ACUTE ON CHRONICACUTE ON CHRONICLIVER FAILURE (ACLF)LIVER FAILURE (ACLF)

ByBy

Dr. Tarek ShetaDr. Tarek ShetaLecturer of internal medicineLecturer of internal medicine

Mansoura Faculty of MedicineMansoura Faculty of Medicine

INTRODUCTIONINTRODUCTION

-- The term (AcuteThe term (Acute--onon--chronic liver failure) waschronic liver failure) wasfirst used infirst used in 19951995 to describe a condition into describe a condition inwhich two insults to liver are operatingwhich two insults to liver are operatingsimultaneously, one of them being ongoingsimultaneously, one of them being ongoingand chronic and the other acute.and chronic and the other acute.

-- The Asian Pacific Association (APASL) setThe Asian Pacific Association (APASL) setup consensus statements about acuteup consensus statements about acute--onon--chronic liver failure (ACLF) inchronic liver failure (ACLF) in 20082008..

-- The term (AcuteThe term (Acute--onon--chronic liver failure) waschronic liver failure) wasfirst used infirst used in 19951995 to describe a condition into describe a condition inwhich two insults to liver are operatingwhich two insults to liver are operatingsimultaneously, one of them being ongoingsimultaneously, one of them being ongoingand chronic and the other acute.and chronic and the other acute.

-- The Asian Pacific Association (APASL) setThe Asian Pacific Association (APASL) setup consensus statements about acuteup consensus statements about acute--onon--chronic liver failure (ACLF) inchronic liver failure (ACLF) in 20082008..

Definition of ACLFDefinition of ACLF

ACLF had been an ill-defined condition until the TheTheAsian Pacific Association for the Study of the LiverAsian Pacific Association for the Study of the Liver((APASL) set up consensus statements about acute-on-chronic liver failure (ACLF) in 2008.

Definition of ACLFDefinition of ACLF The APASL Consensus Meeting (2008) defined

ACLF as acute hepatic insult (manifesting asjaundice and coagulopathy, complicated within4 weeks by ascites and/or encephalopathy) in apatient with previously diagnosed orundiagnosed chronic liver disease.

-- This acute rapid deterioration of liver function isaccompanied by subsequent rapidly evolvingmultiple end-organ failure in a patient withpreviously well-compensated liver disease dueto the effects of a precipitating event.

The APASL Consensus Meeting (2008) definedACLF as acute hepatic insult (manifesting asjaundice and coagulopathy, complicated within4 weeks by ascites and/or encephalopathy) in apatient with previously diagnosed orundiagnosed chronic liver disease.

-- This acute rapid deterioration of liver function isaccompanied by subsequent rapidly evolvingmultiple end-organ failure in a patient withpreviously well-compensated liver disease dueto the effects of a precipitating event.

Defining the liver failure in ACLFDefining the liver failure in ACLF

-- Jaundice (serum bilirubin ≥Jaundice (serum bilirubin ≥55 mg/dl)mg/dl)-- coagulopathy (INR ≥coagulopathy (INR ≥11..55 oror

prothrombin activity <prothrombin activity <4040%).%).-- Ascites and/or encephalopathy.Ascites and/or encephalopathy.

-- Jaundice (serum bilirubin ≥Jaundice (serum bilirubin ≥55 mg/dl)mg/dl)-- coagulopathy (INR ≥coagulopathy (INR ≥11..55 oror

prothrombin activity <prothrombin activity <4040%).%).-- Ascites and/or encephalopathy.Ascites and/or encephalopathy.

ACLF versus Chronic hepaticACLF versus Chronic hepaticdecompensationdecompensation

ACLF differs from chronic hepaticACLF differs from chronic hepaticdecompensation (CHD) in two keydecompensation (CHD) in two keyelements:elements:

-- First, the development of liver failure andFirst, the development of liver failure andendend--organ dysfunction in ACLF is muchorgan dysfunction in ACLF is muchfaster than in CHD. In the literature, thisfaster than in CHD. In the literature, thisperiod ranges fromperiod ranges from 22 toto 1212 weeks.weeks.

-- Second (and may be of more importance),Second (and may be of more importance),in ACLF, there is still a chance of recovery ofin ACLF, there is still a chance of recovery ofliver function.liver function.

