Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Serum ammonia does not guide management and is overutilised in patients with cirrhosis in hospital settings.

BACKGROUND: Hepatic encephalopathy is a confusional state associated with cirrhosis. Serum ammonia levels are neither sensitive nor specific for the diagnosis. AIMS: We audited the ordering location and hospital unit whilst assessing the impact on management at a major Australian tertiary centre. METHODS: We conducted a single-centre retrospective chart review of the ordering of serum ammonia levels between 1 March 2019 and 29 February 2020 at The Royal Melbourne Hospital, a tertiary-referral centre in Melbourne, Victoria. Demographic, medication and pathology results, including serum ammonia measurements, were collected. The main outcomes assessed were ordering location, sensitivity, specificity and impact on management. RESULTS: A total of 1007 serum ammonia tests were ordered in 425 patients. Nearly all ammonia ordering was by non-gastroenterologists, 24.2% by the intensive care unit, 23.1% by general medicine and 19.5% by the emergency department (ED). Only 21.6% of patients had a history of cirrhosis, with hepatic encephalopathy diagnosed in 13.6%. On subgroup analysis, 217 ammonia tests were performed in 92 patients with cirrhosis. Cirrhotic patients were older (64 vs 59 years, P = 0.012) and had higher median ammonia levels (64.46 vs 59 µmol/L, P < 0.001) compared with non-cirrhotic patients. In cirrhotic patients, the sensitivity and specificity for serum ammonia and diagnosis of hepatic encephalopathy were 75% and 52.3% respectively. CONCLUSION: We affirm the poor utility of serum ammonia levels for guiding management of hepatic encephalopathy within the Australian context. ED and general medical units account for the majority of test ordering within the hospital. Understanding where ordering occurs provides a target for targeted education.

Fontan Hepatopathy-Managing Unknowns.

BACKGROUND AND AIMS: How to best monitor Fontan-associated liver disease (FALD) remains unclear. We describe results from a prospective liver care pathway in adults (n=84) with a Fontan circulation. METHODS: Routine assessment of the liver, by acoustic radiation force frequency and ultrasound was undertaken. Results, including liver biochemistry, systemic ventricular function (echocardiography), functional class, medication use and clinical endpoints (varices, hepatocellular carcinoma, heart transplantation and death) were collated. RESULTS: Most individuals returned a cirrhotic range acoustic radiation force impulse imaging (ARFI) result. ARFI values were greater in the proportion of individuals with hepatic nodularity (p=0.024). Univariate analysis demonstrated moderate correlation with platelet number (Spearmans rho= -0.376, p=0.049). Patients with clinical endpoints had lower platelets (p=0.012) but only a trend to hepatic nodularity (p=0.057). Clinical endpoints were more common in those with ventricular dysfunction (p=0.011). Multivariate analysis revealed that age at Fontan and being on angiotensin converting enzyme inhibitors (ACEI) predicted ARFI score (ß=0.06 [95% CI 0.01-0.09], p=0.007 and ß=0.53 [95% CI 0.17-0.89], p=0.005, respectively). However, these associations were not significant once adjusted for Fontan type, age at ARFI, systemic ventricle morphology, ventricle function, or Model for End-stage Liver Disease (MELD-XI) excluding international normalised ratio (INR) (p>0.05 for all). CONCLUSIONS: Ideal FALD monitoring remains unclear. ARFI has utility as a binary non-invasive indicator of cirrhosis, highlighting individuals who may need more frequent ongoing monitoring for hepatocellular carcinoma. However, no definite advantage to serial ARFI, once cirrhotic range ARFI results are present, has been identified.

