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Aims: We examined the associations between liver volume and other quantitative and qualitative markers of hepatic steatosis with all-cause mortality in the general population., Methods: We included 2769 German middle-aged individuals with a median follow-up of 8.9 years (23,898 person-years). Quantitative markers used were serum liver enzymes and FIB-4 score, while qualitative markers of hepatic steatosis included magnetic resonance imaging (MRI) measurements of liver fat content and total liver volume. Cox proportional hazards models, adjusted for confounding factors, were undertaken to investigate the associations of liver volume and other markers of hepatic steatosis with all-cause mortality., Results: A larger MRI-assessed liver volume was associated with a nearly three-fold increased risk of all-cause mortality (Hazard Ratio = 3.16; 95% confidence interval 1.88; 5.30), independent of age, sex, body mass index, food frequency score, alcohol consumption and education level. This association was consistent in all subgroups considered (men vs. women; presence or absence of overweight/obesity, metabolic syndrome or diabetes). Higher serum liver enzyme levels and FIB-4 score were also significantly associated with higher all-cause mortality in the total population and in all subgroups. No independent associations were found between other quantitative and qualitative markers of hepatic steatosis and the risk of all-cause mortality., Conclusions: We showed for the first time that larger liver volume was associated with a three-fold increase in long-term risk of all-cause mortality. This association remained significant after adjustment for age, sex, alcohol consumption, obesity and other coexisting metabolic disorders., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition characterized by hepatic fat accumulation combined with underlying metabolic dysregulation. Having evolved from the previous term of nonalcoholic fatty liver disease (NAFLD), the term MAFLD more closely implicates the presence of overweight/obesity, type 2 diabetes, or metabolic dysregulation as essential pathogenic factors, leading to better identification of individuals with this metabolic liver disease. Low-grade inflammation, increased oxidative stress, mitochondrial dysfunction, and intestinal dysbiosis are also involved in its pathogenesis. MAFLD is not only associated with liver-related complications, but also with adverse cardiometabolic outcomes. Further studies are needed to assess whether the newly proposed definition of MAFLD is more accurate than the NAFLD in predicting the adverse liver-related and extrahepatic outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The prevalence of nonalcoholic fatty liver disease (NAFLD) is continuing to rise in many countries, paralleling the epidemic of obesity worldwide. In the last years, the concept of metabolically healthy obesity [MHO, generally defined as obesity without metabolic syndrome (MetS)] has raised considerable scientific interest. MHO is a complex phenotype with risks intermediate between metabolically healthy individuals with normal-weight (NWMH) and patients who are obese and metabolically unhealthy (MUO, i.e. obesity with MetS). In this review we aimed to examine the association and pathophysiological link of NAFLD with MHO and MUO. Compared to NWMH individuals, patients with obesity, regardless of the presence of MetS features, are at higher risk of all-cause mortality and cardiovascular events. Moreover, MHO patients have a greater risk of NAFLD development and progression compared to NWMH individuals. However, this risk is generally lower than that of MUO patients, suggesting a stronger adverse effect of coexisting MetS disorders than obesity per se on the severity of NAFLD. Nevertheless, since MHO is a dynamic state (with a significant proportion of MHO subjects progressing to MUO over time) and NAFLD itself may predict the transition from MHO to MUO, we believe that any effort should be made to identify NAFLD in all obese individuals, although they appear to be "metabolically healthy". Future research is needed to better understand the role of NAFLD and other pathogenic factors potentially involved in the transition from MHO to MUO and to elucidate how this transition may affect the presence and severity of NAFLD., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are worldwide public health problems, affecting