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Background: Celiac disease (CD) is still underestimated. To close this diagnostic gap, the Health Sicilian Authorities have constituted the "Sicilian Network for CD". Aims: A) To verify the quality of the current diagnostic approach using the data sheet of the Network. B) To evaluate the clinical, serologic and histologic data of new diagnoses in the context of the Network METHODS: We retrospectively evaluated the data collection forms of 369 patients with CD from three Centers within the Sicilian Network. All the Centers used a standard data collection form. Results: A non-classical CD presentation was more frequent than the classical one, anemia being the most frequent symptom (50%). An IBS-like presentation was found in one third of the cases. A diagnostic delay of about 9 years following the onset of symptoms was observed. Almost half of the patients had not undergone multiple duodenal biopsies; unrecommended CD serology assays were prescribed in 59.9% of the cases. Conclusions: The regional data sheets allowed an assessment of the diagnostic delay. We recorded a frequent use of unrecommended tests prescribed before referring patients to the regional Centers. Updating the education of physicians regarding CD is necessary to avoid unwarranted health expenditure.

Background: There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. Objective: This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. Methods: An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. Results: Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. Conclusions: Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.

Background and aimsA wheat-free diet (WFD) represents the elective treatment for Non-celiac Wheat Sensitivity (NCWS) patients. Preliminary reports have shown a possible better tolerability of ancient grains in these subjects. The aim of this observational study was to evaluate the frequency of consumption of ancient grains and its correlation with clinical manifestations in NCWS patients.Methods223 NCWS patients were recruited, and their consumption of ancient grains was monitored. Participants were first administered a modified version of the Pavia/Biagi questionnaire to investigate their adherence to “modern WFD.” The appearance/exacerbation of symptoms after ingestion of ancient grains was then assessed with WHO toxicity grading scale.Results50.2% of the recruited patients reported consuming ancient grains before NCWS diagnosis; the diagnostic delay in this group was significantly higher than in non-consumers [median (range) 72 (6–612) vs. 60 months (3–684), P = 0.03] and these patients reported lower frequency of constipation (P = 0.04). Of the 107 patients with optimal adherence to modern WFD, 14 reported eating ancient wheat after NCWS diagnosis. Among them, 5 reported milder symptoms than those caused by modern wheat intake and 3 had an excellent tolerability without symptoms. Timilia/Tumminia variety was the most frequently used ancient grain.ConclusionsNCWS patients who consume ancient grains may receive a late diagnosis due to the possible clinical benefit (tolerability) obtained with these grains. Even after diagnosis, 10% of the patients still consumed ancient grains and had mild or no symptoms. Further studies are required to define the pathophysiological mechanism behind their putative greater tolerability.

Anemia is considered to be the most frequent extra-intestinal manifestation of Celiac Disease (CD). We assessed frequency, severity, morphologic features, and pathogenic factors of anemia in patients of the Sicilian Regional Network of Celiac Disease and attempted to identify putative pre-diet factors influencing anemia persistence. We retrospectively analyzed CD patients admitted to three centers between 2016–2020. 159 patients entered the study (129 females). More than half (54.7%) had mild-moderate, hypochromic and microcytic anemia, associated with below normal total serum iron and ferritin, indicative of iron deficiency anemia (IDA). One year after diagnosis, 134 patients were following ‘strict’ GFD. Hypochromic and microcytic anemia persisted in 46% of subjects who were anemic at diagnosis. Patients with persistent anemia had at diagnosis a higher prevalence of female gender (p = 0.02), lower body mass index (BMI, p = 0.01), higher prevalence of poly/hypermenorrhea (p = 0.02) and atopy (p = 0.04), and lower ferritin levels (p = 0.05) than the whole group of non-anemic ones. IDA is found in more than 50% of CD patients at diagnosis; nevertheless, in a lot of women IDA is not corrected by ‘strict’ GFD. Low BMI and poly/hypermenorrhea at diagnosis characterize this subgroup, suggesting that IDA might be due to iron loss rather than malabsorption, or to their coexistence/overlap.

Type 2 diabetes mellitus (T2DM) is a serious public health concern as it is one of the most common chronic diseases worldwide due to social and economic developments that have led to unhealthy lifestyles, with a considerable impact both in terms of morbidity and mortality. The management of T2DM, before starting specific therapies, includes cornerstones such as healthy eating, regular exercise and weight loss. Strict adherence to the Mediterranean diet (MedDiet) has been related to an inverse association with the risk of T2DM onset, as well as an improvement in glycaemic control; in particular, thanks to the consumption of extra virgin olive oil (EVOO). Agonists of gut-derived glucagon-like peptide-1 (GLP-1), gastrointestinal hormones able to increase insulin secretion in response to hyperglycaemia (incretins), have been recently introduced in T2DM therapy, quickly entering the international guidelines. Recent studies have linked the action of EVOO in reducing postprandial glycaemia to the increase in GLP-1 and the reduction of its inactivating protease, dipeptidyl peptidase-4 (DPP-4). In this review, we explore observations regarding the pathophysiological basis of the existence of an enhanced effect between the action of EVOO and incretins and, consequently, try to understand whether there is a rationale for their use in combination for T2DM therapy.

Background: Patients suffering from non-celiac wheat sensitivity (NCWS) frequently report extra- intestinal symptoms, such as anemia. Aims: We investigated the prevalence and associated clinical features of anemia in NCWS patients. Methods: Data from 244 NCWS patients, diagnosed by double-blind placebo-controlled wheat challenge, were retrospectively reviewed and compared with 2 control groups (celiac disease (CD) and irritable bowel syndrome (IBS)). Furthermore, 31 NCWS anemic patients were prospectively re-evaluated after at least 12 months on the “strict”wheat-free diet (WFD). Results: Anemia prevalence in NCWS patients was 34.8% (mean hemoglobin 10.4 ±1.4 g/dl), significantly higher than in IBS (17.4%, P = 0.03), but not in CD ones. The NCWS group, on the whole, had sideropenic- like features with low serum iron and altered iron deposits. Both anemia prevalence and sideropenic-like features were more evident in CD than in NCWS patients, whereas only a few IBS subjects showed such features. Significant differences were found in anemic vs non-anemic NCWS patients as regards to female sex, diagnostic delay, poly/hypermenorrhea, iron deficiency, and higher TSH values. A long-term WFD significantly reduced anemia and improved iron metabolism. Conclusion: Microcytic/hypochromic anemia and altered iron metabolism occur frequently in NCWS and can be treated with a long-term strict WFD. NCWS should be included in differential diagnosis of anemic patients with “functional gastrointestinal troubles”.

