Liver Support Systems - Julie A. Thompson, MD Assistant Professor, Division of Gastroenterology & Hepatology Medical Director, Liver Transplant ...
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Liver Support Systems
Julie A. Thompson, MD
Assistant Professor, Division of
Gastroenterology & Hepatology
Medical Director, Liver Transplant Program
Disclosures • Principal investigator for U of M site, Vital Therapies • No other relevant disclosures • I will be discussing investigational devices
What are liver support systems
1. Mechanical devices: no cellular components
– Albumin dialysis
– Plasma exchange
– Remove toxins by filtration and absorption
2. Bioartificial liver support systems: Contain
cellular components
– Remove toxins by filtration and absorption, along
with performing biotransformation and synthetic
functions of biochemically active hepatocytes
Nyberg. Liver Transpl 2012
Why do we need liver support
systems?
• Acute liver failure: jaundice, encephalopathy
and coagulopathy in a previously normal liver
The Failing Liver • Synthesis and clearance • When liver disease results in function below a critical level, a clinical syndrome develops • Result: toxin build up, coagulopathy, hemodynamic dysregulation, toxicity to other organs…MSOF
Fulminant hepatic failure • Acute liver failure: 2500 cases in the US per year, much higher worldwide • Common cause of death: cerebral edema and intracranial hypertension, leading to brain death
Fulminant hepatic failure treatment • Only one thing: liver transplantation • Majority of patients with acute liver failure will die without liver transplantation • One year outcomes in patients with ALF are poorer than for chronic liver diseases
Goals of liver support therapy • Prevent manifestations of liver failure • Bridge patients to liver transplantation or allow time for recovery of the native liver in order to avoid liver transplantation
A good liver assist device would… • Remove toxic substances • Provide temporary liver function
A good liver assist device would… • Remove toxic substances – Currently this is possible without cellular material But, even so, no liver device that does this has been reliably shown to reduce mortality, therefore… • Provide temporary liver function – This requires use of cellular material
History of the concept
• 50 years ago, it was shown that intact
parenchyma/liver homogenate was capable or
ureagenesis and other functions
• Hepatocytes from various sources have since
been used to create a bioartificial liver
Kimoto. ASAIO J. 1959As of 2003
• 2003 review
– 12 randomized trials
• 10 ALF + acute-on-chronic, 2 ALF
– 483 patients
• Suggestion of survival benefit on acute on
chronic, but not in ALF
• Improved hepatic encephalopathy
• Trend toward successful bridging to
transplantation
Kjaergard et al. JAMA 2003.50 years ago, yet not ready • Complexity • Difficulty in obtaining and maintaining hepatocytes in a differentiated state • $$$$$$$$$
Where we are now: Options • Mechanical options • Cell-based options
Where we are now: Options
• Mechanical options
– Plasma exchange
– Albumin dialysis
• Cell-based options
Stange. Organogenesis 2011.Technology
Albumin: Human Plasma Protein
Carrying
Toxins
- to the
Liver
-which
detoxifies
for further
eliminationMechanism of Toxin Removal
in the LiverMechanism of Toxin Removal
in the LiverLiver Blood Vessels („Sinosoids“)
Inside a sinusoidal vessel: Hepatocytes
Erythrocytes stay in blood
Albumin enters „pores“
„porous“ endothelial layerAlbumin loaded with
TOXINSProcessed Toxins drained into Bile „Ductuli“
Detoxification Enzymes „detoxify“
„cleaned“ Albumin re-enters
Albumin loaded with
Blood Circulation with free
Binding Sites to bring more Toxin
TOXINSIn Liver Failure:
Detoxification Enzymes „broken“
Albumin loaded with
TOXINSIn Liver Failure:
Liver cell can not take toxinsIn Liver Failure: Albumin remains uncleaned and accumulates Toxins
In Liver Failure: Toxin overloaded Albumin is not equipped with Binding Sites anymore to take more Toxins
In Liver Failure: Toxin overloaded Albumin is not equipped with Binding Sites anymore to take more Toxins
Small fatty acids
Metabolites of aromatic amino acids
Metabolites of tryptophane
Bilirubin
Nitric Oxide
Vasoactive Substances
Shock
Renal Failure
Liver Coma
Inhibit Regeneration and
RecoveryHemodialyis removes
smaller Molecules
by Filtration and Diffusion
Albumin bound toxins can not
pass, Albumin keeps them
In Blood“Liver Dialysis”
• The only FDA approved extracorporeal therapy
approved: albumin dialysis (molecular
absorbents recirculating system [MARS]) for
treatment of drug overdose and toxicity
• Dialysis:
– the separation of particles in a liquid on the basis of
differences in their ability to pass through a
membrane
– the clinical purification of blood by dialysis, as a
substitute for the normal function of the kidneyWhat they’re used for • Have been used primarily for ALF but also used to support patients with sudden decompensation in underlying liver disease/ established cirrhosis (so-called “acute on chronic liver failure”)
