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After Diagnosis: Family Caregiving with Hospice Patients 1st Edition John G. Bruhn (Auth.)
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I dedicate this text to my mother, Mirella, who has always supported and encouraged me to realize my dreams and to whom I owe my life, my professional career, and my accomplishments.
I thank my mentors, Dr. José Luis Martínez and Dr. Amado Athié, who influenced my medical and nutritional career and who trusted me to grow every day in this exciting area of medicine. I also thank Dr. Alexis Bolio who trusted me to write this book.
I thank Dr. Gilberto Romero, MD who colaborated with the last chapter in this book and who always been a great friend.
Preface
Obesity is a worldwide epidemic that can lead to conditions such as type 2 diabetes and cardiovascular disease, two of the principal five causes of death worldwide. Obesity is a preventable and treatable disease and every physician must be qualified to diagnose and treat it during a routine visit. Anthropometric assessment is already an obligatory component of the medical clinical record, but even when physicians detect increased weight or a high body mass index, they are often unprepared to initiate a first-line approach to treatment.
In this book, I suggest an easy and comprehensive approach to the treatment of obesity, including a general overview of the pathophysiology, clinical diagnosis, and medical-nutritional treatment, which can provide medical professionals with a basis for managing patients. If every health care provider is aware of and qualified in the diagnosis and treatment of overweight and obesity, we can expect to have an impact on bringing this epidemic under control.
México City, Mexico Hania González, MD
1 Overview of Obesity
2 Pathophysiology of
7.3.1
7.3.4
7.3.5
7.4.3 Suture
7.4.4 Malabsorptive Techniques.
Chapter 1 Overview of Obesity
1.1 Introduction
Obesity, a chronic, multifactorial disease that develops from the interaction of behavioral, physiological, metabolic, cellular, and molecular factors, is a worldwide public health concern. There are more than 1 billion overweight and obese adults around the world, and it is expected that the obesity epidemic will double by the year 2030 to become the major health problem of this century [1].
1.2 Definition
Obesity is a chronic inflammatory disease characterized by an increased total body fat mass of sufficient magnitude to produce adverse health consequences, and is associated with increased morbidity and mortality.
1.3 Epidemiology
1.3.1 Prevalence
Obesity is a chronic disease that affects more than 1 billion overweight and more than 500 million obese patients worldwide [2].
1 H. González, Managing Patients with Obesity, DOI 10.1007/978-3-319-12331-8_1,
Some countries are more affected than others; for example, in the United States more than 78 million adults (or 36% of the population) are estimated to be obese and in Mexico, more than 70% of the adult population is overweight or obese, with evidence suggesting that the prevalence has being increasing for over 100 years [3–5]. Obesity represents a major risk factor for other chronic diseases and is one of the major causes of incapacity. Overweight and obesity are the fifth ranking risk for mortality globally [6]. In 2008, 35% of adults aged 20 years and older were overweight, and 10% of men and 14% of women were obese. The combined prevalence of overweight and obesity is highest in the World Health Organization (WHO)–designated region of the Americas (62% overweight and 26% obese) and lowest in the WHO region of South-East Asia (14% overweight and 3% obese) (Fig. 1.1) [7].
The problem is not solely adult related. In fact, in 2010 it was estimated that more than 40% of children in North American and Eastern Mediterranean regions, 38% in Europe, 27% in the Western Pacific, and 22% in South-East Asia were categorized as overweight or obese [8–10]. The WHO estimates that almost 43 million children younger than 5 years are obese [7].
Older patients are also affected. In the United States, the prevalence of obesity in the elderly is 42.5% in women and
38.1% in men aged 60–69 years, and 19.5% in women and 9.6% in men aged 80 or older [11]. In the elderly, the prevalence of obesity and its effect on morbidity seem to differ quantitatively by gender; female elderly patients show a higher prevalence for obesity than men. After the menopause women’s adipose tissue tends to be redistributed toward the abdomen, partly explaining the differences in prevalence between middle-aged and elderly women [12].
