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Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction‐associated fatty liver disease (MAFLD) and metabolic dysfunction‐associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol. Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver‐related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra‐hepatic cancers (EHC). Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta‐analysis was performed using random‐effects modelling. Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random‐effect OR 1.12, 95% CI 1.04–1.21, p =.004) and CV mortality (random‐effect OR 1.15, 95% CI 1.04–1.26, p =.004), and a marginal trend towards higher rates of developing CKD (random‐effect OR 1.06, 95% CI 1.00–1.12, p =.058) and EHC events (random‐effect OR 1.11, 95% CI 1.00–1.23, p =.052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta‐regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD. Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with overt or occult hepatitis B virus (HBV) infection receiving immunosuppressive treatments have a wide risk of HBV reactivation (HBVr). We performed meta‐analysis with decision curve analyses (DCA) to estimate the risk of HBVr in HBsAg‐negative anti‐HBc‐positive patients naïve to nucleos(t)ide analogues (NAs) receiving immunosuppressive treatments. Approach and Results: Studies were identified through literature search until October 2022. Pooled estimates were obtained using random‐effects model. Subgroup analyses were performed according to underlying disease and immunosuppressive treatments. DCA was used to identify the threshold probability associated with the net benefit of antiviral prophylaxis in HBsAg‐negative anti‐HBc‐positive patients. We selected 68 studies (40 retrospective and 28 prospective), including 8034 patients with HBsAg negative anti‐HBc positive. HBVr was 4% (95% CI 3%–6%) in HBsAg‐negative anti‐HBc‐positive patients, with a significantly high heterogeneity (I2 69%; p <.01). The number‐needed‐to‐treat (NNT) by DCA ranged from 8 to 24 for chemotherapy plus rituximab, from 12 to 24 for targeted therapies in cancer patients and from 13 to 39 for immune‐mediated diseases. Net benefit was small for monoclonal antibodies. Conclusions: Our DCA in HBsAg‐negative anti‐HBc‐positive patients provided evidence that NA prophylaxis is strongly recommended in patients treated with chemotherapy combined with rituximab and could be appropriate in patients with cancer treated with targeted therapies and in patients with immune‐mediated diseases. Finally, in patients with cancer treated with monoclonal antibodies or with chemotherapy without rituximab, the net benefit is even lower. [ABSTRACT FROM AUTHOR]

Background: Glecaprevir and Pibrentasvir (G/P) determine high rates of sustained virological response (SVR) with optimal safety profile in patients with chronic hepatitis C virus (HCV) infection. The efficacy and safety of G/P in Caucasian patients aged 75 years and older have not been widely analysed. Methods: This is a retrospective multicentre real‐world study enrolling all consecutive patients 75 years and older who received G/P between October 2017 and January 2022 at five referral centres in Italy. SVR was analysed by intention‐to‐treat (ITT) and per‐protocol analyses (PP). Results: A total of 570 patients met the inclusion criteria and were analysed: mean age was 80 (75–97) years, 356 (62%) were females, 52% (298/570) had HCV‐1, 44% (252/570) had HCV‐2 and 137 (24%) patients had liver cirrhosis. Four hundred and sixty‐three (81%) patients were taking at least one concomitant drug, with 144 (25%) taking ≥5 concomitant drugs. G/P was given for 8 weeks in 488 patients (86%). During treatment, 48 patients (8%) reported side effects, with 10 (2%) patients discontinuing treatment prematurely. Two patients developed treatment‐unrelated serious adverse events. Overall, the SVR rate was 97.9% (558/570) by ITT analysis and 99.6% (558/560) by PP analysis. SVR rates remained consistently high among subgroup analysis stratified by genotype, treatment duration, fibrosis stage and concomitant medications. Conclusions: Treatment with G/P achieved 97.9% SVR rates in HCV patients older than 75 years of age. Safety was optimal with only 2% of patients discontinuing early. [ABSTRACT FROM AUTHOR]

