EASL clinical practice guidelines: non-invasive liver tests for evaluation of liver disease severity and prognosis.

The European Association for the Study of the Liver has recently published updated guidelines on the use of non-invasive tests to identify and stratify chronic liver disease. Here, we provide a summary of the key recommendations from the guideline.

Evaluating future risk of NAFLD in adolescents: a prediction and decision curve analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest liver condition in the western world and is directly linked to obesity and the metabolic syndrome. Elevated body mass index is regarded as a major risk factor of NAFL (steatosis) and NAFLD fibrosis. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we sought to investigate whether other variables from adolescence could improve prediction of future NAFL and NAFLD fibrosis risk at 24 years, above BMI and sex. METHODS: Aged 24 years, 4018 ALSPAC participants had transient elastography (TE) and controlled attenuation parameter (CAP) measurement using Echosens 502 Touch. 513 participants with harmful alcohol consumption were excluded. Logistic regression models examined which variables measured at 17 years were predictive of NAFL and NAFLD fibrosis in young adults. Predictors included sex, BMI, central adiposity, lipid profile, blood pressure, liver function tests, homeostatic model assessment for insulin resistance (HOMA-IR), and ultrasound defined NAFL at 17 years (when examining fibrosis outcomes). A model including all these variables was termed "routine clinical measures". Models were compared using area under the receiver operator curve (AUROC) and Bayesian Information Criterion (BIC), analysis, which penalises model complexity. Models were tested in all participants and those with overweight or obese standardised BMIs (BMI SDS) centiles at the 17-year time point. A decision curve analysis (DCA) was performed to evaluate the clinical utility of models in overweight and obese adolescents predicting NAFLD fibrosis at a threshold probability of 0.1. RESULTS: The "routine clinical measures" model had the highest AUROC for predicting NAFL in all adolescent participants (AUROC 0.79 [SD 0.00]) and those with an overweight/obese BMI SDS centile (AUROC 0.77 [SD 0.01]). According to BIC analysis, insulin resistance was the best predictor of NAFL in all adolescents, whilst central adiposity was the best predictor in those with an overweight/obese BMI SDS centile. The "routine clinical measures" model also had the highest AUROC for predicting NAFLD fibrosis in all adolescent participants (AUROC 0.78 [SD 0.02]) and participants with an overweight/obese BMI SDS centile (AUROC 0.84 [SD 0.03]). However, following BIC analysis, BMI was the best predictor of NAFLD fibrosis in all adolescents including those with an overweight/obese BMI SDS centile. A decision curve analysis examining overweight/obese adolescent participants showed the model that had the greatest net benefit for increased NAFLD fibrosis detection, above a treat all overweight and obese adolescents' assumption, was the "routine clinical measures" model. However, the net benefit was marginal (0.0054 [0.0034-0.0075]). CONCLUSION: In adolescents, routine clinical measures were not superior to central adiposity and BMI at predicting NAFL and NAFLD fibrosis respectively in young adulthood. Additional routine clinical measurements do provide incremental benefit in detecting true positive fibrosis cases, but the benefit is small. Thus, to reduce morbidity and mortality associated with NASH cirrhosis in adults, the ultimate end point of NAFLD, the focus must be on obesity management at a population level.

Association of maternal pre-pregnancy BMI and breastfeeding with NAFLD in young adults: a parental negative control study.

BACKGROUND: The importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood. METHODS: 4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI. FINDINGS: There was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74]. INTERPRETATION: Higher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD. FUNDING: Medical Research Council UK, Alcohol Research UK, David Telling Charitable Trust.

A Novel Method for Continuous, Noninvasive, Cuff-Less Measurement of Blood Pressure: Evaluation in Patients With Nonalcoholic Fatty Liver Disease.