Impact of a Mediterranean diet on hepatic and metabolic outcomes in non-alcoholic fatty liver disease: The MEDINA randomised controlled trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is predominantly managed by lifestyle intervention, in the absence of effective pharmacotherapies. Mediterranean diet (MedDiet) is the recommended diet, albeit with limited evidence. AIMS: To compare an ad libitum MedDiet to low-fat diet (LFD) in patients with NAFLD for reducing intrahepatic lipids (IHL) by proton magnetic resonance spectroscopy (1 H-MRS). Secondary outcomes include insulin resistance by homeostatic model of assessment (HOMA-IR), visceral fat by bioelectrical impedance analysis (BIA), liver stiffness measurement (LSM) and other metabolic outcomes. METHODS: In this parallel multicentre RCT, subjects were randomised (1:1) to MedDiet or LFD for 12 weeks. RESULTS: Forty-two participants (25 females [60%], mean age 52.3 ± 12.6 years) were included, 23 randomised to LFD and 19 to MedDiet.; 39 completed the study. Following 12 weeks, there were no between-group differences. IHL improved significantly within the LFD group (-17% [log scale]; p = .02) but not within the MedDiet group (-8%, p = .069). HOMA-IR reduced in the LFD group (6.5 ± 5.6 to 5.5 ± 5.5, p < .01) but not in the MedDiet group (4.4 ± 3.2 to 3.9 ± 2.3, p = .07). No differences were found for LSM (MedDiet 7.8 ± 4.0 to 7.6 ± 5.2, p = .429; LFD 11.8 ± 14.3 to 10.8 ± 10.2 p = .99). Visceral fat reduced significantly in both groups; LFD (-76% [log scale], p = <.0005), MedDiet (-61%, p = <.0005). CONCLUSIONS: There were no between-group differences for hepatic and metabolic outcomes when comparing MedDiet to LFD. LFD improved IHL and insulin resistance. Significant improvements in visceral fat were seen within both groups. This study highlights provision of dietary interventions in free-living adults with NAFLD is challenging.

Caustic ingestions over 10 years in Victoria, Australia: high rates in migrants and women.

BACKGROUND: Caustic ingestion is relatively common in developing countries and can result in life-threatening sequelae. There is limited understanding of the epidemiology and incidence in Australia. AIMS: This statewide 10-year audit aims to document the rate of caustic injury in a defined Australian pouplation. METHODS: A retrospective review was conducted over 10 years (2007-2016), including all admissions to hospitals in Victoria. This includes a population of 5.9 million people and 22 hospitals. RESULTS: Three hundred and eighty-four cases of caustic ingestion were admitted to hospital between January 2007 and December 2016. The overall incidence was 7 cases/million/year. This cohort included 217 (56.5%) females, 193 (50.2%) overseas born patients and 196 (51%) people with a history of mental illness. The countries of birth with the highest incidence of caustic ingestion were Ethiopia (11 patients; 227 cases/million/year; relative risk (RR) 31.7; P < 0.0001), Sudan (11 patients; 161 cases/million/year; RR 22.6; P < 0.0001) and India (38 patients; 27 cases/million/year; RR 3.9; P < 0.0001). All had a significantly higher incidence than the Australian-born population of only 6.5 cases/million/year (RR 0.4; P < 0.0001). Of those born in India, Sudan and Ethiopia, rates of females (72%) were considerably higher than males. The overall mortality rate in this cohort was 2.3%. CONCLUSIONS: Caustic ingestion remains a significant cause of morbidity and health expenditure in Victoria, particularly among vulnerable groups such as recent female migrants from areas in Africa and India. The high frequency of events seen in migrant populations highlights the significant need for awareness of risks in these groups for the development of possible prevention strategies that are required.

Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

BACKGROUND: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHODS: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSIONS: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Prognostic role of alpha-fetoprotein in patients with hepatocellular carcinoma treated with repeat transarterial chemoembolisation.

