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Objectives To prospectively compare the diagnostic performance of ultrasound (US), multidetector computed tomography (MDCT) and contrast-enhanced magnetic resonance imaging (MRI) in cirrhotic patients who were candidates for liver transplantation. Methods One hundred and forty consecutive patients with 163 hepatocellular carcinoma (HCC) nodules underwent US, MRI and MDCT. Diagnosis of HCC was based on pathological findings or substantial growth at 12-month follow-up. Four different image datasets were evaluated: US, MDCT, MRI unenhanced and dynamic phases, MRI unenhanced dynamic and hepatobiliary phase. Diagnostic accuracy, sensitivity, specificity, PPV and NPV, with corresponding 95 % confidence intervals, were determined. Statistical analysis was performed for all lesions and for three lesion subgroups (<1 cm, 1-2 cm, >2 cm). Results Significantly higher diagnostic accuracy, sensitivity and NPV was achieved on dynamic + hepatobiliary phase MRI compared with US, MDCT and dynamic phase MRI alone. The specificity and PPV of US was significantly lower than that of MDCT, dynamic phase MRI and dynamic + hepatobiliary phase MRI. Similar results were obtained for all sub-group analyses, with particular benefit for the diagnosis of smaller lesions between 1 and 2 cm. Conclusions Dynamic + hepatobiliary phase MRI improved detection and characterisation of HCC in cirrhotic patients. The greatest benefit is for diagnosing lesions between 1 and 2 cm. Key Points • US, CT and MRI can all identify HCC in cirrhotic patients • US has good sensitivity but suffers from false-positive findings • Dynamic CT and MR have similar diagnostic performance for diagnosing HCC • Dynamic + hepatobiliary phase MRI significantly improves detection and characterisation of HCC • The greatest benefit is for the diagnosis of lesions between 1 and 2 cm

This study aimed to ascertain, for the first time, whether serum magnesium (Mg) concentration is affected by the presence of hepatocellular carcinoma (HCC). We retrospectively enrolled consecutive cirrhotic patients with a diagnosis of HCC (n = 130) or without subsequent evidence of HCC during surveillance (n = 161). Serum levels of Mg were significantly (P < 0.001) lower in patients with HCC than in those without (median [interquartile range]: 1.80 [1.62–1.90] mg/dl vs. 1.90 [1.72–2.08] mg/dl). On multivariate logistic regression, low serum Mg was associated with the presence of HCC (OR 0.047, 95% CI 0.015–0.164; P < 0.0001), independently from factors that can influence magnesaemia and HCC development. In a subset of 94 patients with HCC, a linear mixed effects model adjusted for confounders showed that serum Mg at diagnosis of HCC was lower than before diagnosis of the tumor (β = 0.117, 95% CI 0.039–0.194, P = 0.0035) and compared to after locoregional treatment of HCC (β = 0.079, 95% CI 0.010–0.149, P = 0.0259), with two thirds of patients experiencing these changes of serum Mg over time. We hypothesize that most HCCs, like other cancers, may be avid for Mg and behave like a Mg trap, disturbing the body’s Mg balance and resulting in lowering of serum Mg levels.

Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCV pos MCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCV pos MCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCV pos MCV. The prevalence of HBsAg seroclearance was 48% within 123 HCV pos MCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCV pos MCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCV pos MCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCV pos MCV in male CHC patients.

