Novel, nurse-led early postdischarge clinic is associated with fewer readmissions and lower mortality following hospitalisation with decompensated cirrhosis.

Objective: Patients hospitalised with decompensated cirrhosis have high rates of early unplanned readmission. Many readmissions are avoidable with secondary preventative strategies, but patients are often readmitted prior to outpatient review. To address this, we established a novel, nurse-led early postdischarge (EPD) clinic delivering goal-directed care for cirrhosis complications and evaluated the impact. Methods: Retrospective cohort study comparing outcomes in 78 patients seen in the EPD clinic with 91 phenotypically matched controls receiving standard, consultant hepatologist care. Follow-up for 12 months from index admission with endpoints including survival, time to readmission, number of readmissions and healthcare burden. Results: Median time to readmission was 51 days in controls and 98 days in the intervention group (p<0.01). The intervention cohort had significantly fewer readmissions at 30 days (12% vs 30%, p<0.01) and 90 days (27% vs 49%, p<0.01) but not significantly at 12 months (58% vs 68%, p=0.16) with an overall reduction in bed day usage of 29%. Mortality for the control group was 4% at 30 days with no deaths in the intervention group. There were significantly fewer deaths in the intervention group at 90 days (5% vs 15%, p<0.05) and 12 months (22% vs 41%, p<0.01). Conclusions: Following an index hospitalisation with decompensated cirrhosis, goal-directed postdischarge care can be effectively delivered by specialist nurses, prior to outpatient review by hepatologists. This model was associated with significantly fewer readmissions, lower bed day usage and a reduced mortality. Our data suggest such models of care deserve wider implementation and further evaluation.

Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans.

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.

Evaluation of a primary to secondary care referral pathway and novel nurse-led one-stop clinic for patients with suspected non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) affects approximately one in four adults of the general population, with an important minority of cases at high risk of developing cirrhosis. We evaluated the utility of a primary care NAFLD pathway incorporating a specialist nurse-led NAFLD clinic and a two-step testing approach for advanced liver fibrosis. DESIGN/METHOD: We performed a retrospective evaluation of prospectively collected demographic and clinical data on all patients diagnosed with NAFLD and intermediate NAFLD fibrosis score seen in our nurse-led NAFLD clinic between 1 May 2014 and 30 April 2017. Patients were assessed using a specific clerking pro forma and transient elastography (TE). Discharge to primary care with lifestyle advice was considered where TE<7.9 kPa. RESULTS: 904 patients were identified, 114 (12.6%) of whom did not meet NAFLD criteria. Among the NAFLD population (n=790 (87.4%)), TE<7.9 kPa was present in 558 patients (70.6%), 519 of whom were discharged to primary care. Selected patients were followed up in secondary care despite TE<7.9 kPa or discharged with TE≥7.9 kPa. TE was unreliable in 22 patients (2.7%). Overall, 559 (70.8%) of patients with confirmed NAFLD were discharged from the nurse-led clinic. Introduction of the new pathway was associated with increased screening for hepatitis B and C viruses in primary care, and 17 new cases of alpha-1-antitrypsin deficiency were identified. CONCLUSION: An integrated primary/secondary care NAFLD pathway, including a specialist nurse-led clinic may be a useful way of managing increasing demand on secondary care hepatology services.

Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with nonalcoholic fatty liver disease (NAFLD). We investigated whether administration of a synbiotic combination of probiotic and prebiotic agents affected liver fat content, biomarkers of liver fibrosis, and the composition of the fecal microbiome in patients with NAFLD. METHODS: We performed a double-blind phase 2 trial of 104 patients with NAFLD in the United Kingdom. Participants (mean age, 50.8 ± 12.6 years; 65% men; 37% with diabetes) were randomly assigned to groups given the synbiotic agents (fructo-oligosaccharides, 4 g twice per day, plus Bifidobacterium animalis subspecies lactis BB-12; n = 55) or placebo (n = 49) for 10-14 months. Liver fat content was measured at the start and end of the study by magnetic resonance spectroscopy, and liver fibrosis was determined from a validated biomarker scoring system and vibration-controlled transient elastography. Fecal samples were collected at the start and end of the study, the fecal microbiome were analyzed by 16S ribosomal DNA sequencing. RESULTS: Mean baseline and end-of-study magnetic resonance spectroscopy liver fat percentage values were 32.3% ± 24.8% and 28.5% ± 20.1% in the synbiotic group and 31.3% ± 22% and 25.2% ± 17.2% in the placebo group. In the unadjusted intention-to-treat analysis, we found no significant difference in liver fat reduction between groups (ß = 2.8; 95% confidence interval, -2.2 to 7.8; P = .30). In a fully adjusted regression model (adjusted for baseline measurement of the outcome plus age, sex, weight difference, and baseline weight), only weight loss was associated with a significant decrease in liver fat (ß = 2; 95% confidence interval, 1.5-2.6; P = .03). Fecal samples from patients who received the synbiotic had higher proportions of Bifidobacterium and Faecalibacterium species, and reductions in Oscillibacter and Alistipes species, compared with baseline; these changes were not observed in the placebo group. Changes in the composition of fecal microbiota were not associated with liver fat or markers of fibrosis. CONCLUSIONS: In a randomized trial of patients with NAFLD, 1 year of administration of a synbiotic combination (probiotic and prebiotic) altered the fecal microbiome but did not reduce liver fat content or markers of liver fibrosis. (ClinicalTrials.gov, Number: NCT01680640).

Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation.

Myofibroblastic, activated hepatic stellate cells (HSC) play a pivotal role in the development of liver fibrosis through the secretion of fibrillar collagens and the tissue inhibitors of metalloproteinase (TIMP)-1 and -2. TIMPs are believed to promote hepatic fibrosis by inhibiting both matrix degradation and apoptosis of HSC. In other cell types, there is evidence that TIMP-1 has effects on proliferation, however the role of TIMPs in the regulation of HSC proliferation remains unexplored. Therefore, we have used short interfering RNA (siRNA) to investigate the effects of autocrine TIMP-1 and -2 on HSC proliferation. TIMP-1 and -2 siRNA were highly effective, producing peak target protein knockdown compared to negative control siRNA of 92% and 63%, respectively. Specific silencing of TIMP-1, using siRNA, significantly reduced HSC proliferation. TIMP-1 was localised in part to the HSC nucleus and TIMP-1 siRNA resulted in loss of both cytoplasmic and nuclear TIMP-1. Attenuated proliferation was associated with reduced Akt phosphorylation and was partially rescued by addition of recombinant TIMP-1. We have revealed a novel autocrine mitogenic effect of TIMP-1 on HSC, which may involve Akt-dependent and specific nuclear mechanisms of action. We suggest that TIMP-1 might promote liver fibrosis by means other than its previously described anti-apoptotic effect on HSC. Moreover, these findings, together with our previous reports and the emerging data from in vivo studies of TIMP inhibition, provide strong evidence that TIMP-1 is mechanistically central to liver fibrosis and an important potential therapeutic target.

Telaprevir: a new hope in the treatment of chronic hepatitis C?

More than 180 million people worldwide have chronic hepatitis C (CHC) virus infection, a major cause of liver cirrhosis and its life-threatening complications including liver failure, portal hypertension, and hepatocellular carcinoma. With the current standard of care of pegylated interferon-alpha and ribavirin (PEG-IFN-alpha/RBV), the chances of sustained viral clearance or "cure" are only 40%-50% for genotype 1 infection, which is the most common genotype in western populations. Consequently, there has been a drive to develop new agents specifically targeting essential components of the viral life cycle, such as the hepatitis C virus (HCV) NS3/4A serine protease. Perhaps the most advanced HCV protease inhibitor in clinical development is telaprevir, which has been shown to improve treatment outcomes when combined with PEG-IFN-alpha/RBV in genotype 1 infection, and is currently undergoing phase 3 study. In this review, we summarize the pharmacology, pharmacokinetics, and results of phase 1 and 2 clinical trials of telaprevir, and discuss the likely role of this agent in the future management of CHC.

Renal hepatitis C in the absence of detectable serum or hepatic virus.

We report an apparently unique case where hepatitis C virus (HCV) RNA was identified in renal tissue from a patient with membranoproliferative glomerulonephritis and treated chronic hepatitis C, despite the absence of detectable virus in the serum or liver (COBAS Amplicor qualitative assay, lower limit of detection 50 IU/ml). The implications of this finding are discussed, with particular reference to current concepts regarding 'occult' hepatitis C infection.

Emerging therapies for liver fibrosis.

Liver fibrosis occurs as a result of a wide range of injurious processes and in its end-stage results in cirrhosis. This gross disruption of liver architecture is associated with impaired hepatic function, portal hypertension and significant resultant morbidity and mortality. Indeed, liver fibrosis and cirrhosis represent a major worldwide healthcare burden. Recent progress in liver transplantation, the management of portal hypertension and the treatment of chronic viral hepatitis have had an important impact. However, these approaches are not without their limitations - in particular, issues regarding organ availability for transplantation - and serve to highlight the urgent requirement to influence pharmacologically the underlying fibrotic process in many patients. Liver fibrosis has been shown to be a bidirectional process and increasing data from laboratory and clinical studies reveal that even advanced fibrosis and cirrhosis are potentially reversible. Exploration of the molecular mechanisms underlying this bi-directionality will lead to char acterisation of the essential attributes of an antifibrotic therapy. In this review, these mechanisms are highlighted and the growing number of emerging antifibrotic agents discussed.