Effect of Concurrent Metabolic Dysfunction-Associated Steatotic Liver Disease on Serial Non-invasive Fibrosis Markers in Chronic Hepatitis B.

BACKGROUND & AIMS: Concurrent hepatic steatosis has diverse effects on chronic hepatitis B (CHB), however the combined effects of metabolic dysfunction-associated steatotic liver disease (MASLD) and CHB on liver fibrosis progression remains unclear. The primary aim of this study was to utilize serial fibrosis measurements to compare the dynamic change in fibrosis in CHB patients with/without concurrent MASLD. The secondary aim was to investigate factors associated with steatosis development and regression in CHB patients. METHODS: This was a retrospective cohort study of all non-cirrhotic CHB patients identified from 1/1/2011 to 31/12/2016. Hepatic steatosis was diagnosed by ultrasound. Fibrosis markers included liver stiffness (LSM) by transient elastography, APRI and FIB-4. General linear mixed effects modelling was used to fit polynomial and linear estimates. RESULTS: Of 810 CHB patients (n = 2,373 LSM measurements; median age 44.4y; 48% male; 24% HBeAg positive), 14% had concurrent MASLD. LSM was higher at baseline but decreased in MASLD patients over time, while LSM remained stable in non-MASLD patients, such that all patients had similar LSM beyond 4-5 years. MASLD patients had lower APRI compared to non-MASLD patients, which was predominately due to a higher platelet count and higher ALT over time. There was substantial discordance between LSM, APRI and FIB-4. Baseline BMI was the only factor that predicted steatosis development and regression. CONCLUSIONS: We found no evidence of an association between concurrent MASLD and fibrosis progression amongst CHB patients without baseline advanced liver disease. APRI and FIB-4 may have reduced accuracy in MASLD patients.

Improved Survival Outcomes with Surgical Resection Compared to Ablative Therapy in Early-Stage HCC: A Large, Real-World, Propensity-Matched, Multi-Centre, Australian Cohort Study.

The optimal treatment approach in very-early and early-stage hepatocellular carcinoma (HCC) is not precisely defined, and there is ambiguity in the literature around the comparative efficacy of surgical resection versus ablation as curative therapies for limited disease. We performed this real-world propensity-matched, multi-centre cohort study to assess for differences in survival outcomes between those undergoing resection and those receiving ablation. Patients with Barcelona Clinic Liver Cancer (BCLC) 0/A HCC first diagnosed between 1 January 2016 and 31 December 2020 who received ablation or resection as initial treatment were included in the study. A total of 450 patients were included in the study from 10 major liver centres including two transplant centres. Following propensity score matching using key covariates, 156 patients were available for analysis with 78 in each group. Patients who underwent resection had significantly improved overall survival (log-rank test p = 0.023) and local recurrence-free survival (log rank test p = 0.027) compared to those who received ablation. Based on real-world data, our study supports the use of surgical resection in preference to ablation as first-line curative therapy in appropriately selected BCLC 0/A HCC patients.

A novel point-of-care test for cirrhosis based on dimeric to monomeric IgA ratio in blood: a pilot cohort study.

BACKGROUND AND AIMS: Dimeric IgA to monomeric IgA ratio (dIgA ratio) is a biomarker of gut mucosal leakage in liver cirrhosis. We evaluated the diagnostic performance of a novel point-of-care (POC) dIgA ratio test for cirrhosis. METHODS: Plasma samples from people with chronic liver disease were analyzed using the BioPoint POC dIgA ratio antigen immunoassay lateral flow test. Cirrhosis was defined by Fibroscan>12.5 kPa, clinical evidence of cirrhosis or liver histopathology. POC dIgA test diagnostic accuracy was determined in a test cohort using receiver operating characteristic curve analysis; optimal cutoffs for sensitivity and specificity were then applied to a validation cohort. RESULTS: A total of 1478 plasma samples from 866 patients with chronic liver disease were included (test cohort n = 260, validation cohort n = 606). In all, 32% had cirrhosis; 44% Child-Pugh A, 26% Child-Pugh B, and 29% Child-Pugh C. Median POC dIgA ratio was higher in cirrhosis (0.9) compared with no cirrhosis (0.4, p < 0.001), and in Child-Pugh class B/C compared with A cirrhosis (1.4 Child-Pugh B/C vs. 0.6 Child-Pugh A, p < 0.001). POC dIgA ratio test had good diagnostic accuracy for liver cirrhosis in the test cohort (area under the receiver operating characteristic curve=0.80); a dIgA ratio cutoff of 0.6 had a sensitivity of 74% and specificity of 86%. POC dIgA test accuracy was moderate in the validation cohort (area under the receiver operating characteristic curve=0.75; positive predictive value 64%, negative predictive value 83%). Using a dual cutoff approach, 79% of cirrhosis cases were correctly diagnosed and further testing was avoided in 57%. CONCLUSIONS: POC dIgA ratio test had moderate accuracy for cirrhosis. Further studies evaluating the accuracy of POC dIgA ratio testing for cirrhosis screening are warranted.

