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Metabolic Syndrome
Introduction
Metabolic syndrome is an accumulation of several disorders that raise the risk of atherosclerotic cardiovascular disease, including myocardial infarction, cerebrovascular accidents, peripheral vascular diseases, insulin resistance, and type II diabetes mellitus. The cluster of metabolic disorders that define metabolic syndrome includes central obesity, insulin resistance, hypertension, and atherogenic dyslipidemia.[1]
The diagnosis of metabolic syndrome requires the presence of 3 or more metabolic abnormalities:
- A waist circumference of more than 40 inches in men and 35 inches in women
- Serum triglycerides level of 150 mg/dL or greater
- Reduced high-density lipoprotein cholesterol, less than 40 mg/dL in men or less than 50 mg/dL in women
- Elevated fasting glucose of l00 mg/dL or greater
- Blood pressure values of systolic 130 mm Hg or higher or diastolic 85 mm Hg or higher [2]
Patients with metabolic syndrome are estimated to have a 2-fold increased risk of atherosclerotic cardiovascular diseases and a 5-fold increased risk of diabetes mellitus, as compared to the general population.[3] Metabolic syndrome is also associated with accelerated atherosclerosis, premature atherosclerotic cardiovascular diseases, and early onset type II diabetes mellitus.[4][5] The sedentary lifestyle and excess consumption of calories have significantly increased the proportion of the population with obesity in the last few decades.[6] Due to this exponential growth in population obesity, the incidence of metabolic syndrome has increased significantly over the last 2 decades.[7] Currently, more than one-fifth of Americans, as well as the European population, are suffering from metabolic syndrome.
Central obesity is the primary component of metabolic syndrome, leading to insulin resistance, hypertension, and dyslipidemia.[8] The clinical presentation of metabolic syndrome is variable and depends on the underlying atherosclerotic cardiovascular disease. The common signs of metabolic syndrome include abdominal obesity with high body mass index and increased waist circumference, elevated blood pressure, and signs of insulin resistance.[9] Metabolic syndrome has serious implications for an individual’s health. The prevalence of metabolic syndrome is rising, and through intervention, the progression can be halted and potentially reversed.[10][11]
Etiology
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Etiology
The underlying etiology of metabolic syndrome is multifactorial. The proposed causes include genetic predisposition and multiple environmental or lifestyle factors, including obesity, lack of physical activity, and unhealthy dietary habits.[12] The crux of the syndrome is a buildup of fatty tissue, especially in the abdomen, leading to insulin resistance.[13] Proinflammatory cytokines, such as tumor necrosis factor, leptin, adiponectin, plasminogen activator inhibitor, and resistin, are released from the enlarged adipose tissue, which adversely alters and impacts insulin.[14]
Insulin resistance can be acquired or due to genetic predisposition. Impairment of the signaling pathway, insulin receptor defects, and defective insulin secretion can all contribute to insulin resistance. Visceral obesity has been identified as the main trigger of all pathways involved in the pathogenesis of metabolic syndrome, and high-calorie intake is the primary cause of visceral fat accumulation.[8] Over time, the culmination causes the development of metabolic syndrome that presents as vascular and autonomic damage.[15]
Although environmental factors are considered the leading cause of metabolic syndrome and its pathogenesis, genetic factors can not be ignored. Results from studies have shown that the offspring of obese parents have a higher chance of obesity than healthy individuals.[16] Epidemiologic studies have shown that environmental factors in fetal life and the early postnatal period influence disease risk and pathogenesis in adults. Thus, the mother’s lifestyle and intrauterine and postnatal nutrition play an important role in the etiology and pathogenesis of the metabolic syndrome.[17]
Epidemiology
The global incidence of metabolic syndrome rises almost parallel to the incidence of obesity. According to the National Health and Nutrition Examination Survey (NHNES), the prevalence of metabolic syndrome in adults increased from 25.3% to 34.2% in 2012.[2] The survey further revealed that the South Asian American population had a very high incidence of metabolic syndrome, albeit a lower prevalence of obesity as compared to non-Hispanic white men and women.[18] The prevalence of metabolic syndrome peaked at the start of the 21st century in the United States. The prevalence gradually decreased due to early diagnosis and proper treatment of dyslipidemia and hypertension (although the prevalence of obesity was increasing).[19] In the 2009-2010 NHNES report, the prevalence of metabolic syndrome was 22% in women and 24% in men.[20]
In Europe and Latin America, around one-fourth of the general population is reported to have metabolic syndrome.[21][22][23] The incidence of metabolic syndrome in China has also increased over the last 3 decades. However, it is lower than in the United States and was estimated to reach 15.5% in 2017.[24] Metabolic syndrome is no longer a disease of the adult population; this condition is also reported to involve children and adolescents. In 2020, 3% of children and 5% of adolescents were found to have metabolic syndrome globally. The incidence of metabolic syndrome is slightly higher in children of low-income countries, which suggests the high economy of the country is not a predictor of metabolic syndrome.[25] The prevalence of metabolic syndrome increases with increasing age; almost 40% of people have metabolic syndrome in the 6th decade of their lives.[26] Although metabolic syndrome involves both men and women equally, it is slightly more prevalent in women than men in certain ethnic groups.
