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.

EUS-guided choledochoduodenostomy with electrocautery-enhanced lumen-apposing metal stents in patients with malignant distal biliary obstruction: multicenter collaboration from the United Kingdom and Ireland.

BACKGROUND AND AIMS: EUS-guided choledochoduodenostomy (EUS-CDD) with an electrocautery-enhanced lumen-apposing metal stent (EC-LAMS) has emerged as a viable method of establishing biliary drainage in patients with malignant distal biliary obstruction (MDBO). Our aim was to assess the efficacy, safety, and outcomes in patients with MDBO who underwent EUS-CDD with an EC-LAMS. METHODS: A retrospective review of consecutive patients with MDBO who underwent EUS-CDD with EC-LAMSs at 8 tertiary institutions across the United Kingdom and Ireland between September 2016 and November 2020 was undertaken. RESULTS: One hundred twenty patients (55% men) with a median age of 73 years (interquartile range, 17; range, 43-94) were included. The median follow-up period in 117 patients was 70 days (interquartile range, 169; range, 3-869), and 23 patients (19.2%) were alive at the end of the follow-up. Three patients were lost to follow-up. Technical success was achieved in 109 patients (90.8%). Clinical success (reduction of serum bilirubin to ≤50% of original value within 14 days) was achieved in 94.8% of patients (92/97). The adverse event rate was 17.5% (n = 21). Biliary reintervention after initial technical success was required in 9 patients (8.3%). CONCLUSIONS: EUS-CDD with EC-LAMSs at tertiary institutions within a regional hepatopancreatobiliary network for treatment of MDBO was effective in those where ERCP was not possible or was unsuccessful. When technical failures or adverse events occur, most patients can be managed with conservative or endoscopic therapy.

Utility of palliative EUS-guided biliary drainage using lumen-apposing metal stents: a prospective multicenter feasibility study (with video).

BACKGROUND AND AIMS: Biliary drainage with ERCP is successful in only 80% to 90% of cases of extrahepatic cholangiocarcinoma and pancreatic cancer. We present the results of a multicenter prospective study assessing the safety, feasibility, and quality of life of patients after EUS-guided biliary drainage (EUS-BD) with lumen-apposing metal stents after failed ERCP. METHODS: All consecutive adults with a dilated common bile duct (CBD) ≥14 mm secondary to inoperable malignant distal CBD stricture and failed ERCP biliary drainage were screened and recruited from 3 tertiary UK centers. Technical success of EUS-BD using lumen-apposing metal stents was the primary endpoint. Improvement in serum bilirubin level, 30-day mortality, procedure-related adverse events, and quality of life were secondary endpoints. Improvement in quality of life was measured using a validated questionnaire (EORTC QLQ-BIL21). RESULTS: Twenty patients were included in the analysis. EUS-BD was technically successful in all patients and the clinical success rate was 95% (19 of 20) at day 7 (>50% reduction in bilirubin level) and 92.3% (12 of 13) at day 30 (bilirubin <50 µmol/L). There were significant improvements in overall quality of life score (49 vs 42, P = .03) at day 30. All-cause 30-day mortality was 20% and the moderate adverse event rate was 10% (1 cholangitis and 1 stent migration). CONCLUSION: EUS-BD has acceptable technical success and safety as a second-line palliative treatment for inoperable malignant distal CBD strictures. Randomized controlled studies comparing EUS-BD with percutaneous transhepatic biliary drainage are needed to determine their effectiveness in clinical practice. (ISCRTN registration number: ISRCTN13196704.).

Diagnostic accuracy and interobserver agreement of digital single-operator cholangioscopy for indeterminate biliary strictures.

