Hospital General Universitario Gregorio Marañón. CIBEREHD Trasplante hepático de alto riesgo Insuficiencia Hepática Crónica Reagudizada SETH. Badajoz 9 de octubre 2009 Rafael Bañares Hospital General Universitario Gregorio Marañón. CIBEREHD Agradecimientos Destacar la importancia del tema señalando que es una de las complicaciones más frecuentemente evaluadas por unidades de referencia y de trasplante hepático

¿ Qué es la Insuficiencia Hepática Crónica Reagudizada ? Cambios fisiopatológicos Evaluación del pronóstico Tratamiento y posible papel de los sistemas de soporte artificial

Bacilos gram negativos BTY:Cirrosis con ↑necrosis. GPVH=26 mmHg Bacilos gram negativos SESIONES MARS E. Hepática THO Deterioro de la Función Renal DIAS

Concepto de insuficiencia hepática crónica agudizada Cambios Fisiopatológicos Citoquinas Estrés oxidativo Desequilibrio circulatorio Insuficiencia hepática Fracaso Circulatorio SHR Encefalopatía Situación clínica estable Sepsis Hemorragia Alcohol Fármacos ¿Cuál es la epidemiología de la IHCA? Evento precipitante Organos diana

Ensayo RELIEF Estudio aleatorizado multicéntrico europeo MARS+SMT Vs. SMT Variable principal Supervivencia libre de trasplante a los 28 días Cálculo del tamaño muestral “20 % de reducción en mortalidad en el grupo experimental” (de 40 % a 20 %) 176 pacientes This is the first RCT trial designed to test the impact of MARS therapy in survival in this setting. Sample size was estimated using the assumptions showed in the slide, that is a 20 % reduction in mortality from 40 % in control arm Vs 20 % in experimental arm Although the main results are still awaiting

Inclusion Criteria (I) Acutely decompensated liver cirrhosis Presumed cirrhosis (clinical and imaging) Triggering event (i.e. infection, bleeding etc.) AND… intrahepatic cholestasis (BL>5 mg/dl) without evidence of extrahepatic origin AND… at least one of the following events HRS (according to criteria of International ascites Club) and/or Hepatic encephalopathy > or equal º II and/or Progressive hyperbilirubinemia (Bilirubin > 20 mg/dl or >340 µmol/l, defined as a more than 50% increase before enrollment, whether in referring or in current hospital) The inclusion criteria of the trial are shown in the slide. As you can see these criteria are in agreement with the previously comented definition . In fact they included the existence of previous liver disease with acute deterioration as defined by an increase of bilirubin and, importantly by the presence of end-organ dysfunction

Exclusion Criteria (I) Progressive jaundice as a consequence of the natural course of cirrhosis Very low platelet count (less than 50000/mm3) INR >2.3 Need for renal replacement therapy within 3 days prior to inclusion Uncontrolled infection/ Infection without ABCs for at least 24 hours Active bleeding within 48 hours prior to enrollment HCC> 4 cm or tumoral and non-tumoral portal vein thrombosis Severe cardiopulmonary disease Pregnancy and lactation Hemodynamic instability (MAP < 60 mmHg despite vasopressor therapy) This slide shows main exclusion criteria of the trial. As you can see patients with advanced coagulopathy, with active infection or severe hemodynamic instability as well as patients with malignancies or severe comorbidities were excluded of the trial

Working definition of acute-on-chronic liver failure Pathophysiological changes Cytoquines Oxidative stress NO Liver failure Circulatory failure HRS Encephalopathy Patient in stable clinical condition Sepsis Hemorragia Alcohol Fármacos The first relevant question is to analyze which precipitating event is more prevalent in AoCLF because this aspect may affect the overall management of the disease. Evento precipitante Multiorgan dysfunction

Evento precipitante. Estudio RELIEF Ingesta masiva de alcohol 142 (80%) Infección bacteriana 77 (43.75%) Hemorragia 25 (14.2%) Alteraciones electrolíticas 18 (10.2%) Otras 11 (6.25 %) As you can see in the slide the most frequent triggering event was heavy alcohol intake that was responsable of the decompensation in half of the cases. Interestingly, in more than 25 % of cases bacterial infection was reported. However, bleeding and electrolitic disturbances were clearly less frequent. Es frecuente la presencia de más de un evento precipitante