For years it has been established that the only truly effective treatment of metabolic syndrome (MS) is lifestyle modification to prevent its cardiovascular (e.g., coronary artery disease and atherosclerosis), metabolic (e.g., diabetes mellitus), and hepatic (e.g., steatosis and non-alcoholic steatohepatitis) complications. The focal points of this approach are to increase physical activity and intake of a diet characterized by high quantities of fruits, vegetables, grains, fish, and low-fat dairy products, the so called mediterranean diet (MD); however, the added value of MD is the presence of extra virgin olive oil (EVOO), a healthy food with a high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations (range 50–800 mg/kg) of phenols (oleuropein, ligstroside, and oleocanthal, and their derivatives, phenolic alcohols, such as hydroxytyrosol and tyrosol). Phenolic compounds not only determine EVOO’s main organoleptic qualities (oxidative stability, specific flavor, and taste features) but, theoretically, make it a source of antioxidant, anti-inflammatory, insulin-sensitizing, cardioprotective, antiatherogenic, neuroprotective, immunomodulatory, and anticancer activity. Although many studies have been carried out on EVOO’s clinical effects and attention toward this dietary approach (healthy and palatable food with strong nutraceutical activity) has become increasingly pressing, there are still many dark sides to be clarified, both in terms of actual clinical efficacy and biochemical and molecular activity. Thus, we reviewed the international literature, trying to show the state of the art about EVOO’s clinical properties to treat MS (along with correlated complications) and the future prospective of its nutraceutical use.

Hepatocellular carcinoma (HCC) is a very peculiar cancer because it presents several molecular alterations linked to the activation of survival and antiapoptotic signal pathways that are protein in form and not easily targetable by even the newest targeted therapies. In addition, it is almost always a consequence of liver cirrhosis, a serious disease condition in which several drugs are often not tolerated. This is why the study of HCC was such a challenge for Professor Natale D'Alessandro, to whom this work is dedicated, during the latter years of his career. The aim of this review is to summarize studies on different molecules involved in the development, progression, and chemoresistance of HCC, topics on which we have focused our research over the last decade. In particular, we have analyzed the role of inflammatory mediators, such as the cyclooxygenase (COX) enzymes, nuclear factor ?B (NF-?B), interleukin 6 (IL-6), as well as other important factors, such as Yin Yang 1 (YY1), in HCC. Moreover, we have reviewed some more recent literature on research aimed at identifying druggable targets in HCC as well as candidate agents for its prevention and treatment.

Aims. To analyze the main etiological factors and some clinical features of patients with hepatocellular carcinoma (HCC) at diagnosis and to compare them with those we described ten years ago. Materials and Methods. We compared two groups of patients with HCC, Group 1 consisting of 132 patients (82 M, 50 F) diagnosed in the 2003–2008 period and Group 2 including 119 patients (82 M, 37 F) diagnosed in the 2013–2018 period. For all patients, age, sex, viral markers, alcohol consumption, serum alpha-fetoprotein (AFP) levels, and the main liver function parameters were recorded. The diagnosis of HCC was based on AASLD, EASL guidelines. The staging was classified according to the “Barcelona Clinic Liver Cancer staging system” (BCLC). Results. Mean age was 69.0 ± 8 years in Group 1 and 71.0 ± 9 in Group 2 (P<0.05). HCV subjects were significantly older in Group 2 (P<0.05), and there was no difference for those with other etiologies. The main etiology in the two groups was HCV 80% (Group 1) versus 73% (Group 2) (P=ns), and there was no difference for HBV. Nonviral etiology was higher in Group 2 versus Group 1 (17% versus 9%; P<0.05). The Child class at diagnosis showed no difference between the two groups, whereas in Group 2 the HCC staging according to BCLC was less severe (P<0.02). When comparing the viral versus post-NASH BCLC in patients of the second period alone, the staging was more severe in the latter (P<0.01). AFP serum levels were normal in 37% of cases in Group 1 and in 67% in Group 2 (P<0.0001) and were less frequently diagnostic in post-NASH than in other etiologies (P<0.03). Conclusions. This study shows that over the last decade a number of features of patients with HCC in our region have changed, particularly age at onset, etiological factors, and staging of HCC.

Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04–4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08–9.40) and PTSD (OR = 2.38; 95% CI: 1.06–8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

Background The COVID-19 pandemic has caused the relocation of huge financial resources to departments dedicated to infected patients, at the expense of those suffering from other pathologies. Aim To compare clinical features and outcomes in COVID-19 pneumonia and non-COVID-19 pneumonia patients. Patients and methods 53 patients (35 males, mean age 61.5 years) with COVID-19 pneumonia and 50 patients (32 males, mean age 72.7 years) with non-COVID-19 pneumonia, consecutively admitted between March and May 2020 were included. Clinical, laboratory and radiological data at admission were analyzed. Duration of hospitalization and mortality rates were evaluated. Results Among the non-COVID patients, mean age, presence of comorbidities (neurological diseases, chronic kidney disease and chronic obstructive pulmonary disease), Charlson Comorbidity Index and risk factors (tobacco use and protracted length of stay in geriatric healthcare facilities) were higher than in COVID patients. The non-COVID-19 pneumonia group showed a higher (24% vs. 17%), although not statistically significant in-hospital mortality rate; the average duration of hospitalization was longer for COVID patients (30 vs. 9 days, p = .0001). Conclusions In the early stages of the COVID pandemic, our centre noted no statistical difference in unadjusted in-hospital mortality between COVID and non-COVID patients. Non-COVID patients had higher Charlson Comorbidity Scores, reflecting a greater disease burden in this population.Key MessagesIn March 2020, the COVID-19 disease was declared a pandemic, with enormous consequences for the organization of health systems and in terms of human lives; this has caused the relocation of huge financial resources to departments dedicated to infected patients, at the expense of those suffering from other pathologies.Few published reports have compared COVID-19 and non-COVID-19 pneumonia. In our study, performed in a geographic area with a low prevalence of SARS-CoV-2 infection, we found few statistically significant differences in terms of clinical characteristics between the two groups analyzed.In the early stages of the COVID pandemic, our centre noted no statistical difference in unadjusted in-hospital mortality between COVID and non-COVID patients. Non-COVID patients had higher Charlson Comorbidity Scores, reflecting a greater disease burden in this population

