Decompensation Of Chronic Liver Disease Research Articles

Albumin Dialysis Has No Clear Effect on Cytokine Levels in Patients With Life-Threatening Liver Insufficiency

Cytokines play a important role in life-threatening liver insufficiency. They are released within the liver in response to hepatic injury and inflammation. To study cytokine clearance during albumin dialysis treatment (Molecular Adsorbent Recirculating System [MARS]), we monitored proinflammatory (tumor necrosis factor alpha [TNF-α] and interleukin-8 [IL-8]) and anti-inflammatory (IL-10 and IL-6) cytokines and the lymphocyte activation marker IL-2sRα in 81 consecutive ICU patients displaying serious hepatic decompensation. Cytokine levels were measured before treatment and after the last MARS treatment in 49 acute liver failure (ALF) and 32 acute decompensation of chronic liver disease (AcOChr) patients who were mainly considered for liver transplantation. No significant change in cytokines was observed before versus after the last MARS treatment in the AcOChr group, and only IL-10 decreased significantly in the ALF group. Baseline levels of IL-8 and IL-6 were significantly lower and IL-10 was higher in the ALF group compared with those in the AcOChr group. TNF-α and IL-2sRα levels did not differ between the groups. After treatment, IL-8 was also significantly lower in ALF patients compared with the levels in AcOChr patients. In this study, MARS therapy did not show a clearly identifiable efficacy at removing circulating cytokines. However, the results revealed that ALF and AcOChr patients displayed different profiles of circulating cytokines.

Personal view: current role of artificial liver support devices

Enthusiasm for liver support devices, particularly cell-based biological systems and albumin dialysis, increased over the last decade and there has been considerable clinical activity both within and without the construct of clinical trials. Most data have been generated on patients with acute liver failure or in patients with decompensation of chronic liver disease, often referred to as acute-on-chronic liver failure. In acute liver failure liver, liver support devices are more realistically being used as a 'bridge' to liver transplantation rather than to transplant-free survival. In acute-on-chronic liver failure the clinical objective of attaining clinical stability with treatment appears more achievable. The so-called bioartificial liver device, based on porcine hepatocytes, is the most extensively evaluated biological device. A sizeable clinical trial failed to demonstrate efficacy, but secondary analyses suggest it would be unwise to assume futility had been established with this device. Molecular adsorbent recirculating system leads the way in the non-biological category in terms of the number of patients treated, but data from large clinical trials are not yet available. One of the strongest conclusions of this review is that the amount of high-quality data available on liver support devices dramatically understates the effort and money that have been expended in their assessment. It is very clear that randomized controlled trials are mandatory to establish clinical efficacy, but it is less clear how the ideal trial should be constructed.

Value of albumin dialysis therapy in severe liver insufficiency

A blood purification system, molecular adsorbents re-circulating system (MARS), is based on the removal of both protein-bound and water-soluble substances and toxins in the liver. We treated a total of 88 patients within 2 years. Of these patients, 45 had acute liver failure (ALF), 31 had acute decompensation of chronic liver disease, eight had graft failure and four had miscellaneous conditions. Of the patients with ALF, 80% survived; in 23 patients their own liver recovered and 13 patients underwent successful transplantation. Only 23% of patients with acute-on-chronic liver failure survived. Most of them were not considered for transplantation due to their having liver failure from alcoholism and from not abstaining from drinking. MARS is a promising therapy for ALF, allowing the patient's own liver to recover or allowing enough time to find a liver graft. Best results were achieved in patients who had been intoxicated with a lethal dose of toxin. On the other hand, we did not observe much benefit in patients with severe acute-on-chronic liver failure (AcoChr) who did not undergo liver transplantation.

Complications following transjugular intrahepatic portosystemic shunt: a retrospective analysis

Transjugular intrahepatic portosystemic shunt (TIPS) has been the therapeutic option for severe decompensation of chronic liver disease and as a bridge to liver transplantation. The aim of this study was to analyze the complications of this procedure. The records of 47 patients (39 men) of mean age 48 years underwent TIPS procedures from 1998 to 2003 were reviewed. Forty-one patients received 45 successful TIPS; it failed in six patients. Improvement was observed in 20 of 28 patients with upper gastrointestinal bleeding (71%); 9 of 11 with ascites (82%); and 5 of 8 with impaired renal function (62%). The Child-Pugh scores improved in 6 of the 47 patients (13%). Transplantation was performed in 11 patients (23%). The complications were: encephalopathy (49%); infection (19%); renal failure (17%); TIPS migration to the portal vein (4%) and to the right atrium (4%). Mortality was 32% (15/47) over 3 months. Eight patients developed active bleeding during TIPS installation requiring mechanical ventilation and intensive care, and died within the first week. Other causes of death were sepsis ( n = 2), liver failure ( n = 1), accidental puncture of the Glisson's capsule leading to intra-abdominal bleeding ( n = 1) and refractory upper gastrointestinal bleeding ( n = 3). The latter four patients had TIPS placement failure. In conclusion, TIPS produced clinical improvement among 51% of patients with complications in 49%. The main complications were encephalopathy (49%), infection (19%), and renal failure (17%). The 3-month mortality rate after TIPS placement was 32%.

