The patient has metabolic syndrome. the patient is at increased risk for which condition?

Practice Essentials

Metabolic syndrome (syndrome X, insulin resistance) is a multifactorial disease with multiple risk factors that arises from insulin resistance accompanying abnormal adipose deposition and function. [1, 2] It comprises a combination of risk factors for coronary heart disease, as well as for diabetes, fatty liver, and several cancers.

Signs and symptoms

Clinical manifestations of metabolic syndrome include the following:

• Hypertension

• Hyperglycemia

• Hypertriglyceridemia

• Reduced high-density lipoprotein cholesterol (HDL-C)

• Abdominal obesity

• Chest pain or shortness of breath: Suggesting the rise of cardiovascular and other complications

• Acanthosis nigricans, hirsutism, peripheral neuropathy, and retinopathy: In patients with insulin resistance and hyperglycemia or with diabetes mellitus

• Xanthomas or xanthelasmas: In patients with severe dyslipidemia

See Presentation for more details.

Diagnosis

According to guidelines from the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA), metabolic syndrome is diagnosed when a patient has at least 3 of the following 5 conditions:

• Fasting glucose ≥100 mg/dL (or receiving drug therapy for hyperglycemia)

• Blood pressure ≥130/85 mm Hg (or receiving drug therapy for hypertension)

• Triglycerides ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)

• HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)

• Waist circumference ≥102 cm (40 in) in men or ≥88 cm (35 in) in women; if Asian American, ≥90 cm (35 in) in men or ≥80 cm (32 in) in women

To address variation between professional guidelines, the NHLBI, AHA, International Diabetes Foundation (IDF), and others have proposed a harmonized definition of metabolic syndrome. [3]

Complaints of chest pain, dyspnea, or claudication (symptoms of possible complications) may warrant additional studies, including the following:

• Electrocardiography (rest/stress ECG)

• Ultrasonography (vascular, or rest/stress echocardiography)

• Stress single-photon emission computed tomography (SPECT) or cardiac positron emission tomography (PET)

Investigation into other causes of or exacerbating factors in metabolic syndrome should be considered. For example, sleep-related breathing disorders, such as obstructive sleep apnea, are becoming increasingly relevant and novel risk factors for metabolic syndrome. [4]

See Workup for more detail.

Management

Lifestyle change and weight loss are considered the most important initial steps in treating metabolic syndrome. Studies comparing ethnically similar populations exposed to different dietary environments have suggested that westernized diets are strongly associated with a higher risk of developing metabolic syndrome. [5]

The following medications can be used to treat dyslipidemia and other manifestations of metabolic syndrome:

• Elevated LDL-C levels: Statins

• Decreased HDL-C levels: Consider niacin

• Elevated triglyceride levels: Consider niacin, fibrates, and omega-3 fatty acids

• Hyperglycemia: Insulin-sensitizing agent, such as metformin

Treatment of associated obstructive sleep apnea may also play a significant role in the management of metabolic syndrome.

See Treatment and Medication for more detail.

Background

Metabolic syndrome (syndrome X, insulin resistance) is a multifactorial disease with multiple risk factors that arises from insulin resistance accompanying abnormal adipose deposition and function. [1, 2] It is a risk factor for coronary heart disease, as well as diabetes, fatty liver, and several cancers. The clinical manifestations of this syndrome may include hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C), and abdominal obesity. (See Prognosis, Workup, Treatment, and Medication.)

Under 2005 revised guidelines by the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA), [6] metabolic syndrome is diagnosed when a patient has at least three of the following five conditions (see Presentation and Workup):

• Fasting glucose ≥100 mg/dL (or receiving drug therapy for hyperglycemia)

• Blood pressure ≥130/85 mm Hg (or receiving drug therapy for hypertension)

• Triglycerides ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)

• HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)

• Waist circumference ≥102 cm (40 in) in men or ≥88 cm (35 in) in women; if Asian American, ≥90 cm (35 in) in men or ≥80 cm (32 in) in women (The international diabetes federation [IDF] criteria allow the use of a body mass index [BMI] >30 kg/m2 in lieu of the waist circumference criterion.)

To address variation between professional guidelines, the National Heart, Lung, and Blood Institute (NHLBI), American Hearth Association (AHA), International Diabetes Foundation (IDF), and other organizations have proposed a harmonized definition of metabolic syndrome. [3]

Abundant data suggest that patients meeting these diagnostic criteria have a greater risk of significant clinical consequences, the 2 most prominent of which are the development of diabetes mellitus [7] and of coronary heart disease. Pooled data from 37 studies involving more than 170,000 patients have shown that metabolic syndrome doubles the risk of coronary artery disease. [8] It also increases risk of stroke, fatty liver disease, and cancer. [9] (See Prognosis.)