BACKGROUND AND AIMS: Digital single-operator cholangioscopy (d-SOC) with cholangioscopic biopsy sampling has shown promise in the evaluation of indeterminate biliary strictures. Some studies have suggested higher sensitivity for visual impression compared with biopsy sampling, although assessors were not blinded to previous investigations. We aimed to investigate the diagnostic accuracy and interobserver agreement (IOA) of d-SOC in the visual appraisal of biliary strictures when blinded to additional information. METHODS: A multicenter, international cohort study was performed. Cholangioscopic videos in patients with a known final diagnosis were systematically scored. Pseudonymized videos were reviewed by 19 experts in 2 steps: blinded for patient history and investigations and unblinded. RESULTS: Forty-four high-quality videos were reviewed of 19 benign and 25 malignant strictures. The sensitivity and specificity for the diagnosis of malignancy was 74.2% and 46.9% (blinded) and 72.7% and 62.5% (unblinded). Cholangioscopic certainty of a malignant diagnosis led to overdiagnosis (sensitivity, 90.6%; specificity, 33%), especially if no additional information was provided. The IOA for the presence of malignancy was fair for both assessments (Fleiss' κ = .245 [blinded] and κ = .321 [unblended]). For individual visual features, the IOA ranged from slight to moderate for both assessments (κ = .059-.400 vs κ = .031-.452). CONCLUSIONS: This study showed low sensitivity and specificity for blinded and unblinded d-SOC video appraisal of indeterminate biliary strictures, with considerable interobserver variation. Although reaching a consensus on the optical features of biliary strictures remains important, optimizing visually directed biopsy sampling may be the most important role of cholangioscopy in biliary stricture assessment.

Validation of a Model for Identification of Patients With Compensated Cirrhosis at High Risk of Decompensation.

BACKGROUND & AIMS: It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients' prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation. METHODS: We collected data from 145 patients with compensated cirrhosis (91% Child A cirrhosis and median MELD scores below 8) from a cohort in Nottingham, United Kingdom, followed for a median 4.59 years (development cohort). We collected baseline clinical features and recorded decompensation events. We used these data to develop a model based on liver function (assessed by the ALBI score) and extent of fibrosis (assessed by the FIB-4 index) to determine risk of decompensation. We validated the model in 2 independent external cohorts (1 in Dublin, Ireland and 1 in Menoufia, Egypt) comprising 234 patients. RESULTS: In the development cohort, 19.3% of the patients developed decompensated cirrhosis. Using a combination of ALBI and FIB-4 scores, we developed a model that identified patients at low vs high risk of decompensation (hazard ratio [HR] for decompensation in patients with high risk score was 7.10). When we tested the scoring system in the validation cohorts, the HR for decompensation in patients with a high-risk score was 12.54 in the Ireland cohort and 5.10 in the Egypt cohort. CONCLUSION: We developed scoring system, based on a combination of ALBI and FIB-4 scores, that identifies patients at risk for liver decompensation. We validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it appears to apply to diverse populations.

Multi-organ assessment of compensated cirrhosis patients using quantitative magnetic resonance imaging.

BACKGROUND & AIMS: Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit vs. harm for therapies. Our aim was to establish the feasibility of magnetic resonance imaging (MRI) to assess changes in Compensated Cirrhosis (CC), and relate this to disease severity and future liver-related outcomes (LROs). METHODS: A total of 60 patients with CC, 40 healthy volunteers and 7 patients with decompensated cirrhosis were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T1 longitudinal relaxation time, heart rate, cardiac index, and volume assessment of the liver, spleen and kidneys. We explored the association between MRI parameters and disease severity, analysing differences in baseline MRI parameters in the 11 (18%) patients with CC who experienced future LROs. RESULTS: In the liver, compositional changes were reflected by increased T1 in progressive disease (p <0.001) and an increase in liver volume in CC (p = 0.006), with associated progressive reduction in liver (p <0.001) and splenic (p <0.001) perfusion. A significant reduction in renal cortex T1 and increase in cardiac index and superior mesenteric arterial blood flow was seen with increasing disease severity. Baseline liver T1 (p = 0.01), liver perfusion (p <0.01), and renal cortex T1 (p <0.01) were significantly different in patients with CC who subsequently developed negative LROs. CONCLUSIONS: MRI enables the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement for a contrast agent. MRI parameters of liver T1, renal T1, hepatic and splenic perfusion, and superior mesenteric arterial blood flow were related to the risk of LROs. LAY SUMMARY: This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (Compensated Cirrhosis), using magnetic resonance imaging. The magnetic resonance imaging measures which changed with disease severity and were related to negative liver-related clinical outcomes are described.

