MARS treatment in posthepatectomy liver failure

Abstract Posthepatectomy liver failure (PHLF) is a dramatic complication following extensive liver resection or liver resection in a compromised liver, leading to death in 80% of cases. Molecular Adsorbent Recirculating System (MARS) is able to extract water and protein bound toxins out of the blood in liver failure patients. This paper describes the initial experience in the Netherlands using the MARS liver assist device in five patients with PHLF. In all patients, improvement of biochemical parameters was observed during MARS treatment along with clinical improvement in three patients. One patient survived. No clear guidelines for MARS treatment and prognostic factors for outcome after MARS treatment with regard to this patient group are available. In this paper, a MARS treatment regimen for PHLF is suggested based on literature and our own experience.     

Systematic review of MARS treatment in post-hepatectomy liver failure

BackgroundPost-hepatectomy liver failure (PHLF) remains a serious complication after major liver resection with severe 90-day mortality. Molecular adsorbent recirculating system (MARS) is a potential treatment option in PHLF. This systematic review sought to analyze the experiences and results of MARS in PHLF.MethodsFollowing the PRISMA guidelines, a systematic literature review using PubMed and Embase was performed. Non-randomized trials were assessed by the MINORS criteria.Results2884 records were screened and 22 studies were extracted (no RCT). They contained 809 patients including 82 patients with PHLF. Five studies (n = 34) specifically investigated the role of MARS in patients with PHLF. In these patients, overall 90-day survival was 47%. Patients with primary PHLF had significantly better 90-day survival compared to patients with secondary PHLF (60% vs 14%, p = 0.03) and treatment was started earlier (median POD 6 (range 2–21) vs median POD 30 (range 15–39); p < 0.001). Number of treatments differed non-significantly in these groups. Safety and feasibility of early MARS treatment following hepatectomy was demonstrated in one prospective study. No major adverse events have been reported.ConclusionEarly MARS treatment is safe and feasible in patients with PHLF. Currently, MARS cannot be recommended as standard of care in these patients. Further prospective studies are warranted.     

MCP-1 and MIP3-alpha serum levels in acute liver failure and molecular adsorbent recirculating system (MARS) treatment: A pilot study

Objective. The CC chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-3 alpha (MIP3-alpha) may be involved in the pathogenesis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). In ALF and ACLF, the molecular adsorbent recirculating system (MARS) has been used to support liver function. Enhancement of MCP-1, as seen in other extracorporeal support systems such as haemodialysis, might thus have mitigated the beneficial effects of the MARS system in acute hepatic failure. Material and methods. Serum concentrations of MCP-1 and MIP3-alpha were measured in 10 patients with ALF or ACLF treated with MARS. Thirteen patients suffering from chronic hepatic failure (CHF) and 15 healthy individuals served as controls. Results. Baseline MCP-1 serum concentrations were significantly increased in ALF and ACLF patients as compared to patients with CHF (p=0.0027 and p=0.0046, respectively) and controls (p=0.0006 and p=0.0012, respectively). MIP3-alpha serum concentrations were also significantly enhanced in the ALF and ACLF groups as compared with those in CHF patients (p=0.0002 and p=0.0003, respectively) and controls (p<0.0001 and p<0.0001, respectively). Moreover, MIP3-alpha levels were significantly increased in CHF patients as compared to controls (p=0.0002). MCP-1 and MIP3-alpha concentrations did not change significantly during MARS treatment in ALF and ACLF patients. Conclusions. The CC chemokines MCP-1 and MIP3-alpha are increased in ALF and ACLF patients. MARS had no effect on MCP-1 and MIP3-alpha serum concentrations in patients with ALF and ACLF, and yielded no evidence of any harmful effects of the increase of these potentially hepatocidal chemokines.     

