Impact of catheter tip to hepatic vein ostium distance on the validity and prognostication of hepatic venous pressure gradient in cirrhosis.

Hepatic venous pressure gradient (HVPG) is an accurate measure of portal hypertension in cirrhosis. However, the effect of catheter tip distance from hepatic vein ostium (HVO) on HVPG is unknown. We performed a retrospective study on 228 patients with 307 HVPGs in our institution. The objectives of this study were to assess the effect of catheter position on the validity of HVPG and its prognostication in cirrhosis. In this study, free hepatic vein pressure (FHVP) was considered optimal when difference between FHVP and inferior vena cava pressure was ≤ 2 mmHg. HVPG progressively decreased (p < 0.001) when measured at increasing distance from HVO due to an increasing FHVP (p = 0.036) but an unchanged wedged hepatic vein pressure (p = 0.343). Catheter tip distance > 5 to ≤ 8 cm [odds ratio {OR} 0.16 (95% CI 0.05-0.47), p = 0.001] and > 8 cm [OR 0.14 (95% CI 0.04-0.47), p = 0.002] compared to ≤ 3 cm from HVO were independent predictors of not achieving optimal FHVP. Baseline HVPG ≥ 16 mmHg was strongly associated with deaths due to cirrhosis and liver transplantation for end-stage liver disease compared to HVPG < 16 mmHg when FHVP was optimal (p < 0.001) but not when it was suboptimal (p = 0.359). Our study showed that FHVP is spuriously elevated when measured at > 5 cm from HVO, resulting in inaccurately low HVPG.

Virtual monitoring for stable chronic hepatitis B patients does not reduce adherence to medications: A randomised controlled study.

INTRODUCTION: Chronic hepatitis B (CHB) remains common in endemic regions, causing significant healthcare burden. Patients with CHB may need to be adherent to nucleoside analogue (NA) for a long period of time to prevent complications. This study aims to investigate the safety, efficacy and patient experience of a virtual monitoring clinic (VMC) in monitoring stable patients taking NA for CHB. METHODS: Patients on NA and regular follow-up were randomised to either VMC alternating with doctors' clinic visit or to a control group in which they continued standard follow-up by doctors. Therapy adherence was measured by medication possession ratio (MPR) for NA therapy, incidence of virological breakthrough and hepatocellular carcinoma (HCC) development at two years of follow-up. Patient acceptance was measured on a Likert scale of 1-10. RESULTS: A total 192 patients completed follow-up: 94 and 98 patients in the VMC and control groups, respectively. Mean age was 60.6 ± 10.8 years, with 95.3% Chinese ethnicity and 64.1% males. Age, gender, race, educational, employment and financial status were similar in both groups. Upon study completion, the majority of patients - 76 (80.9%) in VMC group and 74 (75.5%) in control group - had MPR ≥0.8; 88.8% were satisfied and rated VMC better than a traditional follow-up clinic with doctors only. More than 85% of patients rated ≥8/10 on the Likert scale for VMC, and preferred VMC over traditional clinic visits. Clinical outcomes observed were HCC development in one (1.1%) in the VMC group and four (4.1%) in the control group (p = 0.369). Two (2.1%) and one (1.0%) virological breakthroughs were observed in the VMC and control groups, respectively (p = 0.615). No incidence of HCC or abnormal blood tests were missed in the VMC arm. DISCUSSION: VMC is a viable and safe clinical model for monitoring stable CHB patients on NA therapy without compromising patients' adherence to medications and is preferred by patients.

New-onset cardiovascular risk factors following liver transplantation: A cohort analysis in Singapore.

INTRODUCTION: The aims of this study were to establish weight change, incidence of non-alcoholic fatty liver disease (NAFLD) and cardiovascular risk factors (CvRF) in liver transplant recipients (LTRs). METHODS: Eighty-three patients whose mean (standard deviation [SD]) age was 55.6 (8.4) years (median follow-up 73 months) and who underwent their first liver transplantation (LT) at Singapore General Hospital between February 2006 and March 2017 were included in the study. Anthropometric, clinical and demographic data were collected retrospectively from patients' medical records. Diabetes mellitus (DM), hyperlipidaemia and hypertension were regarded as CvRF. RESULTS: Compared to baseline, mean (SD) body weight decreased significantly at 1 month post-LT (60.8kg [11.9] versus 64.3kg [13.7], P<0.001). There was a gradual recovery of body weight thereafter, increasing significantly at year 2 (64.3kg [12.3] vs 61.5kg [13.7], P<0.001) until year 5 (66.9kg [12.4] vs 62.2kg [13.9], P<0.001), respectively. The prevalence of CvRF was significantly higher post-LT. NAFLD occurred in 25.3% of LTRs and it was significantly associated with post-LT DM and hyperlipidaemia. CONCLUSION: CvRF increased significantly post-LT, and NAFLD occurred in 25.3% of LTRs. Body weight dropped drastically within the first month post-LT, which then returned to baseline level just before the end of first year. This novel finding suggests that nutritional intervention needs to be tailored and individualised, based on events and time from transplant. Although long-term obesity is a significant problem, aggressive oral or enteral nutritional supplements take precedence in the early and immediate post-LT period, while interventions targeted at metabolic syndrome become necessary after the first year.