Background & Aims: NAFLD patients usually have an increase in AST/ALT levels, but cholestasis can also be observed. We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver‐related outcomes (MALO). Methods: Five hundred and eighty‐two consecutive patients with biopsy‐proven NAFLD or a clinical diagnosis of NAFLD‐related compensated cirrhosis were classified as hepatocellular (H), C and mixed (M) patterns, by using the formula (ALT/ALT Upper Limit of Normal‐ULN)/(ALP/ALP ULN). MALO were recorded during follow‐up. An external cohort of 1281 biopsy‐proven NAFLD patients was enrolled as validation set. Results: H, M and C patterns were found in 153 (26.3%), 272 (46.7%) and 157 (27%) patients respectively. During a median follow‐up of 78 months, only 1 (0.6%) patient with H pattern experienced MALO, whilst 15 (5.5%) and 38 (24.2%) patients in M and C groups had MALO. At multivariate Cox regression analysis, age >55 years (HR 2.55, 95% CI 1.17–5.54; p =.01), platelets <150 000/mmc (HR 0.14, 95% CI 0.06–0.32; p <.001), albumin <4 g/L(HR 0.62, 95% CI 0.35–1.08; p =.09), C versus M pattern (HR 7.86, 95% CI 1.03–60.1; p =.04), C versus H pattern(HR 12.1, 95% CI 1.61–90.9; p =.01) and fibrosis F3–F4(HR 35.8, 95% CI 4.65–275.2; p <.001) were independent risk factors for MALO occurrence. C versus M pattern(HR 14.3, 95% CI 1.90–105.6; p =.008) and C versus H pattern (HR 15.6, 95% CI 2.10–115.1; p =.0068) were confirmed independently associated with MALO occurrence in the validation set. The immunohistochemical analysis found a significantly higher prevalence of moderate‐high‐grade ductular metaplasia combined with low‐grade ductular proliferation in C pattern when compared with the biochemical H pattern. Gene expression analysis showed a lower expression of NR1H3, RXRα and VCAM1 in patients with the C pattern. Conclusions: The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of MALO independently from other features of liver disease. [ABSTRACT FROM AUTHOR]

Summary: In β‐thalassaemia, the severity of inherited β‐globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long‐term outcomes remain limited. We analysed data from 2109 β‐thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β0/β0, β0/β+, β+/β+, β0/β++, β+/β++, and β++/β++. Patients were followed from birth until death or loss to follow‐up. The median follow‐up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β0 and β+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β0/β0, β0/β+, or β+/β+ had a 2·104‐increased risk of death [95% confidence interval (CI): 1·176–3·763, P = 0·011] and 2·956‐increased odds of multiple morbidity (95% CI: 2·310–3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β‐thalassaemia and suggests inclusion of both β+ and β0 mutations in strata of greatest severity. [ABSTRACT FROM AUTHOR]

Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic‐metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62‐0.95; P =.01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47‐0.83; P =.001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67‐0.98; P =.04). The C allele was associated with higher total circulating cholesterol (P =.01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. Conclusions: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR‐targeted therapy warrants further investigation. [ABSTRACT FROM AUTHOR]

