1 KASL STC Management of ACLF liver support devices vs. liver transplantation Dong Hyun Sinn M.D., Ph.D Samsung Medical Center Department of Medicine, Seoul, Korea
2 Content Liver support device Liver transplantation Room for improvement?
3 Q1. Liver support device Do we need it? Do we have it? Are they useful? Will there be available liver support device in future?
4 Do we need liver support device? 42/M Heavy alcoholics (>100 g/d) URI symptoms for a weeks Sleeping tendency for 3-4 days Drowsy mental status TB: 5.9 AST/ALT: 1123/2678 PT INR: 5.75 Brain CT: non specific Referred to ER
6 Clinical course HD 0 HD 1 HD 2 HD 3 HD 7 Emergent living donor evaluation: deferred DDLT listing Seizure developed not controlled Aggravated neurologic exam, pupil (4mm/4mm fix) EEG (electrical inactivity) CT angiography (no intracranial arterial blood flow) Brain death Expired (multi-organ failure) We need liver support device which is able to bridge effectively until either recovery or transplant.
7 We have artificial liver devices Artificial liver(al) devices non-living components to cleanse the blood or plasma of its toxins Physical/chemical gradients and adsorption MARS, Prometheus, SPAD
8 Inclusion criteria , 19 European centers Acutely decompensated cirrhosis Identifiable triggering event Increase of serum bilirubin > 5 mg/dl At least one of following Hepatorenal syndrome Hepatic encephaloapthy grade II Rapidly progressive hyperbilirubinemia Exclusion criteria Progressive jaundice as a consequence of the natural course of cirrhosis or extrahepatic cholestasis Platelet < 50,000 PT INR > 2.3 or suspected or evident DIC Need for renal replacement therapy Uncontrolled infection Active bleeding HCC > 4cm or portal vein thrombosis Severe cardiopulmonary disease Mean arterial pressure < 60 mmhg despite vasopressor therapy Major surgical procedure within the last 4 weeks HIV infection Banares et al., Hepatology 2013;57:1153
9 Banares et al., Hepatology 2013;57:1153
10 Probability of transplant-free survival Intention to treat Per-protocol Banares et al., Hepatology 2013;57:1153
11 Sub-group analysis Banares et al., Hepatology 2013;57:1153
12 Kribben et al., Gastroenterology 2012;142:782
13 Kribben et al., Gastroenterology 2012;142:782
14 Kribben et al., Gastroenterology 2012;142:782
15 Kribben et al., Gastroenterology 2012;142:782
16 Summary of artificial liver support devices detoxification alone may not be enough Tritto et al., Semin Respir Crit Care Med 2012;33:70
17 Better artificial liver devices? Artificial liver(al) devices non-living components to cleanse the blood or plasma of its toxins Physical/chemical gradients and adsorption MARS, Prometheus, SPAD Bioartificial liver (BAL) devices Cellhousing bioreactor Detoxification + (possibly) other synthetic and metabolic function? ELAD, Hepatassist, BLSS, MELS, AMC-BAL, LifeLiver
18 Bioartificial Liver Support Systems in Clinical Studies Struecker, B. et al. Nat. Rev. Gastroenterol. Hepatol. 2013
19 Summary of bioartificial support devices Tritto et al., Semin Respir Crit Care Med 2012;33:70
