Introduction

An understanding of all the comorbidities potentially associated with overweight and obesity can serve as a guide to providing patients with these problems a comprehensive medical evaluation and early treatment, including vigorous weight management. Obesity is associated with a long list of medical and psychological comorbidities that need to be considered in the evaluation of obese patients.

Comorbidities Help Determine Obesity Treatment

Guidelines for obesity treatment recommend treatments based on the extent of weight-related comorbidities(American Association of Clinical Endocrinology-Garber et al., 2015). For patients who are at least moderately overweight or heavier, the following are the recommended treatment:

• No Weight-Related Comorbidities: Recommend lifestyle change counseling by an MD or dietitian, consider recommending a weight-loss program.
• Low Severity Comorbidities: Recommend lifestyle modification counseling by an MD or dietitian, weight-loss support program, or structured, multidisciplinary weight-loss program that includes these interventions.
• Medium Severity Comorbidities: Recommend weight-loss medications along with lifestyle modification counseling by an MD or dietitian, weight-loss support program or structured, multidisciplinary weight-loss program that includes these interventions.
• High Severity Comorbidities and/or High BMI (35 kg/m² or greater): Recommend surgical therapy along with lifestyle modification by an MD or dietitian, weight-loss support program, and a structured, multidisciplinary weight-loss program.

Also consider the functional status, symptoms, and risk factors in determining level of care for obesity (Padwal, Pajweski, Allison, & et al., 2011).

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Pathogenesis of Obesity Comorbidities

Fat Mass vs. “Sick Fat Mass” or “Adiposopathy” Diseases

An understanding of the pathogenesis behind obesity-related comorbidities is helpful in understanding their prevention, effective treatments, and inter-relationship with other comorbidities. Two forms of obesity-related comorbidities can be distinguished based on pathogenesis:

• Fat Mass Disease: These diseases come from the impact of the bulky, heavy fat mass itself.
  • Examples include congestive heart failure, hypoventilation syndrome, and problems of musculoskeletal functioning and pain (Seger, Horn, Westman, & et al., 2015).
• “Adiposopathy” or “Sick Fat Mass” Disease:
  • These diseases come from physiological changes including increased circulating free fatty acids, pathogenic endocrine responses, disordered immune response, fatty infiltration in various organs, and dysfunction of the fat cells themselves.
  • Diseases are also caused a low-grade, chronic inflammatory state in metabolic tissues including adipose, liver, muscle, pancreas, and brain (Gregor & Hotamisligil, 2011). This inflammation contributes to insulin resistance and metabolic dysfunction.

The physiological changes from obesity appear to be mostly permanent (Ochner, Tsai, Kushner, & Wadden, 2015). Unfortunately, this makes it easier for patients who were once obese to regain weight (MacLean, Higgins, & Giles, 2015). Thus, permanent changes in lifestyle and long-term follow-up are critical after weight loss.

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Health Effects of Obesity

An understanding of all the comorbidities potentially associated with excess weight can serve as a guide to providing patients a comprehensive medical evaluation and early treatment, including vigorous weight management. Many diseases are comorbid with obesity. Causality can go in either direction or both. Therefore, taking a weight-centered approach to treating many comorbid conditions makes sense. For example, for an obese person with diabetes, choose an antidiabestes medication that would also support weight loss and start obesity treatment as part of diabetes treatment.

Not every individual who is obese suffers from even the most common comorbidities. Genetic factors, diet quality, and amount of exercise probably all play a role (Fabbrini, Yoshino, Yoshino, & et al., 2015). Some patients who are obese are metabolically normal initially, but eventually, at least some of the many comorbidities are experienced.

Weight-Related Comorbidities

Which comorbid conditions are most likely in obesity?

