Comparing magnetic resonance liver fat fraction measurements with histology in fibrosis: the difference between proton density fat fraction and tissue mass fat fraction.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) provides a powerful method of measuring fat fraction. However, previous studies have shown that MRS results give lower values compared with visual estimates from biopsies in fibrotic livers. This study investigated these discrepancies and considered whether a tissue water content correction, as assessed by MRI relaxometry, could provide better agreement. MATERIALS AND METHODS: 110 patients were scanned in a 1.5 T Philips scanner and biopsies were obtained. Multiple echo MRS (30 × 30 × 30 mm volume) was used to determine Proton Density Fat Fraction (PDFF). Biopsies were assessed by visual assessment for fibrosis and steatosis grading. Digital image analysis (DIA) was also used to quantify fat fraction within tissue samples. T1 relaxation times were then used to estimate tissue water content to correct PDFF for confounding factors. RESULTS: PDFF values across the four visually assessed steatosis grades were significantly less in the higher fibrosis group (F3-F4) compared to the lower fibrosis group (F0-F2). The slope of the linear regression of PDFF vs DIA fat fraction was ~ 1 in the low fibrosis group and 0.77 in the high fibrosis group. Correcting for water content based on T1 increased the gradient but it did not reach unity. DISCUSSION: In fibrotic livers, PDFF underestimated fat fraction compared to DIA methods. Values were improved by applying a water content correction, but fat fractions were still underestimated.

Diagnostic accuracy of serum ascites albumin gradient (SAAG) in a contemporary unselected medical cohort.

OBJECTIVES: To describe the different aetiologies of ascites and test the validity of serum ascites albumin gradient (SAAG) and cytology in a contemporary unselected medical cohort. METHODS: All adult patients admitted to Nottingham University Hospitals, UK, between 1 May 2013 and 30 April 2018 with new-onset radiologically-confirmed ascites were included. Data were analysed to determine the distribution of different aetiologies of ascites and the diagnostic accuracy of SAAG in portal hypertension and cytology in malignancy as underlying causes of ascites. RESULTS: Over 5 years, 286 patients presented with new-onset ascites; 122 surgical cases were excluded. Most patients were men (n = 84, 51.2%) over 50 years of age (n = 142, 86.6%). Cirrhosis accounted for 54.9% (n = 90) of the cases of ascites followed by malignancy (n = 48, 29.3%) and cardiac failure (n = 10, 6.1%). SAAG ≥11 g/L had a sensitivity of 85.5% and specificity of 60.6% for diagnosing portal hypertension as a cause of ascites (diagnostic accuracy = 78.5%, 95% confidence interval (CI): 69.8-85.5; area under the curve (AUC) = 0.756, 95% CI: 0.652-0.860). Ascitic fluid cytology was positive in 50% of malignant cases and 66% of primary peritoneal carcinomatosis cases. CONCLUSION: The underlying aetiology and the validity of available tests varied substantially compared with previous reports.

Transient Elastography in Community Alcohol Services: Can It Detect Significant Liver Disease and Impact Drinking Behaviour?

Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, and to determine its impact on modifying drinking behaviours. Method: A prospective cohort study was conducted at a community alcohol clinic in Nottingham, UK (April 2012 to March 2014). Patients (>18 years) with a primary alcohol problem were recruited. Those known to liver services or those known to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness of >8 kilopascal (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal liver stiffness versus raised liver stiffness. Results: 156 patients were invited; n = 87 attended and n = 86 underwent successful TE. The majority were male (n = 53, 70.0%), and the mean age was 46.3 years (SD ± 9.8). Median liver stiffness was 6.9 kPa (range 3.1-75.0kPa). Clinically significant liver fibrosis was identified in n = 33 (38.4%), of which n = 6 were in the cirrhotic range (≥15 kPa). The baseline median self-reported alcohol intake for normal stiffness was 126 units per week (range 24-378) and in raised stiffness was 149.0 units per week (range 39.0-420.0); this difference was nonsignificant (p = 0.338). The median reduction in self-reported alcohol intake in the whole cohort was 65.0 units per week (range 27.0-88.0, p < 0.001); in the normal liver stiffness group it was 25.0 units per week (range 18.0-75.0, p = 0.154), and in the raised liver stiffness group it was 78.5 units per week (range 36.0-126.0, p < 0.001). Conclusion: The study demonstrated that transient elastography is a feasible tool to stratify clinically significant liver disease in community alcohol services. It can stimulate a change in high-risk drinking behaviour and a normal liver stiffness result does not provide false reassurance to participants.