1.4 Disease Burden
According to the WHO, at least 2.8 million people die each year as a result of being overweight or obese [7]. Medical costs for obese patients are 42% higher than those for normal-weight patients. The annual financial burden of obesity on the medical system is estimated to be more than US$147 billion annually [4]. This estimate is higher when considering the cost of managing comorbidities of obesity such as cardiovascular disease, hypertension, stroke, coronary artery disease, deep venous thrombosis, type 2 diabetes mellitus, obstructive sleep apnea, osteoarthritis, cognitive impairment, cholecystitis, gastroesophageal reflux, nonalcoholic fatty liver disease, infertility, and cancer. Obesity is the leading cause of cancer after smoking [13].
Obesity accounts for 64% of cases of type 2 diabetes in men and 79% in women. Moreover, it reduces life expectancy by 6–7 years, and severe obesity (defined as a body mass index of 40 kg/m2 or more) reduces life expectancy by 10 years [4].
References
1. Gnacinska M, Stojek M, Lysiak-Szydlowska W, Sworczak K. Role of adipokines in complications related to obesity. A review. Adv Med Sci. 2009;54:150–7.
2. Johnson A, Milner J, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012;249:218–38.
3. Manrique M, Pía M, Carrasco F, Moreno M, Albala C, García J, et al. Diagnóstico, evaluación y tratamiento no farmacológico del paciente con sobrepeso u obesidad. Rev Med Chil. 2009;137:963–71.
4. Yanovski S, Yanovski J. Long-term drug treatment for obesity, a systematic and clinical review. JAMA. 2014;311:74–86.
5. Barrera-Cruz A, Rodríguez-González A, Molina-Ayala M. Escenario actual de la obesidad en México. Rev Med Inst Mex Seguro Soc. 2013;51:292–9.
6. Kim G, Lin J, Blomain E, Waldman S. Anti-obesity pharmacotherapy: new drugs and emerging targets. Clin Pharmacol Ther. 2014;95:53–66.
7. World Health Organization (WHO). Obesity: situation and trends. 2000. WHO website. www.who.int/gho/ncd/risk_factors/ obesity_text/en/. Accessed 26 Mar 2015.
8. Ayling R. Obesity in infancy and childhood: diagnosis, incidence and strategy for change. In: Watson RR, Grimble G, Preddy VR, Zibadi S, editors. Nutrition in infancy, vol. 2. London: Humana Press; 2012. p. 347–55.
9. Ríos-Cortázar V, Gasca-García A, Ordoñez A, Vera M, FrancoMartínez M, Tolentino-Mayo L. Reducción de la obesidad infantil a través del componente de nutrición de una iniciativa de escuela promotora de salud. Salud Publica Mex. 2013;55:431–3.
10. Han J, Lawlor D, Kimm S. Childhood obesity-2010; progress and challenges. Lancet. 2010;375:1737–48.
11. Donini L, Savina C, Gennaro E, De Felice M, Rosano A, Pandolfo M, et al. A systematic review of the literature concerning the relationship between obesity and mortality in the elderly. J Nutr Health Aging. 2012;16:89–98.
12. Kim I, Chun H, Kwon J. Gender differences in the effect of obesity on chronic diseases among the elderly Koreans. J Korean Med Sci. 2001;26:250–7.
13. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49:868–913. Chapter 1.
Chapter 2 Pathophysiology of Obesity
2.1 Appetite and Energy Expenditure Control
Hunger perception and the decision to initiate a meal involve interactions between genetic, social, learned, environmental, circadian, and humoral cues. Several endogenous peptides with the ability to stimulate food intake have been identified in the feeding centers in the hypothalamus. Once feeding commences, the amount consumed is determined by factors involved in satiety perception. These factors involve combined effects of gastric distention and the release of peptide signals from enteroendocrine cells in the gastrointestinal tract. Satiety peptides include cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY (PYY), apolipoprotein A-IV, enterostatin, pancreatic polypeptide, glucagon, and amylin [1] (Fig. 2.1).
