In my presentation to the 4th International

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1 Review Article Correction of disturbed pathophysiology of hepatic failure by albumin dialysis Roger Williams London, UK Introduction In my presentation to the 4th International Symposium on Hepatic Failure and Artificial Liver Support in Chongqing on which this paper is based, I was specifically asked to address the question of whether albumin dialysis, as in the Molecular Adsorbents Recirculating System (MARS), did correct known abnormalities of the disturbed pathophysiology in liver failure. Before doing this, it is necessary to outline the three main categories of liver failure. The first--acute Liver Failure (ALF) is a rare condition and represents the most rapidly developing type being often known as fulminant hepatic failure, in which the patient without previous liver disease develops encephalopathy within 8 weeks of the onset of symptoms. The second--acute-on- Chronic Liver Failure (A-CLF) is the common variety where manifestations of liver failure are precipitated in a patient with known chronic liver disease by acute events such as sepsis, bleeding varices or an alcoholic binge. The third--chronic Liver Failure (CLF) is the clinical decompensation of end stage liver disease without precipitating event. Components of the clinical syndrome, namely jaundice, encephalopathy, systemic vasodilatation, hepatorenal syndrome and other manifestations of multiorgan failure are similar in all three types but with differences in severity and in their contribution to the overall clinical picture. The underlying pathophysiological disturbances are Author Affiliations: Institute of Hepatology, University College London Medical School, Chenies Mews, London, WC1E 6HX, UK (Williams R) Corresponding Author: Roger Williams, CBE, MD, Institute of Hepatology, University College London Medical School, Chenies Mews, London, WC1E 6HX, UK (Tel: /11; Fax: ; reghend@ucl.ac.uk) 2008, Hepatobiliary Pancreat Dis Int. All rights reserved. also likely to be similar, differing mainly in degree and to some extent affected by the nature of the liver disorder. Much has been learnt over the years as to the nature of the substances, toxic or otherwise that accumulate in the blood of patients with liver failure and which through a variety of direct and indirect processes lead to the clinical manifestations and final multiorgan failure. These substances may also aggravate injury to the liver and inhibit liver regeneration. They include not only small molecular weight toxins (ammonia, phenols, false neurotransmitters, free bile acids) but also mediators of inflammation (cytokines and chemokines), vasoactive substances, endotoxin and cell growth inhibitors such as TGF-β1. [1] Many of these substances are bound to proteins in the blood making their removal difficult. In terms of bioartificial and artificial liver support devices, albumin dialysis as exemplified by the MARS device is so far proving the most promising technique. Initially in vitro and later in vivo, this has been shown to be effective in the removal in a wide range of protein bound substances. Toxins are stripped off the albumin in plasma and transferred across the pores in the membrane to bind to 20% human serum albumin on the other side of the membrane which is continuously recycled through columns of charcoal and ion exchange resin, where the toxins are finally absorbed (Fig. 1). [2] The membrane cutoff pore size of 50 kda means that hormones, growth factors as well as albumin are not removed. The exact processes by which substances are removed from the plasma proteins and the contribution of albumin impregnation of the membrane in facilitating movement across it is likely, as will be discussed later, to be considerably more complex than the original concept of molecules being stripped off plasma proteins because of the greater affinity of albumin [3, 4] when attached to a synthetic polymer membrane. Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,

