Extracorporeal liver support therapies

1. Extracorporeal
liver support
Dr AYMAN SEDDIK, MD
ASS. PROF NEPHROLOGIST AIN SHAMS UNIVERSITY

2. Objectives :
 Introduction .
 modalities
Indications
limitations
Complications
 conclusion .

3. •Bile acids
•Bilirubin
•Prostacyclins
•Nitric oxide
•Indol/Phenol-
Metabolites
•Toxic fatty
acids
•Thiols
•Digoxin/Diaze
pam-like
Subst.
•...
•Ammonia
•Lactate
TOXINS:
Further liver damage
via vicious cycle:
necrosis/apoptosis !!!
•Brain Function
•Kidney Function
•Cardiovascular Tone
•Bone Marrow
Activity
Introduction :
Liver failure – endogenous intoxication

4. Introduction :
 Support systems designed to treat patients with
liver failure have been in development for over 30
years. Their designs fall into two main categories
1. Non-cell-based, which include
plasmapheresis and charcoal-based
hemoadsorption .
2. Systems that incorporate living
hepatocytes, also known as
bioartificial liver support systems .

5. Survival rates for acute liver failure with detoxification therapies
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20 (9/45)37 (23/62)67 (2/3)
Method
Treatment percent,
survive/tot
Conrol percent,
survive/tot
Investigato
rs
Yea
r
Hemodialysis 21 (5/24) - Opolon 1976
31 (20/65) 15 (8/53) Silk 1978
23 (9/39) 22 (26/117) Opolon 1981
Hemofiltration with plasmapheresis 60 (3/5) - Rakela 1988
56 (38/68) - Yoshiba 1996
Plasmapheresis 60 (6/10) - Inoue 1981
34 (15/45) 14 (5/35) Yamazaki 1988
27 (7/26) 22 (4/18) Soeda 1991
46 (5/11) - Kondrup 1992
60 (9/15) - Larsen 1994
Hemoperfusion 24 (17/71) 15 (8/53) Silk 1978
65 (20/31)* - Gimson 1982
- Gimson 1982
51 (38/75)* - O'Grady 1988
39 (13/33) O'Grady 1988
Plasma perfusion 19 (5/26) - McGuire 1995
Hemodiabsorption with plasma
sorption
52 (8/15) - Ash 1994
20 (1/5) 60 (3/5) Hughes
0 (0/1) - Ash

6. Bioartificial liver support for acute liver failure
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Investigator Year
Device
configurati
on Cell type
Treatment
percent,
survive/tot
al
Control percent
survive/tot
al
Matsumura 1987 Plate dialyzer, Rabbit
hepatocyte
s
100 (1/1) cell
suspension
-
Margulis 1989 AV shunt, cell Pig
hepatocyte
s
63 (37/59)
suspension
41 (27/67)
Li 1993 Glass bead
packed
Pig 67 (2/3) -
Sussman 1994 Hollow fiber Cultured 45 (5/11) -
Ellis, Williams 1996 Bioreactor Human 78 (7/9)* 75 (6/8)*
Hepatoma line
Gerlach 1997 Multiple
compartme
nt hollow
fiber
bioreactor
Cultured pig
hepatocyte
s
100 (8/8) -
Demetrious 1995 Hollow fiber Pig 89 (8/9) -
Watanabe 1997 Bioreactor Hepatocytes -

7. A) Non cell based systems
1) Molecular adsorbents recirculation system
The molecular adsorbents recirculation system also referred to
as extracorporeal albumin dialysis (ECAD) is non-cell-
based system designed to treat liver and renal failure.
The MARS system exposes patient ultrafiltrate to an albumin-
rich solution across a membrane. The concept is based
upon the assumption that bilirubin and other albumin-
bound substances and toxins will move across a
concentration gradient from the patient to a circulating
25 percent albumin solution. The ultrafiltrate then
courses through another cartridge to undergo
conventional renal dialysis, thus providing both hepatic
and renal support.

9. The MARS principle

10. MARS - dialyser

11. Albumin bound toxins
The pores in the MARS
membrane have a cut of of
50µm - too small for
albuminThe gradient between the high concentration of albumin
in the dialysate with free binding sites and the low
concentration of albumin in the blood with toxin laden
binding sites is the driving force
The albumin coated membrane
provides binding sites for the
transport of toxins
The Albumin is recicled by the
adsorbers of the MARS system

12. LMW water soluble toxins
The pores in the MARS
membrane have a cut of of
50µm - water soluble
substances can flow freely
while proteins can not
cross the membrane
These toxins are removed in the
conventional dialysis combined with the
MARS therapy in the same treatment
session

13. Other proteins
The pores size of the
MARS membrane prevents
proteins carrying valuable
substances like clotting
factors to cross the
membrane

14. MARS Main Indications
Liver dysfunction
Liver cell failure
compensated
chronic liver disease
Acute liver failure
Acute decompensation
of chronic LD
Chronic cholestatic
syndromes
LF post LTx
Liver failure after
liver surgery

15.  A published report summarized the experience
in 13 patients with chronic liver disease (UNOS
Status 2A or 2B) with encephalopathy.
 Bilirubin, bile acids, and creatinine improved
with treatment while ammonia did not. Nine out
of the 13 (69 percent) demonstrated
improvement in both liver and renal function
indices. (Stange et al :Artif Organs 1999; 23:319).