Validation of a novel point-of-care test for alanine aminotransferase measurement: A pilot cohort study.

BACKGROUND: Alanine aminotransferase (ALT) measurement is essential for evaluation of liver disease. We validated a novel rapid point-of-care (POC) test for ALT1 against laboratory ALT. METHODS: Stored plasma samples from adults with chronic liver disease (Test cohort n = 240; Validation cohort n = 491) were analysed using the BioPoint® antigen immunoassay POC ALT1 lateral flow test, which provides quantitative ALT results (Axxin handheld reader) or semi-quantitative results (visual read, cut off 40 IU/ml). The accuracy of POC ALT1 to detect ALT > 40 IU/L was determined by ROC analysis. In patients with chronic hepatitis B, treatment eligibility (EASL criteria) was determined using POC ALT1 and compared to laboratory ALT. RESULTS: POC ALT1 test had good accuracy for laboratory ALT > 40 IU/L: AUROC 0.93 (95% CI: 0.89-0.96) in the Test cohort and AUROC 0.92 (95% CI: 0.88-0.95) in the Validation cohort. POC ALT1 cut off of 0.8 for ALT > 40 IU/L maximised sensitivity (97%) and specificity (71%) in the Test cohort (42% laboratory ALT > 40 IU/L) and yielded PPV 84% and NPV 91% in the Validation cohort (19% laboratory ALT > 40 IU/L). Semi-quantitative POC ALT1 had good accuracy for laboratory ALT in the Validation cohort (AUROC 0.85, 95% CI: 0.81-0.99; sensitivity 77% and specificity 93%). Combined with HBV DNA and transient elastography, both quantitative and semi-quantitative POC ALT1 tests had good accuracy for excluding hepatitis B treatment needs (sensitivity 96%, specificity 78% and NPV 99%). CONCLUSION: The POC ALT1 test had good accuracy for elevated ALT levels and for determining treatment eligibility among people with chronic hepatitis B.

Zinc supplementation and its benefits in the management of chronic liver disease: An in-depth literature review.

Malnutrition among patients with chronic liver disease (CLD) is a common complication with significant prognostic implications for patients with liver cirrhosis. Micronutrient deficiency has been associated with an increased risk of hepatic decompensation and is an independent risk factor for mortality among cirrhotic patients. Micronutrient deficiencies in patients with CLD include zinc, vitamin A, vitamin D and selenium. This review article aims to evaluate the literature to date on the complications of zinc deficiency in patients with CLD. A management algorithm for zinc replacement has also been proposed.

A nurse-led, telehealth-driven hepatitis C management initiative in regional Victoria: Cascade of care from referral to cure.

INTRODUCTION: Elimination of hepatitis C virus stands as an unresolved World Health Organization target, and is associated with complications including cirrhosis and hepatocellular carcinoma. Hepatitis C virus management has been revolutionised following the widespread availability of direct-acting antiviral agents in Australia since 2016; however, large proportions of the population remain untreated. Telehealth-based service delivery is an accessible and effective alternative, and we aimed to assess qualitative and clinical outcomes in a clinical nurse consultant-led regional telehealth model. METHODS: A prospective cohort analysis of all patients referred to a Victorian regional hospital's hepatitis C virus telehealth clinic between 1 April 2017 and 10 June 2020 was conducted. Data were collated from outpatient and electronic medical records. RESULTS: Fifty-five out of 71 referred patients were booked, with 44 patients (80%) attending at least one appointment. A history of alcohol use disorder and psychiatric comorbidity was seen in 25 (54%) and 24 (52%) patients, respectively. Twenty-one out of 24 (88%) eligible patients had direct-acting antiviral agent treatment and 14 out of 21 (67%) successfully completed the treatment. An average of 46.5 km, 54.6 min and $AUD30.70 was saved per patient for each visit. Observed benefits included: increased medical engagement, adherence to and completion of HCV treatment and cirrhosis monitoring. Telehealth-driven hepatocellular carcinoma surveillance was successful in the cirrhotic subgroup. CONCLUSION: Clinical nurse consultant-led hepatitis C virus management via telehealth allows access to marginalised regional populations. Clinical outcomes were comparable to other cohorts with additional cost-benefit, efficiency gains and carbon footprint reduction amongst a previously unreported regional Victorian hepatitis C virus population.