Background and Aims: Non‐alcoholic fatty liver (NAFLD) is a major cause of liver disease worldwide leading also to a higher risk of cardiovascular events. We aimed to evaluate the impact of fatty liver and fibrosis on cardiovascular risk in a general population. Methods: Five hundred and forty‐two subjects included in the community‐based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study were recruited. Steatosis (controlled attenuation parameter > 288 dB/m) and severe fibrosis (low risk, liver stiffness measurement [LSM] < 7.9 KPa with M probe and < 5.7 KPa with XL probe; intermediate risk, LSM 7.9–9.5 KPa with M probe and 5.7–9.2 KPa with XL probe; high risk, LSM ≥ 9.6 KPa with M probe and ≥ 9.3 KPa with XL probe) were assessed with FibroScan. Cardiovascular risk was evaluated by the atherosclerotic cardiovascular disease (ASCVD) risk estimator and defined low if < 5%, borderline if 5–7.4%, intermediate if 7.5–19.9% and high if ≥ 20%. Intima‐media thickness (IMT) was measured with ultrasound. Results: Prevalence of steatosis and of severe fibrosis in this cohort was 31.7% and 4.8%, respectively. ASCVD score was evaluated in patients with and without steatosis and according to the risk of severe fibrosis. By ordinal regression analysis, both steatosis (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.13–2.33, P = 0.009) and severity of fibrosis (OR 1.67, 95% CI 1.18–2.36, P = 0.003) were independent risk factors for a higher ASCVD risk after adjusting for obesity. Subjects with NAFLD, when compared with those without, did not differ for IMT (0.75 vs 0.72 mm; P = 0.11) and IMT ≥ 1 mm (15.6% vs 12.1%; P = 0.24). Higher prevalence of IMT ≥ 1 mm was found in patients at high or intermediate risk of severe fibrosis (24% and 28.6%, respectively) compared with those at low risk (12.1%) (P = 0.03); this association was maintained after adjusting for confounders (OR 2.70, 95% CI 1.01–2.86, P = 0.04). Conclusion: In the setting of a general adult population, the presence of NAFLD and severe fibrosis are associated with to a higher cardiovascular risk profile, pointing towards the need for specific preventive measures. [ABSTRACT FROM AUTHOR]

Background & Aims: The risk of progression of indeterminate observations to hepatocellular carcinoma (HCC) after direct‐acting antivirals (DAA) is still undetermined. To assess whether DAA therapy changes the risk of progression of observations with low (LR‐2), intermediate (LR‐3) and high (LR‐4) probability for HCC in cirrhotic patients and to identify predictors of progression. Methods: This retrospective study included cirrhotic patients treated with DAA who achieved sustained virological response between 2015 and 2019. A total of 68 patients had pre‐DAA indeterminate observations and at least six months CT/MRI follow‐up before and after DAA. Two radiologists reviewed CT/MRI studies to categorize observations according to the LI‐RADSv2018 and assess the evolution on subsequent follow‐ups. Predictors of evolutions were evaluated by using the Cox proportional hazard model, Kaplan‐Meier method and log‐rank test. Results: A total of 109 untreated observations were evaluated, including 31 (28.4%) LR‐2, 67 (61.5%) LR‐3 and 11 (10.1%) LR‐4. During a median follow‐up of 41 months, 17.4% and 13.3% of observations evolved to LR‐5 or LR‐M and LR‐5, before and after DAA respectively (P =.428). There was no difference in rate of progression of neither LR‐2 (P = 1.000), LR‐3 (P =.833) or LR‐4 (P =.505). At multivariate analysis, only initial LI‐RADS category was an independent predictor of progression to LR‐5 or LR‐M for all observations (hazard ratio 6.75, P <.001), and of progression to LR‐5 after DAA (hazard ratio 4.34, P =.047). Conclusions: DAA therapy does not increase progression of indeterminate observations to malignant categories. The initial LI‐RADS category is an independent predictor of observations upgrade. [ABSTRACT FROM AUTHOR]

Summary: The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion‐dependent thalassaemia (TDT)], Group B [transfused non‐TDT (NTDT)] and Group C (non‐transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left‐ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment. [ABSTRACT FROM AUTHOR]

Aim: To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence. Methods: A prospective multicentre case–control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0‐F2 and 58% of whom had liver fibrosis stage F3‐F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct‐acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow‐up period of 30 (28–42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan–Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated‐measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis. Results: The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person‐years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA‐insulin resistance and HOMA‐β‐cell function and an increase in HOMA‐insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk. Conclusion: The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV‐induced alteration of glucose homeostasis mechanisms. [ABSTRACT FROM AUTHOR]