We have identified a clinical association between self-reported non-celiac wheat sensitivity (NCWS) and Familial Mediterranean Fever (FMF). Objectives: A) To determine whether a 2-week double-blind placebo-controlled (DBPC) cross-over wheat vs. rice challenge exacerbates the clinical manifestations of FMF, B) to evaluate innate immune responses in NCWS/FMF patients challenged with wheat vs. rice. The study was conducted at the Department of Internal Medicine of the University Hospital of Palermo and the Hospital of Sciacca, Italy. Six female volunteers with FMF/NCWS (mean age 36 &plusmn, 6 years) were enrolled, 12 age-matched non-FMF, NCWS females, and 8 sex- and age-matched healthy subjects served as controls. We evaluated: 1. clinical symptoms by the FMF-specific AIDAI (Auto-Inflammatory Diseases Activity Index) score, 2. serum soluble CD14 (sCD14), C-reactive protein (CRP), and serum amyloid A (SSA), 3. circulating CD14+ monocytes expressing interleukin (IL)-1&beta, and tumor necrosis factor (TNF)-&alpha, The AIDAI score significantly increased in FMF patients during DBPC with wheat, but not with rice (19 &plusmn, 6.3 vs. 7 &plusmn, 1.6, p = 0.028). sCD14 values did not differ in FMF patients before and after the challenge, but were higher in FMF patients than in healthy controls (median values 11357 vs. 8710 pg/ml, p = 0.002). The percentage of circulating CD14+/IL-1&beta, + and of CD14+/TNF-&alpha, + monocytes increased significantly after DBPC with wheat vs. baseline or rice challenge. Self-reported NCWS can hide an FMF diagnosis. Wheat ingestion exacerbated clinical and immunological features of FMF. Future studies performed on consecutive FMF patients recruited in centers for auto-inflammatory diseases will determine the real frequency and relevance of this association.

Objective: 'Self-reported wheat sensitivity' (SRWS) is a self-reported condition caused by wheat ingestion in the absence of celiac disease or wheat allergy. The aim of the study was to investigate the frequency and characteristics of SRWS in outpatients referred for digestive endoscopy. Methods: The study, performed at the University of Palermo, enrolled 496 outpatients. Results: Seven individuals (1.4%) had an already established diagnosis of celiac disease. The questionnaire was administered to the other 489 individuals: 98 subjects (20%) were SRWS, the remaining 391 served as controls (i.e. not-SRWS). SRWS patients were younger (P

A significant percentage of the general population reports gastrointestinal and non-gastrointestinal symptoms caused by wheat and/or gluten ingestion, even though they do not suffer from celiac disease (CD) or wheat allergy (WS), because they test negative both for CD-specific serology and histopathology. All patients report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS). The objective of this paper was to review some studies regarding the pathogenesis of NCGS to summarize the current hypotheses about the mechanisms, which can lead to NCGS. Particular attention was given to the immunologic and the malabsorptive hypotheses. We reviewed data of our previous studies involving patients diagnosed with NCWS by means of double-blind placebo-controlled wheat challenge. The data indicating a possible wheat allergy diagnosis were examined and other data in the literature were reviewed; we also reviewed the putative role of fermentable oligosaccharides disaccharides monosaccharides and polyols (FODMAPs) and of α-amylasetrypsin inhibitors (ATIs) proteins in the NCGS pathogenesis. NCGS pathogenesis has been attributed to very different mechanisms, among others: i) activation of innate and adaptive immunity (the immune/allergic mechanisms) induced by gluten or the non-gluten ATI family; ii) incomplete digestion and/or absorption of FODMAPs (the intolerance mechanisms); and iii) psychological effect.We suggest that NCGS is a heterogeneous condition, which includes different subgroups of patients who have different pathogenic mechanisms: strong data suggest a direct pathogenic immunogenic/inflammatory role of wheat-cereal proteins (not only gluten) in a subgroup, probably the largest, of these patients.

Background and AimsNon-alcoholic fatty liver disease and related hepatic syndromes affect up to one third of the adult population. The molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs and recently we report its active participation in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.MethodsWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 expression is inversely correlated to hepatic steatosis progression. We found that NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.ObjectiveNon-alcoholic fatty liver (NAFL) disease and related hepatic syndromes affect up to one third of the adult population in industrialised and developing countries. However, the molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including the liver. Recently, we report NUPR1 actively participates in activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.DesignWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.ConclusionsAs PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.Lay summaryNUPR1 is activated during high caloric intake in both mice and patients. Decrease in expression or inhibition of NUPR1 worsens lipid deposition and hepatic damage.Graphical abstractHighlightsNUPR1 protects liver from high caloric intake hepatic damageThe function of NUPR1 in this context is to control the lipid homeostasis through the UPR and more specifically through PPAR-α signalling.NUPR1 could be used as a predictive marker for the gravity of NAFL progression. Moreover, as clinical interest is being raised around NUPR1 inhibitors to treat liver and pancreatic cancer, care should be taken in monitoring lipotoxic parameters.

Management for HCV has undergone a notable change using direct-acting antiviral drugs (DAAs), which are safe and effective even in elderly. Here, we define impact of comorbidities, concomitant medication and drug–drug interactions in elder patients with HCV related disease before starting DAAs regimen. We analyzed data of 814 patients prospectively enrolled at our Unit within the web based model HCV Sicily Network. Out of 814, 590 were treated with DAAs and 414 of them were older than 65 years. We divided those 414 in two groups, one including 215 patients, aged between 65 and 74 years, and another with 199 patients, aged of 75 years and over. Charlson Comorbidity Index (CCI) was assessed for each patient; drug–drug interactions (DDI) and de-prescribing process were carried out appropriately. Within 414 patients included, percentage rates of women treated was higher than males, BMI was lower and cirrhosis was frequently reported in patients older than 75 years. Hypertension, diabetes mellitus, dyslipidemia (p p p p

Background: Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics. Methods: 278 clinical records of NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge between 2006 and 2020, were retrospectively revised. Fifty-two patients with Celiac Disease (CD) and 54 patients with Irritable Bowel Syndrome (IBS) served as controls. Results: 87% of the NCWS patients had an IBS-like clinical presentation. The NCWS group showed a longer duration of symptoms, a higher frequency of positive serum anti-nuclear antibodies than CD and IBS patients, and a higher frequency of DQ2/DQ8 haplotypes and duodenal mucosa lymphocytosis than IBS controls. In addition, 50% of NCWS patients showed neuropsychiatric manifestations, while lower percentages were observed in CD (25%) and IBS (28%) controls. Neuropsychiatric symptoms in NCWS were more frequently associated with the male sex, longer duration of symptoms, and IBS-diarrhea-like clinical presentation. Conclusions: Our data suggest that in patients with IBS-like symptoms and neuropsychiatric manifestations of unknown cause, it could be useful to investigate a correlation of these symptoms with wheat ingestion to identify NCWS patients with this ‘atypical’ manifestation.

