Giovanni De Pergola

Obesity as a Major Risk Factor for Cancer

The number of cancer cases caused by being obese is estimated to be 20% with the increased risk of malignancies being influenced by diet, weight change, and body fat distribution together with physical activity. Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal, whereas the less common malignancies are leukemia, non-Hodgkins lymphoma, multiple myeloma, malignant melanoma, and thyroid tumours. To be able to develop novel methods in prevention and treatment, we first must understand the underlying processes which link cancer to obesity. Four main systems have been identified as potential producers of cancer in obesity: insulin, insulin-like growth factor-I, sex steroids, and adipokines. Various novel candidate mechanisms have been proposed: chronic inflammation, oxidative stress, crosstalk between tumour cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and the functional defeat of immune function. Herein, we review the major pathogenic links between obesity and susceptibility to cancer.

Coagulation and fibrinolysis abnormalities in obesity

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-α in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.

Body composition changes in stable-weight elderly subjects: the effect of sex.

Background and aims: Although cross-sectional and longitudinal studies have shown age-related changes in body composition and fat distribution, they may be related to body weight changes. The aim of this study was to evaluate yearly age-related changes in body composition and fat distribution, over a two-year period, in 101 women and 60 men (age range: 68 to 78 years at baseline). Methods: Body composition was evaluated by dual energy X-ray absorptiometry (DXA), and fat distribution by waist and hip circumferences and waist-to-hip circumference ratio. Baseline free testosterone, IGF-1 and serum albumin were evaluated in all subjects, as well as physical activity. Clinical evaluation was performed at baseline and yearly in order to exclude subjects with any condition inducing pathological changes in body composition or fat distribution. Subjects with a weight change >5% of their baseline body weight during the study period, were excluded. Results: Significant increases occurred in Body Mass Index (BMI) (1.18% in women, 1.13% in men), waist (1.75% in women, 1.39% in men), and hip circumference (1.06% in women, 1.31% in men), whereas height decreased significantly in both men (0A2%) and women (0.55%). Significant increases in total body fat (1.31%) and percent body fat (1.27%) were observed in women but not in men. Lean body mass did not change significantly throughout the study in either sex. Significant losses in leg muscle mass and appendicular skeletal muscle mass (ASM), calculated as the sum of arm and leg fat-free soft tissue, were observed in men (respectively 3.56 and 2.77%) and women (respectively 2A1 and 1.59%). A significant decrease in ASM adjusted by stature (ASM/height2), a proposed proxy for sarcopenia, was found in men only (1.97%). The rates of loss in leg muscle mass and appendicular muscle mass were significantly higher in men than in women, even after adjusting for free testosterone, IGF-1, physical activity and serum albumin. Conclusions: These data demonstrate significant changes in body composition and fat distribution in independently living, weight-stable elderly men and women. These changes are dependent on sex and independent of physical activity, hormones or serum albumin.

Inhibitory Effect of Obesity on Gonadotropin, Estradiol, and Inhibin B Levels in Fertile Women

Objective: To examine whether obesity and insulin resistance have an independent effect on the gonadotropin, estradiol, and inhibin B serum levels and follicle count in the early follicular phase of fertile women with a wide range of BMI and without signs of hyperandrogenism.

Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men

The purpose of this study was to examine the relationships between androgenic status and plasma levels of both prothrombotic and antithrombotic factors in men, irrespective of obesity, body fat distribution, and metabolic parameters. Sixty-four apparently healthy men, 40 with a body mass index (BMI) greater than 25 kg/m2 (overweight and obese [OO]) and 24 non-obese controls with a BMI less than 25, were selected and evaluated for (1) plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity, fibrinogen, von Willebrand factor (vWF) antigen, vWF activity, and factor VII (FVII) as the prothrombotic factors; (2) plasma levels of tissue plasminogen activator (TPA) antigen, protein C, and antithrombin III as the antithrombotic factors; (3) fasting plasma concentrations of insulin and glucose and the lipid pattern (triglycerides [TG] and total and high-density lipoprotein [HDL] cholesterol) as the metabolic parameters; and (4) free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) serum levels as the parameters of androgenicity. Body fat distribution was evaluated by the waist to hip ratio (WHR). In OO and non-obese subjects taken together, plasma levels of PAI-1 antigen, fibrinogen, and FVII were inversely associated with FT (r = .255, P < .05, r = -3.14, P < .05, and r = -.278, P < .05, respectively), and the negative relationships of both fibrinogen and FVII with FT were maintained after stepwise multiple regression analysis. Plasma concentrations of PAI-1 antigen and PAI-1 activity were also negatively correlated with SHBG (r = -.315, P < .05 and r = -.362, P < .01, respectively), and these associations held irrespective of the other parameters investigated. None of the antithrombotic and fibrinolytic factors were independently related to serum androgen levels. Subjects with a BMI higher than 25 kg/m2 had higher plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen as compared with non-obese controls (P < .001, P < .001, and P < .01, respectively). In addition, in OO and control subjects as a whole, multiple stepwise regression analysis showed that the associations of BMI with PAI-1 activity, fibrinogen, vWF antigen, and vWF activity were independent of any other metabolic and hormonal parameters. Plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen were also directly correlated with WHR in all subjects taken together, irrespective of the other parameters investigated. Evaluation of antithrombotic factors showed that OO subjects had higher TPA plasma concentrations than non-obese controls (P < .001), whereas protein C and antithrombin III did not differ in the two groups. TPA was also directly correlated with BMI (r = .415, P < .001) and WHR (r = .393, P < .001) in all subjects. The results of this study indicate that (1) men with lower FT serum levels have higher fibrinogen and FVII plasma concentrations, and those with lower SHBG serum levels also have higher levels of PAI-1 antigen and activity; (2) irrespective of other factors, obesity per se may account for higher concentrations of PAI-1, fibrinogen, and vWF; (3) plasma levels of PAI-1 (antigen and activity) and fibrinogen correlate independently with WHR; and (4) among the investigated antithrombotic factors (TPA antigen, protein C, antithrombin III), only TPA antigen plasma concentrations are higher in men with abdominal obesity. Thus, because of the increase in several prothrombotic factors, men with central obesity, particularly those with lower androgenicity, seem to be at greater risk for coronary heart disease (CHD). Apparently, this risk is not counteracted by a parallel increase in plasma concentrations of antithrombotic factors.

Increased carotid IMT in overweight and obese women affected by Hashimoto's thyroiditis: an adiposity and autoimmune linkage?

BackgroundHashimotos thyroiditis is the most important cause of hypothyroidism. It is a systemic disease that can even affect the cardiovascular system, by accelerating the atherosclerotic process. Aim of this study was to examine whether autoimmune thyroiditis has an effect on the intima-media thickness of the common carotid artery (IMT-CCT), independently of the thyroid function and well-known cardiovascular risk factors. Hashimotos thyroiditis is a systemic disease. The aim is to examine whether autoimmune thyroiditis and adiposity can effect carotid IMT independently of thyroid hormones and cardiovascular risk factors.MethodsA total of 104 obese women (BMI ≥ 25.0 kg/m-2), with FT3 and FT4 serum levels in the normal range and TSH levels < 4.5 μU/ml, were investigated. None of these patients was taking any kind of drug influencing thyroid function. Measurements were made of the IMT-CCT, BMI, waist circumference, blood pressure levels, as well as fasting TSH, FT3, FT4, anti-thyroid antibodies, insulin, fasting glycemia, triglycerides, total and HDL-cholesterol serum concentrations.ResultsOf the 104 women, 30 (28.8%) were affected by autoimmune thyroiditis. Significantly higher values of IMT-CCT (p < 0.05), TSH (p < 0.05), and triglycerides (p < 0.05) were obtained, and significantly lower values of FT4 (p < 0.05), in patients with Hashimotos thyroiditis as compared to those with a normal thyroid function. When examining the whole group together, at multiple regression analysis Hashimotos thyroiditis maintained a positive association with the IMT (p < 0.001), independently of age, hypertension, BMI, and the fasting serum levels of TSH, FT3, FT4, insulin, fasting glycemia, triglycerides, total and HDL-cholesterol levels.ConclusionsThe present study shows that Hashimotos thyroiditis is associated to an increased IMT only in overweight and obese, independently of the thyroid function, BMI and cardiovascular risk factors. These results suggest that Hashimotos thyroiditis is a marker of evolution of the atherosclerosis if combined to adiposity.

Carotid artery intima-media thickness: normal and percentile values in the Italian population (camp study)

Aims: Carotid intima-media thickness (IMT) is one of the best non-invasive parameters for evaluating previous vascular lesions and could be used to identify a preclinical stage of the atherosclerotic process. The aim of our research was to develop an epidemiological study of the normal mean values of IMT of the common carotid artery, adjusted for age and sex, in the Italian population. Methods and results: In this multicenter study, a total of 1017 patients (596 males, mean age: 58.5 + 13.2 years) were enrolled at four different Italian centers. Inclusion criteria were the absence of cardiovascular risk factors or presence of not more than one. Patients underwent two-dimensional echo-color Doppler scanning of the carotid arteries, adopting a high-definition vascular echographic apparatus and a 11–3 MHz linear electronic probe. The arithmetical mean of the IMT value was calculated. Data obtained from this study show the carotid IMT changes in relation to age and sex. In particular, it grows higher with increasing age, and is always higher in men than in women. Conclusion: In relation to the percentile distribution of the values in the population analyzed, the normal range of m-IMT could be established just on the basis of the patient’s age and sex. In this way, the ultrasound scan operator can rely on a simple reference scheme. This will help to refine the use of carotid ultrasound as an excellent tool for detecting asymptomatic carotid alterations and patients at high risk for cerebral and cardiovascular disease.