Working definition of acute-on-chronic liver failure Pathophysiological changes Cytoquines Oxidative stress NO Insuficiencia hepática Circulatory failure HRS Encephalopathy Patient in stable clinical condition Sepsis Bleeding Alcohol Drugs The second important question in this context is the severity of liver failure presented under the definition of ACLF Precipitating event Multiorgan dysfunction

Gravedad del fracaso hepático Bilirrubina (mg/dl) 26.2 (11.2) INR 1,77 (0.39) MELD (puntos) 26,11 (8.03) Child-Pugh (puntos) 10,64 (1.61) 75 % de casos MELD> 22 60 50 40 30 20 10 Total bilirubin at admission 75 % de casos Bil> 18 mg/dl 50 45 40 35 30 25 20 15 10 MELD score at admission 25 % de casos MELD> 32 25 % de casos Bil> 35 mg/dl The most relevant findings related to liver failure are shown in this slide. As you can see mean bilirubin and MELD score were above 25 mg/dl. At the bottom part of the slide you can see boxplots of MELD and INR distribution. Interestingly 75 % of cases had a serum bilirubin value above 18 mg/dl and MELD score more than 22. These findings reflect a very poor severity profile

Working definition of acute-on-chronic liver failure Pathophysiological changes Cytoquines Oxidative stress NO Insufic.hepática Fracaso Circulatorio SHR Encefalopatía Patient in stable clinical condition Sepsis Bleeding Alcohol Drugs The third important question is to analyze the prevalence and severity of multiorgan dysfunction Precipitating event Organos diana

46.7 % Hepatorenal syndrome 98 (55.7 %) Hyperbilirubinemia>20 mg/dl 10 8 6 4 2 Serum Creatinine at baseline 25 % de casos Cr> 2.5 mg/dl Hepatorenal syndrome 98 (55.7 %) Hyperbilirubinemia>20 mg/dl 125 (71%) Hepatic encephalopathy ≥ grade 2 78 (44 %) Hepatic Encephalopathy ≥ grade 2 29 (15.4%) Hepatorenal syndrome 21 (11.2 %) Hyperbilirubinemia >20 mg/dl 50 (26.6 %) HE plus HRS 13 (6.9 %) HE plus Hyperbilirubinemia 11 (5.8 %) HRS plus Hyperbilirubinemia 39 (20.7 %) Three events 25 (13.3 %) 46.7 % As you can see, hepatorenal syndrome was present in 32.6 % of SOFA 7 (6-9) % of SOFA>8 25 % Necesidad de ventilación 23 (12.6 %)

Resumen La definición actual de IHCA se caracteriza por: Estar habitualmente asociada a ingesta enólica excesiva Marcado deterioro de la función hepática Asociación frecuente a fracaso multiorgánico Pacientes de muy alto riesgo para trasplante hepático

Diferencias entre la progresión de la enfermedad crónica y la IHCA Progresión de la enfermedad hepática crónica Ausencia de factor desencadenante Curso generalmente irreversible Mecanismos patogénicos: progresión de la enfermedad Insuficiencia hepática crónica agudizada Factor desencadenante (sepsis, alcohol, hemorragia) “POTENCIALMENTE REVERSIBLE” Mecanismos patogénicos: Característicos de la IHCA

¿ Qué es la Insuficiencia Hepática Crónica Agudizada ? Cambios fisiopatológicos Alteración circulatoria y renal Alteración cerebral Evaluación del pronóstico Tratamiento y posible papel de los sistemas de soporte artificial