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial.

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

A study of T1 relaxation time as a measure of liver fibrosis and the influence of confounding histological factors.

Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65-0.96) and 0.92 (0.81-1.0) respectively (p < 0.01). Inflammation and iron accumulation were shown to significantly alter T1 in opposing directions in the absence of advanced fibrosis; inflammation increasing T1 and iron decreasing T1. A decision tree model was developed to allow the assessment of early liver disease based on relaxation times and ELF, and to screen for the need for biopsy. T1 relaxation time increases with advanced fibrosis in liver patients, but is also influenced by iron accumulation and inflammation. Together with ELF, relaxation time measures provide a marker to stratify patients with suspected liver disease for biopsy.

The performance of transient elastography compared to clinical acumen and routine tests - what is the incremental diagnostic value?

BACKGROUND/AIMS: There is substantial evidence suggesting transient elastography (TE) is a useful tool in assessing liver fibrosis. We aimed to determine whether TE has incremental diagnostic value over clinical acumen and routinely available tests. METHODS: We performed a retrospective study of 130 patients to assess the ability of hepatologists to predict severity of fibrosis using clinical acumen; clinical acumen with routine tests; and elastography in patients with chronic liver disease. The incremental diagnostic benefit was assessed using the area under the ROC curve (AUC) and the Net Reclassification Index (NRI). RESULTS: Using universally available tests, including clinical acumen, the AUCs for detection of cirrhosis ranged from 0.70 to 0.80 for the four hepatologists. Elastography led to statistically non-significant improvements in AUC statistics (range 0.83-0.89; P > 0.01). The detection of significant fibrosis using clinical acumen and routine tests was less accurate, with AUCs of 0.52-0.59. Elastography had incremental diagnostic value (AUC performance range 0.76-0.82; P < 0.01). The NRI indicated that 39-58% were correctly reclassified using elastography, especially with respect to sensitivity. CONCLUSIONS: Our study suggests that the diagnostic value of clinical acumen and routine tests is acceptable for detection of cirrhosis, but not significant fibrosis. Elastography detects significant fibrosis or cirrhosis with acceptable accuracy and offered incremental diagnostic value in detecting significant fibrosis, but not cirrhosis. These findings have implications for determining the diagnostic value of tests over and above routine clinical assessment, which will aid incorporation of novel tests into clinical algorithms.

Next-generation sequencing of pancreatic cyst wall specimens obtained using micro-forceps for improving diagnostic accuracy.

Background and study aims Pancreatic cysts are common incidental findings, with an estimated prevalence of 13% to 15% in imaging done for other reasons. Diagnosis often relies on collection of cyst fluid, but tissue sampling using micro-forceps may allow for a more reliable diagnosis and higher yield of DNA for next-generation sequencing (NGS). The primary aim was to assess the performance of NGS in identifying mucinous cyst. The secondary aims were to assess DNA yield between the cyst fluid and cyst wall tissue, complication rate and performance of conventional investigations. Patients and methods Twenty-four patients referred for endoscopic ultrasound were recruited. Biopsies were taken using micro-forceps and the AmpliSeq Cancer Hotspot panel was used for NGS, a polymerase chain reaction assay targeting several hotspots within 50 genes, including GNAS , KRAS and VHL . Results The concentration of DNA extracted from 24 cyst wall samples was significantly higher than in the nine of 24 available matched cyst fluid samples. The sensitivity, specificity, and diagnostic accuracy of NGS for diagnosing mucinous cyst were 93%, 50% and 84%; for standard of care, they were -66.6%, 50% and 63.1%; and for standard of care with NGS, they were 100%, 50%, and 89.4% respectively. Cyst wall biopsy was able to diagnose 19 of 24 cysts (4 high risk, 7 intraductal papillary mucinous neoplasms, 4 cysts of mucinous origin, and 4 benign). Conclusions NGS data correlate well with histology and may aid in diagnosis and risk stratification of pancreatic cysts. Cyst wall biopsy performs well in diagnosing cysts but was inadequate in five of 24 patients.