ACLF differs from chronic hepaticACLF differs from chronic hepaticdecompensation (CHD) in two keydecompensation (CHD) in two keyelements:elements:

-- First, the development of liver failure andFirst, the development of liver failure andendend--organ dysfunction in ACLF is muchorgan dysfunction in ACLF is muchfaster than in CHD. In the literature, thisfaster than in CHD. In the literature, thisperiod ranges fromperiod ranges from 22 toto 1212 weeks.weeks.

-- Second (and may be of more importance),Second (and may be of more importance),in ACLF, there is still a chance of recovery ofin ACLF, there is still a chance of recovery ofliver function.liver function.

Pathophysiology of ACLFPathophysiology of ACLFPathogenesis of ACLF is unclear but manyPathogenesis of ACLF is unclear but many

theories are proposed:theories are proposed:

11-- SystemicSystemicinflammatoryinflammatoryresponseresponsesyndrome (SIRS)syndrome (SIRS)is the mainis the mainpathophysiologicpathophysiologicmarker in patientsmarker in patientswith ACLF withwith ACLF withoverproduction ofoverproduction ofproinflammatoryproinflammatorycytokinescytokines(especially TNF(especially TNF--ααand ILand IL--66), nitric), nitricoxide.oxide.

11-- SystemicSystemicinflammatoryinflammatoryresponseresponsesyndrome (SIRS)syndrome (SIRS)is the mainis the mainpathophysiologicpathophysiologicmarker in patientsmarker in patientswith ACLF withwith ACLF withoverproduction ofoverproduction ofproinflammatoryproinflammatorycytokinescytokines(especially TNF(especially TNF--ααand ILand IL--66), nitric), nitricoxide.oxide.

22-- Neutrophil dysfunctin:Neutrophil dysfunctin: leading a reducedleading a reducedphagocytic capacity and increased risk ofphagocytic capacity and increased risk ofinfection .infection .

33-- Circulatory changesCirculatory changes following thefollowing theaccumulation of vasodilators leading toaccumulation of vasodilators leading tomultiorgan failure.multiorgan failure.

44 -- Oxidative stress:Oxidative stress: high load of ROShigh load of ROS(reactive oxygen species).(reactive oxygen species).

22-- Neutrophil dysfunctin:Neutrophil dysfunctin: leading a reducedleading a reducedphagocytic capacity and increased risk ofphagocytic capacity and increased risk ofinfection .infection .

33-- Circulatory changesCirculatory changes following thefollowing theaccumulation of vasodilators leading toaccumulation of vasodilators leading tomultiorgan failure.multiorgan failure.

44 -- Oxidative stress:Oxidative stress: high load of ROShigh load of ROS(reactive oxygen species).(reactive oxygen species).

44-- The Toxin Hypothesis: :The Toxin Hypothesis: :Circulating toxinsCirculating toxins –– mainly asymmetric dimethylmainly asymmetric dimethyl--ll--arginine (ADMA) and stereoarginine (ADMA) and stereo--isomer symmetric dimethylisomer symmetric dimethylarginine (SDMA)arginine (SDMA) –– lead to end organ dysfunction.lead to end organ dysfunction.

-- The combinedThe combinedactions ofactions ofaccumulated toxinsaccumulated toxinsand endand end--organorgandysfunction furtherdysfunction furtheraggravate liveraggravate liverinjury andinjury andincapacitate theincapacitate theregenerativeregenerativecapacity.capacity.

-- The combinedThe combinedactions ofactions ofaccumulated toxinsaccumulated toxinsand endand end--organorgandysfunction furtherdysfunction furtheraggravate liveraggravate liverinjury andinjury andincapacitate theincapacitate theregenerativeregenerativecapacity.capacity.

PRECIPITATING FACTORSPRECIPITATING FACTORS11-- Infectious etiology:Infectious etiology:-- Infection is one of the most common precipitatingInfection is one of the most common precipitating

factors.factors.-- Patients with cirrhosis are prone to sepsis due toPatients with cirrhosis are prone to sepsis due to

poor immune responses, often termed immunepoor immune responses, often termed immuneparalysis.paralysis.