Hepatic venous-portal gradient (HVPG) measurement: pearls and pitfalls.

Hepatic venous pressure gradient (HVPG) is the gold-standard for measurement of portal hypertension, a common cause for life-threatening conditions such as variceal bleeding and hepatic encephalopathy. HVPG also plays a crucial role in risk stratification, treatment selection and assessment of treatment response. Thus recognition of common pitfalls and unusual hepatic venous conditions is crucial. This article aims to provide a radiographical and clinical guide to HVPG with representative clinical cases.

Poor Outcomes of Cirrhosis due to Nonalcoholic Steatohepatitis Compared With Hepatitis B After Decompensation With Ascites.

INTRODUCTION: Decompensation with ascites portends a poor prognosis in cirrhosis. The aim of this study was to compare the outcomes of patients with nonalcoholic steatohepatitis (NASH) with hepatitis B virus (HBV) cirrhosis after decompensation with ascites. METHODS: We conducted a retrospective study to evaluate the outcomes of patients with NASH and HBV cirrhosis who were admitted to hospital for first-onset ascites from January 1, 2004, to June 30, 2015. They were followed up until death, liver transplantation, or loss to follow up. RESULTS: Patients with NASH had lower median (interquartile range) Model for End-Stage Liver Disease score (11 [9-14] vs 14 [11-17], P < 0.001). Over 60 months, patients with NASH cirrhosis had higher cumulative incidence of dilutional hyponatremia (P < 0.001) and refractory ascites (P = 0.028). They also had higher cumulative incidence of cirrhosis-related deaths and liver transplantation compared with HBV cirrhosis (65.7%; [95% confidence interval (CI) 53.6-75.4] vs 42.5% [95% CI 32.4-55.2], P = 0.008). Multivariable competing risk analysis showed that NASH (subdistribution hazard ratio [sHR] 1.88 [95% CI 1.14-3.11], P = 0.014), non-Chinese ethnicity (sHR 1.63 [95% CI 1.06-2.50], P = 0.027), history of hepatocellular carcinoma (sHR 1.76 [95% CI 1.05-2.95], P = 0.033), estimated glomerular filtration rate <60 mL/min/1.73 m2 (sHR 1.70 [95% CI 1.09-2.65], P = 0.020), and Model for End-Stage Liver Disease score ≥15 (sHR 3.26 [95% CI 2.11-5.05], P < 0.001) were independent predictors of poor transplant-free survival. DISCUSSION: Patients with decompensated cirrhosis due to NASH had much poorer prognosis compared with HBV with more complications and greater healthcare resource utilization. Greater awareness is necessary for early diagnosis of NASH before decompensation.

Clinical validation of the chronic liver disease questionnaire for the Chinese population in Singapore.

BACKGROUND AND AIM: Assessment of health-related quality-of-life (HRQOL) in patients with chronic liver disease (CLD) requires the use of validated instruments that are understood by patients in their native language. We previously translated the Chronic Liver Disease Questionnaire into the Singapore-Mandarin version (CLDQ-SG). This study aims to examine the internal consistency and validity of the CLDQ-SG in patients with CLD. METHODS: We conducted a cross-sectional study of adult patients with CLD seen in a tertiary center in Singapore who completed both the CLDQ-SG and Short Form Health Survey 36 version 2 (SF-36v2) questionnaires. Internal consistency of the CLDQ-SG was assessed using Cronbach's alpha coefficient. Convergent and divergent validity of the SF-36v2 was assessed using the Spearman correlation coefficient, while discriminant validity was assessed using the Jonckheere-Terpstra test for trend. Exploratory factor analysis was performed to evaluate the factor structure of the CLDQ-SG. RESULTS: We enrolled 242 subjects (68.2% males, median age 67 years). Predominant etiology of CLD was chronic hepatitis B. Severity of CLD was divided into noncirrhotic (67.3%), compensated cirrhosis (24.0%), and decompensated cirrhosis (8.7%). Item convergent and discriminant validity of the CLDQ-SG was excellent, with 100% scaling success in all six domains. All domains exhibited good internal consistency, with Cronbach's α > 0.70. We observed a consistent trend of a reduction in mean CLDQ-SG score in the three groups reflecting the discriminant validity of the CLDQ-SG to assess changes in HRQOL in different severities of CLD. Factor analysis of the CLDQ-SG demonstrated an independent factor assessing sleep. CONCLUSION: The Singapore-Mandarin version of CLDQ-SG is a valid and reliable instrument to measure HRQOL in patients with CLD.

Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with hepatitis B virus (HBV) infection. Cells of most HBV-related HCCs contain HBV-DNA fragments that do not encode entire HBV antigens. We investigated whether these integrated HBV-DNA fragments encode epitopes that are recognized by T cells and whether their presence in HCCs can be used to select HBV-specific T-cell receptors (TCRs) for immunotherapy. METHODS: HCC cells negative for HBV antigens, based on immunohistochemistry, were analyzed for the presence of HBV messenger RNAs (mRNAs) by real-time polymerase chain reaction, sequencing, and Nanostring approaches. We tested the ability of HBV mRNA-positive HCC cells to generate epitopes that are recognized by T cells using HBV-specific T cells and TCR-like antibodies. We then analyzed HBV gene expression profiles of primary HCCs and metastases from 2 patients with HCC recurrence after liver transplantation. Using the HBV-transcript profiles, we selected, from a library of TCRs previously characterized from patients with self-limited HBV infection, the TCR specific for the HBV epitope encoded by the detected HBV mRNA. Autologous T cells were engineered to express the selected TCRs, through electroporation of mRNA into cells, and these TCR T cells were adoptively transferred to the patients in increasing numbers (1 × 104-10 × 106 TCR+ T cells/kg) weekly for 112 days or 1 year. We monitored patients' liver function, serum levels of cytokines, and standard blood parameters. Antitumor efficacy was assessed based on serum levels of alpha fetoprotein and computed tomography of metastases. RESULTS: HCC cells that did not express whole HBV antigens contained short HBV mRNAs, which encode epitopes that are recognized by and activate HBV-specific T cells. Autologous T cells engineered to express TCRs specific for epitopes expressed from HBV-DNA in patients' metastases were given to 2 patients without notable adverse events. The cells did not affect liver function over a 1-year period. In 1 patient, 5 of 6 pulmonary metastases decreased in volume during the 1-year period of T-cell administration. CONCLUSIONS: HCC cells contain short segments of integrated HBV-DNA that encodes epitopes that are recognized by and activate T cells. HBV transcriptomes of these cells could be used to engineer T cells for personalized immunotherapy. This approach might be used to treat a wider population of patients with HBV-associated HCC.

Albumin May Prevent the Morbidity of Paracentesis-Induced Circulatory Dysfunction in Cirrhosis and Refractory Ascites: A Pilot Study.

BACKGROUND: Large-volume total paracentesis may result in paracentesis-induced circulatory dysfunction, which is associated with poor outcomes. AIMS: To explore the short- and long-term effects of paracentesis-induced circulatory dysfunction on systemic hemodynamics, renal function and other cirrhosis-related complications in patients with refractory ascites, following subtotal large-volume paracentesis. METHODS: Patients with cirrhosis and refractory ascites without renal dysfunction had systemic hemodynamics, renal function, and neurohormones (plasma active renin, aldosterone, norepinephrine and angiotensin II) measured pre- and 6 days post-paracentesis. Paracentesis was limited to ≤8 L with 6-8 g of albumin per liter ascites drained. Patients were followed up until transjugular intrahepatic portosystemic shunt insertion, liver transplantation, or death. Paracentesis-induced circulatory dysfunction was defined as >50 % increase in plasma active renin 6 days post-paracentesis. RESULTS: Fifty-seven patients (mean age 59.0 ± 9.4 years) had mean 6.8 ± 1.8 L of ascites removed with 9 ± 3 g of albumin given/L of ascites drained. Patients were followed up for 715 ± 104 days. Twenty-three patients (40.4 %) developed paracentesis-induced circulatory dysfunction with unchanged serum creatinine on day six, despite worsening of hemodynamics (mean arterial pressure 90 ± 10 mmHg at baseline vs. 84 ± 8 mmHg on day six, p < 0.05). Similar hemodynamic changes were observed among patients without paracentesis-induced circulatory dysfunction. There was no significant difference in the long-term renal function or cirrhosis-related complications between the groups. CONCLUSION: The occurrence of paracentesis-induced circulatory dysfunction, as defined by plasma active renin, may not have a significant short- and long-term impact on renal function or cirrhosis-related complications in patients with refractory ascites who undergo subtotal paracentesis with albumin infusion.

Clinical applications, limitations and future role of transient elastography in the management of liver disease.

