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Obesity: A preventable, treatable, but relapsing disease
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Obesity: a preventable, treatable, but relapsing disease. A. De Lorenzo , L. Romano , L. Di Renzo , N. Di Lorenzo , G. Cenname , P. Gualtieri PII: DOI: Reference:
S0899-9007(19)30198-4 https://doi.org/10.1016/j.nut.2019.110615 NUT 110615
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Nutrition
Received date: Revised date: Accepted date:
4 June 2019 19 August 2019 5 October 2019
Please cite this article as: A. De Lorenzo , L. Romano , L. Di Renzo , N. Di Lorenzo , G. Cenname , P. Gualtieri , Obesity: a preventable, treatable, but relapsing disease., Nutrition (2019), doi: https://doi.org/10.1016/j.nut.2019.110615
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Highlights The spread of primary obesity is pandemic, like an infectious disease The expansion of visceral fat plays role in the metabolic and functional alterations Poor nutrition is represented by the typical foods of the Western Diet Obesity and poor nutrition deaths were around 11 million only in 2017 The stigma of fat is pervasive and results in "fat-shaming"
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Obesity: a preventable, treatable, but relapsing disease. A. De Lorenzo1, L. Romano1,2, L. Di Renzo*1, N. Di Lorenzo3, G. Cenname4, P. Gualtieri1 1
Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of
Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. 2
School of Specialization in Food Sciences, University of Rome Tor Vergata, Rome, Italy.
3
Department of Surgical Sciences, University of Tor Vergata, Policlinico Tor Vergata, Rome, Italy.
4
Comando Generale Arma Carabinieri, Direzione di Sanità, Italy.
*Corresponding Author: Laura Di Renzo Email:[email protected]; Phone: +390672596855.
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Abstract: In 2013, the American Medical Association completing the recognition of obesity as a disease, led to a growing scientific, social and political interest. In 2016 in the United States, prevalence rates of pre-obesity and obesity exceeded 60%, also in Italy they exceeded 40%. Total costs related to excess weight reached 9.3% of US gross domestic product, while in Italy only the total cost of diabetes was estimated at 20.3 billion euros/year. The expansion of adipose tissue and visceral fat causes compression, joint stress, metabolic disorders, organ dysfunction and increased mortality. The increase in peripheral and central fat mass is a chronic and potentially reversible process with appropriate diagnosis and treatment. Conversely, fattening can turn in chronic relapsing form, complicated by comorbidities and cardiovascular events. The increased risk of mortality and morbidity can also affect metabolically healthy obese subjects, if the condition is underestimated, with disease progression. Due to BMI inaccuracy, it must be replaced with the body composition for obesity diagnosis. The chances of obesity reversibility are closely linked to improving the diagnosis and timely nutritional interventions. Generalization and stigma hinder the treatment of the obese. The recognition of obesity as a disease and institutional interest can shift the focus on obesity and not on the obese, with improvements in adherence to prevention plans. Anthropogenic factors and gut microbiota can influence the human behavior and food choice, such as food addiction. Obesity has all the criteria to be recognized as a disease. Proper clinical management will lead to cost and complications savings, such as diabetes.
Keywords: Obesity; Adiposopathy; Stigma; Body Composition; Disease; Diabetes.
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Introduction In the process of recognition of primary obesity as a disease, milestones were the declarations of the National Institute of Health in 1998, by The Obesity Society, of the American Obesity Society in 2008 and of the American Medical Association (AMA) in 2013. Since 2013, the scientific, political and social interest in the "obesity disease" has grown [1]. A new concept emerges, primary obesity must be considered a social disease, with overcoming of stigma, discrimination and generalization. The spread of primary obesity is pandemic, like an infectious disease [2-3]. For this reason, a preventive policy in childhood, an increasingly stricken population, can act as a vaccination campaign. This in order to limit the spread, raise public awareness and reduce prevalence in adulthood [4]. Currently, primary obesity is no longer a symbol of power and well-being, but a disease of low-income people. In fact, the subjects with a higher qualification and with a high social class have a lower incidence of primary obesity. Today, the high diffusion of low-priced junk food, qualitatively poor, taste and rich in calories is one the causes of obesity [5]. Nowadays, many scientific societies from all over the world have presented various position statements on this argument and also several authors have produced reviews to support this thesis. Again in 2018, The Obesity Society presented its position on primary obesity as a chronic disease, overcoming the previous definitions. [6] Even if the public authority of drug control (Food and Drug Administration and European Medicines Agency) has approved the marketing for the pharmacological treatment of obesity, obesity itself has not been overall recognized as a disease [7]. Erroneously, some authors identify obesity only as a risk factor, similarly to the metabolic syndrome (MS). In fact, MS is a risk factor and it does not have an approved pharmacological therapy. The results on diabetes reversion of the DiRECT study indicate a possible path to follow in the reactive and preventive medicine. Indeed, obese patients achieved a diabetes reversion with only 8 weeks of caloric restriction. It's highlighted that dietary and lifestyle interventions must have the same space as drugs in the treatment of obesity related disease. [8-9]. Health systems and scientific societies should get this knowledge to anticipate therapies and achieve a reversibility of diabetes and obesity. Also, in medical oncology the misclassification of obesity and the discrepancy between the diagnosis and the definition cause difficulties for the doctor. Also in medical oncology the misclassification of obesity and the discrepancy between the diagnosis and the definition cause difficulties for the doctor. Only with Body Mass Index (BMI), using weight and height, it is not possible to appreciate the complex changes in the cancer patient. In oncology, the adiposity excess, associated with sarcopenia, is often hidden by BMI. This leads to a delay in diagnosis, complicates the prevention process and weakens some therapies [10]. 4
The purpose of this work will be to discuss in detail the criteria for defining step by step primary obesity as a disease. In fact, it is urgent to recognize obesity as a disease in order to prevent comorbidities and health expenditure. So far argued.