11-- Infectious etiology:Infectious etiology:-- Infection is one of the most common precipitatingInfection is one of the most common precipitating

factors.factors.-- Patients with cirrhosis are prone to sepsis due toPatients with cirrhosis are prone to sepsis due to

poor immune responses, often termed immunepoor immune responses, often termed immuneparalysis.paralysis.

Causative infections include:Causative infections include:

-- Intestinal bacterial flora (SIRS leads to increasedIntestinal bacterial flora (SIRS leads to increasedintestinal permeability permitting bacteria and itsintestinal permeability permitting bacteria and itsproducts into systemic circulation).products into systemic circulation).

Causative infections (cont.)Causative infections (cont.)

-- Hepatotropic and non hepatotropic viruses:Hepatotropic and non hepatotropic viruses:- Reactivation of hepatitis B (overt or occult)

(constitutes 70% of ACLF in the Asian region).- Superinfection with hepatitis A and E- Hepatitis C reactivation.

-- Other infectious agentsOther infectious agents include Spirochetal,protozoal, helminthic or fungal

-- Hepatotropic and non hepatotropic viruses:Hepatotropic and non hepatotropic viruses:- Reactivation of hepatitis B (overt or occult)

(constitutes 70% of ACLF in the Asian region).- Superinfection with hepatitis A and E- Hepatitis C reactivation.

-- Other infectious agentsOther infectious agents include Spirochetal,protozoal, helminthic or fungal

Possible factors leading to acute exacerbation ofPossible factors leading to acute exacerbation ofhepatitis B and acute deterioration of cirrhotichepatitis B and acute deterioration of cirrhoticpatients:patients:

Herbal medicineHerbal medicine SteroidSteroid Hepatitis E infectionHepatitis E infection YMDD mutantYMDD mutant Withdrawal of nucleoside analogue.Withdrawal of nucleoside analogue. AntiAnti--tuberculosis drugs.tuberculosis drugs. Unknown Wilson diseaseUnknown Wilson disease

Herbal medicineHerbal medicine SteroidSteroid Hepatitis E infectionHepatitis E infection YMDD mutantYMDD mutant Withdrawal of nucleoside analogue.Withdrawal of nucleoside analogue. AntiAnti--tuberculosis drugs.tuberculosis drugs. Unknown Wilson diseaseUnknown Wilson disease

PRECIPITATING FACTORS (cont.)PRECIPITATING FACTORS (cont.)Noninfectious etiologyNoninfectious etiology

Alcohol: active drinking within the lastAlcohol: active drinking within the last 44 weeks (weeks (50-70% of ACLF in the western countries).

Use of hepatotoxic drugs, herbal treatments.Use of hepatotoxic drugs, herbal treatments. Flare of autoimmune hepatitis or Wilson’s disease.Flare of autoimmune hepatitis or Wilson’s disease. Surgical intervention.Surgical intervention. GI bleeding.GI bleeding. SurgerySurgery Unknown hepatotoxic etiology.Unknown hepatotoxic etiology.

Noninfectious etiologyNoninfectious etiology Alcohol: active drinking within the lastAlcohol: active drinking within the last 44 weeks (weeks (50-

70% of ACLF in the western countries). Use of hepatotoxic drugs, herbal treatments.Use of hepatotoxic drugs, herbal treatments. Flare of autoimmune hepatitis or Wilson’s disease.Flare of autoimmune hepatitis or Wilson’s disease. Surgical intervention.Surgical intervention. GI bleeding.GI bleeding. SurgerySurgery Unknown hepatotoxic etiology.Unknown hepatotoxic etiology.

Etiology of underlying chronic liverEtiology of underlying chronic liverdisease in ACLFdisease in ACLF

Diseases established as underlying CLDDiseases established as underlying CLDIncluded:Included:

•• Compensated cirrhosis of any etiology.Compensated cirrhosis of any etiology.•• Chronic hepatitis.Chronic hepatitis.•• Nonalcoholic steatohepatitis.Nonalcoholic steatohepatitis.•• Cholestatic liver disease.Cholestatic liver disease.•• Metabolic liver disease.Metabolic liver disease.

Not included:Not included:Steatosis.Steatosis.

