Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure

Background and Aim: Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. Methods: Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague‐Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto‐Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)‐α were determined. Results: In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL‐1β, IL‐6, IL‐10 and TNF‐α or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF‐α levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM‐treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline‐treated rats. Conclusions: Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA‐induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.     

Infection and the progression of hepatic encephalopathy in acute liver failure

BACKGROUND & AIMS: Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. METHODS: We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. RESULTS: On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.     

Role of circulating neurotoxins in the pathogenesis of hepatic encephalopathy: potential for improvement following their removal by liver assist devices

Abstract Both acute and chronic liver failure result in impaired cerebral function known as hepatic encephalopathy (HE). Evidence suggests that HE is the consequence of the accumulation in brain of neurotoxic and/or neuroactive substance including ammonia, manganese, aromatic amino acids, mercaptans, phenols, short‐chain fatty acids, bilirubin and a variety of neuroactive medications prescribed as sedatives to patients with liver failure. Brain ammonia concentrations may attain levels in excess of 2 mm , concentrations which are known to adversely affect both excitatory and inhibitory neurotransmission as well as brain energy metabolism. Manganese exerts toxic effects on dopaminergic neurones. Prevention and treatment of HE continues to rely heavily on the reduction of circulating ammonia either by reduction of gut production using lactulose or antibiotics or by increasing its metabolism using l ‐ornithine‐l ‐aspartate. No specific therapies have so far been designed to reduce circulating concentrations of other toxins. Liver assist devices offer a potential new approach to the reduction of circulating neurotoxins generated in liver failure. In this regard, the Molecular Absorbents Recirculating System (MARS) appears to offer distinct advantages over hepatocyte‐based systems.     

Serum levels of tumor necrosis factor‐α correlate with severity of hepatic encephalopathy due to chronic liver failure

Background: Several studies have shown that serum levels of tumor necrosis factor‐α (TNF) are significantly elevated in patients with acute and chronic liver diseases, where these elevations are independent of the etiology of the underlying disease. Serum levels of TNF are significantly higher in patients with cirrhosis than in those without cirrhosis, reaching the highest levels in decompensated cirrhosis. It has also been shown that plasma levels of TNF correlate with the severity of hepatic encephalopathy (HE) in fulminant hepatic failure. However, still there are no published data regarding the relationship between blood levels of TNF and the presence or severity of HE in patients with chronic liver failure. Aim: The aim of this study is to determine the relationship between serum levels of TNF and clinical grades of HE in patients with liver cirrhosis. Methods: Using a commercially available high‐sensitivity enzyme‐linked immunosorbent assay kit, serum levels of TNF were measured in 74 patients with liver cirrhosis in various clinical grades of HE (grades 0–4). Results: The mean±SEM values of serum levels of TNF at presentation in patients with grade 0 of HE (n=23), grade 1 (n=12), grade 2 (n=14), grade 3 (n=16), and grade 4 (n=9) were 4.50±0.46, 9.10±1.0, 12.98±1.22, 21.51±2.63, and 58.26±19.7 pg/ml, respectively. A significant positive correlation was found between serum levels of TNF and the severity of HE (P<0.0001). Conclusion: Serum levels of TNF correlate positively with the severity of HE in patients with chronic liver failure.     

Economic evaluation and 1‐year survival analysis of MARS in patients with alcoholic liver disease