2 Hepatobiliary & Pancreatic Diseases International Fig. 2. Serum bilirubin levels with serial MARS treatments in the first patient treated by us with A-CLF at University College London Hospital (Copyright received from Elsevier) (Modified from Jalan R, et al. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis. J Hepatol 2003;38:24-31.). Fig. 1. Illustrating primary circuit (1) and secondary dialysate circuit including the adsorbents-anion exchange (2), and an activated charcoal (3) columns and final dialysis for water soluble toxins (4). The blown up insert shows postulated transport of albumin bound toxins across the membrane (Copyright received from John Wiley & Sons, Inc.) (From Heemann U, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 2002;36: ). The marker protein bound substance most usually measured is the serum bilirubin and numerous studies have shown the efficacy of MARS in lowering high levels in the serum by successive extracorporeal perfusions in patients with liver failure. Substantial decreases in serum bilirubin level have also been obtained in patients with severe obstructive type jaundice from various cholestatic syndromes. The very first patient we treated at University College London Hospital had A-CLF from acute alcoholic hepatitis. As so often happens he had a progressive rise in serum bilirubin after admission to hospital from 170 to 400 μmol/l, despite withdrawal of alcohol and full medical care (Fig. 2). [5] After three MARS perfusions over a five-day period, not only was the serum bilirubin level lowered but the encephalopathy was corrected and he finally improved sufficiently to be discharged from hospital. This impressive clinical result was obtained in a number of the subsequent patients treated with acute alcoholic hepatitis giving a much improved hospital discharge and threemonth survival rate compared with that anticipated from calculation of the Maddrey Index. [5] Significant improvement in the hepatorenal syndrome of A-CLF was convincingly shown in one of the early controlled clinical trials of the MARS device carried out by the workers at Rostock. [6] In the subsequent randomized controlled study of 18 patients with alcohol related A-CLF due to inflammation-related precipitants carried out primarily to elucidate the effects of MARS on pathophysiological processes in A-CLF, [7] we showed that clinical changes were independent of changes in plasma ammonia or cytokine level. The vasoconstrictor neurohumoral profile (plasma noradrenaline, renin, angiotension level) measured in 3 patients was improved, presumably the result of a decrease in vasoconstriction of renal vessels, consequent on correction of systemic vasodilatation. The fall observed in plasma nitrate-the major component and a marker of NO production, is likely to be of considerable importance in beneficial effects of MARS on the systemic circulation and on the cerebral hyperemia which underlies the development of brain oedema and increases in intracranial pressure. Sorkine et al [8] showed that the ICP and jugular bulb oxygen saturation was decreased by MARS treatments along with an increase in cerebral perfusion pressure in three patients with A-CLF. Schmidt et al [9] determined the mean velocity of flow in the middle cerebral artery by transcranial Doppler, as a measure of cerebral perfusion. Values increased from 42 to 72 cm/s over a single 10 hour session in 8 patients. The Copenhagen group has also shown the beneficial effects of MARS on systemic haemodynamics and oxygen consumption in patients with hyperacute liver failure. [10] One interesting observation in the patients with A-CLF from acute alcoholic hepatitis was a decrease in portal pressure during MARS treatment along with a reduction in cardiac output and improvement in 20 Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,2008

3 Albumin dialysis in hepatic failure Fig. 3. Illustrating reduction in portal pressure during MARS treatment compared with levels during standard medical treatment. Mean values shown for patients in each group (Data from Sen S) (From Sen S, et al. Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis. J Hepatol 2005;43: ). mean arterial pressure (Fig. 3). [11] This could represent a most welcome effect in patients with varices and a substantial risk of bleeding from them. We have also looked at the efficacy of MARS in the correction of parameters of oxidative stress. The latter is thought to be one of the important damaging mechanisms on organ function both in A-CLF and ALF. Levels of malondialdehyde (MDA) were reduced after seven days of treatment as compared with baseline values which had increased further in the standard medical treatment. Using a 'spin trap' (PBN) and electron paramagnetic resonance (EPR) a reduction in blood levels of oxygen-based free radicals was demonstrated. [12] The findings I have illustrated have been confirmed by several other research groups showing that disturbed pathophysiological mechanisms, however assessed, are corrected along with a striking reduction in blood levels of putative or known toxic substances. Whether the associated clinical improvement-particularly in encephalopathy grade and in circulatory state, equates to better short or longer-term survival will have to await