Background and Aim
The World Health Organization (WHO) goal of hepatitis C virus (HCV) elimination by 2030 relies on the scaling‐up of both identification and linkage to care of the infected ...population, worldwide. In Italy, the estimated burden of HCV carriers who are unaware of their infection amounts to 200 000 persons, a projection that reinforces the need for broadening population access to effective screening programmes.
Methods
A pivotal screening programme targeting subjects born between 1969 and 1989 has been conducted in Lombardy, Northern Italy, where point‐of‐care (POC) testing was offered for free concomitantly to COVID‐19 vaccination.
Results
Amongst 7219 subjects born between 1969 and 1989 who underwent HCV screening through POC, 7 (0.10%) subjects tested anti‐HCV positive: 5 (0.07%) had confirmed anti‐HCV positivity (Table 1) and 4 of them (0.05%) were HCV‐RNA positive by standard confirmation tests.
Conclusions
This pivotal study demonstrated the feasibility of a POC‐based anti‐HCV screening programme in young adults undergoing COVID‐19 vaccination. The prevalence of HCV infection in subjects born in the 1969–1989 cohort in Italy seems to be lower than previously estimated. Whether the extension of this programme to subjects born before 1969 could lead to improved screening effectiveness should be a matter of debate.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Liver biopsy (LB) has lost popularity to stage liver fibrosis in the era of highly effective anti-hepatitis C virus (HCV) therapy, yet diagnosis of persistent cirrhosis may have important ...implications following HCV eradication. As performance of serological non-invasive tests (NITs) to predict residual fibrosis in non-viremic HCV patients is unknown, we investigated accuracy of NITs to predict residual fibrosis in cirrhotics after a sustained virological response (SVR) to interferon (IFN).
Thirty-eight patients with a pre-treatment histological diagnosis of cirrhosis and a 48-104 months post-SVR LB were tested with APRI, CDS, FIB-4, FibroQ, Forns Score, GUCI Index, King Score, Lok Index, PLF, ELF. In 23 (61%) patients, cirrhosis had histologically regressed.
All NITs values declined after SVR without any significant difference between regressors and non-regressors (AUROC 0.52-0.75). Using viremic cut-offs, PPV ranged from 34% to 100%, with lower NPV (63% - 68%). NITs performance did not improve using derived cut-offs (PPV: 40% - 80%; NPV: 66% - 100%). PLF, which combines several NITs with transient elastography, had the best diagnostic performance (AUROC 0.75, Sn 61%, Sp 90%, PPV 80%, NPV 78%). After treatment, none of the NITs resulted significantly associated with any of the histological features (activity grade, fibrosis stage, area of fibrosis).
The diagnostic estimates obtained using both viremic and derived cut-off values of NITs were suboptimal, indicating that none of these tests helps predicting residual fibrosis and that LB remains the gold standard for this purpose.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Prothrombin induced by vitamin K absence or antagonist‐II (PIVKA‐II) and alpha fetoprotein (AFP) are biomarkers for hepatocellular carcinoma (HCC). However, their performance in ...patients with cirrhosis related to hepatitis C virus (HCV) treated with direct‐acting antiviral agents (DAA) is unknown.
Aim
To evaluate PIVKA‐II and AFP as HCC predictors in DAA‐treated patients with HCV‐related cirrhosis
Methods
In this single centre study, patients with cirrhosis from chronic HCV infection and with a sustained virological response (SVR) to DAA were tested for PIVKA‐II and AFP (Fujirebio, Japan) at the start of DAA treatment (baseline), end of treatment (EOT) and at HCC diagnosis.
Results
We included 400 patients with mean age 65 (24‐92); 56% were men. From baseline to EOT, PIVKA‐II did not change (35 vs 35 mAU/mL, P = 0.43) while AFP significantly decreased (12 vs 6 ng/mL, P < 0.0001). After 52 (3‐66) months from baseline, 34 (8.5%) patients developed de novo HCC; median AFP 9 (2‐12 868) ng/mL and PIVKA‐II 80 (22‐1813) mAU/mL. EOT‐PIVKA‐II (HR 3.05, P < 0.0001) and AFP (HR 2.77, P = 0.001) independently predicted HCC together with diabetes (HR 6.12, P < 0.001) and GGT (HR 1.01, P = 0.03). The 4‐year cumulative probability of HCC was 24% vs 2% in patients with EOT‐PIVKA‐II > or ≤41 mAU/mL (P < 0.0001), and 26% vs 9% for EOT‐AFP > or ≤15 ng/mL (P = 0.02). By combining EOT‐PIVKA‐II and AFP, the 4‐year probabilities of HCC were 3% in patients testing negative for both markers, 18% in patients positive for both, and 38% in patients positive for at least one (P < 0.0001).
Conclusions
In patients with HCV‐related cirrhosis treated with DAA, PIVKA‐II and AFP independently predicted HCC, while their combination improved risk stratification.
PIVKA‐II and AFP as HCC predictors in DAA‐treated patients with HCV‐related cirrhosis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD ...by examining rare variants.
We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level.
In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio OR 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers.
We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.
We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.