20 Characteristics of BAL systems Specifications of bioreactors Classification Name / Developer Bioreactor design Culture type Hepatocyte source (mass) Immunolog-i cal barrier Reactor perf usion / flow rate (ml/min) Clinical study Status ELAD (Vital therapies inc. / USA) Tightly packed ag Human cell line ( gregates C3A) (60g) Yes (70 kd) Blood / 200 Phase II (complete) ELAD, current ver. (Vital therapies inc. / USA) Tightly packed ag Human cell line ( gregates C3A) (400g) Yes (120 kd) Plasma / 500 Phase III (ongoing) Hollow-fiber systems HepatAssist (circe Biomedical Co. / USA Microcarrier-atta ched irregular ag gregates Cryopreserved p orcine hepatocytes (5~7x10 9 ) None Plasma / 400 Phase II/III (complete) HepaMate (current ver. of He patassist) (HepaLife Technologies / USA) LSS (Charité Universitaetsmedizin Berlin / Germany) Tightly packed ag gregates Tissue-like Organoid Porcine embryon ic cell line (PICM-19H) (1.5x10 10 ) Porcine hepatocytes ( g) None Yes (300 kd) Plasma / 800 Plasma / 100~200 Phase II (inactive) Phase I (complete) Porous matrix systems RFB-BAL (Univ. of Ferrara / Italy) AMC-BAL (Amsterdam Univ. / Netherlands) Aggregates Small Aggregates Porcine hepatocytes (200g) Porcine hepatocytes (1.2 x10 10 ) None None Plama / 200~300 Plasma / 150 Phase I (complete) Phase I (complete) Encapsulation system LifeLiver ( Lifeliver Co. Ltd / Korea) Spheroids Porcine hepatocytes (2 x10 10 ) Yes (600 kd) Plasma / 300 Phase I/IIa (ongoing) Hanyang Med Rev 2014;34:
22 임상시험개요 (1/2) 임상시험제목 시험실시기관및시험책임자 급성간부전환자에서 LifeLiver ( 체외순환형생인공간 ) 의안전성과유효성을탐색하기위한제 1 상 /2a 상임상시험 삼성서울병원외과이석구교수 임상시험수탁기관 LSK Global PS ( 엘에스케이글로벌파마서비스 ) 대상질환 임상시험단계 임상시험디자인 시험목적 주성분 용법및용량 ( 시간 ) 피험자수 급성간부전환자 안전성 ( 제 1 상 ) 및치료적탐색시험 (2 상 a) 동시임상시험 비비교, 공개, 단일기관 급성간부전환자에서 LifeLiver 투여시의안전성 / 유효성을평가하고이를통해 LifeLiver 치료의타당성 (feasibility) 을평가한다. 무균돼지유래일차배양간세포 1.5 내지 2.0 ⅹ 개 1. 투여방법환자의혈액으로부터연속적으로혈장을분리하여간세포가충전된반응기에순환시키는체외순환의형태로투여함. 2. 투여시간, 횟수및간격 1 회 12 시간이내로투여하며 1 단계 3 명은 1 회투여하며, 이에대한안전성이확인되면 2 단계 3 명은 1 차투여후선정기준에계속만족하면 3 일이내에 2 차투여를실시한다. 선정기준을만족하는 6 명
23 임상시험개요 (2/2) 선정기준 제외기준 평가지표 1. 만 18세이상 60세이하 2. 급성간부전으로인한간이식대기자 (Status 1, 2a) 3. 뇌사자기증간을기다리는환자 4. 간성뇌병증등급 II 이상 5. INR (international normalized ratio) 2.0 이상 6. Serum ammonia 100 μg /dl 이상 7. Total bilirubin 5 mg/dl 이상 8. 체중 45 kg 이상 1. 혈장분반술금기증환자 2. 중증저혈압 ( 수축기혈압 80mmHg 이하 ) 3. 혈소판감소 < 15,000/mm 3 4. 간이식의금기증 5. 뇌출혈 6. HIV 양성 7. 시험개시직전에중대한혹은생명을위협하는출혈이있는경우 1. 체외순환안정성 (stability) 평가 - 활력징후 / 혈액학적검사 / 혈액응고검사 2. 이종세포안전성평가 - 알러지반응 / 면역항체반응 / 보체농도 / 림프구수변화 - PERV (Porcine endogeneous retrovirus) 전이여부 3. 유효성평가 - 전격성간부전환자에서 LifeLiver 투여시의 MELD score (MELD score는 creatinine, bilirubin 및 INR 복합점수임 ) - LifeLiver 투여전후의혈중암모니아농도 - LifeLiver 투여전후의신경학적상태평가
24 LifeLiver TM three patients MELD score MELD score 1st 2nd 3rd Ammonia ( g/dl) Ammonia 1st 2nd 3rd 28 before after 80 before after 5 HE grade Hepatic Encephalopathy grade st 2nd 3rd 0 before after
25 Liver support device Do we have it? Artificial devices (MARS, Prometheus): YES Bioartificial devices: under development Are they useful? Artificial devices: NO Bioartificial devices: under trial An artificial liver support system which is able to bridge effectively until either recovery or transplant remains elusive at present.
