MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report

Abstract Background/methods: Molecular Adsorbent Recirculating System (MARS) was used in three consecutive critically ill patients at the Singapore General Hospital with advanced malignancy and acute liver failure (ALF). Case 1 was a male patient with hepatocellular carcinoma (HCC) for which initial right hepatectomy was followed by left hepatectomy 5 months later for recurrent HCC. The postoperative course following second surgery was complicated by severe methicillin‐resistant Staphylococcus aureus (MRSA) sepsis, mild azotaemia and subacute cholestatic liver failure. MARS was used thrice in this patient. Case 2 was a female patient with advanced acute lymphoblastic leukaemia (ALL) with postbone marrow transplantation (BMT) acute haemolytic–uraemic syndrome (HUS) secondary to cyclosporin A (Cy A), cytomegalovirus (CMV) infection, severe nosocomial pneumonia, acute renal failure (ARF) treated with continuous haemofiltration and acute veno‐occlusive disease resulting in Budd–Chiari syndrome. The latter precipitated ALF. MARS was instituted twice. Case 3 was a male patient with advanced, refractory Hodgkin's disease previously treated with multiple courses of chemotherapy. ALF developed secondary to acute viral hepatitis B flare. He was given a trial of MARS once in the ICU. All the three patients eventually died. Results: Mean MARS intradialytic systemic pressures were as follows: systolic pressure range was 95 ± 17 to 128 ± 17 mmHg and diastolic pressure range was 51 ± 5 to 67 ± 7 mmHg. Pressure at albumin dialysate exit point from dialyser 1 (Ae) ranged from 253 ± 11 to 339 ± 15 mmHg and that at albumin dialysate entry point into dialyser 1 (Aa) ranged from 142 ± 11 to 210 ± 6 mmHg. Ultrafiltration (UF) was 633 ± 622 mL over mean treatment duration of 6.3 ± 0.9 h with a total heparin dose of 1583 ± 817 IU. Coagulation status pre‐ and 6‐h post‐MARS was similar: aPTT (P = 0.116) and platelet count (P = 0.753). There were no bleeding complications or circuit thromboses. MARS had a significant de‐uraemization effect (pre‐ and post‐MARS serum creatinine and urea: P = 0.046 and 0.028, respectively) but did not significantly attenuate blood lactate, ammonia or total bilirubin levels. Albumin dialysate (Ae ? Aa) urea and creatinine concentrations appeared to be sharply attenuated after 6 h of MARS. In contrast, the removal of total bilirubin by albumin dialysate from the blood compartment appeared to plateau after 4 h of continuous MARS operation. Conclusions: MARS was well‐tolerated in critically ill patients with advanced and complicated cancer. Low‐dose heparin was safe and did not compromise MARS circuit integrity. Although MARS had a significant de‐uraemization effect, this appeared to be limited by the duration of MARS operation. Our data suggested that such a limit was reached earlier for total bilirubin. More data are needed to confirm the present findings and further delineate the saturation limit of MARS for different toxins that accumulate in ALF. This would affect the optimal duration of MARS therapy.     

Successful treatment of an adult with Amanita phalloides-induced fulminant liver failure with molecular adsorbent recirculating system (MARS)

Despite significant advances in intensive care management of Amanita phalloides-induced fulminant liver failure (FLF), patients with this condition still have a high mortality rate in the absence of orthotopic liver transplantation. Molecular Adsorbent Recirculating System (MARS) is a new, cell-free, extracorporeal liver assistance method utilizing an albumin dialysate for the removal of albumin-bound toxins, and a highly effective depurative therapy in adults with wild mushroom-induced FLF. We report the case of a 39 year old woman with Amanita phalloides-induced FLF, admitted to our intensive care unit (ICU) and treated with MARS. Our patient had severe hepatic dysfunction: hepatic encephalopathy (grade II), ALT = 5022 (2475-10098) IU/L, bilirubin = 7.18 (4.8-10.1) mg/dL, prothrombin time (PT) = 90.4 (29.3-140.4) s. MARS sessions had an immediate impact on liver tests: statistically significant decrease in ammonia, ALT and PT. Hepatic encephalopathy was successfully reduced. The patient survived and the hepatic function completely recovered. MARS appears to be a safe and highly effective depurative therapy in adults with Amanita phalloides-induced FLF.     