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.

Background & Aims Ancient wheat varieties are considered to be healthier than modern ones, but the data are not univocal. We investigated changes in hematochemical parameters and evaluated microbiota data before and after a set period on a diet containing a whole-meal ancient wheat mix. Patients and Methods 29 cloistered nuns were recruited. The study comprised two consecutive 30-day periods; during the first one (T1), the nuns received wheat-based foods produced with refined “modern” flour (“Simeto”); during the second one (T2) received wheat-based foods produced with an unrefined flour mix composed of “ancient” cultivars. At entry to the study (T0) and at the end of T1 and T2 hematochemical parameters and fecal microbiota and metabolome were evaluated. Results At the end of T2, there was a significant reduction in serum iron, ferritin, creatinine, sodium, potassium, magnesium, total cholesterol, LDL- and HDL-cholesterol and folic acid. Furthermore, increased the abundance of cultivable enterococci, lactic acid bacteria and total anaerobes. The ability of the gut microbiome to metabolize carbohydrates increased after the period of diet containing ancient grain products. Several volatile organic compounds increased after the one month on the diet enriched with ancient grain products. Conclusions Our data showed the beneficial effects deriving from a diet including ancient whole-meal/unrefined wheat flours.

Extra virgin olive oil (EVOO) intake is associated with reduced cardiovascular risk, and its phenolic compound oleocanthal (OC) has anti-oxidant and anti-inflammatory properties. The cardiometabolic effects of EVOO with a high OC concentration have not been fully elucidated. We administered EVOO with a high OC concentration daily to 23 subjects with the metabolic syndrome (MetS) and hepatic steatosis (15 men and 8 women, age: 60 &plusmn, 11 years) for 2 months. Anthropometric data, metabolic parameters, hepatic steatosis (by fatty liver index, FLI), abdominal fat distribution (by ultrasound), and pro- and anti-inflammatory cytokines were assessed before and after the intervention. EVOO supplementation was associated with a reduction in body weight, waist circumference, body mass index (BMI), alanine transaminase and FLI, as well as interleukin (IL)-6, IL-17A, tumor necrosis factor-&alpha, and IL-1B, while IL-10 increased. Maximum subcutaneous fat thickness (SFT max) also increased, with a concomitant decrease in the ratio of visceral fat layer thickness/SFT max. Correlation analysis revealed positive associations between changes in body weight and BMI and those in SFT max, along with an inverse association between changes in IL-6 and those in SFT max. In conclusion, ingestion of EVOO with a high OC concentration had beneficial effects on metabolic parameters, inflammatory cytokines and abdominal fat distribution in MetS subjects with hepatic steatosis, a category of patients at high cardiometabolic risk.

In recent years, a new gluten- or wheat-related disease has emerged, a condition labeled "nonceliac gluten sensitivity" (NCGS) or "nonceliac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T-lymphocyte subsets in the rectal mucosa of NCWS patients to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 women, 1 man, age range 23-61 yr, median 32 yr) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells, as well as of IL-17 by CD4+ cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8+ cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response.NEW & NOTEWORTHY Nonceliac wheat sensitivity (NCWS) is a syndrome characterized by symptoms triggered by gluten intake. The pathogenesis is still uncertain. Studies have shown a role for innate immunity. We demonstrated that production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells and of IL-17 by CD4+ cells is higher in the rectal tissue of NCWS patients than in controls. We clearly demonstrated that in patients with NCWS there is a significant role for the adaptive response.

Spontaneous rectus sheath hematoma (SRSH) is an uncommon cause of acute abdominal pain characterized by bleeding within the rectus sheath; it is a benign condition and, in most cases, it is treated conservatively. Bleeding of the abdominal wall is an unusual condition that is quite challenging to identify promptly and can be easily overlooked during a routine physical examination. In daily practice, anticoagulant therapy is one of the main risk factors for hemorrhagic events. In this respect, we report a rare case of spontaneous hematoma of the abdominal wall (diagnosed and monitored through an ultrasound examination) that arose after sneezing in a patient receiving anticoagulant treatment.

INTRODUCTION: Nonceliac wheat sensitivity (NCWS) is characterized by intestinal and extraintestinal manifestations consequent to wheat ingestion in subjects without celiac disease and wheat allergy. Few studies investigated the relationship between NCWS and autoimmunity. The aim of this study is to evaluate the frequency of autoimmune diseases (ADs) and autoantibodies in patients with NCWS. METHODS: Ninety-one patients (13 men and 78 women; mean age of 40.9 years) with NCWS, recruited in a single center, were included. Seventy-six healthy blood donors (HBD) and 55 patients with a diagnosis of irritable bowel syndrome (IBS) unrelated to NCWS served as controls. Autoantibodies levels were measured. Human leukocyte antigen haplotypes were determined, and duodenal histology performed in all patients carrying the DQ2/DQ8 haplotypes. Participants completed a questionnaire, and their medical records were reviewed to identify those with ADs. RESULTS: Twenty-three patients with NCWS (25.3%) presented with ADs; autoimmune thyroiditis (16 patients, 17.6%) was the most frequent. The frequency of ADs was higher in patients with NCWS than in HBD (P 5 0.002) and in patients with IBS (P 5 0.05). In the NCWS group, antinuclear antibodies tested positive in 71.4%vsHBD19.7%, and vs patients with IBS 21.8% (P < 0.0001 for both). The frequency of extractable nuclear antigen antibody (ENA) positivity was significantly higher in patients with NCWS (21.9%) than in HBD (0%) and patients with IBS (3.6%) (P 5 0.0001 and P 5 0.004, respectively). Among the patients with NCWS, 9.9% tested positive for antithyroglobulin, 16.5% for antithyroid peroxidase, and 14.3% for antiparietal cell antibodies; frequencies were not statistically different from controls. The presence of ADs was related to older age at NCWS diagnosis, female sex, duodenal lymphocytosis, and eosinophil infiltration. DISCUSSION: One in 4 patients withNCWS suffered from AD, and serum antinuclear antibodies were positive in a very high percentage of cases. These data led us to consider NCWS to be associated to ADs.