up to 25-30% (NAFLD), and up to 10-15% (CKD) of the general population. Recently, it has also been established that there is a strong association between NAFLD and CKD, regardless of the presence of potential confounding diseases such as obesity, hypertension and type 2 diabetes. Since NAFLD and CKD are both common diseases that often occur alongside other metabolic conditions, such as type 2 diabetes or metabolic syndrome, elucidating the relative impact of NAFLD on the risk of incident CKD presents a substantial challenge for investigators working in this research field. A growing body of epidemiological evidence suggests that NAFLD is an independent risk factor for CKD and recent evidence also suggests that associated factors such as metabolic syndrome, dysbiosis, unhealthy diets, platelet activation and processes associated with ageing could also contribute mechanisms linking NAFLD and CKD. This narrative review provides an overview of the literature on: a) the evidence for an association and causal link between NAFLD and CKD and b) the underlying mechanisms by which NAFLD (and factors strongly linked with NAFLD) may increase the risk of developing CKD., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Chronic plaque psoriasis is an immune-mediated inflammatory skin disease that is strongly associated with the clinical features of the metabolic syndrome (MetS), including abdominal obesity, hypertension, atherogenic dyslipidemia, type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease. The strength of these associations has been repeatedly confirmed by several observational studies. In particular, the prevalence of MetS in patients with psoriasis ranges from 20% to 50%, with a risk of having MetS is at least double in psoriatic patients compared with nonpsoriatic control individuals. MetS is also more common in patients with severe psoriasis than in those with mild skin disease. Emerging evidence now suggests that psoriasis and MetS share multiple metabolic risk factors, genetic background, and pathogenic pathways. The association between psoriasis and MetS has important clinical implications. Systemic conventional treatments should be used with caution in psoriatic patients with MetS, because they could adversely affect the coexisting metabolic disorders, especially in the case of their chronic use. Biologics appear to have a different safety profile compared with conventional treatments, and so they are usually tolerated. Collectively, dermatologists should pay close attention to the early recognition of coexisting metabolic disorders and give appropriate pharmacologic and nonpharmacologic (hypocaloric diet and regular exercise) recommendations to their patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: A number of clinical studies have demonstrated that leptin concentrations are related to the metabolic disturbances that constitute the metabolic syndrome (MetS) and to diabetes mellitus (DM)., Aim: To investigate possible determinants of leptin concentrations in a sample of patients at high cardiovascular (CV) risk carrying two or more features of the MetS and to investigate if any difference exist between at risk patients with or without DM., Methods: Serum leptin concentrations were measured in 60 consecutive male patients affected by at least two CV risk factors which belong to the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) definition of MetS: 30 patients affected by type 2 DM (T2DM) and 30 nondiabetic patients (non-T2DM). Nineteen healthy subjects were included in the study as a control group (HC)., Results: Leptin was significantly higher in patients carrying two or more features of the MetS compared with HC (P = 0.02). Stratifying MetS patients for DM, we found that leptin level was higher in non-T2DM patients (7.8 ng/ml), intermediate in T2DM (6.2 ng/ml), and lower in HC (4.6 ng/ml). In MetS patients, a positive correlation was found between leptin and waist, triglycerides, and number of MetS criteria. After stratification for T2DM, the correlations were still significant in the non-T2DM but not in the T2DM group., Conclusions: In our sample of moderate-to-high-risk patients, leptin level is positively associated with waist circumference and triglycerides but only in non-T2DM patients. Our data suggest that diabetic subjects could modulate leptin production in a different way compared with patients carrying other MetS-related anomalies., (© 2016 Wiley Periodicals, Inc.)

