Update Article

Artificial Liver Support Systems

J George

Abstract
Though artificial support systems for kidney failure have been widely available for the past several
decades, it is only recently that they have become a promising treatment modality for liver failure. The
various liver support systems include conventional dialysis, charcoal hemoperfusion, high volume plasma
exchange, liver dialysis using sorbent technology, molecular readsorption recirculating system using
albumin as the dialysate, bioartificial livers, extracorporeal liver assist device and extracorporeal organ
perfusion. They are mainly used as a bridge to liver transplantation and occasionally in acute liver failure
till the liver regenerates. The various methods of extracorporeal liver support that are available at
present are assessed and those that appear to be promising are described. ©

INTRODUCTION aim of removing fluid, including some hepatic toxins and

ammonia.3 Improvement of hepatic encephalopathy and
U nlike renal failure, artificial support systems were not
widely used in liver failure, mainly because hepatic toxins
are albumin-bound unlike most uremic toxins and hence
survival of patients with fulminant hepatitis has been
reported, 4 though others have not found a favourable
outcome.5
cannot be removed by conventional dialysis. It has been
only recently that advances have been made concerning 4. Continuous renal replacement therapy
removal of hepatic toxins. It is thus now possible to support Use of permeable membranes with a slower blood pump
the patient with liver failure till the liver recovers or until liver speed for prolonged periods in hepatic encephalopathy is
transplantation is feasible. This article describes the various associated with greater cardiovascular and intracranial
methods of artificial liver support systems and highlights the stability compared to intermittent HD or HF.6 When an arterial
recent developments in this field. line is obtained, a blood pump is not required and is termed
continuous arteriovenous hemodialysis (CAVHD). With
TYPES OF ARTIFICIAL LIVER SUPPORT venous lines, a pump is required and is called continuous
SYSTEMS venovenous hemodialysis (CVVHD). This method may
improve hepatic encephalopathy by decreasing intracranial
1. Peritoneal dialysis pressure,7 and may be useful when sepsis is a precipitating
Though this has been used occasionally in patients with factor by removing inflammatory cytokines.8 Lactate based
combined liver and renal failure with ascites,1 it has a limited replacement fluids or dialysate are however to be avoided in
role due to inadequate removal of hepatic toxins especially in liver failure due to defective conversion of lactate to
those having poor peritoneal blood flow.2 bicarbonate. Hence bicarbonate based fluids have to be used.9
2. Hemodialysis 5. Charcoal hemoperfusion.
Conventional hemodialysis (HD) removes only water Blood is passed through a cartridge containing charcoal
soluble small molecules by diffusion, including some removal particles which adsorbs lipid-soluble toxins and thus is
of ammonia and amino acids. However, since majority of theoretically superior to HD or HF though randomized
hepatic toxins are albumin-bound or lipid soluble, they are controlled trials have not shown any additional benefit in
not removed by HD and hence this has a limited role. prolonging survival.10
3. Hemofiltration (HF) 6. Plasma exchange
Highly permeable membranes like polysulphone or By using high volume plasma exchange using highly
polyacrylonitrile have been used in hepatic failure with an permeable plasma filters, it is possible to remove lipid-soluble
and albumin-bound hepatic toxins.11 An additional charcoal
sorbent cartridge can have additive effect in removal of toxins
Assistant Professor in Nephrology, Medical College Hospital,
Thiruvananthapuram. and can support patients with fulminant hepatic failure for
Received : 20.12.2003; Revised : 29.01.2004; Accepted : 8.7.2004 several days.12

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 Fig. 1 : The molecular adsorbent recirculating system (MARS) circuit