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Epidemiology and costs After the AMA's recognition of the disease, there has been a growing interest in obesity. This led to the carrying out of studies on the epidemiological and economic impact of excess weight, classified according to the BMI. In 2016, in the United States (US), adult obesity rates reached 36.2%, those overweight 67.9%, while in 1975 obesity did not exceed 11.9%. Dramatically, in the pediatric and adolescent population, the prevalence rate of obesity reached 21.4% [11]. The annual medical care cost for obese and pre obese was around 2000 dollars, for a total of more than 1 trillion dollars at national level, equal to 9.3% of gross domestic product [12, 13]. In 2016, In Italy, data show a prevalence of obesity equal to 19.4%, while pre-obese people were equal to 58.5% [11]. Costa de Miranda et al [14] have shown that in one of the most affected regions of Italy from obesity the prevalence of children with excess weight is similar to that in the US. Given the absence of official data on spending in Italy due to obesity, in 2015, it was estimated that all excess weight related cost amounted to 4% of total health care expenditure of the Italian national health service, about € 4.5 million/year [15]. The costs reported are underestimated due to the misclassification of BMI, which underestimates the real prevalence of obesity in the population [16]. Obesity is a disease with a higher mortality rate, but it is preventable and reversible. Spending on the co-morbidities and complications of cardiovascular disease, depended on obesity, represents an expenditure and a failure of clinical management. In fact, an estimate of the direct and indirect costs deriving from the diabetes is € 20.3 billion / year. [17] This economic data and the misclassification of obesity must warn about the real costs related to obesity in Italy. The screening and prevention policies and strategies have proved effective for health and economic savings. The initial cost of prevention campaigns, the training of specialists, the promotion of healthy eating and the production of quality food should not block these interventions. Savings and health benefits will be rewarded over the long term [18].
Evolution and natural history of the disease The expansion and visceral spill-over of fat mass leads to an alteration of homeostasis and causes a dysfunction in the organs [19]. The adaptation to the expansion is potentially reversible if obesity is correctly diagnosed and treated. In contrast, the expansion tends to assume a chronic-relapsing trend with a reduction in life expectancy [20]. The expansion of visceral fat, in particular of omentum and mesentery, causes metabolic alterations and increased intra-abdominal pressure may increase the risk of esophageal reflux. At the same time, the adipose tissue, surrounding the kidneys and vessels, contributes to hypertension. Therefore, the increase fat in the soft tissues of the pharynx can contribute to the obstruction of the respiratory tract. Finally, the increase in weight 6
related to excess fat causes damage to the joints, predisposing to osteoarthritis [21]. Depending on the degree of the expansion specific alteration of the anthropometric and biochemical parameters are observable. Overall, the fat distribution rather than quantity is crucial in the development of obesity-associated abnormalities. In particular, the expansion of visceral and abdominal fat plays a primary role in the metabolic and functional alterations [20]. Prodromal phase In the first phase, a peripheral accumulation of adiposity is observed due to a calorie intake higher than total energy expenditure. At the same time, low-grade inflammation and systemic homeostasis are present [22]. Before the appearance of metabolic alterations, the accumulation of adipose tissue involves functional limitations like increased tissue friction, joint stress, soft tissue compression with consequent sleep apnea and gastroesophageal reflux [23]. This phase and the complications already mentioned are to be considered fully reversible. Intermediate phase The fat accumulated in the organs is known as ectopic fat. This is the result of lipotoxicity, with spill-over of excess fat in the visceral districts. The ectopic deposition can determine adiposopathy, dysfunctional alteration of the adipose tissue and of the affected tissues or organs [24]. There is also an increase in adipokines and inflammatory cytokines, a metabolic inflexibility, an altered metabolism of triglycerides and carbohydrates, which produces insulin resistance and an increase in oxidative stress. In the intermediate phase, adiposopathy involves a breakdown of homeostasis and predisposes to the presence of co-morbidities, such as diabetes, hypertension and dyslipidemia [25]. This phase and its complications are reversible. Last phase The chronic expansion of fat mass, the accumulation of damage caused by adiposopathy and the comorbidities lead to a greater risk of cardiovascular events [26]. At the occurrence of a major complication the risk of mortality increases, aggravated by all functional limitations and comorbidities. After a cardiovascular event, the obese and complicated patient is fragile and limited in the daily life activities [27]. Unfortunately, the outcomes of major complications are not reversible. Recognition of reversible conditions and tertiary prevention of major complications are essential for the recovery of quality of life [28]. Metabolically healthy obese patients are in a reversible condition but, if not recognized at this stage, the degree of pathology and risk persists.
The pathophysiology of obesity 7
Obesity is a clinical condition that manifests itself with the excess of subcutaneous and/or visceral fat mass. It is frequently associated with weight gain but can also occur in normal weight subjects. With a limited frequency it is associated with osteopenia and sarcopenia. Obesity is a multifactorial disease. Furthermore, the excess of weight in childhood predisposes to a greater risk of obesity in adulthood. In particular, adiposity rebound, i.e. The increase in BMI starting between 5-7 years, exposes to a greater risk of obesity and metabolic syndrome [29, 30]. The main cause of primary obesity is the combination between excessive intake of unhealthy foods, "poor nutrition", reduced physical activity, alteration of the microbiome, congenital alterations, genetic susceptibility and epigenetic alterations. Primary obesity is distinguished from the rare monogenic forms of obesity, determined by the mutation of a key gene in weight regulation, despite having a polygenic base. Unlike monogenic forms, in primary obesity different polymorphisms can be present, i.e. singlenucleotide polymorphisms, predisposing to obesity [31]. The primary obesity
Poor nutrition is represented by the typical foods of the Western Diet. These are poor in micronutrients, antioxidants and polyphenols, highly processed and calorie dense, contain environmental (persistent organic pollutants, glyphosate, bisphenols, anthropogenic and endocrine disruptors) and process (acrylamide, furosine, advanced glycation end-products) contaminants [32, 33].
Physical activity is reduced by a sedentary lifestyle, depression, mood alteration, neuroinflammation, hyperalgesia and reduction of functional biomechanical reserves due to the expansion of adipose tissue [34].
The alteration of the microbiota occurs with an imbalance of the intestinal flora, a reduction of the variability of the species and an increase of the firmicutes with respect to the bacteroidetes [35]. This leads to a disruption in the intestinal permeability (Leaky Gut Syndrome), the increase in energy extracted from food and the induction of changes in food choices [36].