Background/aims: We examined the relationship between controlled attenuation parameter (CAP) and liver stiffness measurements (LSM), as assessed by transient elastography (TE), and different clinical and biochemical parameters in patients with one or more components of the metabolic syndrome (MetS). The hypothesis of the study was that LSM and CAP values correlate with the number of MetS components., Methods: In this cross-sectional study a total of 648 consecutive patients were recruited during the years 2013-2015. Significant liver steatosis was defined as a CAP value≥238dB/m, whereas significant fibrosis was defined as an LSM value>7.0 kPa., Results: The prevalences of patients with CAP≥238dB/m and LSM>7.0 kPa were 88.3% and 16.5%, respectively. Patients with CAP≥238dB/m (n=572) had a markedly higher prevalence of the MetS and all its individual components, as well as higher levels of serum liver enzymes and uric acid compared with those with normal CAP. Moreover, CAP measurements increased progressively with the number of MetS components. Similarly, among patients with CAP≥238dB/m, those with LSM>7.0 kPa (n=103) had higher serum liver enzymes and a greater prevalence of the MetS and its individual components than those with LSM≤7.0 kPa. In multivariable regression analysis the factors independently associated with elevated CAP were the presence of the MetS (or its individual components), insulin resistance (defined by HOMA-IR score), increased serum uric acid and LSM>7 kPa. Similarly, the MetS (or its individual components), insulin resistance and increased serum uric acid levels were also independently associated with LSM>7.0 kPa., Conclusions: Patients with one or more MetS components have a high prevalence of NAFLD and advanced liver fibrosis. LSM and CAP correlate with the number of MetS components., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aim: The magnitude of the risk of incident type 2 diabetes (T2D) and metabolic syndrome (MetS) among patients with nonalcoholic fatty liver disease (NAFLD) is poorly known. We gauged the risk of developing T2D and MetS in patients with NAFLD diagnosed by either serum liver enzymes (aminotransferases or gamma-glutamyltransferase [GGT]) or ultrasonography., Methods: Pertinent prospective studies were identified through extensive electronic database research, and studies fulfilling enrolment criteria were included in the meta-analysis., Results: Overall, in a pooled population of 117020 patients (from 20 studies), who were followed-up for a median period of 5 years (range: 3-14.7 years), NAFLD was associated with an increased risk of incident T2D with a pooled relative risk of 1.97 (95% confidence interval [CI], 1.80-2.15) for alanine aminotransferase, 1.58 (95% CI, 1.43-1.74) for aspartate aminotransferase, 1.86 (95% CI, 1.71-2.03) for GGT (last vs first quartile or quintile), and 1.86 (95% CI, 1.76-1.95) for ultrasonography, respectively. Overall, in a pooled population of 81411 patients (from eight studies) who were followed-up for a median period of 4.5 years (range: 3-11 years), NAFLD was associated with an increased risk of incident MetS with a pooled relative risk of 1.80 (95% CI, 1.72-1.89) for alanine aminotransferase (last vs first quartile or quintile), 1.98 (95% CI, 1.89-2.07) for GGT, and 3.22 (95% CI, 3.05-3.41) for ultrasonography, respectively., Conclusions: Nonalcoholic fatty liver disease, as diagnosed by either liver enzymes or ultrasonography, significantly increases the risk of incident T2D and MetS over a median 5-year follow-up., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

An improved understanding of non-alcoholic fatty liver disease epidemiology would lead to identification of individuals at high risk of developing chronic liver disease and extra-hepatic complications, thus contributing to more effective case finding of non-alcoholic fatty liver disease among selected groups. We aimed to illustrate the epidemiology of non-alcoholic fatty liver disease in high-risk groups, which were identified based on existing literature. To this end, PubMed was searched to retrieve original articles published until May 2015 using relevant and pertinent keywords "nonalcoholic fatty liver disease" and "diabetes", "obesity", "hyperlipidaemia", "familial heterozygous hypobetalipoproteinaemia", "hypertension", "metabolic syndrome", "ethnicity", "family history" or "genetic polymorphisms". We found that age, sex and ethnicity are major physiological modifiers of the risk of non-alcoholic fatty liver disease, along with belonging to "non-alcoholic fatty liver disease families" and carrying risk alleles for selected genetic polymorphisms. Metabolic syndrome, diabetes, obesity, mixed hyperlipidaemia and hypocholesterolaemia due to familial hypobetalipoproteinaemia are the major metabolic modifiers of non-alcoholic fatty liver disease risk. Compared with these metabolic conditions, however, arterial hypertension appears to carry a relatively more modest risk of non-alcoholic fatty liver disease. A better understanding of the epidemiology of non-alcoholic fatty liver disease may result in a more liberal policy of case finding among high-risk groups., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed worldwide and is strongly associated with the features of metabolic syndrome. In this brief review, we discuss two key questions relating to NAFLD and metabolic syndrome: (1) Does NAFLD predict the development of type 2 diabetes mellitus and metabolic syndrome, or is it simply an epiphenomenon? (2) Are there differences between metabolic syndrome-associated NAFLD and NAFLD associated with genetic variation in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene? Accumulating evidence indicates that NAFLD is not simply the hepatic manifestation of the metabolic syndrome, but is a pathogenic determinant of the syndrome. Genetic variation within the PNPLA3 gene (e.g., I148M homozygosity) confers a higher risk of developing more severe histological features of NAFLD, but a lower risk of developing metabolic syndrome traits. We suggest that future research is now required to elucidate whether both metabolic syndrome-related NAFLD and PNPLA3-related NAFLD produce the same risk of developing extrahepatic complications.