The aim of this study is the creation of a 5-step ultrasound examination to evaluate and monitor Heart Failure (HF) patients during hospitalization and follow-up. “ABCDE” is the acronym of an Italian multicentre study composed of a consecutive sample of HF patients admitted from the Emergency to the Internal Medicine/Geriatric Departments of several Italian hospitals. The “ABCDE” score includes the evaluations of A, the Ankle-brachial index (ABI), B, the B-lines, C, the Carotid intima media thickness (CIMT), D, the Diameter of the abdominal aorta and of the inferior cave vein and E, the echocardiographic assessment of the ejection fraction. This paper reports the preliminary results. Up to now, the “ABCDE” multicenter study seems an exciting opportunity to create an integrative ultrasound approach in HF. The definitive confirmation of these preliminary results and the effective usefulness of the “ABCDE” will be available in 2022, at the end of the study.

Non-alcoholic fatty liver disease (NAFLD) is becoming the main cause of liver disease in Western countries, especially in morbidly obese patients (MOPs). The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently studied because of its possible involvement in the pathogenesis of NAFLD, but its role, at least in MOPs, is still controversial. The aim of this study was to clarify the correlation between the circulating levels of the PCSK9 protein (cPCSK9) and its hepatic expression with the severity of liver damage in a population of MOPs with NAFLD undergoing bariatric surgery. PCSK9 mRNA was positively correlated with FASN, PPARγ and PPARα mRNAs, while no significant differences were found in PCSK9 mRNA expression in relation to the severity of liver steatosis, lobular inflammation and hepatocellular ballooning. In addition, hepatic PCSK9 protein expression levels were not related to histological parameters of lobular inflammation and hepatocyte ballooning, decreased significantly only in relation to the severity of hepatic steatosis, and were inversely correlated with ALT and AST serum levels. cPCSK9 levels in the whole population were associated with the severity of hepatic steatosis and were positively correlated to total cholesterol levels. In multivariate analysis, cPCSK9 levels were associated with age, total cholesterol and HbA1c. In conclusion, in MOPs our findings support a role for PCSK9 in liver fat accumulation, but not in liver damage progression, and confirm its role in the increase of blood cholesterol, which ultimately may contribute to increased cardiovascular risk in this population.

Background: Non-celiac wheat sensitivity (NCWS) most frequently presents clinically with irritable bowel syndrome (IBS)-like symptoms, although many extra-intestinal manifestations have also been attributed to it. No studies to date have evaluated the presence and frequency of gynecological symptoms in NCWS. Aim: To evaluate the frequency of gynecological disorders in patients with NCWS. Patients and Methods: Sixty-eight women with NCWS were included in the study. A questionnaire investigating gynecological symptoms and recurrent cystitis was administered, and patients reporting symptoms were then examined by specialists. Three control groups were selected: 52 patients with IBS not related to NCWS, 56 patients with celiac disease (CD), and 71 healthy controls. Results: 59% of the patients with NCWS showed gynecological symptoms, a higher frequency than in healthy controls (P = 0.04), IBS controls (P = 0.01) and CD controls (P = 0.02). Menstrual cycle alterations were more frequent in patients with NCWS than in healthy controls (26.5% vs 11.3%; P = 0.03); the patients with NCWS suffered from recurrent vaginitis (16%) and dyspareunia (6%) significantly more frequently than healthy controls. Twenty-nine percent of patients with NCWS reported recurrent cystitis, a finding higher than in the control groups (vs healthy P = 0.0001, vs IBS P = 0.001, vs CD controls P = 0.04). Microbiological examinations were negative in most of the patients with NCWS and recurrent vaginitis or cystitis. During the 1-year follow-up, 46% of patients with menstrual disorders and 36% with recurrent vaginitis reported resolution of symptoms on a wheat-free diet. Conclusions: Patients with NCWS showed a significantly higher frequency of gynecological symptoms and recurrent cystitis than patients with IBS.

BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPAR? and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).

The median arcuate ligament syndrome (MALS) is a rare disease characterized by abdominal pain caused by the external compression of the celiac artery by the median arcuate ligament. Surgical treatment is indicated, but given the non-specific symptoms, these patients are often hospitalized in the Departments of Internal Medicine where the diagnosis may be unknown. We present a case of MALS admitted to our Internal Medicine Division. An abdominal ultrasound in a woman with longstanding abdominal pain showed elevated celiac artery velocities during forced expiration. Computed tomography angiography (CTA) of the abdomen showed stenosis of the origin of the celiac artery and confirmed the diagnosis of MALS. MALS is a syndrome that has to be considered, especially in young women with abdominal pain of unclear etiology; evaluated by color Doppler ultrasound, in the presence of elevated hepatic artery velocities during forced expiration, the confirmatory test is CTA.

PURPOSE: Conventional grayscale ultrasound (US) is accurate in the diagnosis of gallbladder disease (GD), but in some cases, it is not decisive. Contrast-enhanced ultrasound (CEUS) improves the diagnostic accuracy of US. The primary objective of this study is to assess the reliability of CEUS in the diagnosis of sludge; the secondary objective is to assess the ability of CEUS to diagnose cancer. METHODS: We retrospectively reviewed the US of 4137 patients positive for GD. In 43/4137 (1.04%), the use of could not discriminate between sludge and neoplasms. Then, we evaluated CEUS in only 39 of these patients, and in 4/43 (9%) cases it was not performable. After CEUS, the absence of enhancement was considered diagnostic for sludge, while contrast washout within 60 s diagnosed malignant lesions. RESULTS: Among the 39 patients, 16 had biliary sludge and 23 had lesions of the gallbladder wall; 9 of these were carcinomas and 14 were benign tumors. The absence of enhancement was present in 16/16 patients with sludge and in 0/23 patients with lesions of the gallbladder (sensitivity and specificity 100%). Washout was within 60 s in 9/9 gallbladder carcinomas and 2/14 benign lesions (sensitivity 100%; specificity 85%). CONCLUSIONS: US is confirmed to be accurate in the diagnosis of GD. In doubtful cases, CEUS is very accurate in biliary sludge diagnosis. An intralesional washout at 60 s is a pattern of malignancy that can orient towards a correct diagnosis, but it is limited by the presence of false positive results, especially for smaller lesions.