OBJECTIVE: One promising approach for a continuous, noninvasive, cuff-less ambulatory blood pressure (BP) monitor is to measure the pulse wave velocity or the inversely proportional pulse transit time (PTT), based on electrical and optical physiological measurements in the chest area. A device termed IsenseU-BP+ has been developed for measuring continuous BP, as well as other physiological data. The objective of this paper is to present results from the first clinical evaluation with a wide range of patients. The study was set up to verify whether IsenseU-BP+ can be used to measure raw signals with sufficient quality to derive PTT.  Methods: The test protocol, run 23 times on 18 different patients with nonalcoholic fatty liver disease, includes both supine measurement at rest as well as measurements during indoor cycling. Changes in PTT were compared with the BP changes measured using validated reference sensors.  Results: IsenseU-BP+ measured signals with good quality during rest on 17 of 18 patients despite the high diversity in age, body shape, and body mass index. Evaluation during cycling was difficult due to a lack of good reference measurements. CONCLUSION: IsenseU-BP+ measures PTT with high quality during supine rest and exercise and could therefore be suitable for deriving noninvasive continuous BP, although evaluation during exercise was limited due to inaccurate reference BP measurements. SIGNIFICANCE: Continuous, noninvasive measurement of BP would be highly beneficial in a number of clinical settings. Systems currently considered as the gold standard for the investigation of hypertension carry considerable limitations, which could be overcome by the method proposed here.

Natural History of Patients Taking Rifaximin-α for Recurrent Hepatic Encephalopathy and Risk of Future Overt Episodes and Mortality: A Post-hoc Analysis of Clinical Trials Data.

PURPOSE: Hepatic encephalopathy (HE) is a complication of cirrhosis signaling decompensation and is associated with mortality. There has been little characterization of HE once an incident episode has occurred and of what effect the transition to overt HE might have on outcomes. We characterized the relationships between the number of previous HE episodes and risk of subsequent episodes and mortality to better understand the natural history of HE. METHODS: Data on 321 patients from a 24-month, open-label, nonrandomized trial evaluating the long-term safety profile and tolerability of twice-daily rifaximin-α 550 mg were analyzed. Patients were followed for a mean of 1.5 years (total follow-up of 467 years). FINDINGS: There were a total of 334 HE episodes and 75 deaths, corresponding to unadjusted event rates of 715 HE episodes and 161 deaths per 1000 years. There was a direct association between rate of subsequent HE episodes and number of prior HE episodes; the risk of subsequent HE episodes was elevated for each additional HE episode (hazard ratio = 1.23; 95% CI, 1.19-1.29). There was a nonlinear, nonmonotonic relationship between risk of death and number of prior HE episodes; risk initially increased, then decreased, and finally plateaued as the number of prior HE episodes increased. IMPLICATIONS: Patients with a larger number of previous, overt HE episodes had a greater risk for subsequent episodes. However, mortality risk decreased after the third episode of HE. A plausible hypothesis to explain this finding is that risk of mortality may be reduced in patients receiving long-term rifaximin-α therapy.

Imagestream detection and characterisation of circulating tumour cells - A liquid biopsy for hepatocellular carcinoma?

BACKGROUND & AIMS: The lack of progress in developing and delivering new therapies for hepatocellular carcinoma (HCC) is in part attributed to the risk related avoidance of tumour biopsy at diagnosis. Circulating tumour cells (CTCs) are a potential source of tumour tissue that could aid biological or biomarker research, treatment stratification and monitoring. METHODS: An imaging flow cytometry method, using immunofluorescence of cytokeratin, EpCAM, AFP, glypican-3 and DNA-PK together with analysis of size, morphology and DNA content, for detection of HCC CTCs was developed and applied to 69 patient and 31 control samples. The presence of CTCs as a prognostic indicator was assessed in multivariate analyses encompassing recognised prognostic parameters. RESULTS: Between 1 and 1642 CTCs were detected in blood samples from 45/69 HCC patients compared to 0/31 controls. CTCs positive for the epithelial markers cytokeratin and EpCAM were detected in 29% and 18% of patients respectively, while an additional 28% of patients had CTCs negative for all markers other than size and evidence of hyperploidy. CTC number correlated significantly with tumour size and portal vein thrombosis (PVT). The median survival of patients with >1 CTC was 7.5months versus >34months for patients with <1 CTC (p<0.001, log-rank), with significance retained in a multivariate analysis (HR 2.34, 95% CI 1.005-5.425, p=0.049) including tumour size and PVT. CONCLUSIONS: The use of multiple parameters enhanced HCC CTC detection sensitivity, revealing biological associations and predictive biomarker potential that may be able to guide stratified medicine decisions and future research. LAY SUMMARY: Characteristics of tumour tissues can be used to predict outcomes for individual patients with cancer, as well as help to choose their best treatment. Biopsy of liver cancers carries risks, however, and is usually avoided. Some cancer cells enter the blood, and although they are very rare, we have developed a method of finding and characterising them in patients with liver cancer, which we hope will provide a low risk means of guiding treatment.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