Controversy

There has been debate over whether obesity or insulin resistance is the unifying feature and underlying cause for metabolic syndrome. [10] However, more fundamentally, the clinical value of the recognition of metabolic syndrome as a distinct entity has been challenged. One study questioned the predictive value of the metabolic syndrome diagnosis for the development of diabetes and cardiovascular events in older populations (aged 70-82 y and 60-79 y). [11]

Neither population showed a relationship between cardiovascular outcomes and three of the metabolic syndrome criteria (for waist circumference, triglycerides, and glucose). Moreover, in this group of older patients, the diagnosis of metabolic syndrome was not more predictive of incident diabetes than was the fasting plasma glucose level alone.

Clearly, the individual clinical features that make up the syndrome are predictive of clinical outcomes, but whether grouping these features together under the umbrella of metabolic syndrome adds additional diagnostic, therapeutic, and prognostic value remains the subject of ongoing debate. [12, 13]

Pathophysiology

Target organ damage occurs through multiple mechanisms in metabolic syndrome. The individual diseases leading to metabolic syndrome produce adverse clinical consequences. For example, hypertension in metabolic syndrome causes left ventricular hypertrophy, progressive peripheral arterial disease, and renal dysfunction. [14] However, the cumulative risk for metabolic syndrome appears to cause microvascular dysfunction, which further amplifies insulin resistance and promotes hypertension. [15]

Metabolic syndrome promotes coronary heart disease through several mechanisms. It increases the thrombogenicity of circulating blood, in part by raising plasminogen activator type 1 and adipokine levels, and it causes endothelial dysfunction. [16] Metabolic syndrome may also increase cardiovascular risks by increasing arterial stiffness. [17] Additional mechanisms include oxidative stress, [18] which has been associated with numerous components of metabolic syndrome. [19]

Etiology

The underlying etiology for metabolic syndrome remains unclear. [20] However, known risk factors for metabolic syndrome include family history, poor diet, and inadequate exercise. Two forces that have spread metabolic syndrome globally are the increased availability and consumption of high calorie-low fiber fast food as well as decreased physical activity engendered by sedentary lifestyles and mechanized transportation. [21]  Contributing factors and mechanisms appear to include the following [20] :

• Insulin resistance

• Pancreatic beta-cell dysfunction

• Cellular dysfunction by protein kinases and phoshatases

• Suppression of insulin receptor substrate-1 and 2 (IRS1/IRS2) gene expression and function

• Obesity and lipid toxicity

• Oxidative stress and glucose toxicity

• Chronic inflammation

• Dysrupted circadian rhythm

• Genetics and epigenetics

• Gut microbial imbalance

• Dietary effects

Metabolic syndrome is thought to be caused by adipose tissue dysfunction and insulin resistance. Dysfunctional adipose tissue also plays an important role in the pathogenesis of obesity-related insulin resistance. [22]  Both adipose cell enlargement and infiltration of macrophages into adipose tissue result in the release of proinflammatory cytokines and promote insulin resistance. [23]

Insulin resistance appears to be the primary mediator of metabolic syndrome. [24] Insulin promotes glucose uptake in muscle, fat, and liver cells and can influence lipolysis and the production of glucose by hepatocytes.

Additional contributors to insulin resistance include abnormalities in insulin secretion and insulin receptor signaling, impaired glucose disposal, and proinflammatory cytokines. These abnormalities, in turn, may result from obesity with related increases in free fatty acid levels and changes in insulin distribution (insulin accumulates in fat).

The distribution of adipose tissue appears to affect its role in metabolic syndrome. Fat that is visceral or intra-abdominal correlates with inflammation, whereas subcutaneous fat does not. There are a number of potential explanations for this, including experimental observations that omental fat is more resistant to insulin and may result in a higher concentration of toxic free fatty acids in the portal circulation. [25]

Abdominal fat is known to produce potentially harmful levels of cytokines, such as tumor necrosis factor, adiponectin, leptin, resistin, and plasminogen activator inhibitor. [26]

Psychological characteristics, including anger, depression, and hostility, may be linked to increased risk for metabolic syndrome. [27] However, psychological disorders, especially anxiety, may represent comorbidity or a complication of metabolic syndrome. [28] Clearly, further study is warranted.