Congenital alterations, predisposing to obesity, occur from "poor nutrition", the mother's incorrect lifestyles and exposure to contaminants during pregnancy [37].
The genetic susceptibility, represented by the individual's genotype, determines the predisposition to the development and maintenance of obesity in the interaction with environmental and social factors [38].
Epigenetic alteration represents all the changes that the environment, lifestyle, diet, parents and social factors, can determine on gene expression, with the possibility of increasing the
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predisposition of the subject to become obese in the absence of gene mutations/polymorphisms [39,40].
Obesity-associated abnormalities In primary obesity, it is possible to find specific abnormalities [41]:
Neuropsychological: neuroinflammation; reduction of brain volume; depression; mood alteration; modification of the processes of gratification / reward up to the development of food addiction; neuropathy; development of eating disorders [42, 43].
Pneumological: spirometry alterations, with reduction of vital capacity and expiration indices; hypercapnia tendency to alter the respiratory quotient. Hypoventilation syndromes (eg Pickwick's syndrome); asthma, chronic respiratory infections; oropharyngeal anomalies; Obstructive Sleep Apnea Syndrome (OSAS) [45, 46].
Digestive: alteration of buccal health with cariogenic disease and periodontitis for oral dysbiosis; gastroesophageal reflux diseases; esophageal hernia; dyskinesias; biliary lithiasis; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; colitis from dysbiosis; the small intestinal bacterial overgrowth (SIBO) with leaky gut syndrome; inflammatory bowel diseases (IBD); fissures; hemorrhoids [47].
Metabolic: insulin resistance, hyperinsulinemia, hyperglycemia, hypertriglyceridaemia, hypercholesterolemia, hypoalphalipoproteinemia, hyperuricaemia, gout, hypercortisolemia, metabolic syndrome [48].
Fertility: Early menarche, menstrual irregularities, feminization due to metabolic alteration; sub-fertility/infertility of male and female; Male obesity secondary hypogonadism (MOSH); PolyCystic Ovary Syndrome (PCOS); erectile dysfunction [49,50].
Pregnancy: aggravation of latent hypertension, preeclampsia, gestational diabetes, increased maternal mortality [51].
Dermatological: increased susceptibility to skin infections; discoloration; dystrophies; nail mycosis; inverse psoriasis [52].
Rheumatological and immunological: chronic inflammation with increased inflammation rates; arthrosis; mechanical arthropathy, increased susceptibility to virus and reduction of immune system resilience [53].
Oncological: increase of the general risk to malignant tumor, in particular cancers of the colonrectum, liver. In women increase also the risk to breast and endometrium cancers [54].
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Cardiological: arterial hypertension, atherosclerotic disease, cardiovascular disease, stroke, venous insufficiency and arteriopathies, heart failure with pulmonary congestion; cardiomegaly; increase thrombo-embolic risk [55].
Nephrological: chronic renal failure, microalbuminuria and nephrotic syndrome; prolapses [56].
Skeletal muscle: osteoarthritis, reduction of the aerobic reserve and fitness, chronic orthopedic problems, increased susceptibility to insults, osteoporosis / osteopenia, myostestatosis, myopenia, sarcopenia, increased risk of injury and reduced ambulation [57].
Surgical: increased morbidity and perioperative mortality [58].
Table 1. Clinical manifestations of obesity: main signs and symptoms. Weight gain and body circumferences
Visceral and peripheral fat expansion
Reduced joint mobility
Swelling of the lower limbs
Arthralgia
Muscular Weakness
Depressed mood
Social isolation
Hyperphagia
Food craving
General
Loss of selfesteem
Neuro psychological
Apathy
Reduction of cognitive ability
Lack of affection
Irritability
Impaired body perception
Headaches
Alteration of taste
Hyperalgesia
Drowsiness
Fatigue
Asthenia
Dyspnea
Nocturnal snoring
Apneas
Insomnia
Coughing
Oppression
Wheezing
Reduction in the caliber of the upper airways
Pneumological
Acid reflux
Stomach pain
Reduced tolerance to physical effort
Dyspepsia
Constipation
Bloating
Diarrhea
Abdominal distension and swelling
Altered alve
Biliary colic
Bromhidrosis
Hyperhidrosis
Lymphedema
Acne
Intertrigo
Folliculitis
Red stretch mark
Acanthosis nigricans
Hirsutism
Hypertrichosis
Gynecomastia
Hepatomegaly
Baldness
Oligomenorrhoea
Amenorrhea
Decreased of libido
Subfertility
Infertility
Bladder dysfunctions
Prolapse
Erectile dysfunction
Penis length reduction
Urinary infections
Gastroenterological
Endocrinological Dermatological
Urological
Abdominal colic
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Diagnosis Currently, BMI is used by many as an index to diagnose obesity. On the other hand, it has been recognized by several authors and scientific societies as an imperfect index, not able to correctly quantify adiposity. The BMI provides a useful tool for assessing overweight and obesity, but one of the limitations is the use of a single scale for both sexes and for all ages. However, it should be considered an approximate method because BMI may not correspond to the same percentage of body fat [59]. Determination of adiposity with anthropometry, skinfold and ultrasonographic techniques is limited by the distribution of gender and age-ethnic-specific fat and operator-dependent error. Image diagnostics, supported by technological innovation, are able to provide an accurate and repeatable body composition. In particular, computerized tomography, nuclear magnetic resonance and the Dual X-ray absorptiometry (DXA). The latter is considered the reference method for body composition, for the excellent relationship between quality, invasiveness, price and machine time. The DXA evaluates, on the whole or on a segment of the body, the fat, lean and bone mass with an average acquisition time of 10 minutes and an irradiation comparable to the one-day sun exposure [60, 61]. In clinical practice, various fat mass cut-offs based on ethnicity and gender have been proposed. According to various studies for the Italian population, they correspond to FM% 30% for women and 25% for men, from DXA [62-64]. Other techniques are also known, such as plethysmography and, more widely, bio analysis impedenziometry, but not considered diagnostic techniques due to lack of accuracy.
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Figure 1. Clinical evolution of obesity
Figure 1. The expansion of adipose tissues and visceral fat leads to an alteration of homeostasis, causes a dysfunction in the organs and increase the mortality risk. FM: Fat Mass. M: male; F: Female.