Is It Possible to Gain Extra Waiting Time to Liver Transplantation in Acute Liver Failure Patients Using Albumin Dialysis?

Hepatic encephalopathy (HE)‐associated brain edema is a common cause of death in acute liver failure (ALF). Molecular Adsorbent Recirculating System (MARS) albumin dialysis detoxifies endogenous and exogenous toxins from blood and improves HE. In this study we assessed the effect of MARS on increasing the length of time available while waiting for liver graft. Thirty‐seven patients with ALF who received a high‐urgent liver transplant (LTx) were divided into three groups according to the amount of histological necrosis in the explanted liver: group I = 100% necrosis; group II = 80–99% necrosis; group III = less than 80% necrosis. MARS was used continuously until LTx. Median time (range) on MARS treatment prior to LTx in groups I–III was 7 days (2–26), 6 days (1–17), and 5 days (1–15), and the median time on the waiting list was 5 days (1–11), 3 days (0–13), and 1 day (0–12), respectively. The HE grade prior to and after MARS was similar in all groups. In two patients the HE grade decreased during MARS treatment, even though the explanted liver showed a complete lack of viable cells. Overall 30‐day and one‐year survival were 97% and 92%, respectively, without differences between the three groups. In ALF patients the liver cell damage progressed to total or near total necrosis of the liver when the waiting time was prolonged. Yet, with MARS treatment some patients with total hepatic necrosis showed an absence of encephalopathy. With MARS treatment some patients might be able to wait longer for a LTx with good results.     

The molecular adsorbent recirculating system as a liver support system. Summary of Mexican experience

Aim. The aim of this study was to assess the effects of the molecular absorbent recirculating system (MARS) on patients with acute liver failure (ALF) and liver failure with cirrhosis (AoCLF) as well as in cholestatic patients with intractable pruritus in a Mexican population.Material and methods. From August 2003 to December 2011, MARS was used in 38 patients with ALF, 15 patients with AoCLF, and 17 cholestatic patients with intractable pruritus. The patients were examined using a standard liver function test and for vital signs, presence of ascites and encephalopathy before and after each treatment. The therapeutic response, patient status, follow-up status, and need for liver transplantation were determined.Results. Seventy-nine MARS procedures were performed. MARS was used for ALF in 54.3% of patients, AoCLF in 24.2%, and cholestatic disease in 21.5%. There were significant improvements in serum bilirubin (p = 0.000), aspartate aminotransferase (p = 0.000), alanine aminotransferase (p = 0.030), gamma-glytamyl transpeptidase (p = 0.044), alkaline phosphatase (p = 0.006), and encephalopathy grade (p = 0.000). Thirty-eight ALF patients were listed for emergency liver transplantation and treated with MARS; 20 of these patients died on a waiting list, 18 survived. only four underwent liver transplantation and 14 (37%) recovered without transplantation after the MARS procedure.Conclusion. MARS is a safe and effective procedure, especially for ALF patients. Our results suggest that MARS therapy can contribute to native liver recovery in ALF patients.     

Improvements in Hepatic Serological Biomarkers Are Associated with Clinical Benefit of Intravenous N-Acetylcysteine in Early Stage Non-Acetaminophen Acute Liver Failure

Background

N-acetylcysteine (NAC) improves transplant-free survival in early coma grade (I–II) patients with non-acetaminophen induced acute liver failure (ALF). We determined whether the clinical benefit was associated with improvements in hepatic function.

Methods

In a prospective, double blind trial, 173 ALF patients without evidence of acetaminophen overdose were stratified by coma grade (I–II vs. III–IV) and randomly assigned to receive either intravenous NAC or dextrose (placebo) for 72 h, resulting in four patient groups. INR, ALT, bilirubin, creatinine, and AST obtained on admission (day 1) and subsequent days (days 2–4) were used for secondary analysis performed by fitting longitudinal logistic regression models to predict death or transplantation or transplantation alone.

Results

Treatment group and day of study in models including bilirubin or ALT were predictors of transplantation or death (maximum p < 0.03). Those patients with early coma grade who were treated with NAC showed significant improvement in bilirubin and ALT levels when compared to the other three groups (maximum p < 0.02 for NAC 1–2 vs. the 3 other treatments) when predicting death or transplantation. Treatment group, day of study, and bilirubin were predictors of transplantation (maximum p < 0.03) in ALF patients.