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•NAFLD is the leading cause of liver disorders and has a strong heritable component.•Rare loss-of-function ATG7 gene mutations increase the risk of severe liver disease in patients with NAFLD.•ATG7 mutations cause altered protein function and impairment of autophagy, leading to hepatocellular ballooning and inflammation.•The most frequent variant is responsible for a meaningful fraction of predisposition to ballooning and hepatocellular carcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Data on the role of hypothyroidism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are conflicting, although selective Thyroid Hormone Receptor (THR)-β agonists ...have been identified as potential therapy in patients with non-alcoholic steatohepatitis (NASH). Therefore, we investigated the association between hypothyroidism and NAFLD histological features potentially associated with progressive liver disease.
Between 2014 and 2016, consecutive patients with histologically proven NAFLD and frozen serum available for thyroid function tests assessment were included. NAFLD was staged according to the NAFLD Activity Score (NAS), and fibrosis according to Kleiner. NASH was defined as NAS ≥4, significant fibrosis as F2-F4 and significant steatosis as S2-S3. Thyroid function tests (TFT; TSH, FT3, FT4, rT3), TPO-Ab and Tg-Ab were also assessed.
Fifty-two patients were analyzed: median age 54 years, 58% females, LSM 7.8 kPa, 27% diabetics, 14% hypothyroid. At histology, NASH was present in 21 (40%), F2-F4 in 28 (54%) and S2-S3 in 30 (58%) patients. Rates of hypothyroidism were similar independently of the presence of NASH (p = 0.11), significant fibrosis (p = 0.21) or steatosis (p = 0.75). However, hypothyroid patients displayed a higher NAS (p = 0.02) and NASH (p = 0.06) prevalence. At multivariate analysis, TFT were not independently associated with histology.
Hypothyroidism was highly prevalent in NAFLD patients, and was associated with increased NAFLD activity, but not with fibrosis and steatosis severity. Thus, thyroid dysfunction might play a direct and/or indirect in the pathogenesis of NAFLD and NASH.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims Ribavirin (RBV) combined with either pegylated interferon (PegIFN) α2a or PegIFNα2b is the standard of care for chronic hepatitis C virus (HCV) infection. Due to the lack of ...head-to-head studies, the 2 PegIFNs have not been directly compared. The endpoints of our study were safety and antiviral efficacy of the 2 regimens. Methods Treatment-naïve patients with chronic hepatitis C were randomly (1:1) assigned after stratification for HCV genotype to receive either 1.5 mcg/Kg/week PegIFNα2b plus RBV 800–1200 mg/day or 180 mcg/week PegIFNα2a plus RBV 800–1200 mg/day for 24 or 48 weeks according to HCV genotype. The study was powered to detect a difference of at least 10% in safety and efficacy of the 2 regimens. Results The 212 patients on PegIFNα2a and the 219 patients on PegIFNα2b had similar baseline characteristics, including cirrhosis (20% vs 18%, respectively). By intention to treat, the 2 groups showed similar rates of treatment-related serious adverse events (1% vs 1%, respectively) and drop out rates for adverse effects (7% vs 6%, respectively). Overall, sustained virologic response (SVR) rate was higher in PegIFNα2a than in PegIFNα2b patients (66% vs 54%, respectively, P = .02), being 48% vs 32% in the 222 HCV-1 and -4 patients ( P = .04), and 96% vs 82%, respectively, in the 143 HCV-2 patients ( P = .01). PegIFNα2a independently predicted SVR in the logistic regression analysis (odds ratio, 1.88; 95% confidence interval: 1.20–2.96). Conclusions Although the 2 regimens showed a similar safety profile, the PegIFNα2a-based treatment yielded significantly more SVR than PegIFNα2b.
Chronic infection with hepatitis C virus (HCV) may complicate with hepatocellular carcinoma (HCC), especially in patients with cirrhosis. Although the achievement of a sustained virological response ...(SVR) had been associated with a reduction in the risk of HCC already in the Interferon era, some concerns initially raised following the use of direct-acting antivirals (DAA), as their use was associated with increased risk of HCC development and aggressiveness. However, studies demonstrated that the risk of HCC was strongly influenced by pre-treatment fibrosis stage and, eventually, prior HCC history more than the type of antiviral therapy. According to published studies, rates of de-novo HCC ranged between 1.4% and 13.6% in patients with cirrhosis or advanced fibrosis vs 0.9% and 5.9% in those with chronic hepatitis C (CHC). Conversely, rates of recurrent HCC were higher, ranging between 3.2% and 49% in cirrhotics vs 0% and 40% in CHC patients. Most studies tried to identify predictors of HCC development, either de-novo or recurrent, and some authors were also able to build predictive scores for HCC risk stratification, which however still need prospective validation. Whereas some clinical features, such as age, gender, presence of comorbidities and fibrosis stage, may influence both de-novo and recurrent HCC, previous tumour burden before DAA seems to prevail over these features in recurrent HCC risk prediction.
Hepatitis C virus (HCV) variants characterized by genomic deletions in the structural protein region have been sporadically detected in liver and serum of hepatitis C patients. These defective ...genomes are capable of autonomous RNA replication and are packaged into infectious viral particles in cells co-infected with the wild-type virus. The prevalence of such forms in the chronically HCV-infected population and the impact on the severity of liver disease or treatment outcome are currently unknown. In order to determine the prevalence of HCV defective variants and to study their association with clinical characteristics, a screening campaign was performed on pre-therapy serum samples from a well-characterized cohort of previously untreated genotype 1 HCV-infected patients who received treatment with PEG-IFNα and RBV. 132 subjects were successfully analyzed for the presence of defective species exploiting a long-distance nested PCR assay. HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%). Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver. While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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