Guidelines for the management of iron deficiency anaemia.

BACKGROUND: Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A). INVESTIGATIONS: Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A). All patients should be screened for coeliac disease (B). If oesophagogastroduodenoscopy (OGD) is performed as the initial GI investigation, only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B). In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found (B). Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable (B). Either is preferable to barium enema, which is useful if they are not available. Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease, or if the haemoglobin cannot be restored or maintained with iron therapy (B). In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present. (C). Faecal occult blood testing is of no benefit in the investigation of IDA (B). All premenopausal women with IDA should be screened for coeliac disease, but other upper and lower GI investigation should be reserved for those aged 50 years or older, those with symptoms suggesting gastrointestinal disease, and those with a strong family history of colorectal cancer (B). Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B). In patients with iron deficiency without anaemia, endoscopic investigation rarely detects malignancy. Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C). Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C). Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy. Urine testing for blood is important in the examination of patients with IDA (B). MANAGEMENT: All patients should have iron supplementation both to correct anaemia and replenish body stores (B). Parenteral iron can be used when oral preparations are not tolerated (C). Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C).

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.

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.

Detecting chronic liver disease: are liver function tests the solution?

By 2020, chronic liver disease will have eclipsed ischaemic heart disease as the leading cause of working life years lost in the UK. As mortality from chronic liver disease continues to rise, the landscape of aetiology has shifted from infectious to non-communicable causes. In parallel with the growing prevalence of obesity and type 2 diabetes, non-alcoholic fatty liver disease is estimated to affect 25% of the UK adult population. Simultaneously, escalating alcohol consumption has fuelled public health and economic concerns regarding its widespread impact on working-age adults. Given that chronic liver disease remains clinically silent until its advanced stages, there is an urgent unmet need to identify affected individuals earlier in the disease process, enabling targeted intervention strategies which may improve prognosis. Robust epidemiological data have shown that liver fibrosis is the strongest predictor of clinically meaningful outcomes, including decompensation, liver cancer and overall mortality. Detecting fibrosis among at-risk individuals, in a manner that is reproducible, non-invasive, safe and cost effective, has become a major challenge of our time. This article addresses the pitfalls of the standard panel of liver function tests, discusses other non-invasive biomarkers and reviews imaging technologies which may revolutionise community-based diagnosis and stratification of chronic liver disease.

Comparison of the reverse bevel versus Franseen type endoscopic ultrasound needle.

BACKGROUND: Reverse bevel (RB) needle is widely used for endoscopic ultrasound fine needle biopsy (EUS-FNB). A 3-plane symmetrical needle with Franseen geometry (FG) has recently become available. AIM: To compare the clinical efficacy of FG to that of RB needle. METHODS: A retrospective cohort study of all adult patients who underwent EUS-FNB for solid and mixed lesions either with 22G RB needle or 22G FG needle between January 2016 and February 2019 was undertaken. All cytology slides were reviewed by an independent gastrointestinal cytopathologist blinded to the needle used and the initial cytology report. The primary and secondary outcomes were to assess the sample adequacy using Euro-cytology criteria and the number of cell clusters, respectively. RESULTS: Two hundred and twenty six procedures were included in the study. RB needle was used in 128 procedures and FG needle in 98 procedures. The baseline characteristics of both groups were comparable. On multivariable analysis, FG needle (P = 0.02) and location of the lesion (P < 0.01) were independently associated with adequate tissue. Further, the use of FG needle (P = 0.04) and the size of the lesion (P = 0.02) were independently associated with acquisition of increased number of cell clusters. CONCLUSION: FG needle is superior to RB needle in acquiring adequate tissue and attaining higher number of cell clusters for solid and mixed lesions.