Aim/Objective/Background Direct-acting oral anticoagulant drugs are marketed worldwide for the primary and secondary prevention and treatment of thromboembolic disorders. Rivaroxaban, an oral, direct factor Xa inhibitor, is one of the most used. Rivaroxaban-induced hepatotoxicity is unusual, although a number of adverse reports have recently been reported. Here, we report two new cases of rivaroxaban-induced hepatitis. Methods A systematic search of case reports on the MEDLINE database encompassing the years 2008–2016 was carried out.Additional references were obtained following a manual search of the retrieved papers. We report two new cases of adverse events occurred in patients treated with rivaroxaban (20 mg/die) to prevent systemic embolism, who presented with hepatocellular liver injury with onset at 8 weeks after initiation of the drug intake. Results Twenty-six cases were retrieved from MEDLINE (57.7% female, 42.3% male). Using the Roussel Uclaf Causality Assessment Method (RUCAM) scale, liver injury was classified as hepatocellular (42.3%), cholestatic (26.9%), or mixed (15.4%). Older age (≥65 years) was present as a risk factor in 57.7%. The time lapse between initiation of treatment and onset of hepatic injury ranged from 2 to 180 days (median: 15 days). Our two new patients were diagnosed with drug-induced liver injury (hepatocellular pattern) using the ‘consensus criteria’, for drug-induced liver injury. Their RUCAM scores were calculated and assessed as highly probable and probable, respectively. A clinical recovery after rivaroxaban withdrawal was observed. Conclusion Direct-acting oral anticoagulants have been commonly prescribed, even if safety issues regarding the use of these drugs are still an ongoing concern, especially in patients experiencing chronic liver disease. Dedicated postauthorization safety studies should be undertaken to better define rivaroxaban-induced drug-induced liver injury.

Over the past few years, growing interest has been shown for the impact of dietary requirements and nutritional factors on chronic diseases. As a result, nutritional programs have been reinforced by public health policies. The precise role of micronutrients in chronic liver disease is currently receiving particular attention since abnormalities in vitamin levels are often detected. At present, treatment programs are focused on correcting vitamin deficiencies, which are frequently correlated to higher rates of comorbidities with poor outcomes. The literature reviewed here indicates that liver diseases are often related to vitamin disorders, due to both liver impairment and abnormal intake. More specific knowledge about the role of vitamins in liver disease is currently emerging from various results and recent evidence. The most significant benefits in this area may be observed when improved vitamin intake is combined with a pharmacological treatment that may also affect the progression of the liver disease, especially in the case of liver tumors. However, further studies are needed.

Background: Lactose intolerance is the most frequent food intolerance, but many subjects with self-reported milk intolerance (SRMI) are asymptomatic at lactose hydrogen breath test (LHBT). The aim of this study was to evaluate the frequency of lactose intolerance in SRMI patients and their clinical characteristics. Methods: In a retrospective study, the clinical records of 314 SRMI patients (259 females, mean age: 39.1 ± 13.5 years) were reviewed; 102 patients with irritable bowel syndrome (IBS) served as controls. In a prospective study, 42 SRMI patients, negatives at the LHBT, underwent a double-blind, placebo-controlled (DBPC) whole cow’s milk challenge. Results: In the retrospective study, only 178 patients (56%) were lactose maldigesters and intolerant at LHBT; 68% of the subjects with SRMI were suffering from IBS; 74% reported dyspepsia (p = 0.0001 vs. IBS controls); and weight loss was recorded in 62 SRMI patients (20%) (p = 0.01 vs. IBS controls). Duodenal histology showed intra-epithelial lymphocytosis in about 60% of cases. In the prospective study, 36 patients (86%) experienced symptoms during the DBPC cow’s milk challenge, and only 4 patients (9%) reacted to placebo (p = 0.0001). Conclusions: A percentage of SRMI patients were not suffering from lactose intolerance. DBPC revealed that SRMI patients had clinical reactions when exposed to whole cow’s milk.

Background: Non-Celiac Wheat Sensitivity (NCWS) is still a largely undefined condition, due to the lack of a diagnostic marker. Few data are available about the nutritional characteristics of NCWS patients at diagnosis. Aims: To evaluate the proportion of NCWS patients who were underweight, normal weight, overweight, or obese at diagnosis, and to search for possible correlations between their Body Mass Index (BMI) and other NCWS-related disease characteristics. Patients and Methods: The clinical charts of 145 NCWS patients (125 F, 20 M, mean age 37.1 &plusmn, 11.4 years), diagnosed between January 2012 and March 2018, were reviewed. As a comparison, 84 celiac disease (CD) patients (73 F, 11 M, mean age 39.8 &plusmn, 13.9 years) were evaluated. All NCWS diagnoses were based on a double-blind placebo-controlled wheat challenge (DBPCWC) method. Results: BMI distribution was similar in the NCWS (6.2% underweight and 15.2% obese subjects) and CD patients (6% underweight and 7.1% obese subjects). Underweight NCWS subjects were significantly younger and had a shorter clinical history than the overweight or obese ones. Unlike the other NCWS patients, none of them had a DQ2 and/or DQ8 haplotype. Overweight and obese NCWS patients were more frequently suffering from associated autoimmune diseases than the other BMI categories (P = 0.05). Compared to the CD controls, NCWS patients showed a higher frequency of Irritable Bowel Syndrome (IBS)-like (P = 0.01) and extraintestinal symptoms (P = 0.03) and a longer clinical history (P = 0.04), whereas weight loss was more frequent in CD (P = 0.02). Conclusions: NCWS patients showed a BMI distribution similar to CD patients. However, NCWS was found to be a heterogenous condition that regards BMI, and clinical characteristics differed between the underweight and overweight/obese patients.

GOALS: The goal of this study was (A) to evaluate abdominal ultrasound signs in nonceliac wheat sensitivity (NCWS) patients for features useful in diagnosis and (B) to compare these aspects with those of celiac patients to assess whether ultrasound can be useful in the differential diagnosis between NCWS and celiac disease (CD). BACKGROUND: NCWS diagnosis is difficult as no biomarkers of this condition have as yet been identified. In CD ultrasound aspects have been identified that have a good diagnostic accuracy. STUDY: We prospectively recruited 45 NCWS patients (11 males, 34 females; mean age 35.7 y). Three control groups were included: (A) 99 age-matched CD patients; (B) 18 patients with seronegative CD; (C) 50 patients with irritable bowel syndrome (IBS) who did not improve on a wheat-free diet. NCWS diagnosis was confirmed on the basis of an elimination diet and double-blind placebo-controlled (DBPC) challenge. Ultrasound sign investigation included: dilatation of the small bowel loops, thickening of the small bowel wall, hyperperistalsis, enlarged mesenteric lymph nodes, ascites, hyposplenism, altered diameter of the portal vein. RESULTS: NCWS patients showed a low frequency of pathologic ultrasound findings. Dilated or thickened loops appeared more often in CD patients than in NCWS patients (88.8% vs. 20%; P