Estimating the clinical prevalence of Wilson's disease in the UK.

BACKGROUND & AIMS: The clinical prevalence of Wilson's disease (WD) in the UK remains unknown. The estimated genetic prevalence in the UK, 142/million, is higher than the clinical prevalence (15/million) reported in other European studies. The aim of this study was to estimate the clinical prevalence of WD utilising readily available laboratory and clinical data. METHOD: Patients with WD who attended Nottingham University Hospital NHS Trust (NUH) between 2011 and 2018 were identified using multiple sources of case ascertainment: serum ceruloplasmin, 24-hour urinary copper, 'Wilson' in liver biopsy report, hospital prescription for penicillamine/trientine/zinc and admission coded with ICD-10 Code E83.0 (disorder of copper metabolism). Potential cases were identified using the Leipzig score, diagnosis was confirmed in hospital records and the point prevalence was calculated using the Office for National Statistics mid-2017 population estimates. RESULTS: A total of 1,794 patients were identified from ≥1 source; 19 patients had WD, of whom 11 were from within the study catchment area and alive at the time of point prevalence estimation. Twenty-nine patients had a Leipzig score ≥2 without a diagnosis of WD, but none had WD on screening (n = 16). The overall prevalence of WD was 15.5/million; males 16.9/million and females 14.1/million. CONCLUSION: This is the first UK population-based study to assess the clinical prevalence of WD. The reported clinical prevalence is lower than the UK genetic prevalence, but comparable to the clinical prevalence reported in Europe. The case ascertainment approach used in this study may be cost-effective, and similar practises could be adopted nationally. LAY SUMMARY: Our study estimates the clinical prevalence of Wilson's disease, a rare genetic disorder of copper metabolism, in the UK. The estimated clinical prevalence is this study is markedly lower than the estimated UK genetic prevalence.

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: Care closer to home.

INTRODUCTION: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this 'hub-and-spoke' healthcare model. METHODS: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed. RESULTS: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008). CONCLUSION: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.

Guidelines on the management of ascites in cirrhosis.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.

Diagnosis of Barrett's esophagus and esophageal varices using a magnetically assisted capsule endoscopy system.

BACKGROUND AND AIMS: Magnetically assisted capsule endoscopy (MACE) potentially offers a comfortable, patient friendly, and community-based alternative to gastroscopy (EGD). This pilot study aims to explore whether this approach can be used to accurately diagnose Barrett's esophagus (BE) and esophageal varices. METHOD: The MiroCam Navi capsule system was used to examine the upper GI tract in patients due to undergo a clinically indicated EGD. A total of 50 participants were enrolled: 34 had known pathology (17 BE, 17 esophageal varices [EV]) and 16 controls. Patients underwent the MACE procedure with the operator blinded to the indication and any previous endoscopic diagnoses. The subsequent EGD was performed by an endoscopist blinded to the MACE findings. Diagnostic yield, comfort, and patient preference between the 2 modalities were compared. RESULTS: The mean age of the participants was 61 years, the male/female ratio was 2.1:1, the mean body mass index was 29.5 kg/m2, and the average chest measurement was 105.3 cm. Forty-seven patients underwent both procedures; 3 patients were unable to swallow the capsule. With the use of the magnet, it was possible to hold the capsule within the esophagus for a mean duration of 190 seconds and up to a maximum of 634 seconds. A correct real-time MACE diagnosis was made in 11 of 15 patients with EV (sensitivity 73.3% [95% confidence interval (CI), 44.9%-92.2%] and specificity 100% [95% CI, 89.1%-100%]) and 15 of 16 patients with BE (sensitivity 93.8% [95% CI, 69.8%-99.8%] and specificity of 100% [95% CI, 88.8%-100%]). MACE was considered more comfortable than conventional endoscopy (P < .0001); the mean score was 9.2 for MACE compared with 6.7 for EGD when assessed on a 10-point scale. No MACE- or EGD-related adverse events occurred. CONCLUSION: This pilot study demonstrates that MACE is both safe and well tolerated by patients. Accuracy for the diagnosis of BE was high, and therefore MACE may have a role in screening for this condition. (Clinical trial registration number: NCT02852161.).

