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

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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

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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