Diseases established as underlying CLDDiseases established as underlying CLDIncluded:Included:

•• Compensated cirrhosis of any etiology.Compensated cirrhosis of any etiology.•• Chronic hepatitis.Chronic hepatitis.•• Nonalcoholic steatohepatitis.Nonalcoholic steatohepatitis.•• Cholestatic liver disease.Cholestatic liver disease.•• Metabolic liver disease.Metabolic liver disease.

Not included:Not included:Steatosis.Steatosis.

Liver histology in ACLFLiver histology in ACLF-- The need of liver biopsy in ACLF should beThe need of liver biopsy in ACLF should be

individualized.individualized. Transjugular liver biopsy is relatively safe and is

the best approach to get a liver biopsy.-- Two histologic patterns are seen:Two histologic patterns are seen:Pattern I:Pattern I: Hepatocyte ballooning, rosette formation,Hepatocyte ballooning, rosette formation,

cellular cholestasis, variable interface activity, andcellular cholestasis, variable interface activity, andfibrosisfibrosis

Pattern II:Pattern II: Marked ductular proliferation, coarse,Marked ductular proliferation, coarse,inspissated bile plugs, foci of confluentinspissated bile plugs, foci of confluentnecrosis/bridging necrosis, eosinophilicnecrosis/bridging necrosis, eosinophilicdegeneration of hepatocytes, higher stage ofdegeneration of hepatocytes, higher stage offibrosis.fibrosis.

-- The need of liver biopsy in ACLF should beThe need of liver biopsy in ACLF should beindividualized.individualized.

Transjugular liver biopsy is relatively safe and isthe best approach to get a liver biopsy.

-- Two histologic patterns are seen:Two histologic patterns are seen:Pattern I:Pattern I: Hepatocyte ballooning, rosette formation,Hepatocyte ballooning, rosette formation,

cellular cholestasis, variable interface activity, andcellular cholestasis, variable interface activity, andfibrosisfibrosis

Pattern II:Pattern II: Marked ductular proliferation, coarse,Marked ductular proliferation, coarse,inspissated bile plugs, foci of confluentinspissated bile plugs, foci of confluentnecrosis/bridging necrosis, eosinophilicnecrosis/bridging necrosis, eosinophilicdegeneration of hepatocytes, higher stage ofdegeneration of hepatocytes, higher stage offibrosis.fibrosis.

Liver histology in ACLF (cont.)Liver histology in ACLF (cont.)

On clinical correlation: Pattern I was observed in majority of

patients who had recovered, while,Pattern II was a feature of all patientswho had died.

On clinical correlation: Pattern I was observed in majority of

patients who had recovered, while,Pattern II was a feature of all patientswho had died.

A:A: Liver biopsy showing intracanalicular bile plugs (black arrow)Liver biopsy showing intracanalicular bile plugs (black arrow)and enlarged hepatocytes with feathery degeneration, indicativeand enlarged hepatocytes with feathery degeneration, indicativeof intrahepatic cholestasis. Moderate inflammatory infiltration,of intrahepatic cholestasis. Moderate inflammatory infiltration,composed of lymphocytes, neutrophils, as well as eosinophilscomposed of lymphocytes, neutrophils, as well as eosinophils(inset), was presented in portal area.(inset), was presented in portal area. B:B: Expanded portal tractsExpanded portal tractsaccompanied by significant hepatic fibrosis .accompanied by significant hepatic fibrosis .

Prognosis of ACLFPrognosis of ACLF

-- ACLF prognosis depends both onACLF prognosis depends both onthe severity of the underlying liverthe severity of the underlying liverdisease and the nature of thedisease and the nature of theacute insult.acute insult.

-- ACLF prognosis depends both onACLF prognosis depends both onthe severity of the underlying liverthe severity of the underlying liverdisease and the nature of thedisease and the nature of theacute insult.acute insult.