Cambios hemodinámicos en la IHCA 1200 20,5 22,9 19,8 5 10 15 20 25 30 mmHg ٭ 8 9,4 7,5 2 4 6 10 12 14 l/min ٭ 1000 ٭ ٭ din.seg.cm-5 800 821 833 600 666 400 200 SVR HVPG CO Etoh Cirrhosis AAH HCV Cirrhosis 100 As you all know, ACLF is frequently characterized by the existence of marked derangements of hemodynamic situation. AS you can see in this slide patients with ACLF associated to AAH, represented in blue bars, had a marked increase in portal pressure and cardiac output and a decrease in SVR as compared with patients with alcoholic cirrhosis with ACLF in red bars and HCV cirrhosis in green bars. Interestingly, Rincón et al. APT 2007; Mookerjee et al. Hepatology 2007

Modulación de la actividad inflamatoria y cambios hemodinámicos en la IHCA Infliximab Infliximab La inhibición del TNF produjo cambios intensos en la hemodinámica esplácnica y sistémica Jalan et al. Gut 2003

Incremento de la concentración de amonio en IHCA 400 300 Amonio arterial 200 100 Sanos Cirrosis TIPS IHCA FHF ↑ PIC

Mecanismos patogénicos comunes de la encefalopatía hepática de la IHCA y del fracaso hepático agudo Aumento de la presión intracraneal Cirrosis Trastorno neuropsiquiátrico Edema cerebral Encefalopatía hepática Lesión aguda hepática Sepsis

¿ Qué es la Insuficiencia Hepática Crónica Agudizada ? Cambios fisiopatológicos Evaluación del pronóstico Tratamiento y posible papel de los sistemas de soporte artificial

Requerimientos de un sistema pronóstico en la IHCA Mortalidad del episodio Identificación de necesidad de tratamientos específicos Respuesta a tratamiento Necesidad de tratamientos alternativos Indicación de soporte hepático artificial Posible indicación de trasplante hepático

Estimación del pronóstico de la IHCA No existen estimaciones fiables del pronóstico Mortalidad del grupo control de los estudios controlados (40-60 %) Los sistemas pronósticos habituales no parecen ajustarse a las características de la enfermedad Child: “Es igual de importante 4 mg/dl que 40 mg/dl” MELD: “Pocos pacientes con MELD tan elevado en la elaboración del modelo” SOFA/APACHE: Proceden de pacientes de cuidados críticos y no incorporan aspectos esenciales de la enfermedad hepática Es necesario incorporar otros elementos

APROXIMACIONES AL PRONOSTICO Influencia pronóstica de cambios fisiopatológicos Sistemas pronósticos Diseño de tratamientos basados en la patogenia de la enfermedad Supervivencia Respuesta al tratamiento Alteración circulatoria Hipertensión portal Rincón et al. APT 2007 Disfunción endotelial Mookerjee et al. Hepatology 2007 Mediadores inflamatorios Disfunción leucocitaria Flujo portal Duvoux et al. Hepatology 2004 Receptores TNF Spahr et al. J Hepatol 2004 Activación en reposo Fagocitosis Genes candidatos Expresión genética diferencial Colmenero et al. Gastro 2007

Requisitos de un sistema pronóstico Puntuación pronóstica Evaluación de la calidad del diagnóstico: Nº de Pacientes Validación Procedimiento estadístico adecuado Variables fáciles, objetivas y reproducibles Niveles de corte Estratos Pronósticos Capacidad pronóstica en a) Diferentes intervalos de tiempo:

Sistemas pronósticos Función discriminante MELD Glasgow Lille Clinic Bilirrubina Tiempo de protrombina Bilirrubina INR Creatinina Edad Leucocitos Urea Bilirrubina Protrombina Edad Insuficiencia renal Albúmina Tiempo de protrombina Bilirrubina Bilirrubina 7 º día Edad Bilirrubina INR Creatinina <6.7 6.7-8.99 > 9 Nivel de corte no definido > ó < 32 > ó < 9 > ó < 0.45

Comparación entre la calidad de los diferentes scores pronósticos Nº de pacientes Validación Modelo Estadist. Variables Objetivas Cut-off Estratos pronósticos Predicción de respuesta Maddrey + No ¿? ++ +++ 2 estratos MELD RLOG Glasgow Interna Sí Lille CLINIC Externa Cox 3 estratos

