ADVANCES IN EXTRACORPOREAL
LIVER SUPPORT
Ram Subramanian
Emory Transplant Center
Atlanta
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
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
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
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
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
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
LIVER ASSIST DEVICES
• MARS ( Molecular Adsorbent Recirculating System)– “ Artificial Liver Support ” ( albumin dialysate)
• ELAD ( Extracorporeal Liver Assist Device) – “ Bioartificial Liver Support ” ( perfusion across
hepatocytes)
MARS
Molecular Adsorbent Recirculating System
© Gambro Renal Products US 071209 DG
MARS® Therapy
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
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
RCTS with MARS
ELAD
Extracorporeal Liver Assist Device
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
ELAD System
ELAD Extracorporeal Liver Assist Device
19CONFIDENTIAL
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
ELAD C3A Cells
Allogeneic Cell TherapyC3A hepatocytes divide to fill available
extra-capillary space in the cartridgesPlasma flows through semipermeable
hollow fibersBidirectional diffusion between UF and C3A cellToxins processed and metabolites secreted
across membrane to UF
13
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
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
33 15
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
Provides continuous
extracorporeal treatment
of ultrafiltrated plasma
for up to 5 days
ELAD®
Bioartificial Liver Support System
17CONFIDENTIAL
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
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