The overall mortality ranging fromThe overall mortality ranging from 4343% to% to 7474%%

Causes of hospital mortalitiesCauses of hospital mortalities Septic complicationsSeptic complications Severe hemorrhage (especially varicealSevere hemorrhage (especially variceal

bleed).bleed). Intracranial pathologyIntracranial pathology Respiratory complicationsRespiratory complications Cardiac complicationsCardiac complications Multiorgan failureMultiorgan failure Graft complicationsGraft complications

Septic complicationsSeptic complications Severe hemorrhage (especially varicealSevere hemorrhage (especially variceal

bleed).bleed). Intracranial pathologyIntracranial pathology Respiratory complicationsRespiratory complications Cardiac complicationsCardiac complications Multiorgan failureMultiorgan failure Graft complicationsGraft complications

Treatment of ACLFTreatment of ACLF•• Control of precipitating factors:Control of precipitating factors:

-- Aggressive search for infection and givingAggressive search for infection and givingthe appropriate targeted antibioticthe appropriate targeted antibiotictreatment.treatment.-- Alcohol abstinence.Alcohol abstinence.-- Control of gastrointestinal bleeding.Control of gastrointestinal bleeding.

•• Control of precipitating factors:Control of precipitating factors:-- Aggressive search for infection and givingAggressive search for infection and givingthe appropriate targeted antibioticthe appropriate targeted antibiotictreatment.treatment.-- Alcohol abstinence.Alcohol abstinence.-- Control of gastrointestinal bleeding.Control of gastrointestinal bleeding.

Treatment of ACLF (cont.)Treatment of ACLF (cont.)

•• Support of end organsSupport of end organs :: egeg•• Terlipressin /albumin for HRSTerlipressin /albumin for HRS•• L ornithineL ornithine--LL--aspartate for HE.aspartate for HE.

•• Treatment of the inflammatory response byTreatment of the inflammatory response bynitric oxide inhibition, antioxidants andnitric oxide inhibition, antioxidants andantianti--cytokine therapies are under research.cytokine therapies are under research.

•• Support of end organsSupport of end organs :: egeg•• Terlipressin /albumin for HRSTerlipressin /albumin for HRS•• L ornithineL ornithine--LL--aspartate for HE.aspartate for HE.

•• Treatment of the inflammatory response byTreatment of the inflammatory response bynitric oxide inhibition, antioxidants andnitric oxide inhibition, antioxidants andantianti--cytokine therapies are under research.cytokine therapies are under research.

Treatment of ACLF (cont.)Treatment of ACLF (cont.)

Use of antivirals in ACLFUse of antivirals in ACLF Antiviral therapy should be initiated in patientsAntiviral therapy should be initiated in patients

with ACLF due to hepatitis B.with ACLF due to hepatitis B. Lamivudine may be used for a shortLamivudine may be used for a short--term period,term period,

but other potent drugs such as entecavir orbut other potent drugs such as entecavir ortenofovir may be preferred in view of the longtenofovir may be preferred in view of the long--term need for viral suppression with lowterm need for viral suppression with lowfrequency of drug resistance.frequency of drug resistance.

Prophylactic therapy is recommended forProphylactic therapy is recommended forHBsAgHBsAg--positive patients undergoingpositive patients undergoingchemotherapy.chemotherapy.

Treatment of ACLF (cont.)Treatment of ACLF (cont.)

Use of antivirals in ACLFUse of antivirals in ACLF Antiviral therapy should be initiated in patientsAntiviral therapy should be initiated in patients

with ACLF due to hepatitis B.with ACLF due to hepatitis B. Lamivudine may be used for a shortLamivudine may be used for a short--term period,term period,

but other potent drugs such as entecavir orbut other potent drugs such as entecavir ortenofovir may be preferred in view of the longtenofovir may be preferred in view of the long--term need for viral suppression with lowterm need for viral suppression with lowfrequency of drug resistance.frequency of drug resistance.

Prophylactic therapy is recommended forProphylactic therapy is recommended forHBsAgHBsAg--positive patients undergoingpositive patients undergoingchemotherapy.chemotherapy.

Use of extracorporeal liverUse of extracorporeal liversupport in ACLFsupport in ACLF-- Nonbiological liver support might represent aNonbiological liver support might represent a

therapeutic tool in ACLF to eithertherapeutic tool in ACLF to eitherrecompensaterecompensate oror bridgebridge the patient up tothe patient up totransplantation.transplantation.

-- Considered in patients unresponsive to standardConsidered in patients unresponsive to standardmedical treatment.medical treatment.

-- Nonbiological liver support might represent aNonbiological liver support might represent atherapeutic tool in ACLF to eithertherapeutic tool in ACLF to eitherrecompensaterecompensate oror bridgebridge the patient up tothe patient up totransplantation.transplantation.