Relative Risk:-Above 5

• Type 2 diabetes
• Dyslipidemia
• Obstructive sleep apnea
• Obesity hypoventilation syndrome
• Shortness of breath
• Excessive daytime fatigue
• Fatty liver

Relative Risk: 2 to 5

• Cardiovascular disease (Heart attack and stroke)
• High blood pressure
• Gallstones
• Gout
• Osteoarthritis
• Endometrial cancer
• Overall mortality

Relative Risk: 1 to 2

• Cancer (breast, prostate, colon)
• Fertility Problems
• Pregnancy complications
• Asthma
• GERD

(Dixon, 2010)

Cardiovascular Risk of Obesity

Obesity is especially harmful to the cardiovascular system. It causes direct harm through:

• Epicardial fat deposition
• Increased intra-myocardial triglyceride deposition
• Lipotoxicity
• Cardiomyocyte apoptosis which produces cardiac dysfunction

(Horwich & Fonarow, 2010)

Obesity also causes an elevation of cardiovascular risk factors:

• Dyslipidemia
• Hypertension
• Elevated fibrinogen
• Increased plasminogen activator inhibitor-1 (impaired fibrinolysis)

(Steelman & Westman, 2010)

Type 2 Diabetes Risk of Obesity

A high percentage of the population (44%) has type 2 diabetes mellitus or prediabetes and this percentage is increasing along with the increase in obesity (Center for Disease Control and Prevention, 2014). The impact of the associated morbidity is significant.

Obstructive Sleep Apnea

Sleep apnea is characterized by pauses in breathing or shallow breaths that bring the individual from deep to light sleep (National Heart, Lung, and Blood Institute (NHLBI), 2012). Apnea lasts a few seconds to minutes as often as 30 times an hour. The result is daytime sleepiness, unrefreshing sleep, fatigue, insomnia, and snoring. Approximately 70% of patients with obstructive sleep apnea are also obese (Tuomilehto, Seppä, & Uusitupa, 2013). Weight loss is an important treatment. Referral for evaluation in a sleep study with polysomnography is ideal.

Obesity Hypoventilation Syndrome (OHS)

Obesity hypoventilation syndrome results in lower oxygen and higher carbon dioxide in the blood. It is believed to be due to excess weight against the chest wall and a defect in the brain’s control of breathing. Symptoms include being chronically tired, daytime sleepiness, depression, and headaches. Obesity hypoventilation syndrome can be reversed with weight loss. Most patients with this syndrome also have sleep apnea (A.D.A.M., 2012).

Psychosocial Comorbidities

• Social stigmatization
• Problems with personal hygiene
• Eating disorders
• Mood disorders
• Other psychological disorders

(Luppino, de Wit, Bouvy, & et al., 2010)

Other Comorbidities and Risks

• Pseudotumor cerebri: Neurological symptoms from increased intracranial pressure
• Skin comorbidities: Intertrigo (bacterial and/or fungal), acanthosis nigricans, hirsutism, risk for cellulitis and carbuncles
• Surgical risks: Increased surgical risk and postoperative complications (wound infection, postoperative pneumonia, deep venous thrombosis, and pulmonary embolism)

(American Society for Metabolic & Bariatric Surgery, 2013; National Institute of Neurological Disorders and Stroke, 2010; Nudel & Sanchez, 2019)

Obesity-Related Mortality

The overall mortality rate is increased 29% for overweight and obesity; the increase goes up almost linearly as BMI increases(Global BMI Mortality Collaboration et al., 2016). The longer an individual is obese, the greater the impact on longevity (Chang, Pollack, & Colditz, 2013). The effect is greater for blacks than whites and men than women.

• For non-smoking individuals age 40-49 with a BMI over 40, from 4.7 to 5.4 years of life is lost (Chang et al., 2013).

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Benefits of Weight Loss

Weight-Related Comorbidities and Treatment

Obesity treatment should not be delayed while focusing on the treatment of its comorbid conditions (Ochner et al., 2015). Obesity should be treated at the same time as associated serious comorbidities because reducing weight is a treatment for many of these comorbidities (M. D. Jensen et al., 2013).