Conclusion

The decreased risk of transplantation or death or of transplantation alone with intravenous NAC in early coma grade patients with non-acetaminophen induced ALF was reflected in improvement in parameters related to hepatocyte necrosis and bile excretion including ALT and bilirubin, but not in INR, creatinine, or AST. Hepatic recovery appears hastened by NAC as measured by several important lab values.     

Predictive formula of coma onset and prothrombin time to distinguish patients who recover from acute liver injury

Background and Aim

Acute liver failure (ALF) is defined as acute liver injury (ALI) associated with coagulopathy. A follow‐up strategy for ALI and characterization of ALI patients with a risk of progressing to ALF have never been established. To establish predictive markers for progression from ALI to ALF, this study compared the clinical characteristics and laboratory data on the day of registration to data from a regional referral system of patients with ALI.

Methods

This prospective, observational study enrolled 365 consecutive patients with ALI/ALF between 2007 and 2016. We evaluated 109 ALI patients, 27 of whom satisfied the ALF criteria during observation and another 82 patients who recovered without progression to ALF.

Results

Four patients died; all were in the ALF group. The variables of age, incidence of autoimmune hepatitis, model of end‐stage liver disease score, values for total bilirubin and prothrombin time (PT)‐international ratio, and Japan Hepatic Encephalopathy Prediction Model (JHEPM) probability at registration were significantly higher in ALF patients than in ALI patients. In multivariate analysis, PT and JHEPM were identified as risk factors for progression to ALF. The cut‐off values of 13%, 4.9%, 65%, and 1.32% for the model of end‐stage liver disease score, JHEPM probability, PT, and PT‐international ratio values, respectively, had high negative predictive values. Furthermore, among patients whose JHEPM was underestimated, none died due to ALF.

Conclusion

The JHEPM probability is a predictive parameter that can be used to decide a follow‐up treatment strategy for ALI patients.     

Rare clinically significant hepatic events and hepatitis B reactivation occur more frequently following rather than during direct‐acting antiviral therapy for chronic hepatitis C: Data from a national US cohort

Recently, cases of hepatitis B virus reactivation (HBVr) with direct‐acting antiviral therapy (DAAs) for HCV have been reported. However, few data exist from large, Western cohorts. The study objectives were to evaluate the incidence of alanine aminotransferase (ALT) flares, clinically significant hepatic events, and HBVr among a national cohort of US veterans with prior exposure to HBV (anti‐HBc+) treated with DAAs. We used a national administrative database to identify patients treated with DAAs from January 2014 through November 2016 and obtained clinical and demographic as well as HBV and HCV treatment data. HBVr was defined as an at least 1‐log increase in HBV DNA titre. Among 17 779 anti‐HBc+ patients, 17 400 were HIV? and 379 were HIV+. Among the HIV? patients, 17 266 (99%) were HBsAg? prior to DAA therapy and 134 were HBsAg+. Among HIV‐, HBsAg? patients, ALT elevations greater than 10 times the upper limit of normal (ULN; ≥300 IU/mL) were rare and occurred more frequently after treatment completion: 31 cases (<0.1%) during vs 85 (0.6%) following treatment. Clinically significant hepatic events defined as ALT increases >100 IU/L with total bilirubin >2.5 mg/dL occurred in 39 cases (0.3%), most often following DAA completion (n = 35 cases, 3/35 in setting of HCV relapse). Among 31 patients with post‐DAA hepatic events without HCV relapse, 10 (32%) were confirmed unrelated to HBVr by HBsAg and/or HBV DNA testing, 1 (3%) confirmed due to HBVr, and 20 (65%) did not have documented HBV‐related testing. One additional case of HBsAg? to + seroreversion was identified. Among HBsAg+ DAA recipients, 2/97 (2%), both with cirrhosis, experienced ALT elevations ≥300 IU/mL in the setting of HBVr. In conclusion, clinically significant hepatic events and HBVr were rare and much more likely among HBsAg‐positive individuals. Anti‐HBc + patients should be monitored for ALT flares and HBVr during and possibly for up to 6 months post‐DAA therapy.     

