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More recently, several studies have shown a significant improvement of HE in patients treated with MARS. In the studies by Heemann et al.<ref>{{cite journal|last=Heemann|first=U|coauthors=Treichel, U; Loock, J; Philipp, T; Gerken, G; Malago, M; Klammt, S; Loehr, M; Liebe, S; Mitzner, S; Schmidt, R; Stange, J|title=Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.|journal=Hepatology (Baltimore, Md.)|date=2002 Oct|volume=36|issue=4 Pt 1|pages=949-58|pmid=12297843}}</ref> and Sen et al.<ref>{{cite journal|last=Sen|first=S|coauthors=Davies, NA; Mookerjee, RP; Cheshire, LM; Hodges, SJ; Williams, R; Jalan, R|title=Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.|journal=Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society|date=2004 Sep|volume=10|issue=9|pages=1109-19|pmid=15350001}}</ref> an improvement in HE was considered when encephalopathy grade was reduced by one or more grades vs. basal values; for Hassenein et al., in their randomized controlled trial, improvement was considered when a decrease of two grades was observed.<ref>{{cite journal|last=Hassanein|first=TI|coauthors=Tofteng, F; Brown RS, Jr; McGuire, B; Lynch, P; Mehta, R; Larsen, FS; Gornbein, J; Stange, J; Blei, AT|title=Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.|journal=Hepatology (Baltimore, Md.)|date=2007 Dec|volume=46|issue=6|pages=1853-62|pmid=17975845}}</ref> In the latter, 70 patients with acute on chronic liver failure and encephalopathy grade III and IV were included. Likewise, Kramer et al.<ref>{{cite journal|last=Kramer|first=L|coauthors=Gendo, A; Madl, C; Mullen, KD; Kaminski-Russ, K; Sunder-Plassmann, G; Schaffer, A; Bauer, E; Roth, E; Ferenci, P|title=A controlled study of sorbent suspension dialysis in chronic liver disease and hepatic encephalopathy.|journal=The International journal of artificial organs|date=2001 Jul|volume=24|issue=7|pages=434-42|pmid=11510914}}</ref> estimated an HE improvement when an improvement in peak N70 latency in electroencephalograms was observed.
More recently, several studies have shown a significant improvement of HE in patients treated with MARS. In the studies by Heemann et al.<ref>{{cite journal|last=Heemann|first=U|coauthors=Treichel, U; Loock, J; Philipp, T; Gerken, G; Malago, M; Klammt, S; Loehr, M; Liebe, S; Mitzner, S; Schmidt, R; Stange, J|title=Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.|journal=Hepatology (Baltimore, Md.)|date=2002 Oct|volume=36|issue=4 Pt 1|pages=949-58|pmid=12297843}}</ref> and Sen et al.<ref>{{cite journal|last=Sen|first=S|coauthors=Davies, NA; Mookerjee, RP; Cheshire, LM; Hodges, SJ; Williams, R; Jalan, R|title=Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.|journal=Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society|date=2004 Sep|volume=10|issue=9|pages=1109-19|pmid=15350001}}</ref> an improvement in HE was considered when encephalopathy grade was reduced by one or more grades vs. basal values; for Hassenein et al., in their randomized controlled trial, improvement was considered when a decrease of two grades was observed.<ref>{{cite journal|last=Hassanein|first=TI|coauthors=Tofteng, F; Brown RS, Jr; McGuire, B; Lynch, P; Mehta, R; Larsen, FS; Gornbein, J; Stange, J; Blei, AT|title=Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.|journal=Hepatology (Baltimore, Md.)|date=2007 Dec|volume=46|issue=6|pages=1853-62|pmid=17975845}}</ref> In the latter, 70 patients with acute on chronic liver failure and encephalopathy grade III and IV were included. Likewise, Kramer et al.<ref>{{cite journal|last=Kramer|first=L|coauthors=Gendo, A; Madl, C; Mullen, KD; Kaminski-Russ, K; Sunder-Plassmann, G; Schaffer, A; Bauer, E; Roth, E; Ferenci, P|title=A controlled study of sorbent suspension dialysis in chronic liver disease and hepatic encephalopathy.|journal=The International journal of artificial organs|date=2001 Jul|volume=24|issue=7|pages=434-42|pmid=11510914}}</ref> estimated an HE improvement when an improvement in peak N70 latency in electroencephalograms was observed.
Sen et al..44 observed a significant reduction in Child-Pugh Score (p<0,01) at 7 days following a MARS® treatment, without any significant change in the controls. Nevertheles, when they looked at the Model for End-Stage Liver Disease Score (MELD), a significant reduction in both groups, MARS® and controls, was recorded (p<0,01 y p<0,05, respectively).