Healthcare costs of transarterial chemoembolization in the treatment of hepatocellular carcinoma.

BACKGROUND: A meta-analysis comparing drug-eluting beads transarterial chemoembolization (DEB-TACE) with conventional transarterial chemoembolization (cTACE) has recently been published. On balance, no significant differences were found in terms of objective response and overall survival. The impact on healthcare costs had been studied in small series based on a hypothetical model and was in favor of DEB-TACE. We aimed to evaluate and compare health-care costs and effectiveness of both modalities in a cohort of patients from Nottingham, UK. METHODS: Using a dedicated radiology database, we identified all patients who had undergone cTACE or DEB-TACE between 2006 and 2012 at a single tertiary referral center based in Nottingham. We collected clinical data, including treatment response, postprocedure complications and 30-day mortality. Costing models were constructed to present both our local hospital perspective as well as the national health service position. RESULTS: During our study period, 101 procedures were performed on 43 patients (76 cTACE procedures on 26 patients and 25 DEB-TACE procedures on 17 patients). Overall, 11/26 in cTACE and 5/17 in DEB-TACE group had progressive disease (p=0.52). Adverse events were seen in 6/76 cTACE compared with 7/25 DEB-TACE group (p=0.16). Based on the predetermined standard pathway there was an unadjusted average cost difference of £3770.30 (TACE =£9070.44, DEB-TACE =£5300.14) in favor of the DEB-TACE. Results from our costing models indicated a £2715.33 (95% CI £580.88-4849.77) cost difference in favor of the same procedure. CONCLUSIONS: Even when the extra costs of DEB-TACE were considered, the overall treatment costs per patient were lower in relation to cTACE.

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS: We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING: Bayer PLC and BTG PLC.

Risk factors for gastrointestinal malignancy in patients with iron-deficiency anaemia.

OBJECTIVES: Iron-deficiency anaemia (IDA) is common and may be caused by blood loss from gastrointestinal tumours. The aim of this study was to define risk factors for gastrointestinal malignancy in patients with IDA. METHODS: Patients with suspected IDA referred for gastrointestinal investigations were prospectively identified from two neighbouring UK hospitals (serving a population of 550,000 patients) between 1 January 1998 and 31 December 1999. Final diagnoses were determined after 2 years, and those patients with and without gastrointestinal cancer as a cause for their IDA were compared. Data collected included sex, age, haemoglobin, serum ferritin, mean cell volume and drug history. RESULTS: A total of 695 patients (236 men, mean age 68.5 years; 459 women, mean age 66.2 years) with IDA were investigated. Malignancy was diagnosed in 91/695 (13.1%) and gastrointestinal malignancy in 78/91 (11.2%). The most frequently diagnosed cancers were colonic (n = 44, 6.3%), gastric (n = 25, 3.6%) and renal tract (n = 7, 1%). The adjusted odds ratio (+/-95% confidence interval) for gastrointestinal cancer as a cause of IDA was significantly higher for male sex [2.96 (1.80, 4.87)], age over 50 years [7.04 (1.69, 29.32)] and haemoglobin level at presentation (< or =9.0 g/dl) [2.25 (1.29, 3.90)]. There was no significant difference in gastrointestinal malignancy in those taking aspirin (12/111, 10.8%), non-aspirin non-steroidal anti-inflammatory drugs (5/84, 6.0%) or warfarin (4/31, 12.9%) compared with those not taking these drugs (57/470, 12.1%). No cause for IDA was found in 53.7%. CONCLUSIONS: Cancer was diagnosed in 13.1% and gastrointestinal cancer in 11.2% of patients with IDA. Significant risk factors for gastrointestinal malignancy in IDA patients are male sex, age over 50 years and haemoglobin at presentation < or =9.0 g/dl. IDA should not be attributed to aspirin, non-steroidal anti-inflammatory drugs or warfarin use.