Leptin regulates energy balance via hypothalamic receptors in the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamic nucleus, and lateral hypothalamic area (LHA). The ARC integrates peripheral energy balance signals, including hormones such as leptin, insulin, and ghrelin, and nutrients (fatty acids, amino acids, and glucose).
The hypothalamus controls feeding by integrating peripheral humoral signals that influence food intake and energy expenditure with neural signals from the brainstem and higher cortical centers. Energy homeostasis involves many hypothalamic nuclei: the ARC, PVN, ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and LHA.
• In the ARC, there are two neuronal populations: neurons that coexpress neuropeptide Y (NPY) and agouti-related peptide (AgRP) to stimulate food intake, and neurons coexpressing pro-opiomelanocortin (POMC) and cocaineand amphetamine-regulated transcript (CART), which suppress food intake.
• POMC produces α -melanocyte-stimulating hormone (α-MSH), which binds to melanocortin-3 and -4 receptors (MC3R and MC4R) to suppress food intake.
• NPY is the most abundant neuropeptide in the central nervous system. Its orexigenic effect is mediated by hypothalamic Y1 and Y5 receptor stimulation.
• AgRP is an MC3R and MC4R antagonist with an orexigenic effect. Appetite center, Hypothalamus
2.1
Appetite and Energy Expenditure Control
• The PVN receives projections of NPY/agRP and POMC/ CART from the ARC and contains neurons that express anorectic factors: thyrotropin-releasing hormone and corticotropin-releasing hormone.
• The LHA receives projections from the ARC and contains two orexigenic neuropeptides: melanin-concentrating hormone (MCH) and orexin. These neurons project to the olfactory bulb, cerebral cortex, thalamus, hypothalamus, brainstem, locus coeruleus, tuberomammillary nucleus, and raphe nucleus.
• The DMN receives NPY/AgRP projections from the ARC and projects the α-MSH fiber to the PVN. DMN lesions cause hyperphagia and obesity.
Negative energy balance and loss of body fat activate feedback signals (leptin and insulin) while raising ghrelin levels. In response, NPY/AgRP neurons are activated and POMC cells are inhibited. This combination promotes food intake, positive energy balance, and the recovery of lost fat.
2.1.2 Brainstem
The dorsal vagal complex relays peripheral signals via vagal afferent fibers from the gut to the hypothalamus (Fig. 2.2) [2]. It comprises the dorsal motor nucleus of vagus (DVN), area postrema (AP), and the nucleus of the solitary tract (NTS).
α-MSH projections from POMC neurons terminate in close anatomical proximity to neurons in the NTS, which respond to gastric distention. The medial NTS receives the most extensive projections of PVN.
Vagal afferent neurons within the brainstem express CCK-1R and CCK-2R, leptin receptor (Ob-R), NPY receptor (Y2R), GLP-1R and GLP-2R, growth hormone secretagogue receptor (GHS)-R1, and orexin receptor (OX-R1). The vagus nerve also transmits gut hormone signals such as CCK, ghrelin, PYY, pancreatic polypeptide (PP), and GLP-1.
Reward is a process whereby certain behaviors are reinforced in response to specific environmental stimuli. We learn to associate olfactory, gustatory, and environmental cues with food properties that reinforce behaviors related to acquisition and consumption of rewarding food (Fig. 2.3) [3, 4].
Corticolimbic pathways are responsible for rewardassociated feeding behavior; these include the striatum, central segmental area, nucleus accumbens, insular cortex, anterior cingulate cortex, and orbitofrontal cortex. The orbitofrontal cortex regulates gustatory, olfactory, visual, and somatosensory function, and sensory factors such as taste and smell, and has an important role in reward-related feeding.