Background and aims: HCV eradication improves non‐hepatic outcomes such as cardiovascular diseases, although without clearly defined mechanisms. In this study we aimed to assess whether improvement of carotid atherosclerosis may be linked to a reduction in systemic oxidative stress after viral clearance. Methods: We studied a retrospective cohort of 105 patients (age 62.4 ± 11.2 years; 62 men) with F3/F4 fibrosis, characterized by carotid ultrasonography at baseline and at sustained virologic response (SVR) follow‐up. Levels of 8‐iso‐prostaglandin F2α (F2‐isoprostanes) and other oxidative stress markers were measured on frozen sera. Association between change (denoted as Δ) in oxidative stress markers (exposures) and change in carotid intima‐media thickness (cIMT) (outcome) was examined using multiple linear regression. Results: Subclinical atherosclerosis, defined as the presence of carotid plaque and/or cIMT ≥ 0.9, was present in 72% of the cohort. All patients achieved SVR that led to reduction in cIMT (0.92 ± 0.20 vs 0.83 ± 0.21 mm, P <.001). HCV eradication markedly decreased serum levels of F2‐isoprostanes (620.5 [143.2; 1904.1] vs 119.51 [63.2; 400.6] pg/mL, P <.0001), lipid hydroperoxides (13.8 [6.3; 20.7] vs 4.9 [2.3; 9.6] nmol/μl, P <.0001) and 8‐hydroxy‐2'‐deoxyguanosine (558.9 [321.0; 6301.2] vs 294.51 [215.31; 408.95] pg/mL, P <.0001), whereas increased serum GPx activity (10.44 [4.6; 16.3] vs 13.75 [9.42; 20.63] nmol/min/mL, P =.001). By multiple linear regression analysis ΔcIMT was independently associated with ΔF2‐isoprostanes (β: 1.746 [0.948; 2.543]; P <.0001) after adjustment for age, baseline F2‐isoprostanes and baseline IMT. Conclusions: Besides association of lipid peroxidation with severity of liver disease, the reduction in F2‐isoprostanes may be involved in the improvement of atherosclerosis after HCV eradication. [ABSTRACT FROM AUTHOR]

Background & Aims: In patients with hepatitis C virus (HCV)‐related advanced cirrhosis, the effects of sustained virological response (SVR) by direct antiviral agents (DAAs) on decompensation and liver deaths are less clearcut, since up to 30% of patients do not improve, and no predictors of outcome have been identified. We used 13C‐aminopyrine breath test (ABT) to assess whether its changes can predict liver‐related outcomes after DAA treatment in patients with HCV cirrhosis. Methods: Fifty consecutive patients with HCV cirrhosis were enrolled. Patients were included if they had Child A cirrhosis at risk for decompensation – defined as Child A6 (N = 22, 44%) or previous decompensation (N = 7, 14%) – or Child B cirrhosis (N = 21, 42%) eligible for DAA‐based antiviral therapy. ABT was performed at baseline and 12 weeks after the end of antiviral therapy. Patients received sofosbuvir‐based regimens. Results: Aminopyrine breath test was available for all 50 patients at baseline. The 120' cumulative dose was directly associated at regression analysis only with albumin levels (P =.001). ABT was available at follow‐up week 12 for 41 patients (FUW12), all with SVR, and followed for a median of 25.2 months (range 12.2‐32.1 months). Lower Ʌ ABT – defined as changes of 120' cumulative dose from FUW12 to baseline – (HR 0.97, 95% CI 0.94‐0.99; P =.02) and FUW12 hepatic encephalopathy (HR 19.0, 95% CI 1.16‐310.3; P =.03) were the only independent predictors of liver events/death at multivariate Cox regression analysis. The AUC of Ʌ ABT was good (0.87, 95% CI 0.75‐0.97), with a delta ≥0% well discriminating patients at lower vs patients at higher risk of liver‐related events/death (P <.001). Conclusions: In patients with advanced HCV cirrhosis who achieve SVR with DAA, Ʌ ABT assists in assessing the residual likelihood of liver‐related events and deaths after viral cure. [ABSTRACT FROM AUTHOR]