Introduction In Italy, the prevalence of hepatitis C virus (HCV) infection is higher in the elderly, although the efficacy and safety of treatment in this population has not been extensively studied. Moreover, little is known about how much pharmacological interaction affects eligibility to treatment and to what extent the treatment affects subsequent outcomes. Methods We retrospectively analyzed the efficacy and safety of directly acting antivirals (DAAs), drug‐to‐drug interactions, and post‐treatment outcomes in 138 patients with HCV aged 70 years or older, who were consecutively treated in our center between 2015 and 2020. Results The mean age was 77 years old (range = 70–95 years old). The Cumulative Illness Rating Scale of pretherapy severity was classified as moderate to severe in 65% of patients. Fifty‐five patients (40%) presented compensated cirrhosis, eight of which were complicated by hepatocellular carcinoma (HCC) and all were cured before treatment. One hundred two patients (74%) were taking two or more drugs (range = 0–5 concomitant drugs registered) and in 29 patients (21%) we found potential drug‐to‐drug interaction. In 11 of those 29 patients (38%), we were forced to change the chronic therapy, when all therapeutic regimens were equal in terms of efficacy and interactions, to avoid potentially serious drug interactions. One serious adverse event occurred in our sample population (i.e., diverticular bleeding due to interaction with direct oral anticoagulants [DOACs]), whereas mild side effects occurred in 37% of patients. The undetectability of HCV RNA at the end of treatment was achieved in 97% of patients, whereas a sustained virological response (SVR) 12 and SVR 24 were obtained in 98% of patients. When comparing pretherapy with post‐therapy data, after a medium follow‐up of 15 months (median = 1 year, minimum = 2 months, and maximum = 4 years), we observed a reduction in the incidence of episodes of liver decompensation in patients with cirrhosis and a slight increase in the incidence of HCC (with 6 recurrent and 5 de novo HCC), diagnosed within 13 months from the end of therapy. In all patients, we found a significant improvement in all ultrasound variables and a significant reduction in the elastographic measurements. No significant differences in outcomes were observed dividing the population into patients aged ≥ 80 and < 80 years old. Conclusions Directly acting antiviral therapy was found to be safe and effective in elderly people, and, despite the large number of concomitant drugs, pharmacological interactions appeared to not affect the adherence to therapy or the incidence of adverse events. Side effects were mostly independent from the type of DAA used and from the burden of comorbidity. In long‐term follow‐up, the benefit of DAA therapy mainly concerned liver pathology and should be strongly advised in patients with cirrhosis. The therapy was found to not affect extrahepatic comorbidities but allowed to end follow‐up in noncirrhotic patients with savings in terms of resources. Finally, patients should not be excluded based on age if they have a good performance status. We retrospectively analyzed data of 138 HCV patients aged 70 years or older, who were consecutively treated in our center between 2015 and 2020. We found out that in a real‐life population, HCV treatment is safe (with only a few potential drug‐to‐drug interactions that require management and few adverse events), effective (98% SVR at 12 weeks), and useful (it reduce decompensating events in cirrhotics and ameliorates prognostics score and clinical parameters).

Background/Objectives: Low fasting blood lysosomal acid lipase (LAL) activity is associated with the pathogenesis of metabolic hepatic steatosis. We measured LAL activity in blood and plasma before and after an oral fat tolerance test (OFTT) in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD). Methods: Twenty-six controls and seventeen patients with MASLD but without diabetes were genotyped for the patatin-like phospholipase 3 (PNPLA3) rs738409 variant by RT-PCR and subjected to an OFTT, measuring LAL activity in blood and plasma with a fluorimetric method. Results: LAL activity in blood both under fasting and 4 h after OFTT (0.846 ± 0.309 nmol/spot/h vs. 1.180 ± 0.503 nmol/spot/h p < 0.01) was lower in patients with MASLD compared to controls. These differences were present only in carriers of the PNPLA3 variant. In controls not carrying the PNPLA3 variant, the postprandial increase in blood LAL activity was negatively correlated with that of serum triglycerides (p < 0.05). Extracellular LAL activity in plasma was lower in patients with MASLD (n = 9) compared to controls (n = 8) in the fasting state (p < 0.01) and 4 h post-meal (p < 0.05). The area under the curve up to 6 h of plasma LAL activity was lower in patients with MASLD than in controls (p < 0.05) and correlated negatively with that of triglycerides only in controls (r = −0.841; p < 0.01). Conclusions: Patients with MASLD have reduced LAL activity in blood and plasma both before and 4 h after a meal. In patients with MASLD, the physiological negative correlation between circulating LAL levels and postprandial hypertriglyceridemia is lost.