BACKGROUND: Repeat transarterial chemoembolisation (rTACE) is often required for hepatocellular carcinoma (HCC) to achieve disease control, however, current practice guidelines regarding treatment allocation vary significantly. This study aims to identify key factors associated with patient survival following rTACE to facilitate treatment allocation and prognostic discussion. METHOD: Patients with HCC undergoing rTACE at six Australian tertiary centers from 2009 to 2014 were included. Variables encompassing clinical, tumour, treatment type and response factors were analysed against the primary outcome of overall survival. Univariate analysis and multivariate Cox regression modelling were used to identify factors pre- and post-TACE therapy significantly associated with survival. RESULTS: Total of 292 consecutive patients underwent rTACE with mainly Child Pugh A cirrhosis (61%) and BCLC stage A (57%) disease. Median overall survival (OS) was 30 months (IQR 15.2-50.2) from initial TACE. On multivariate analysis greater tumour number (p = 0.02), higher serum bilirubin (p = 0.007) post initial TACE, and hepatic decompensation (p = 0.001) post second TACE were associated with reduced survival. Patients with serum AFP ≥ 200 ng/ml following initial TACE had lower survival (p = 0.001), compared to patients with serum AFP level that remained < 200 ng/ml post-initial TACE, with an overall survival of 19.4 months versus 34.7 months (p = 0.0001) respectively. CONCLUSION: Serum AFP level following initial treatment in patients undergoing repeat TACE for HCC is a simple and useful clinical prognostic marker. Moreover, it has the potential to facilitate appropriate patient selection for rTACE particularly when used in conjunction with baseline tumour burden and severity of hepatic dysfunction post-initial TACE.

Efficacy and safety profile of calcineurin inhibitor salvage therapy in autoimmune hepatitis.

BACKGROUND: As data is limited on the outcomes of calcineurin inhibitors (CNI) in autoimmune hepatitis (AIH), we evaluated the efficacy and safety of CNI in AIH patients who failed prior treatment(s). METHODS: A retrospective study was performed of AIH patients who received cyclosporine A (CsA) and/or tacrolimus (TAC) after prior treatment(s) failure. Records were reviewed for baseline demographic and clinical characteristics, and treatment outcomes. The primary outcome was biochemical remission.Results: Thirty-three AIH patients received CNI across seven liver centers:17 received CsA, 21 TAC and 5 TAC after CsA failure/intolerance. 82% received CNI for an insufficient response to treatment(s). Overall, 48% of CNI treated patients achieved biochemical remission including 41% in prior non-responders and 83% in treatment intolerant patients. Remission rates with CNI as second-line and third-line therapy were 63% and 29% respectively. There were no baseline predictors of response to CNI on multivariate analysis. Eighteen (55%) patients developed significant side effects and 8 (24%) discontinued due to intolerance. Three patients required liver transplantation for decompensated cirrhosis and 6 patients died including one from malignancy possibly related to CNI. CONCLUSION: CNI salvage therapy is well tolerated and moderately effective achieving remission in around 50% of AIH who failed standard therapy.

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.

Management of People With a Fontan Circulation: a Cardiac Society of Australia and New Zealand Position statement.

The Fontan circulation describes the circulatory state resulting from an operation in congenital heart disease where systemic venous return is directed to the lungs without an intervening active pumping chamber. As survival increases, so too does recognition of the potential health challenges. This document aims to allow clinicians, people with a Fontan circulation, and their families to benefit from consensus agreement about management of the person with a Fontan circulation. The document was crafted with input from a multidisciplinary group of health care providers as well as individuals with a Fontan circulation and families. It is hoped that the shared common vision of long-term wellbeing will continue to drive improvements in care and quality of life in this patient population and eventually translate into improved survival. KEYPOINTS.

Skin-Liver Distance and Interquartile Range-Median Ratio as Determinants of Interoperator Concordance in Acoustic Radiation Force Impulse Imaging.