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Phenotype of obesity The obese subject is characterized by several factors: distribution and expansion of adipose tissue, body composition, energy expenditure, altered metabolism of macronutrients, genetic predisposition and inflammation, which together determine a phenotype. A phenotypic classification of obesity has been proposed to understand the complex relationships between factors and clinical manifestations. Four phenotypes of obesity have been described: normal weight obese (NWO); metabolically unhealthy normal weight obese; metabolically healthy obese; metabolically unhealthy obese. The phenotypes are functional to the overcoming of the erroneous classification based on the BMI that damages the health system delaying the therapeutic interventions [64]. The BMI does not evaluate body compartments, such as fat mass, and is inaccurate for cardiovascular risk assessment. For this reason, the new concept of NWO has been achieved from the study on the limits of BMI and from the research for risk prevention. The NWO subjects have a normal BMI and a high percentage of fat mass accompanied by low-grade inflammation, increased cardiometabolic risk, higher blood pressure, alteration of metabolism, genetic polymorphisms predisposing to inflammation and a reduction in lean mass and expenditure energy [65]. Furthermore, the classification clarifies the paradox of obesity: in some individuals with high BMI the frequency of cardiovascular events is low. The paradox is explained by adiposopathy, visceral and ectopic fat. In fact, obese subjects, with fewer cardiovascular events, have a subcutaneous and peripheral distribution of fat. In contrast, the metabolically unhealthy subjects, have a central distribution of fat with adiposopathy and more at cardiovascular risk. Subjects classified as normal weight obese or metabolically healthy have the same cardiovascular risk as metabolically unhealthy at 10 years of age, this indicates a continuous progression of obesity [66]. From simple fat deposition, adipose tissue is considered one of the protagonists of a complex molecular crosstalk. Adipose tissue is an endocrine organ that modulates metabolism, hormones and inflammation. The expansion of the subcutaneous adipose tissue is followed by visceral and ectopic infiltration of fat with increased inflammation and infiltration [67]. Certainly, visceral fat and excess free fatty acids are common factors in metabolically unhealthy individuals, which increase the risk of developing diabetes. Obesity is systemic due to inflammation, metabolic hormonal dysregulation and cross-talk with bones and muscles. Fat expansion leads to a negative molecular cascade that reduces strength and muscle mass as well as bone mass. In addition to the phenotypes described, we add the Sarcopenic Obesity and even more alarming Osteosarcopenic Obesity [68].
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Stigma of obesity The stigma of fat is pervasive and results in "fat-shaming". This happens when the perception, the looks and the judgments towards the obese cause shame. This is a phenomenon of family, social, health, education and work, which causes suffering in the victims of this act of humiliation. On the one hand, the stigma is justified for health benefits and on the other, stigma is selfsustaining. In fact, obese failing weight loss treatments placate their guilt by considering themselves stigmatized. In the last 20 years, the media, with their sociocultural ideals of thinness as a symbol of beauty, have linked the idea of success to this archetype. The consequence is the obsessive search for a diet to achieve social acceptance and not the improvement of one's health. Generalization and stigma have led to a disavowal of obesity as a disease and a lack of interest in government institutions, imputing responsibility of the individual. Following the recognition of obesity as a disease by the main scientific societies, the problem has become of public interest. As a result, attention has shifted from obese to obesity, "war to obese" to become "war to obesity". This conceptual passage is the will to overcome the generalization and the stigma of "obesity as a bad choice of life" [69]. Two passages are essential for the recognition and treatment of this disease: the overcoming of the stigma and the recognition of the responsibility of obesity by the institutions. At all ages, everyone is the center of a system that influences his choices. Advertising, social networks, video games, cinema, TV series, anthropogenic factors, obesogenic environment, junk food and poor nutrition with consequent alteration of taste lead to the modification of the reward / reward system. This falls on food choices, giving rise to the development of food addiction, eating disorders and dysmorphophobia due to the degeneration of lifestyle. In addition to anthropogenic factors, it has been shown that microorganisms can influence human behavior, changing many aspects including prudence and a sense of personal safety [70]. Precisely, the intestinal microbiota and its metabolites influence the craving and the food choices of the host. The western diet, harmful to health, alters the microbiota, causing the guest to continually search for highly processed, energetic and overwhelming foods [71]. So, several superstructures, internal (microbiota) and external (anthropogenic factors), drive the choices of the individual, which is unconscious of all. In this regard, it is essential that the institutions deconstruct this system, recognize obesity as a disease and implement appropriate intervention policies.
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Conclusion In conclusion, there are all the criteria to define obesity as a disease. In fact, specific scientific societies, different diagnostic techniques, clinical classifications, drugs and medical devices for treatment are already present. The high economic impact on health systems, on the state and on the individual has been recognized by various authors and scientific societies. The enormous costs of treatment and sequelae, due to the complications of obesity, require prevention, the only way to reduce costs. The problem of obesity and poor nutrition is global with the deaths of around 11 million only in 2017. The causes of death were mainly for cardiovascular diseases, type 2 diabetes and cancer. [72]. It is recognized that a targeted, reactive, non-waiting clinical management are able to reverse obesity and some comorbidities, such as diabetes. According to Jastreboff et al [6], different conditions and clinical responses can be recognized based on the multiple phenotypes of obesity. The under diagnosis and the misclassification of obesity, due to the use of inaccurate indicators, slow down the diagnosis, treatment and reduce the chances of success. Also in 2015 in the adult American population, over 80,000 new cases of cancer have been linked to poor and sub-optimal nutrition and obesity. This has been observed above all in the low income and most disadvantaged [73-74]. Conversely, a rich and optimal diet and fat loss can reduce the risk of cancer. Especially in menopausal breast cancer, the healthy diet associated with fat loss has significantly reduced the onset of cancer and the chance of death after diagnosis [75]. This evidence underlines the responsibility of politicians to prevent cancer [76]. It is necessary to cure obesity, recognizing it and guaranteeing everyone access to a healthy and rich diet. With the end of the stigma and generalizations, health care policies aimed to limit spending, tackle inequalities and defended vulnerable population groups are urgent.