Epidemiology

Occurrence in the United States

Metabolic syndrome is increasing in prevalence, paralleling an increasing epidemic of obesity. In the United States, almost two thirds of the population in 2008 was overweight or obese, with more than one fourth of the population meeting diagnostic criteria for metabolic syndrome. [29]  2004 Data from a 1999-2000 survey showed that the age-adjusted prevalence of metabolic syndrome among US adults aged 20 years or older had risen from 27% (1988-1994 data) to 32%. [30]  2011-2014 National Health and Nutrition Examination Survey (NHANES) data showed a crude estimate of 36.5% for the prevalence of adult obesity (32.3% in adults aged 20-39 years; 40.2% in those aged 40-59 years; 37.0% in those aged ≥60 years). [20] There was a 38.3% overall prevalence of obesity in women and a 34.3% in men. Among youth aged 2-19 years, there was a 17% prevalence of obesity over the same period (8.9% in those aged 2-5 years; 17.5% in those aged 6-11 years; 20.5% in those aged 12-19 years). [20]  

Fortunately, since peaking in 2001-2002, the overall prevalence of metabolic syndrome in the United States has fallen, primarily due to decreases in the prevalences of hypertriglyceridemia and hypertension—and in spite of increases in the prevalences of hyperglycemia and obesity/waist circumference. [31]  Data from the 2009-2010 NHANES showed that the age-adjusted prevalence of metabolic syndrome had fallen to approximately 24% in men and 22% in women. [32]

International occurrence

Metabolic syndrome is a burgeoning global problem, with an increasing prevalence in urban populations of some developing countries. [10, 21] Approximately one fourth of the adult European population is estimated to have metabolic syndrome, with a similar prevalence in Latin America. [29] It is also considered an emerging epidemic in developing East Asian countries, including China, Japan, and Korea. The prevalence of metabolic syndrome in East Asia may range from 8-13% in men and from 2-18% in women, depending on the population and definitions used. [33, 34, 35]

In Japan, the Ministry of Health, Labor, and Welfare has instituted a screening and interventional program. [36] Metabolic syndrome has been recognized as a highly prevalent problem in many other countries worldwide. [37, 38, 39, 40, 41, 42]

Race-related demographics

The fact that the diagnostic criteria for metabolic syndrome vary between ethnic populations is testimony to significant nuances in the manifestation of metabolic syndrome in these groups. The original metabolic syndrome criteria were derived in mostly Caucasian populations, and some have argued for modification of individual criteria for specific ethnic subgroups, as has been done with waist circumference for patients of Asian origin. [43]

In the United States, metabolic syndrome has a high prevalence in African Americans, particularly African American women, and this has been attributed to the higher prevalence of obesity, hypertension, and diabetes in this population. [44] However, the highest age-adjusted prevalence of metabolic syndrome in the United States is found in Mexican Americans, approximately 31.9% of whom had the condition (compared with 27% of the general population) in a 1988-1994 survey. [45]

A study by Ukegbu et al found that African immigrants have a worse metabolic profile than do African Americans but that they have a similar prevalence of metabolic syndrome. This may mean that metabolic syndrome may underpredict metabolic risk in Africans. [46]

Sex-related demographics

Metabolic syndrome is similarly prevalent in men (24%) and women (22%), after adjusting for age. [32] However, several considerations are unique to women with metabolic syndrome, including pregnancy, use of oral contraceptives, and polycystic ovarian syndrome. [47] Metabolic syndrome and polycystic ovarian syndrome share the common feature of insulin resistance; they therefore share treatment implications as well. [48] Cardiometabolic risk is thought to be elevated in both groups. [49]

In addition, a modest association is apparent between metabolic syndrome and breast cancer, especially in postmenopausal women. [50] Overall, the prevalence of metabolic syndrome in women appears to be increasing, particularly in those of childbearing age. [51]

Bhasin et al, as part of the Framingham Heart Study, found that sex hormone-binding globulin is independently associated with the risk of metabolic syndrome, whereas testosterone is not. Age, body mass index (BMI), and insulin sensitivity independently affect sex hormone-binding globulin and testosterone levels. [52] More recent studies have raised the possibility of an association between testosterone deficiency and metabolic syndrome. [53]

Age-related demographics

The prevalence of metabolic syndrome increases with age, with about 40% of people older than 60 years meeting the criteria. [30] However, metabolic syndrome can no longer be considered a disease of only adult populations. Alarmingly, metabolic syndrome and diabetes mellitus are increasingly prevalent in the pediatric population, again in parallel with a rise in obesity. [54]