Pathophysiology
Metabolic syndrome has been studied extensively over the past few decades. Insulin resistance, adipose tissue dysfunction, and chronic inflammation have been proposed as the basic components of the pathogenesis of metabolic syndrome.[27][28] Under normal circumstances, a sudden rise in serum glucose level triggers insulin secretion from the pancreatic β-cells, which promote cellular glucose uptake via glucose transporters. However, in those with insulin resistance, tissues are less sensitive to this acute rise in insulin, resulting in a higher serum glucose level and hyperinsulinemia.[29] The impairment in insulin secretion and abnormal insulin signaling results in impaired glucose metabolism, fat deposition, cardiotoxicity, and chronic inflammation, the characteristic features of metabolic syndrome.[30]
Visceral obesity is another essential component of metabolic syndrome. Free fatty acids released by the adipose tissues promote insulin resistance and inhibit insulin secretion from the pancreatic beta cells.[31] The high-free fatty acids inhibit glucose uptake in skeletal muscles and increase hepatic gluconeogenesis and lipid synthesis by inducing protein kinases. Both insulin resistance and free fatty acids play a major role in the pathogenesis of hypertension, prothrombotic state, and chronic inflammation.[14] Visceral adipose tissues also secrete multiple active metabolites and various pro-inflammatory cytokines, C-reactive protein, leptin, and resistin, which induce chronic inflammation, a possible mechanism of various complications of metabolic syndrome.[32][33]
The inflammatory cytokines further increase insulin resistance in skeletal muscles, liver, and adipose tissues by inhibiting the insulin signaling pathway in these tissues. These cytokines, especially tumor necrosis factor-alpha, promote insulin resistance by inactivating insulin receptors in the skeletal muscles.[34] Insulin resistance further activates inflammatory cytokines and promotes thrombogenesis by increasing the fibrinogen level.[35]
Metabolic syndrome adversely influences several body systems. Insulin resistance causes microvascular damage, predisposing patients to endothelial dysfunction, vascular resistance, hypertension, and vessel wall inflammation. Endothelial damage can impact the body’s homeostasis, causing atherosclerotic disease and the development of hypertension.[36] Furthermore, hypertension adversely affects several body functions, including increased vascular resistance and stiffness, causing peripheral vascular disease, structural heart disease comprising of left ventricular hypertrophy and cardiomyopathy, and leading to renal impairment.
Accumulated effects of endothelial dysfunction and hypertension due to metabolic syndrome can further result in ischemic heart disease. Endothelial dysfunction due to increased levels of plasminogen activator inhibitor-1 and adipokine levels can cause thrombogenicity, while hypertension causes vascular resistance by which coronary artery disease can develop. Dyslipidemia associated with metabolic syndrome can drive the atherosclerotic process, leading to symptomatic ischemic heart disease.[37][38]
History and Physical
History
Although metabolic syndrome is diagnosed based on physical examination findings and laboratory investigations, history is essential to screening patients suspected to have metabolic syndrome. A detailed history of the patient’s lifestyle, eating habits, and family history may help identify the risk factors for metabolic syndrome and guide its management—the history of premature coronary artery disease warrants evaluation of the different components of metabolic syndrome. At the same time, the classic symptoms of polyuria, polydipsia, and polyphagia suggest diabetes mellitus, a well-known element or complication of metabolic syndrome. History and physical exams are vital for disease recognition, treatment, and prevention.[39] Social history should also be obtained to screen for modifiable factors eg, smoking, that can impact the development of cardiovascular complications in metabolic syndrome
Physical Exam
The patient encounter starts with vitals and general appearance, which can point toward the diagnosis of metabolic syndrome. As mentioned above, 3 abnormalities indicate the diagnosis, so specific metrics are necessary. Every patient presenting for the evaluation should have waist circumference measured.[40] The physical examination may reveal signs of insulin resistance, such as acanthosis nigricans, and signs of dyslipidemia, such as xanthomas.[41]
Evaluation
Initial Laboratory Investigations
After a thorough history and physical examination, the evaluation for metabolic syndrome needs to be complemented with laboratory analysis. The initial blood work should include fasting blood glucose and hemoglobin A1c to screen for insulin resistance and diabetes mellitus. A lipid panel should also be drawn to assess abnormally elevated triglyceride levels, low HDL levels, and elevated low-density lipoprotein levels. The initial evaluation should also include a basic metabolic panel to evaluate for renal dysfunction. Further studies such as C-reactive protein, liver function tests, thyroid studies, and uric acid can be considered in a selected group of patients to evaluate associated disorders.[42] Hypothyroidism is associated with an increased risk of metabolic syndrome, while hyperuricemia is commonly found in patients with metabolic syndrome due to a chronic inflammatory state.[43]