HCV‐RNA assessment during therapy with Direct‐Acting Antiviral (DAA) regimens still relies on assays requiring blood collection and transport to a specialised laboratory, which may compromise linkage to care. GeneXpert‐HCV Viral Load (GXHVL) (Cepheid) is a plasma‐based assay used at point of care (POC) with a sensitivity of ≤10 IU/mL, and, results available within 2 hours. Fifty‐nine consecutive HCV‐patients ready for DAAs treatment were enrolled. HCV‐RNA was simultaneously tested using Roche TaqMan RT‐PCR (venous blood sample) and GXHVL (capillary blood collected by fingerstick), at baseline (BL), week 4 (W4) of therapy, end of therapy (EOT) and week 12 of follow‐up (W12FU). Both assays demonstrated undetectable HCV‐RNA in all patients at EOT and identified the single case of HCV‐relapse at W12FU. GXHVL used as a point‐of‐care assay in the outpatient setting provides results fully comparable to the laboratory‐based test. Its excellent performance and ease of use suggest its adoption in non‐specialist settings where simplicity of care is paramount to implement HCV eradication campaigns. [ABSTRACT FROM AUTHOR]

Background & Aims: The worldwide spread of obesity is leading to a dramatic increase in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its complications. We aimed to evaluate both prevalence and factors associated with NAFLD in a general population in a Mediterranean area. Methods: We considered 890 consecutive individuals included in the community‐based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340). Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were measured with FibroScan. Participants were genotyped for PNPLA3 rs738409 and TM6SF2 rs58542926 variants. Results: The prevalence of NAFLD in the cohort was 48%. NAFLD participants exhibited elevated LSM values, suggesting advanced fibrosis (6.5% of cases). Both NAFLD and advanced fibrosis were independently associated with traditional risk factors (NAFLD: age >50 years, obesity, hypertension, elevated ALT and low HDL‐cholesterol serum concentrations. Advanced fibrosis: IFG/diabetes, elevated ALT serum concentrations). A high prevalence (>60%) of NAFLD was found in obese people, while it varied widely in non‐obese people according to the presence of metabolic risk factors. PNPLA3 G variant (OR = 1.33, 95% C.I. = 1.01‐1.8; P < .05) was independently associated with NAFLD. Prevalence of advanced fibrosis (high LSM values) ranged from 3.4% (no risk factors) to 60% (presence of all risk factors). TM6SF2 T variant (OR = 3.06, 95% C.I. = 1.08‐8.65, P < .05) was independently associated with advanced fibrosis (high LSM values). Conclusions: In a cohort of a general population, the prevalence of NAFLD was very high, and among NAFLD patients a significant proportion had advanced fibrosis (high LSM values). Apart from traditional risk factors, genetic factors may have a significant role that needs to be further investigated. [ABSTRACT FROM AUTHOR]