26 Content Liver support device Liver transplantation Room for improvement?
27 Liver transplantation Liver transplantation saves life. However
28 간장이식응급도 STATUS 1 18 세이상의전격성간부전증환자가 7 일이내에간이식을받지않으면생명연장의희망이없는상태로다음중한가지이상에해당하는경우를말한다. - 만성간질환없이간질환의증상이나타난후 8 주이내에급성전격성간부전증이발생하고뚜렷한간성혼수가동반된경우 - 간이식후 7 일이내에이식된간이기능을하지못하는경우 - 간이식후 7 일이내에간동맥성혈전증이있는경우 - 윌슨병환자에게급성간기능부전이동반된경우 STATUS 2A 만성간부전증환자가집중치료실에입원해야만하는상태로 7 일이내에간이식을받지않으면생명연장의희망이없는경우 - Child-Pugh 점수가 10 점이상이면서다음중한가지이상에해당해야한다. - 치료에반응하지않는활동성정맥류출혈로판명된경우 - 간신증후군 - 난치성복수 / 간 - 흉수증 - 내과적치료에반응하지않는 stage III/IV 인간성뇌증 STATUS 2B Child-Pugh 점수가 10 점이상이거나 7 점이상이면서다음하나이상해당하는경우 - 치료에반응하지않는활동성정맥류출혈 - 특발성세균성복막염 - 난치성복수 / 간 - 흉수증 - Stage I 이나 II 로판명된간세포암 STATUS 3 - 지속적인치료를요하고 Child-Pugh 점수가 7 점이상이나 2B 에해당하지않는경우 - 간세포암이면서 stage III 이상인환자
29 Liver transplantation 간장응급도기준개선방안연구최종결과보고서 대상군 2009년 1월 1일 ~ 2011년 12월 31일 (3년) 간이식등록대기자 11개다기관연구 Kim MS et al., J Korean Soc Transplant 2014;28:59
30 Transplant rate Overall DDLT Kim MS et al., J Korean Soc Transplant 2014;28:59
31 Patients survival on waitlist Overall by status IIa by MELD Kim MS et al., J Korean Soc Transplant 2014;28:59
32 Liver transplantation Limitations Organ shortage Cost Long-term management ACLF, is conceptually reversible! Sarin et al., Hepatol Int 2014;8:453
33 Case M/35 Heavy alcoholics Jaundice, abdominal distension Referred for liver transplant evaluation Initial evaluation CBC: k PT-INR: 1.6 Albumin: 2.9 TB: 41.3 AST/ALT: 137/46 BUN/Cr = 25.4/1.98 HBsAg- HBsAb+ HBcIgG- Anti-HCV- HAV IgM- HAV IgG+
34 Case description Complicated with ascites Experienced variceal bleeding during hospital course ACLF d/t alcoholic hepatitis Pentoxifylline was used
35 Hospital course Transjugular liver biopsy Steatohepatitis with moderate fatty change, perisinusoidal and bridging fibrosis and many Mallory-bodies
36 HBV-related ACLF outcome Retrospective cohort 67 patients meeting ACLF definition by APASL criteria Jaundice (bilirubin > 5 mg/dl) + coagulopathy (PT INR > 1.5) Complicated within 4 weeks by ascites and/or encephalopathy Ha JM et al., under submission
37 Survival Overall survival Transplant-free survival 73.1% at 90 days 34.3% at 90 days Ha JM et al., under submission
38 Prognostic factors Importance of MELD Risk factors for mortality Baseline bilirubin MELD 28 Ascites grade 2 or 3 Hepatorenal syndrome During hospital course Aggravation of encephalopathy Presence of infection Independent predictors Baseline MELD 28 Baseline ascites grade 2 or 3 Aggravation of encephalopathy Ha JM, Paik YH et al., under submission
39 Liver transplant indication ACLF some patients are reversible! Do we have surrogate indicator for reversibility? While there are many predictors for mortality, there are no reliable predictors of reversibility of ACLF Sarin et al., APASL consensus recommendation on ACLF, Hepatol Int 2014 Currently available prognostic scoring systems do not adequately predict outcome and determine candidacy for LT. Reliance entirely upon these guideline is thus not recommended (III) Lee et al., AASLD position paper for acute liver failure Hepatology 2011
40 LT contraindications? Those who will recover with medical therapy? Yes, but reliable predictors are not present Expected survival after recovery?
41 ACLF type Reversibility is a concern 1-year of 15% & 5-year 50% mortality for grade 2-3 ascites Reversibility? Contraindicated for LT? Jalan R et al., Gastroenterology 2014;147:4
43 Survival by ACLF types Overall survival Transplant-free survival 78.1% 81.3% 76.4% 78.8% 63.6% 46.3% 50.0% 60.0% 66.3% 46.9% 36.4% 26.3% No additional mortality after initial early period for chronic hepatitis Additional mortality even after 90 days for cirrhosis patients Hong YS et al., Intrim review
44 Survival by liver disease severity and LT At 1 year: 83.7% vs. 47.5% 36.2% hepatitis At 1 year: 90.9% vs. 71.4% 19.5% 45.0% cirrhosis At 1 year: 83.3% vs. 42.1% 41.2% Decompensated cirrhosis At 1 year: 80.0% vs. 35.0% Hong YS et al., Intrim review
45 Liver transplant indication LT should be considered for ACLF type C (or B), given long-term prognosis. Always proceed if LT is available?