Many illnesses are improved by even a modest intentional loss of weight:

• Cardiovascular Disease (M. Jensen, Ryan, Apovian, & et al., 2013; Koliaki, Liatis, & Kokkinos, 2019) – Weight loss improves cardiovascular disease especially if body fat is lost without loss of lean muscle mass.
• Type 2 Diabetes Mellitus – Weight loss helps prevent diabetes and improves the disease for those who already have it.
  (Cohen, Pinheiro, & Schiavon, 2012; Mingrone, Panzunzi, De Gaetano, & et al., 2012; Schauer, Bhatt, & Kirwan, 2014)
• Non-Alcoholic Fatty Liver Disease
  Weight loss sometimes improves this condition, especially in conjunction with other medical treatment. (Polyzos, Kountouras, & Mantzoros, 2019)
• Osteoarthritis – Weight loss improves symptoms and functionality and sometimes slows disease progression.
  (Bliddal, Leeds, & Christensen, 2014)
• Cancer – Weigh loss decreases some risk, lowers mortality
  (Adams, Stroup, & Gress, 2009; Sjöström, Gummesson, & Sjöström, 2009)
• Sleep Apnea – Improves(Kuna, Reboussin, Borradaile, & et al., 2013).
• Others: Weight loss improves pancreatitis, cholecystitis, gout, kidney disease, infertility, carpal tunnel syndrome, rheumatoid arthritis, impaired immunity, asthma/reactive airway disease, polycystic ovaries, male hypogonadism, GERD, urinary incontinence, and low back pain (W. T. Garvey et al., 2016; Rader, 2014)

Cardiovascular Risk Factor Improvement from Weight Loss

Serum Lipids
Weight loss of as little as 6.6 lbs lowers serum triglyceride and LDL and increases HDL modestly (Feingold, Grunfeld, Boyce, & et al, 2018; National Heart, Lung, and Blood Institute, 2013; Vekic, Zeljkovic, Stefanovic, Jelic-Ivanovic, & Spasojevic-Kalimanovska, 2019). There is a dose-response relationship between the amount of weight lost and improvement in the patient’s lipid profile(NHLBI, 2013).

Hypertension Improvement With Weight Loss

There is a dose-response relationship between the amount of weight loss achieved for up to 3 years and the lowering of blood pressure (NHLBI, 2013).

• Weight loss of 5% results in systolic and diastolic blood pressure reduced by a weighted mean of 3 and 2 mm Hg respectively (NHLBI, 2013).

Atrial Fibrillation Improvement With Weight Loss

Long-term weight loss of 10% reduces symptoms of atrial fibrillation (Pathak, Middeldorp, Meredith, & et al., 2015). However, fluctuations in weight of 6% or more in a year resulted in worsening of atrial fibrillation (Pathak et al., 2015).

Diabetes and Weight Loss

Weight loss for overweight or obese patients with type 2 diabetes produces improvements in HbA1c and fasting plasma glucose and reduction in need for diabetes medications. Greater weight loss corresponds to greater improvements(NHLBI, 2013). Diabetes medications having modest weight loss or at least weight neutral should be used if possible while still achieving A1C targets.

• Weight loss of 2% – 5% of current weight maintained for at least 1 – 4 years results in HbA1c being lowered 0.2% – 0.3% and fasting plasma glucose reduced modestly (NHLBI, 2013).

Reduced Progression from Prediabetes to Diabetes

• Weight loss of 5.5 –12.1 lbs (2.5 – 5.5 kg) maintained for at least 2 years results in the risk of developing diabetes being reduced by 30 – 60% (NHLBI, 2013).
• 10% weight loss is recommended in pre-diabetes(W. T. Garvey et al., 2016).

Obstructive Sleep Apnea Improvement With Weight Loss

Sleep apnea is likely to improve with weight loss as part of the treatment. Breaking the cycle between inadequate sleep and obesity is an important part of obesity treatment for many patients (National Heart, Lung, and Blood Institute (NHLBI), 2012).

Non-Alcoholic Fatty Liver Disease

A modest weight loss has a dose-dependent improvement in nonalcoholic steatosis, but up to 40% may be needed to reduce inflammation (W. T. Garvey et al., 2016). Mediterranean diet, calorie restriction, moderate to vigorous physical activity, and weight loss medications may also be helpful(Polyzos et al., 2019).