清热化瘀中药对急性肝衰竭模型大鼠肝功能及生存期的影响

目的:探讨清热化瘀中药对急性肝衰竭(acuteliver failure,ALF)模型大鼠肝功能及生存期的影响.方法:采用D-氨基半乳糖(D-GalN)单次腹腔注射构建ALF大鼠模型,125只SD大鼠以是否接受造模和药物干预随机分为空白组、模型组、复方甘草酸苷组和清热化瘀中药组;每组再以36、96h两个时间点继续随机分为1、2两个亚组,共8组,其中亚组1用于造模后36h取血及肝组织标本,亚组2用于观察96h内大鼠的生存率.以全自动生化分析法检测血清丙氨酸氨基转移酶(alanineaminotransferase,ALT)、门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、总胆红素(total bilirubin,TBIL)、白蛋白(albumin,ALB)和胆碱酯酶(cholinesterase,CHE),全自动血凝分析法检测血浆凝血酶原时间(prothrombintime,PT),常规HE染色作肝组织病理学观察.结果:模型组、复方甘草酸苷组及清热化瘀中药组估计平均生存时间分别为64.6、71.9、83.3h;log-rank检验提示清热化瘀中药组累积生存率高于模型组(2=4.428,P<0.05).与模型组相比,空白组、清热化瘀中药组和复方甘草酸苷组血清ALT、AST、TBIL及血浆PT水平均显著下降(P<0.01),清热化瘀中药组低于复方甘草酸苷组(P<0.01).与模型组相比,空白组、清热化瘀中药组和复方甘草酸苷组在血清ALB和CHE水平均明显升高(P<0.01),清热化瘀中药组高于复方甘草酸苷组(P<0.01).与模型组相比,清热化瘀中药组和复方甘草酸苷组肝组织损伤程度积分明显下降(1.84±0.13,2.85±0.20vs3.56±0.24,均P<0.01),清热化瘀中药组低于复方甘草酸苷组(P<0.01).结论:清热化瘀中药可显著减轻D-GalN诱导急性肝衰竭大鼠肝细胞的损伤,改善肝功能及肝脏病理并降低ALF模型大鼠的病死率、延长生存期,对ALF患者有潜在的临床应用价值.     

Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6?h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92?±?7.79?mmol/L to 7.16?±?5.64?mmol/L (P?P?Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.     

Pre-transplant optimization by Molecular Adsorbent Recirculating System in patients with severely decompensated chronic liver disease.

BACKGROUND: The outcome of liver transplantation (LT) is influenced by the recipient's clinical condition. In a retrospective observational study, we evaluated the role of pre-LT Molecular Adsorbent Recirculating System (MARS) treatment in improving the clinical status and thereby the outcome of patients with chronic liver disease and severe hepatic decompensation. METHODS: Between March 2002 and September 2006, 70 patients with end-stage chronic liver disease underwent living-donor LT (LDLT). Of these, 9 (13%) patients with severely decompensated liver function (serum bilirubin> 350 micromol/L [20 mg/dL] and/or hepatic encephalopathy > or = grade 2) received pre-LT MARS treatment. RESULTS: The median MELD score was 33 (range, 26-47). A median of 2 (range, 1-6) sessions (8 hour/session) of MARS dialysis was performed per patient. MARS treatment was associated with reduction in serum bilirubin, creatinine and ammonia levels and no procedure-related complications. CONCLUSION: Pre-LT MARS is well tolerated and results in reduction of jaundice and improvement in renal function and may be useful in the management of patients with severe hepatic decompensation.     