the results of ongoing controlled clinical trials. Outcome measures are likely also to be affected by the nature of the underlying disease. Precipitating factors particularly variceal bleeding or infection may have such adverse effects on the underlying liver disease by inducing further hepatocyte damage that functional compensation cannot be regained. An improvement in short-term outcome even if longer-term prognosis is not affected, could be of considerable benefit to the patient awaiting a liver transplant. Having the patient in a better condition with respect to renal function and high levels of bilirubin and toxic substances in the serum is likely to mean a less stormy post transplant recovery. Temporary liver support should also give a longer period of time for a donor organ to be obtained. Two cases of A-CLF with severe renal failure, encephalopathy and recurrent infective episodes that I treated by repeated MARS perfusions over several weeks, finally had a successful living donor liver transplant carried out. Short-term benefit may also allow initiation of active measures of treatment for the underlying liver disease, for instance antiviral drugs in patients with cirrhosis from HBV infection. The results of the prospective randomly allocated controlled clinical trial recently carried out in the USA were highly convincing. A two grade improvement in hepatic encephalopathy (grade Ⅳ Ⅱ or grade Ⅲ Ⅰ) was reached significantly more frequently in the MARS group. The improvement was accompanied by significant decrease in ammonia, bilirubin, bile acids, creatinine and aromatic amino acids. [13] Factors affecting removal of albumin bound toxins Transport across the MARS membrane, as already referred too, involves stripping of toxins from the plasma albumin (deligandisation) with transport of the ligands through the pores of the membrane to bind to the albumin in the dialysate. Early in vitro data demonstrated almost complete equilibration in bilirubin concentration between plasma and dialysate compartments after 125 minutes. However, the recent in vivo studies of Evenepoel et al, have shown persistence of a major concentration gradient for the duration of the perfusion, particularly when taking into account the difference of albumin concentration [14, 15] in the two compartments. The molar ratio of total bilirubin to albumin was approximately tenfold lower in the dialysate compartment compared with that in blood. Persistence of the concentration gradient is likely to be a reflection of the nature of the binding of bilirubin to albumin in plasma. 60% to 80% of the total bilirubin is tightly (covalently) bound and only the bilirubin bound by non-covalent forces and the free component is likely to be cleared across the membrane. The magnitude of diffusion transport of the free component is determined by the mass transfer area co-efficient (MTAC) for the solute and the concentration gradient of it between blood and dialysate. Coating of the MARS membrane with albumin increases the MTAC by approximately Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,

4 Hepatobiliary & Pancreatic Diseases International Table. Qualitative assessment of albumin functional capacity using a spin label (16-doxil stearic acid) & electro magnetic spectroscopy Fatty acid binding (kb) Conformational stability (L2) Detoxification ability (DTE) Healthy controls Stable cirrhotic A-CLF MARS day A-CLF MARS day 7 (Copyright received from John Wiley & Sons, Inc.) (Modified from Davies NA, et al. Serum albumin shows conformational, structural and functional abnormalities in cirrhotic patients, which worsen with severity of liver disease and are unaffected by albumin dialysis. Hepatology 2005 Suppl 1;42:222A.). of recorded spectra provides information on albumin conformational and binding properties. Values were reduced in samples from stable cirrhotics and were even lower in those taken from patients immediately before treatment by MARS, at the stage of A-CLF. No improvement in functional capacity was observed after the MARS treatment and the structural changes in the albumin molecule are presumably irreversible. Klammt and colleagues, [17] have demonstrated a reduced albumin-binding capacity for a site Ⅱ specific marker in decompensated liver cirrhosis which they found to be closely correlated with the severity of the liver disease. Other studies have stressed the importance of the molar ratio of bilirubin to albumin in the binding and transporting function of albumin [18, 19] and removal of bilirubin by the MARS device. [14, 15] fourfold for unconjugated bilirubin. Factors in the dialysate circuit will also affect the magnitude