Founding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interest: None. Author Contributions: All the authors read and approved the final manuscript. All the authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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Obesity: a preventable, treatable, but relapsing disease. A. De Lorenzo , L. Romano , L. Di Renzo , N. Di Lorenzo , G. Cenname , P. Gualtieri PII: DOI: Reference:
S0899-9007(19)30198-4 https://doi.org/10.1016/j.nut.2019.110615 NUT 110615
To appear in:
Nutrition
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Please cite this article as: A. De Lorenzo , L. Romano , L. Di Renzo , N. Di Lorenzo , G. Cenname , P. Gualtieri , Obesity: a preventable, treatable, but relapsing disease., Nutrition (2019), doi: https://doi.org/10.1016/j.nut.2019.110615
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Highlights The spread of primary obesity is pandemic, like an infectious disease The expansion of visceral fat plays role in the metabolic and functional alterations Poor nutrition is represented by the typical foods of the Western Diet Obesity and poor nutrition deaths were around 11 million only in 2017 The stigma of fat is pervasive and results in "fat-shaming"
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Obesity: a preventable, treatable, but relapsing disease. A. De Lorenzo1, L. Romano1,2, L. Di Renzo*1, N. Di Lorenzo3, G. Cenname4, P. Gualtieri1 1
Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of
Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. 2
School of Specialization in Food Sciences, University of Rome Tor Vergata, Rome, Italy.
3
Department of Surgical Sciences, University of Tor Vergata, Policlinico Tor Vergata, Rome, Italy.
4
Comando Generale Arma Carabinieri, Direzione di Sanità, Italy.
*Corresponding Author: Laura Di Renzo Email:[email protected]; Phone: +390672596855.
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Abstract: In 2013, the American Medical Association completing the recognition of obesity as a disease, led to a growing scientific, social and political interest. In 2016 in the United States, prevalence rates of pre-obesity and obesity exceeded 60%, also in Italy they exceeded 40%. Total costs related to excess weight reached 9.3% of US gross domestic product, while in Italy only the total cost of diabetes was estimated at 20.3 billion euros/year. The expansion of adipose tissue and visceral fat causes compression, joint stress, metabolic disorders, organ dysfunction and increased mortality. The increase in peripheral and central fat mass is a chronic and potentially reversible process with appropriate diagnosis and treatment. Conversely, fattening can turn in chronic relapsing form, complicated by comorbidities and cardiovascular events. The increased risk of mortality and morbidity can also affect metabolically healthy obese subjects, if the condition is underestimated, with disease progression. Due to BMI inaccuracy, it must be replaced with the body composition for obesity diagnosis. The chances of obesity reversibility are closely linked to improving the diagnosis and timely nutritional interventions. Generalization and stigma hinder the treatment of the obese. The recognition of obesity as a disease and institutional interest can shift the focus on obesity and not on the obese, with improvements in adherence to prevention plans. Anthropogenic factors and gut microbiota can influence the human behavior and food choice, such as food addiction. Obesity has all the criteria to be recognized as a disease. Proper clinical management will lead to cost and complications savings, such as diabetes.
Keywords: Obesity; Adiposopathy; Stigma; Body Composition; Disease; Diabetes.
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Introduction In the process of recognition of primary obesity as a disease, milestones were the declarations of the National Institute of Health in 1998, by The Obesity Society, of the American Obesity Society in 2008 and of the American Medical Association (AMA) in 2013. Since 2013, the scientific, political and social interest in the "obesity disease" has grown [1]. A new concept emerges, primary obesity must be considered a social disease, with overcoming of stigma, discrimination and generalization. The spread of primary obesity is pandemic, like an infectious disease [2-3]. For this reason, a preventive policy in childhood, an increasingly stricken population, can act as a vaccination campaign. This in order to limit the spread, raise public awareness and reduce prevalence in adulthood [4]. Currently, primary obesity is no longer a symbol of power and well-being, but a disease of low-income people. In fact, the subjects with a higher qualification and with a high social class have a lower incidence of primary obesity. Today, the high diffusion of low-priced junk food, qualitatively poor, taste and rich in calories is one the causes of obesity [5]. Nowadays, many scientific societies from all over the world have presented various position statements on this argument and also several authors have produced reviews to support this thesis. Again in 2018, The Obesity Society presented its position on primary obesity as a chronic disease, overcoming the previous definitions. [6] Even if the public authority of drug control (Food and Drug Administration and European Medicines Agency) has approved the marketing for the pharmacological treatment of obesity, obesity itself has not been overall recognized as a disease [7]. Erroneously, some authors identify obesity only as a risk factor, similarly to the metabolic syndrome (MS). In fact, MS is a risk factor and it does not have an approved pharmacological therapy. The results on diabetes reversion of the DiRECT study indicate a possible path to follow in the reactive and preventive medicine. Indeed, obese patients achieved a diabetes reversion with only 8 weeks of caloric restriction. It's highlighted that dietary and lifestyle interventions must have the same space as drugs in the treatment of obesity related disease. [8-9]. Health systems and scientific societies should get this knowledge to anticipate therapies and achieve a reversibility of diabetes and obesity. Also, in medical oncology the misclassification of obesity and the discrepancy between the diagnosis and the definition cause difficulties for the doctor. Also in medical oncology the misclassification of obesity and the discrepancy between the diagnosis and the definition cause difficulties for the doctor. Only with Body Mass Index (BMI), using weight and height, it is not possible to appreciate the complex changes in the cancer patient. In oncology, the adiposity excess, associated with sarcopenia, is often hidden by BMI. This leads to a delay in diagnosis, complicates the prevention process and weakens some therapies [10]. 4
The purpose of this work will be to discuss in detail the criteria for defining step by step primary obesity as a disease. In fact, it is urgent to recognize obesity as a disease in order to prevent comorbidities and health expenditure. So far argued.