The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: We determined whether non-alcoholic fatty liver is associated with an increased prevalence of chronic kidney disease in Type 1 diabetes., Methods: We studied 343 patients with Type 1 diabetes, who had no history of excessive alcohol consumption or other secondary causes of chronic liver disease. Non-alcoholic fatty liver was diagnosed by ultrasonography. Chronic kidney disease was defined as presence of either abnormal albuminuria (i.e., urinary albumin/creatinine ratio ≥ 30 mg/g) or estimated glomerular filtration rate of less than 60 ml min(-1)  1.73 m(-2) ., Results: Compared with those without steatosis, patients with non-alcoholic fatty liver (n = 182) had significantly lower estimated GFR (83.0 ± 27 vs. 93.3 ± 29 ml min(-1)  1.73 m(-2) , P < 0.001) and a greater prevalence of abnormal albuminuria (50.0 vs. 20.5%, P < 0.0001) and chronic kidney disease (54.4 vs. 24.2%, P < 0.0001). Multivariable logistic regression analysis revealed that non-alcoholic fatty liver was associated with an increased risk of either abnormal albuminuria (adjusted odds ratio 2.21, 95% CI 1.2-4.1, P = 0.01) or chronic kidney disease (adjusted odds ratio 1.93, 95% CI 1.1-3.6, P = 0.02), independently of age, gender, smoking status, physical activity, diabetes duration, HbA(1c) , BMI, systolic blood pressure, plasma lipids and use of anti-hypertensive and lipid-lowering medications., Conclusions: Our findings demonstrate that ultrasound-diagnosed non-alcoholic fatty liver is associated with a higher prevalence of chronic kidney disease in patients with Type 1 diabetes, independently of several risk factors, including the components of the metabolic syndrome., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Background: We assessed the risk of coronary heart disease (CHD) in subjects with metabolic syndrome using different reference categories and focusing on the number of traits in the cluster., Methods: For 15 years, we followed 840 subjects from the general population living in Bruneck, northeastern Italy, aged 40-79 years, without CHD at baseline. Metabolic syndrome was diagnosed at baseline using American Heart Association/National Heart, Lung, and Blood Institute criteria. Subjects with the syndrome were compared to subjects without, as well as to subjects without any metabolic abnormality, using Cox models adjusted for sex, age, smoking, and low-density lipoprotein-cholesterol. There were 89 incident CHD cases., Results: In subjects with the metabolic syndrome, the risk of CHD was1.5-fold higher when subjects without the syndrome were the reference category. CHD risk, however, was 12.5-fold higher (95% confidence interval [CI], 1.7-92.7, P=0.014) when subjects without any metabolic abnormality composed the reference category. As compared to subjects with no abnormalities (who had a trivial number of CHD events), the risk increased from subjects with one (hazard ratio 7.6, 95% CI 1.0-56.5, P=0.047) to those with 2, 3, and 4/5 abnormalities (11.6, 1.6-84.9, P=0.016; 12.9, 1.7-96.0, P=0.013; and 10.1, 1.3-79.2, P=0.028), respectively., Conclusions: When compared to the reference category of people without any metabolic abnormality, those with the metabolic syndrome had high cardiovascular risk. However, in the Bruneck population, the risk of CHD seems to be similar in subjects having two or three to five clinical features of metabolic syndrome. Therefore, the clinical utility of identifying subjects with the syndrome using current diagnostic criteria remains uncertain and might be the focus of further specific studies.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. Increasing recognition of the importance of NAFLD and its association with the features of the metabolic syndrome has stimulated an interest in its putative role in the development and progression of chronic kidney disease (CKD). Accumulating evidence suggests that NAFLD and CKD share many important cardio-metabolic risk factors and common pathogenetic mechanisms and that NAFLD is associated with an increased prevalence and incidence of CKD. This association appears to be independent of obesity, hypertension, and other potentially confounding factors, and it occurs both in patients without diabetes and in those with diabetes. Although further research is needed to establish a definitive conclusion, these observations raise the possibility that NAFLD is not only a marker of CKD but also might play a part in the pathogenesis of CKD, possibly through the systemic release of several pro-inflammatory/pro-coagulant mediators from the steatotic/inflamed liver or through the contribution of NAFLD itself to insulin resistance and atherogenic dyslipidemia. However, given the heterogeneity and small number of observational longitudinal studies, further research is urgently required to corroborate the prognostic significance of NAFLD for the incidence of CKD, and to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. If confirmed in future large-scale prospective studies, the