Predictors of outcome in children with acute viral hepatitis and coagulopathy

The presence of coagulopathy in acute viral hepatitis (AVH) in children raises issues about prognosis and need for liver transplantation. We evaluated factors predicting outcome in such patients and determined the applicability of the paediatric acute liver failure study group (PALFSG) definition of acute liver failure (ALF) of coagulopathy alone in comparison with coagulopathy and encephalopathy. Children with AVH (clinical features, raised transaminases and positive viral serology) with uncorrectable coagulopathy [prothrombin time (PT) > 15 s] with or without hepatic encephalopathy (HE) were enrolled. Comparative analysis was based on (i) outcome: survivors/nonsurvivors and (ii) ALF criteria: group A coagulopathy (PT > 15 s) and encephalopathy and group B coagulopathy (PT > 20 s). We studied 130 children (86 boys, mean age 7.5 ± 4.5 years): 86 recovered and 44 died. Single virus infection was present in 96 (74%), hepatitis A being the commonest (n-69). On multiple stepwise logistic regression analysis, age <3.5 years, serum bilirubin ≥ 16.7 mg/dL, PT ≥ 40.5 s and clinical signs of cerebral oedema were independent predictors of mortality. Mortality increased from 0% with single to 100% with four risk factors. Ninety-seven cases met the PALFSG criteria: group A-79 and group B-18. Group A subjects had higher mortality (55.6%vs 0%) and poorer liver functions (bilirubin 18.1 ± 8.9 vs 13.8 ± 6.9 mg/dL, PT 63.9 ± 35.1 vs 27.2 ± 5.2 s) than group B. PT deteriorated significantly with the appearance and progression of HE. One-third of children with AVH with coagulopathy die without transplantation. Age <3.5 years, bilirubin ≥ 16.7 mg/dL, PT ≥ 40.5 s and signs of cerebral oedema are predictors of poor outcome. Children with encephalopathy and coagulopathy have a poorer outcome than those with coagulopathy alone.     

Preconditioning by extracorporeal liver support (MARS) of patients with cirrhosis and severe liver failure evaluated for living donor liver transplantation -- a pilot study.

PURPOSE: The aim of this prospective study was to evaluate the effectiveness of preconditioning molecular adsorbent recirculating system (MARS) treatment on patients with acute-on-chronic liver failure (AoCLF), who were awaiting living donor liver transplantation (LDLT). PATIENTS AND METHODS: Between January and December 2001, 10 consecutive AoCLF patients (with progressive hyperbilirubinemia (>20 mg/dl) and hepatic encephalopathy grade > or =2) were studied. MARS was used in eight of these patients who were evaluated for LDLT during 2001. Three AoCLF patients who received LDLT before clinical use of MARS were used as historical controls. RESULTS: Because of a shortage of donors, only five out of 10 patients considered for LDLT could receive transplants. Three patients were treated with MARS for 8 h the day before receiving LDLT, and all three survived. The remaining two patients who received transplants, and who were not pretreated with MARS, died from sepsis and multi-organ failure within 2 weeks. Four of the patients who did not receive transplants because of donor shortage died despite 1 or 3 MARS treatments, however bilirubin levels and grade of encephalopathy were significantly reduced in these patients. CONCLUSIONS: Results of this small pilot study suggest that MARS, by reducing the severity of jaundice and encephalopathy, might be effective as a bridging option in AoCLF patients awaiting LDLT.     

Experimental research on TECA-I bioartificial liver support system to treat canines with acute liver failure

AIM To evaluate the efficacy and safety of the TECA-Ibloartificial liver support system(BALSS)in treatingcanines with acute liver failure(ALF).METHODS Ten canines with ALF induced by 80% liverresection received BALSS treatment(BALSS group).Blood was perfused through a hollow fiber tube containing1×10~(10) porcine hepatocytes.Four canines with ALF weretreated with BALSS without porcine hepatocytes(controlgroup),and five canines with ALF received drugtreatment(drug group).Each treatment lasted 6 hours.RESULTS BALSS treatment yielded beneficial effects forpartial liver resection-induced ALF canines with survivaland decreased plasma ammonia,ALT,AST and BIL.Therewas an obvious decrease in PT level and increase in PAlevel,and there were no changes in the count oflymphocytes,immunoglobulins(IgA,IgG and IgM)andcomplement(C3 and CA)levels after BALSS treatment.Incontrast,for the canines with ALF in non-hepatocyteBALSS group(control group)and drug group,there wereno significant changes in ammonia,ALT,AST,BIL,PTand PA levels.ALF canines in BALSS group,controlgroup and drug group lived respectively an average timeof 108.0h±12.0h,24.0h±6.0h and 20.4h±6.4h,andthree canines with ALF survived in BALSS group.CONCLUSION TECA-I BALSS is efficacious and safe forALF canines induced by parcial liver resection.     

