApixaban and 9 patientsreceivedRivaroxaban. In comparison, 13 patientsreceived VKA, and 6 patientsreceived LMWH astraditionalanticoagulation agents. • The rate of anybleedingeventwasnotsignificantlydifferentbetween the twogroups. The studyconcludedthatDOACshavesimilarsafetycharacteristicscompared to traditionalanticoagulation in patients with cirrhosis • Thisstudyonlyincluded CTP A and B patients and consequently, itsresultscannot be extrapolated to patients with CTP score C.

  34. Whatishepaticencephalopathy?

  35. Hepatic encephalopathy • Ismarked by personalitychanges, intellectualimpairment, and a depressedlevel of consciousness. • The diversion of portalbloodinto the systemiccirculationappears to be a prerequisite. • Indeed, maydevelop in patientswithoutcirrhosiswhoundergoportocaval shunt surgery.

  36. How ishepaticencephalopathy (HE) categorized?

  37. The pathophysiology of HE

  38. The pathophysiology of HE • Severalorganscontribute to the development of hyperammonaemia. • In addition, othertoxicsubstances are produced by an alteredgutmicrobiota. • Peripheralcytokines and ammoniaactivate the brain microglia, which, in turn, amplifies the inflammatoryreaction. • Ammonia and othersubstances, determinesastrocyteswelling, causingoxidative and nitrosative stress, and determinesastrocyte-neurondysfunction. • In addition, ammoniaimpinges on neurotransmission and oxidativemetabolismdirectly, by promoting the production of inhibitoryneurosteroids.

  39. Whatis the role of astrocytefunction in the pathogenesis of hepaticencephalopathy (HE)? • They play a keyrole in the regulation of the blood-brain barrier. • Theyalso play a role in the detoxification of ammonia • Itistheorizedthatneurotoxicsubstances, includingammonia and manganese, may gain entry into the brain in the setting of liver failure. • Theseneurotoxicsubstancesmaythencontribute to morphologicchanges: in cirrhosis, astrocytesmayundergo Alzheimer type II astrocytosis. Here, astrocytesbecomeswollen.

  40. Whatis the prognosis of hepaticencephalopathy? • The development of hepaticencephalopathynegativelyimpactspatientsurvival. • The occurrence of encephalopathy severe enough to lead to hospitalizationisassociated with a survivalprobability of 42% at 1 year of follow-up and 23% at 3 years. • Approximately 30% of patientsdying of end-stage liver disease experiencesignificantencephalopathy, approaching coma

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