16.  Thirteen additional patients with hepatorenal
syndrome were treated with the MARS system
in a prospective randomized controlled trial
Treated patients (n=8) had improved bilirubin
and creatinine versus controls (n=5). Mortality
was 100 percent in the control group and 75
percent in the MARS-treated group; however,
this endpoint did not achieve statistical
significance. (Mitzner et al :Liver Transpl 2000
May;6(3):277-86 )

17.  Future randomized controlled trials
targeting patients with decompensated
cirrhosis and particularly patients with
hepatorenal syndrome. A survival
advantage with MARS was observed in
a controlled trial involving 24 patients
with cirrhosis who developed
superimposed acute liver injury (30-
day survival in 11 of 12 treated with
MARS versus 6 of 11 controls) (Heemann
: Hepatology 2002 Oct;36(4 Pt 1):949-58).

18. 2) HemoTherapies liver dialysis unit
 The HemoTherapies system is the only FDA approved
liver support device currently in use in at least 18 US
clinical centers.
 The HemoTherapies liver dialysis unit is a charcoal-
based, blood detoxification product that has been
approved for the treatment of drug toxicity and liver
failure
 In accordance with FDA regulations, the Liver Dialysis
Unit™ system has demonstrated safety. However, small
controlled trials have not demonstrated a survival benefit
from treatment in either acute or chronic liver disease
(Ash et al :Artif Organs 1994May;18(5):355-62).

19. Liver Dialysis Unit
 Plate dialyzer with blood on
one side, dialysate is a
mixture of sorbents,
activated charcoal being the
essential component.
 For a substance to be
removed, must be
dialyzable and able to bind
to charcoal.
 “Bridge to recovery” for
treat acute hepatic
encephalopathy and
overdoses of drugs

20. 3)Prometheus
 Prometheus, a liver support system in which
albumin-bound substances are directly removed
from blood by special adsorber.
 In a simultaneous step, high-flux hemodialysis
is performed.

21.  Eleven patients with acute-on-chronic liver failure and
accompanying renal failure were treated with
Prometheus on 2 consecutive days for >4 h.
 RESULTS: Prometheus treatment significantly
improved serum levels of conjugated bilirubin, bile
acids, ammonia, cholinesterase, creatinine, urea
and blood pH.
 There were no significant changes in hemoglobin and
platelet levels, whereas leucocytes increased
without signs of systemic infection. No treatment-
related complications except a blood pressure drop in
two patients with systemic infection were noted. In one
patient (Child-Pugh score: 15) Prometheus treatment
could not be completed due to onset of uncontrolled
bleeding 16 h after dialysis.


22.  CONCLUSIONS: Prometheus is a safe supportive
therapy for patients with liver failure. A significant
improvement of the biochemical milieu was observed
already after two treatments. Prospective controlled
studies with the Prometheus system are necessary to
evaluate hard clinical end-points. (Rifai et al : J Hepatol
2003 Dec;39(6):984-90).
 a significant decline in the serum level of water-soluble
and protein-bound toxins was achieved with both mars
& prometheus . PROM produces higher blood
clearances for most toxins, which results in higher
delivered treatment doses compared with a matching
treatment with MARS. (PieterArtificial Organs 30 (4) , 276–284).

23. B) Cell-based systems
 The limitations of non-cell-based systems
provided a rationale for the development of
bioartificial liver support systems designed to
provide hepatic synthetic support by
incorporating hepatocytes into plasmapheresis
or whole blood extracorporeal systems

24. HepatAssist 2000 system ,Courtesy of A Christopher Stevens, MD.
©2008 UpToDate®

25. Extracorporeal liver assist device

26.  Clinical experience with these systems has been mostly
confined to small numbers of patients in uncontrolled
trials. An exception is a controlled trial involving 126
patients with fulminant hepatic failure; all were treated
with conventional therapy while one-half also received
hemoperfusion through a suspension of living porcine
hepatocytes
 Survival was higher in patients who received
hemoperfusion (63 versus 41 percent). This study was
criticized because of disparities in liver disease severity
between patients enrolled in each group.. (Margulis
Resuscitation 1989; 18:85).

27. CONCLUSION :
 All of the liver support systems are available in clinical
trials in which their safety and efficacy are being
evaluated. Only the Hemotherapies Liver Dialysis
Unit™ is approved by the Food and Drug
Administration of the United States based upon safety
data alone for use in drug toxicity and liver failure.
 The MARS product is available in Europe for the
treatment of liver failure, however most experience is in
treating chronic liver disease. Despite its availability,
statistically powered randomized clinical trials with
defined efficacy endpoints are lacking.

28.  All the extracorporeal systems require
anticoagulation, either with heparin or citrate. As
a result, special attention must be paid to
potential bleeding complications, volume shifts,
and electrolyte derangements
 when considering the use of any liver assist
system, each practitioner needs to carefully
evaluate the available safety and efficacy data
and weigh the risks and potential benefits for an
individual liver failure patient.