-- Considered in patients unresponsive to standardConsidered in patients unresponsive to standardmedical treatment.medical treatment.

Currently Available DevicesCurrently Available Devices

11-- MARS® ( The MolecularMARS® ( The MolecularAdsorbent RecirculatingAdsorbent RecirculatingSystem):System):

((MARS®, Gambro, Stockholm,MARS®, Gambro, Stockholm,Sweden) device was developedSweden) device was developedby Stange and Mitzner inby Stange and Mitzner in 19931993and applied for the first time inand applied for the first time inhumans inhumans in 19961996..

11-- MARS® ( The MolecularMARS® ( The MolecularAdsorbent RecirculatingAdsorbent RecirculatingSystem):System):

((MARS®, Gambro, Stockholm,MARS®, Gambro, Stockholm,Sweden) device was developedSweden) device was developedby Stange and Mitzner inby Stange and Mitzner in 19931993and applied for the first time inand applied for the first time inhumans inhumans in 19961996..

MARS® (cont.)MARS® (cont.) MARS removes the endogenous albumin bound

toxins that accumulate in liver failure (eg:Aromatic amino acids, bilirubin, bile acids,endogenous benzodiazepines, indols, mercaptans,middle and short chain fatty acids, NO, phenols,prostacyclins, tryptophan).

It also help by lowering the levels ofproinflammatory cytokines TNF-alpha , IL-10, andIL-6 that may perpetuate the liver damage andextend the inflammatory cascade to other organs.

MARS removes the endogenous albumin boundtoxins that accumulate in liver failure (eg:Aromatic amino acids, bilirubin, bile acids,endogenous benzodiazepines, indols, mercaptans,middle and short chain fatty acids, NO, phenols,prostacyclins, tryptophan).

It also help by lowering the levels ofproinflammatory cytokines TNF-alpha , IL-10, andIL-6 that may perpetuate the liver damage andextend the inflammatory cascade to other organs.

MARS® (cont.)MARS® (cont.)

The measurable changes noted after MARS areReduction in serum bilirubin, Improvement inencephalopathy, Child-Turcotte-Pugh score, Increasein systemic vascular resistance, mean arterialpressure, Decrease in cardiac output, Improvementin Cerebral blood flow and cerebral perfusion andrenal function.

No survival benefits for MARSNo survival benefits for MARS -- howeverhowever -- werewererecorded.recorded.

The measurable changes noted after MARS areReduction in serum bilirubin, Improvement inencephalopathy, Child-Turcotte-Pugh score, Increasein systemic vascular resistance, mean arterialpressure, Decrease in cardiac output, Improvementin Cerebral blood flow and cerebral perfusion andrenal function.

No survival benefits for MARSNo survival benefits for MARS -- howeverhowever -- werewererecorded.recorded.

22-- Prometheus® or Fractionated PlasmaPrometheus® or Fractionated PlasmaSeparation & Adsorption:Separation & Adsorption:(Fresenius Medical Care AG, Bad Homburg, Germany)(Fresenius Medical Care AG, Bad Homburg, Germany)This system combines fractionated plasma separationThis system combines fractionated plasma separationand adsorption with highand adsorption with high--flux hemodialysis for theflux hemodialysis for theremoval ofremoval of both albuminboth albumin--bound and waterbound and water--solublesoluble toxinstoxinsand was introduced by Falkenhagen inand was introduced by Falkenhagen in 19991999..

22-- Prometheus® or Fractionated PlasmaPrometheus® or Fractionated PlasmaSeparation & Adsorption:Separation & Adsorption:(Fresenius Medical Care AG, Bad Homburg, Germany)(Fresenius Medical Care AG, Bad Homburg, Germany)This system combines fractionated plasma separationThis system combines fractionated plasma separationand adsorption with highand adsorption with high--flux hemodialysis for theflux hemodialysis for theremoval ofremoval of both albuminboth albumin--bound and waterbound and water--solublesoluble toxinstoxinsand was introduced by Falkenhagen inand was introduced by Falkenhagen in 19991999..