In the United States, children are becoming obese at triple the rate compared with the 1960s, making the study and treatment of this problem paramount. The epidemic of metabolic syndrome in children and adolescents is an international phenomenon, leading the International Diabetes Foundation to publish an updated consensus statement to guide diagnosis and further study of the condition. [55, 56]

Prognosis

The complications of metabolic syndrome are broad. Numerous associated cardiovascular complications exist, particularly coronary heart disease, but also atrial fibrillation, [57, 58] heart failure, [59] aortic stenosis, [60] ischemic stroke, [61] and, possibly, venothromboembolic disease. [62]  Cardiovascular disease and diabetes mellitus coexist and are two leading causes of death. [10, 20]  Evidence also exists to indicate that upregulation of the renin-angiotensin-aldosterone system and derangements to metabolic pathways (eg, glucose and fat metabolism) can also promote pulmonary vascular disease (eg, pulmonary arterial hypertension) and right heart failure. [59]

Emerging data suggest an important correlation between metabolic syndrome and risk of stroke. [63] Each of the components of metabolic syndrome has been associated with elevated stroke risk, and evidence demonstrates a relationship between the collective metabolic syndrome and risk of ischemic stroke. [64] Metabolic syndrome may also be linked to neuropathy beyond hyperglycemic mechanisms through inflammatory mediators. [65]

The metabolic derangements that characterize metabolic syndrome have been implicated in the development of nonalcoholic fatty liver disease. [66, 67] Indeed, the fatty liver is thought to play an important role in the development of metabolic syndrome. [68]

In addition, metabolic syndrome has been implicated in the pathophysiology of several other diseases, including obstructive sleep apnea. Breast cancer has also been linked to metabolic syndrome, possibly through dysregulation of the plasminogen activator inhibitor-1 (PAI-1) cycle. [69] Additional studies have linked metabolic syndrome with cancers of the colon, gallbladder, kidney, and, possibly, prostate gland. [70] Evidence is emerging of an association with psoriasis. [71, 72]

Metabolic syndrome between pregnancies increases the risk of recurrent preeclampsia, according to a retrospective cohort study of 197 women who had preeclampsia during their first pregnancy. Of the 197 women, 40 (20%) had metabolic syndrome between pregnancies. Of these 40 women, 18 (45%) had preeclampsia during their second pregnancy, compared with 27 (17%) of the 157 women without metabolic syndrome between pregnancies. The risk of recurrent preeclampsia increased with the number of components of the metabolic syndrome present. [73, 74]

Additional research has raised the possibility that metabolic syndrome adversely affects neurocognitive performance. [75] In particular, metabolic syndrome has been blamed for accelerated cognitive aging. [76] Patients with mental illnesses also face increased cardiometabolic risk due at least in part to socioeconomic factors such as greater poverty and poorer access to medical care. [77, 78]

Paradoxically, metabolic syndrome was associated with a lower risk of bone fractures in a meta-analysis. [79] Further study is warranted.

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Author

Stanley S Wang, JD, MD, MPH Clinical Cardiologist, Austin Heart South; Director of Legislative Affairs, Austin Heart; Medical Director, Sleep Disorders Center at Heart Hospital of Austin; Assistant Professor of Medicine (Adjunct), University of North Carolina School of Medicine

Stanley S Wang, JD, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, American Stroke Association, Texas Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Yasmine S Ali, MD, MSCI, FACC, FACP Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine; President, LastSky Writing, LLC

Yasmine S Ali, MD, MSCI, FACC, FACP is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Medical Writers Association, National Lipid Association, Tennessee Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LastSky Writing;Philips Healthcare;M Health;Athena Health;PeerView Institute;Verywell Health; HealthCentral;MedEdicus;Pharmaceutical Training Institute;Elsevier;MedStudy;North American Thrombosis Forum;WellnessVerge;Prose Media; AKH, Inc.<br/>Serve(d) as a speaker or a member of a speakers bureau for: North American Thrombosis Forum.

Acknowledgements

Justin D Pearlman, MD, ME, PhD, FACC, MA Chief, Division of Cardiology, Director of Cardiology Consultative Service, Director of Cardiology Clinic Service, Director of Cardiology Non-Invasive Laboratory, Director of Cardiology Quality Program KMC, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School

Justin D Pearlman, MD, ME, PhD, FACC, MA is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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