Non-Alcoholic Fatty Liver Disease: From Pathogenesis to Clinical Impact

Non-Alcoholic Fatty Liver Disease (NAFLD) is caused by the accumulation of fat in over 5% of hepatocytes in the absence of alcohol consumption. NAFLD is considered the hepatic manifestation of metabolic syndrome (MS). Recently, an expert consensus suggested as more appropriate the term MAFLD (metabolic-associated fatty liver disease). Insulin resistance (IR) plays a key role in the development of NAFLD, as it causes an increase in hepatic lipogenesis and an inhibition of adipose tissue lipolysis. Beyond the imbalance of adipokine levels, the increase in the mass of visceral adipose tissue also determines an increase in free fatty acid (FFA) levels. In turn, an excess of FFA is able to determine IR through the inhibition of the post-receptor insulin signal. Adipocytes secrete chemokines, which are able to enroll macrophages inside the adipose tissue, responsible, in turn, for the increased levels of TNF-. The latter, as well as resistin and other pro-inflammatory cytokines such as IL-6, enhances insulin resistance and correlates with endothelial dysfunction and an increased cardiovascular (CV) risk. In this review, the role of diet, intestinal microbiota, genetic and epigenetic factors, low-degree chronic systemic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress on NAFLD have been addressed. Finally, the clinical impact of NAFLD on cardiovascular and renal outcomes, and its direct link with type 2 diabetes have been discussed

Role of Tight Glycemic Control during Acute Coronary Syndrome on CV Outcome in Type 2 Diabetes

Both incidence and mortality of acute coronary syndrome (ACS) among diabetic patients are much higher than those among nondiabetics. Actually, there are many studies that addressed glycemic control and CV risk, whilst the literature on the role of tight glycemic control during ACS is currently poor. Therefore, in this review, we critically discussed the studies that investigated this specific topic. Hyperglycemia is implicated in vascular damage and cardiac myocyte death through different molecular mechanisms as advanced glycation end products, protein kinase C, polyol pathway flux, and the hexosamine pathway. Moreover, high FFA concentrations may be toxic in acute ischemic myocardium due to several mechanisms, thus leading to endothelial dysfunction. A reduction in free fatty acid plasma levels and an increased availability of glucose can be achieved by using a glucose-insulin-potassium infusion (GIKi) during AMI. The GIKi is associated with an improvement of either long-term prognosis or left ventricular mechanical performance. DIGAMI studies suggested blood glucose level as a significant and independent mortality predictor among diabetic patients with recent ACS, enhancing the important role of glucose control in their management. Several mechanisms supporting the protective role of tight glycemic control during ACS, as well as position statements of Scientific Societies, were highlighted

The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes

We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD)

Genetic predictors of response to treatment of chronic hepatitis C virus infection in patients from southern Italy

Various clinical and genetic factors affect response to antiviral treatment of chronic hepatitis C virus (HCV) infection. The IL28B single-nucleotide polymorphism (SNP) rs12979860 is associated with a sustained viral response (SVR), and the suppressor cytokine signaling 3 (SOCS3) gene is over-expressed in HCV-1b non-responders. The aim of this study was to look for correlations between genetic, clinical and viral factors implicated in response to antiviral treatment in chronic HCV infection. We evaluated 190 controls and 148 HCV-infected patients (102 HCV-1 and 46 HCV-2). Demographic, metabolic and histological features related to antiviral treatment were recorded. Univariate and multivariate analyses were used to identify correlations between the genetic and non-genetic features examined and response to antiviral treatment. IL28B expression was higher in CC SNPs versus other alleles in controls (P=0.01) and this difference was associated with viral infection (HCV vs controls P=0.006), particularly in HCV-2 patients (P=0.003). SOCS3 and IL28B expression was correlated with controls (P=0.011), whereas there was an inverse correlation between the expression of the two genes in HCV patients and HCV-1b non-responders (P=0.014 and P=0.03, respectively). Multivariate analysis showed that the only independent SVR predictive factor was rapid virological response. The frequency of IL28B rs12979860 SNP alleles in controls (C allele=71.1% and T allele= 28.9%) was comparable to that of the HCV population (C allele=66.6% and T allele=33.4%). Rapid virological response seems to be the only significant independent predictor of an SVR to antiviral treatment. The inverse correlation between SOCS3 and IL28B expression in genotype 1b non-responders suggests that SOCS3 may affect IL28B expression thereby influencing response to antiviral therapy