Sen et al..44 observed a significant reduction in Child-Pugh Score (p<0,01) at 7 days following a MARS® treatment, without any significant change in the controls. Nevertheles, when they looked at the Model for End-Stage Liver Disease Score (MELD), a significant reduction in both groups, MARS® and controls, was recorded (p<0,01 y p<0,05, respectively).
Likewise, in several case series, an improvement in HE grade with MARS® therapy is also reported.<ref>{{cite journal|last=Yuan|first=JZ|coauthors=Ye, QF; Zhao, LL; Ming, YZ; Sun, H; Zhu, SH; Huang, ZF; Wang, MM|title=Preoperative risk factor analysis in orthotopic liver transplantation with pretransplant artificial liver support therapy.|journal=World journal of gastroenterology : WJG|date=2006 Aug 21|volume=12|issue=31|pages=5055-9|pmid=16937506}}</ref> <ref>{{cite journal|last=Gaspari|first=R|coauthors=Cavaliere, F; Sollazzi, L; Perilli, V; Melchionda, I; Agnes, S; Gasbarrini, A; Avolio, AW|title=Molecular adsorbent recirculating system (Mars) in patients with primary nonfunction and other causes of graft dysfunction after liver transplantation in the era of extended criteria donor organs.|journal=Transplantation proceedings|date=2009 Jan-Feb|volume=41|issue=1|pages=253-8|pmid=19249528}}</ref> <ref>{{cite journal|last=Stefoni|first=S|coauthors=Colì, L; Bolondi, L; Donati, G; Ruggeri, G; Feliciangeli, G; Piscaglia, F; Silvagni, E; Sirri, M; Donati, G; Baraldi, O; Soverini, ML; Cianciolo, G; Boni, P; Patrono, D; Ramazzotti, E; Motta, R; Roda, A; Simoni, P; Magliulo, M; Borgnino, LC; Ricci, D; Mezzopane, D; Cappuccilli, ML|title=Molecular adsorbent recirculating system (MARS) application in liver failure: clinical and hemodepurative results in 22 patients.|journal=The International journal of artificial organs|date=2006 Feb|volume=29|issue=2|pages=207-18|pmid=16552668}}</ref> <ref>{{cite journal|last=Di Campli|first=C|coauthors=Santoro, MC; Gaspari, R; Merra, G; Zileri Dal Verme, L; Zocco, MA; Piscaglia, AC; Di Gioacchino, G; Novi, M; Santoliquido, A; Flore, R; Tondi, P; Proietti, R; Gasbarrini, G; Pola, P; Gasbarrini, A|title=Catholic university experience with molecular adsorbent recycling system in patients with severe liver failure.|journal=Transplantation proceedings|date=2005 Jul-Aug|volume=37|issue=6|pages=2547-50|pmid=16182739}}</ref> <ref>{{cite journal|last=Hetz|first=H|coauthors=Faybik, P; Berlakovich, G; Baker, A; Bacher, A; Burghuber, C; Sandner, SE; Steltzer, H; Krenn, CG|title=Molecular adsorbent recirculating system in patients with early allograft dysfunction after liver transplantation: a pilot study.|journal=Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society|date=2006 Sep|volume=12|issue=9|pages=1357-64|pmid=16741899}}</ref> <ref>{{cite journal|last=Camus|first=C|coauthors=Lavoué, S; Gacouin, A; Compagnon, P; Boudjéma, K; Jacquelinet, C; Thomas, R; Le Tulzo, Y|title=Liver transplantation avoided in patients with fulminant hepatic failure who received albumin dialysis with the molecular adsorbent recirculating system while on the waiting list: impact of the duration of therapy.|journal=Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy|date=2009 Dec|volume=13|issue=6|pages=549-55|pmid=19954480}}</ref> <ref>{{cite journal|last=Steiner|first=C|coauthors=Mitzner, S|title=Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry.|journal=Liver|date=2002|volume=22 Suppl 2|pages=20-5|pmid=12220298}}</ref> <ref>{{cite journal|last=Camus|first=C|coauthors=Lavoué, S; Gacouin, A; Le Tulzo, Y; Lorho, R; Boudjéma, K; Jacquelinet, C; Thomas, R|title=Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation.|journal=Intensive care medicine|date=2006 Nov|volume=32|issue=11|pages=1817-25|pmid=16941171}}</ref> <ref>{{cite journal|last=Parés|first=A|coauthors=Deulofeu, R; Cisneros, L; Escorsell, A; Salmerón, JM; Caballería, J; Mas, A|title=Albumin dialysis improves hepatic encephalopathy and decreases circulating phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure.|journal=Critical care (London, England)|date=2009|volume=13|issue=1|pages=R8|pmid=19175915}}</ref>
Likewise, in several case series, an improvement in HE grade with MARS® therapy is also reported. , , , , , , , ,


