Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis.

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.

Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study.

BACKGROUND: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. METHODS: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. RESULTS: We analysed data from 511 patients observing significant associations between quality of life's physical score and both age and adherence to Mediterranean diet (p < .01). A significant negative correlation was observed between mental score and the sedentary activity (p < .05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. CONCLUSIONS: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.

Efficacy, Safety, and Predictors of Direct-acting antivirals in Hepatitis C Virus Patients with Heterogeneous Liver Diseases.

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.

Hepatocellular carcinoma treated by conventional transarterial chemoembolization in field-practice: serum sodium predicts survival.

AIM: To assess the prognostic role of baseline clinical, biochemical and radiological characteristics of patients with hepatocellular carcinoma (HCC) treated with the first transarterial chemoembolization (TACE) procedure. METHODS: Patients with HCC treated with conventional TACE in a tertiary care setting from 1997 to 2008 were retrospectively reviewed. Predictors of survival were identified using the Cox proportional regression model. RESULTS: Two hundred and seventy patients were included. Median age was 66 years, 81% were male, 58% were HCV-positive, 18% hepatitis B surface antigen-positive, 64% had a Child A status, 40% patients had a largest nodule diameter ≥ 5 cm and 32% had more than 3 tumor nodules. Median overall survival of the whole cohort was 25 mo (95%CI: 21.8-28.2) and the 1-, 2- and 3-year probability of survival was 80%, 50% and 31%, respectively. Non-tumor segmental portal vein thrombosis (HR = 1.76, 95%CI: 1.22-2.54), serum sodium (HR = 1.65, 95%CI: 1.25-2.18), diameter of largest nodule (HR = 1.59, 95%CI: 1.22-2.091), number of nodules (HR = 1.41, 95%CI: 1.06-1.88), alpha-fetoprotein (HR = 1.35, 95%CI: 1.03-1.76) and alkaline phosphatase (HR = 1.33, 95%CI: 1.01-1.74) were independent prognostic factors for overall survival on multivariate analysis. CONCLUSION: The inclusion of serum sodium alongside the already known prognostic factors may allow a better prognostic definition of patients with HCC as candidates for conventional TACE.

Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms.

BACKGROUND: Gastro-oesophageal reflux symptoms are usually reported by patients with obesity and metabolic syndrome. Aim of this study was to assess the prevalence and clinical characteristics of gastro-oesophageal reflux symptoms in subjects with non-alcoholic fatty liver disease. METHODS: Cross-sectional, case-control study of 185 consecutive patients with non-alcoholic fatty liver disease and an age- and sex-matched control group of 112 healthy volunteers. Participants were interviewed with the aid of a previously validated questionnaire to assess lifestyle and reflux symptoms in the 3 months preceding enrolment. Odds ratios were determined before and after adjustment for body mass index, increased waist circumference, physical activity, metabolic syndrome and proton pump inhibitors and/or antiacid medication. RESULTS: The prevalence of heartburn and/or regurgitation and of at least one of gastro-oesophageal reflux symptoms was significantly higher in the non-alcoholic fatty liver disease group. Non-alcoholic fatty liver disease subjects were associated to higher prevalence of heartburn (adjusted odds ratios: 2.17, 95% confidence intervals: 1.16-4.04), regurgitation (adjusted odds ratios: 2.61, 95% confidence intervals: 1.24-5.48) and belching (adjusted odds ratios: 2.01, 95% confidence intervals: 1.12-3.59) and had higher prevalence of at least one GER symptom (adjusted odds ratios: 3.34, 95% confidence intervals: 1.76-6.36). CONCLUSION: Non-alcoholic fatty liver disease is associated with a higher prevalence of gastro-oesophageal reflux symptoms.

The EFSA health claims 'learning experience'.

The European Food Safety Authority (EFSA) has recently highlighted the need to provide scientific requirements for health claims and to find new regulatory issues for healthy food products. For this reason, EFSA asked its Dietetic Products, Nutrition and Allergies (NDA) panel to draft additional guidelines on scientific assessment of these claims. A new approach for a strict substantiation of health issues in selected fields: the Regulation (EC) No. 1924/2006 established in fact that health claims applications should only be authorized after a high level of scientific validation conducted by EFSA using appropriate measures in this evaluation. The legislation should not only protect consumers but also define specific research areas with appropriate outcome measures to assess the quality, relevance and adequacy of studies conducted for scientific validation of health claims. The new system was not only a necessary support for consumers to make the correct choice of products, but rather a way for EFSA to demonstrate transparency of this new approach. This was the field of the pharmaceutical industry, this new regulation is, therefore, also for EFSA, an expensive learning process.

Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease.