Abstract Objective of this study was to determine 1‐year survival, costs and cost‐effectiveness of the artificial liver support system Molecular Adsorbent Recirculating System (MARS) in patients with acute‐on‐chronic liver failure (ACLF) and an underlying alcoholic liver disease. In a case–control study, 13 patients treated with MARS were compared to 23 controls of similar age, sex and severity of disease. Inpatient hospital costs data were extracted from patients' files and hospital's internal costing. Patients and treating GPs were contacted, thus determining resource use and survival 1‐year after treatment. Mean 1‐year survival time in MARS group was 261 days and 148 days in controls. Kaplan–Meier analysis shows advantages of MARS patients (Logrank: P = 0.057). Direct medical costs per patient for initial hospital stay and 1‐year follow‐up from a payer's perspective were €18 792 for MARS patients and €9638 for controls. The costs per life‐year gained are €29 719 (time horizon 1 year). From a societal perspective, the numbers are higher (costs per life‐year gained: €79 075), mainly because of the fact that there is no regular reimbursement of MARS and therefore intervention costs were not calculated from payer's perspective. A trade‐off between medical benefit and higher costs has to be made, but 1‐year results suggest an acceptable cost‐effectiveness of MARS. Prolonging the time horizon and including indirect costs, which will be done in future research, would probably improve cost‐effectiveness.     

Fatty liver index and hepatic steatosis index for prediction of non‐alcoholic fatty liver disease in type 1 diabetes

Background and Aim

Little is known about the diagnostic value of hepatic steatosis index (HSI) and fatty liver index (FLI), as well as their link to metabolic syndrome in type 1 diabetes mellitus. We have screened the effectiveness of FLI and HSI in an observational pilot study of 40 patients with type 1 diabetes.

Methods

FLI and HSI were calculated for 201 patients with type 1 diabetes. Forty patients with FLI/HSI values corresponding to different risk of liver steatosis were invited for liver magnetic resonance study. In‐phase/opposed‐phase technique of magnetic resonance was used. Accuracy of indices was assessed from the area under the receiver operating characteristic curve.

Results

Twelve (30.0%) patients had liver steatosis. For FLI, sensitivity was 90%; specificity, 74%; positive likelihood ratio, 3.46; negative likelihood ratio, 0.14; positive predictive value, 0.64; and negative predictive value, 0.93. For HSI, sensitivity was 86%; specificity, 66%; positive likelihood ratio, 1.95; negative likelihood ratio, 0.21; positive predictive value, 0.50; and negative predictive value, 0.92. Area under the receiver operating characteristic curve for FLI was 0.86 (95% confidence interval [0.72; 0.99]); for HSI 0.75 [0.58; 0.91]. Liver fat correlated with liver enzymes, waist circumference, triglycerides, and C‐reactive protein. FLI correlated with C‐reactive protein, liver enzymes, and blood pressure. HSI correlated with waist circumference and C‐reactive protein. FLI ≥ 60 and HSI ≥ 36 were significantly associated with metabolic syndrome and nephropathy.

Conclusions

The tested indices, especially FLI, can serve as surrogate markers for liver fat content and metabolic syndrome in type 1 diabetes.     

Revised criteria for classification of the etiologies of acute liver failure and late‐onset hepatic failure in Japan: A report by the Intractable Hepato‐biliary Diseases Study Group of Japan in 2015

In 2011, the Intractable Liver Diseases Study Group of Japan, established novel diagnostic criteria for “acute liver failure ”, and published the classification criteria for the etiologies of acute liver failure and late‐onset hepatic failure (LOHF) in 2013. According to this classification, HBV carriers showing acute hepatitis exacerbation were divided into 3 subgroups; asymptomatic or inactive HBV carriers without drug exposure, asymptomatic or inactive HBV carriers developing HBV reactivation during and after immunosuppressive therapies and/or antineoplastic chemotherapies and those with previously resolved HBV infection showing iatrogenic HBV reactivation. In an annual nationwide survey in 2013, however, a patient with previously resolved HBV infection was enrolled, in whom LOHF developed as a result of HBV reactivation despite in the absence of immunosuppressive therapies and/or antineoplastic chemotherapies. Thus, the study group revised the classification criteria in 2015; HBV carriers developing acute hepatitis exacerbation were classified into asymptomatic or inactive HBV carriers and patients with previously resolved HBV infection, and both groups were further sub‐classified into those receiving immunosuppressive therapies and/or antineoplastic chemotherapies and those without such drugs exposure.