potential adverse impact of NAFLD on kidney disease progression will deserve particular attention, especially with respect to the implications for screening and surveillance strategies in the growing number of patients with NAFLD., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A better knowledge of the biochemical mechanisms implicated in the development and progression of nonalcoholic fatty liver disease, linking fatty liver to insulin resistance and the metabolic syndrome, has shifted the goal of treatment from a mere clearing of fat from the liver to a systematic treatment of metabolic risk factors for fatty liver. Any attempt to modify the "unhealthy" habits responsible for fatty liver requires an integrated approach, based on the cognitive theory of behaviour by a multidisciplinary team including physicians, psychologists, dieticians and physical exercise experts, and recent data demonstrate that this is feasible and effective. Whenever this goal is not attained, a treatment based on insulin-sensitizers remains the best option, to simultaneously tackle all metabolic alterations of the metabolic syndrome. However, in individual patients, both raised blood pressure and dyslipidemia need to be controlled, in order to reduce cardiovascular risk. In these areas, any attempt should be made to use of drugs less likely to induce a deterioration of glucose control. It remains to be determined whether these treatments are able to modify the natural history of nonalcoholic fatty liver disease in the long term., (Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

The metabolic syndrome is a cluster of cardiometabolic risk abnormalities related to atherosclerosis. It represents a public health problem as it affects nearly 20-30% of the general population in various countries. While the metabolic syndrome is a well recognized risk factor for cardiovascular diseases, there is little evidence about its association with venous thromboembolism. In this review, we will summarize the current knowledge on the relationship between the metabolic syndrome and arterial and venous thrombosis from a pathogenic and clinical point of view.

Non-alcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is frequently associated with many features of the metabolic syndrome (MetS). Currently, the importance of NAFLD and its relationship with the MetS is being increasingly recognized, and this has stimulated an interest in the possible role of NAFLD in the development of atherosclerosis. Recent studies have reported the association of NAFLD with multiple classical and non-classical risk factors for cardiovascular disease (CVD). Moreover, there is a strong association between the severity of liver histopathology in NAFLD patients and greater carotid artery intima-media thickness and plaque, and lower endothelial flow-mediated vasodilation (as markers of subclinical atherosclerosis) independent of obesity and other MetS components. Finally, it has recently been demonstrated that NAFLD is associated with an increased risk of all-cause death and predicts future CVD events independently of other prognostic factors, including MetS components. Overall, therefore, the evidence from these recent studies strongly emphasizes the importance of assessing the global CVD risk in patients with NAFLD. Moreover, these novel findings suggest a more complex picture and raise the possibility that NAFLD, as a component of the MetS, might not only be a marker but also an early mediator of CVD.

Aims: To estimate the prevalence of cardiovascular disease (CVD) in Type 2 diabetic patients with and without non-alcoholic fatty liver disease (NAFLD), and to assess whether NAFLD is independently related to prevalent CVD., Methods: We studied 400 Type 2 diabetic patients with NAFLD and 400 diabetic patients without NAFLD who were matched for age and sex. Main outcome measures were prevalent CVD (as ascertained by medical history, physical examination, electrocardiogram and echo-Doppler scanning of carotid and lower limb arteries), NAFLD (by ultrasonography) and presence of the metabolic syndrome (MetS) as defined by the World Health Organization or Adult Treatment Panel III criteria., Results: The prevalences of coronary (23.0 vs. 15.5%), cerebrovascular (17.2 vs. 10.2%) and peripheral (12.8 vs. 7.0%) vascular disease were significantly increased in those with NAFLD as compared with those without NAFLD (P < 0.001), with no differences between sexes. The MetS (by any criteria) and all its individual components were more frequent in NAFLD patients (P < 0.001). In logistic regression analysis, male sex, age, smoking history and MetS were independently related to prevalent CVD, whereas NAFLD was not., Conclusions: The prevalence of CVD is increased in patients with Type 2 diabetes and NAFLD in association with an increased prevalence of MetS as compared with diabetic patients without NAFLD. Follow-up studies are necessary to determine whether this higher prevalence of CVD among diabetic patients with NAFLD affects long-term mortality.