This review covers the role of ultrasonography as an essential non-invasive diagnostic approach when facing patients with anemia, a common clinical problem. Abdomen ultrasound is well recognized as a first-line examination in the setting of blood loss, both acute and chronic. Less is clear about the additional opportunities, given by ultrasound in anemia, due to the many other possible causes. Here we provide information on the utility of ultrasound in different contexts and a practical guide for clinicians facing anemic patients

Bicuspid aortic valve (BAV) is the most common congenital heart malformation. BAV patients are at increased risk for aortic valve disease (stenosis/regurgitation), infective endocarditis, thrombi formation and, in particular, aortic dilatation, aneurysm and dissection. This review aims at exploring the possible interplay among genetics, extracellular matrix remodeling, abnormal signaling pathways, oxidative stress and inflammation in contributing to BAV-associated aortopathy (BAV-A-A). Novel circulating biomarkers have been proposed as diagnostic tools able to improve risk stratification in BAV-A-A. However, to date, the precise molecular and cellular mechanisms that lead to BAV-A-A remain unknown. Genetic, hemodynamic and cardiovascular risk factors have been implicated in the development and progression of BAV-A-A. Oxidative stress may also play a role, similarly to what observed in atherosclerosis and vulnerable plaque formation. The identification of common pathways between these 2 conditions may provide a platform for future therapeutic solutions.

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Drug-induced liver injury (DILI) is often a trial even to expert clinicians, because sometimes diagnosis is not easy to be made. Guidelines of the American College of Gastroenterology (ACG) yielded in 2014, help to better understand the problem. The diagnosis of DILI is made through a detailed evaluation of clinical, serological, radiological and histological aspects. Biochemical data include liver function tests that allow to assess the pattern of damage, such as hepatocellular, cholestatic and mixed liver injury; serological data include testing for major and possibly minor hepatotropic viruses, non-organ specific autoantibodies. Clinical scenario might include jaundice, nausea, vomiting and extra-hepatic manifestations such as fever, pruritus, rash and eosinophilia. Investigation of the potential culprit drugs should involve firstly the temporal relationship between intake of the medication and onset of symptoms, thus the improvement after drug withdrawal. Overall, to complete the diagnostic evaluation, an abdominal ultrasound can be performed, as well as measurement of liver stiffness by transient elastography, and finally liver biopsy, which still represents the most accurate method to definitely assess liver damage. Sometimes, in such cases, computed tomography scan and magnetic resonance could help in the diagnosis of cases presenting with focal lesions of the liver, with cholestatic-like disease or vascular alterations, such as veno-occlusive disease. DILI diagnostic criteria help clinicians thinking of liver injury induced by drug, excluding other causes of liver disease. According to severity of liver damage and type of drug, it is possible to carefully predict the patient’s outcome.

In Asian countries, the increasing incidence of obesity has only recently opened a debate that has been ongoing in the West for a long time, not only regarding its cardiovascular consequences, but also the relationship between obesity, non-alcoholic fatty liver disease (NAFLD), and cancer

Objective: Nonselective β-blockers (NSBB) are used in liver cirrhosis (LC) to prevent variceal bleeding because they decrease portal pressure. A main risk factor for the development of portal vein thrombosis (PVT) in LC is decreased portal vein inflow velocity. The aim of our study was to examine retrospectively the incidence of PVT and its correlation with the use of β-blockers in a cohort of LC patients. Subjects and Methods: Data from 230 LC patients (90% Child-Pugh class A), who had been followed up for at least 5 years, were reviewed. The diagnosis of PVT was made by ultrasound. The presence of PVT was evaluated with multiple logistic regression analysis where the independent variables were those significant in the univariate analysis. Results: The prevalence of PVT at baseline was 4.5%, and the incidence was 4.3% at 5 years; among the subjects taking β blockers, 46.4% were taking NSBB. A total of 19 PVT cases were found. Grade of esophageal varices (p < 0.01), PLT (p < 0.003), INR (p < 0.03), spleen diameter (p < 0.001) and PLT/spleen ratio (p < 0.0005) were significantly associated with PVT. The use of NSBB indicated a higher risk of PVT compared to selective β-blockers (SBB) (p < 0.05). In logistic regression analysis only the grade of esophageal varices was significant (p < 0.02). Univariate analysis of patients taking β-blockers showed an association of PVT with grade of esophageal varices (p < 0.01), CP class (p < 0.02), AST (p < 0.03), ALT and albumin (p < 0.02), PLT count and PLT/LD (p < 0.03), longitudinal diameter of the spleen (p < 0.005), ascites (p < 0.05), portal vein (p < 0.0001) and NSBB (OR 8.1; 95% CI 1.7–38.8). Conclusion: NSBB seem to play a role in PV thrombogenesis. Further studies are needed, especially in decompensated LC patients.

Heart failure (HF) is a clinical syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. It is the leading cause of hospitalization in Internal Medicine departments. This article aims at reviewing evidence of the importance of ultrasound in HF both for hospitalized patients and in the follow-up. Ultrasound may be used as a recovery monitoring instrument at the bedside and also as a global cardiovascular assessment tool for these patients. HF represents an exciting opportunity to create an integrative ultrasound approach in Internal Medicine and/or Geriatric departments. The authors plan a five-step ultrasound examination to evaluate and monitor HF patients during hospitalization and follow-up. They call this examination: the “ABCDE” score. It includes the evaluations of A, the ankle-brachial index, B, the B-lines, C, the carotid intima media thickness, D, the diameter of the abdominal aorta and of the inferior cava vein and E, the echocardiographic assessment of the ejection fraction. This score may represent an integrative ultrasound approach in Internal Medicine and/or Geriatric departments.