Background Management of chronic hepatitis C (CHC) has significantly accelerated in the last few years. Currently, second generation direct acting antivirals (DAAs) promise clearance of infection in most of patients. Here we present the results of the first analysis carried out on data of Lazio clinical network for DAAs. Methods The study was designed as a multicenter cohort: a) to assess the evolution of treatment during the first 24 months of the activity of the Clinical Network; b) to report overall efficacy of treatments; c) to analyze potential factors associated with lack of virological response at 12 weeks after therapy (SVR12); d) to evaluate the variation of ALT at baseline and 12 weeks after therapy in those who achieved SVR12 in comparison to those who did not. Analyses of efficacy were carried out with multilevel mixed effect logistic regression model. ALT temporal variation was assessed by mixed effect model mixed models with random intercept at patient’s level and random slope at the level of the time; i.e. either before or after therapy. Results Between 30 December 2014 and 31 December 2016 5279 patients started a DAA treatment; of those, 5127 (in 14 clinical centers) had completed the 12-week follow-up. Overall proportion of SVR12 was 93.41% ( N  = 4780) with no heterogeneity between the 14 clinical centers. Interruption as the consequence of severe side effect was very low (only 23 patients). Unadjusted analysis indicates that proportion of SVR12 significantly changes according to patient’s baseline characteristics, however after adjusting for potential confounders only adherence to current guidelines, stage of liver diseases, gender, transplant and HIV status were independently associated with the response to therapy. Analysis of ALT temporal variation showed that ALT level normalized in most, but not, all patients who achieved SVR12. Conclusion Our study confirmed the extraordinary efficacy of DAAs outside clinical trials. The advantage of DAAs was particularly significant for those patients who were previously considered as difficult-to-treat and did not have treatment options before DAAs era. Intervention based on network of select centers and prioritization of patients according to diseases severity was successful. Further studies are needed to establish whether clearance of HCV after DAAs therapy can arrest or even revert liver fibrosis in non-cirrhotic patients and/or improve life quality and expectancy in those who achieve SVR12 with cirrhosis.

Background Liver involvement in adults with acute myeloid leukemia is uncommon. Most of the case reports describe acute liver failure or obstructive jaundice, while acute hepatitis is rarely mentioned. We report a patient with acute myeloid leukemia who presented with clinical, biochemical, and radiological signs of acute hepatitis that totally regressed after chemotherapy. Case presentation A 38-year-old Caucasian man presented with fever, cough, and mild fatigue. Laboratory workup showed anemia, thrombocytopenia, severe leukocytosis, transaminitis, and hyperbilirubinemia. Imaging of the abdomen (ultrasound and magnetic resonance) showed hepatomegaly, splenomegaly, upper limits portal veins diameters, increased thickness of the gallbladder wall, and significant abdominal lymph nodes. Peripheral blood smear and bone marrow evaluation were consistent with acute myeloid leukemia, and liver biopsy showed massive sinusoidal and portal infiltration by leukemic cells. After remission-inducing chemotherapy, there was complete normalization of liver function tests, and liver, spleen, and portal vein size. Conclusions This case highlights the importance of taking acute myeloid leukemia into account as a possible cause of liver damage to make a rapid diagnosis and start appropriate treatment that may lead to hematological remission and hepatic dysfunction resolution.

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

Background and Aim. Portal hypertension has been reported in association with acquired and primary immune deficiencies without a comprehensive description of associated spleno-portal axis abnormalities. Pathological mechanisms are poorly defined. Methods. Observational, single centre study with the aim of assessing the prevalence of spleno-portal axis abnormalities in an unselected cohort of 123 patients with primary antibody deficiencies and without known causes of liver diseases regularly followed up for a mean time of 18 ± 14 years. A cumulative period of 1867 patients-year was analysed. Clinical and immunological data, abdominal ultrasounds, CT scans, and endoscopy features were included in the analysis. Results. Twenty-five percent of patients with primary antibody deficiencies had signs of portal vein enlargement but only 4% of them had portal hypertension, with portal systemic collaterals. Liver biopsies showed liver sinusoids congestive dilatation, endothelization, and micronodularity fulfilling the criteria for noncirrhotic portal hypertension. Patients with portal vein enlargement had severe clinical and immunological phenotypes. Conclusions. In primary antibody deficient patients, infections, inflammations, splenomegaly, increased blood venous flow, and lymphocyte abnormalities contribute to establishment of liver damage possibly leading to noncirrhotic portal hypertension. Patients with primary antibody deficiency should be considered a good model to give insight into the pathological mechanisms underlying noncirrhotic portal hypertension.

To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD. In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD. Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL. LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.