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Epidemiology and costs After the AMA's recognition of the disease, there has been a growing interest in obesity. This led to the carrying out of studies on the epidemiological and economic impact of excess weight, classified according to the BMI. In 2016, in the United States (US), adult obesity rates reached 36.2%, those overweight 67.9%, while in 1975 obesity did not exceed 11.9%. Dramatically, in the pediatric and adolescent population, the prevalence rate of obesity reached 21.4% [11]. The annual medical care cost for obese and pre obese was around 2000 dollars, for a total of more than 1 trillion dollars at national level, equal to 9.3% of gross domestic product [12, 13]. In 2016, In Italy, data show a prevalence of obesity equal to 19.4%, while pre-obese people were equal to 58.5% [11]. Costa de Miranda et al [14] have shown that in one of the most affected regions of Italy from obesity the prevalence of children with excess weight is similar to that in the US. Given the absence of official data on spending in Italy due to obesity, in 2015, it was estimated that all excess weight related cost amounted to 4% of total health care expenditure of the Italian national health service, about € 4.5 million/year [15]. The costs reported are underestimated due to the misclassification of BMI, which underestimates the real prevalence of obesity in the population [16]. Obesity is a disease with a higher mortality rate, but it is preventable and reversible. Spending on the co-morbidities and complications of cardiovascular disease, depended on obesity, represents an expenditure and a failure of clinical management. In fact, an estimate of the direct and indirect costs deriving from the diabetes is € 20.3 billion / year. [17] This economic data and the misclassification of obesity must warn about the real costs related to obesity in Italy. The screening and prevention policies and strategies have proved effective for health and economic savings. The initial cost of prevention campaigns, the training of specialists, the promotion of healthy eating and the production of quality food should not block these interventions. Savings and health benefits will be rewarded over the long term [18].
Evolution and natural history of the disease The expansion and visceral spill-over of fat mass leads to an alteration of homeostasis and causes a dysfunction in the organs [19]. The adaptation to the expansion is potentially reversible if obesity is correctly diagnosed and treated. In contrast, the expansion tends to assume a chronic-relapsing trend with a reduction in life expectancy [20]. The expansion of visceral fat, in particular of omentum and mesentery, causes metabolic alterations and increased intra-abdominal pressure may increase the risk of esophageal reflux. At the same time, the adipose tissue, surrounding the kidneys and vessels, contributes to hypertension. Therefore, the increase fat in the soft tissues of the pharynx can contribute to the obstruction of the respiratory tract. Finally, the increase in weight 6
related to excess fat causes damage to the joints, predisposing to osteoarthritis [21]. Depending on the degree of the expansion specific alteration of the anthropometric and biochemical parameters are observable. Overall, the fat distribution rather than quantity is crucial in the development of obesity-associated abnormalities. In particular, the expansion of visceral and abdominal fat plays a primary role in the metabolic and functional alterations [20]. Prodromal phase In the first phase, a peripheral accumulation of adiposity is observed due to a calorie intake higher than total energy expenditure. At the same time, low-grade inflammation and systemic homeostasis are present [22]. Before the appearance of metabolic alterations, the accumulation of adipose tissue involves functional limitations like increased tissue friction, joint stress, soft tissue compression with consequent sleep apnea and gastroesophageal reflux [23]. This phase and the complications already mentioned are to be considered fully reversible. Intermediate phase The fat accumulated in the organs is known as ectopic fat. This is the result of lipotoxicity, with spill-over of excess fat in the visceral districts. The ectopic deposition can determine adiposopathy, dysfunctional alteration of the adipose tissue and of the affected tissues or organs [24]. There is also an increase in adipokines and inflammatory cytokines, a metabolic inflexibility, an altered metabolism of triglycerides and carbohydrates, which produces insulin resistance and an increase in oxidative stress. In the intermediate phase, adiposopathy involves a breakdown of homeostasis and predisposes to the presence of co-morbidities, such as diabetes, hypertension and dyslipidemia [25]. This phase and its complications are reversible. Last phase The chronic expansion of fat mass, the accumulation of damage caused by adiposopathy and the comorbidities lead to a greater risk of cardiovascular events [26]. At the occurrence of a major complication the risk of mortality increases, aggravated by all functional limitations and comorbidities. After a cardiovascular event, the obese and complicated patient is fragile and limited in the daily life activities [27]. Unfortunately, the outcomes of major complications are not reversible. Recognition of reversible conditions and tertiary prevention of major complications are essential for the recovery of quality of life [28]. Metabolically healthy obese patients are in a reversible condition but, if not recognized at this stage, the degree of pathology and risk persists.
The pathophysiology of obesity 7
Obesity is a clinical condition that manifests itself with the excess of subcutaneous and/or visceral fat mass. It is frequently associated with weight gain but can also occur in normal weight subjects. With a limited frequency it is associated with osteopenia and sarcopenia. Obesity is a multifactorial disease. Furthermore, the excess of weight in childhood predisposes to a greater risk of obesity in adulthood. In particular, adiposity rebound, i.e. The increase in BMI starting between 5-7 years, exposes to a greater risk of obesity and metabolic syndrome [29, 30]. The main cause of primary obesity is the combination between excessive intake of unhealthy foods, "poor nutrition", reduced physical activity, alteration of the microbiome, congenital alterations, genetic susceptibility and epigenetic alterations. Primary obesity is distinguished from the rare monogenic forms of obesity, determined by the mutation of a key gene in weight regulation, despite having a polygenic base. Unlike monogenic forms, in primary obesity different polymorphisms can be present, i.e. singlenucleotide polymorphisms, predisposing to obesity [31]. The primary obesity
Poor nutrition is represented by the typical foods of the Western Diet. These are poor in micronutrients, antioxidants and polyphenols, highly processed and calorie dense, contain environmental (persistent organic pollutants, glyphosate, bisphenols, anthropogenic and endocrine disruptors) and process (acrylamide, furosine, advanced glycation end-products) contaminants [32, 33].
Physical activity is reduced by a sedentary lifestyle, depression, mood alteration, neuroinflammation, hyperalgesia and reduction of functional biomechanical reserves due to the expansion of adipose tissue [34].
The alteration of the microbiota occurs with an imbalance of the intestinal flora, a reduction of the variability of the species and an increase of the firmicutes with respect to the bacteroidetes [35]. This leads to a disruption in the intestinal permeability (Leaky Gut Syndrome), the increase in energy extracted from food and the induction of changes in food choices [36].
Congenital alterations, predisposing to obesity, occur from "poor nutrition", the mother's incorrect lifestyles and exposure to contaminants during pregnancy [37].