Importance of Sustaining and Continuing Weight Loss

Health benefits are realized if the weight loss is sustained; a life-long reduction in caloric intake is needed.. It is important to support the patient in maintaining each incremental weight loss. The promise of even more health benefits with further weight loss can help motivate patients to continue their weight-loss efforts. With sustained additional weight loss beyond an initial 5% weight loss, patients are likely to experience further improvement in serum lipids, blood pressure, diabetes risk, and fasting plasma glucose(M. D. Jensen et al., 2013).

Weight-Loss Goal for Treating Comorbidities

Help patients set goals that are realistic and achievable while also considering medical goals. The overall goal for initial weight-loss therapy is a weight reduction of approximately 5-10% of body weight (M. D. Jensen et al., 2013). This moderate level of weight loss, if sustained, can significantly decrease the severity of many obesity-related comorbidities. A moderate pace of 1 to 2 lbs per week is often recommended (M. D. Jensen et al., 2013). More rapid weight loss is almost always followed by regain of weight – often more weight than was lost with negative mental and physical health consequences(NHLBI, 2013). However, in very high BMI or morbid obesity, rapid weight loss is often important in order to achieve functioning and reduce medical risk rapidly.

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Medical Evaluation of Obesity

Because of a high rate of comorbidities associated with obesity, extensive medical assessment is often needed, including:

• Medications and medical conditions that contribute to weight gain
• Potential laboratory and other tests for comorbidities of obesity

Physical Exam

An algorithm for the physical examination of overweight/obesity should include the following(Bays, Seger, Primack, & et al., 2017):

• Height
• Weight
• Blood pressure
• Body composition analysis
• Waist measurement
• Neck circumference
• Complete physical – Include a check for common comorbidities and mobility problems.

(Bays et al., 2017)

Additionally:

• Labs should include evaluation for comorbidities.
• Evaluation for psychological disorders including eating disorders and psychosocial factors contributing to weight
• Check for medications that may contribute to weight gain

Check for Medications Causing Weight Gain

A number of medications increase weight or distribution of body fat (lipodystrophy). Those that clearly cause weight gain should be avoided in overweight or obese patient if there is a suitable alternative. Entire classes of medications may cause weight gain or just some medications within a class. The amount of weight gained varies but can be significant.

Medications That May Cause Weight Gain:

• Antidiabetics
• Psychotropic medications:
  • Antipsychotics
  • Mood stabilizers
  • Antidepressants
  • Antiepileptics
• Antihypertensives

Medications That Cause Weight Gain and Lipodystrophy:

• Antiretroviral
• Glucocorticoids
• Hypolipidemics

Other possible medications:

• Contraceptives
• Sedating antihistamines

(Domecq, Prutsky, Leppin, & et al., 2015; Verhaegen & Gaal, 2019)

Diagnostic Tests Often Indicated

Diagnostic tests in overweight and obesity should be individualized. However, the following tests are often part of a comprehensive evaluation:

Electrocardiogram in Obesity

Obesity is associated with multiple hemodynamic effects and cardiovascular adaptations including increased intravascular blood volume, stroke volume, heart rate, cardiac output, systemic vascular resistance, blood pressure, pulmonary artery systolic pressure, filling pressures in the left and right heart cavities (Koliaki et al., 2019).

Sleep Study

History-taking for possible sleep apnea should include questions on fatigue, sleepiness, witnessed breathing cessation). The neck circumference measurement associated with sleep apnea risk is >17″ for men, > 16″ for women.

Secondary Studies Commonly Needed in Obesity

The following secondary studies may be needed if indicated by the primary exam:

• GERD – endoscopy, esophageal motility
• Conditions causing secondary obesity including polycystic ovary syndrome, hormonal or genetic causes, may require genetic or hormonal testing.
• Non-alcoholic fatty liver disease – Liver inspection and function, secondary imaging, biopsy if needed
• Osteoarthritis – secondary radiographic imaging
• Urinary Stress Incontinence – secondary urine culture, urodynamic testing

(Bays et al., 2017; W. Garvey, Mechanick, & Einhorn, 2014)

Additional possible weight-related comorbidities include asthma/reactive airway disease, hypogonadism, infertility in females, polycystic ovary syndrome (premenopausal females with overweight/obesity and/or metabolic syndrome)(W.