33-- HepaWash®HepaWash®(Hepa wash, Munich, Germany)(Hepa wash, Munich, Germany)

A newly developedA newly developed liver and renalliver and renal support systemsupport systemthat is based on the use of recycled albuminthat is based on the use of recycled albumindialysate.dialysate.

The new system has shown a high detoxificationThe new system has shown a high detoxificationcapacity in incapacity in in--vitro and preclinical studies.vitro and preclinical studies.

The HepaWash® system is very similar to theThe HepaWash® system is very similar to theMARS device but differs by the fact that itMARS device but differs by the fact that itregenerates (cleans) the exogenous albumin in theregenerates (cleans) the exogenous albumin in thesecondary circuit to at much larger extent, based onsecondary circuit to at much larger extent, based onadditional specific pH and temperature changes atadditional specific pH and temperature changes atthe filter levelthe filter level

A newly developedA newly developed liver and renalliver and renal support systemsupport systemthat is based on the use of recycled albuminthat is based on the use of recycled albumindialysate.dialysate.

The new system has shown a high detoxificationThe new system has shown a high detoxificationcapacity in incapacity in in--vitro and preclinical studies.vitro and preclinical studies.

The HepaWash® system is very similar to theThe HepaWash® system is very similar to theMARS device but differs by the fact that itMARS device but differs by the fact that itregenerates (cleans) the exogenous albumin in theregenerates (cleans) the exogenous albumin in thesecondary circuit to at much larger extent, based onsecondary circuit to at much larger extent, based onadditional specific pH and temperature changes atadditional specific pH and temperature changes atthe filter levelthe filter level

Orthotopic liver transplantation remains the onlydefinitive therapy for patients who do not improvewith supportive measures to sustain life.

The shortThe short--term and longterm and long--term survival rates afterterm survival rates afterliver transplantation for ACLF are similar to thoseliver transplantation for ACLF are similar to thoseafter transplantation for other liver conditions.after transplantation for other liver conditions.

However, the timing and indication forHowever, the timing and indication fortransplantation for this illness are not yet welltransplantation for this illness are not yet welldefined.defined.

Liver Transplantation inLiver Transplantation inACLFACLF

Orthotopic liver transplantation remains the onlydefinitive therapy for patients who do not improvewith supportive measures to sustain life.

The shortThe short--term and longterm and long--term survival rates afterterm survival rates afterliver transplantation for ACLF are similar to thoseliver transplantation for ACLF are similar to thoseafter transplantation for other liver conditions.after transplantation for other liver conditions.

However, the timing and indication forHowever, the timing and indication fortransplantation for this illness are not yet welltransplantation for this illness are not yet welldefined.defined.

Contraindications to liverContraindications to livertransplantation in ACLFtransplantation in ACLF

Hemodynamic instability and highHemodynamic instability and high--dosedoseinotropic requirement (sepsis, bleeding).inotropic requirement (sepsis, bleeding).

Severe bacterial infection.Severe bacterial infection. Fungal infection.Fungal infection. Cerebral edema or intracranial bleeding.Cerebral edema or intracranial bleeding.

Hemodynamic instability and highHemodynamic instability and high--dosedoseinotropic requirement (sepsis, bleeding).inotropic requirement (sepsis, bleeding).

Severe bacterial infection.Severe bacterial infection. Fungal infection.Fungal infection. Cerebral edema or intracranial bleeding.Cerebral edema or intracranial bleeding.

Prognostic scores in ACLFPrognostic scores in ACLF

Several prognostic scoring systems are usedfor patients with ACLF.

Two categories of prognostic models arecommonly used:1- Scores evaluating the severity of illness: Acute Physiology and Chronic Health Evaluation

(APACHE) II and III, Simplified Acute Physiology Score (SAPS) II and Mortality Prediction Model (MPM) II

Several prognostic scoring systems are usedfor patients with ACLF.

Two categories of prognostic models arecommonly used:1- Scores evaluating the severity of illness: Acute Physiology and Chronic Health Evaluation

(APACHE) II and III, Simplified Acute Physiology Score (SAPS) II and Mortality Prediction Model (MPM) II

Prognostic scores (cont.)Prognostic scores (cont.)

2- Scores quantifying organ dysfunction andfailure:

Logistic Organ Dysfunction System Multiple Organ Dysfunction Score Organ System Failure (OSF) Sequential Organ Failure Assessment

(SOFA).