MARS治疗6例肝功能衰竭体会

目的本研究探讨分子吸附再循环系统（MARS）在6例急性肝衰竭和慢性基础上急性加重患者中应用的效果。方法6例患者包括毒蘑菇中毒、肝癌、败血症休克、慢性肝衰竭急性加重等，其肝功能均严重受损，检测指标包括血氨、血总胆红素、直接胆红素、血尿素氮、血肌酐、肝性脑病级别等。结果经单次MARS治疗后血氨均有所下降，血总胆红素下降17．6％～40．0％，血肌酐及尿素氮均有不同程度下降。结论MARS是一种有效的人工肝支持系统，血胆红素越高其清除效果越明显，但对肝癌的效果差，治疗败血症休克需联合其他血液透析方式。     

Medical and psychiatric outcomes for patients transplanted for acetaminophen‐induced acute liver failure: a case–control study

Background: Acetaminophen‐induced hepatotoxicity is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence. Aims and methods: We compared the severity of pretransplant illness, psychiatric co‐morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999–2004 for acetaminophen‐induced ALF (n=36) with age‐ and sex‐matched patients undergoing emergent LT for non‐acetaminophen‐induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34). Results: Acetaminophen‐induced ALF patients undergoing LT had a greater severity of pre‐LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) acetaminophen‐induced ALF patients had a formal psychiatric diagnosis before LT (non‐acetaminophen‐induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow‐up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (acetaminophen‐induced ALF 1 year 87%, 5 years 75%; non‐acetaminophen‐induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two acetaminophen‐induced ALF patients reattempted suicide post‐LT (one died 8 years post‐LT). Conclusions: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for acetaminophen‐induced ALF were comparable to those transplanted for non‐acetaminophen‐induced ALF and electively for CLD. Multidisciplinary approaches with long‐term psychiatric follow‐up may contribute to low post‐transplant suicide rates seen and low rates of graft loss because of non‐compliance.     

Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure

We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups. Conclusion: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation.     

Salvage effect of E5564, Toll‐like receptor 4 antagonist on d‐galactosamine and lipopolysaccharide‐induced acute liver failure in rats

Background and Aims: The transmembrane protein Toll‐like receptor 4 (TLR4), which exists mainly in macrophages such as Kupffer cells of the liver, plays an important role in recognizing and mediating macrophage activation and pro‐inflammatory cytokine release. Activation of the pro‐inflammatory cytokine cascade, including tumor necrosis factor‐alpha (TNF‐α), has a pivotal role in the progression of severe liver injury. D‐galactosamine (GalN) and lipopolysaccharide (LPS)‐induced liver injury in rats is an experimental model of fulminant hepatic failure, where TNF‐α plays a central role in the progression of liver injury. E5564, a synthetic analogue of the lipid A component of endotoxin, inhibits endotoxin‐stimulated inflammation and is under study for patients with sepsis. In the present study, we sought to explore the salvage effect of TLR4 antagonist E5564 on GalN+LPS‐induced acute liver failure (ALF) in rats. Methods: ALF was induced in male Wistar rats by the intraperitoneal injection of GalN (500 mg/kg) and LPS (50 µg/kg). Immediately after GalN+LPS injection, rats were treated with intravenous injection of E5564 (3 mg/kg). The cumulative survival rates of GalN+LPS‐induced ALF rats were compared between those with and without E5564 treatment. Results: The intravenous injection of E5564 reduced the elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase and TNF‐α levels in rats at 3 h after GalN+LPS injection, and improved the survival rate of GalN+LPS‐induced ALF rats at 24 h (8% vs 43%). Conclusions: TLR4 antagonist E5564 reduced GalN+LPS‐induced acute liver injury in rats and improved the overall survival rate of GalN+LPS‐induced ALF rats. It may contribute to the treatment of ALF through blocking endotoxin‐induced TNF‐α overproduction of macrophages.     