Endocannabinoid and opioid systems are also related to reward feeding. Administration of an opioid receptor agonist to the nucleus accumbens stimulates intake of a high-fat diet with a higher expression of orexin. Preadministration of a cannabinoid receptor antagonist prevents the orexigenic effect of the endocannabinoid agonist anandamide in food intake. Leptin reduces endocannabinoid levels in the hypothalamus. Dopamine is associated with reward-related food intake and with behaviors required to maintain feeding that is essential for survival [5]. Cannabinoid antagonists cause weight loss but are not approved for obesity treatment because of their psychiatric side effects, including an increased risk of suicide [3].
2.1.4 Gut Hormones
Pancreatic Polypeptide-Fold Peptides
Pancreatic polypeptide-fold peptides include NPY, PYY, and PP. NPY is secreted and distributed in the central nervous system, and PYY and PP are secreted from the gastrointestinal tract. These peptides act via the G-protein-coupled receptors Y1, Y2, Y4, Y5, and Y6.
PYY is an appetite suppressor released from L cells of the distal gut in response to food intake, along with two other gut hormones, GLP-1 and oxyntomodulin (OXM). Circulating levels of PYY are low in the fasted state and increase rapidly after food intake, remaining elevated for several hours, with levels increasing in proportion to calorie intake. Peripheral PP administration shows a reduction in food intake and gain in body weight [6]. PYY also regulates energy expenditure, delays gastric emptying, reduces acid secretion, and inhibits gallbladder contraction and pancreatic exocrine secretions. In comparison with control subjects, PYY levels are decreased in obese subjects and increased in patients with anorexia nervosa. PYY acts in the hypothalamic ARC.
Glucagon-Like Peptide 1
Glucagon-like peptide 1 (GLP-1) is secreted from L cells in the intestine in response to food intake. GLP-1 reactive neurons are located in the PVN, DMN, NTS, dorsal vagal complex, pituitary, and thalamus. GLP-1 receptors are widely distributed throughout the brain, gastrointestinal tract, and pancreas. Circulating levels increase postprandially and decrease in the fasted state. GLP-1 reduces food intake, suppresses glucagon secretion, and delays gastric emptying. This hormone possesses an incretin effect that stimulates insulin secretion in a glucose-dependent manner following carbohydrate intake. Its use as an obesity treatment is limited by its short plasma half-life of 1–2 min, which is attributed to enzyChapter 2. Pathophysiology of
2.1 Appetite and Energy Expenditure Control
matic degradation by dipeptidyl peptidase 4 (DPP-4) and renal clearance that rapidly inactivate and remove GLP-1 from plasma circulation.
Oxyntomodulin
OXM is secreted by the L cells of the distal gastrointestinal tract in response to food intake and in proportion to caloric intake. It has anorectic effects and shows incretin activity. It also inhibits gastric acid secretion and delays gastric emptying. OXM administration decreases food intake and increases energy expenditure, and is inactivated by DPP-4.
Glucagon
Glucagon is produced by α cells of the pancreatic islets and increases glucose concentration in response to hypoglycemia. Glucagon enhances the body’s physiological response to stress by increasing energy expenditure. It decreases food intake by modulating vagal tone and gastric emptying.
Ghrelin
Ghrelin is the only known orexigenic gut hormone. It is secreted from X/A-like cells within gastric oxyntic glands. Gastrectomy results in an 80% reduction of plasma ghrelin levels. The remainder is secreted from the intestine, pancreas, pituitary, and colon. It is also expressed within the ARC and periventricular area of the hypothalamus. Ghrelin increases during fasting and decreases after eating. There is a negative correlation between circulating ghrelin and body mass index. Ghrelin mediates its orexigenic action by stimulating NPY/ AgRP coexpressing neurons within the ARC of the hypothalamus. It also increases gastric motility, stimulates the hypothalamo-pituitary-adrenal axis, and possesses cardiovascular effects such as vasodilatation and enhanced cardiac contractility.
Chapter 2. Pathophysiology of Obesity
Cholecystokinin
CCK is secreted by the I cells of the small intestine. Its levels increase within 15 min of food intake. CCK also stimulates the release of pancreatic and gallbladder enzymes, promotes intestinal motility, and delays gastric emptying. It has an anorexigenic effect.