Albumin dialysis MARS 2003: what evidence, how to proceed?

It was 10 years ago that the concept of albumin dialysis was introduced into the field of liver support devices by a research group at the University of Rostock (1). The Molecular Adsorbent Recirculating System (MARS as it became known) is based on a specially impregnated albumin membrane with pore size of 50 KD, and a recycling toxin removal system as well as filtration dialysis component. Since 1999, the device has been commercially available throughout Europe and in a number of Asian countries. More than 3000 patients have been treated. The reported indications range from fulminant liver failure and primary graft dysfunction post-liver transplantation to acute on-chronic liver failure and intractable pruritus in cholestatic syndromes (2). The substantial amount of data that have been obtained on both pre-clinical and clinical aspects of the technique show that albumin dialysis can have a positive effect on many of the manifestations of liver failure including haemodynamic changes and multiorgan dysfunction. The small number of controlled trials performed in patients with acute decompensation of chronic liver disease or acute liver failure also point to an improvement in survival 3-6). Moreover, the pathophysiology investigations of albumin dialysis have indicated a working hypothesis in terms of toxin/cytokine/reactive oxygen species interaction (7). However, final proof of the efficacy of this device in liver failure must await the results of the large clinical trials which have been set up. Two multicentre trials are currently in place, one in Europe and one in America but the results are not expected before 2004/2005. How should we proceed with the use of the method until then? Our view is that until the evidence of multicentre trials becomes available it would be helpful to formulate a consensus statement regarding single indications to give guidance to those who want to continue to use the liver support device on the basis of current evidence. The statements should be generated by independent expert groups and after thorough review of available data and adequate discussions. This shall give proper indications, starting and stopping rules and thus help to avoid medical and economical misuse. Those recommendations shall be updated regularly in the light of relevant new evidence such as from larger clinical trials or alike. The upcoming 5th International Symposium on Albumin Dialysis in Liver Disease (ISAD) 2003 (http://www.albumin-dialysis.org), and other meetings dedicated to liver support might give good opportunities to bring forward such a matter. This Supplement of Liver International contains the proceedings of the 4th meeting organized by workers of the University of Rostock in September 2002. It represents another piece of information on the way towards better understanding of the pathomechanisms of liver disease and how albumin dialysis can interfere in a biochemical and a clinical sense. Moreover, it addresses the important question of health economics with two papers discussing cost-benefit issues. We hope that you will find reading as interesting and inspiring as we did and that it will help to further stimulate research in the field of liver support and liver disease in general.

Treatment with the molecular adsorbent recirculating system in patients with acute liver failure

MOLECULAR adsorbent recirculating system (MARS) is a new treatment for liver failure based on the same principle as hemodialysis. However, the blood is dialyzed against an albumin-enriched dialyzate to facilitate the removal of albumin-bound toxins as well as bilirubin, aromatic amino acids and water-soluble substances. This method, which has been introduced clinically in recent years, is best used in patients with acute decompensation of chronic liver disease, but there are also some reports in patients with acute liver failure (ALF). We decided to use MARS in patients with ALF who also were considered to need a liver transplant.

Review article: the molecular adsorbents recirculating system (MARS) in liver failure.

In recent years different artificial liver support systems are being developed for use in patients with acute decompensation of chronic liver disease or acute liver failure. The molecular adsorbents recirculating system (MARS), a device in which patient's blood is dialysed across an albumin-impregnated membrane against a recirculated albumin-containing solution, seems to be effective in removing albumin-bound toxins, such as fatty acids, bile acids and bilirubin. Although the clinical experience with MARS is scarce, some pilot studies have reported its effectiveness at improving liver function and hepatic encephalopathy in patients with acute decompensation of chronic liver disease, and renal function in patients with hepatorenal syndrome type I. Data regarding MARS experience in acute liver failure and in primary graft dysfunction are encouraging but limited. Its real usefulness in these settings is, at present, under evaluation in randomized controlled clinical trials.

