Late diagnosis of chronic liver disease in a community cohort (UK biobank): determinants and impact on subsequent survival.

BACKGROUND: Chronic liver disease (CLD) is frequently diagnosed at a late stage when prognosis is poor. We aimed to determine the patient factors associated with a late CLD diagnosis and its subsequent impact on survival to support early diagnosis initiatives. METHODS: We identified participants of UK biobank (UKB) study who developed first-time advanced CLD within 5 years. We identified the factors associated with late diagnosis via logistic regression and used survival analysis to measure the association between late CLD diagnosis and mortality risk. RESULTS: A total of 725 UKB participants developed first-time advanced CLD event within 5 years. In total, 83% of cases were diagnosed late. Late diagnosis was associated with aetiology; the odds of late diagnosis were 12 times higher for an individual with alcohol-related liver disease (ArLD) vs viral hepatitis (aOR:12.01; P < 0.001). Cumulative mortality 5 years after incident advanced CLD was 43.4% (95% CI:39.6-47.0). Late diagnosis was associated with a higher risk of postadvanced CLD mortality for patients with non-alcoholic fatty liver disease (aHR:2.18; 95% CI:0.86-5.51; P = 0.10), but not for other aetiologies. CONCLUSIONS: Late CLD diagnosis varies according to aetiology and is highest for patients with ArLD and non-alcoholic fatty liver disease. The association between late diagnosis and postadvanced CLD mortality may also vary by aetiology.

Short-term changes observed in multiparametric liver MRI following therapy with direct-acting antivirals in chronic hepatitis C virus patients.

METHODS: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). RESULTS: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. CONCLUSION: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. KEY POINTS: • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

The effect of prone positioning with surgical bolsters on liver blood flow in healthy volunteers.

This study sought to identify changes in hepatic flood flow and cardiac output during prone positioning on surgical bolsters in awake volunteers, and was prompted by a local incident of significant hepatic dysfunction following surgery in the prone position. Cardiac output was determined using the non-invasive Peñáz technique, and plasma disappearance rate of indocyanine green (ICG-PDR) was measured as a surrogate maker for hepatic blood flow along with serum hepatic enzyme assays. Measurements were made after one hour in supine, prone and returned supine positions. Ten volunteers completed the study. There were significant changes in the disappearance rate of indocyanine green, which decreased this from mean (SD) 31.1 (9.70) supine to 19.6 (4.37)%.min prone, respectively (p = 0.02), increasing on return to the supine position to 24.6 (5.54)%.min (p = 0.019). Cardiac output was also significantly reduced when changing from the supine to the prone position, from mean (SD) 4.7 (1.0 to 3.5 (1.1) (l.min(-1) ), respectively (p = 0.002). We demonstrated an acute and reversible change in both hepatocellular function and cardiac output associated with the prone position.

Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C.

Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.

Prediction, prevention and management of postresection liver failure.

BACKGROUND: Postresection liver failure (PLF) is the major cause of death following liver resection. However, there is no unified definition, the pathophysiology is understood poorly and there are few controlled trials to optimize its management. The aim of this review article is to present strategies to predict, prevent and manage PLF. METHODS: The Web of Science, MEDLINE, PubMed, Google Scholar and Cochrane Library databases were searched for studies using the terms 'liver resection', 'partial hepatectomy', 'liver dysfunction' and 'liver failure' for relevant studies from the 15 years preceding May 2011. Key papers published more than 15 years ago were included if more recent data were not available. Papers published in languages other than English were excluded. RESULTS: The incidence of PLF ranges from 0 to 13 per cent. The absence of a unified definition prevents direct comparison between studies. The major risk factors are the extent of resection and the presence of underlying parenchymal disease. Small-for-size syndrome, sepsis and ischaemia-reperfusion injury are key mechanisms in the pathophysiology of PLF. Jaundice is the most sensitive predictor of outcome. An evidence-based approach to the prevention and management of PLF is presented. CONCLUSION: PLF is the major cause of morbidity and mortality after liver resection. There is a need for a unified definition and improved strategies to treat it.

Safe discharge of patients with low-risk upper gastrointestinal bleeding (UGIB): can the use of Glasgow-Blatchford Bleeding Score be extended?