Mechanical Options • Fractionated plasma separation and adsorption (FPSA): first used in 2003 • Extracorporeal albumin dialysis (ECAD, MARS): first clinical trial in 1999 • How they’re different: – membrane pore size (FPSA bigger) – Flow rate (FPSA faster) – FPSA appears to be more effective than ECAD – FPSA has more complications from coagulopathy
Mechanical devices: efficacy • Efficacy: suggestion of benefit in the sickest patients • Approved for drug overdose and poisoning • MARS has also been used for treatment of intractable pruritus (not FDA approved)
Albumin Dialysis (MARS)
MARS-Therapy uses specific dialysis membranes with active adsorption capacity for bound toxins
MARS-Therapy uses specific dialysis membranes with active adsorption capacity for bound toxins
MARS-Therapy uses specific dialysis membranes with active adsorption capacity for bound toxins
Toxins
intermediately stored on membrane
are finally taken over by
engineered proteins
in the dialysateToxins
intermediately stored on membrane
are finally taken over by
engineered proteins
in the dialysateClinical Evidence for MARS in Liver
Failure
• Improves hemodynamics • Small RCT
slightly
• Improves kidney function • Small RCT
• Improves progressive • Small RCT
jaundice
• Improves hepatic coma • FDA controlled multi-
center RCT
• Improves pruritus • 80% success in
intractable patients
Survival?Where we are now: Options • Mechanical options • Cell-based options
Cell-based Bioartificial Options • Provide blood purification through dialysis • Provide hepatocyte-specific functions that are lost in ALF – Protein synthesis – Ureogenesis – Glucogenesis detoxification
Cell-based Options: Human Cells
• Primary human hepatocyte limitations
– limited in vitro regeneration
• Solution: use of hepatoblastoma cells (but..decreased
metabolic profiles…)
– decreased function in culture due to loss of gap
junctions
• Solution: attach the cells to a matrix to simulate cell-
cell interactionCell-based options: Porcine cells • Maintain higher differentiation and metabolism • Better ammonia detoxification • More available • Limitation: concern about xenozoonosis (although no cases have been reported)
Cell-based Devices • More than 30 devices have been reported since 1987 • More than 14 systems have undergone clinical trials • More than 400 patients treated • None have obtained FDA approval
Cell-based Devices: HepatAssist
• First liver assist device tested on a large scale
• Hollow-fiber extracoporeal
bioreactor
• 7 billion cryopreserved porcine
hepatocytes
• Human cells separated from
porcine cells by a membrane
(pore size 0.15 microm)
• Animal studies and phase 1 trial
promising results
By CirceHepatAssist
• Large multicenter randomized phase 3 trial with
fulminant/subfulminant liver failure and primary
nonfunction (PNF) after LT
• 171 patients, 20 sites. 85 treated
• Demonstrated safety, but no improvement in 30-
day survival in overall population
• Survival benefit in the fulminant/subfulminant
group
• Patients with known cause of FHF had the best
survival with the bioartificial liver (not including
PNF)
Demetriou et al. Ann Surg 2004.HepatAssist Survival
All patients,
P=0.1
FDA: Not approved
due to missing primary end-Patients with
known cause of
point FHF,
PCell-based Devices: ELAD (Extracorporeal Liver Assist Device) • Largest clinical experience • Made by Vital Therapies • Uses multiple hollow-fiber cartridges loaded with human hepatoblastoma cell line
ELAD Bioartificial Liver Support System
• Selective plasmafiltration into
a bioreactor containing appr.
500 g C3A human hepatoma
cells
• Cells metabolize small
molecules
• Cells provide active p450
detoxification system
• Cells secret numerous
proteins, such as albumin,
acute phase response
proteins, growth factorsGoals of ELAD To provide liver functions in order to support patients failing liver Thereby improving/delaying/preventing secondary organ failure Thereby buying time for the patient‘s liver to recover from failure/decompensation by regeneration/resolution of precipitating events
By removing Toxins
Liver Support cleans albumin
Create new Binding Sites
with:
cleaned
Patient ALBUMIN
ALBUMIN
cleaned
ALBUMIN
…Inside a blood vessel…ELAD
• Combines conventional hemodialysis with
filtration through 4 cartridges
• Multiple clinical trials
• Largest at a United Nations hospital in Beijing
– Transplant-free survival at 28 days
• Treated: 84.1%
• Untreated 50.2%
Duan et al. Hepatology 2007ELAD Interim Survival Data
Series 1
90
80
Transplant-free survival, %
70
60
ELAD
50
Control
40
ELAD
30
Control
20
10
0
ELAD Control ELAD Control
28 days 84 daysELAD Trials at the University of
Minnesota
• Ongoing for alcoholic hepatitis
• Will open shortly for fulminant hepatic failure
• If you have a patient with alcoholic hepatitis
and want to know if s/he qualifies, please
contact me thom0235@umn.eduSummary • There have been notable achievements in artificial and bioartificial liver devices • Limited supply of hepatocytes is still a problem • Long term safety, tolerability and efficacy is not yet established • I think we will get there…
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