2- Scores quantifying organ dysfunction andfailure:

Logistic Organ Dysfunction System Multiple Organ Dysfunction Score Organ System Failure (OSF) Sequential Organ Failure Assessment

(SOFA).

Prognostic scores (cont.)Prognostic scores (cont.) Multicenter studies revealed thatMulticenter studies revealed that 33 prognosticprognostic

markers were the best predictors of survival:markers were the best predictors of survival: The SOFA score (Sequential Organ Failure(Sequential Organ Failure

Assessment score) :this score is based on sixAssessment score) :this score is based on sixdifferent scores, one each for the respiratory,different scores, one each for the respiratory,cardiovascular, hepatic, coagulation, renal andcardiovascular, hepatic, coagulation, renal andneurological systems.neurological systems.SOFA at 48 h > 10 predicted mortality in 93% ofpatients

The International Normalized Ratio (INR).

Multicenter studies revealed thatMulticenter studies revealed that 33 prognosticprognosticmarkers were the best predictors of survival:markers were the best predictors of survival: The SOFA score (Sequential Organ Failure(Sequential Organ Failure

Assessment score) :this score is based on sixAssessment score) :this score is based on sixdifferent scores, one each for the respiratory,different scores, one each for the respiratory,cardiovascular, hepatic, coagulation, renal andcardiovascular, hepatic, coagulation, renal andneurological systems.neurological systems.SOFA at 48 h > 10 predicted mortality in 93% ofpatients

The International Normalized Ratio (INR).

Prognostic scores (cont.)Prognostic scores (cont.)

ADMA (Asymmetric di methyl arginine),SDMA (stereo-isomer symmetric di methylarginine) and their combined sum, which istermed as di methyl arginine score.

Elevated di methyl arginines may serve asimportant biological markers of deleteriousoutcome especially in alcoholic hepatitis

ADMA (Asymmetric di methyl arginine),SDMA (stereo-isomer symmetric di methylarginine) and their combined sum, which istermed as di methyl arginine score.

Elevated di methyl arginines may serve asimportant biological markers of deleteriousoutcome especially in alcoholic hepatitis

TAKE HOME MESSAGESTAKE HOME MESSAGES AcuteAcute--onon--chronic liver failure is a unique clinicalchronic liver failure is a unique clinical

entity with acute deterioration of liver function andentity with acute deterioration of liver function andsubsequently of other end organs over a period ofsubsequently of other end organs over a period ofweeks following a precipitating event in a patient withweeks following a precipitating event in a patient withpreviously wellpreviously well--compensated cirrhosis.compensated cirrhosis.

The precipitating events include either an infeciousThe precipitating events include either an infecious(such as hepatotropic viruses, intestinal bacterial(such as hepatotropic viruses, intestinal bacterialpermeation) or non infectious factor (such aspermeation) or non infectious factor (such ashepatotoxic drugs, surgery).hepatotoxic drugs, surgery).

ACLF carries an ominous prognosis.ACLF carries an ominous prognosis. Potential therapeutic interventions arePotential therapeutic interventions are

mainly extracorporeal liver supportmainly extracorporeal liver supportor liver transplantation.or liver transplantation.

AcuteAcute--onon--chronic liver failure is a unique clinicalchronic liver failure is a unique clinicalentity with acute deterioration of liver function andentity with acute deterioration of liver function andsubsequently of other end organs over a period ofsubsequently of other end organs over a period ofweeks following a precipitating event in a patient withweeks following a precipitating event in a patient withpreviously wellpreviously well--compensated cirrhosis.compensated cirrhosis.

The precipitating events include either an infeciousThe precipitating events include either an infecious(such as hepatotropic viruses, intestinal bacterial(such as hepatotropic viruses, intestinal bacterialpermeation) or non infectious factor (such aspermeation) or non infectious factor (such ashepatotoxic drugs, surgery).hepatotoxic drugs, surgery).

ACLF carries an ominous prognosis.ACLF carries an ominous prognosis. Potential therapeutic interventions arePotential therapeutic interventions are

mainly extracorporeal liver supportmainly extracorporeal liver supportor liver transplantation.or liver transplantation.

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