Extracorporeal blood detoxification by sorbents in treatment of hepatic encephalopathy.

Extracorporeal blood detoxification by sorbent therapy long has been applied in treatment of hepatic failure and encephalopathy, starting with hemoperfusion columns and more recently with the currently marketed Liver Dialysis Unit. Liver Dialysis employs hemodiabsorption (dialysis of blood against powdered sorbents including charcoal and cation exchanger) to remove selectively numerous small-molecular-weight toxins of hepatic failure. Liver Dialysis is used in treatment of acute hepatic encephalopathy (AHE) because of decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective and randomized studies of daily 6-hour Liver Dialysis have shown physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, and 35.7% control, P =.036), but had an insignificant improvement in outcome of patients with FHF as compared with the control group. Other extracorporeal sorbent devices are now in clinical testing phase. The molecular adsorbent regenerating system (MARS) device employs a polysulfone high-permeability dialyzer with albumin on the dialysate side to aid transfer of protein-bound toxins such as bilirubin and bile acids across the membranes. Sorbent columns of charcoal and an anion exchanger remove hepatic toxins from the albumin dialysate, and a second dialyzer removes water-soluble toxins, such as ammonium. Clinical results of daily MARS treatments of patients with hepatic failure are similar to that of Liver Dialysis, with neurologic and physical improvement occurs in most patients with AHE, and improved outcome for patients with A-on-C. The system extends the life of patients with hepatorenal syndrome. PF-Liver Dialysis is an experimental device combining hemodiabsorption with push-pull sorbent-based pheresis with powdered sorbent surrounding plasmafilters. PF-Liver Dialysis (Hemocleanse, Inc, W. Lafayette, IN) has been tested in a few patients with hepatic failure, grade 3-4 encephalopathy, and respiratory and kidney insufficiency. Treatments appeared to be safe and resulted in marked decreases in plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and interleukin-1beta (IL-1beta). The PF add-on module adds the capability to Liver Dialysis to remove bilirubin, bile acids, and other strongly protein-bound toxins from treated patients and may be of clinical benefit in management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.

Powdered sorbent liver dialysis and pheresis in treatment of hepatic failure.

The Liver Dialysis Unit (the Unit) is a liver-assist device that employs hemodiabsorption (dialysis of blood against powdered sorbents) to selectively remove numerous small molecular weight toxins of hepatic failure. The Unit has been cleared by the Food and Drug Administration and is indicated and marketed for treatment of acute hepatic encephalopathy (AHE) due to decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective, and randomized studies of liver dialysis were conducted at several centers, enrolling 56 patients with AHE, grades II-IV with or without renal and respiratory insufficiency or failure. Liver dialysis treatments were for 6 h daily, 1-5 days with similar observation periods for control patients. Physiologic status, neurologic status, and outcome (recovery of hepatic function, improvement for transplant, or death) were measured, and results were compared for treated patients versus controls for patients with A-on-C and patients with FHF. Liver dialysis resulted in physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, 35.7% control, p = 0.036), but had an insignificant improvement in the outcome of patients with FHF as compared with the control group. Among the overall 31 treated patients, 51.6% survived. Outcome was not negatively affected by the presence of kidney failure or respiratory failure. The plasmafilter unit (PF-Unit) combines hemodiabsorption with push-pull sorbent-based pheresis (the PF add-on module, with powdered sorbent surrounding plasmafilters). At blood flow rates of 200 ml/min, the system clears creatinine and aromatic amino acids at 120-160 ml/min, unconjugated bilirubin at 20-40 ml/min, and cytokines at 15-25 ml/min. The PF-Unit has been tested in a few patients with hepatic failure with Grades III and IV encephalopathy, and respiratory, and kidney insufficiency. Treatment appeared to be safe, and there were no significant hematologic changes. Physiologic changes included improved blood pressure, and encephalopathy, and stable urine output. Chemical changes included a decrease in the plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and IL-1beta. The PF add-on module adds the capability to the Unit to remove bilirubin and other strongly protein-bound toxins from treated patients and may be of clinical benefit in the management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.

Patient selection and listing policies for liver transplantation.