Aims: To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects., Methods: Subjects with the Metabolic Syndrome, defined by WHO criteria, were identified in a large sample of non-insulin-treated Type 2 diabetic patients examined within the Verona Diabetes Complications Study (n = 946). At baseline and after a mean of 4.5 years follow-up, cardiovascular disease (CVD) was assessed by medical history, physical examination, electrocardiogram (ECG) and echo-duplex of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were scrutinized in order to identify CVD deaths. In statistical analyses, CVD was considered as an aggregate end-point, including fatal and non-fatal coronary, cerebrovascular and peripheral vascular disease as well as ischaemic ECG abnormalities and vascular lesions at the echo-duplex., Results: The proportion of subjects with the Metabolic Syndrome was very high (92.3%). At the baseline, 31.7% of subjects were coded positive for CVD, which was more prevalent in subjects with the Metabolic Syndrome (32.9 vs. 17.8%, P = 0.005). Among subjects free of CVD at the baseline (n = 559), CVD events during the follow-up were significantly increased in patients with the Metabolic Syndrome as compared with those without it (19.9% vs. 3.9%, P < 0.001). Multiple logistic regression analysis showed that, along with sex, age, smoking and HbA1c, the presence of the Metabolic Syndrome independently predicted prevalent (OR 2.01, P = 0.045) and incident CVD (OR 4.89, P = 0.031)., Conclusions: In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk.

Aims To compare plasma biomarkers of inflammation and endothelial dysfunction in individuals with and without non-alcoholic hepatic steatosis (HS), and to evaluate whether such differences were mediated by the adverse metabolic pattern, typically found in these subjects. Methods HS (by ultrasound and computed tomography), visceral fat (by computed tomography), insulin resistance (by homeostasis model assessment—HOMA), plasma biomarkers of inflammation and endothelial dysfunction (hs-C reactive protein, fibrinogen, von Willebrand factor, plasminogen activator inhibitor-1 activity) were measured in 100 non-smoking, healthy, male volunteers. Results Plasma hs-CRP, fibrinogen, v-WF and plasminogen activator inhibitor-1 (PAI-1) activity levels were markedly higher ( P < 0.01 or less) in subjects with non-alcoholic HS ( n = 35) than in those without HS ( n = 65). The former also had significantly higher values for body mass index (BMI), visceral fat, diastolic blood pressure, HOMA insulin resistance score, plasma insulin (both fasting and after glucose load), triglycerides, liver enzymes, and lower high-density lipoprotein (HDL)-cholesterol concentration. While the marked differences in these pro-inflammatory biomarkers observed between the groups were little affected by adjustment for age, BMI, blood pressure values, HOMA insulin resistance score, plasma triglyceride and liver enzyme concentrations, they were completely abolished after controlling for visceral fat. Similarly, in multivariate regression analyses, increased visceral fat significantly predicted the pro-inflammatory biomarkers, independently of HS and other potential confounders. Conclusions These results indicate that, in non-smoking, non-diabetic men, the significant increase of plasma biomarkers of inflammation and endothelial dysfunction in the presence of non-alcoholic HS is largely mediated by abdominal visceral fat accumulation. [ABSTRACT FROM AUTHOR]

To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 ± 4 vs. 102 ± 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 ± 2 vs. 14.4 ± 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist–hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations ( P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals. Diabet. Med. 22, 1146 –1150 (2005) [ABSTRACT FROM AUTHOR]