7. Biologic - DT sorbent system (Liver dialysis)

This uses a cellulose membrane dialyzer with the dialysate
consisting of a charcoal suspension and a sodium loaded
cation exchange resin. Small molecular weight toxins that pass
through the cellulose membrane can be removed. 13
Modifications include use of plasma filters with powdered Fig. 2 : Bioartificial liver
sorbent surrounding it.14 A decrease in bilirubin and creatinine
levels with improvement in encephalopathy can occur, but sittings may be adequate in acute liver failure where a decrease
overall improvement in patient survival was not noted. The in bilirubin, bile acids, liver enzymes, plasma ammonia levels
cost of each sitting of 6 hours duration is around Rs.2 lakhs. as well as urea levels can occur. Beneficial effects have been
Generally, 1-5 sittings may be needed. shown with a decrease in mortality in type I hepatorenal
8. Molecular adsorbents recirculating system (MARS) syndrome patients18 and acute alcoholic hepatitis where a
dialysis marked fall in serum bilirubin can occur.19 An improvement in
cardiovascular hemodynamics and subsequent renal function
This is a modification of dialysis in which an albumin-
can occur.20 Improvement in encephalopathy21 and a decrease
based dialysate is employed with the aim of removing
in intracranial pressure and pruritus has been shown.22 Its
albumin-bound toxins which accumulate in liver failure.15
efficacy has also been demonstrated in small children.23
These include aromatic amines, bile acids, bilirubin, indoles,
Thrombocytopenia is a common though usually mild
phenols, mercaptans, middle chain fatty acids, etc. This is
complication 21 and occasionally arrhythmias can occur.
hence also called albumin dialysis. This is based on the fact
Though more than 400 patients have been treated worldwide
that albumin molecules have important transport and
with MARS, 2 there has been no systematic controlled
detoxification functions due to a large number of binding
prospective study of its benefits. Although improvements in
sites. This simulates the normal transfer of albumin bound
encephalopathy can occur, whether eventual survival is
toxins to the hepatocytes. The MARS system consists of
prolonged is not clear unless the patient undergoes liver
three compartments: a blood circuit, an albumin circuit and
transplant. The approximate cost for the disposable items
either a HD or HF compartment (Fig. 1). The blood circuit
used in each session is around 2 lakhs. However, studies
generally employs a venovenous access with a blood pump
have shown that overall costs may be less when compared to
at a speed of around 150 ml/min. Blood is passed through a
conservative management as complications, which require
special non-albumin permeable high flux dialyzer membrane
costly interventions, can be avoided.24
usually made of polysulphone, which is capable of adsorbing
albumin-bound toxins. The albumin circuit generally contains 9. Bioartificial liver (BAL)
about 600 ml of 20% human albumin and is also driven by a In this system, patient's blood or plasma is pumped into
pump at a speed of around 150 ml/mint. This is passed through bioreactors, which are hollow fibre devices, seeded on the
the dialysate compartment of the blood dialyzer where it dialysate side with freshly isolated or cryopreserved porcine
removes the toxins bound to the dialyzer membrane. The hepatocytes or transformed human hepatoma cell line.25 (Fig.
dialysate is then regenerated by passing through an activated 2). Blood initially passes through a plasma filter and the
charcoal column and then through another column containing plasma filtrate perfuses through the bioartificial liver and is
an anion exchange resin. In addition, water-soluble toxins are returned to the patient after passing through a charcoal
removed from the dialysate by passing it across a low flux adsorption column. Thus, this has the advantage of performing
HD membrane with a bicarbonate dialysate as in conventional hepatic synthetic functions in addition to detoxification
HD. Heparin is used as anticoagulant at a dose of 250 - 1000 functions performed by the other ALS systems. They have
IU / hr. Each session is around eight hours and is performed been employed in treatment of acute liver failure and in
either daily or on alternate day.16 The number of sessions is primary non-function of a liver transplant. An improvement
decided based on the patient’s response.17 Generally five in encephalopathy and an increase in cerebral perfusion