Role of Albuminuria in Detecting Cardio-Renal Risk and Outcome in Diabetic Subjects

The clinical significance of albuminuria in diabetic subjects and the impact of its reduction on the main cardiorenal outcomes by different drug classes are among the most interesting research focuses of recent years. Although nephrologists and cardiologists have been paying attention to the study of proteinuria for years, currently among diabetics, increased urine albumin excretion ascertains the highest cardio-renal risk. In fact, diabetes is a condition by itself associated with a high-risk of both micro/macrovascular complications. Moreover, proteinuria reduction in diabetic subjects by several treatments lowers both renal and cardiovascular disease progression. The 2019 joint ESC-EASD guidelines on diabetes, prediabetes and cardiovascular (CV) disease assign to proteinuria a crucial role in defining CV risk level in the diabetic patient. In fact, proteinuria by itself allows the diabetic patient to be staged at very high CV risk, thus affecting the choice of antihyperglycemic drug class. The purpose of this review is to present a clear update on the role of albuminuria as a cardio-renal risk marker, starting from pathophysiological mechanisms in support of this role. Besides this, we will show the prognostic value in observational studies, as well as randomized clinical trials (RCTs) demonstrating the potential improvement of cardio-renal outcomes in diabetic patients by reducing proteinuria

Bipolar Patients and Bullous Pemphigoid after Risperidone Long-Acting Injectable: A Case Report and a Review of the Literature

Neuropsychiatric disorders are found to be associated with bullous pemphigoid (BP), an autoimmune subepidermal blistering disease. Antipsychotics have emerged as possible inducing factors of BP. However, large sample studies concerning BP associated with antipsychotics, as well as with specific mental disorders, are still lacking. Our review retrieved a few clinical studies and case reports on the topic, producing controversial results. We report for the first time a bipolar patient case presenting BP following five-month therapy with risperidone long-acting injectable (LAI). We hypothesize that the dermatological event is associated with the medication administered. The issue emerged during psychiatric consultation and was confirmed by histological examination, direct and indirect immunofluorescence studies, plus positive plasma and cutaneous BP180 and BP230 IgG. Neurodegeneration or neuroinflammation might represent a primary process leading to a cross-reactive immune response between neural and cutaneous antigens and contributing to self-tolerance failure. Furthermore, the time sequence of the shared biological mechanisms leading to clinical manifestations of the neuropsychiatric disorder and BP remains undefined. BP comorbid with bipolar disorder might occasionally represent a serious health risk and affect patients’ physical and psychosocial quality of life. Thus, clinicians treating psychiatric patients should consider BP as a possible adverse effect of psychotropic medications

Brief episodes of silent atrial fibrillation predict clinical vascular brain disease in type 2 diabetic patients

ObjectivesThis study evaluated whether subclinical episodes of atrial fibrillation (AF) were associated with an increased risk of silent cerebral infarct (SCI) and stroke in diabetic patients younger than 60 years who did not have other clinical evidence of AF and cerebrovascular disease at baseline.BackgroundIn type 2 diabetic patients, one-fourth of strokes are of unknown cause, and subclinical episodes of AF may be a common etiologic factor.MethodsA total of 464 type 2 diabetic patients younger than 60 years were included in a longitudinal observational study and matched to patients without diabetes. Patients underwent 48-h electrocardiographic Holter monitoring quarterly to detect brief subclinical episodes of AF (duration of AF <48 h) and were followed up for 37 months. The outcomes were SCI, assessed by magnetic resonance imaging of the brain, and stroke events during the follow-up period.ResultsThe prevalence of subclinical episodes of AF was significantly greater among patients with diabetes compared with matched healthy subjects (11% vs. 1.6%, p < 0.0001). During an average duration of 37 months, 43 stroke events occurred in the diabetic population and no events occurred in healthy subjects. Diabetic patients with silent episodes of AF (n = 176) had a higher baseline prevalence of SCI (61% vs. 29%; p < 0.01) and a higher number of stroke events (17.3% vs. 5.9%; p < 0.01) during the follow-up period than the other patients (n = 288). An episode of silent AF was an independent determinant of SCI (odds ratio: 4.441; p < 0.001; confidence interval: 2.42 to 8.16) and an independent predictor of the occurrence of stroke in diabetic patients (hazard ratio: 4.6; p < 0.01; confidence interval: 2.7 to 9.1).ConclusionsSubclinical episodes of AF occurred frequently in type 2 diabetic patients and were associated with a significantly increased risk of SCI and stroke