BACKGROUND & AIMS: Rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-α on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-α. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between £4858 and £6607 per year. Taking into account drug costs of £3379 for 1-year treatment with rifaximin-α, there was an estimated annual mean saving of £1480-£3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-α for hepatic encephalopathy was generally cost saving.

Where are we going? Translational research in hepatic encephalopathy.

Translational medicine, rather than being a unidirectional clinical utilization of basic research discoveries, should be a bidirectional process of cross-fertilization between basic science, medical knowledge and clinical utilization. While steps and processes differ across these branches of research, clear language and proper definitions are prerequisites for effective interaction of researchers to facilitate knowledge development. With respect to Hepatic Encephalopathy, at first glance the areas which require development are around prevention, both to reduce the risk of relapse following an episode of overt HE and to reduce the risk of the first episode of HE. In addition, shortening the duration of episodes of overt HE may also be relevant. Comparisons of treatments and combinations of treatments, acting by different but potentially synergistic mechanisms, are reasonable targets for both basic and applied research.

Health related quality of life in people with advanced chronic liver disease.

Cirrhosis has a long natural history with considerable symptomatic impacts, particularly in advancing disease. Measuring health related quality of life (HRQOL) in liver disease provides detail about the nature and extent of its effects on individuals. Understanding the drivers of impaired HRQOL can help identify targets for improvement through new treatments or health systems service delivery. Evaluation of novel therapies which target symptomatic improvement, should be done with suitable outcome measures, including HRQOL assessment. In this article, we provide an overview of HRQOL in advanced liver disease for the clinician. A clear description of the important HRQOL tools is given alongside a discussion of the factors, which are known to contribute to impaired HRQOL in advanced liver disease.

Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells.

Gliotoxin has been shown to promote a reversal of liver fibrosis in an animal model of the disease although its mechanism of action in the liver is poorly defined. The effects of gliotoxin on activated hepatic stellate cells (HSCs) and hepatocytes have therefore been examined. Addition of gliotoxin (1.5 microM) to culture-activated HSCs resulted in its rapid accumulation, resulting in increased levels of glutathione and apoptosis without any evidence of oxidative stress. In contrast, although hepatocytes also rapidly sequestered gliotoxin, cell death only occurred at high (50-microM) concentrations of gliotoxin and by necrosis. At high concentrations, gliotoxin was metabolized by hepatocytes to a reduced (dithiol) metabolite and glutathione was rapidly oxidized. Fluorescent dye loading experiments showed that gliotoxin caused oxidative stress in hepatocytes. Antioxidants--but not thiol redox active compounds--inhibited both oxidative stress and necrosis in hepatocytes. In contrast, HSC apoptosis was not affected by antioxidants but was potently abrogated by thiol redox active compounds. The adenine nucleotide transporter (ANT) is implicated in mitochondrial-dependent apoptosis. HSCs expressed predominantly nonliver ANT isoform 1, and gliotoxin treatment resulted in a thiol redox-dependent alteration in ANT mobility in HSC extracts, but not hepatocyte extracts. In conclusion, these data suggest that gliotoxin stimulates the apoptosis of HSCs through a specific thiol redox-dependent interaction with the ANT. Further understanding of this mechanism of cell death will aid in finding therapeutics that specifically stimulate HSC apoptosis in the liver, a promising approach to antifibrotic therapy.