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pressure were noted. The effective hepatocytes account for SUMMARY AND CONCLUSIONS
only 2% of a normal hepatic function and is hence not very
successful in acute decompensation of chronic liver disease. A variety of extracorporeal therapies of liver failure have
Though there is theoretical risk of transmission of porcine been developed in the last decade which now offer
endogenous virus, no such incident has been reported.26 management options in liver failure which was till recently
There is however still the potential risk of exposure to widely available only in the case of renal failure. Since
xenogenic proteins and serum sickness like reactions. Hence nephrologists are familiar with extracorporeal therapy, they
further studies are required to establish their safety and are often involved in this treatment modality.34 Their main aim
efficacy. is to provide support to the liver while it recovers or
regenerates and often as a method of stabilizing patients
10. Extracorporeal liver assist device (ELAD) prior to liver transplantation. In the absence of facilities for
In this system, blood is made to pass through one or more liver transplantation, indications for extracorporeal therapy
hollow fibre devices containing up to 200 gm of human should be limited to conditions where the liver would recover
hepatocytes, usually derived from hepatoblastoma cell line, like in hepatitis A, acetaminophen toxicity, etc. Of the available
on the dialysate side. 27 Patients generally tolerate the extracorporeal therapies, MARS and its modifications appear
procedure well with improvement in encephalopathy and can to be the most promising while peritoneal dialysis, HD, HF
be used in patients awaiting liver transplantation. and charcoal perfusion have been mostly given up due to
11. Xenogenic perfusion their limited efficacy. With the rapid progress made in this
Attempts to prolong life in fulminant hepatic failure using field, it appears that ALS systems may play an important role
extracorporeal whole organ perfusion with baboon or pig in the future management of liver failure. However, since there
liver have not shown significant advantage over conventional is limited experience with the use of these modalities, further
treatment.28 studies are needed with regard to their safety as well as
whether they contribute to the long-term survival of patients
12. Extracorporeal hepatic perfusion with liver failure.
Performing extracorporeal perfusion using human liver not
suitable for transplantation may show a transient REFERENCES
improvement.29 This may hence have a role just prior to liver 1. Poulos AM, Howard L, Eisele G, Rodgers JB Peritoneal
transplantation.30 dialysis therapy for patients with liver and renal failure with
ascites. Am J Gastroenterol 1993;88:109-12.
INDICATIONS FOR CONSIDERING ARTIFICIAL 2. Davenport A. Extracorporeal support for patients with
LIVER SUPPORT SYSTEMS hepatic failure. Hemodial Int 2003;7:256-63.
3. Davenport A. Hemofiltration in patients with fulminant
The main indication for considering artificial liver support hepatic failure. Lancet 1991;338:1604.
(ALS) systems in liver failure is to give additional time for
4. Opolon P. High permeability membrane hemodialysis and
liver regeneration or spontaneous recovery to occur. The
hemofiltration in acute hepatic coma: experimental and clinical
usual situations include acute fulminant hepatitis due to aspects. Int J Artif Organs 1979;3:354-60.
hepatitis A and B, toxicity due to acetaminophen and
5. Matsubara S, Okabe K, Ouchi K, et al. Continuous removal of
occasionally in severe acute alcoholic hepatitis, conditions middle molecules by hemofiltration in patients with acute
producing an acute exacerbation of a chronic liver disease liver failure. Crit Care Med 1990;18:1331-38.
like a gastrointestinal bleed, spontaneous bacterial peritonitis
6. Davenport A, Will EJ, Losowsky MS, Swindells S. Continuous
and sepsis may also benefit as a return to previous arteriovenous hemofiltration in patients with hepatic
compensated state can occur. In hepatorenal syndrome type encephalopathy and renal failure. Br Med J 1987;295:1028.
1, sudden deterioration of liver function with acute renal 7. Davenport A, Will EJ, Davison AM. Effective renal
failure following precipitating events may warrant use of ALS replacement therapy in patients with combined acute renal
systems as well as dialytic support.31 In chronic liver disease and fulminant hepatic failure. Kidney Int 1993;43:S245-S251.
and in hepatorenal syndrome type 2 where a slow 8. Bellomo R, Baldwin I, Cole L, Ronco C. Preliminary
deterioration of liver function occurs, ALS systems are experience with high volume hemofiltration in human septic
seldom justified unless it is to buy time till a liver transplant is shock. Kidney Int 1988;53:S182-5.
feasible. In patients awaiting liver transplantation, ALS may 9. Mc Lean AG, Davenport A, Cox D, Sweeny P. Effects of
be indicated to tide over complications like hepatic lactate buffered and lactate free dialysate in CAVHD patients
encephalopathy where accumulation of toxins could produce with and without liver dysfunction. Kidney Int 2000;58:1765-
permanent brain damage due to cerebral edema. It may also 72.
be employed in irreversible liver damage when there is a delay 10. O Grady JG, Gimson AES, O’Brien CJ, et al. Controlled trials
in procuring a suitable organ,32 though this is more applicable of charcoal hemoperfusion and prognostic factors in fulminant
to countries where cadaver transplantation is well established. hepatic failure. Gastroenterology 1988;94:1186-92.
Following liver transplantation, ALS may be indicated in 11. Li L, Yang Q, Huang J et al. Treatment of hepatic failure with
primary non-function or delayed function of the graft.33 artificial liver support. Chin Med J 2001;114:941-5.
Intractable pruritus may also be reversed by ALS.31 12. Tetta C, Carvaillon JM, Camussi G, et al. Continuous plasma