of diffusion transport of bilirubin. For example it has been shown that the stabilizer in the commercial albumin preparation used for priming the closed dialysis circuit reduces the binding capacity of the albumin. Also, although the dialysate is considered to be continuously cleansed of albumin bound toxins by recirculation through the anion exchange and charcoal columns, measurement of dialysate clearance rates for bilirubin shows a progressive decline over time indicating saturation of the filters and absorption columns. [14, 15] The latter could at least partly explain why the blood clearances of bilirubin fall off so rapidly after the start of MARS treatment. Clearance is maximal during the first hour and after that is substantially less. Indeed negative values can be observed in some cases after 6 hours. The binding of bile acids to albumin in plasma is not nearly so complete and not withstanding the much smaller molar ratio gradient at all time points, blood clearance is substantially higher than for bilirubin and also remains stable for the duration of the perfusion [14, 15] period. Another aspect relevant to the removal of toxins from plasma which has been studied by my colleague Dr. Rajiv Jalan and his group in the Institute relates to the functional properties of the patient's albumin and whether these are altered in liver failure and whether changes are reversible by MARS treatment. Some of the results of a qualitative assessment of albumin functionality using a spin label for albumin (16-doxil stearic acid) and electron paramagnetic resonance spectroscopy are given in Table. [16] Analysis Comparing single-pass albumin dialysis and Prometheus device Comparing other dialysis systems with MARS is informative in relation to the removal of protein bound toxic substances and correction of pathophysiological disturbances in liver failure. The single-pass albumin system (SPAD) uses the same high flux membrane as in the MARS device and presumably similar factors apply to the transport of bilirubin and bile salts across the membrane. The omission of a recirculation dialysate system and the lack therefore of an effect from column saturation may explain why clearance rates for plasma bilirubin [20, 21] and bile salts can be higher than with MARS. The Prometheus device is based on a different concept and should not properly be included within the category of albumin dialysis. It is a form of fractionated plasma separation and uses an albumin permeable membrane of 300 kda pore size. The separated plasma is perfused through neutral resin and anion exchanger absorber where bilirubin, bile acids and other protein bound substances are removed. The purified plasma is then returned to the patient after conventional haemodialysis to eliminate water soluble toxins. [22-24] In comparison with MARS, no dissociation of albumin or membrane diffusion with all its limitations is necessary. There is no need either for exogenous albumin in the dialysate circuit. Measured clearances of various protein bound substances, however, are similar though in one study a substantially higher clearance rate was obtained for unconjugated bilirubin which is the most tightly bound of the bilirubin fractions in plasma. [22] In the 22 Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,2008

5 Albumin dialysis in hepatic failure most recent comparative study of Laleman et al, [24] the Prometheus device was more effective in decreasing serum bilirubin levels but interestingly only with the MARS device was there a significant improvement in the mean arterial pressure and systemic vascular resistance index. Circulatory improvement in the MARS group was paralleled by a decrease in plasma renin, aldosterone, norepinephrine, vasopressin, and nitrate/nitrite levels. Presumably, it is the removal of these endogenous vasoactive substances which determines the improvement in the hyperdynamic vasodilatory state of A-CLF. Splanchnic arterial vasodilatation is known to be of importance in initiating the systemic haemodynamic disturbance and excessive production of NO as referred to earlier may play a central role. Conclusion 1) Clinical evidence consistent with correction of pathophysiological disturbances by MARS includes improvement in encephalopathy, systemic vasodilatation, impaired renal blood flow and raised portal pressure. 2) Reduction in protein bound putative and known toxins together with vasoactive pressor substances, NOx, reactive oxygen species are all measurable effects contributing to the clinical improvement. 3) Similarities and differences of MARS to other devices, particularly SPAD and the fractionated plasma separation of the Prometheus system, may give further insight into the processes involved. 