INTRODUCTION: Risk stratification of patients with suspected upper gastrointestinal bleeding (UGIB) using either Glasgow-Blatchford Bleeding Score (GBS) or preendoscopy Rockall score to facilitate early safe discharge (GBS=0, pre-Rockall=0) has been reported. This observational study compared score utility and considered the impact of extending the range of GBS or pre-Rockall scores permitting safe discharge. METHODS: Consecutive adult patients presenting to acute medical admissions or the emergency department from September 2008-March 2009 with suspected UGIB had clinical history, vital signs, laboratory and endoscopy results prospectively recorded using electronic databases. GBS, pre-Rockall scores and a composite endpoint (blood transfusion, endoscopic therapy, interventional radiology, surgery or 30-day mortality) were calculated. RESULTS: 388 patients with suspected UGIB were identified of which 92.3% were admitted (median (range) GBS=5 (0-19) and pre-Rockall=2 (0-11)) and 7.7% discharged (GBS=0 (0-4) and pre-Rockall=0 (0-4)). 186 (47.9%) underwent in-patient endoscopy. 151 (38.9%) were found to have the composite endpoint with 77.5% having transfusion, 45.7% endoscopic treatment and an 8.0% mortality within 30 days. AUROC (95% CI) for 30-day composite endpoint was 0.92 (0.89-0.94) using GBS and 0.75 (0.70-0.80) using pre-Rockall scores. Analysis using different GBS thresholds demonstrated that GBS=0, GBS ≤1 and GBS≤2 had superior utility in identifying freedom from an adverse clinical outcome at 30-days than pre-Rockall score 0. CONCLUSIONS: GBS is superior to pre-Rockall score in identifying patients with suspected UGIB who have a low likelihood of an adverse clinical outcome and can be considered for early discharge. Diagnostic performance at different thresholds suggests that patients with GBS≤2 could be considered for early discharge, doubling the number of eligible patients (15.2 to 32.5%). This has important patient safety and resource implications.

The Development and Implementation of a Commissioned Pathway for the Identification and Stratification of Liver Disease in the Community.

OBJECTIVE: To describe the development of the Nottingham liver disease stratification pathway, present a 12-month evaluation of uptake, stratification results and compare the pathway to current British Society of Gastroenterology (BSG) guidelines. DESIGN: A referral pathway between primary and secondary care for the detection and risk stratification of liver disease. SETTING: Four Nottinghamshire Clinical Commissioning Groups (700,000 population). PATIENTS: Patients are referred to the pathway with i) raised AST/ALT ratio ii) harmful alcohol use or iii) risk or presence of non-alcoholic fatty liver disease (NAFLD). INTERVENTIONS: Clinic attendance within secondary care for transient elastography (TE) and brief lifestyle intervention. The TE result is reported back to the GP with advice on interpretation and referral guidance. MAIN OUTCOME MEASURES: Pathway uptake, patient characteristics, liver disease stratification results and stakeholder feedback. RESULTS: Over the first 12 months 968 patients attended a TE clinic appointment, with raised AST/ALT ratio being the most common single reason for referral (36.9%). Of the total, 222 (22.9%) patients had an elevated liver stiffness (≥8kPa) and in 60 (27.0%) liver stiffness was indicative of advanced chronic liver disease. If a traditional approach based on raised liver enzymes (BSG guidance) had been followed, 38.7% of those with significant liver disease (≥8kPa) would have gone undetected among those referred for either NAFLD or raised AST:ALT. CONCLUSIONS: Targeting patients with risk factors for chronic liver disease and stratifying them using TE can detect significant chronic liver disease above and beyond the approach based on liver enzyme elevation.

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

BACKGROUND: Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. AIM: To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. METHODS: The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. RESULTS: Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). CONCLUSIONS: The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. AIMS: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. DESIGN: Prospective cohort study. METHODS: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. RESULTS: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (allP < 0.001). CONCLUSIONS: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.

Case report of an arterioportal fistula, presenting with accelerated decompensation and sepsis, twenty-six years after initial liver biopsy.

We describe the case of a 55-year-old lady who presented with accelerated hepatic decompensation from an arterioportal fistula (APF). There is histological evidence the APF proceeded a percutaneous liver biopsy performed 26 years ago. She had shown no symptoms or signs of liver disease in the intervening period. The clinical presentation initially was that of portal hypertension but evolved into a systemic inflammatory response syndrome associated with renal and liver failure. We describe how the APF was embolised by interventional radiology and how the timing of this decision was a balance between reversing abnormal haemodynamics and trying to avoid instrumentation of a potentially septic environment. This unusual case reflects the relationship between portal hypertension, sepsis and renal failure.

Noninvasive assessment of liver fibrosis: serum markers, imaging, and other modalities.

Liver fibrosis is a common pathway of injury after chronic insult to the liver. The evolution of liver fibrosis to cirrhosis has many clinical implications, including bleeding, infection, hepatocellular carcinoma, and death. The reference standard for diagnosing liver fibrosis is currently histologic assessment of tissue obtained through liver biopsy. Although this provides valuable information, it has limitations, including its invasiveness, sampling error, observer variability, and the use of categorical scoring systems. This article outlines the various noninvasive markers, including blood tests, imaging, and novel technologies. It examines the principles behind their development, their diagnostic accuracy, and their evolution.

Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease.

The diagnosis of fibrosis within liver disease is important for prognosis, stratification for treatment, and monitoring of treatment efficacy. The rising incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) has driven the search for accurate non-invasive tools of liver fibrosis within this condition. With the aid of a systematic review, we explore how the field has evolved from the discovery of simple blood parameters to panel markers of liver fibrosis. We will discuss the biological plausibility, limitations, potential uses, and emerging diagnostic techniques of non-invasive markers in this rapidly expanding field.