High Systolic Blood Pressure Increases Prevalence and Severity Of Retinopathy in NIDDM Patients

OBJECTIVE To determine whether the severity of retinopathy is higher in a group of NIDDM patients with sBP ≥ 140 mmHg compared with NIDDM patients with sBP < 140 mmHg. RESEARCH DESIGN AND METHODS Ophthalmoscopy and FAG were conducted among a group of NIDDM patients with either a sBP above (n = 54) or below (n = 55) 140 mmHg. The groups were matched according to diabetes duration, metabolic control (HbA1c), and AER. RESULTS Patients with sBP > 140 mmHg had a higher prevalence of retinopathy, as established according to a rating scale (4.9 ± 3.8 vs. 3.2 ± 3.3, P < 0.02); furthermore, their BMI values were higher (28.1 ± 4.5 vs. 24.9 ± 4.1 kg/m2, P < 0.001). The group of normotensive subjects showed the highest rate of low grading (0–2) values. However, the highest prevalence rates of 8–10 grading values (proliferative retinopathy) were found in the hypertensive group. CONCLUSIONS These data suggest that sBP values ≥ 140 mmHg favor the onset of retinopathy in NIDDM patients during their 1st 10 yr of disease.

Morphological and functional vascular changes induced by childhood obesity

Background: To investigate endothelial dysfunction and morphological vascular changes in childhood obesity. Methods: 93 overweight/obese children (body mass index 26 ± 5 kg/m2; median 26 kg/m2; interquartile range 22–28 kg/m2), mean age 10.9 ± 2.7 years, underwent a check-up of total, high-density lipoprotein- and low-density lipoprotein-cholesterol, triglycerides, C-reactive protein, erythrocyte sedimentation rate, and white blood cell count, together with ultrasound measures of flow-mediated dilatation, carotid intima-media thickness, and anterior-posterior diameter of the abdominal aorta. Results: The body mass index of overweight/obese children had a statistically significant linear relationship (p < 0.05) with triglycerides, erythrocyte sedimentation rate, carotid intima-media thickness, anterior-posterior diameter of the abdominal aorta, and flow-mediated dilatation values. Conclusions: Overweight/obese children have an initial endothelial dysfunction and vascular damage, i.e., the first stage in the development of atherosclerosis.

Independent Influence of Insulin, Catecholamines, and Thyroid Hormones on Metabolic Syndrome

The objective of this study was to examine whether metabolic syndrome, defined according to adult treatment panel III criteria, is associated with insulin, catecholamines, and thyroid hormones, independently of age and gender. A cohort of 651 euthyroid overweight and obese patients, 440 women and 211 men, aged 18–68 years, were examined. Central fat accumulation (indirectly measured by waist circumference), fasting thyroid‐stimulating hormone (TSH), FT3, FT4, insulin, glucose, and lipid (cholesterol, HDL‐cholesterol, and triglyceride) serum concentrations, 24‐h urinary catecholamines, and the level of insulin resistance (estimated by homeostasis model assessment for insulin resistance (HOMAIR)) were measured. Patients with metabolic syndrome showed higher insulin (P < 0.001) and FT3 (P < 0.001) serum levels and higher 24‐h urinary noradrenaline (P < 0.001) than subjects without this syndrome. The number of metabolic syndrome parameters was directly associated with insulin (P < 0.001) and FT3 (P < 0.05) serum levels, and with 24‐h urinary noradrenaline (P < 0.001) in the whole population. When a multiple regression analysis was performed with the metabolic syndrome as the dependent variable, and age, gender, and insulin, and TSH, FT3, FT4 serum levels, and 24‐h urinary noradrenaline and adrenaline as independent variables, the metabolic syndrome maintained an independent positive association with age (P < 0.001), male sex (P < 0.001), insulin (P < 0.001), and 24‐h urinary noradrenaline (P < 0.001). In conclusion, this study suggests that insulin and noradrenaline cooperate independently to the development of the metabolic syndrome.