Hepatitis C virus (HCV) is the leading cause of liver transplantation in Europe and is associated with an increased risk of hepatocellular carcinoma (HCC). Because of the chronic nature of the ...disease, estimates suggest that the burden on healthcare will increase dramatically for this entity. Clinical care of patients with HCV‐related liver disease has advanced considerably in the last two decades, thanks to increasing knowledge about the mechanisms of the disease, development of diagnostic procedures, and advances in therapeutic and preventive approaches. HCV RNA testing, HCV genotyping and staging of liver disease are essential for the diagnosis and the management of HCV therapy. Furthermore, the important role of host polymorphisms of the IL28B gene on virological response to treatment with pegylated interferon (PEG‐IFN) alpha and ribavirin (RBV) has recently been clearly demonstrated. In relation to treatment, although numerous drugs for HCV are in various stages of preclinical and clinical development, the current standard of care (SoC) is the combination of PEG‐IFN‐α and RBV for chronic hepatitis C. With SoC, a sustained viral response (SVR) is achieved in approximately 45% of patients infected with HCV genotype 1 and in approximately 80% of patients infected with HCV genotypes 2 and 3. The EASL HCV guidelines recommend treating all naïve patients with compensated disease from HCV without contraindications to treatment and strongly suggest initiating SoC promptly in patients with advanced fibrosis. Further recommendations on monitoring treatment efficacy, treatment duration, dose reduction indications and the role of co‐factors are provided.
Long‐lasting HBV‐DNA suppression is considered to be the best surrogate end‐point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a ...prerequisite to prevent liver‐related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well‐tolerated for long‐term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.
The Baveno VI consensus proposed a dual liver stiffness (LS) by transient elastography threshold of <10 and >15 kPa for excluding and diagnosing compensated advanced chronic liver disease (cACLD) in ...the absence of other clinical signs. Herein, we aimed to validate these criteria in a real-world multicentre study.
We included 5,648 patients (mean age 51 ± 13 years, 53% males) from 10 European liver centres who had a liver biopsy and LS measurement within 6 months. We included patients with chronic hepatitis C (n = 2,913, 52%), non-alcoholic fatty liver disease (NAFLD, n = 1,073, 19%), alcohol-related liver disease (ALD, n = 946, 17%) or chronic hepatitis B (n = 716, 13%). cACLD was defined as fibrosis stage ≥F3.
Overall, 3,606 (66%) and 987 (18%) patients had LS <10 and >15 kPa, respectively, while cACLD was histologically confirmed in 1,772 (31%) patients. The cut-offs of <10 and >15 kPa showed 75% sensitivity and 96% specificity to exclude and diagnose cACLD, respectively. Examining the ROC curve, a more optimal dual cut-off at <7 and >12 kPa, with 91% sensitivity and 92% specificity for excluding and diagnosing cACLD (AUC 0.87; 95% CI 0.86–0.88; p <0.001) was derived. Specifically, for ALD and NAFLD, a low cut-off of 8 kPa can be used (sensitivity=93%). For the unclassified patients, we derived a risk model based on common patient characteristics with better discrimination than LS alone (AUC 0.74 vs. 0.69; p <0.001).
Instead of the Baveno VI proposed <10 and >15 kPa dual cut-offs, we found that the <8 kPa (or <7 kPa for viral hepatitis) and >12 kPa dual cut-offs have better diagnostic accuracy in cACLD.
The term compensated advanced chronic liver disease (cACLD) was introduced in 2015 to describe the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients. It was also suggested that cACLD could be diagnosed or ruled out based on specific liver stiffness values, which can be non-invasively measured by transient elastography. Herein, we assessed the suggested cut-off values and identified alternative values that offered better overall accuracy for diagnosing or ruling out cACLD.
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•cACLD is the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients.•The Baveno VI consensus suggested a dual liver stiffness cut-off to diagnose/rule out cACLD.•Proposed liver stiffness cut-offs of 15 kPa had 75%/96% Se/Sp to rule out/in cACLD.•We showed that liver stiffness cut-offs of 12 kPa are optimal (Se/Sp 91%/92%).•In ALD and NAFLD, a cut-off <8 kPa can be used to rule out cACLD (Se=93%).
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•DAAs improve survival in patients with HCV-related early HCC that has been successfully treated.•The improvement in survival seems to be caused by a reduction in hepatic ...decompensation.•DAAs did not impact on HCC recurrence.
The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation.
We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared.