Capacidad de los scores pronósticos para diferenciar la respuesta al tratamiento Un valor de la puntuación de Lille > 0.45 parece identificar un grupo de pacientes refractarios a tratamiento esteroideo susceptibles de recibir tratamiento alternativo Los pacientes con puntuación de Glasgow inferior a 9 puntos no presentan beneficio significativos del tratamiento con corticoesteroides

Asociación entre en estadio RIFLE y Mortalidad 100 80 60 40 20 No disfunción Riesgo Daño Fracaso Renal % Muertos % Vivos Huerta et al. AASLD 2009 29

MH: Análisis Multivariado Edad Motivo ingreso UCC (No HDA Vs. HDA) Encefalopatía hepática (Sí Vs. No) Grado de ascitis (I – II – III) Puntuación MELD Categoria RIFLE* (0 – 1 – 2) Categoria FOS. OR IC 95% p Ascitis 45.8 5.2 - 403,7 .001 Categoria FOS 6 2.6 – 14.2 <.000 Categoria RIFLE* 2.5 1.2 – 5.2

MH: Comparación curvas ROC Sensitivity 100 80 AUC IC 95% p Modelo .91 (.03) .84 -.96 MELD .83 (.04) .74 - .89 .046 SOFA .81 (.04) .73 - .88 .001 CTP p .76 (.05) .67 - .84 60 40 20 100-Specificity 20 40 60 80 100 31

¿ Qué es la Insuficiencia Hepática Crónica Agudizada ? Cambios fisiopatológicos Evaluación del pronóstico Tratamiento y posible papel de los sistemas de soporte artificial

Tratamiento Tratamiento de las complicaciones Tratamiento de la hemorragia digestiva Tratamiento del síndrome hepatorrenal Tratamiento de la encefalopatía Tratamiento de la coagulopatía Soporte nutricional Tratamiento de las infecciones Tratamiento de la I. suprarrenal relativa Tratamiento del factor desencadenante Tratamiento de la hepatitis aguda alcohólica ¿ Soporte hepático artificial ?

Effect of albumin dialysis on portal pressure Baseline End first session WHVP FHVP p = 0.04 5 10 15 20 25 30 35 40 45 NS 5 10 15 20 25 30 35 40 45 Baseline 4 h End of session mmHg HVPG change during MARS therapy 22.3±6 mmHg 17.5±7.3 mmHg P = 0,02 Mean decrease 23±18 % 2,4 2,2 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 Baseline ADMA Final ADMA μM In fact, HVPG value has been associated to survival in these population. In our hemodynamic laboratory we have evaluated the effect of MARS in patients with severe AAH. As you can see albumin dialysis strongly but transiently decreased portal pressure in the majority of patients leading to a mean reduction of 20 % of baseline value. The question whether this effect may be mediated by extracorporeal circulation has been evaluated in a further study by Dr. Jalan group P = 0,01

The effect of MARS on portal pressure is independent of extracorporeal circulation As you can see in the slide the decreasing effect on portal pressure is not mediated by extracorporeal circulation as shown by the paper of Dr. Jalan group in which MARS but not hemofiltration decreased portal pressure in a similar population. Sen S et al. J Hepatol 2005

Effect of albumin dialysis on systemic hemodynamics In our unit we have analyzed the effect of albumin dialysis with MARS in a relatively large series of patients with severe acute alcoholic hepatitis. As you can see MARS induced a significant increase in MAP and SVR with a significant decrease in cardiac output while heart filling pressures were maintained. These results suggest that albumin dialysis attenuates the circulatory disfunction of patients with AAH. Catalina et al. AASLD 2004

Effect of albumin dialysis on vasoactive mediators 5 10 15 20 25 30 35 40 Baseline End sessions 100 200 400 500 600 700 800 PRA ALDOSTERONE p=0.04 1000 1500 2000 2500 3000 NE p=0.08 pg / ml ng /h ANP 50 150 250 300 18 % 62 % 53 % 55 % This data are reinforced when analysing changes in vasoactive systems. As you can see MARS significantly decreased Plasma renin activity, plasmatic aldosterone level and Norepinephrine. Catalina et al. AASLD 2004