BACKGROUND Cirrhosis is associated with morpho-functional cardiovascular alterations. AIMS To detect early features of cardiovascular damage in HCV-compensated cirrhotic patients using myocardial deformation indices and carotid arterial stiffness, and, further, to evaluate their short-term behaviour after HCV eradication with direct antiviral agents (DAAs). METHODS Thirty-nine consecutive patients with HCV cirrhosis, without previous cardiovascular events, were studied and matched for age, gender and cardiovascular risk factors to 39 controls without liver or cardiovascular disease. Patients and controls underwent a baseline echocardiographic evaluation including global longitudinal strain and ultrasound scan of carotid arteries. HCV-cirrhotics were reassessed by echocardiography and carotid ultrasound after obtaining sustained virological response (SVR) on DAAs. RESULTS HCV-cirrhotics showed at baseline a significantly reduced global longitudinal strain compared to controls -18.1 (16.3-20.5) vs -21.2 (20.4-22.3), P

International guidelines suggest ultrasound surveillance for hepatocellular carcinoma (HCC) early diagnosis in liver cirrhosis (LC) patients, but 40% of nodules <2 cm escape detection. We investigated the existence of an ultrasound pattern indicating a higher risk of developing HCC in patients under surveillance. 359 patients with LC (Child-Pugh A-B8) underwent ultrasound screening (median follow-up 54 months, range 12–90 months), liver function tests, alpha-fetoprotein assay, and portal hypertension evaluation. Echo patterns were homogeneous, bright liver, coarse, coarse small nodular pattern, and coarse large nodular pattern. During follow-up 13.9% developed HCC. At multivariate analysis using Cox’s model alpha-fetoprotein, coarse large nodular pattern, portal hypertension, and age were independent predictors of HCC development. Kaplan-Meier estimates of HCC cumulative risk in relation to the baseline echo patterns showed risk of 75% in coarse large nodular pattern patients, 23% coarse small nodular pattern, 21% coarse pattern, 0% homogeneous, and bright liver echo patterns (log-rank test = 23.6, P<0.001). Coarse large nodular pattern indicates a major risk factor for HCC as 40.7% of patients with this pattern developed HCC. Homogeneous and bright liver echo patterns and the absence of portal hypertension were not related to HCC. This observation could raise the question of possibly modifying the follow-up timing in this subset of patients.

Background: Non‐celiac wheat sensitivity (NCWS) is a new clinical entity in the world of gluten‐related diseases. Nickel, the most frequent cause of contact allergy, can be found in wheat and results in systemic nickel allergy syndrome and mimics irritable bowel syndrome (IBS). Objective: To evaluate the frequency of contact dermatitis due to nickel allergy in NCWS patients diagnosed by a double‐blind placebo‐controlled(DBPC)challenge,and to identify the characteristics of NCWS patients with nickel allergy. Methods: We performed a prospective study of 60 patients (54 females, 6 males; mean age 34.1 ± 8.1 years) diagnosed with NCWS from December 2014 to November 2016; 80 age‐ and sex‐matched subjects with functional gastrointestina l symptoms served as controls. Patients reporting contact dermatitis related to nickel‐containing objects underwent nickel patch test (Clinicaltrials.gov registration number: NCT02750735).Results: Six out of sixty patients (10%) with NCWS suffered from contact dermatitis and nickel allergy and this frequency was statistically higher (p = 0.04)than observed in the control group(5%. The main clinical characteristic of NCWS patients with nickel allergy was a higher frequency of cutaneous symptoms after wheat ingestion compared to NCWS patients who did not suffer from nickel allergy (p

Lung ultrasound (LUS) is a valid tool for the assessment of heart failure (HF) through the quantification of the B-lines. This study in HF patients aims to evaluate if LUS: (1) can accelerate the discharge time; (2) can efficiently drive diuretic therapy dosage; and (3) may have better performance compared to the amino-terminal portion of B type natriuretic peptide (NT-proBNP) levels in monitoring HF recovery. A consecutive sample of 120 HF patients was admitted from the Emergency Department (ED) to the Internal Medicine Department (Verona University Hospital). The Chest X-ray (CXR) group underwent standard CXR examination on admission and discharge. The LUS group underwent LUS on admission, 24, 48 and 72 h later, and on discharge. The Inferior Cava Vein Collapsibility Index, ICVCI, and the NT-proBNP were assessed. LUS discharge time was significantly shorter if compared to CXR group (p < 0.01). During hospitalization, the LUS group underwent an increased number of diuretic dosage modulations compared to the CXR group (p < 0.001). There was a stronger association between partial pressure of oxygen in arterial blood (PaO2) and B-lines compared to the association between PaO2 and NT-proBNP both on admission and on discharge (p < 0.001). The B-lines numbers were significantly higher on admission in patients with more severe HF, and the ICVCI was inversely associated with B-lines number (p < 0.001). The potential of LUS in tailoring diuretic therapy and accelerating the discharge time in HF patients is confirmed. Until the technique comes into common use in different departments, it is plausible that LUS will evolve with different facets.

Cytomegalovirus (CMV) infection is usually asymptomatic and self-limiting in healthy individuals, but significant complications can develop in immunosuppressed patients. Venous or arterial thromboembolic phenomena are uncommon yet very serious complications of CMV infection. Most published reports describe immunosuppressed patients, but thrombotic events in CMV-infected immunocompetent individuals may also occur. We describe the case of an immunocompetent young man with acute CMV hepatitis that was complicated with portal vein thrombosis (PVT). We also review the literature regarding the association between PVT and CMV in immunocompetent patients. Thromboembolism is an underestimated but significant complication of acute CMV infection. Several local and systemic factors are involved in the pathogenesis of acute PVT. This case emphasizes the central role of ultrasound in its diagnosis and the potentially serious complications that can occur in immunocompetent individuals with no other prothrombotic risk factors.L’infezione da Cytomegalovirus (CMV) è solitamente asintomatica e autolimitantesi nei pazienti immunocompetenti, mentre in quelli immunocompromessi può determinare manifestazioni cliniche severe. I fenomeni tromboembolici venosi e arteriosi sono complicanze rare ma severe di una infezione da CMV. Molti lavori della letteratura hanno riportato le complicanze trombotiche dell’infezione da CMV in pazienti immunocompromessi. Esistono, tuttavia, casi di trombosi anche in soggetti immunocompetenti. Noi riportiamo il caso di un giovane adulto immunocompetente con epatite acuta da CMV complicata da trombosi della vena porta (TVP). Abbiamo condotto una revisione della letteratura sull’associazione tra la trombosi della vena porta e l’infezione da CMV nei pazienti immunocompetenti. Il tromboembolismo è una complicanza sottostimata ma severa dell’infezione acuta da CMV. Numerosi fattori locali e sistemici sono coinvolti nella patogenesi della trombosi della vena porta. Questo caso descrive l’insorgenza di questa severa complicanza nel paziente immunocompetente ed il ruolo centrale dell’ecografia nella sua diagnosi.