In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio HR 0.39; 95% CI0.17–0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR0.70; 95% CI0.44–1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR0.32; 95% CI0.13–0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00–0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11–0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02–0.38; p = 0.02).
In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment.
We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced.
HCV is associated with an increased risk of cardiovascular events (CV). Whether HCV clearance by direct-acting antivirals (DAA) reduces incident CV disease is poorly understood. We investigate ...whether HCV eradication reduces CV events.
In a prospective multicentre study, 2204 HCV patients (F0–F2:29.5%, F3–F4: 70.5%) were enrolled. Males were 48%, median age was 68 (59–74) years and BMI 25.9 (23.1–28); 24.7% were smokers, 18% had diabetes, 13.2% had cholesterol levels >200 mg/dl and 9.1% took statins, 44% had hypertension. During an overall median follow-up of 28 (24–39) months, incident CV events, such as ischemic heart disease (IHD) and ischemic cerebral stroke (ICS), were recorded. An overall of 2204 patients were evaluated as control group and 1668 patients after HCV elimination were followed as a case group. Factors associated with CV events were evaluated by uni- and multi-variate analyses.
Incident CV rates per 100 patient years in pre-treatment and untreated controls and treated cases were 1.12, 1.14 and 0.44 (p = 0.0001 vs. controls), respectively, and a decreased of relative risk (RR = 0.379; p = 0.0002) was observed. CV risk was 2.0–3.5 times lower then in controls (HR 3.671; 95%C.I.:1.871–7.201; p < 0.001). The calculated number of patients to be treated to get a benefit in a patient was 55.26. The annual incidence reduction of CV events was 0.68%. HCV clearance was independently associated with CV events reduction (OR, 4.716; 95% C.I.:1.832–12.138; p = 0.001).
HCV clearance by DAA reduces CV events (IHD and ICS) with both clinical and socio-economic benefits.
•HCV clearance by direct-acting antivirals (DAA) significantly reduces the annual incidence of cardio vascular events by 0.68%.•Incident cardiovascular events (CV) rates for 100 patient years in controls was 1.14 and in cases 0.44.•The CV risk after HCV clearance was reduced by 2.0–3.5 folds.•The calculated number of patients to be treated to get a benefit in a patient was 55.26.•HCV clearance was independently associated with CV events reduction.
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•Expanded Baveno VI works better than Baveno VI criteria for ruling out the presence of VNT in NAFLD-cirrhosis.•New NAFLD-cirrhosis criteria based on LSM and platelet values and ...optimized for M and XL FibroScan probes are optimal.•The accuracy of noninvasive scores for VNT is lower in non-obese patients.
Baveno VI and expanded Baveno VI criteria can avoid the need for esophagogastroduodenoscopy (EGD) to screen for varices needing treatment (VNT) in a substantial proportion of compensated patients with viral and/or alcoholic cirrhosis. This multicenter, cross-sectional study aims to validate these criteria in patients with compensated cirrhosis due to non-alcoholic fatty liver disease (NAFLD), accounting for possible differences in liver stiffness measurement (LSM) values between M and XL probes.
We assessed 790 patients with NAFLD-related compensated cirrhosis who had EGD within six months of a reliable LSM, measured by FibroScan® using M and/or XL probe. Baveno VI and expanded Baveno VI criteria were tested. The main variable used to optimize criteria was the percentage of endoscopies spared, keeping the risk of missing large VNT below a 5% threshold.
LSM was measured by both M and XL probes (training set) in 314 patients, while only M or XL probe (validation sets) were used to measure LSM in 338 and 138 patients, respectively. In the training set, use of Baveno VI and expanded Baveno VI criteria reduced the number of EGD by 33.3% and by 58%, with 0.9% and 3.8% of large esophageal varices missed, respectively. The best thresholds to rule-out VNT were identified as platelet count >110,000/mm3 and LSM <30 kPa for M probe, and platelet count >110,000/mm3 and LSM <25 kPa for XL probe (NAFLD cirrhosis criteria). Thus, usage of NAFLD cirrhosis criteria would have led to an absolute reduction in the number of EGD screened patients of 34.7% and 10.5% with respect to Baveno VI and expanded Baveno VI criteria, respectively.
The new NAFLD cirrhosis criteria, established for the FibroScan probe, can reduce the use of EGD for screening of VNT in NAFLD cirrhosis by more than half, with a chance of missing VNT below 5%.