Amylin
Amylin is released in response to food intake and acts as an anorectic hormone. Amylin administration reduces food intake and body weight. These effects are mediated by modulating activity of serotonin, histamine, and the dopaminergic system in the brain in addition to inhibition of NPY release. Gut hormones involved in obesity can be categorized as orexigenic and anorexigenic, and are listed in Table 2.1.
2.2 Adipose Tissue and Adipokines
Adipocytes are wrapped in a sheath of extracellular matrix (ECM), particularly collagens. In obesity, excessive and dysregulated deposition of collagens and other ECM compo-
Table 2.1 Gut hormones involved in the central nervous system circuits related to food reward because of their orexigenic and anorexigenic effects
nents eventually constrain adipocyte expansion, promoting adipocyte stress, inflammatory stress kinase activation, and adipose tissue and systemic metabolic dysfunction [7].
Adipose tissue is an active endocrine organ and is a source of more than 100 substances including proinflammatory cytokines, chemokines, growth factors, and complement proteins called adipokines or adipocytokines. These molecules function as systemic, paracrine, or autocrine hormones. Adipokines are responsible for the interactions between the adipose tissue, muscular tissue, adrenal cortex, and the central and sympathetic nervous systems (Tables 2.2 and 2.3; Figs. 2.3 and 2.4) [8]. They play a role in controlling appetite, maintaining energy balance, determining insulin sensitivity, and regulating blood pressure, immune response, angiogenesis, lipid metabolism, and hemostasis. Proinflammatory cytokines, produced by macrophages and adipocytes, increase in parallel with fat body mass. For this reason obesity may be characterized by a coexisting chronic, benign, inflammatory state. Because metabolic homeostasis and immune response are closely related, obesity is associated with inadequate immune reaction and an increased risk of inflammatory diseases such as diabetes and atherosclerosis [9].
Leptin and adiponectin increase tissue sensitivity to insulin. These adipokines stimulate fatty acid oxidation, decreasing the accumulation of triglycerides. In patients with obesity, there is an increased leptin concentration caused by leptin resistance. Adiponectin concentration decreases with increasing body fat content. In obese individuals there is altered insulin sensitivity and no prevention of vascular injury.
2.2.1 Leptin
Leptin is a protein produced in adipose tissue by the obesity gene (ob), and is also released from the brain. Leptin acts as a negative feedback regulator of adiposity, constraining fat mass by limiting energy intake and supporting energy expenditure. Decreased leptin signaling increases food intake, and
Dehydrogenase 11β-hydroxysteroid type 1 (11β-HSD1)
Angiotensin I, II
Lipoprotein lipase (LPL)
Insulin growth factor (IGF-1)
Aromatase cytochrome p450
Adipsin (complement factor D)
Cholesteryl ester transfer protein (CETP)
Adipocyte fatty acid binding protein (aP2)
Dehydrogenase 17β-hydroxysteroid (17β-HSD)
Renin Angiotensinogen
Apelin
Angiotensinconverting enzyme (ACE)
Visfatin
Resistin
Nerve growth factor (NGF)
promotes positive energy balance and fat accumulation [3]. Leptin regulates food intake by decreasing appetite and preventing weight gain. It has been reported that a mutation in the ob/ob obesity gene in mice causes lack of leptin with the subsequent hyperphagia, insulin resistance, and obesity. Leptin administration in these mice decreases food intake, increases insulin sensitivity, and leads to reduced body mass. Leptin and insulin act together in glucose metabolism. They both act in the central nervous system, decreasing food intake and increasing energy expenditure while regulating
2.2 Adipose Tissue and Adipokines
Table 2.3 Adipose tissue receptors
Insulin Glucagon
Thyroidstimulating hormone (TSH)
Gastrin
Cholecystokinin B (CCK-B)
Glucagon-like peptide 1
Angiotensin II Glucocorticoids Androgens
Estrogens
Progesterone Leptin
Interleukin-6 TNF-α
Resistin
Adiponectin
Visfatin
Vaspin?