49 LT contraindications? General contraindication Irreversible cerebral damage Active infection (esp. pneumonia) Hemodynamic instability LT in ACLF by non-hepatic insult?
50 Case M/47 Heavy alcoholics, known HBV (no tx history) Vibrio sepsis Septic shock Rt leg cellulitis necrosis fasciotomy Renal failure with anuria CRRT HBV DNA HBV DNA 8600 IU/ml entecavir start
51 Case Comatous metal status Lab CBC: (90%) k PT-INR: 2.2 Albumin: 3.4, Total bilirubin: 14.7, AST/ALT:49/27 BUN/Cr = 33.2/0.45 (on CRRT) ACLF type B (infection)
52 Hospital course (134 days, LT at HD 71) Infarcted regenerative nodules, S8 and S4 (4 nodules, up to 0.3x0.3x0.3 cm) Micronodular cirrhosis, active with marked cholestasis and bile duct proliferation, clinically HBVrelated LT LT
53 LT by insult type (hepatic vs. non-hepatic) 91%, LT (+), Hepatic insult 77%, LT (+), Non-hepatic insult 63%, LT (-), Hepatic insult 33%, LT (-), Non-hepatic insult Hong YS et al., Intrim review
54 LT contraindications? General contraindication Irreversible cerebral damage Active infection (esp. pneumonia) Hemodynamic instability LT in ACLF by non-hepatic insult? contraindication? LT in ACLF type C?
55 Case M/52 LC-A/B Previous decompensation (ascites, hepatic hydrothorax, hepatic encephalopathy) Pulmonary TB with TB pleurisy on TB medication for previous 7 months Admitted due to aggravated mental status
56 Evaluation results V/S: 110/ Drowsy mental status Lab CBC: 6080 (seg 76%) k PT-INR: 2.4 Albumin: 2.7, Total bilirubin: 10.6, AST/ALT:154/21 BUN/Cr = 53.9/1.85 UA: WBC +++, pyuria, culture = E.Coli ACLF type C (UTI?)
57 Hospital course LDLT (donor: wife)
58 LT in cirrhosis with previous decompensation and acute deteriorated liver function 100%, LT (+), EASL-CLIF ACLF (-) 56%, LT (+), EASL-CLIF ACLF (+) 45%, LT (-), EASL-CLIF ACLF (-) 18%, LT (-), EASL-CLIF ACLF (+) Hong YS et al., Intrim review
59 LT in ACLF type B or C? LT should be considered for ACLF type C or B, given long-term prognosis after recovery from ACLF. Outcome of LT was worse when EASL-CLIF ACLF criteria (+) patients, however, those patients also had survival advantage by emergent LT. Optimal timing for LT remains to be determined.
60 How SMC do it? Transplant Surgeon Anesthesiologist Transplant coordinator Transplant Hepatologist Multidisciplinary Approach Radiologist Critical care intensivist Dietitian Neurologist Nephrologist
61 Liver support device vs. LT Liver support device Effective model not yet present! Liver transplantation Organ shortage, cost, long-term immune suppression Difficult to assess reversibility. Difficult to decide optimal timing. Multidisciplinary approach is needed.