© JAPI • VOL. 52 • SEPTEMBER 2004 [Link] 721

 filtration coupled with sorbents. Kidney Int 1998;66:S186-9. 23. Homman M, Kasakow LB, Geohegan J, et al. Application of
13. Ash SR, Blake DE, Carr, et al. Clinical effects of a sorbent MARS artificial liver support as bridging therapy before split
suspension dialysis system in treatment of hepatic coma (the renal transplantation in a 15 month old child. Ped Tranplant
Bio Logic-DT). Int J Artif Organs 1992;15:151-61. 2002;6:340-3.
14. Ash SR. Powdered sorbent liver dialysis and pheresis in 24. Hassanein T, Oliver D, Strange J, Steiner. Albumin dialysis in
treatment of hepatic failure. Ther Apher 2001;5:404-16. cirrhosis with superimposed acute liver injury: possible
impact of albumin dialysis on hospitalization costs. Liver Int
15. Strange J, Mitzner SR, Risler T, Erley CM, et al. Molecular
2003;Suppl 3:61-5.
adsorbent recycling system (MARS): Clinical results of a new
membrane based blood purification system for bioartificial 25. Rozga J, Podesta L, Lepage E, et al. A Bioartificial liver to treat
liver support. Artif Organs 1999;23:319-30. severe acute liver failure. Ann Surg 1994;218:538-46.
16. McIntyre CW, Fluck RJ, Freeman JG, Lambie SH. 26. Morsiani E, Pazzi P, Puviani AC, et al. Early experience with a
Characterisation of treatment dose delivered by albumin porcine hepatocyte based bioartificial liver in acute hepatic
dialysis in the treatment of acute renal failure associated failure patients. Int J Artif Organs 2002;25:192-200.
with severe hepatic dysfunction. Clin Nephrol 2002;58:376- 27. Sussman NL, Gislason G, Conlin CA, Kelly JJH. The hepatic
83. extracorporeal liver assist device: initial clinical experience.
17. Jalan R, Williams R. Acute in Chronic liver failure: Artif Organs 1994;18:390-96.
pathophysiological basis of therapeutic options. Blood Purif 28. Pascher A, Sauer IM, Hammer C, Gerlach JC, Neuhaus P.
2002;20:252-61. Extracorporeal liver perfusion as hepatic assist in acute liver
18. Mitzner SR, Strange J Klammt S, Risler T, et al. Improvement failure: a review of world experience. Xenotransplantation
of hepatorenal syndrome with extracorporeal albumin 2002;9:309-24.
dialysis MARS: results of a prospective, randomised, 29. McChesney LP, Fagan EA, Rowell DL, et al. Extracorporeal
controlled clinical trial. Liver Transpl 2000; 6:277-86. liver perfusion. Lancet 1999;353:120-21.
19. Jalan R, Sen S, Steiner C, et al. Extracorporeal liver support 30. Sechser A, Osorio J, Freise C, Osorio RW. Artificial liver
with molecular adsorbents recirculating system in patient support devices for fulminant liver failure. Clin Liver Dis 2001;
with severe acute alcoholic hepatitis. J Hepatol 2003;38:24- 5: 415-30.
31. 31. Strange J, Hassanein TI, Mehta R, et al. The molecular
20. Kapoor D, Williams R, Jalan R. MARS: a new treatment for absorbents recycling system as a liver support system. Artif
hepatorenal failure. Gastroenterology 2000;119:1799-800. Organs 2002;26:103-10.
21. Seige M, Kreymann B, Jeschke B, et al. Long term treatment 32. Kramen L, Bauer E. Extracorporeal treatment in fulminant
of patients with acute exacerbation of chronic liver failure by hepatic failure: pathophysiologic considerations. Int J Artif
albumin dialysis. Transplant Proc 1999;31:1371-5. Organs 2002;25:929-34.
22. Schmidt LE, Svendsen LB, Sorensen VR, et al. Cerebral blood 33. Mitzner SR, Strange J, Klammt S, et al, Improvement of
flow velocity increases during a single treatment with MARS hepatorenal syndrome with extracorporeal albumin dialysis.
in patients with acute on chronic liver failure. Liver transplant Liver Transpl 2000;6:277-86.
2001;7:709-12. 34. Manz T, Ochs A, Bisse E, Strey C, Grotz W. Liver support -
a task for nephrologists? Blood Purif 2003;21:232-6.

Announcement
The office bearers of Association of Physicians of India Gwalior Chapter
Founder Chairman : A Shanker
Chairman : NN Laha
Vice Chairman : PC Mathur
: KP Bhatnagar
Secretary : S Gajendragadkar
Joint Secretary : V Singh
Treasurer : P Punekar
Executive Members : HS Bansal
: JP Sharma
: VB Verma
: R Agrawal
: Sushma Trikha
: Archana Kansal

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