Glucokinase Regulatory Protein Gene Polymorphism Affects Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

Variant in glucokinase regulatory protein (GCKR), associated with lipid and glucose traits, has been suggested to affect fatty liver infiltration. We aimed to assess whether GCKR rs780094 C→T SNP influences the expression of steatosis, lobular inflammation and fibrosis in NAFLD patients, after correction for PNPLA3 genotype.In 366 consecutive NAFLD patients (197 from Sicily, and 169 from center/northern Italy), we assessed anthropometric, biochemical and metabolic features; liver biopsy was scored according to Kleiner. PNPLA3 rs738409 C>G and GCKR rs780094 C>T single nucleotide polymorphisms were also assessed.<0.001). Similar results were observed considering separately the two different NAFLD cohorts. GCKR C>T SNP was also associated with higher serum triglycerides (ANOVA, p = 0.02) in the entire cohort.In patients with NAFLD, GCKR rs780094 C>T is associated with the severity of liver fibrosis and with higher serum triglyceride levels

Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program

We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n\u2009=\u2009221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n\u2009=\u200954, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p\u2009=\u20090.56 and 24.2% vs 11.4%, p\u2009=\u20090.13, respectively). SVR rate was significantly higher with the combination DCV\u2009+\u2009SOF compared with DCV\u2009+\u2009SIM or ASU (93.2% vs 63.0%, p\u2009<\u20090.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p\u2009=\u20090.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p\u2009<\u20090.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production &gt;99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p&lt;0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted \u3b4 and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted \u3bb, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p&lt;0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis

Reply to: \u201cIs industrial fructose just a marker of an unhealthy dietary pattern?\u201d

We recently reported a link between fructose intake and the severity of liver \ufb01brosis in a cohort of Italian patients with genotype 1 (G1) chronic hepatitis C (CHC) [1]. In particular, the association holds true for \u2018\u2018industrial\u2019\u2019 only, not for \u2018\u2018fruit\u2019\u2019 fructose intake. We thank Chiavaroli and colleagues for their comments that give us the opportunity to further strengthen data from our analyses

SARS-CoV-2 Viral Load, IFN\u3bb Polymorphisms and the Course of COVID-19: An Observational Study

The course of SARS-CoV-2 infection ranges from asymptomatic to a multiorgan disease. In this observational study, we investigated SARS-CoV-2 infected subjects with defined outcomes, evaluating the relationship between viral load and single nucleotide polymorphisms of genes codifying for IFN\u3bbs (interferon). The study enrolled 381 patients with laboratory-confirmed SARS-CoV-2 infection. For each patient, a standardized form was filled including sociodemographic variables and clinical outcomes. The host's gene polymorphisms (IFNL3 rs1297860 C/T and INFL4 rs368234815 TT/\u394G) and RtReal-Time PCR cycle threshold (PCR Ct) value on SARS-CoV-2 were assessed on nasal, pharyngeal or nasopharyngeal swabs. Higher viral loads were found in patients aged &gt; 74 years and homozygous mutant polymorphisms DG in IFNL4 (adj-OR = 1.16, 95% CI = 1.01-1.34 and adj-OR = 1.24, 95% CI = 1.09-1.40, respectively). After adjusting for age and sex, a statistically significantly lower risk of hospitalization was observed in subjects with higher RtReal-Time PCR cycle threshold values (adj-OR = 0.95, 95% CI = 0.91, 0.99; p = 0.028). Our data support the correlation between SARS-CoV-2 load and disease severity, and suggest that IFN\u3bb polymorphisms could affect the ability of the host to modulate viral infection without a clear impact on the outcome of COVID-19

A return to humane medicine: Osler's legacy

Sir William Osler is celebrated today not only for his contributions to the advancement of medical education, but also for the humanism he brought to the practice of medicine. He was a doctor whose bedside skills and manners were emulated, and can legitimately be called an infectious diseases specialist. Nonetheless, he was also a humanist in the broader sense of the term, a student of human affairs and human nature, who emphasised compassion for the individual. To what extent, if any, are today\ue2\u80\u99s challenges influenced by departures from the paradigms created by Osler? In this paper we sought to ascertain whether such a tradition is still relevant to current practice and may foster a new perspective. We analysed two features of Osler\ue2\u80\u99s legacy that may be useful to clinicians: the first is his vision of the patient-physician relationship; the second is his approach to humanities. William Osler saw medicine in its wider scope, with the right and duty to be concerned with the human condition as a whole. Indeed, his rounded concept of the medical profession as being engaged in helping and caring for the whole human being could help physicians build a more humanised medicine. Adopted in the age of evidence-based medicine, the Oslerian approach can enhance the relationship with patients and give physicians a role based on trust and authoritativeness rather than on authority

From current status to optimization of HCV treatment: Recommendations from an expert panel

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper

Aminopyrine Breath Test Predict Liver-related Events and Death in HCV-related Cirrhosis on SVR after DAA Therapy

In patients with HCV-related advanced cirrhosis, the effects of SVR by DAAs on decompensation and liver deaths is less clearcut, since up to 30 % of patients do not improve, and no predictors of outcome have been identified. We used 13 C-aminopyrine breath test (ABT) to assess whether its changes can predict liver-related outcomes after DAA treatment in patients with HCV cirrhosis