Effect of MARS in cytokine levels Nº of patients Author/year IL 18, caspase 1 Unaffected 10/ACLF Roth/Dig Liv Dis 2009 IL6, TNFα 5 /HRS Wong/ Gut 2009 IL6, IL1, IL10, TNFα, HGF Improvement 15/ACLF Novelli/ Transp Proc 2009 IL6, IL8, IL10, TNFα, TNFαR 9/ACLF RCT Stadlbauer/ Crit Care 2006 Sen/ Liv Transpl 2004 TNF α, IL8, IL10, IL6 32/ACLF Iloeni/ Transp Proc 2006 Ambronio/ Acta Biomed, 2003 TNFα, IL1 β, IL6, IL10 13 Dicampli/ Transp Proc 2005 TNFα, IL6, IL8, IFNγ 24 Ho/ Liv Int 2003 Another aspect that has been explorated in the past years is the impact of MARS on the inflammatory profile of patients with ACLF. As you can see several cytokines were explored and as you can see the results of the differente studies are quite different. Importantly the two controlled studies showed negative results No firm conclusion may be obtained about the role of MARS in cytokine profile

Lack of effect of MARS in improving albumin function in ACLF Finally the effect of MARS in improving albumin function has been evaluated in a recent study by Dr Jalan group aimed to define functional abnormalities of albumin in cirrhosis and in patient with ACLFhas explored the ability of MARS to improve detoxifyng capacities of the functionally abnormal bilirubin usually present in patients with liver failure. As you can see MARS did not improve the deto… Jalan et al. Hepatology 2009

Pathophysiological effects of MARS in AoCLF: summary Proven beneficial effect Decrease portal pressure Amelioration of hyperdinamic circulation Controversial effects Plasmatic cytokine levels Absence of effects Effective albumin detoxification

Clinical studies with MARS in ACLF Study Nº RCT Biochemical improvement Hemodynamic effects HE effects Survival Stange 13 No Yes N/A 69 % Schmidt 8 50 % Jalan Di Campli 38 % Mitzner 37.5 % Vs 0 % Heemann 23 90 % Vs. 55 % Sen 18 No 45 %in both Hassanaien 70 Laleman This slide summarizes clinical studies using MARS in ACLF. As you can see the total number of patients is around 200. Overall MARS induces biochemical improvement, an improvement in hemodynamic situation and a amelioration of hepatic encephalopathy. Let me show you in more detail the results of RCT..

MARS in hepatorenal syndrome Type I Hepatorenal syndrome n=13 Hemodiafiltration n=5 MARS albumin dialysis n=8 Primary end-point 30-day survival This slide shows the results of one of the first RCT published with MARS. This is a two centre study done in 13 patients with Type I hepatorenal syndrome that were randomized to receive conventional hemodiafiltration or albumin dialysis with MARS. The end-point of the study was 30 day survival. MARS therapy was associated to a more marked reduction in br and Cr level than in hemodiafiltration patients, and these effects were translated to a significant increase in survival in MARS patients. However, the small sample size, the poor condition of the patients with a very poor survival in both groups and most of all the absence of an appropriate estándar therapy with vasoconstrictiors and albumin precludes the obtention of consistent conclusions Small sample size (n=13) SMT not appropriate (terlipressin+albumin) Mitzner et al. Liver Transplantation 2000

MARS in HRS refractory to vasoconstrictor therapy Pilot, observational, pathophysiological study HRS-1 refractory to vasoconstrictors + albumin n=6 GFR, RPF, Neurohormones, NO, TNFα, IL6 A recent pilot pathophysiological study performed study in 5 patients with HRS refractory to vasoconstrictors has been published. As you can see MARS induced a transient decrease in Cr levels and a significant decrease in NO plasmatic concentrations. However, GFR was not change as well as P No changes in GFR, RPF, cytokine profile nor neurohormones No apparent impact on survival Wong F et al; Gut epub