Other Medical Conditions Causing Weight Gain:

• Growth hormone imbalance
• Hypercortisolism (Cushing’s disease)
• Hyperphagia (e.g. associated with injury to the hypothalamus)
• Hypothyroidism
• Insulinoma
• Smoking cessation
  (Luppino et al., 2010; Pistelli, Aquilini, & Carrozzi, 2009; Shlisky, Hartman, Kris-Etherton, & et al., 2012; Sicat, 2014)

Genetics and Excess Weight

Genetics is commonly a contributing factor in obesity, affecting satiety and hunger, but simple genetic causes for obesity are rare. Examples include the uncommon autosomal dominant Prader-Willi Syndrome or the autosomal recessive Bardet Biedl Syndrome.

Smoking Cessation and Weight Gain

Smoking cessation is often associated with weight gain. In a 10-year study, obese smokers who quit smoking gained an average of 7.1 kg more than those who did not quit (Veldheer, Yingst, Zhu, & et al., 2015). Some smoking cessation pharmacotherapies and antidepressants appear to limit weight gain in the short-term(Farley, Hajek, Lycett, & Aveyard, 2012). Exercise appears to be effective in the long-term.

Psychological and Psychosocial Problems and Weight Gain

Patients having obesity should be screened and counseled for depression and other psychological disorders. Other issues contributing to weight gain or that are affected by excess weight include low self-esteem, body-image dissatisfaction, ability to work, and ability for sexual intimacy(Bays et al., 2017).

Relationship of Stress and Weight

Prolonged chronic stress can lead to a cyclical pattern of stress hormones, leading to obesity, and then chronic obesity itself contributing stressors, such as chronic pain, social effects, and limited mobility, which, in turn, leads to release of more stress hormones and more obesity (Chrousos, 2009; Kassi, Pervanidou, Kaltsas, & et al., 2011).

Mood Disorders and Obesity

Mood disorders and obesity have a high level of co-occurrence(Mansur, Brietzke, & McIntyre, 2015). They share clinical, neurobiological, genetic, and environmental factors.

Depression: The association between obesity and depression is clear and strong, especially in women (de Wit, Luppino, van Straten, & et al., 2010; Mansur et al., 2015). The relationship between excess weight and depression appears to be reciprocal (Luppino et al., 2010). Having depression increases the risk of later development of obesity. Having obesity increases the risk for developing depression.

Bipolar Disorder: Individuals with bipolar disorder have a higher rate of metabolic syndrome than the overall population(Yatham et al., 2018). A high BMI in Bipolar disorder is a risk factor for suicide.

Anxiety Disorders and Obesity: Being overweight or obese was associated with lifetime diagnosis of anxiety in women (Zhao, Ford, Dhingra, & et al., 2009). The association does not appear to be as strong as for depression(Gadalla, 2009).

Suicide Risk: Suicide risk increases with BMI for women but may even be a little decreased with increase BMI in men(Danielle Barry, 2009).

Eating Disorders and Obesity

Binge Eating Disorder

Binge eating disorder (BED) is the most common eating disorder among people who are obese, affecting between 15% and 50% of obese patients (Myers & Wiman, 2014; WIN Network, 2011). It is characterized by

• Recurring episodes of eating significantly more food in a short period of time than most people would without purging
• Related feelings of lack of control and marked distress
• May eat too quickly, even when not hungry
• May have feelings of guilt, embarrassment, or disgust and may hide binging behaviors
• Occurs, on average, at least once a week over three months

(American Psychiatric Association, 2013a; Myers & Wiman, 2014)

Other Eating Disorders and Obesity

Bulimia Nervosa: Bulimia is characterized by binge eating plus recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-induced vomiting, misuse of laxatives, diuretics, enemas, fasting, or excessive exercise.Most individuals with bulimia are normal weight or even below, but some are overweight or obese(Harrington, Jimerson, Haxton, & et al., 2015).