Investigations for Evaluation of Complications
The contemporary guidelines recommend the estimation of atherosclerotic cardiovascular disease (ASCVD) risk in all patients with metabolic syndrome to devise the primary prevention strategy.[44] In asymptomatic patients with a significant risk of ASCVD or a family history of premature ASCVD, coronary calcium score can be considered for the assessment of cardiovascular diseases and appropriate management.[45] Meanwhile, when appropriate, invasive or non-evasive imaging studies should be ordered in symptomatic patients. If warranted, patients should be evaluated further with cardiac stress testing, including an electrocardiogram stress test, stress echocardiography, stress single-photon emission computed tomography, or myocardial perfusion imaging.[46][47]
Treatment / Management
Metabolic syndrome is a global pandemic involving millions of people in different regions of the world. The primary goal of the management is to identify and treat the risk factors and reduce the cardiovascular complications of metabolic syndrome. The management of metabolic syndrome can be divided into lifestyle modifications and medical management.
Lifestyle Modifications
All components of metabolic syndrome are linked with lifestyle; a healthy lifestyle is an effective way of treating the risk factors for metabolic syndrome and preventing associated cardiovascular complications. The primary goal of the intervention is to create a balance between calorie requirement and intake.[31] The recommended lifestyle modifications include physical activity, a healthy diet, avoiding tobacco use, good sleep hygiene, and decreased alcohol consumption. The contemporary guidelines recommend a 7% to 10% reduction in the baseline body weight over 12 months, with physical activity and calorie deficit. The long-term goal is to achieve a body mass index of less than 25 kg/m2 and maintain the ideal body weight.[48] The American Heart Association and American College of Cardiology recommend 150 minutes of moderate-intensity or 70 minutes of high-intensity physical activity weekly.[49] A diet rich in vegetables, fruits, legumes, whole grains, nuts, and fish is recommended to reduce cardiovascular diseases. It is also recommended to avoid processed foods, refined carbohydrates, a diet rich in saturated fat, and reduce the amount of sodium.[50] Social support and the management of psychosocial stresses are significant for the maintenance of a healthy lifestyle. Individualized lifestyle modification according to patients' age, gender, and availability of resources helps maintain a healthy lifestyle.(A1)
Pharmacologic Managament
It is imperative to ensure the implementation of a healthy lifestyle before considering pharmacologic options for managing metabolic syndrome. In patients with metabolic syndrome, drug therapy is commonly recommended for the treatment of dyslipidemia, hypertension, and insulin resistance or diabetes mellitus. Patients with dyslipidemia should be evaluated for reversible causes, and pharmacotherapies must be advised according to the clinical practice guidelines.[51] Hypertension is another component of metabolic syndrome that requires pharmacotherapy.(A1)
The practice guidelines recommend accurate measurement and documentation of blood pressure.[52] It is mandatory to diagnose and treat the reversible causes and aggravating factors of hypertension. At the same time, the choice of antihypertensive drugs depends on the associated co-morbid conditions and other risk factors.[52][53][52] The drugs recommended for treating insulin resistance include metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1(GLP-1) agonists, and pioglitazone.[54][55][56][55] Recent studies have found evidence of plant extracts' role in managing metabolic syndrome and its components; however, contemporary clinical practice guidelines do not recommend them.[57] Further research is required to evaluate medicinal plants' role in managing the metabolic syndrome. Patients with metabolic syndrome require multiple medications for the management of dyslipidemia, hypertension, insulin resistance, and obesity, and it is essential to monitor the patients closely for compliance with the treatment. (A1)
Surgical Management
Patients with severe obesity may benefit from bariatric surgery. Bariatric surgery is considered the most influential single therapy for metabolic syndrome. The most common procedures are laparoscopic adjustable gastric banding, laparoscopic Roux-en-Y gastric bypass, and laparoscopic sleeve gastrectomy. Bariatric surgery is recommended for patients with a BMI ≥40 kg/m2 or those with a BMI ≥35 kg/m2 and other comorbidities. Patients should have a long-term follow-up after surgery to avoid surgical, nutritional, and psychiatric complications.[58]
Differential Diagnosis
Metabolic syndrome is a combination of different atherosclerotic cardiovascular disease risk factors—the secondary causes of each are a component of the differential diagnosis. Renal parenchymal diseases, renovascular diseases, endocrine disorders, and coarctation of the aorta can be considered.[59] Hypothyroidism is one of the causes of hypertension, dyslipidemia, and obesity, so it is regarded as a close differential of metabolic syndrome.[60] The other differential diagnoses may include polycystic ovarian syndrome, pheochromocytoma, Cushing syndrome, and acromegaly.[61]
