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Hepatocellular carcinoma (HCC) represents an entity of poor prognosis, especially in cases of delayed diagnosis. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, patients in BCLC-A are the most suitable for potentially curative treatments (surgery or radiofrequency ablation), whereas those in BCLC-C should be treated only with systemic treatment, as locoregional interventions are ineffective due to the tumor’s extensiveness. For patients in the BCLC-B stage, trans-arterial chemoembolization (TACE) is the reference treatment, but the role of systemic treatment has been constantly increasing. As this group of patients is extremely heterogeneous, a case-by-case therapeutic strategy instead of a one-fits-all treatment is certainly required to achieve adequate results against HCC. The decision of selecting among immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), TACE, or a combination of them depends on the patient’s tumor load, the severity of liver dysfunction, the general performance status, and the presence of concomitant extrahepatic diseases. The objective of this review is to critically appraise the recent data regarding the systemic treatment of BCLC-B HCCs, aiming to emphasize its potential role in the management of these difficult-to-treat patients.

Introduction PCOS is associated with mood/eating disorders. Negative body image due to obesity, acne, hirsutism seems to play significant role, but hormonal derangements are probably implicated. Aim To investigate the relation between insulin resistance (IR), obesity and hyperandrogenism with mood and eating disorders in women with PCOS. Methods Forty-nine (60.5%) PCOS women and 32(39.5%) age- and BMI-matched healthy controls were enrolled. Emotional/food disorders were evaluated by using self-administered questionnaires: Eating Attitudes Test (EAT)-26, Beck Depression Inventory-II (BDI-II), Hamilton anxiety scale (HAS) and Food Craving Questionnaire-Trait (FCQ-T). Results The two groups had no significant differences regarding age, BMI and HOMA2-IR. PCOS women had significantly higher DHEA-S ( p  < 0.0001), Δ4Α ( p  < 0.0001) and Testosterone ( p  < 0.0001). When the two groups were subclassified according to the BMI, in lean (BMI < 25 kg/m 2 ) or overweight (BMI ≥ 25 kg/m 2 ), no significant differences were found with respect to EAT-26 and HAS. BDI-II was associated with obesity (overweight vs lean PCOS: 20.5 ± 6.4 vs 9.8 ± 3.9; p  = 0.037) and hyperandrogenism (overweight PCOS vs overweight controls: 20.5 ± 6.4 vs 14.8 ± 8.1; p  < 0.0001; lean PCOS vs overweight controls: 16.7 ± 4.7 vs 14.8 ± 8.1; p  = 0.01). Additionally, a significant correlation between BDI-II and DHEA-S (rho = 0.305; p  = 0.006), Δ4Α (rho = 0.259; p  = 0.02) and Testosterone (rho = 0.328; p  = 0.003) was reported. FCQ-T was associated with obesity (overweight PCOS vs lean PCOS: 47.6 ± 9.9 vs 29.3 ± 8.9; p  < 0.0001; overweight controls vs lean PCOS: 45.5 ± 15.7 vs 29.3 ± 8.9; p  < 0.0001), whereas a correlation between FCQ-T and BMI (rho = 0.593; p  = 0.0001), waist circumference (rho = 0.554; p  = 0.0001) and HOMA2-IR (rho = 0.328; p  = 0.003) was documented. Conclusions Obesity and hyperandrogenism increase the risk of depression and food cravings in women with PCOS, leading to a vicious circle of further aggravation of obesity and metabolic syndrome.

Primary biliary cholangitis (PBC) is a chronic, cholestatic disease with a female predominance and a long disease duration. The pathogenesis of PBC is still unclear; however, genetic, epigenetic, and environmental factors, alongside immune dysregulation, seem to lead to a dysfunction of the biliary ‘bicarbonate umbrella’ and increased biliary epithelial cells apoptosis. Ursodeoxycholic acid (UDCA) has been the treatment of choice for PBC since its approval back in 1994; however, a percentage varying from 15-40% of all patients fail to achieve biochemical response or alkaline phosphatase normalization. Obeticholic acid, though promising at first, failed to show benefit after long-term use and was retracted from the market. Two peroxisome proliferator–activated receptor agonists (PPARs) have recently been approved for use in patients with PBC, showing biochemical response in non-responders and improvement of pruritus. However, a substantial percentage of patients fail to achieve serum alkaline phosphatase and bilirubin normalization; as a result, many drugs with different mechanisms of action are in phase 2 or 3 trials. The aim of this review is to present available data regarding PBC treatment and explain the pathogenetic pathway each one targets.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