High serum erythropoietin levels are normalized during treatment of congestive heart failure with enalapril

Eighteen patients with dilated cardiomyopathy (three female, mean age 57 years), were treated for 48 weeks with enalapril added to digoxin and diuretic therapy for congestive heart failure of New York Heart Association (NYHA) functional class II (three patients). III (eight patients) and IV (seven patients), respectively. Serum levels of erythropoietin (EPO) were raised at the start (37 +/- 12.8 pmol 1(-1); mean +/- SD) and were normalized during enalapril treatment (17.5 +/- 9.9 pmol 1(-1) at 48 weeks; P less than 0.001). Serum EPO correlated at the start with NYHA functional class (r = 0.68; P less than 0.05). Normalization of elevated serum EPO concentrations during treatment with enalapril paralleled clinical and haemodynamic improvement, and probably reflected relief from renal hypoxia.     

Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry

Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.     

Elevated neopterin levels are associated with acute-on-chronic liver failure and mortality in patients with liver cirrhosis

BackgroundMacrophage activation plays a central role in hepatic and systemic inflammation and is involved in the pathogenesis of acute-on-chronic liver failure (ACLF).AimsThis study aimed to investigate neopterin levels in patients admitted for acute decompensation (AD) of cirrhosis, evaluating its relationship with ACLF and prognosis.MethodsThis prospective cohort study included 205 adult subjects hospitalized for AD of cirrhosis. Twenty-one healthy subjects and 89 patients with stable cirrhosis were evaluated as controls.ResultsCirculating neopterin was higher in AD as compared to stable cirrhosis and healthy controls (p<0.001). ACLF was independently associated with higher neopterin levels (OR 1.015, 95% CI 1.002–1.028, p = 0.025). In the multivariate Cox regression analysis, neopterin levels (HR = 1.002, IC 95% 1.000–1.004, p = 0.041), Child–Pugh class C, and ACLF were predictors of 30-day survival. Among patients with ACLF, the Kaplan–Meier survival probability was 71.4% in those with neopterin levels < 25 nmol/L and 31.0% if neopterin ≥ 25 nmol/L (p<0.001).ConclusionsHigher circulating neopterin was associated with ACLF in patients hospitalized for AD of cirrhosis. Neopterin levels were also independently predictors of high short-term mortality, especially among patients with ACLF, and could represent a useful biomarker of macrophage activation in clinical practice.     

Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure

INTRODUCTION: Increased local and systemic elaboration of cytokines have an important role in the pathogenesis of congestive heart failure (CHF) through diverse mechanisms. Because cytokines are known to act at the neuronal level in both the peripheral and central nervous system, we sought to determine whether increased cytokine levels are associated with the autonomic dysfunction that characterizes CHF. METHODS AND RESULTS: We studied 64 patients admitted for decompensated CHF (mean age 59+/-12 years). Autonomic function was assessed using time- and frequency-domain heart rate variability (HRV) measures, obtained from 24-hour Holter recordings. In addition, norepinephrine, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured in all patients. TNF-alpha levels did not correlate with any of the HRV measures. IL-6 inversely correlated with the time-domain parameters of standard deviation of RR intervals (SDNN) (r = -0.36, P = 0.004) and standard deviation of all 5-minute mean RR intervals (SDANN) (r = -0.39, P = 0.001), and with the frequency-domain parameters of total power (TP) (r = -0.37, P = 0.003) and ultralow-frequency (ULF) power (r = -0.43, P = 0.001). No correlation was found between IL-6 and indices of parasympathetic modulation. Using multiple linear regression models, adjusting for clinical variables and drug therapies, the strong inverse relationship between IL-6 and SDNN (P = 0.006), SDANN (P = 0.001), TP (P = 0.04), and ULF power (P = 0.0007) persisted. CONCLUSION: Reduction of long-term HRV indices is associated with increased levels of IL-6 in patients with decompensated heart failure. The ability of long-term HRV parameters to better reflect activation of diverse hormonal systems may explain their greater prognostic power for risk stratification in patients with CHF.     

MARS人工肝治疗急慢性肝功能衰竭的临床研究

目的　评价应用分子吸附再循环系统治疗各类原因所致肝功能衰竭的治疗效果。方法　回顾并随访分析5 0例次MARS人工肝治疗的疗效。结果　单次 6～ 8小时MARS人工肝治疗显著降低患者血清总胆红素 ( 5 19.3 7±15 2 .70 μmol/L降至 3 61.0 6± 177.98μmol/L ,p <0 .0 5 )和血氨 ( 167.44± 80 .73 μmol/L降至 86.82± 15 .5 2 μmol/L ,P <0 .0 5 )水平 ;升高凝血酶原活动度 ( 3 6.5 5 %± 15 .2 9%到 74.13 %± 2 5 .40 %,P <0 .0 5 )。而电解质、血常规和血气分析等指标无显著变化 (P >0 .0 5 )。 2 5例患者中治愈和好转 15例 ,10例死亡 ,存活率 60 %。结论　MARS人工肝是治疗肝功能衰竭患者安全、有效的辅助方法     

血清高迁移率族蛋白1在乙型肝炎病毒相关慢加急性肝衰竭患者中的特点及其临床意义

目的 探讨血清高迁移率族蛋白1 (HMGB1)在HBV相关的慢加急性肝衰竭(HBV-ACLF)患者中的特点及其临床意义.方法 对60例HBV-ACLF患者血清HMGB1水平进行检测分析,并与30例慢性乙型肝炎患者和24例健康查体者进行对照研究,分析其与患者肝功能生物化学指标的相关性,并分析其与患者预后的关系.两组间比较采用独立样本的t检验或非参数检验,多组间比较采用方差分析,相关性分析采用多元线性回归法.结果 HBV-ACLF患者血清HMGB1水平高于慢性乙型肝炎患者[(10.03±3.08) μg/L比对(7.47+2.06) μg/L,t=2.667,P＜0.01],晚期HBV-ACLF患者血清HMGB1水平高于早期患者[(11.68±1.93) μg/L比对(9.11±3.15)μ g/L,t=2.214,P＜0.01],HBV-ACLF患者血清HMGB1水平与AST水平呈正相关(r=0.655,P＜0.01).随访2个月,感染组患者的HMGB1水平高于非感染组[(11.85±2.21)μ g/L比对(9.83±2.75) μg/L,Z=4.027,P＜0.05],死亡组患者的HMGB1水平高于生存组[(11.03±2.31)μg/L比对(9.52±3.01)μg/L,t=2.428,P＜0.05].结论 HBV-ACLF患者血清HMGB1水平随病情进展呈进行性升高,并可部分预测HBV-ACLF患者的预后.     

Increased serum and hepatic tissue levels of interleukin-18 in patients with fulminant hepatic failure

BACKGROUND: Fulminant hepatic failure is a serious clinical condition associated with a high mortality rate. Interleukin (IL)-18 is a pro-inflammatory cytokine that is associated with several inflammatory diseases. The purpose of the present paper was therefore to investigate whether IL-18 is elevated in patients with fulminant hepatic failure. METHODS: Serum levels of IL-18 were measured in patients with fulminant hepatic failure before and after liver transplantation. Native liver tissue samples were collected and the tissue levels of IL-18 were determined. Liver tissues were stained immunohistochemically with antihuman IL-18 antibody. The serum levels of IL-1beta, IL-6, IL-8, IL-12, interferon-gamma, and tumor necrosis factor-alpha were also determined in patients with fulminant hepatic failure before and after liver transplantation. RESULTS: Elevated levels of IL-18 in serum and hepatic tissue were observed in patients with fulminant hepatic failure. Native liver tissue samples were immunohistochemically positive for IL-18. Interleukin-18 levels were markedly reduced after liver replacement. No other inflammatory cytokines were substantially elevated in patients with fulminant hepatic failure. CONCLUSION: The serum levels of IL-18 levels are elevated much more than those of other cytokines in patients with fulminant hepatic failure.     

