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. Molecular Adsorbent Recirculating System
MARS
Molecular Adsorbent Recirculating System

17. MARS® Therapy
© Gambro Renal Products US DG

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
CONFIDENTIAL 19

30. ELAD® Bioartificial Liver Support System
ELAD System Schematics
ELAD® Bioartificial Liver Support System
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) 12
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31. ELAD System Schematics
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
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32. Allogeneic Cell Therapy
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. Retain Primary Hepatocyte Function
ELAD C3A Cells
Retain Primary Hepatocyte Function
Process toxins / metabolites
Consume large amounts of O2 and glucose
Active P-450 enzyme system
Synthesize liver proteins including AFP 15

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