Extracorporeal

liver support

Dr AYMAN SEDDIK, MD

ASS. PROF NEPHROLOGIST AIN SHAMS UNIVERSITY

Objectives :

Introduction .

modalities

Indications

limitations

Complications

conclusion .

•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

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 .

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

Investigators

Year

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

Albumin dialysis - Seige 1998

- Stange 1998

Bioartificial liver support for acute liver failure

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Investigator Year

Device configuration Cell type

Treatment percent, survive/total

Control percent survive/total

Matsumura 1987 Plate dialyzer, Rabbit hepatocytes

100 (1/1) cell suspension

-

Margulis 1989 AV shunt, cell Pig hepatocytes

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 compartment hollow fiber bioreactor

Cultured pig hepatocytes

100 (8/8) -

Demetrious 1995 Hollow fiber Pig 89 (8/9) -

Watanabe 1997 Bioreactor Hepatocytes -

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.

The MARS principle

MARS - dialyser

Albumin bound toxins

The pores in the MARS

membrane have a cut of of

50µm - too small for

albumin The 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

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

Other proteins

The pores size of the

MARS membrane prevents

proteins carrying valuable

substances like clotting

factors to cross the

membrane

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

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).

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 )

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).

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 1994 May;18(5):355-62).

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

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.

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.

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. (Pieter Artificial Organs 30 (4) , 276–284 ).

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

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

Extracorporeal liver assist device

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).

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.

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.