Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most ...common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher (∼70–80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is ...considered the hepatic component of the metabolic syndrome and insulin resistance represents its pathophysiological hallmark. Insulin resistance in NAFLD is characterized by reduced whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanism(s) underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Liver fat is highly correlated with all the components of the metabolic syndrome, independent of obesity, and NAFLD may increase the risk of type 2 diabetes and atherosclerosis. Overproduction of glucose, very low-density lipoproteins, C-reactive protein and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease. The reason(s) why some patients will develop NASH are poorly understood. Circulating free fatty acids may be cytotoxic by inducing lipid peroxidation and hepatocyte apoptosis. Insulin resistance is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes may contribute liver damage and liver disease progression. Understanding the molecular mediators of liver injury would promote the development of mechanism-based therapeutic interventions. This article briefly summarizes the recent advances in our understanding of the relationship between NAFLD/NASH, insulin resistance and the metabolic syndrome.
Summary
Background
Non‐alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of clinical conditions, actually representing an emerging disease of great clinical interest. Currently, its ...diagnosis requires liver biopsy, an invasive procedure not free from potential complications. However, several non‐invasive diagnostic strategies have been proposed as potential diagnostic alternatives, each with different sensitivities and accuracies.
Aim
To review non‐invasive diagnostic parameters and tools for NAFLD diagnosis and to formulate a diagnostic and prognostic algorithm for a better classification of patients.
Methods
A literature search was carried out on MEDLINE, EMBASE, Web of Science and Scopus for articles and s in English. The search terms used included ‘NAFLD’, ‘non invasive method and NAFLD’, ‘transient elastography’ and ‘liver fibrosis’. The articles cited were selected based on their relevancy to the objective of the review.
Results
Ultrasonography still represents the first‐line diagnostic tool for simple liver steatosis; its sensitivity could be enhanced by the complex biochemical score SteatoTest. Serum cytokeratin‐18 is a promising and accurate non‐invasive parameter (AUROCs: 0.83; 0.91) for the diagnosis of non‐alcoholic steatohepatitis (NASH). The staging of liver fibrosis still represents the most important prognostic problem: the most accurate estimating methods are FibroMeter, FIB‐4, NAFLD fibrosis score (AUROCs: 0.94; 0.86; 0.82) and transient elastography (AUROC: 0.84–1.00).
Conclusions
Different non‐invasive parameters are available for the accurate diagnosis and prognostic stratification of non‐alcoholic fatty liver disease which, if employed in a sequential algorithm, may lead to a reduced use of invasive methods, i.e. liver biopsy.
The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes.
Besides health monitoring, a regular check of dairy ...heifers' growth rate is desirable, but it is rarely done because procedures that require restraint and handling can be associated with substantial stress for both animals and farmers. Inexperienced heifers, especially if they are highly responsive to humans, may find restraint and handling potentially aversive. This study investigated whether training heifers of different age and responsiveness toward humans (RTH), through operant conditioning, could reduce stress in animals, ease close contact and handling, and be feasible in terms of farmers' effort. We assessed 60 Holstein heifers of 2 age classes (young, n = 29, 291 ± 39 d; old, n = 31, 346 ± 62 d) according to the avoidance distance test and classified them as confident (n = 20), neutral (n = 21), or nonconfident (n = 19). Half of the heifers of each age and RTH class were trained (n = 29), whereas the other half was not (n = 31). The trained heifers were subjected to target training for 8 sessions and positively reinforced with feed to allow being touched on the muzzle, rump, and perineum. If a heifer refused positive reinforcement, the trainer stepped back as negative reinforcement. In the last week of the experiment, the effect of training on the reaction to handling was assessed in all heifers. We measured heart rate, root mean square of successive interbeat interval differences (RMSSD), and fecal cortisol metabolites (FCMet). The presence of behavioral distress signs was recorded as well. The avoidance distance test was performed a second time 24 h after the measuring session. All of the trained heifers, regardless of RTH class, successfully accomplished the target training task in 6 sessions, each spending on average 25.3 s per session. All of the trained heifers allowed touches on the rump and perineum at the end of the fourth session. Training nonconfident heifers required more time compared with the others. Trained heifers showed higher RMSSD than nontrained heifers (14.2 vs. 16.9 ms, respectively), indicating a lower vagal tone, and thus, a slightly lower stress level than nontrained heifers. Training did not lead to differences in HR, FCMet, or presence of stress behavioral signs. Nonconfident heifers had the highest mean baseline FCMet values compared with neutral and confident heifers (38.4 vs. 30.3 vs. 29.1 ng/g, respectively). Nonconfident heifers also showed the lowest value of FCMet 12 h after the measuring session (36.7 vs. 44.6 vs. 49.7 ng/g), likely due to a decreased responsiveness of the adrenal gland to a stressor. The average avoidance distance decreased between the beginning and the end of the experiment, especially for neutral and nonconfident heifers, regardless of whether they were trained or not. These results show how using operant conditioning on some heifers not only decreased their vagal tone, but also reduced the responsiveness to humans of all the animals, trained and not trained; in the latter case, this reduction was through nonassociative learning, such as habituation.
Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) have consistently demonstrated a clinically significant reduction of cardiovascular mortality. However, their safety in clinical practice is ...still incompletely characterized, and post-marketing monitoring is required considering the expected increase in clinical use. Different analyses of international spontaneous reporting systems, known as disproportionality analyses (DAs), have highlighted the occurrence of ketoacidosis, amputations, acute renal failure and skin toxicity.