Night Eating Syndrome: Characterized by a combination of eating disorder, sleep disorder, and mood disorder characterized by consuming 25-50% of daily calories, typically high in carbohydrates, after the evening meal(Vander Wal, 2012, 2014)

Anorexia Nervosa: The onset of anorexia, which is characterized by pathological fear of gaining weight, restrained eating, insufficient body weight, and distorted body image (American Psychiatric Association, 2013b; National Institutes of Health (NIH), 2014), is often preceded by dieting (Attia & Walsh, 2009; Clarke, Weiss, & Berrettini, 2011). However, given that dieting to lose weight is very common and the incidence of anorexia is low (Swanson, Crow, Le Grange, & et al., 2011), the rate of transition from dieting to anorexia is very low (Walsh, 2013). Screen for this eating disorder in vulnerable patients. Patients who develop anorexia or who have a history of anorexia should have healthy lifestyle emphasized over dieting options.

Assess Mobility

Impaired mobility is a common problem in chronic obesity. The severity increases with increased BMI, years of obesity, osteoarthritis, and history of injuries(Muir & Archer-Heese, 2009; Vincent, Vincent, & Lamb, 2010).

A baseline evaluation of functioning and tracking changes over time is part of a complete physical evaluation of obesity (Muir & Archer-Heese, 2009). Mobility assessments can be used in:

• Deciding on more aggressive treatments, such as bariatric surgery or very low-calorie diets.
• Determining what, if any, equipment is needed (e.g. canes, walkers, wheelchairs) (Muir & Archer-Heese, 2009).
• Tracking improvements in response to obesity treatment.

Patients are assessed on their ability to sit and stand, walk forward and backward, and turn (Boynton, Kelly, & Perez, 2014). Other movements used in evaluations include stair climbing, chair rise time, and time to get up and go (Vincent et al., 2010). Slower walking and movement speeds and shorter stride lengths are evidence of decreased mobility. Patients can be questioned on pain, stiffness, activities of daily living, indoor mobility, housework, outdoor activities, occupational activities, and social life (Donini, Brunani, Sirtori, & et al., 2011). A classification system can be used to accurately describe and track the severity of the problem (Rajeski, Ip, Bertoni, & et al., 2012).

An examination by a physical therapist can identify movement and posture impairments. Very few obese patients seek physical therapy for obesity, but do see PT for pain, likely caused or worsened by obesity, such as for sprains/strains, osteoarthritis, or disc herniation(Janiszewski, 2012).

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Module Summary

Health Effects of Obesity and Benefits of Weight Loss

The following six diseases/conditions are most likely to co-occur with obesity:

• Cardiovascular Disease
• Type 2 Diabetes Mellitus/Prediabetes
• Hypertension
• Dyslipidemia
• Sleep Apnea
• Cancer: Breast, Cervical, Ovarian, Endometrial, Prostate, Thyroid, Colon, Rectal, Pancreatic, Biliary Tract, Gallbladder

(Mayo Clinic Staff, 2018; National Cancer Institute, 2012; National Diabetes Information Clearinghouse (NDIC), 2013)

Many comorbidities and risks are improved significantly by as little as a 3 to 5% weight loss and further weight loss often produces even more health benefits.

Medical Evaluation of Obesity

It is important to rule out other potential causes of weight gain, including medications, medical conditions, eating disorders, and other psychological disorders.

Conditions that can cause weight gain include:

• Hypothyroidism
• Sleep apnea/reduced sleep
• Genetics
• Smoking cessation

Medications that can cause weight gain include:

• Anticonvulsants
• Antidepressants (Both tricyclic & MAOI’s)
• Antihypertensives
• Antidiabetics

(Domecq et al., 2015; Kolasa, Cable, & Collier, 2010; Pistelli et al., 2009; Shlisky et al., 2012; Sicat, 2014)

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References Used In This Module: