History and exam
Key diagnostic factors
common
hypertension
Insulin resistance and compensatory hyperinsulinemia are strongly related to hypertension.
increased BMI
Obesity and being overweight are strongly related to insulin resistance and impaired glucose metabolism, increased plasma concentrations of free fatty acids, hypertriglyceridemia, low HDL-cholesterol, hypertension, and metabolic dysfunction-associated steatotic liver disease.
increased waist and hip circumferences
Cutoffs for increased waist and hip circumferences vary depending on the criteria used to define metabolic syndrome and ethnicity of the patient. Waist-to-hip ratio should also be calculated.
These are essential criteria for diagnosis of metabolic syndrome.
Other diagnostic factors
common
hyperglycemia
Symptoms of hyperglycemia or type 2 diabetes mellitus (polyuria, polydipsia) may be present.
metabolic dysfunction-associated steatotic liver disease (MASLD)
Previously known as nonalcoholic fatty liver disease. Comorbidity commonly associated with metabolic syndrome. Strong predictor of metabolic syndrome; correlates with all components of metabolic syndrome.
angina
Comorbidity commonly associated with metabolic syndrome. Chest pain on exertion indicates cardiovascular disease. Metabolic syndrome doubles cardiovascular risk, and patients with dyslipidemia often have ischemic cardiac disease.
claudication
Comorbidity commonly associated with metabolic syndrome. Calf pain on walking that resolves at rest (intermittent claudication) indicates peripheral vascular disease, which is often present in patients with dyslipidemia.
hyperuricemia
An independent predictor of metabolic syndrome in both males and females. For both genders, metabolic syndrome risk increases with increased serum uric acid levels; however, it should be noted that, while common in patients with metabolic syndrome, hyperuricemia is a laboratory index and not a diagnostic criterion.[70][74]
uncommon
menstrual disturbances
Presence of menstrual irregularity (oligo-amenorrhea) and heavy menses are consistent with symptoms of polycystic ovary syndrome (PCOS), a comorbidity commonly associated with metabolic syndrome. PCOS is strongly associated with insulin resistance and increased risk of type 2 DM and cardiovascular disease.
abdominal pain
Uncommon symptom of MASLD; a comorbidity commonly associated with metabolic syndrome. MASLD is a strong predictor of metabolic syndrome and correlates with all components of metabolic syndrome.
corneal arcus and xanthelasma
Yellow plaques on the eyelids secondary to lipid deposition and corneal arcus are signs of hyperlipidemia.
hirsutism
Sign of polycystic ovary syndrome, a condition strongly associated with insulin resistance and increased risk of type 2 DM and cardiovascular disease.
acanthosis nigricans
Skin disorder characterized by hyperpigmentation and hyperkeratosis, occurring mainly in folds of skin in axilla, groin, and back of neck; consistent with severe insulin resistance syndromes. It may be seen in PCOS, a comorbidity commonly associated with metabolic syndrome.
PCOS is strongly associated with insulin resistance and increased risk of type 2 DM and cardiovascular disease.
acne
Sign of polycystic ovary syndrome, a condition strongly associated with insulin resistance and increased risk of type 2 DM and cardiovascular disease.
hepatomegaly
May be present in MASLD; a comorbidity commonly associated with metabolic syndrome. MASLD is a strong predictor of metabolic syndrome and correlates with all components of metabolic syndrome.
Risk factors
strong
obesity
Although not all overweight or obese people are metabolically unhealthy, most are insulin resistant.[30] Excess adiposity is strongly related to insulin resistance and impaired glucose metabolism, as well as increased mobilization and plasma concentrations of free fatty acids, which lead to hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, hypertension, and fatty liver disease. Obesity is also associated with increased levels of inflammatory factors such as C-reactive protein, tumor necrosis factor-alpha, leptin, resistin, and interleukins 6, 10, and 18, and low levels of adiponectin.[4][12][27][28][29] Both metabolically unhealthy and obese people are at higher risk for cardiovascular disease compared with metabolically healthy and lean people, respectively.[31]
Data from the third US National Health and Nutrition Examination Survey (1988-1994) showed that metabolic syndrome was present in 5% of those of normal weight, 22% of those who were overweight, and 60% of those who were obese.[32]
insulin resistance
Strongly associated with an impaired fasting glucose and/or impaired glucose tolerance, increased free fatty acid concentration, high triglyceride and low HDL-cholesterol levels, and small and dense HDL-cholesterol and low-density lipoprotein (LDL)-cholesterol particles. These factors increase risk of atherosclerosis and cardiovascular disease.[4][12][16][17][18]
Insulin resistance and compensatory hyperinsulinemia are also strongly linked to hypertension.[4][22]
Presence of insulin resistance with metabolic syndrome has an additive effect, and people with both conditions have a 6 to 7 times increased risk of type 2 diabetes mellitus.
physical inactivity
About 70% of the US population are estimated to have a sedentary lifestyle.[14] Physical activity is inversely associated with insulin resistance and the development of metabolic syndrome, especially with waist circumference, triglyceride and blood glucose levels, and the Homeostasis Model Assessment Index. Physical inactivity is also directly associated with low HDL-cholesterol levels.[33][34]
Regular moderate to intense physical activity may prevent metabolic syndrome, and activity of greater intensity may confer more benefit.[35]
high-saturated-fat diet
Positively associated with fasting insulin levels.[36] A 5% increase in saturated-fat intake is associated with a 17% increase in coronary risk.[37] In a large prospective study, nearly 40% of participants consuming a "Western" high-saturated-fat diet developed metabolic syndrome after 9 years of follow-up. After adjustment for demographic factors such as smoking, physical activity, and energy intake, consuming a Westernized diet was associated with an 18% increased risk of developing metabolic syndrome, whereas a prudent diet, including vegetables, fruit, fish, whole grains, and low-fat dairy products, had a neutral effect on development of the condition.[38]
high-carbohydrate diet
May accentuate atherogenic dyslipidemia. The effects of this risk factor seem to be reduced by substituting carbohydrates with unsaturated fats of equal calories.[14]
excess alcohol consumption
Consumption of alcohol and, in particular, heavy drinking increases the risk of metabolic syndrome by influencing its components, especially triglyceride levels.[39]
increasing age
Prevalence of metabolic syndrome increases consistently with age (independently of sex) in the US and across the globe, from 6.7% for ages 20 to 29 years, to 43.5% for ages 60 to 69 years, and 42% for ages >70 years.[5][6]
However, prevalence varies in the sixth and seventh decades due to a survival effect, as people most susceptible to obesity-related death have probably already died by this point.[4][5]
ethnicity
Prevalence of metabolic syndrome seems to be lower in white, non-Hispanic women than in men and higher in African-American women than in men.[4] Hispanic and South Asian people are particularly susceptible to developing metabolic syndrome. Black men have a lower frequency of metabolic syndrome than white men, perhaps due to the lower prevalence of atherogenic dyslipidemia, although black men are more susceptible to hypertension and type 2 diabetes mellitus.[14]
Incidence of metabolic syndrome components defined by the same criteria varies by ethnicity. In particular, obesity-related conditions (type 2 diabetes mellitus, hypertension, dyslipidemia) occur more frequently at a lower body mass index in Asian people than in white people, and people of Far East Asian origin have a higher risk of cardiovascular disease.[9][10]
smoking
Current smokers (both male and female) are at increased risk of metabolic syndrome compared with those who have never smoked.[32]
positive family history
polycystic ovary syndrome (PCOS)
Comorbidity commonly associated with metabolic syndrome. Strongly associated with insulin resistance and increased risk of type 2 diabetes mellitus and coronary vascular disease.[43] Prevalence of metabolic syndrome is 2 times higher (about 43% to 47%) in women with PCOS than in women in the general population.[44] Another study found a lower rate of 33.4%.[45]
PCOS seems to aggravate insulin resistance and metabolic risk factors in obese women, whereas in those of normal weight, PCOS is not associated with impaired insulin sensitivity.[46]
hypogonadism
Comorbidity commonly associated with metabolic syndrome. In men, testosterone deficiency is associated with insulin resistance and an increased risk for type 2 diabetes mellitus and metabolic syndrome.[47] Testosterone replacement therapy in hypogonadal men with metabolic syndrome may improve metabolic control.[48][49]
Estrogen deficiency is also associated with an increased incidence of the components of metabolic syndrome (abdominal obesity, hyperglycemia, arterial hypertension and dyslipidemia) predisposing to increased risk of type 2 diabetes and cardiovascular disease. This is mostly evident in women with premature ovarian insufficiency and early menopause.[50]
hypercortisolism
Metabolic syndrome and Cushing syndrome (which results from endogenous or exogenous hypercortisolism) share many clinical features. Thus cortisol may contribute to the pathogenesis of metabolic syndrome.[15] Emerging data suggest that circulating cortisol concentrations are higher in patients with metabolic syndrome than in healthy people, both under basal conditions and during dynamic stimulation. Peripheral cortisol activity is increased and the hypothalamus-pituitary-adrenal axis is dysregulated in metabolic syndrome.[15][51][52]
antipsychotics
Atypical antipsychotic medications, especially clozapine, significantly increase the risk of developing metabolic syndrome.[53]
sleep disorders
Comorbid sleep disorders associated with metabolic syndrome include sleep apnea, insomnia, suboptimal sleep duration, and circadian misalignment.[54]
Obstructive sleep apnea (OSA) frequently coexists with metabolic syndrome (some use the term "syndrome Z" to refer to the two conditions together), and obesity is a key risk factor for development of OSA; however, there is also evidence that OSA leads to development of metabolic syndrome as intermittent hypoxia and arousal increase insulin resistance.[55][56]
Insomnia has been independently associated with increased risk of metabolic syndrome and its components (dyslipidemia, hypertension, obesity).[54][57] Both short and long sleep duration have been associated with a higher risk of metabolic syndrome compared with those who sleep 7-8 hours per day.[58] Circadian misalignment (sleeping and eating outside of the normal light-dark cycle) is associated with impaired glucose control and increased inflammatory markers.[54]
weak
lipodystrophy
Inherited or acquired disorders characterized by loss of selective adipose tissue depots. Patients with partial or generalized forms of lipodystrophy often have insulin resistance and share clinical features of metabolic syndrome.[4]
HIV infection
Insulin resistance is common in HIV-infected patients, particularly among those being treated with protease inhibitors. Long-term adverse effects of this therapy include dyslipidemia, changes in body fat distribution (lipodystrophy), and development of metabolic syndrome.[59]
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