CONTEXT AND AIMS: The accuracy of acoustic radiation force impulse (ARFI) ultrasound compared to liver biopsy is higher when there is concordance between F-scores of two or more operators. We hypothesized that when the first operator interquartile range/median-velocity ratio (IMR) is <0.3 and skin-liver distance (SLD) is <2.5 cm, there is greater interoperator concordance and a second operator is not necessary. SUBJECTS AND METHODS: Two-operator ARFI ultrasound measurements (F-score, SLD, and IMR) were recorded for 927 consecutive patients. Chi-squared testing compared interoperator concordance for SLD <2.5 cm versus SLD ≥2.5 cm and IMR <0.3 versus IMR ≥0.3 when SLD <2.5 cm, in each of the F-score groups of 0/1, 2, 3, and 4. RESULTS: Statistically significant differences were demonstrated between SLD <2.5 cm and SLD ≥2.5 cm groups for F-scores 0/1 or 4 (P = 0.005) and F-scores 2 or 3 (P < 0.001). Concordance, when SLD measured <2.5 cm, was more than 85% for all F-score groups. In the SLD <2.5 cm group, concordance fell below 85% when IMR ≥0.3, for all F-scores except F2. Specifically, P values comparing IMR <0.3 and IMR ≥0.3 in the various first operator F-score groups were P = 0.040 for F0/F1, P = 0.580 for F2, P = 0.342 for F3, and P < 0.001 for F4. CONCLUSIONS: ARFI measurements from one operator can be considered acceptable when SLD <2.5 cm and IMR <0.3. Otherwise, adding a second operator can improve confidence in the result.

Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C.

BACKGROUND & AIMS: As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events. METHODS: A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events. RESULTS: Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM ≥12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM ≥12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001). CONCLUSION: The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events. LAY SUMMARY: The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver-related adverse events.

Efficacy and Safety of Mycophenolate Mofetil in Patients With Autoimmune Hepatitis and Suboptimal Outcomes After Standard Therapy.

BACKGROUND & AIMS: Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. METHODS: We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. RESULTS: The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. CONCLUSION: In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.

Treatment choice for early-stage hepatocellular carcinoma in real-world practice: impact of treatment stage migration to transarterial chemoembolization and treatment response on survival.

OBJECTIVE: The objectives of our study were firstly to characterize the treatment stage migration phenomenon in early (Barcelona Clinic Liver Cancer [BCLC]-0/A) stage hepatocellular carcinoma (HCC) by comparing the efficacy of curative therapies with trans-arterial chemoembolization [TACE] and secondly, determining baseline and on-treatment predictors of survival. METHODS: All patients within BCLC-0/A stage from six tertiary hospitals who received curative therapy with either resection, transplantation, or ablation or TACE as first-line treatment were included in the analyses. The primary endpoint was overall survival; secondary end-points were transplant-free survival and recurrence-free survival. RESULTS: Between January 2000 and December 2013, we identified 253 BCLC-0/A HCC patients of whom 148 (58.5%) received curative therapy and 105 (41.5%) migrated to TACE. Patients undergoing TACE had lower median survival (2.7 vs. 6.7 years; p < .0001), transplant-free survival (2.6 vs. 4.8 years; p < .0001) and recurrence-free survival (1.3 vs. 2.7 years; p < .001). On multivariate analysis treatment allocation to TACE was an independent prognostic predictor for both lower overall survival (HR 1.70, p = .04) and for HCC recurrence (HR 2.25, p < .001). The main prognostic determinant for each target outcome was Child-Pugh score. CONCLUSIONS: Our study confirms that curative treatments should always be preferred when applicable in early-stage HCC, but that in cases where this is not possible, TACE is a reasonable albeit inferior treatment option. In addition, it provides unique prognostic information on a significant proportion of patients with early-stage disease in whom curative therapy is not applicable.

Variability of Liver Shear Wave Measurements Using a New Ultrasound Elastographic Technique.