In this viewpoint, we critically appraise these pharmacovigilance data on SGLT2-Is, with the aim of supporting clinicians in proper interpretation of these studies, and discussing their risk-benefit profile. To this aim, we offer a broad perspective on basic technical aspects subtending DAs of spontaneous reporting databases (describing peculiarities of the Food and Drug Administration Adverse Event Reporting System), their common and evolving uses, key pitfalls in presenting study results (in terms of “risk” or “association”) and relevant strategies to account for major confounders. This will also facilitate reviewers and editors in proper evaluation of DAs, and prompt pharmacovigilance experts in converging towards a set of minimum requirements in standardization of design, performance and reporting of DAs. A consensus on quality assessment of DAs will finally establish their transferability to clinical practice. It is anticipated that DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient.
Abstract Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. Over the last 10 ...years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes.
Summary
Background
Sarcopenia recognises insulin resistance and obesity as risk factors, and is frequently associated with cardiometabolic disorders, including non‐alcoholic fatty liver disease ...(NAFLD).
Aim
To test the prevalence of sarcopenia and its relation with the severity of fibrosis (main outcome) and the entire spectrum of liver histology in patients with NAFLD.
Methods
We considered 225 consecutive patients with histological diagnosis of NAFLD (Kleiner score). The skeletal muscle index (%) (total appendicular skeletal muscle mass (kg)/weight (kg) × 100), a validated measure of sarcopenia, was assessed by bioelectrical impedance analysis. Sarcopenia was defined as a skeletal muscle mass index ≤37 in males and ≤28 in females.
Results
The prevalence of sarcopenia showed a linear increase with the severity of fibrosis, and severe fibrosis (F3–F4) was more than doubled in sarcopenia (48.3% vs. 20.4% in fibrosis ≤F2, P < 0.001). After adjusting for confounders, the association of sarcopenia with severe fibrosis was maintained (OR 2.36, CI 1.16–4.77, P = 0.01), together with age > 50 (OR 6.53, CI 2.95–14.4, P < 0.001), IFG/Diabetes (OR 2.14, CI 1.05–4.35, P = 0.03) and NASH (OR 13.3, CI 1.64–108.1, P = 0.01). Similarly, a significant association was found between sarcopenia and NASH (P = 0.01), steatosis severity (P = 0.006), and ballooning (P = 0.01), but only the association with severe steatosis was maintained (OR 2.02, CI 1.06–3.83, P = 0.03) after adjusting for confounders.
Conclusions
In Western patients with NAFLD, with high prevalence of metabolic disorders and advanced liver disease, sarcopenia was associated with the severity of fibrosis and steatosis, independently of hepatic and metabolic risk factors. Studies are needed to assess the impact of interventions to reduce sarcopenia on NAFLD progression.
Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin-resistance syndrome, at present defined as the metabolic syndrome, whose limits were recently set. We assessed the ...prevalence of the metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes, on the basis of 3 or more criteria out of 5 defined by the U.S. National Institutes of Health (waist circumference, glucose, high-density lipoprotein HDL-cholesterol, triglycerides, and arterial pressure). The prevalence of the metabolic syndrome increased with increasing body mass index, from 18% in normal-weight subjects to 67% in obesity. Insulin resistance (Homeostasis Model Assessment method) was significantly associated with the metabolic syndrome (odds ratio OR, 2.5; 95% CI, 1.5-4.2;
P < .001). Liver biopsy was available in 163 cases (54%). A total of 120 patients (73.6%) were classified as having nonalcoholic steatohepatitis (NASH); 88% of them had a metabolic syndrome (vs. 53% of patients with pure fatty liver;
P < .0001). Logistic regression analysis confirmed that the presence of metabolic syndrome carried a high risk of NASH among NAFLD subjects (OR, 3.2; 95% CI, 1.2-8.9;
P = .026) after correction for sex, age, and body mass. In particular, the syndrome was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1-11.2;
P = .032). In conclusion, the presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease. The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades. (H
epatology 2003;37:917-923.)
Purpose
To investigate the impact of diabetes in immigrants on the Italian healthcare system, as well as their compliance with standard protocols of control and treatment.
Methods
The prevalence of ...immigrants with diabetes living in the metropolitan area of Bologna (about 1 million inhabitants) in 2019 was investigated using a database containing all subjects in active follow-up for diabetes, based on antidiabetic drug use, disease-specific copayment exemption, ICD-9 codes, continuous care in diabetes units. Country of origin was derived from fiscal code.
Results
The overall prevalence of diabetes (n = 53,941; 51.8% males, median age 64) was 6.1% in both Italy-born and immigrant cohorts. Immigrant prevalence was 12.4%, moderately higher than that observed in the total population (12.2%). Diabetes risk was increased in the whole immigrant cohort (odds ratio (OR) 1.74; 95% Confidence Interval (CI) 1.69–1.79). Among cases with incident diabetes, the proportion of immigrants (median age, 49 vs. 65 in Italy-born individuals) increased progressively from 11.7% to 26.5% from 2011 to 2019 (males, 8.9–21.0%; females, 14.9–32.8%) in all age groups, particularly in young adults, but also in older subjects. Metabolic control was lower in immigrants, as was adherence to shared diagnostic and therapeutic protocols, without systematic differences in antidiabetic drug use, but much lower use of drugs for comorbid conditions.
Conclusions
The population with diabetes in the metropolitan area of Bologna is rapidly changing. Quality improvement initiatives are needed to reduce the burden for the universalistic Italian health care system generated by the rapidly-growing high-risk immigrant population.
Summary
Background
Blood tests of liver injury are less well validated in non‐alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis.
Aims
To improve the validation of ...three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading.
Methods
We pre‐included new NAFLD patients with biopsy and blood tests from a single‐centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary‐ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing.
Results
A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05).
Conclusions
In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non‐invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis.
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