白细胞介素-18和1型糖尿病

白细胞介素-18(IL-18)是一种炎症细胞因子,它可以促进Th1免疫反应,诱导T细胞增生并分泌大量的干扰素-γ。作为一种新的细胞因子,IL-18的产生和1型糖尿病密切相关。文中主要从1型糖尿病时IL-18表达水平的改变、IL-18在1型糖尿病发病机制中的作用、IL-18基因单核苷酸多态性与1型糖尿病的关系、阻止IL-18的表达与1型糖尿病的治疗方面介绍了IL-18与1型糖尿病相关的研究进展。     

Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation

Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Concentrations of ghrelin are controversial in liver cirrhosis. Our aim was to study fasting ghrelin and their response to an oral glucose tolerance test (OGTT) in liver failure patients and normal subjects. Methods We included 16 patients with severe liver failure prior to liver transplantation. As a control group we included 10 age- and BMI-matched healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min, respectively. Results Fasting ghrelin (median and range) were statistically significantly lower for patients compared to the controls, 527 (377–971) pg/ml vs. 643 (523–2163) pg/ml, P = 0.045, for patients and controls, respectively. The area under the curve for total ghrelin post-OGTT were lower in end-stage liver failure patients than in the control group, 58815 (44730–87420) pg/ml min vs. 76560 (56160–206385) pg/ml min, for patients and controls, respectively, P = 0.027. Conclusions Ghrelin levels are significantly decreased both fasting and post-OGTT in patients with liver failure candidates for transplantation. Decreased ghrelin levels could contribute to anorexia in patients with cirrhosis.     

Admission levels and early changes in serum interleukin‐10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis

Backround & Aim: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti‐inflammatory cytokine interleukin (IL)‐10. We investigated the prognostic value of admission IL‐10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro‐inflammatory cytokines IL‐6 and tumour necrosis factor (TNF)‐α. Methods: We measured these cytokines within 48 h of admission in 51 ALF and 39 decompensated cirrhosis patients admitted to intensive care, and obtained follow‐up measurement a median of 2 days later in 35 patients. Results: Levels of all cytokines were higher in those with a poor outcome. IL‐10 performed as well as TNF‐α and IL‐6 in the whole cohort (area under receiver operator curve 0.73 vs 0.66 and 0.72). However IL‐10 outperfomed pro‐inflammatory cytokines in the subgroups with ALF (0.80 vs 0.63 and 0.70) and acetaminophen‐induced ALF (0.92 vs 0.67 and 0.81). Levels of all cytokines rose significantly in non‐surviving patients (n=15); IL‐10 by a factor of 2, TNF‐α by 2.6 and IL‐6 by 1.13. No significant changes were seen in the surviving patients. In ALF, IL‐10 was an independent predictor of outcome in multivariate analysis. Conclusion: The magnitude of the compensatory anti‐inflammatory response at admission, and its development during the early phase of treatment, predicts outcome as well as the pro‐inflammatory response in acute hepatic syndromes and supports a vital role for this immunological phenomenon in the outcome of these patients.     

Angiopoietin-2 serum levels are elevated in patients with liver cirrhosis and hepatocellular carcinoma

OBJECTIVES: Liver cirrhosis is characterized by remodeling leading to nodules that are difficult to discern from hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) serum levels are used for the screening for HCC, with limited success. We evaluated angiopoietin-2 as a serum marker in patients with cirrhosis and with HCC. METHODS: In a retrospective study, we measured angiopoietin-2 serum levels in 131 patients with HCC, 180 patients with cirrhosis, and 40 healthy controls. We also determined AFP serum levels in patients with HCC and compared the test characteristics of both serum markers. The expression patterns of angiopoietin-2 were determined by in situ hybridization in healthy and cirrhotic livers as well as in HCC. RESULTS: Angiopoietin-2 serum levels were elevated in patients with liver cirrhosis (P < 0.0001) compared with healthy controls. Levels were further elevated in patients with HCC compared with healthy controls (P < 0.0001) and cirrhotic patients (P < 0.0001). The combination with AFP measurements led to improved discrimination between HCC and cirrhosis. Angiopoietin-2 message was present in tumor cells of HCCs but was absent from hepatocytes of cirrhotic and healthy livers. In cirrhosis, message was detected within the strands of fibrous tissue. CONCLUSIONS: Serum angiopoietin-2 levels are elevated in patients with cirrhosis, implicating a possible role of the angiopoietin-Tie-2 system for neoangiogenesis in cirrhosis. Serum levels are further elevated in patients with HCC, suggesting the potential use of angiopoietin-2 as a marker for the detection of cirrhosis and HCC.