OBJECTIVES: A new 2-dimensional (2D) shear wave elastographic (SWE) device has been developed for the noninvasive assessment of liver fibrosis. Guidelines on measurement acquisition parameters are not yet well established for this technique. Our study aimed to assess 2D SWE measurement variability and to determine the number of measurements required per patient to reliably assess liver stiffness. METHODS: Two-dimensional SWE was assessed in 55 patients with mixed-etiology chronic liver disease on an Aplio 500 ultrasound system (Toshiba Medical Systems Corporation, Tochigi, Japan). Ten measurements were obtained per patient by an operator blinded to all preceding readings. Results were analyzed with clinical information obtained from medical records. RESULTS: The median interquartile range/median ratio for 2D SWE was 0.131 (quartiles 1-3, 0.089-0.174). Five readings provided an approximation within 0.11 m/s, or 4.2% of the median velocity of 10 measurements. Factors associated with increased measurement variability included body mass index (ρ = 0.388; P = .01), increased skin-to-liver capsule distance (ρ = 0.426; P = .002), and measurements taken within 1.5 cm of the liver capsule (P < .001). Measurements with heterogeneous shear wave profiles (indicated by a region of interest [ROI] SD/speed ratio > 0.15) showed greater deviation from the set's median velocity than those with an ROI SD/speed ratio of 0.15 or lower (0.42 versus 0.22 m/s; P = .001). CONCLUSIONS: Two-dimensional SWE showed low overall measurement variability, with a minimum of 5 readings providing equivalent precision to the existing method using 10 samples. Obesity, increasing abdominal wall thickness, subcapsular measurements and an ROI SD/speed ratio of greater than 0.15 were all associated with increased measurement variability. The ROI SD/speed ratio warrants further evaluation as a quality assessment metric, to allow objective operator assessment of individual 2D SWE measurement reliability in real time.

A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation.

Balancing immunosuppression after liver transplant is difficult, with clinical events common. We investigate whether a novel immune biomarker based on a laboratory platform with widespread availability that measures interferon γ (IFNγ) after stimulation with a lyophilized ball containing an adaptive and innate immune stimulant can predict events following transplantation. A total of 75 adult transplant recipients were prospectively monitored in a blinded, observational study; 55/75 (73.3%) patients experienced a total of 89 clinical events. Most events occurred within the first month. Low week 1 results were significantly associated with risk of early infection (area under the receiver operating characteristic curve [AUROC], 0.74; P = 0.008). IFNγ ≤ 1.30 IU/mL (likelihood ratio positive, 1.93; sensitivity, 71.4%; specificity, 63.0%) was associated with the highest risk for infection with minimal rejection risk. Nearly half the cohort (27/60, 45.0%) expressed IFNγ ≤ 1.30 IU/mL. Moreover, an elevated week 1 result was significantly associated with the risk of rejection within the first month after transplant (AUROC, 0.77; P = 0.002), but no episodes of infection. On multivariate logistic regression, IFNγ ≥ 4.49 IU/mL (odds ratio, 4.75) may be an independent predictor of rejection (P = 0.05). In conclusion, low IFNγ suggesting oversuppression is associated with infections, whereas high IFNγ indicating undersuppression is associated with rejection. This assay offers the potential to allow individualization and optimization of immunosuppression that could fundamentally alter the way patients are managed following transplantation. Liver Transplantation 23 487-497 2017 AASLD.

Targeted individual prophylaxis offers superior risk stratification for cytomegalovirus reactivation after liver transplantation.

Cytomegalovirus (CMV) can reactivate following liver transplantation. Management of patients currently considered low risk based on pretransplant serology remains contentious, with universal prophylaxis and preemptive strategies suffering from significant deficiencies. We hypothesized that a CMV-specific T cell assay performed early after transplant as part of a preemptive strategy could better stratify "low-risk" (recipient seropositive) patients. We conducted a prospective, blinded, observational study in 75 adult recipients. QuantiFERON-cytomegalovirus was performed both before and at multiple times after transplant. Low-risk patients (n = 58) were monitored as per unit protocol and treatment was commenced if CMV > 1000 copies/mL (DNAemia). Twenty patients needed antiviral treatment for other reasons and were censored (mainly for rejection or herpes simplex virus infection); 19/38 (50%) of the remaining low-risk patients developed DNAemia at mean 34.6 days after transplant. A week 2 result of <0.1 IU/mL was significantly associated with risk of subsequent DNAemia (hazard ratio [HR], 6.9; P = 0.002). The positive predictive value of 80% suggests these patients are inappropriately labeled low risk and are actually at high likelihood of CMV reactivation. A secondary cutoff of <0.2 IU/mL was associated with moderate risk (HR, 2.8; P = 0.01). In conclusion, a protocol based on a single early CMV-specific T cell based assay would offer improved risk stratification and individualization of patient management after transplant. This could offer improved drug and service utilization and potentially result in significant improvements over both currently used protocols to manage supposedly low-risk patients.