Peroxisome
proliferator-activated receptor γ (PPARγ)
Catecholamines B1, B2, B3, A1, A2
IL-6
RBP4
Resistin?
Cortisol
FFA
PAI-1
Angiotensinogen
Apelin
MCP1
TNF- α
IL-6
Various cytokines
CRP and other acute phase proteins
*From stromal vascular cells in visceral adipose depots • TNF-α
long-term energy homeostasis. Leptin decreases insulin secretion via negative feedback. In obesity, the resistance to leptin activity results in hyperinsulinemia, which stimulates adipogenesis, leading to a further increase in insulin secretion. This
Adipose tissue
Chapter 2. Pathophysiology of Obesity
process constitutes a risk factor for pancreatic B-cell dysfunction and the development of type 2 diabetes mellitus [9]. Leptin resistance limits the therapeutic utility of this adipokine, and may result from reduced leptin receptor signal transduction and impaired transport of leptin across the blood-brain barrier.
Leptin receptors in the hypothalamic ARC appear to be responsible for regulating glucose homeostasis and body weight, and may also act to signal sympathetic nervous system (SNS) activity. High leptin levels in obesity may act centrally to affect SNS overactivity [ 10 ]. Leptin inhibits NPY/AgRP neurons and activates POMC/CART neurons.
2.2.2 Adiponectin
Adiponectin is also known as adipocyte-complementrelated protein of 30 kDa (Acrp30), AdipoQ, gelatin binding protein of 28 kDa (GBP28), and adipose most abundant gene transcript 1 (apM1). It is produced predominantly by the adipose tissue. This adipokine improves insulin sensitivity, glucose tolerance, and blood lipid levels. Levels of adiponectin are inversely proportionate to circulating leptin. Adiponectin levels are decreased in obesity and insulin resistance.
2.2.3
Resistin
This adipokine is also known as found in inflammatory zone (FIZZ3) and adipocyte-specific secretory factor (ADSF). Resistin administration leads to decreased insulin sensitivity. Target organs for resistin action are the liver, adipose tissue, and skeletal muscle. Resistin increases hepatic glucose production and decreases fatty acid uptake and metabolism. In obese individuals resistin concentration, especially in visceral adipose tissue, is significantly higher than in normal-weight subjects [9].
2.3 Inflammation and Oxidative Stress
2.2.4 Tumor Necrosis Factor α
Tumor necrosis factor α (TNF-α) is a protein that stimulates the acute phase of inflammation, and is capable of crossing the blood-brain barrier. This proinflammatory cytokine is increased in obesity and hyperinsulinemia. TNF-α increases interleukin (IL)-6 production, and together they coactivate SNS activity.
2.2.5 Interleukin-6
Thirty percent of IL-6 concentration comes from adipose tissue, and it increases proportionally with body mass. It is also produced from smooth muscle and helper T cells. IL-6 expression correlates with insulin resistance. IL-6 secretion is two or three times higher in visceral than in subcutaneous adipose tissue [9]. It also decreases insulin receptor expression in peripheral tissues. IL-6 inhibits glycogen synthesis and activates lipolysis, and inhibits adipogenesis and adiponectin secretion. This protein also releases acute-phase proteins into the blood, including C-reactive protein (CRP).
In addition to secreted proteins, lipids are also released from adipose tissue, and act locally and systemically; such lipids are called lipokines. Limited insulin responsiveness in obese adipocytes results in elevated levels of circulating nonessential fatty acids (NEFAs), which have lipotoxic effects associated with inflammation [8].
2.3 Inflammation and Oxidative Stress
Cytokines associated with inflammation and secreted by adipocytes include TNF-α, IL-1, -6, -8, and -10, the monocyte chemotactic protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). Adipocytes also secrete acute-phase proteins such as amyloid A, haptoglobin, plasminogen activator inhibitor 1 (PAI-1), and acylation-stimulating protein. The
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