4) Albumin binding capacity at different stages of liver disease and in relation to the use of liver support devices is an important aspect meriting further study. Funding: None. Ethical approval: Not needed. Contributors: WR wrote the whole article. WR is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. References 1 Rozga J. Liver support technology--an update. Xenotransplantation 2006;13: Heemann U, Treichel U, Loock J, Philipp T, Gerken G, Malago M, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 2002;36: Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H. Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins. Artif Organs 1993;17: Stange J, Mitzner S. A carrier-mediated transport of toxins in a hybrid membrane. Safety barrier between a patients blood and a bioartificial liver. Int J Artif Organs 1996;19: Jalan R, Sen S, Steiner C, Kapoor D, Alisa A, Williams R. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis. J Hepatol 2003;38: Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl 2000;6: Sen S, Davies NA, Mookerjee RP, Cheshire LM, Hodges SJ, Williams R, et al. Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl 2004;10: Sorkine P, Ben Abraham R, Szold O, Biderman P, Kidron A, Merchav H, et al. Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure. Crit Care Med 2001;29: Schmidt LE, Svendsen LB, Sorensen VR, Hansen BA, Larsen FS. Cerebral blood flow velocity increases during a single treatment with the molecular adsorbents recirculating system in patients with acute on chronic liver failure. Liver Transpl 2001;7: Schmidt LE, Wang LP, Hansen BA, Larsen FS. Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a prospective controlled trial. Liver Transpl 2003;9: Sen S, Mookerjee RP, Cheshire LM, Davies NA, Williams R, Jalan R. Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis. J Hepatol 2005; 43: Sen S, Ratnaraj N, Davies NA, Mookerjee RP, Cooper CE, Patsalos PN, et al. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia 2003;44: Hassanein T, Tofteng F, Brown Jr RS, McGuire BM, Lynch P, Mehta R, et al. Efficacy of albumin dialysis (MARS) in patients with cirrhosis and advanced grades of hepatic encephalopathy: a prospective, controlled, randomized multicenter trial. Hepatology 2004;40:726A. 14 Evenepoel P, Maes B, Wilmer A, Nevens F, Fevery J, Kuypers D, et al. Detoxifying capacity and kinetics of the molecular adsorbent recycling system. Contribution of the different inbuilt filters. Blood Purif 2003;21: Evenepoel P, Bammens B, Nevens F, Wilmer A, Vanrenterghem Y. The molecular adsorbent recycling system (MARS) and transmembrane transport of albumin-bound toxins. Liver Transpl 2005;11: Davies NA, Schnurr K, Sen S, Hodges SJ, Matthes G, Jalan R. Serum albumin shows conformational, structural and functional abnormalities in cirrhotic patients, which worsen with severity of liver disease and are unaffected by albumin dialysis. Hepatology 2005;42:222A. Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,

6 Hepatobiliary & Pancreatic Diseases International 17 Klammt S, Mitzner S, Stange J, Brinkmann B, Drewelow B, Emmrich J, et al. Albumin-binding function is reduced in patients with decompensated cirrhosis and correlates inversely with severity of liver disease assessed by model for end-stage liver disease. Eur J Gastroenterol Hepatol 2007;19: Lee KH, Wendon J, Lee M, Da Costa M, Lim SG, Tan KC. Predicting the decrease of conjugated bilirubin with extracorporeal albumin dialysis MARS using the predialysis molar ratio of conjugated bilirubin to albumin. Liver Transpl 2002;8: Steiner C, Sen S, Stange J, Williams R, Jalan R. Binding of bilirubin and bromosulphthalein to albumin: implications for understanding the pathophysiology of liver failure and its management. Liver Transpl 2004;10: Sauer IM, Goetz M, Steffen I, Walter G, Kehr DC, Schwartlander R, et al. In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD). Hepatology 2004;39: Peszynski P, Klammt S, Peters E, Mitzner S, Stange J, Schmidt R. Albumin dialysis: single pass vs. recirculation (MARS). Liver 2002;22 Suppl 2: Krisper P, Haditsch B, Stauber R, Jung A, Stadlbauer V, Trauner M, et al. In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation. J Hepatol 2005;43: Santoro A, Faenza S, Mancini E, Ferramosca E, Grammatico F, Zucchelli A, et al. Prometheus system: a technological support in liver failure. Transplant Proc 2006;38: Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure. Crit Care 2006;10: R108. Received June 22, 2007 Accepted after revision December 29, Hepatobiliary Pancreat Dis Int,Vol 7,No 1 February 15,2008