==References==
==References==

Revision as of 15:17, 8 July 2013

Introduction

Hepatic insufficiency implies the inability of the liver to carry out its metabolic, excretory and detoxifying functions owing to a decrease in the number of functional hepatocytes or because their normal activity is altered. Hepatic insufficiency can be acute or chronic. Acute liver failure (ALF) is produced without a previous liver disease whereas the chronic liver failure is the consequence of a liver disease evolution over a long period of time, independently of its etiology and degree. The incidence of acute liver failure is estimated to be of 1-6 cases per million of person.[1] ALF can be subclassified into hyperacute, acute and subacute based on when hepatic encephalopathy occurs following the onset of jaundice (O`Grady et al., 1993),[2] and this classification can sometimes help to identify the etiology, potential complications and patient prognosis (Table 1).


Classification for hepatic insufficiency
Classification for hepatic insufficiency
Table 1: Classification for hepatic insufficiency



In hyperacute and acute liver failure the clinical picture develops rapidly with progressive encephalopathy and multiorgan dysfunction such as hyperdynamic circulation, coagulopathy, acute renal and respiratory insufficiency, severe metabolic alterations and cerebral edema that can lead to brain death.[3][4] In these cases the mortality without liver transplantation (LTx) ranges between 40-80%.[5][6] LTx is the only effective treatment for these patients although it requires a precise indication and timing to achieve good results. Nevertheless, due to the scarcity of organs to carry out liver transplantations, it is estimated that one third of patients with ALF die while waiting to be transplanted.[7] On the other hand, a patient with a chronic hepatic disease can suffer an acute decompensation of liver function following a precipitating event such as variceal bleeding, sepsis and excessive alcohol intake among others that can lead to a condition referred to as acute-on-chronic liver failure (ACLF). Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event. LTx is the only treatment that has shown an improvement in the prognosis and survival with most severe cases of ALF. Nevertheless, cost and donor scarcity have prompted researchers to look for new supportive treatments that can act as “bridge” to the transplant procedure. By stabilizing the patient’s clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF.[8] Basically, three different types of supportive therapies have been developed: bio-artificial, artificial and hybrid liver support systems (Table 2).


Bio-artificial Artificial Hybrids
ELAD[9]

Extracorporeal liver assist device

MARS[10]

Molecular adsorbent recirculating system

Hepat-Assist[11]
BLSS[12]

Bioartificial Liver Support System

Prometheus FPSA[13]

Fractionated plasma separation and adsorption system

TECLA-HALSS[14]

TECA-Hybrid Artificial Liver Support System

RFB[15]

Radial Flow Bioreactor

SPAD[16]

Single-pass albumin dialysis

MELS[17]

Modular Extracorporeal Liver Support

AMC-BAL[18]

Bioartificial Liver

SEPET[19]