In cirrhotic patients, non-selective b-blockers (NSBBs) constitute the reference treatment of choice as monotherapy or combined with band ligation for the prevention of first variceal bleeding and rebleeding, respectively. Furthermore, the last Baveno VII guidelines recommended carvedilol, a b-blocker with additional anti-a1 receptor activity, in all compensated cirrhotics with clinically significant portal hypertension, to prevent liver decompensation. Interestingly enough, NSBBs have been reported to have a potentially positive impact on the short-term mortality of patients with acute-on-chronic liver failure. However, concerns remain about the use of b-blockers in the presence of severe complications, such as refractory ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, or established cirrhotic cardiomyopathy. In addition, it has not been verified yet whether carvedilol supersedes all the other NSBBs in every stage of liver disease, even when severe complications have developed. Therefore, this review aims to illustrate recent data regarding the potential role of b-blockers across all stages of liver disease, beyond the primary and secondary prophylaxis of variceal bleeding, and address the authors’ proposals on the use of NSBBs concerning the severity of liver disease and the patient’s performance status.

Objective Discovering biological correlates of depression (and symptom dimensions) and anxiety is a topic of ongoing research. We aimed to examine the associations of uric acid (UA) and lipids with depression (sum and emotional, neurovegetative, cognitive dimension) and anxiety symptoms. Methods Participants were screened for depression and anxiety symptoms using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) questionnaires, respectively, in primary care in Greece during January-June 2022. Serum UA and lipids were recorded and socio-demographic, behavioral, and personal history covariates were also collected. Poisson regression analyses were performed to determine associations between recorded parameters and the PHQ-9 (sum-score and emotional, neurovegetative, cognitive dimension) and GAD-7 scores. Results A total of 181 individuals answered the questionnaires. The mean age was 61.8 ± 10.8 years, and 68% were female. The prevalence of clinically significant depression (PHQ-9 ≥ 10) and anxiety (GAD-7 ≥ 10) symptoms was 20.4%, respectively. PHQ-9 score was negatively associated with UA, high-density lipoprotein cholesterol (HDL-C) and income, and positively with low-density lipoprotein cholesterol (LDL-C) and physical activity. The neurovegetative dimension of the PHQ-9 score was negatively associated with UA and HDL-C, while the cognitive was positively associated with LDL-C. GAD-7 score was negatively associated with HDL-C and income, and positively with LDL-C and physical activity, while it was higher in females and smokers. Conclusions Both UA and lipids were associated with depression and anxiety symptoms. The neurovegetative and cognitive symptoms of depression exhibited different biological correlates with low UA and HDL-C, and high LDL-C, respectively.

Background: Type 2 diabetes mellitus (T2DM) is often complicated by steatotic liver disease, cardiovascular disease (CVD), and extrahepatic cancer. We investigated whether FIB-4, an indicator of liver fibrosis, is associated with a higher risk of CVD and extrahepatic cancer history in T2DM. Methods: Two hundred and nine of 244 diabetics admitted to our center in one year were included and retrospectively evaluated. Results: One hundred and fifty-two (72.7%) were males and 57 (27.3%) females. The mean age and FIB-4 were 64.3 ± 11 years, and 1.15 ± 0.5, respectively. One hundred and fifty patients (71.8%) had FIB-4 ≤ 1.3, and 59 (28.2%) had FIB-4 > 1.3. A history of CVD was presented in 76 (36.4%) patients, and of extrahepatic cancer in 39 (18.7%). Patients with CVD were significantly older than those without (68.4 ± 8.5 vs. 63.2 ± 11.5 years; p = 0.002), with significantly higher FIB-4 (1.26 ± 0.5 vs. 1.08 ± 0.5; p = 0.012). Patients with cancer were older, with higher FIB-4 compared to those without (68.2 ± 9.5 vs. 64.4 ± 10.9 years; p = 0.098 and 1.37 ± 0.6 vs. 1.1 ± 0.5; p = 0.004, respectively). FIB-4 > 1.3 was associated with a 2.1-fold probability for CVD (χ2 = 5.810; p = 0.025) and 2.7-fold probability for cancer history (χ2 = 7.603; p = 0.01). Conclusions: FIB-4 ≥ 1.3 is associated with a higher probability of CVD or extrahepatic cancer history. FIB-4 could potentially discriminate patients at risk, justifying stricter surveillance.