MARS in acute-on-chronic liver failure Cirrhosis with “superimposed” liver injury Serum bilirubin > 20 mg/dL Screened patients n=46 Exclusion criteria; n=8 ALF (1) Sepsis (1) Active bleeding (1) HRS (4) Spontaneous decrease in Br n=12 Included patients n=24 SMT n=12 SMT + MARS n=12 A more recent RCT analyzed the clinical effect of MARS in patients with cirrhosis and superimposed liver injury as defined by an increase in bilirubin over 20 mg/dl. 46 patients were screened including a final number of 24 patients that represents a 52 % of screened. 12 patients were randomized in each group to receive SMT or SMT plus MARS. The primary end-point was to reach a persistent decrease on Brb levels, and the secondary end-point was survival. As expected, more patients in the MARS group had a persistent decrease on BR as compared to SMT. In addition MARS treated patients had also an improvement in in-hospital mortality Primary end-point Bilirubin< 15 mg/dL (3 days) Secondary end-point In-hospital mortality 2/12 (17 %) 5/12 (42 %) 6/12 (50 %) 1/12 (8 %) Heeman et al. Hepatology 2002

MARS in acute-on-chronic liver failure Cons Small sample size End-point different to mortality Patient selection Therefore the probability of survival was greater in patients randomized to MARS group. However, this study was not designed to show differences in mortality, the patient selection was not careful and mainly the sample size was small. In fact, only one more death in the MARS group had changed the overall effect on mortality. Therefore the promising results of the study should be carefully analyzed. Again adverse events were no different between groups. No differences in adverse events between groups Heeman et al. Hepatology 2002

MARS in hepatic encephalopathy Cirrhosis with severe HE (grade III or IV) Absence of inclusion criteria n=10 Screened patients n=82 Exclusion criteria n=2 Included patients n=70 MARS n=39 Primary end-point: Two grade improvement in HE SMT n=31 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 12 24 36 48 60 72 84 96 108 120 hours mean cum num of improvements/person MARS SMT 0% 10% 20% 30% 40% 50% 60% 70% 80% percent with 1st improvement Effect of albumin dialysis in severe HE Time to improvement The more recent study is the larger randomized trial performed to date with MARS that was aimed to analyze the impact of albumin dialysis with MARS in patients with severe encephalopathy. 70 patients were included and were randomized to receive MARS vs standard medical therapy. The end-point of the study was the proportion of patients reaching a 2-grade improvement in HE. As you can see, the improvement in EH was more frequent and rapid in patients treated with MARS.

MARS in hepatic encephalopathy Predictors of response: MARS therapy (adjusted OR: 3.8) Child-Pugh score Glasgow Coma Scale Survival rate was greater in patients with rapid recovery of encephalopathy The predictors of response were related to the degree of liver disfunction, to the severity of neurologic impairment and to the assigned therapy. Interestingly, survival rate was greater in those patients who had a rapid recovery of EH. Finally adverse events rate was no different between groups. Although this trial was criticized due to the method to assess HE, it strongly suggest a positive impact in HE. No significant adverse events Hassanaien et al. Hepatology 2007

Impact of liver transplantation in survival of MARS treated patients Finally a recent cohort study has shown that… Pacientes trasplantados Pacientes no trasplantados Kantola et al. World J Surgery 2009

Papel del trasplante hepático en la IHCA Teóricamente atractivo Paciente de muy alto riesgo Indefinición de la indicación ¿Cuándo? Indefinición de la priorización Existencia de contraindicaciones Absolutas: Edad/Infección no controlada Relativas: Hepatitis aguda alcohólica/FMO ¡¡ Necesidad de definición de la Hª natural !!

Posible influencia del momento de inicio del soporte artificial en la eficacia Deterioro agudo de una cirrosis “estable” Recuperación de la función hepática hasta el nivel previo “Puente” hasta el trasplante hepático Desencadenante 100 % Función hepática Umbral para el fracaso de órganos diana ¿ Demasiado tarde ? Tiempo (meses)