62 Content Liver support device Liver transplantation Room for improvement?
63 One-size fits all model?
64 ACLF management Triggerspecific management Sarin et al., Hepatol Int 2014;8:453
65 Events known to precipitate ACLF Acute hepatotrophic viral infection Acute hepatitis A, B, D, E Reactivation of hepatitis B Alcoholic hepatitis Drug induced liver injury Infection Gastointestinal bleeding Ischemia Asrani et al., Clin Liver Dis 2014;18:561
66 Which NUCs are best option? Monotherapy? Lamivudine Telbivudine Clevudine Adefovir Entecavir Tenofovir Combination therapy? EASL recommendation NUC treatment is the treatment of choice in severe acute hepatitis B or reactivation of chronic hepatitis B (B1) AASLD recommendation NUC should be considered for hepatitis B-associated acute liver failure (III) APASL recommendation NUC should be started immediately in all HBV-infected patients. Potent antiviral drugs (tenofovir, entecavir or telbivudine) should be used (2a, B)
67 Inclusion criteria ALT > 5 ULN 57% vs. 15%, p = 0.03 HBV DNA > 10 5 copies/ml ACLF bilirubin 5mg/dl PT INR > 1.5 Complicated within 4 weeks ascites and/or encephalopathy Garg et al., Hepatology 2011;53:774
68 Risk factors for mortality Platelet count > 2 log reduction at 2 weeks High HVPG Treatment with tenofovir Independent predictors > 2 log reduction at 2 weeks Garg et al., Hepatology 2011;53:774
69 Inclusion criteria ALT > 10 ULN + bilirubin > 3 ULN No patients had hepatic encephalopathy, ascites or abnormal renal function tests at baseline. Wong VW et al., J Hepatology 2011;54:236
70 Risk factors for mortality Age Bilirubin INR Entecavir Independent predictors INR Entecavir Wong VW et al., J Hepatology 2011;54:236
72 SMC data: Impact of NUC (ETV vs. LAM/CLV) ETV based = 23 LAM/CLV/ADV/Combo = 38 Overall survival Transplant-free survival 73.9% vs. 78.9%, p = 0.90 ETV vs. Others 30.4% vs. 42.1%, p = 0.74 ETV vs. Others Ha JM, et al., under submission
73 Which NUCs are best option? Combination therapy? no data ETV resistant patients Immune tolerant patents Lim YS et al., Gut 2015; In press Chan et al., Gastroenterology 2014;146:1248
74 Events known to precipitate ACLF Acute hepatotrophic viral infection Acute hepatitis A, B, D, E Reactivation of hepatitis B Which is best NUCs? Alcoholic hepatitis Drug induced liver injury Infection Gastointestinal bleeding Ischemia
75 Events known to precipitate ACLF Acute hepatotrophic viral infection Acute hepatitis A, B, D, E Reactivation of hepatitis B Alcoholic hepatitis Drug induced liver injury Infection Gastointestinal bleeding Ischemia Asrani et al., Clin Liver Dis 2014;18:561
76 Management of alcoholic hepatitis KASL guideline
77 72.9% vs. 64.5% 81.8% vs. 54.9% Park SH et al., J Hepatology 2014
78 Management of alcoholic hepatitis Key inclusion criteria MDF 32 Lille model 0.45 after medical therapy Mathurin et al., N Engl J Med 2011; 365:19
79 Clinical results(single physician early experience) Six clinically-diagnosed severe alcoholic hepatitis patients who underwent steroid therapy. Death = 4 Bleeding/infection = 3 Multi-organ failure = 1 Referred for liver transplantation = 1 Survival = 1
80 Diagnostic challenge EASL guideline Although presence of ASH can be suspected on clinical and biochemical grounds, a definite diagnosis of ASH requires a liver biopsy (A1)
81 Management of alcoholic hepatitis-related ACLF Inclusion criteria Age years Alcohol intake > 40g/d Supporting clinical features Recent onset jaundice + Severe alcoholic hepatitis = ACLF? Is steroid safe in alcohol-related ACLF? At least one (HE, ascites, hepatomegaly, leukocytosis, fever, elevated liver enzyme) MDF 32
82 Management of alcoholic hepatitis GI bleeding, renal failure, pancreatitis, uncontrolled infection KASL guideline
83 Management of alcoholic hepatitis Nguyen-Khac et al, N Engl J Med 2011;19:1781 Singh et al., Am J Gastroenterol 2014;109:1417
84 Events known to precipitate ACLF Acute hepatotrophic viral infection Acute hepatitis A, B, D, E Reactivation of hepatitis B Alcoholic hepatitis Drug induced liver injury Infection Gastointestinal bleeding Ischemia Asrani et al., Clin Liver Dis 2014;18:561
85 Acute liver failure (ALF) Drug induced-alf (DI-ALF) Intrinsic hepatotoxin (acetaminophen...) Idiosyncratic drug reactions (presumably immunemediated liver injury due to the metabolic generation of a neo-antigen) Smith et al., Lancet 1993;342:963: Stravitz et al., Hepatology 2011;53:517
86 Monocytes/macrophage function in ALF Possamai et al., J Hepatol 2014
87 Effects of steroid in Monocytes/macrophage function in ALF Possamai et al., J Hepatol 2014
95 Room for improvement? more questions than answers Optimal NUCs for HBV-related ACLF? Steroid use in alcohol-related ACLF? N-acetylcystein or G-CSF for in alcohol-related ACLF? Steroid and plasmapheresis in drug-related ACLF?