Background and AimTo evaluate if spleen stiffness measurement (SSM) can rule out the presence of high-risk varices in patients with cirrhosis, avoiding an upper gastrointestinal endoscopy (UGE).MethodsWe enrolled 71 cirrhotic patients irrespective of liver disease’s etiology. 2D shear wave elastography (SWE) of spleen and UGE was performed. High-risk varices (HRV) were defined as esophageal varices ≥ 5 mm and/or red spots and any gastric varices.ResultsEsophageal varices were documented in 37 (52.1%) and HRV in 25 (35.2%) patients. SSM was not technically feasible in 7/71 patients (9.8%). From the remaining 64 patients, when those with cholestatic liver disease were excluded (n = 17), SSM < 35.8 kPa was found to exclude well the existence of HRV offering an AUROC of 0.854 (p < 0.001), sensitivity 88.9%, negative predictive value (NPV) 91.3%, specificity 72.4%, and positive predictive value (PPV) 66.7%. Only 2/47 patients (4.3%) were misclassified, and 23 (48.9%) could avoid endoscopy. In the total cohort of 64 patients, SSM < 33.7 kPa was found to exclude well the presence of HRV offering AUROC 0.792 (p < 0.001), sensitivity 91.7%, specificity 60%, NPV 92.3%, and PPV 57.9%. The misclassification rate was 3.1% (2/64), while 26/64 (40.6%) could avoid endoscopy.Conclusions2D-SWE of spleen is a reliable method for ruling out the presence of HRV in cirrhotic patients. If larger studies confirm our results, a large number of endoscopies could be avoided.

It is well known that both type 1 and type 2 diabetes mellitus (DM) are related to increased risk for cardiovascular (CV) and chronic kidney disease (CKD). However, besides these prominently presented complications, DM has also been associated with reproductive dysfunctions. It seems that these disorders are met in up to 40% of women with DM and consist of delayed menarche, all types of menstrual disorders, such as amenorrhea, oligomenorrhea, menstrual irregularity, as well as menorrhagia, infertility, characteristics of polycystic ovary syndrome (PCOS) and early (or rarely late) menopause. In type 1 DM (T1DM), insulin treatment, although it has reduced the rates of insulinopenic-induced hypogonadotropic hypogonadism, an entity commonly presented in many women with the disease in the past decades, when it is used in excess it can also promote hyperandrogenism. Regarding type 2 DM (T2DM), insulin resistance (IR) and hyperinsulinemia have mainly been implicated in the pathogenesis of reproductive dysfunctions, as insulin can act as gonadotropin on the theca cells of the ovary and can lead to hyperandrogenism and inhibition of proper ovulation. This review aims to detail the reproductive dysfunctions associated with DM and provide scientific data to enlighten the underlying pathogenetic mechanisms.

Cirrhotic cardiomyopathy, a cardiac dysfunction presented in patients with cirrhosis, represents a recently recognized clinical entity. It is characterized by altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, in particular prolongation of the QT interval. Several mechanisms seem to be involved in the pathogenesis of cirrhotic cardiomyopathy, including impaired function of beta-receptors, altered transmembrane currents, and overproduction of cardiodepressant factors, like nitric oxide, tumor necrosis factor α, and endogenous cannabinoids. Diastolic dysfunction is the first manifestation of cirrhotic cardiomyopathy and reflects the increased stiffness of the cardiac mass, which leads to delayed left ventricular filling. On the other hand, systolic incompetence is presented later, is usually unmasked during pharmacological or physical stress, and predisposes to the development of hepatorenal syndrome. The prolongation of QT is found in about 50 % of cirrhotic patients, but rarely leads to fatal arrhythmias. Cirrhotics with blunted cardiac function seem to have poorer survival rates compared to those without, and the risk is particularly increased during the insertion of transjugular intrahepatic portosystemic shunt or liver transplantation. Till now, there is no specific treatment for the management of cirrhotic cardiomyopathy. New agents, targeting to its pathogenetical mechanisms, may play some role as future therapeutic options.