Ultrastructural changes in enterocytes in subjects with Hashimoto's thyroiditis

We have recently described1 mucosal ultrastructural impairments, such as height and thickness of microvilli, space between microvilli, and thickness of tight junctions, in non-coeliac type 1 diabetic patients after a preliminary report of an alteration in intestinal mucosal permeability (IP) evaluated by the lactulose/mannitol (LA/MA) test.2,3 Therefore, in the “aetiological” classification of autoimmunity based on initiating factors,4 the category of diet induced diseases could be expanded to include type 1 diabetes and, perhaps, other endocrine autoimmune diseases. Thyroiditis is the most frequently associated autoimmune endocrine disease with type 1 diabetes. Moreover, type 1 diabetes and Hashimoto thyroiditis present similar pathogenetic mechanisms of cellular damage, a cell mediated autoimmunity induced by Th1 cytokines. However, mucosal intestinal morphology and function have not yet been studied in autoimmune thyroiditis patients. Hence we investigated intestinal mucosal ultrastructural morphology and IP in a group of patients with autoimmune thyroiditis. The study was approved by the local ethics committee. Fourteen patients (12 females and 2 males; mean age 33.2 (SD 10.2) years) and 23 controls (12 females and 11 males; mean age 27.9 (SD 8.01) years) were enrolled into the study after giving written informed consent. The diagnosis of autoimmune thyroiditis was based on the following criteria: plasma autoantibody TPO positive at high titre and a typical thyroiditis ultrasound pattern. All patients were in euthyroidism (normal FT3, FT4, and TSH plasma levels without hormonal therapy). Mean duration of known disease was 5.2 (2.5) years. All patients were negative for the presence of antigliadin antibodies IgA and IgG, antiendomysium antibodies IgA, as well as antihuman transglutaminase IgA following a gluten rich Mediterranean diet. Type 1 diabetes mellitus was excluded according to the 1997 American Diabetes Association criteria, and none of the participants had a family history of diabetes mellitus. Other intestinal and endocrine diseases were excluded through clinical and, when indicated, laboratory evaluation. Food or other allergies were excluded. None of the subjects reported gastrointestinal signs or symptoms, or was a habitual smoker, abuser of alcohol, or regularly took non-steroidal anti-inflammatory drugs

Familial Hemophagocytic Lymphohistiocytosis May Present during Adulthood: Clinical and Genetic Features of a Small Series

Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation

Cardiac Hypertrophy: from Pathophysiological Mechanisms to Heart Failure Development

Cardiac hypertrophy develops in response to increased workload to reduce ventricular wall stress and maintain function and efficiency. Pathological hypertrophy can be adaptive at the beginning. However, if the stimulus persists, it may progress to ventricular chamber dilatation, contractile dysfunction, and heart failure, resulting in poorer outcome and increased social burden. The main pathophysiological mechanisms of pathological hypertrophy are cell death, fibrosis, mitochondrial dysfunction, dysregulation of Ca2+-handling proteins, metabolic changes, fetal gene expression reactivation, impaired protein and mitochondrial quality control, altered sarcomere structure, and inadequate angiogenesis. Diabetic cardiomyopathy is a condition in which cardiac pathological hypertrophy mainly develop due to insulin resistance and subsequent hyperglycaemia, associated with altered fatty acid metabolism, altered calcium homeostasis and inflammation. In this review, we summarize the underlying molecular mechanisms of pathological hypertrophy development and progression, which can be applied in the development of future novel therapeutic strategies in both reversal and prevention