Sambit Sen

Pathophysiological effects of albumin dialysis in acute‐on‐chronic liver failure: A randomized controlled study

The pathophysiological basis of acute‐on‐chronic liver failure (ACLF) is unclear but systemic inflammatory response is thought to be important. In patients with ACLF, the molecular adsorbents recirculating system (MARS) improves individual organ function, but the effect of MARS on the proposed mediators of systemic inflammatory response is unclear. The present study was designed to determine the effect of MARS on the cytokine profile, oxidative stress, nitric oxide, and ammonia. A total of 18 patients with alcohol‐related ACLF due to inflammation‐related precipitants were randomized to receive standard medical therapy (SMT) alone, or with MARS therapy over 7 days. Plasma cytokines, malondialdehyde (MDA), free radical production, nitrate / nitrite (NOx), and ammonia were measured. Encephalopathy improved significantly with MARS (P < .01), but not with SMT. Mean arterial pressure and renal function remained unchanged. No significant change of plasma cytokines and ammonia levels were observed in either group. Plasma MDA levels did not change either. There was a fall in NOx (P < .05) with MARS, but not with SMT. In conclusion, in inflammation‐related ACLF patients, albumin dialysis using MARS results in improvement of encephalopathy, independent of changes of ammonia or cytokines, without improving blood pressure or renal function. These results should temper the liberal use of MARS until further data is available. (Liver Transpl 2004;10:1109–1119.)

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

Acute‐on‐chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per‐protocol (PP) analysis (PP population n = 156). Up to 10 6‐8‐hour MARS sessions were scheduled. The main endpoint was 28‐day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28‐day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44‐1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis

BACKGROUND/AIMS The mortality of patients with severe acute alcoholic hepatitis (AH) remains high, leading to interest in the use of extracorporeal liver support. The molecular adsorbents recirculating system (MARS) is a liver support device based upon a hollow fibre module in which the patients blood is dialyzed across an albumin-impregnated membrane. The aim of this paper is to assess the safety, efficacy and feasibility of using MARS in patients with severe AH. METHODS Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and haemodynamic assessments were done. RESULTS Five patients were discharged from hospital, and four are alive at 3 months of follow-up, compared with an estimated survival of about 20%. There were significant improvement in serum bilirubin (P=0.008), creatinine (P=0.02), prothrombin time (P=0.04), and grade of encephalopathy (P=0.05). Sustained improvements in mean arterial pressure, systemic vascular resistance and cardiac output were observed. Thrombocytopaenia was the only MARS-related adverse event observed. CONCLUSIONS MARS resulted in improved liver biochemistry, cardiovascular haemodynamics, renal function and encephalopathy in patients with severe AH, with an apparent reduction in mortality. On this basis, a multi-centre, randomized clinical trial has been initiated.

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine‐dimethylamino‐hydrolase, and is derived by the action of protein‐arginine‐methyltransferases. Our study assessed whether ADMA, and its stereo‐isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty‐two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine‐dimethylamino‐hydrolase protein expression was reduced and protein‐arginine‐methyltransferase‐1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddreys discriminant‐function. Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine‐dimethylamino‐hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis. (HEPATOLOGY 2007;45:62–71.)

Emerging indications for albumin dialysis

The accumulation of albumin-bound toxins in liver failure is believed to be responsible for the development of associated end-organ dysfunctions (kidney, circulation, brain). Albumin dialysis utilizes the scavenging functions of albumin for the removal of toxins. The Molecular Adsorbents Recirculating System (MARS) is one such extracorporeal liver support device where blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resin columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies in the last decade have demonstrated proven reduction in hyperbilirubinemia, along with an improvement in encephalopathy in liver failure patients, as well as apparent improvement in survival. Some studies have also reported improvement of systemic hemodynamics and renal function in these patients. Amelioration of intractable pruritus and treatment of toxicities with albumin-bound substances are some of the newer indications emerging. However, the specific underlying pathophysiological mechanisms are still not clear. Two other systems based on the removal of albumin-bound toxins, the Prometheus (using the principle of fractionated plasma separation and adsorption [FPSA]), and the single pass albumin dialysis (SPAD) are also currently under development but available clinical data are limited.

EFFECT OF ALBUMIN DIALYSIS ON INTRACRANIAL PRESSURE INCREASE IN PIGS WITH ACUTE LIVER FAILURE: A RANDOMIZED STUDY

Background:Increased intracranial pressure (ICP) worsens the outcome of acute liver failure (ALF). This study investigates the underlying pathophysiological mechanisms and evaluates the therapeutic effect of albumin dialysis in ALF with use of the Molecular Adsorbents Recirculating System without hemofiltration/dialysis (modified, M-MARS). Methods:Pigs were randomized into three groups: sham, ALF, and ALF + M-MARS. ALF was induced by hepatic devascularization (time = 0). M-MARS began at time = 2 and ended with the experiment at time = 6. ICP, arterial ammonia, brain water, cerebral blood flow (CBF), and plasma inflammatory markers were measured. Results:ICP and arterial ammonia increased significantly over 6 hrs in the ALF group, in comparison with the sham group. M-MARS attenuated (did not normalize) the increased ICP in the ALF group, whereas arterial ammonia was unaltered by M-MARS. Brain water in the frontal cortex (grey matter) and in the subcortical white matter at 6 hrs was significantly higher in the ALF group than in the sham group. M-MARS prevented a rise in water content, but only in white matter. CBF and inflammatory mediators remained unchanged in all groups. Conclusion:The initial development of cerebral edema and increased ICP occurs independently of CBF changes in this noninflammatory model of ALF. Factor(s) other than or in addition to hyperammonemia are important, however, and may be more amenable to alteration by albumin dialysis.

Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study

IntroductionAcute deterioration of cirrhosis is associated with high mortality rates particularly in the patients who develop organ failure (OF), a condition that is referred to as acute-on-chronic liver failure (ACLF), which is currently not completely defined. This study aimed to determine the role of predisposing factors, the nature of the precipitating illness and inflammatory response in the progression to OF according to the PIRO (predisposition, injury, response, organ failure) concept to define the risk of in-hospital mortality.MethodsA total of 477 patients admitted with acute deterioration of cirrhosis following a defined precipitant over a 5.5-year period were prospectively studied. Baseline clinical, demographic and biochemical data were recorded for all patients and extended serial data from the group that progressed to OF were analysed to define the role of PIRO in determining in-hospital mortality.ResultsOne hundred and fifty-nine (33%) patients developed OF, of whom 93 patients died (58%) compared with 25/318 (8%) deaths in the non-OF group (P < 0.0001). Progression to OF was associated with more severe underlying liver disease and inflammation. In the OF group, previous hospitalisation (P of PIRO); severity of inflammation and lack of its resolution (R of PIRO); and severity of organ failure (O of PIRO) were associated with significantly greater risk of death. In the patients who recovered from OF, mortality at three years was almost universal.ConclusionsThe results of this prospective study shows that the occurrence of OF alters the natural history of cirrhosis. A classification based on the PIRO concept may allow categorization of patients into distinct pathophysiologic and prognostic groups and allow a multidimensional definition of ACLF.

Hepatopulmonary syndrome in inferior vena cava obstruction responding to cavoplasty

Reports show that hepatopulmonary syndrome mostly occurs in the setting of advanced hepatic dysfunction, with the associated vasoactive substance imbalance believed to be responsible for its pathogenesis. However, hepatopulmonary syndrome has also been reported in cases of mild hepatic dysfunction or noncirrhotic portal hypertension, indicating that portal hypertension also plays a part in the pathogenesis. Liver transplantation remains the only therapeutic option of proven benefit. We describe 2 cases of hepatopulmonary syndrome in the setting of inferior vena cava (suprahepatic) obstruction, but with minimal hepatic dysfunction. After balloon cavoplasty, 1 patient showed, in addition to improvement of the features of hepatic outflow obstruction, significant reduction of dyspnea, cyanosis, and hypoxemia with arterial blood gas normalization within 2 weeks and intrapulmonary shunt reversal within 8 weeks. This implies that hemodynamic alterations (such as portal hypertension) independently contribute to the pathogenesis of hepatopulmonary syndrome in at least some of the cases. Therapies aimed at correcting these abnormal hemodynamics may be important in the treatment of this condition, especially when the hepatic functional status by itself does not warrant a liver transplant.

Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS).

Summary:  Purpose: Toxicity is common in patients of epilepsy treated with phenytoin (PHT), requiring careful drug level monitoring and supportive care. Specific treatment options are limited, although charcoal haemofiltration has been used previously. We attempted to demonstrate that severe PHT toxicity can be treated successfully with the Molecular Adsorbents Recirculating System (MARS). The mechanism of drug removal by the system also was studied.

Artificial liver support systems in the management of complications of cirrhosis

Acute-on-chronic liver failure (ACLF) is associated with multiorgan dysfunction requiring intensive care support and carries an exceptionally high risk of mortality. Decompensation of liver cirrhosis is triggered by different precipitating events but the final common pathway is hypothesized to be unregulated systemic inflammation. The concept of an artificial liver that may impact favorably upon the inflammatory response and provide liver function to prevent complications seems to be promising. This article aims to describe the currently available artificial and bioartificial systems and reviews their effect on different complications of cirrhosis, such as liver function and hepatic hemodynamics, renal function and systemic hemodynamics, hepatic encephalopathy, inflammation/infection, and coagulation. Due to the difficulties in studying large patient numbers with ACLF and the heterogeneity of this patient group, only limited data on survival are available. The currently available studies indicate that there is a survival benefit for artificial and bioartificial liver support in certain subgroups of patients; however, further studies are warranted. At present several studies in this field are under way. In this review several of the companies interested in the manufacture of the respective devices provide an up-to-date report of ongoing trials. In summary, artificial and bioartificial liver support are already playing important roles in the treatment of complications of ACLF. Better understanding of the pathophysiology of ACLF, further development of the current systems, and their evaluation in appropriately controlled clinical studies are necessary to translate their application to improvement in outcome of patients with ACLF.