Background Few studies examined the outcome of patients with hepatitis C virus ( HCV)-related cirrhosis who developed hepatocellular carcinoma ( HCC). The relative weight as determinant of death for cancer vs end-stage liver disease ( ESLD) and the benefit of HCV eradication remain undefined. This multicentre, retrospective analysis evaluates overall survival ( OS), rate of decompensation and tumour recurrence in compensated HCC patients treated with interferon ( IFN) according to HCV status since HCC diagnosis. Methods Two groups of patients with HCV-related cirrhosis and HCC were followed since HCC diagnosis: (i) compensated cirrhotics with prior sustained virological response ( SVR) on IFN-based regimens (N=19); (ii) compensated cirrhotics without SVR (viraemic) (N=156). RESULTS Over a median follow-up of 3.0 years since the onset of HCC, OS was longer for HCC patients with SVR than for viraemic patients (log-rank P=.004). The 5-year OS rate was 65.9% in patients with SVR vs 31.9% in viraemic patients. Similar trends were reported for hepatic decompensation (log-rank P=.01) and tumour recurrence (log-rank P=.01). These findings were confirmed at multivariable and propensity score analysis. At propensity analysis, 0/19 compensated patients with SVR died for ESLD vs 7/19 (37%) viraemic patients ( P=.004). HCC mortality was similar in the two groups. Conclusions Hepatocellular carcinoma patients with prior SVR and compensated cirrhosis at the time of tumour diagnosis have prolonged OS than viraemic patients. Given the lack of cirrhosis progression, no SVR patient ultimately died for ESLD while this condition appears the main cause of death among viraemic patients. [ABSTRACT FROM AUTHOR]

Background & Aims No published study to date has provided a careful analysis of the effects of a sustained viral response ( SVR) on the outcomes of patients with compensated hepatitis C virus ( HCV)-related cirrhosis in relation to the degree of portal hypertension. Therefore, we estimated the impact of achieving SVR on disease progression, hepatocellular carcinoma ( HCC) development and mortality in a large cohort of HCV patients with cirrhosis with or without oesophageal varices ( OVs) at the start of antiviral therapy. Methods A total of 535 Caucasian patients were prospectively recruited to this study. All patients had a clinical or histological diagnosis of compensated HCV-related cirrhosis and underwent interferon-based therapy. Competing risks and a multistate model were analysed according to the presence or absence of OVs at baseline. Results Compared to patients without SVR, a greater proportion of patients who achieved SVR showed no liver disease progression after 10 years (36.3% vs. 61.3% of patients without baseline OVs; 29.6% vs. 64.3% of patients with baseline OVs). Achievement of SVR was significantly associated with reduced occurrence rates of de-novo OVs, hepatic decompensation and HCC. Compared to patients without SVR, patients with SVR had lower likelihoods of liver-related death at 10 years (20.6% vs. 10.3% of patients without baseline OVs; 50.5% vs. 21.8% of patients with baseline OVs). Conclusions In patients with compensated HCV-related cirrhosis with or without OVs at baseline, SVR is associated with reduced disease progression and liver-related mortality. [ABSTRACT FROM AUTHOR]

Background & Aims We tested the putative association of the rs58542926 variant of TM6 SF2, a recently described genetic determinant of nonalcoholic fatty liver disease, with steatosis and fibrosis in genotype 1(G1) chronic hepatitis C( CHC) patients. Methods A total of 694 consecutively biopsied Caucasian G1 CHC patients were genotyped for TM6 SF2 rs58542926, IL28B rs12979860 and PNPLA3 rs738409. Steatosis was classified as absent (<5%), mild-moderate(5-29%) and severe(≥30%), Fibrosis was considered severe if=F3-F4. Results Carriers of TM6 SF2 rs58542926 (6.3% of patients) exhibited lower serum levels of cholesterol ( P = 0.04) and triglycerides ( P = 0.01), but a similar distribution of steatosis severity ( P = 0.63), compared to noncarriers. Prevalence and severity of steatosis were reduced in IL28B C allele carriers ( P = 0.005) and elevated in PNPLA3 G allele carriers ( P < 0.001). After adjustment for age, gender, body mass index and homoeostasis model assessment score, steatosis severity was independently associated with IL28B rs12979860 (odds ratio [ OR] 0.69, 95% confidence interval [ CI] 0.55-0.86, P = 0.001) and PNPLA3 rs738409 ( OR 1.84, 95% CI 1.46-2.83, P < 0.001), but not TM6 SF2 rs58542926 ( OR 1.48, 95% CI 0.82-2.69, P = 0.19). Variants of TM6 SF2 (30.9% vs. 25%, P = 0.40), IL28B and PNPLA3 were not directly associated with fibrosis severity, although variants of IL28B and PNPLA3 promoted steatosis ( OR 1.36, 95% CI 1.06-1.75, P = 0.01) that in turn is associated with severe fibrosis. Conclusions In G1 CHC patients, TM6 SF2 rs58542926 does not affect the histological severity of liver damage. However, IL28B rs12979860 and PNPLA3 rs738409 modify steatosis. [ABSTRACT FROM AUTHOR]