Improvement of Multiple Organ Functions in Hepatorenal Syndrome During Albumin Dialysis with the Molecular Adsorbent Recirculating System

Abstract: Recently, significant improvement of renal function and prolongation of survival were reported in hepatorenal syndrome (HRS) patients treated with the Molecular Adsorbent Recirculating System (MARS). As no impact on extrarenal organ function was documented, this trial looked into multiple organ function changes during MARS in HRS patients. Eight HRS patients (4 male, mean age 42. 1 years, range 30–58, all United Network for Organ Sharing [UNOS] status 2A) were treated intermittendly 4–14 times (total 47, mean 5.9 ± 3.4) between 4 and 8 h/single treatment. The following changes were observed pre‐ and posttreatment: bilirubin 466 ± 146 to 284 ± 134 γmol/L, creatinine 380 ± 182 to 163 ± 119 μmol/L, urea 26.4 ± 10.3 to 12.9 ± 4.9 mmol/L, plasma sodium 127.5 ± 7.7 to 137.5 ± 4.8 mmol/L (all p < 0.01). Mean arterial pressure (MAP) increased from 71.9 ± 12.8 to 95.6 ± 7.8 Torr (p < 0.001). Oliguria or anuria, present in all patients, was successfully reverted. Ascites, present in all patients, was not detectable after the treatment period. The hepatic encephalopathy grade decreased from 2.8 ± 0.8 to 0.8 ± 0.7 (p < 0.0001). Child‐Index decreased from 13.25 ± 1.3 to 9.4 ± 1.8 (p < 0.001). The hospital survival rate was 62%. One man underwent successful liver transplantation 18 months after the treatment. We conclude that MARS can improve multiple organ functions in patients with HRS.     

Diagnostic criteria for acute liver failure due to Wilson disease

AIM: To describe the diagnostic criteria for acute liver failure due to Wilson disease (WD), which is an uncommon cause of acute liver failure (ALF). METHODS: We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS: Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate aminotransferase (AST) to alanine aminotransferase (ALT), failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities (53 ± 43 vs 1982 ± 938, P < 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively), low choline esterase activity (1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009), high urine copper concentrations (93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001) and low hemoglobin (7.0 ± 2.2 vs 12.6 ± 1.8, P < 0.0001) in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION: In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slit- lamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.     

A better method for assessment of hepatic function in hepatocellular carcinoma patients treated with radiofrequency ablation: Usefulness of albumin–bilirubin grade

Aim

To evaluate the efficacy of the newly proposed albumin–bilirubin (ALBI) grade for therapy selection, clinical features of patients treated with radiofrequency ablation (RFA) were elucidated.

Methods

From 2000 to 2015, 1101 patients with HCC (<3 cm, ≤3 tumors) treated with RFA were enrolled, with the following clinical features: 734 men and 367 women; 779 with hepatitis C virus, 153 with hepatitis B virus, 5 with hepatitis C and B, and 164 others; and Child–Pugh classification (CP) A : B ratio of 842:259. Liver damage classification (LD) using the indocyanine green retention rate at 15 min and ALBI‐grade were compared in regard to the prognoses of those patients.

Results

Median tumor size was 1.7 cm (interquartile range, 1.4–2.2 cm) and single tumors were found in 802 cases (72.8%) (tumor–node–metastasis stage of the Liver Cancer Study Group of Japan I : II : III = 536:454:111). In the LD‐A group, the number of cases with ALBI‐grade 1, 2, and 3 were 294, 224, and 1, respectively, while those in the LD‐B group were 47, 490, and 12, respectively. In the LD‐C group, 19 and 14 patients were ALBI‐2 and ‐3, respectively. Akaike Information Criterion values for CP, LD‐grade, and ALBI‐grade were 6015.4, 5988.8, and 5990.7, respectively. However, there was no significant difference regarding prognosis between LD‐A/B (n = 228) and C (n = 31) (median survival time, 4.8 vs. 3.9 years, P = 0.0818) in CP‐B, whereas a significant difference was observed regarding prognosis for ALBI‐1/2 (n = 232) and ALBI‐3 (n = 27) (median survival time, 4.8 vs. 2.7 years, P = 0.0168).

Conclusion

Albumin–bilirubin grade showed an assessment ability similar to that of LD‐grade. Furthermore, there was a small improvement in prognosis following RFA in patients with an ALBI‐grade of 3. Although only two serological parameters, albumin and total bilirubin, are used, assessment with ALBI‐grade may be more useful than with LD‐grade for avoiding a non‐beneficial RFA procedure.