Approach
Typically, patients are asymptomatic and metabolic syndrome is detected on routine blood tests or physical examination for other causes. Suspicion should be raised in patients with a personal or family history of coronary artery disease (CAD) or type 2 diabetes mellitus (DM). Patients who are older, from an urban area, with a Western lifestyle, or exhibiting certain features such as polycystic ovary syndrome (PCOS) are more susceptible to metabolic syndrome and should be more carefully investigated.
The use of multiple different sets of criteria complicates the diagnosis of metabolic syndrome, as an individual patient can meet one set and not another and those meeting any two sets of criteria seem to be at no less risk than those meeting three sets. It has been suggested that all coronary vascular disease risk factors should be individually and aggressively treated, and that achieving these goals removes the need for a diagnosis of metabolic syndrome.[69]
Clinical history
Systemic enquiry
Symptoms of type 2 DM (polyuria, polydipsia, and weight loss), cardiovascular disease (angina, claudication), metabolic dysfunction-associated steatotic liver disease (MASLD; abdominal pain), PCOS (menstrual disturbances, abnormal hair growth), and obstructive sleep apnoea (sleep disturbance, excessive daytime sleepiness, snoring, gasping breaths) should be elicited.
Medical history
A personal history of type 2 DM, hypertension, insulin resistance, hyperlipidaemia, or HIV infection should be sought.
Drug history
A thorough history of current and previous medications, including glucocorticoids, antipsychotics, and anti-HIV therapy, should be obtained.
Family history
Any family history of cardiovascular disease (angina, myocardial infarction, stroke, claudication), type 2 DM, hyperlipidaemia, obesity, PCOS, or lipodystrophy should be documented.
Social history
Patients should be asked about their general lifestyle, including exercise habits, diet, alcohol intake, and smoking.
Physical examination
Examination should include measurement of blood pressure, body mass index, and waist and hip circumferences, and calculation of the waist-to-hip ratio, as these are essential criteria for the diagnosis of metabolic syndrome.
The cardiovascular system, the respiratory system, and the abdomen should be thoroughly examined. Particular attention should be given to corneal arcus and xanthelasma (yellow plaques on eyelids secondary to lipid deposition) in hyperlipidaemia, hepatomegaly in MASLD, and hirsutism, acne, and acanthosis nigricans (a skin disorder characterised by hyperpigmentation and hyperkeratosis, occurring mainly in the folds of the skin in the axilla, groin, and back of the neck) in PCOS.
Initial blood tests
All patients suspected of having metabolic syndrome should undergo the following blood tests, as they are essential for the diagnosis.
Fasting blood glucose:
Normal fasting blood glucose is <5.5 mmol/L (<100 mg/dL).
Diabetes is diagnosed if the fasting blood glucose is >6.9 mmol/L (>125 mg/dL) on 2 occasions.
Fasting triglycerides:
Patient must fast for 12 hours for optimal results.
Acute physiological stress, including infections and acute coronary syndromes, can raise levels.
Fasting total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol:
Patient must fast for 12 hours for optimal results.
Further blood and urine tests
Haemoglobin A1c (HbA1c) and oral glucose tolerance test (OGTT):
When fasting blood glucose is between 5.6 and 6.9 mmol/L (101 and 125 mg/dL), a HbA1c should be performed and an OGTT (2-hour glucose determination after a 75 g glucose load) may be considered.
HbA1c ≥6.5% (≥48 mmol/mol) is diagnostic of type 2 DM.
Blood glucose of 11.1 mmol/L (200 mg/dL) or more after the OGTT is diagnostic of type 2 DM.
Blood glucose <11.1 mmol/L (<200 mg/dL) and >7.8 mmol/L (>140 mg/dL) after the OGTT is diagnostic of impaired glucose tolerance.
Renal function:
Serum urea, creatinine, and electrolytes should be measured, as nephropathy and renal failure are common clinical features in metabolic syndrome, especially in those with impaired glucose levels.
Liver function tests:
Aminotransferases should be measured, as metabolic syndrome is frequently associated with MASLD leading to elevated alanine aminotransferase and aspartate aminotransferase.
Patients with elevated aminotransferases and metabolic syndrome should be referred to a hepatologist.
Urinary albumin:
Microalbumin/creatinine ratio may show increased urinary albumin excretion, indicating diabetic or hypertensive nephropathy.
Thyroid function tests:
Hypothyroidism is often associated with dyslipidaemia and should be excluded at initial assessment.
If thyroid-stimulating hormone (TSH) is elevated, free T4 should be assessed.
Elevated TSH combined with low free T4 indicates primary hypothyroidism.
Serum uric acid levels:
Hyperuricaemia is an independent predictor of metabolic syndrome in both sexes, and the risk of metabolic syndrome increases with increased serum uric acid levels; however, it should be noted that, while common in patients with metabolic syndrome, hyperuricaemia is a laboratory index and not a diagnostic criterion.[70]
ECG
Cardiovascular disease is common in metabolic syndrome. An ECG may show ischaemic changes or evidence of a previous myocardial infarction (such as inverted T waves, or Q waves greater than one quarter the height of the R wave and >0.04 seconds), atrial fibrillation, and left ventricular hypertrophy (suggesting unrecognised chronic hypertension). A normal ECG does not rule out coronary artery disease. Patients with an abnormal resting ECG may require further cardiac investigation.
Investigation of associated comorbidities
If the presence of conditions closely associated with metabolic syndrome (in addition to the individual components of metabolic syndrome) is clinically suspected, further tests to investigate these should be undertaken.
MASLD (previously known as non-alcoholic fatty liver disease):
Abdominal ultrasound is undertaken if the aminotransferases are elevated, to exclude other causes of abnormal liver function tests. It may show evidence of steatotic (fatty) liver disease, such as increased hepatic parenchymal echotexture and vascular blurring. It cannot distinguish alcoholic from non-alcoholic steatotic liver disease.
Patients at risk of progressive MASLD can be identified through measurement of liver stiffness on transient elastography, controlled attenuation parameter measured using an ultrasound FibroScan device, and aspartate aminotransferase. The results of these three tests are used to generate a FAST (FibroScan-AST) score which predicts risk of progression from MASLD to liver fibrosis.[71]
PCOS:
Serum hormone levels: total and free testosterone, dehydroepiandrosterone sulfate, androstenedione, sex hormone binding globulin, luteinising hormone, follicle-stimulating hormone, and prolactin should be measured.
Ultrasound of the ovaries shows polycystic ovaries.[72]
Oligo-amenorrhoea will be present.
Hypogonadism:
Metabolic syndrome is associated with male hypogonadism. It may therefore be reasonable to assess the levels of total and free testosterone and sex hormone binding globulin in male patients with metabolic syndrome.[48][49]
See Hypogonadism in men.
Female hypogonadism (menopause and premature ovarian insufficiency) is also associated with an increased incidence of the components of metabolic syndrome (abdominal obesity, hyperglycaemia, arterial hypertension, and dyslipidaemia). Measurement of serum estradiol and follicle-stimulating hormone may be considered.
See Menopause and Premature ovarian failure.
Sleep disorders:
Obstructive sleep apnoea is strongly associated with obesity and may be associated with insulin resistance.[4][55][56][73]Insomnia, suboptimal sleep duration, and circadian misalignment have also been associated with metabolic syndrome.
Patients with metabolic syndrome should undergo routine sleep assessment.[54]
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