Validation of the AASLD recommendations for classification of oesophageal varices in clinical practice.

BACKGROUND & AIMS: The American Association for the Study of Liver Diseases recommends the use of a 2-grade classification system (small and large) to describe the size of oesophageal varices (OV). Data on observer agreement (OA) on this system are currently lacking. We aimed to evaluate this classification and compare it to the widely used 3-grade classification (grade 1 'small', grade 2 'medium', grade 3 'large') among operators of variable experience. METHODS: High-definition video recordings of 100 patients with cirrhosis were prospectively collected using standardised criteria. Nine observers of variable experience performed independent evaluations of the videos in random order. OV were scored using both systems. All assessments were repeated a year later by the same observers to assess intra-observer agreement. RESULTS: Interobserver agreement (all observers) using the 2-grade and the 3-grade system was k = 0.71 (95% CI: 0.64-0.78) and k = 0.73 (95% CI: 0.66-0.79) respectively. When using the 2-grade system, intra-observer agreement between hepatologists (n = 3), luminal gastroenterologists (n = 3) and trainee gastroenterologists (n = 3) was k = 0.89 (95% CI: 0.86-0.91), k = 0.72 (95% CI: 0.67-0.77), and k = 0.74 (95% CI: 0.67-0.8) respectively. With the 3-grade system; intra-observer agreement between the same three subgroups were k = 0.9 (95% CI: 0.87-0.92), k = 0.73 (95% CI: 0.68-0.78), k = 0.77 (95% CI: 0.71-0.82) respectively. CONCLUSIONS: There was no difference in OA between the 2-grade and 3-grade classification systems. Hepatologists had significantly higher levels of consistency in grading OV. This may have implications to create alternative training models for residents and fellows in the recognition and grading of OV.

The detection of oesophageal varices using a novel, disposable, probe-based transnasal endoscope: a prospective diagnostic pilot study.

BACKGROUND & AIMS: Screening for oesophageal varices (OV) using conventional oesophagogastroduodenoscopy (C-OGD) is invasive and requires costly monitoring, recovery, and decontamination facilities. We aimed to evaluate the technical feasibility, acceptability and accuracy of a novel, portable and disposable office-based transnasal endoscope (EG Scan™ ) compared to C-OGD as the reference standard. METHODS: This was a prospective cohort study. Consecutive adult patients with cirrhosis were invited to participate. All subjects underwent the two procedures on the same day performed by two endoscopists in a blinded design. Patients completed preference and validated tolerability (10-point visual analogue scale (VAS)) questionnaires on day 0 and day 14 post procedures. RESULTS: Forty-five of 50 patients (90%) completed both interventions. Mean age was 59 years and OV prevalence was 49%. Patients reported higher preference (percentage) and better experience (mean VAS) with EG Scan compared to C-OGD on day 0 (76.5% vs. 23.5%, P < 0.001; 7.8 vs. 6.8, P = 0.058, respectively) and day 14 (77.8% vs. 22.2%, P < 0.001; 7.0 vs. 5.5, P = 0.0013 respectively). Sensitivity and specificity of the EG Scan for the diagnosis of any size OV were 0.82 (95% confidence interval (CI) 0.60-0.95), and 0.78 (95% CI 0.56-0.93) respectively. Corresponding values for the diagnosis of clinically significant (medium/large) OV were 0.92 (95% CI 0.62-1.0), 0.97 (95% CI 0.84-1.0) respectively. No serious adverse events occurred. CONCLUSIONS: EG Scan accuracy was higher for the diagnosis of medium/large OV compared to any size OV. Patients' preference and overall experience of the EG Scan was favourable compared to C-OGD 14 days after procedures.

Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography.

OBJECTIVES: To assess the feasibility of a novel diagnostic algorithm targeting patients with risk factors for chronic liver disease in a community setting. DESIGN: Prospective cross-sectional study. SETTING: Two primary care practices (adult patient population 10,479) in Nottingham, UK. PARTICIPANTS: Adult patients (aged 18 years or over) fulfilling one or more selected risk factors for developing chronic liver disease: (1) hazardous alcohol use, (2) type 2 diabetes or (3) persistently elevated alanine aminotransferase (ALT) liver function enzyme with negative serology. INTERVENTIONS: A serial biomarker algorithm, using a simple blood-based marker (aspartate aminotransferase:ALT ratio for hazardous alcohol users, BARD score for other risk groups) and subsequently liver stiffness measurement using transient elastography (TE). MAIN OUTCOME MEASURES: Diagnosis of clinically significant liver disease (defined as liver stiffness ≥8 kPa); definitive diagnosis of liver cirrhosis. RESULTS: We identified 920 patients with the defined risk factors of whom 504 patients agreed to undergo investigation. A normal blood biomarker was found in 62 patients (12.3%) who required no further investigation. Subsequently, 378 patients agreed to undergo TE, of whom 98 (26.8% of valid scans) had elevated liver stiffness. Importantly, 71/98 (72.4%) patients with elevated liver stiffness had normal liver enzymes and would be missed by traditional investigation algorithms. We identified 11 new patients with definite cirrhosis, representing a 140% increase in the number of diagnosed cases in this population. CONCLUSIONS: A non-invasive liver investigation algorithm based in a community setting is feasible to implement. Targeting risk factors using a non-invasive biomarker approach identified a substantial number of patients with previously undetected cirrhosis. TRIAL REGISTRATION NUMBER: The diagnostic algorithm utilised for this study can be found on clinicaltrials.gov (NCT02037867), and is part of a continuing longitudinal cohort study.

Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age-related sarcopenia.

BACKGROUND: Reduced postprandial muscle proteolysis is mainly due to increased insulin availability. Whether rates of proteolysis in response to low physiologic doses of insulin are affected by aging is unknown. OBJECTIVES: We tested the hypothesis that suppression of leg protein breakdown (LPB) by insulin is blunted in older subjects, together with blunted activation of Akt-protein kinase B (PKB). DESIGN: Groups of 8 young [mean (+/-SD) age: 24.5 +/- 1.8 y] and older (65.0 +/- 1.3 y) participants were studied during euglycemic (5 mmol/L), isoaminoacidemic (blood leucine approximately 120 micromol/L) clamp procedures at plasma insulin concentrations of approximately 5 and approximately 15 microIU/mL for 1.5 h. Leg amino acid balance, whole-leg protein turnover (as dilution of amino acid tracers), and muscle protein synthesis were measured with D(5)-phenylalanine and [1,2-(13)C(2)]leucine. The kinase activity of muscle Akt-PKB and the extent of phosphorylation of signaling proteins associated with the mTOR (mammalian target of rapamycin) pathway were measured before and after the clamp procedures. RESULTS: Basal LPB rates were not different between groups (66 +/- 11 compared with 51 +/- 10 nmol leucine x 100 mL leg(-1) x min(-1) and 30 +/- 5 compared with 24 +/- 4 nmol phenylalanine x 100 mL leg(-1) x min(-1) in young and older groups, respectively). However, although insulin at approximately 15 microIU/mL lowered LPB by 47% in the young subjects (P < 0.05) and abolished the negative leg amino acid balance, this caused only a 12% fall (P > 0.05) in the older group. Akt-PKB activity mirrored decreases in LPB. No differences were seen in muscle protein synthesis or associated anabolic signaling phosphoproteins. CONCLUSIONS: At moderate availability, the effect of insulin on LPB is diminished in older human beings, and this effect may be mediated through blunted Akt-PKB activation.

Insertion of expandable metallic stents in esophageal cancer without fluoroscopy is safe and effective: a 5-year experience.

BACKGROUND: Self-expanding metallic stent (SEMS) placement is an important method of dysphagia palliation for patients with inoperable esophageal cancer. In most institutions, it is performed with fluoroscopic guidance; however, in 2001, we described a novel, direct-vision approach to SEMS placement, which does not require fluoroscopy. Here we report an audit of our experience over the last 5 years when using this methodology. OBJECTIVE: To describe our 5-year experience of 98 patients in whom esophageal stents were inserted when using the direct-vision technique and compare outcomes with published series of radiography-guided stents. DESIGN: Retrospective review of single-center experience. SETTING: English National Health Service Cancer Centre Hospital. PATIENTS: All patients who underwent esophageal stent insertion for a primary esophageal malignancy. INTERVENTIONS: SEMS insertion by direct endoscopic vision. RESULTS: Ninety-eight patients underwent SEMS insertion for malignant dysphagia during the study period, 92% of which were inserted without fluoroscopy. The technique had a low complication rate, which was consistent with published fluoroscopic data, and the median survival beyond stent insertion was 100 days (interquartile range, 62, 256; range, 4-921 days). In 59 patients, no further endoscopic palliative procedure was required. LIMITATIONS: Retrospective data collection. CONCLUSIONS: This series confirms direct-vision SEMS placement as a safe and efficacious method of malignant dysphagia palliation, providing definitive treatment in almost two thirds of cases.

Anabolic signaling and protein synthesis in human skeletal muscle after dynamic shortening or lengthening exercise.

We hypothesized a differential activation of the anabolic signaling proteins protein kinase B (PKB) and p70 S6 kinase (p70(S6K)) and subsequent differential stimulation of human muscle protein synthesis (MPS) after dynamic shortening or lengthening exercise. Eight healthy men [25 +/- 5 yr, BMI 26 +/- 3 kg/m(-2) (means +/- SD)] were studied before and after 12 min of repeated stepping up to knee height, and down again, while carrying 25% of their body weight, i.e., shortening exercise with the "up" leg and lengthening exercise with contralateral "down" leg. Quadriceps biopsies were taken before and 3, 6, and 24 h after exercise. After exercise, over 2 h before the biopsies, the subjects ingested 500 ml of water containing 45 g of essential amino acids and 135 g of sucrose. Rates of muscle protein synthesis were determined via incorporation over time of [1-(13)C]leucine (

Maintenance of the musculoskeletal mass by control of protein turnover: the concept of anabolic resistance and its relevance to the transplant recipient.

Although the overall size of the musculoskeletal mass is constrained by genetic limitations, both the day to day maintenance and muscle wasting and rehabilitation are regulated by protein synthesis (particularly the initiation and elongation stages of translation) and by protein breakdown. These are directly influenced by the nutritional state (size and composition of meals) and type, mode and duration of exercise. In the context of food-related changes, recent work has demonstrated that human muscle protein synthesis is almost entirely controlled by the availability of essential amino acids and protein breakdown by availability of insulin. Muscle protein synthesis is also markedly stimulated by preceding exercise in a manner independent of but additive to any effect of food. The sensing and signalling pathways within muscle are activated by food and exercise in normal healthy subjects to elevate net muscle balance for many hours after strenuous exercise. In many circumstances such as immobilisation, ageing and many chronic diseases of the lung, kidney, heart, etc (such as those often suffered by pre-transplant patients), the general debilitation includes muscle wasting. In these subjects there appears to be a general failure to respond adequately to food--so called "anabolic resistance". It seems highly likely that this circumstance will also apply to transplant recipients. It is also likely that anabolic resistance can be, to some extent, reversed by regular physical activity which may "tune up" the anabolic pathways to act in a more normal fashion. Nevertheless, the extent of re-growth and adaptation of composition of muscle in transplant patients could be hindered by drug treatment including the use of rapamycin (sirolimus) cyclosporine and corticosteroids. These predictions should be tested by examining longitudinal effects of different modes of exercise and nutritional regimens on rehabilitation of muscle in transplant patients.