In non-alcoholic fatty liver disease-related compensated cirrhosis, the expanded Baveno VI criteria work better than the Baveno VI criteria for ruling out the presence of varices needing treatment, sparing unnecessary and invasive screening procedures. New diagnostic criteria for this patient group, based on liver stiffness measurement and platelet count, and optimized for the specific FibroScan® probe used, work better than both Baveno VI and expanded Baveno VI criteria. The accuracy of all non-invasive scoring criteria was lower in non-obese patients.
Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by ...computer‐assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2‐45), correlating with Ishak stage (stage 6 range, 13%‐45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more odds ratio, 1.206; 95% confidence interval (CI), 1.094‐1.331; P < 0.001, or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026‐1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis. (HEPATOLOGY 2009.)
The Baveno VI consensus guidelines and an expanded algorithm suggest that transient elastography (TE) and platelet (PLT) count can be used to identify patients with cirrhosis who can avoid ...esophagogastroduodenoscopy (EGD). The primary aims of this study were to assess the ability of a simple algorithm, which uses only laboratory parameters, to predict medium/large esophageal varices (EV) in patients with hepatitis C virus (HCV) and cirrhosis from the Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) cohort and to compare the performance of the algorithm with Baveno VI and Expanded Baveno VI criteria. The secondary aim was to assess the role of TE in ruling out large EV.
In total, 1,381 patients with HCV-associated cirrhosis who had EGD and TE within 1 year of starting treatment with direct-acting antivirals were evaluated. Using multivariate logistic analysis, laboratory variables were selected to determine which were independently associated with medium/large EV to create the RESIST-HCV criteria. These criteria were tested in a training cohort with patients from a single center (Palermo) and validated with patients from the 21 other centers of the RESIST-HCV program (validation cohort).
In the entire cohort, medium/large EV were identified in 5 of 216 patients (2.3%) using the Baveno VI criteria and 13 of 497 patients (2.6%) using the Expanded Baveno VI criteria. PLT count and albumin level were independently associated with medium/large EV. The best cut-off values were a PLT count greater than 120 × 10 cells/μL and serum albumin level greater than 3.6 g/dL; negative predictive values (NPVs) were 97.2% and 94.7%, respectively. In the training cohort of 326 patients, 119 (36.5%) met the RESIST-HCV criteria and the NPV was 99.2%. Among 1,055 patients in the validation cohort, 315 (30%) met the RESIST-HCV criteria and the NPV was 98.1%. Adding TE to the RESIST-HCV criteria reduced the avoided EGDs for approximately 25% of patients and the NPV was 98.2%.
The "easy-to-use" RESIST-HCV algorithm avoids EGD for high-risk EV screening for more than 30% of patients and has the same performance criteria as TE. Using these criteria simplifies the diagnosis of portal hypertension.
Chronic liver disease is usually asymptomatic until its late stages and also significant hepatic necroinflammation and fibrosis may be present in persistently normal ALT levels HBV, HCV carriers or ...similarly, in patients with nonalcoholic fatty liver disease. Given the large number of persons in the general population which may harbor a clinically significant liver disease behind the screen of normal alanine aminotransferase, more attention should be devoted to future research for alternative noninvasive markers of liver damage.
Background
MerTK is a tyrosine kinase receptor that belongs to the TAM (Tyro3/Axl/Mer) receptor family. It is involved in different processes including cellular proliferation/survival, cellular ...adhesion/migration, and release of the inflammatory/anti-inflammatory cytokines. Although it is reported that MERTK polymorphisms affect the severity of viral and metabolic liver diseases, being able to influence fibrosis progression and hepatocellular carcinoma development, the mechanisms remain unknown. Methods: using a microarray approach, we evaluated the liver expression of genes involved in fibrogenesis and hepatocarcinogenesis in patient with chronic hepatitis C (CHC), stratified for MERTK genotype and MERTK expression. Results: we found that the rs 4374383 AA homozygosity is associated with lower MERTK expression in CHC patients and that, depending on MERTK genotype, Matrix Metallopeptidase 9 (MMP9), Matrix Metallopeptidase 7 (MMP7), Secreted Frizzled Related Protein 1 (SFRP1) and WNT gene family 11(WNT11) show differential expression in patients with CHC with or without neoplastic progression. Conclusions: our results confirm that MERTK represents a genetic biomarker for progression of liver disease and are suggestive of translational relevance for the study of downstream pathways involved in fibrogenesis and hepatocarcinogenesis.
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