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ADVANCES IN EXTRACORPOREAL LIVER SUPPORT Ram Subramanian Emory Transplant Center Atlanta.

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Presentation on theme: "ADVANCES IN EXTRACORPOREAL LIVER SUPPORT Ram Subramanian Emory Transplant Center Atlanta."— Presentation transcript:

1 ADVANCES IN EXTRACORPOREAL LIVER SUPPORT Ram Subramanian Emory Transplant Center Atlanta

2 Case Description 40 y/o F, with no significant past medical history, presents to an OSH ER with a 2 day h/o worsening jaundice and fatigue. Initial Labs: INR 2.5, AST 2500, ALT 3000, Bili 20 Transferred to our hospital ICU for worsening encephalopathy. Subsequent workup consistent with auto-immune hepatitis induced Acute Liver Failure Worsening encephalopathy requires intubation for airway protection

3 Case progression INR progressively increases from 2.5 to 10, despite a decrease in her ALT and AST Severe hypoglycemia requires a D10 drip Unclear psychosocial support prevents immediate consideration for transplant Extracorporeal liver support initiated with MARS therapy, which is maintained for 4 days to support anhepatic state Patient subsequently is approved for transplant, and undergoes successful liver transplant without peri-operative complications. Explant pathology: > 90% hepatic necrosis

4 OUTLINE Review the rationale for the need for extracorporeal liver support Describe classification of liver failure Review current modalities of extracorporeal liver support Propose future applications of liver support

5 Rationale for Extracorporeal Liver Support According to UNOS, in 2012: –Number of waitlist recipients: 117,114 –Number of donors in 2012: 12, 872 –Death on waitlist: ~ 18 waitlist recipients/ day Given the enormous discrepancy between organ demand and supply, it is imperative that strategies to improve waitlist mortality are actively implemented

6 Classification of Liver Failure Acute Liver Failure: –Acute hepatic dysfunction in the absence of chronic liver disease (e.g. acetaminophen overdose) –Potentially reversible to normal hepatic function following hepatic regeneration Acute on Chronic Liver Failure: –Decompensation of prior cirrhosis (e.g. Hep C cirrhosis) –Resolution of acute insult does not result in resolution of underlying chronic hepatic dysfunction


8 LIVER FAILURE (LF) Acute Liver Failure (ALF)Acute on Chronic LF (ACLF) Extracorporeal Liver Support Bridge to intrinsic recovery or LT Bridge to temporary stabilization or LT

9 LIVER ASSIST DEVICES MARS ( Molecular Adsorbent Recirculating System) – Artificial Liver Support ( albumin dialysate) ELAD ( Extracorporeal Liver Assist Device) – Bioartificial Liver Support ( perfusion across hepatocytes)

10 MARS Molecular Adsorbent Recirculating System







17 © Gambro Renal Products US 071209 DG MARS ® Therapy


19 Treatment Regimen FDA approved for treatment of ALF due to drugs or toxins and for advanced HE in ACLF 8 hours of MARS therapy / day for 3 consecutive days. Albumin dialysate: 600 ml of 16 % albumin Exchange of MARS cartridges after every treatment session May continue CRRT portion of circuit after completion of MARS therapy Heparin or citrate anticoagulation





24 Beneficial Effects of MARS Improvement of jaundice and pruritis Improvement of hemodynamic instability Reduction in portal pressure Reduction in ICP in ALF Improvement of renal function in hepatorenal syndrome Improvement in hepatic encephalopathy

25 RCTS with MARS

26 ELAD Extracorporeal Liver Assist Device

27 ELAD Synopsis Form of Bioartificial Liver Support (mimics both detoxifying and synthetic functions of the liver) Prior small studies demonstrate a non- statistical survival benefit in alcohol induced liver disease ( AILD) and ALF Multi-center studies in progress to study the efficacy of ELAD in AILD and ALF

28 ELAD System

29 ELAD Extracorporeal Liver Assist Device 19 CONFIDENTIAL

30 4 ELAD Cartridges (Bioreactors) Hollow fibers (#8000/cartridge) Pore 0.2µm (allowing exchange of toxins and proteins) 440g Immortalized human C3A liver hepatocytes (Subclone human hepatoblastoma cell line HepG2) ELAD ® Bioartificial Liver Support System 12

31 ELAD C3A Cells Allogeneic Cell Therapy C3A hepatocytes divide to fill available extra-capillary space in the cartridges Plasma flows through semipermeable hollow fibers Bidirectional diffusion between UF and C3A cell Toxins processed and metabolites secreted across membrane to UF 13

32 ELAD C3A Cells Allogeneic Cell Therapy Human: no animal or safety issues identified Stable: can be stored, grown in unlimited quantities and shipped worldwide with minimal bedside preparation Immortal: Retain hepatocyte functions 14

33 ELAD C3A Cells Retain Primary Hepatocyte Function Process toxins / metabolites Consume large amounts of O 2 and glucose Active P-450 enzyme system Synthesize liver proteins including AFP 33 15

34 ELAD C3A Cells Human Liver Proteins Synthesized by C3A Cells Albumin α-Fetoprotein α-1-Antichymotrypsin α-1-Antitrypsin C3 Complement HGF Antithrombin III Factor V Fibrinogen Transferrin Factor VII TGF-α 16

35 Provides continuous extracorporeal treatment of ultrafiltrated plasma for up to 5 days ELAD ® Bioartificial Liver Support System 17 CONFIDENTIAL

36 Current ELAD Trials Efficacy and safety of ELAD in Alcoholic Liver Disease compared to current standard of care Efficacy and safety of ELAD in Acute Liver Failure compared to current standard of care

37 Future Directions Studies with MARS have demonstrated safety and tolerability, and may therefore foster wider application Larger RCTs with defined end points are needed to examine efficacy of therapy; results of current ELAD trials awaited Studies should differentiate between the disease processes of ALF and ACLF, since clinically relevant study endpoints may differ

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