The genetic susceptibility, represented by the individual's genotype, determines the predisposition to the development and maintenance of obesity in the interaction with environmental and social factors [38].
Epigenetic alteration represents all the changes that the environment, lifestyle, diet, parents and social factors, can determine on gene expression, with the possibility of increasing the
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predisposition of the subject to become obese in the absence of gene mutations/polymorphisms [39,40].
Obesity-associated abnormalities In primary obesity, it is possible to find specific abnormalities [41]:
Neuropsychological: neuroinflammation; reduction of brain volume; depression; mood alteration; modification of the processes of gratification / reward up to the development of food addiction; neuropathy; development of eating disorders [42, 43].
Pneumological: spirometry alterations, with reduction of vital capacity and expiration indices; hypercapnia tendency to alter the respiratory quotient. Hypoventilation syndromes (eg Pickwick's syndrome); asthma, chronic respiratory infections; oropharyngeal anomalies; Obstructive Sleep Apnea Syndrome (OSAS) [45, 46].
Digestive: alteration of buccal health with cariogenic disease and periodontitis for oral dysbiosis; gastroesophageal reflux diseases; esophageal hernia; dyskinesias; biliary lithiasis; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; colitis from dysbiosis; the small intestinal bacterial overgrowth (SIBO) with leaky gut syndrome; inflammatory bowel diseases (IBD); fissures; hemorrhoids [47].
Metabolic: insulin resistance, hyperinsulinemia, hyperglycemia, hypertriglyceridaemia, hypercholesterolemia, hypoalphalipoproteinemia, hyperuricaemia, gout, hypercortisolemia, metabolic syndrome [48].
Fertility: Early menarche, menstrual irregularities, feminization due to metabolic alteration; sub-fertility/infertility of male and female; Male obesity secondary hypogonadism (MOSH); PolyCystic Ovary Syndrome (PCOS); erectile dysfunction [49,50].
Pregnancy: aggravation of latent hypertension, preeclampsia, gestational diabetes, increased maternal mortality [51].
Dermatological: increased susceptibility to skin infections; discoloration; dystrophies; nail mycosis; inverse psoriasis [52].
Rheumatological and immunological: chronic inflammation with increased inflammation rates; arthrosis; mechanical arthropathy, increased susceptibility to virus and reduction of immune system resilience [53].
Oncological: increase of the general risk to malignant tumor, in particular cancers of the colonrectum, liver. In women increase also the risk to breast and endometrium cancers [54].
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Cardiological: arterial hypertension, atherosclerotic disease, cardiovascular disease, stroke, venous insufficiency and arteriopathies, heart failure with pulmonary congestion; cardiomegaly; increase thrombo-embolic risk [55].
Nephrological: chronic renal failure, microalbuminuria and nephrotic syndrome; prolapses [56].
Skeletal muscle: osteoarthritis, reduction of the aerobic reserve and fitness, chronic orthopedic problems, increased susceptibility to insults, osteoporosis / osteopenia, myostestatosis, myopenia, sarcopenia, increased risk of injury and reduced ambulation [57].
Surgical: increased morbidity and perioperative mortality [58].
Table 1. Clinical manifestations of obesity: main signs and symptoms. Weight gain and body circumferences
Visceral and peripheral fat expansion
Reduced joint mobility
Swelling of the lower limbs
Arthralgia
Muscular Weakness
Depressed mood
Social isolation
Hyperphagia
Food craving
General
Loss of selfesteem
Neuro psychological
Apathy
Reduction of cognitive ability
Lack of affection
Irritability
Impaired body perception
Headaches
Alteration of taste
Hyperalgesia
Drowsiness
Fatigue
Asthenia
Dyspnea
Nocturnal snoring
Apneas
Insomnia
Coughing
Oppression
Wheezing
Reduction in the caliber of the upper airways
Pneumological
Acid reflux
Stomach pain
Reduced tolerance to physical effort
Dyspepsia
Constipation
Bloating
Diarrhea
Abdominal distension and swelling
Altered alve
Biliary colic
Bromhidrosis
Hyperhidrosis
Lymphedema
Acne
Intertrigo
Folliculitis
Red stretch mark
Acanthosis nigricans
Hirsutism
Hypertrichosis
Gynecomastia
Hepatomegaly
Baldness
Oligomenorrhoea
Amenorrhea
Decreased of libido
Subfertility
Infertility
Bladder dysfunctions
Prolapse
Erectile dysfunction
Penis length reduction
Urinary infections
Gastroenterological
Endocrinological Dermatological
Urological
Abdominal colic
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Diagnosis Currently, BMI is used by many as an index to diagnose obesity. On the other hand, it has been recognized by several authors and scientific societies as an imperfect index, not able to correctly quantify adiposity. The BMI provides a useful tool for assessing overweight and obesity, but one of the limitations is the use of a single scale for both sexes and for all ages. However, it should be considered an approximate method because BMI may not correspond to the same percentage of body fat [59]. Determination of adiposity with anthropometry, skinfold and ultrasonographic techniques is limited by the distribution of gender and age-ethnic-specific fat and operator-dependent error. Image diagnostics, supported by technological innovation, are able to provide an accurate and repeatable body composition. In particular, computerized tomography, nuclear magnetic resonance and the Dual X-ray absorptiometry (DXA). The latter is considered the reference method for body composition, for the excellent relationship between quality, invasiveness, price and machine time. The DXA evaluates, on the whole or on a segment of the body, the fat, lean and bone mass with an average acquisition time of 10 minutes and an irradiation comparable to the one-day sun exposure [60, 61]. In clinical practice, various fat mass cut-offs based on ethnicity and gender have been proposed. According to various studies for the Italian population, they correspond to FM% 30% for women and 25% for men, from DXA [62-64]. Other techniques are also known, such as plethysmography and, more widely, bio analysis impedenziometry, but not considered diagnostic techniques due to lack of accuracy.
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Figure 1. Clinical evolution of obesity
Figure 1. The expansion of adipose tissues and visceral fat leads to an alteration of homeostasis, causes a dysfunction in the organs and increase the mortality risk. FM: Fat Mass. M: male; F: Female.
