Giovanni Targher

Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.

NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).

Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients.

CONTEXT A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events. OBJECTIVE To assess whether RDW is associated with plasma markers of inflammation since the mechanism(s) underlying this association remain unknown. DESIGN We retrospectively analyzed results of RDW, hemoglobin, mean corpuscular volume, ferritin, high-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in a large cohort of unselected adult outpatients who were consecutively referred by general practitioners for routine medical check-up. RESULTS Cumulative results of RDW and other factors were retrieved from the database of our laboratory information system for 3845 adult outpatients during a 3-year period. When participants were grouped according to RDW quartiles, there were strong, graded increases of ESR and hsCRP (P < .001), both parameters being up to 3-fold higher in the fourth versus the first quartile. Accordingly, the percentages of those with hsCRP greater than 3 mg/L (from 28% to 63%; P < .001) and ESR greater than 40 mm/h (from 8% to 40%; P < .001) increased steadily across RDW quartiles. In multivariable regression analysis, ESR and hsCRP predicted RDW independently of age, sex, mean corpuscular volume, hemoglobin, and ferritin. CONCLUSIONS To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors. If confirmed in future follow-up studies, this association might provide a rationale to introduce the easy, inexpensive RDW in algorithms for cardiovascular risk prediction.

25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey

OBJECTIVE Serum 25-hydroxyvitamin D [25(OH)D] levels are inversely associated with important cardiovascular disease (CVD) risk factors. However, the association between 25(OH)D levels and prevalent CVD has not been extensively examined in the general population. METHODS We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) and examined the association between serum 25(OH)D levels and prevalence of CVD in a representative population-based sample of 16,603 men and women aged 18 years or older. Prevalence of CVD was defined as a composite measure inclusive of self-reported angina, myocardial infarction or stroke. RESULTS In the whole population, there were 1308 (8%) subjects with self-reported CVD. Participants with CVD had a greater frequency of 25(OH)D deficiency [defined as serum 25(OH)D levels <20 ng/mL] than those without (29.3% vs. 21.4%; p<0.0001). After adjustment for age, gender, race/ethnicity, season of measurement, physical activity, body mass index, smoking status, hypertension, diabetes, elevated low-density lipoprotein cholesterol, hypertriglyceridemia, low high-density lipoprotein cholesterol, chronic kidney disease and vitamin D use, participants with 25(OH)D deficiency had an increased risk of prevalent CVD (odds ratio 1.20 [95% confidence interval (CI) 1.01-1.36; p=0.03]). CONCLUSIONS These results indicate a strong and independent relationship of 25(OH)D deficiency with prevalent CVD in a large sample representative of the US adult population.

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

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.

The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study

Aims  To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects.

Serum 25‐hydroxyvitamin D3 concentrations and carotid artery intima‐media thickness among type 2 diabetic patients

Objective  To estimate the prevalence of hypovitaminosis D among type 2 diabetic adults and to assess the relationship between hypovitaminosis D and intimal medial thickening (IMT) of the common carotid artery, a marker of preclinical atherosclerosis.

Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis

BACKGROUND/AIMS Non-alcoholic fatty liver disease (NAFLD) and chronic plaque psoriasis are both associated with metabolic syndrome and increased risk of incident cardiovascular disease. We assessed the frequency and characteristics of NAFLD in patients with chronic plaque psoriasis. METHODS One hundred and thirty consecutive patients with chronic plaque psoriasis and 260 apparently healthy controls matched for age, sex and body mass index were enrolled. NAFLD was diagnosed by abdominal ultrasound after excluding other secondary causes of chronic liver disease. RESULTS The frequency of NAFLD was remarkably greater in psoriasis patients than in controls (47% vs. 28%; p<0.0001). Patients with psoriasis and NAFLD (n=61) were more likely to have metabolic syndrome and had higher serum C-reactive protein concentrations and greater severity of psoriasis according to the Psoriasis Area and Severity Index (PASI) score (14.2+/-12.6 vs. 9.6+/-7.4; p<0.01) than those with psoriasis alone (n=69). In a subgroup of psoriasis patients (n=43), those with NAFLD (n=21) also had significantly higher serum interleukin-6 and lower serum adiponectin levels. Notably, in multivariate regression analysis, NAFLD was associated with higher PASI score independently of age, gender, body mass index, psoriasis duration, and alcohol consumption. CONCLUSIONS NAFLD is frequent in patients with chronic plaque psoriasis - affecting up to nearly half of these patients - and is strongly associated with psoriasis severity. Early recognition of NAFLD by radiological imaging tests in this group of patients is warranted.

Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease

Objectives  To explore associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease (NAFLD).

The paradoxical relationship between serum uric acid and cardiovascular disease.

Uric acid (urate), an organic compound comprised of carbon, nitrogen, oxygen and hydrogen, is the final oxidation product of purine catabolism in humans, higher primates and in a particular species of dog (Dalmatians). For decades it has been hypothesized that the antioxidant properties of uric acid might be protective against aging, oxidative stress, and oxidative cell injury. However, recent epidemiological and clinical evidences suggest that hyperuricaemia might be a risk factor for cardiovascular disease, where enhanced oxidative stress plays an important pathophysiological role. It has also been hypothesized that hyperuricaemia might be involved in chronic heart failure and metabolic syndrome. The apparent paradox between protective and toxic effects is supported by clinical evidences that antioxidant compounds may become pro-oxidant compounds in certain situations, particularly when they are present in blood at supranormal levels. The aim of this article is to review uric acid metabolism and physiology, highlighting its association with cardiovascular disease.

Intimal-Medial Thickness of the Carotid Artery in Nondiabetic and NIDDM Patients: Relationship with insulin resistance

OBJECTIVE The aim of this study was 1) to compare intimal-medial thickness (IMT) of the carotid artery in nondiabetic and NIDDM patients and 2) to evaluate the association of this early marker of atherosclerosis with several cardiovascular risk factors, including plasma insulin and insulin resistance. RESEARCH DESIGN AND METHODS A total of 58 nondiabetic and 56 NIDDM patients, randomly selected among those attending the outpatient Diabetes Clinic or the Clinic for Internal Medicine were examined. BMI, waist-to-hip ratio (WHR), blood pressure, glycohemoglobin (HbA1c), and fasting concentrations of plasma glucose, serum lipids (total and HDL cholesterol, triglycerides), and serum insulin were measured. Insulin resistance was assessed by computing glucose disappearance rate from plasma after intravenous insulin injection (Kitt). IMT of the carotid artery was measured by ultrasonography. RESULTS IMT was significantly higher in diabetic patients, and the difference remained highly significant after adjusting for sex, age, BMI, WHR, presence of hypertension and dyslipidemia, and smoking status (1.39 vs. 1.24 mm, common SD 0.12, P < 0.001). Univariate regression analyses showed that IMT was negatively correlated with Kitt in either nondiabetic (r = −0.348, P < 0.01) or diabetic patients (r = −0.492, P < 0.001). However, multiple regression analyses showed that IMT was independently associated with age and WHR in nondiabetic subjects, whereas in diabetic patients, IMT was independently predicted by Kitt and hypertension. These two variables explained ∼ 62% and ∼35% of the variability of IMT in nondiabetic and diabetic patients, respectively. Plasma insulin was not independently associated with IMT in either groups. CONCLUSIONS These results indicate that 1) diabetes is characterized by a greater thickness of the carotid artery independently of other established risk factor of atherosclerosis, 2) early atherosclerosis is independently associated with insulin resistance in diabetic but not in nondiabetic patients, 3) central adiposity is an independent predictor of IMT in nondiabetic individuals.