Prognosis
The prognosis of patients with metabolic syndrome is determined by the severity of its components and cardiovascular complications. Cardiovascular complications predict poor prognosis in patients with metabolic syndrome, and the risk of cardiovascular complications is proposed to be amplified due to the combination of multiple ASCVD risk factors.[62] Patients with metabolic syndrome have more than 2-fold higher risk of cardiovascular events as compared to those without metabolic syndrome, which predicts a poor prognosis. However, recent advances in managing atherosclerotic cardiovascular diseases have improved outcomes significantly.[63]
Complications
Patients with metabolic syndrome have multiple cardiovascular complications due to the underlying risk factors. These patients are found to have more than two-fold higher incidence of cardiovascular events, including myocardial infarction, cerebrovascular accidents, and heart failure, independent of age, gender, and the presence of diabetes.[64] Diabetes mellitus is another complication of metabolic syndrome. Almost all patients with metabolic syndrome develop diabetes mellitus, which further elevates the risk of cardiovascular diseases and leads to microvascular complications.[65] Obesity-related complications of metabolic syndrome may include obstructive sleep apnea, pulmonary hypertension, and osteoarthritis.
Consultations
The management of metabolic syndrome requires a multidisciplinary team. Following consultations are essential for the appropriate management of patients with metabolic syndrome.
- A cardiologist is required for the management of hypertension and cardiovascular complications.
- An endocrinologist is essential for treating insulin resistance and its complications.
- A dietitian is needed for a comprehensive diet plan.
- A physical trainer is needed to guide and monitor physical activity and exercise.
- A neurologist may be required for the management of cerebrovascular accidents.
Deterrence and Patient Education
The following are recommendations for patients with metabolic syndrome:
- Practice a healthy lifestyle and target a <25 kg/m2 BMI.
- Physical activity reduces cardiovascular diseases and improves survival.
- Engage in at least 150 minutes of moderate-intensity physical activity in a week.
- Eat a diet rich in vegetables, fruits, legumes, whole grains, and fish.
- Avoid refined carbohydrates and a diet rich in sodium and saturated fats.
- Quit smoking and avoid excessive alcohol intake.
- Have adequate sleep and get treated for obstructive sleep apnea, if needed.
Pearls and Other Issues
Sleep health and hygiene should also be discussed with patients who have metabolic syndrome because sleep apnea and sleep deprivation can lead to the development of metabolic syndrome. Studies have shown that 3 months of continuous positive airway pressure can reduce blood pressure in patients with moderate to severe sleep apnea and potentially reverse some metabolic syndrome abnormalities.[66]
Recognizing the development of metabolic syndrome is crucial to treating, preventing, and reversing the disease process. Through history and physical exam, as well as patient education and workup of the contributing factors, clinicians can treat the metabolic syndrome and potentially alter the trajectory of disease development.
Enhancing Healthcare Team Outcomes
The management of metabolic syndrome is best accomplished with an interprofessional team that includes a dietitian, physical therapist, pharmacist, cardiologist, internist, neurologist, bariatric surgeon, nurse practitioner, endocrinologist, and social worker. The key to managing this disorder is patient education. The patient must be told of the importance of changes in lifestyle and weight loss. The dietitian should educate the patient on a Mediterranean-style diet and the importance of exercise. The patient should be urged to stop smoking and abstain from alcohol. The pharmacist must ensure that the patient is compliant with the medications. Probably the most important intervention is exercise because it can lower body weight, cholesterol, blood pressure, and blood glucose at the same time. Finally, patients with metabolic syndrome should be educated on good sleep hygiene.[67][68]
Patients with metabolic complications can develop a wide range of complications, including heart disease, aortic stenosis, atrial fibrillation, stroke, and thromboembolic disease. Today, evidence seems to indicate that the risk of an ischemic stroke is much higher in patients with metabolic syndrome than previously thought. In addition, other problems associated with metabolic syndrome include a risk for malignancies of the kidney, gallbladder, colon, and prostate gland. Further, the metabolic syndrome may also increase the risk of eclampsia and affect cognitive performance. Finally, patients with metabolic syndrome also face higher medical bills, are more likely to face financial difficulties, and may experience barriers to healthcare.[69][70]
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