Hyaluronic acid (HA) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are reliable markers of liver fibrosis and are closely linked to the proinflammatory status. In this pilot cohort study, we attempted to identify a clinical score that would predict the severity of nonalcoholic fatty liver disease (NAFLD) based on clinical variables and serum markers of fibrosis and inflammation. The cohort included 46 patients with histologically confirmed NAFLD (76.1% male; mean age, 43+/-13 years; mean body mass index [BMI], 27.8+/-3.5). Serum transforming growth factor beta (TGF-beta), HA, TIMP, and matrix metalloproteinase (MMP) levels were measured with commercial enzyme-linked immunoassay (ELISA) kits. Demographic features and clinical and laboratory findings were subjected to univariate and multivariate binary logistic regression analysis to construct the mathematical model. Receiver operating characteristic curve (ROC) analysis was used to identify a threshold value for diagnosis of NASH and to assess its sensitivity and specificity. Serum levels of HA and TIMP-1 were statistically different in patients with nonalcoholic steatohepatitis (NASH) (P<0.05). Logistic regression analysis of several clinical variables indicated patient age as the only independent predictor of NASH (odds ratio [OR], 1.129, 95% confidence interval [CI], 1.019-1.251, P=0.020). The mathematical model constructed on the basis of these results included age, TIMP-1, and HA levels. A value of 148.27 or more identified patients with NASH with 85.7% sensitivity, 87.1% specificity, and negative and positive predictive values of 96.4% and 60%, respectively. This model seems to represent a reliable noninvasive tool for excluding the presence of NASH. If validated in larger prospective cohort studies, it might be useful for determining when a liver biopsy is actually warranted in patients with NAFLD.

Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis.

BACKGROUND/AIMS: The association between NAFLD and psoriasis has never been explored in prospective epidemiological studies. The aim of this 2-phase study was to study the clinical features of NAFLD in patients with psoriasis. METHODS: Phase 1: Investigation of prevalence and characteristics of NAFLD in an unselected cohort of 142 adult Italian outpatients with psoriasis vulgaris. Phase 2: Comparison of the psoriasis cohort subgroup with NAFLD and an age- and body mass index-matched retrospective cohort of 125 non-psoriasis patients with biopsy proven NAFLD. RESULTS: Based on histories, laboratory tests, and ultrasound studies, 84 (59.2%) received clinical diagnosis of NAFLD; 30 had factors potentially associated with liver disease other than NAFLD (e.g., viral hepatitis, significant ethanol, methotrexate use); and 28 (19.7%) had normal livers. Comparison of the normal-liver and NAFLD subgroups revealed that NAFLD in psoriasis patients (Ps-NAFLD) was significantly correlated with metabolic syndrome (p<0.05); obesity (p=0.043); hypercholesterolemia (p=0.029); hypertriglyceridemia (p<0.001); AST/ALT ratio >1 (p=0.019), and psoriatic arthritis (PsA) (p=0.036). The association with PsA remained significant after logistic regression analysis (OR=3.94 [CI, 1.07-14.46]). Compared with the retrospective non-psoriatic NAFLD cohort (controls), Ps-NAFLD patients (cases) were likely to have severe NAFLD reflected by non-invasive NAFLD Fibrosis Scores and AST/ALT >1. CONCLUSIONS: NAFLD is highly prevalent among psoriasis patients, where it is closely associated with obesity (overall and abdominal), metabolic syndrome, and PsA, and more likely to cause severe liver fibrosis (compared with nonPs-NAFLD). Routine work-up for NAFLD may be warranted in patients with psoriasis, especially when potentially hepatotoxic drug therapy is being considered.

Cystic lymphangioma of the mesentery and hyposplenism in celiac disease.

Celiac disease is characterized by intestinal inflammation and mucosal atrophy that improves on a gluten-free diet. Delayed diagnosis can result in diet-refractory disease known as refractory sprue, which is linked to other disorders (intestinal lymphoma, ulcerative jejunoileitis, mesenteric lymph-node cavitation, collagenous sprue, malignancy) and carries a poor prognosis. Here we report the case of a young woman diagnosed with Marsh stage 3C celiac disease with intestinal occlusion due to intra-abdominal cystic lymphangioma mimicking mesenteric lymph-node cavitation, and hyposplenism. Despite a number of prognostically negative features, the disease has been managed successfully for the past 2 years with a gluten-free diet. The pathogenesis, prognosis and therapeutic implications are discussed.

[Oxidative stress in metabolic syndrome and nonalcoholic steatohepatitis. Is it possible a role for vitamins in clinical practice?]. / Lo stress ossidativo nella sindrome metabolica e nella steatoepatite non alcolica. E possibile un ruolo delle vitamine nella pratica clinica?

Metabolic syndrome (MS) is a worldwide medical problem characterized by a cluster of cardiovascular risk factors and metabolic modifications involving peripheral insulin resistance. Nonalcoholic steatohepatitis (NASH) represents the liver expression of this pathological condition. Both MS and NASH are characterized by proinflammatory status and increased oxidative stress. According this, we aimed to review the literature for considering a possible role for vitamins as therapeutical support in MS and NASH.

[Gastroesophageal reflux disease: facts and uncertainties]. / Malattia da reflusso gastroesofageo: fatti e incertezze.

In these years the increasing interest regarding clinical presentation of Gastro-Esophageal Reflux Disease (GERD) is certainly due to the complex pathogenic mechanism and the poor correlations between symptoms, clinical picture and endoscopic findings. In this paper we review clinical, pathological and therapeutical features of GERD focusing on controversial findings in clinical practice.

[Diverticuli of the colon]. / Diverticoli del colon.

Colon diverticular disease is one of the most common pathologies of the western world; the aim of our review was to collect shortly but in a systematic way the main and more recent news on the etiopathogenesis, prevention, natural history, possible clinical presentations and complications of this disease without omitting, at the end, a short report on the diagnostic techniques and on the various medical and/or surgical therapy.