Liver transplantation expanded rapidly during the first three decades of its application but has undergone slower growth over the past few years because of a limited supply of donor organs. The growing discrepancy between available donor organs and patients listed for transplantation has fuelled recent debate regarding patient selection criteria and listing policies for liver transplantation. Allocation and distribution regulations of the United Network for Organ Sharing have also recently undergone changes to balance the principles of utility (i.e. the overall benefits of liver transplantation to society) and justice (i.e. the needs of the individual patient). The ideal geographical area over which organs can be distributed to balance utility and justice remains uncertain, although there are pressures to widen sharing of donor organs. The sickest patient who has been waiting the longest still receive the next available donor organ, but listing policies for the sickest patients, those with fulminant hepatic failure or acute decompensation of chronic liver disease, were recently revised. A uniform minimal listing criteria that proposes listing patients when their estimated survival with liver disease is less than that expected after liver transplantation was recently proposed and has generally been accepted. Finally, cost-outcome analyses and the reality of managed care with the transfer of financial risk from insurers to providers is beginning to have an influence on patient selection criteria.

OUTCOME ANALYSIS OF MARGINAL DONOR LIVER GRAFTS TRANSPLANTED IN CRITICALLY ILL RECIPIENTS-THE UNOS REGISTRY DATA 1991-1995

86 Background/Purpose: The increasing use of marginal (>50 years) donor livers raises concern whenever a marginal recipient is a potential benefactor. An analysis of the UNOS registry data (1991-1995) for liver transplantation was undertaken to assess the survival differences between stable (UNOS 3) and critically ill (UNOS 1) recipients of marginal(M) and nonmarginal (N) grafts. Methods: Logistic regression analysis of outcomes of 5377 primary adult to adult liver transplants was performed with UNOS 3 recipients (< 50 years) of nonmarginal donor liver grafts as the reference group. UNOS 1 recipients were further stratified into those with acute fulminant failure (AcUNOS 1) and those with acute decompensation of chronic liver disease (ChrUNOS 1). The odds of graft failure, patient mortality and retransplantation for groups demonstrating statistically significant differences in outcomes when compared with the reference group are expressed in Table 1.Results: The use of marginal liver grafts increased the odds of adverse patient and graft outcomes to the greatest degree in AcUNOS 1 recipients. Recipient age had a negligible effect on adverse outcomes in stable or critically ill recipients. The odds of retransplantation were greatest for ChrUNOS 1 recipients. Conclusions: Optimal outcomes with marginal liver grafts are more likely to occur in stable recipients. The preferential use of nonmarginal liver grafts may enhance the outcomes of critically ill recipients. The greater likelihood of retransplantation in patients with acute on chronic decompensation argues in favor of the current allocation policy favoring patients with fulminant failure or acute decompensation.

OUTCOME ANALYSIS OF MARGINAL DONOR LIVER GRAFTS TRANSPLANTED IN CRITICALLY ILL RECIPIENTS-THE UNOS REGISTRY DATA 1991-1995.

86 Background/Purpose: The increasing use of marginal (>50 years) donor livers raises concern whenever a marginal recipient is a potential benefactor. An analysis of the UNOS registry data (1991-1995) for liver transplantation was undertaken to assess the survival differences between stable (UNOS 3) and critically ill (UNOS 1) recipients of marginal (M) and nonmarginal (N) grafts. Methods: Logistic regression analysis of outcomes of 5377 primary adult to adult liver transplants was performed with UNOS 3 recipients (<50 years) of nonmarginal donor liver grafts as the reference group. UNOS 1 recipients were further stratified into those with acute fulminant failure (AcUNOS 1) and those with acute decompensation of chronic liver disease (ChrUNOS 1). The odds of graft failure, patient mortality and retransplantation for groups demonstrating statistically significant differences in outcomes when compared with the reference group are expressed in Table 1. Results: The use of marginal liver grafts increased the odds of adverse patient and graft outcomes to the greatest degree in AcUNOS 1 recipients. Recipient age had a negligible effect on adverse outcomes in stable or critically ill recipients. The odds of retransplantation were greatest for ChrUNOS 1 recipient.Conclusions: Optimal outcomes with marginal liver grafts are more likely to occur in stable recipients. The preferential use of nonmarginal liver grafts may enhance the outcomes of critically ill recipients. The greater likelihood of retransplantation in patients with acute on chronic decompensation argues in favor of the current allocation policy favoring patients with fulminant failure or acute decompensation.

Deleterious effects of low dose interferon therapy for hepatitis B virus (HBV) related decompensated chronic liver disease

Deleterious effects of low dose interferon therapy for hepatitis B virus (HBV) related decompensated chronic liver disease