Transient elastography (TE) is a reliable tool for the non-invasive assessment of liver fibrosis in routine clinical practice. TE is currently approved for use in Europe, Asia and the United States. The widespread adoption of this technology is certain to increase the use of TE worldwide. Although TE has been well validated in chronic viral hepatitis, its clinical role in other liver diseases remains less clear. The advent of new treatment for chronic hepatitis C and emerging prevalence of non-alcoholic steatohepatitis raises new questions on the role of TE in current clinical practice. This review aims to examine the clinical applications, limitations and future role of TE in current clinical practice in light of the changing epidemiology of liver diseases and new clinical management paradigms. In current clinical practice, TE is the most accurate non-invasive method for diagnosis of liver cirrhosis. TE is useful to rule out fibrosis and cirrhosis but does not have sufficient accuracy to discern between various stages of fibrosis. The clinical role of TE has evolved from cross-sectional point-in-time assessment of fibrosis and cirrhosis to the more relevant role of prediction of vital clinical end-points. This provides clinicians with the ability to modify treatment strategies based on the information provided by TE. TE has evolved over the past decade to become an essential tool to assist the clinician in the management of chronic liver disease.

Change in model for end-stage liver disease score at two weeks, as an indicator of mortality or liver transplantation at 60 days in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterised by a sudden deterioration of underlying chronic liver disease, resulting in increased rates of mortality and liver transplantation. Early prognostication can benefit optimal allocation of resources. METHODS: ACLF was defined as per the disease criteria of the Asian Pacific Association for the Study of the Liver. Inpatient discharge summaries from between January 2001 and April 2013 were reviewed. The primary outcome was mortality or liver transplantation within 60 days from onset of ACLF. Absolute 'model for end-stage liver disease' (MELD) score and change in MELD at Weeks 1, 2 and 4 were reviewed in order to identify the earliest point for prediction of mortality or liver transplantation. RESULTS: Clinical data were collected on 53 subjects who fulfilled the inclusion and exclusion criteria. At 60 days from presentation, 20 patients (37.7%) died and 4 (7.5%) underwent liver transplantation. Increased MELD of ≥2 after 2 weeks was 75.0% sensitive and 75.9% specific for predicting mortality or liver transplantation. If the MELD score did not increase at 2 weeks, predictive chance of survival was 93.8% over the next 60 days. MELD change at 1 week showed poor sensitivity and specificity. Change at 4 weeks was too late for intervention. CONCLUSION: Change in MELD score at 2 weeks provides an early opportunity for prognostication in ACLF. A MELD score that does not deteriorate by Week 2 would predict 93.8% chance of survival for the next 60 days. This finding warrants further validation in larger cohort studies.

Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion.

BACKGROUND AND AIM: Transjugular intrahepatic portosystemic shunt (TIPS) is indicated for the treatment of refractory ascites in cirrhosis. The long-term outcome of TIPS for refractory ascites is unknown. The aim of this study is to describe the natural history of patients with refractory ascites post-TIPS, and compare between polytetrafluoroethylene (PTFE)-covered versus bare stents. METHODS: A retrospective chart review of patients who had TIPS for refractory ascites was conducted. Prospectively collected data include demographics, angiographic data, blood work, and urinary sodium excretion. RESULTS: There were 136 patients who received TIPS (bare = 104, covered = 32) for over 22 years. Patients with PTFE stents had lower international normalized ratio and model for end-stage liver disease score. More patients with bare stents developed shunt dysfunction (74.0% vs 24.1%, P < 0.0001) and required more TIPS revisions (1.6 ± 0.2/patient vs 0.2 ± 0.1, P < 0.0001). Urinary sodium excretion increased significantly from first month and progressed to 98 ± 9 mmol/day at 12th month post-TIPS (P < 0.001 vs baseline), concurrent with improved renal function. Most patients (77.6%) completely cleared the ascites without diuretics, but many achieved this beyond 2 years. Number of TIPS revision was predictive of complete response at 12 months (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5-0.9, P < 0.05). Age (hazard ratio [HR] = 1.05 [95% CI 1.02-1.08], P < 0.01), complete response (HR = 0.22 [95% CI 0.12-0.40], P < 0.0001) and polytetrafluoroethylene stents (HR = 0.23 [95% CI 0.05-0.97], P < 0.05) were predictive of survival. CONCLUSION: TIPS is an effective treatment for cirrhotic refractory ascites. Ascites clearance is dependent on number of TIPS revision, whereas survival is predicted by younger age, complete response, and covered stent use, although era effect likely contributed to improved survival with covered stent use.

Acute abdomen secondary to incarcerated umbilical hernia after treatment of massive cirrhotic ascites.

Umbilical herniation is common in patients with liver cirrhosis and ascites. Rarely, they suffer from incarceration and strangulation of the umbilical hernia after treatment of ascites. We report 3 cases of umbilical hernia incarceration following removal of massive ascites with different treatment modalities. Physicians managing this group of patients should be aware of this rare and potentially fatal complication.