Selective plasma filtration therapy

-
Table 2: Liver Support Systems



Bio-artificial liver support systems are experimental extracorporeal devices that use living cell lines to provide detoxification and synthesis support to the failing liver. Bio-artificial liver (BAL) Hepatassist 2000® uses porcine hepatocytes11 whereas ELAD® system employs hepatocytes derived from human hepatoblastoma C3A cell lines.9,[20][21] Both techniques can produce, in fulminat hepatic failure (FHF), an improvement of hepatic encephalopathy grade and biochemical parameters. Nevertheless, they are therapies with high complexity that require a complex logistic approach for implementation; a very high cost and possible inducement of important side effects such as immunological issues (porcine endogenous retrovirus transmission), infectious complications and tumor transmigration have been documented. Other biological hepatic systems are Bioartificial Liver Support (BLSS)12 and Radial Flow Bioreactor (RFB).15 Detoxification capacity of these systems is poor and therefore they must be used combined with other systems to mitigate this deficiency. Today its use is limited to centers with high experience in their application.[22]

Artificial liver support systems are aimed to temporally replace native liver detoxification functions and they use albumin as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them. Between the different albumin dialysis modalities, single pass albumin dialysis (SPAD) has shown some positive results at a very high cost;[23] it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure.[24] Nevertheless, the most widely used systems today are based on hemodialysis and adsorption. These systems use conventional dialysis methods with an albumin containing dialysate that is latter regenerate by means of adsorption columns, filled with activated charcoal and ion exchange resins. At present, there are two artificial extracorporeal liver support systems: the Molecular Adsorbents Recirculating System (MARS)10 from Gambro and Fractionated Plasma Separation and Adsorption (FPSA), commercialised as Prometheus (PROM) from Fresenius Medical Care.13 Of the two therapies, MARS is the most frequently studied, and clinically used system to date.

The MARS® System

MARS was developed by a group of researchers at the University of Rostock (Germany), in 199310 and later commercialized for its clinical use in 1999.[25] The system is able to replace the detoxification function of the liver while minimizing the inconvenience and drawbacks of previously used devices.[26][27][28]

In vivo preliminary investigations indicated the ability of the system to effectively remove bilirubin, biliary salts, free fatty acids and tryptophan while important physiological proteins such as albumin, alpha-1-glicoproteine, alpha 1 antitrypsin, alpha-2-macroglobulin, transferrin, globulin tyrosine, and hormonal systems are unaffected.[29] Also, MARS therapy in conjunction with CRRT/HDF can help clear cytokines acting as inflammatory and immunological mediators in hepatocellular damage, and therefore can create the right environment to favour hepatocellular regeneration and recovery of native liver function.

MARS® System Components

Combined MARS and PrismaFlex monitors

MARS is an extracorporeal hemodialysis system composed of three different circuits: blood, albumin and low flux dialysis. The Blood circuit uses a double lumen catheter and a conventional hemodialysis device to pump the patient’s blood into the MARS®FLUX, a biocompatible polysulfone high-flux dialyser. With a membrane surface area of 2.1 m2, 100 nm of thickness and a cut-off of 50 KDa, the MARSFLUX is essential to retaining the albumin in the dialysate. Blood is dialysed against a human serum albumin (HSA) dialysate solution that allows blood detoxification of both, water soluble and protein bound toxins, by means of the presence of albumin in the dialysate (albumin dialysis). The albumin dialysate is then regenerated in a close loop in the MARS circuit by passing through the fibres of the low-flux diaFLUX filter, to clear water soluble toxins and provide electrolyte/acid-base balance, by a standard dialysis fluid. Next, the albumin dialysate passes through two different adsorption columns; protein-bound substances are removed by the diaMARS AC250, containing activated charcoal and anionic substances are removed by the diaMARS IE250, filled with cholestyramine, an anion exchange resin. The albumin solution is then, ready to initiate another detoxifying cycle of the patients’ blood that can be sustained until both adsorption columns are saturated, eliminating the need to continuously infuse albumin into the system during treatment (Fig. 1).


Albumin dialysis circuit
Albumin dialysis circuit
Figure 1: The MARS system

Results published in the literature with the MARS® system

A systematic review of the literature from 1999 to June 2011 was performed in the following databases:

  1. Specialized in systematic reviews: Cochrane Library Plus and NHS Centre database for Reviews and Dissemination (HTA, DARE and NHSEED).
  2. General databases: Medline, Pubmed and Embase.
  3. On-going clinical trials and research project databases: Clinical Trials Registry (National Institutes of Health, EE.UU.) and Health Services Research Projects in Progress.
  4. General web searching engines: Scholar Google.