Background & Aims The accuracy of noninvasive tools for the diagnosis of severe fibrosis in patients with nonalcoholic fatty liver disease( NAFLD) in clinical practice is still limited. We aimed at assessing the diagnostic performance of combined noninvasive tools in two independent cohorts of Italian NAFLD patients. Methods We analysed data from 321 Italian patients(179 Sicilian-training cohort, and 142 northern Italy-validation cohort) with an histological diagnosis of NAFLD. Severe fibrosis was defined as fibrosis ≥ F3 according to Kleiner classification. The APRI, AST/ ALT, BARD, FIB-4, and NFS scores were calculated according to published algorithms. Liver stiffness measurement( LSM) was performed by FibroScan. Cut-off points of LSM, NFS and FIB-4 for rule-in or rule-out F3-F4 fibrosis were calculated by the reported formulas. Results In the Sicilian cohort AUCs of LSM, NFS, FIB-4, LSM plus NFS, LSM plus FIB-4, and NFS plus FIB-4 were 0.857, 0.803, 0.790, 0.878, 0.888 and 0.807, respectively, while in the northern Italy cohort the corresponding AUCs were 0.848, 0.730, 0.703, 0.844, 0.850, and 0.733 respectively. In the training cohort, the combination of LSM plus NFS was the best performing strategy, providing false positive, false negative and uncertainty area rates of 0%,1.1% and 48% respectively. Similar results were obtained in the validation cohort with false positive, false negative and uncertainty area rates of 0%,7.3% and 40.8%. Conclusions The combination of LSM with NFS, two complementary, easy-to-perform, and widely available tools, is able to accurately diagnose or exclude the presence of severe liver fibrosis, also reducing of about 50-60% the number of needed diagnostic liver biopsies. [ABSTRACT FROM AUTHOR]

Background and Aim. The best staining to evaluate liver fibrosis in liver hepatitis is still a debated topic. This study aimed to compare Masson’s trichrome (MT), Sirius Red (SR), and orcein stainings in evaluating liver fibrosis in chronic HCV hepatitis (CHC) with semiquantitative and quantitative methods (Collagen Proportionate Area (CPA) by Digital Image Analysis (DIA)) and correlate them with transient elastography (TE). Methods. Liver stiffness evaluation of 111 consecutive patients with CHC was performed by TE. Semiquantitative staging by Metavir score system and CPA by DIA were assessed on liver biopsy stained with MT, SR, and orcein. Results. MT, SR, and orcein staining showed concordant results in 89.6% of cases in staging CHC, without significant difference in both semiquantitative and quantitative evaluations of fibrosis. TE values were concordant with orcein levels in 86.5% of the cases and with MT/RS in 77.5% (𝑃 < 0.001). No significant correlation between the grade of necroinflammatory activity and TE values was found. Conclusion. In CHC, SR/MT and orcein stainings are almost concordant and when discordant, orcein staining is better related to TE values than MT/RS. This suggests that elastic fibers play a more important role than reticular or collagenous ones in determining stiffness values in CHC. [ABSTRACT FROM AUTHOR]

Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the factors related to steatosis and IR in CHB patients, compared with CHC subjects, and to evaluate the potential association between these features and fibrosis severity. One hundred and seventy consecutive patients with CHB (28 HBeAg positive, 142 HBeAg negative), were evaluated using liver biopsy and metabolic measurements and matched for sex, age and body mass index with 170 genotype 1 CHC patients. IR was defined if HOMA-IR>2.7. All biopsies were scored for grading and staging by Scheuer's score, and the steatosis was considered significant if ≥10%. The prevalence of significant steatosis was similar in both CHB and CHC patients (31 vs. 38%; P=0.14). IR rate was significantly higher in CHC than in CHB patients (42 vs. 26%; P=0.002). Severe fibrosis (F3-F4), at multivariate analysis, was independently associated with older age (OR 1.050, 95% CI 1.009-1.093), steatosis >10% (OR 4.375, 95% CI 1.749-10.943), and moderate-severe necroinflammatory activity (OR 8.187, 95% CI 2.103-31.875), regardless of HBeAg status, in CHB patients, and with older age (OR 1.080, 95% CI 1.028-1.136), IR (OR 2.640, 95% CI 1.110-6.281), steatosis >10% (OR 3.375, 95% CI 1.394-8.171), and moderate-severe necroinflammatory activity (OR 8.988, 95% CI 1.853-43.593) in CHC patients. CHB patients had high steatosis prevalence, similar to CHC controls, but lower IR rate. Both steatosis and IR in CHC, and only steatosis in CHB, are independently associated with fibrosis severity. [ABSTRACT FROM AUTHOR]

The correlation between liver stiffness, measured by transient elastography, liver fibrosis, using the histological METAVIR score, and iron overload, measured by atomic absorption spectrometry was evaluated in 56 homozygous-β-thalassaemics. Liver stiffness increased proportionally to liver fibrosis staging ( r = 0·70; P > 0·001) independently of liver iron concentration ( r = 0·01; P = 0·932). The area under the receiver-operating characteristic curve for prediction of cirrhosis was 0·997 (95% confidence interval [CI]: 0·925–1·000) with cut-off of 13 kPa with 100% sensitivity (95% CI: 69·0–100·0) and 95% specificity (95% CI: 84·2–99·3). Transient elastography is a reliable non-invasive tool for diagnosing advanced liver fibrosis in homozygous-β-thalassaemics, regardless of the degree of iron overload. [ABSTRACT FROM AUTHOR]

Background/Aim: Patients with an occult hepatitis B virus (HBV) infection undergoing deep immunosuppression are potentially at risk of HBV reactivation. In order to assess whether a polymerase chain reaction (PCR) assay for HBV DNA in serum could be used to predict the reactivation of an occult HBV infection, we performed a retrospective study in a cohort of Sicilian patients with oncohaematological diseases. Methods: We studied by a highly sensitive ad hoc nested PCR for serum HBV DNA 75 HBsAg-negative oncohaematological patients requiring chemotherapy. Results: Thirty-three patients (44%) were HBV seronegative (anti-HBc and anti-HBs negative) and 42 patients (56%) were HBV seropositive (anti-HBc and/or anti-HBs positive). Baseline serum HBV DNA was positive in nine out of 33 HBV-seronegative patients and in nine out of 42 HBV-seropositive patients (27.3 vs. 21.4%; P=NS). HBsAg seroconversion was observed in five out of 33 seronegative vs. six out of 42 seropositive patients (15 vs. 14%, P=0.9), and in five out of 18 HBV DNA-positive vs. six out of 57 HBV DNA-negative patients (27.7 vs. 10.6% P=0.11). Hepatitis C virus infection was found in 18 patients (24.3%), although with no correlation to HBV serological status, presence of serum HBV DNA or frequency of HBsAg seroconversion. Conclusions: In oncohaematological patients undergoing chemotherapy, highly sensitive serum HBV DNA testing at baseline has a 28% predictive ability to forecast HBsAg seroconversion in HBV DNA-positive patients, and a 90% ability to forecast persistent HBsAg negativity in HBV DNA-negative patients, a better performance than serological tests. [ABSTRACT FROM AUTHOR]

Background and Aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy., Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele., Results: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p < .001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p = .007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6., Conclusions: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)