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Phenotype of obesity The obese subject is characterized by several factors: distribution and expansion of adipose tissue, body composition, energy expenditure, altered metabolism of macronutrients, genetic predisposition and inflammation, which together determine a phenotype. A phenotypic classification of obesity has been proposed to understand the complex relationships between factors and clinical manifestations. Four phenotypes of obesity have been described: normal weight obese (NWO); metabolically unhealthy normal weight obese; metabolically healthy obese; metabolically unhealthy obese. The phenotypes are functional to the overcoming of the erroneous classification based on the BMI that damages the health system delaying the therapeutic interventions [64]. The BMI does not evaluate body compartments, such as fat mass, and is inaccurate for cardiovascular risk assessment. For this reason, the new concept of NWO has been achieved from the study on the limits of BMI and from the research for risk prevention. The NWO subjects have a normal BMI and a high percentage of fat mass accompanied by low-grade inflammation, increased cardiometabolic risk, higher blood pressure, alteration of metabolism, genetic polymorphisms predisposing to inflammation and a reduction in lean mass and expenditure energy [65]. Furthermore, the classification clarifies the paradox of obesity: in some individuals with high BMI the frequency of cardiovascular events is low. The paradox is explained by adiposopathy, visceral and ectopic fat. In fact, obese subjects, with fewer cardiovascular events, have a subcutaneous and peripheral distribution of fat. In contrast, the metabolically unhealthy subjects, have a central distribution of fat with adiposopathy and more at cardiovascular risk. Subjects classified as normal weight obese or metabolically healthy have the same cardiovascular risk as metabolically unhealthy at 10 years of age, this indicates a continuous progression of obesity [66]. From simple fat deposition, adipose tissue is considered one of the protagonists of a complex molecular crosstalk. Adipose tissue is an endocrine organ that modulates metabolism, hormones and inflammation. The expansion of the subcutaneous adipose tissue is followed by visceral and ectopic infiltration of fat with increased inflammation and infiltration [67]. Certainly, visceral fat and excess free fatty acids are common factors in metabolically unhealthy individuals, which increase the risk of developing diabetes. Obesity is systemic due to inflammation, metabolic hormonal dysregulation and cross-talk with bones and muscles. Fat expansion leads to a negative molecular cascade that reduces strength and muscle mass as well as bone mass. In addition to the phenotypes described, we add the Sarcopenic Obesity and even more alarming Osteosarcopenic Obesity [68].
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Stigma of obesity The stigma of fat is pervasive and results in "fat-shaming". This happens when the perception, the looks and the judgments towards the obese cause shame. This is a phenomenon of family, social, health, education and work, which causes suffering in the victims of this act of humiliation. On the one hand, the stigma is justified for health benefits and on the other, stigma is selfsustaining. In fact, obese failing weight loss treatments placate their guilt by considering themselves stigmatized. In the last 20 years, the media, with their sociocultural ideals of thinness as a symbol of beauty, have linked the idea of success to this archetype. The consequence is the obsessive search for a diet to achieve social acceptance and not the improvement of one's health. Generalization and stigma have led to a disavowal of obesity as a disease and a lack of interest in government institutions, imputing responsibility of the individual. Following the recognition of obesity as a disease by the main scientific societies, the problem has become of public interest. As a result, attention has shifted from obese to obesity, "war to obese" to become "war to obesity". This conceptual passage is the will to overcome the generalization and the stigma of "obesity as a bad choice of life" [69]. Two passages are essential for the recognition and treatment of this disease: the overcoming of the stigma and the recognition of the responsibility of obesity by the institutions. At all ages, everyone is the center of a system that influences his choices. Advertising, social networks, video games, cinema, TV series, anthropogenic factors, obesogenic environment, junk food and poor nutrition with consequent alteration of taste lead to the modification of the reward / reward system. This falls on food choices, giving rise to the development of food addiction, eating disorders and dysmorphophobia due to the degeneration of lifestyle. In addition to anthropogenic factors, it has been shown that microorganisms can influence human behavior, changing many aspects including prudence and a sense of personal safety [70]. Precisely, the intestinal microbiota and its metabolites influence the craving and the food choices of the host. The western diet, harmful to health, alters the microbiota, causing the guest to continually search for highly processed, energetic and overwhelming foods [71]. So, several superstructures, internal (microbiota) and external (anthropogenic factors), drive the choices of the individual, which is unconscious of all. In this regard, it is essential that the institutions deconstruct this system, recognize obesity as a disease and implement appropriate intervention policies.
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Conclusion In conclusion, there are all the criteria to define obesity as a disease. In fact, specific scientific societies, different diagnostic techniques, clinical classifications, drugs and medical devices for treatment are already present. The high economic impact on health systems, on the state and on the individual has been recognized by various authors and scientific societies. The enormous costs of treatment and sequelae, due to the complications of obesity, require prevention, the only way to reduce costs. The problem of obesity and poor nutrition is global with the deaths of around 11 million only in 2017. The causes of death were mainly for cardiovascular diseases, type 2 diabetes and cancer. [72]. It is recognized that a targeted, reactive, non-waiting clinical management are able to reverse obesity and some comorbidities, such as diabetes. According to Jastreboff et al [6], different conditions and clinical responses can be recognized based on the multiple phenotypes of obesity. The under diagnosis and the misclassification of obesity, due to the use of inaccurate indicators, slow down the diagnosis, treatment and reduce the chances of success. Also in 2015 in the adult American population, over 80,000 new cases of cancer have been linked to poor and sub-optimal nutrition and obesity. This has been observed above all in the low income and most disadvantaged [73-74]. Conversely, a rich and optimal diet and fat loss can reduce the risk of cancer. Especially in menopausal breast cancer, the healthy diet associated with fat loss has significantly reduced the onset of cancer and the chance of death after diagnosis [75]. This evidence underlines the responsibility of politicians to prevent cancer [76]. It is necessary to cure obesity, recognizing it and guaranteeing everyone access to a healthy and rich diet. With the end of the stigma and generalizations, health care policies aimed to limit spending, tackle inequalities and defended vulnerable population groups are urgent.
Founding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interest: None. Author Contributions: All the authors read and approved the final manuscript. All the authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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