Effects of MARS® treatment on Hepatic Encephalopathy (HE)

Hepatic encephalopathy (HE) represents one of the more serious extrahepatic complications associated with liver dysfunction.[30][31] Neuro-psychiatric manifestations of HE affect consciousness and behaviour.

Evidence suggests that HE develops as some neurotoxins and neuro active substances, produced after hepatocellular breakdown, accumulates in the brain as a consequence of a portosystemic shunt and the limited detoxification capability of the liver. Substances involved are ammonia, manganese, aromatic aminoacids, mercaptans, phenols, medium chain fatty acids, bilirubin, endogenous benzodiazepines, etc.
The relationship between ammonia neurotoxicity and HE was first described in animal studies by Pavlov et al.[32]
Subsequently, several studies in either animals or humans have confirmed that, a ratio in ammonia concentration higher than 2 mM between the brain and blood stream, causes HE, and even a comatose state when the value is greater than 5 mM. Some investigators have also reported a decrease in serum ammonia following a MARS treatment (Table 3).


References Nº patients Age (years)

[aver. ±SD]

Treatment

Hours/patient

Ammonia Pre-MARS®

(μg/dl)

Ammonia Post-MARS®

(μg/dl)

p
Awad et al.[33]/ 1999 9 38±5 73.2 130 64 <0.05
Novelli et al.[34]/ 2002 10 42±12 51.2 247 126 <0.003
Schmidt et al.[35]/2001 8 43±5 10.0 150 121 <0.05
Sorkyne et al.[36]/ 2001 8 47±16 28.1 280 65 <0.005
Table 3. Clinical studies showing some improvement in the treatment of HE following a MARS® treatment



Manganese and copper serum levels are increased in patients with either acute or acute on chronic liver failure. Nevertheless, only in those patients with chronic hepatic dysfunction, a bilateral magnetic resonance alteration on Globos Pallidus is observed,[37] probably because this type of patients selectively shows higher cerebral membrane permeability. Imbalance between aromatic and branched chain aminoacids (Fischer index), traditionally involved in HE genesis,[38][39][40] can be normalized following a MARS treatment. The effects are noticeable even after 3 hours of treatment and this reduction in the Fisher index is accompanied with an improvement in the HE.[41]

Novelli G et al.[42] published their three years experience on MARS analyzing the impact of the treatment in the cerebral level for 63 patients reporting an improvement in Glasgow Coma Score (GCS) for all observed in all patients. In the last 22 patients, cerebral perfusion pressure was monitored by Doppler (mean flow velocity in middle cerebral artery), establishing a clear relationship between a clinical improvement (especially neurological) and an improvement in arterial cerebral perfusion. This study confirms other results showing similar increments in cerebral perfusion in patients treated with MARS.[35]

More recently, several studies have shown a significant improvement of HE in patients treated with MARS. In the studies by Heemann et al.[43] and Sen et al.[44] an improvement in HE was considered when encephalopathy grade was reduced by one or more grades vs. basal values; for Hassenein et al., in their randomized controlled trial, improvement was considered when a decrease of two grades was observed.[45] In the latter, 70 patients with acute on chronic liver failure and encephalopathy grade III and IV were included. Likewise, Kramer et al.[46] estimated an HE improvement when an improvement in peak N70 latency in electroencephalograms was observed. Sen et al..44 observed a significant reduction in Child-Pugh Score (p<0,01) at 7 days following a MARS® treatment, without any significant change in the controls. Nevertheles, when they looked at the Model for End-Stage Liver Disease Score (MELD), a significant reduction in both groups, MARS® and controls, was recorded (p<0,01 y p<0,05, respectively). Likewise, in several case series, an improvement in HE grade with MARS® therapy is also reported.[47] [48] [49] [50] [51] [52] [53] [54] [55]

References

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  48. ^ Gaspari, R (2009 Jan-Feb). "Molecular adsorbent recirculating system (Mars) in patients with primary nonfunction and other causes of graft dysfunction after liver transplantation in the era of extended criteria donor organs". Transplantation proceedings. 41 (1): 253–8. PMID 19249528. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  52. ^ Camus, C (2009 Dec). "Liver transplantation avoided in patients with fulminant hepatic failure who received albumin dialysis with the molecular adsorbent recirculating system while on the waiting list: impact of the duration of therapy". Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 13 (6): 549–55. PMID 19954480. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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