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.

SIRT Compared with DEB-TACE for Hepatocellular Carcinoma: a Real-world Study (the SITAR Study).

BACKGROUND: Hepatocellular carcinoma (HCC) is responsible for 1% of deaths worldwide, and the incidence continues to increase. Despite surveillance programs, 70% of HCC patients are not suitable for curative options at diagnosis, and therefore, non-curative treatments are essential to modern clinical practice. There are many novel treatments, though their roles are not well defined. This study aimed to contrast Selective Internal Radiation Therapy (SIRT) and Drug Eluting Bead Transarterial Chemoembolisation (DEB-TACE) to further define their roles. METHODS: This was a retrospective multicentre cohort study. Factors included for analysis were type of HCC treatment, number of lesions, lesion size, multiple disease severity scores, cirrhosis and vascular invasion. The primary endpoint was transplant-free survival. RESULTS: Transplant-free survival was similar between the two cohorts (p = 0.654), despite a variation in median lesion size, SIRT: 54.5 mm, DEB-TACE: 34 mm (p ≤ 0.001). A univariate Cox proportional hazard model utilising treatment modality as the covariate showed no significant difference in survival (DEB-TACE HR 1.4 (95%CI 0.85-2.15 p = 0.207). The size of the largest lesion was the best predictor of 3-year survival (p = 0.035). Lesion size was inversely associated with survival (HR 1.01 (95%CI 1-1.02, p = 0.025)) on multivariate analysis. CONCLUSION: This study is the first to catalogue the experience of using SIRT in HCC in a real-world Australian population. It has demonstrated no difference in survival outcomes between DEB-TACE and SIRT. Further, it has shown SIRT to be a reasonable alternative to DEB-TACE especially in larger lesions and has demonstrated that DEB-TACE has a role in select patients with advanced disease.

A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Lactobacillus casei Shirota in Stable Cirrhotic Patients.

Background: In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Lactobacillus casei Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods: 92 cirrhotic patients (Child-Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results: Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1ß (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1ß (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion: LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.

Significant reduction in heart rate variability is a feature of acute decompensation of cirrhosis and predicts 90-day mortality.

BACKGROUND: Heart rate variability (HRV) is reduced in cirrhosis and in conditions of systemic inflammation. Whether HRV is associated with cirrhosis decompensation and development of acute-on-chronic liver failure (ACLF) is unknown. AIMS: To (a) validate wireless remote HRV monitoring in cirrhosis decompensation; (b) determine if severely reduced HRV is a surrogate for inflammation and progression of cirrhosis decompensation; (c) assess if measuring HRV determines prognosis in cirrhosis decompensation. METHODS: One hundred and eleven patients at risk of cirrhosis decompensation at two clinical sites were monitored for HRV. Standard deviation of all normal beat-beat intervals (SDNN) reflecting HRV was assessed using remote monitoring (Isansys Lifetouch) and/or Holter ECG recording. Clinical outcomes and major prognostic scores were recorded during 90-day follow-up. RESULTS: Reduced HRV denoted by lower baseline SDNN, correlated with severity of decompensation (median 14 (IQR 11-23) vs 33 (25-42); P < 0.001, decompensated patients vs stable outpatient cirrhosis). Furthermore, SDNN was significantly lower in patients developing ACLF compared to those with only decompensation (median 10 (IQR9-12) vs 16 (11-24); P = 0.02), and correlated inversely with MELD and Child-Pugh scores, and C-reactive protein (all P < 0.0001) and white cell count (P < 0.001). SDNN predicted disease progression on repeat measures and appeared an independent predictor of 90-day mortality (12 patients). An SDNN cut-off of 13.25 ms had a 98% negative predictive value. CONCLUSIONS: This study demonstrates that remote wireless HRV monitoring identifies cirrhosis patients at high risk of developing ACLF and death, and suggests such monitoring might guide the need for early intervention in such patients. Clinical Trial number: NIHR clinical research network CPMS ID 4949.

Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients.

Hepatic encephalopathy (HE) is a common feature of acute-on-chronic liver failure (ACLF). Although ammonia, inflammation, and cerebral oxygenation are associated with HE in acute liver failure, their roles in ACLF are unknown. The aim of this prospective, longitudinal study was to determine the role of these pathophysiological variables in ACLF patients with and without HE. We studied 101 patients with ACLF admitted to the intensive care unit. Severity of ACLF and HE, arterial ammonia, jugular venous oxygen saturation (JVO2 ), white blood cell count (WCC), and C-reactive protein were measured at days 0, 1, 3, and 7. Patients were followed until death or hospital discharge. Mortality was high (51 patients, 50.5%), especially in patients with HE of whom 35 of 53 (66.0%) died regardless of ACLF severity. At baseline, increased WCC and abnormal JVO2 (high or low) were independent predictors of death. Further deterioration in inflammation, JVO2 , and ammonia were also predictive of mortality. JVO2 deviation and hyperammonemia were associated with the presence and severity of HE; improvement in these parameters was associated with a reduction in HE grade. No direct interaction was observed between these variables in regards to mortality or HE. In conclusion, this study describes potential mechanisms of HE in ACLF indicating that ammonia and abnormal cerebral oxygenation are important. The results suggest that ammonia, JVO2 , and WCC are important prognostic biomarkers and therapeutic targets. The relative roles of these pathophysiological factors in the pathogenesis of HE in ACLF or guiding therapy to improve survival requires future study. Liver Transplantation 22 732-742 2016 AASLD.

Albumin in chronic liver disease: structure, functions and therapeutic implications.

Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.

The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure.

BACKGROUND & AIMS: Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. METHODS: The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. RESULTS: Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3-7, and 8-15 (C-index: 0.72, 0.75, and 0.77 respectively). CONCLUSIONS: The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early.

Liver: the gut is a key target of therapy in hepatic encephalopathy.

Little progress has been made in the pharmacological management of patients with hepatic encephalopathy, partly because it is difficult to perform clinical trials in this group of patients. A new clinical trial now suggests that polyethylene glycol is more effective than the current standard first-line therapy in these patients.

Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation.

Toll-like receptors (TLRs) play a key role in transplantation biology. The effect of immunosuppression on TLR function after liver transplantation is unknown. Peripheral blood mononuclear cells (PBMCs) from 113 post-liver transplant patients and 13 healthy controls were stimulated with TLR-specific ligands [lipopolysaccharide (TLR4), pan-3-cys (P3C) (TLR2), Poly (I:C) (PIC) (TLR3), R848 (TLR7/8), and CpG (TLR9)] for 24 hours. PBMCs from 5 healthy controls were also cultured with therapeutic concentrations of cyclosporine A (CYA) and tacrolimus (TAC). Cytokine production was measured with enzyme-linked immunosorbent assays and flow cytometry. PBMCs from patients on calcineurin inhibitors after liver transplantation produced less interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in response to TLR2 stimulation (IL-6: P=0.02; TNFα: P=0.01), TLR4 stimulation (IL-6: P=0.02; TNFα: P=0.01), and TLR7/8 stimulation (IL-6: P=0.02; TNFα: P=0.02), compared with healthy controls. Both CD56(bright) and CD56(dim) natural killer (NK) cells from patients on calcineurin inhibitors also produced less interferon-γ (IFNγ) with TLR7/8 stimulation compared with healthy controls (CD56(bright) : P=0.002; CD56(dim) : P=0.004). Similar findings were demonstrated in healthy PBMCs cultured with CYA (PBMCs: TLR2, IL-6: P=0.005; TLR4, IL-6: P=0.03, TNFα: P=0.03; TLR7/8, IL-6: P=0.02, TNFα: P=0.01; CD56(dim) NK cells: TLR7/8, IFNγ: P=0.03). TAC impaired TLR4-mediated IL-6 and TNFα production by PBMCs (IL-6; P = 0.02; TNFα P = 0.009). In conclusion, patients on calcineurin inhibitors had impaired inflammatory cytokine production in response to TLR2, TLR4, and TLR7/8 stimulation compared comparison with healthy controls. Importantly, TAC and CYA appear to have different effects on TLR signaling. Impaired TLR function has important repercussions for risk of infection, graft rejection, and disease recurrence after transplantation, and the different immunosuppressive profiles of CYA and TAC may guide the choice of therapy to improve disease outcomes.