Metabolic Syndrome

Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. In general, it is agreed that hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, are components of the metabolic syndrome. The diagnosis includes measurements of the waist circumference and BP along with serum levels of triglycerides, HDL cholesterol, and fasting glucose. Management consists mostly of lifestyle modifications such as moderate exercise and a balanced diet high in fibers and unsaturated fats and low in sugar.

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Definition and Epidemiology

Definition

Metabolic syndrome is a cluster of biochemical and physiologic abnormalities associated with the development of cardiovascular disease and type 2 diabetes.

Epidemiology

Prevalence:

  • 22%–24% in the United States
  • 32% in Mexican Americans
  • Higher in African American and Mexican American women compared to men of the same ethnicity
  • Increasing with age → up to 44% in people > 60 years of age

Metabolic syndrome doubles the risk for developing cardiovascular disease.

Pathophysiology

With obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, excess adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue releases the following substances, with considerable effects on the body.

Nonesterified fatty acids (NEFAs)

  • Overload muscle and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver with lipid 
  • ↑ Insulin resistance

Proinflammatory cytokines

  • ↑ CRP levels 
  • ↑ Insulin resistance
  • Atherogenesis

Prothrombotic substances

  • ↑ Plasma plasminogen activator inhibitor (PAI)-1 
  • ↑ Fibrinogen (acute-phase reactant like CRP)

Adiponectin

  • A protein hormone and adipokine
  • Involved in regulating glucose levels 
  • Involved in fatty acid breakdown

Clinical Presentation and Diagnosis

Metabolic syndrome is defined as the presence of ≥ 3 of the following conditions:

  • Central, abdominal, or visceral obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity (characterized by adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue accumulation predominantly around the waist and trunk):
    • Waist circumference: ≥ 102 cm (40 in.) in men
    • Waist circumference: ≥ 88 cm (35 in.) in women
  • Elevated serum triglycerides: ≥ 150 mg/dL 
  • Reduced HDL cholesterol levels: 
    • < 40 mg/dL in men
    • < 50 mg/dL in women
  • Elevated BP: ≥ 130/85 mm Hg (or use of antihypertensives)
  • Elevated fasting glucose: ≥ 100 mg/dL (or use of antihyperglycemic agents)

Management

Lifestyle modifications

Diet:

  • Calorie restriction for weight reduction
  • Carbohydrate restriction: < 55% of daily calorie intake to reduce glucose levels
  • Mediterranean diet: 
    • High in fruits, vegetables, nuts, whole grains, and olive oil 
    • Benefits: weight loss, lowered BP, improved lipid profiles, improved insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance, decreased levels of inflammatory markers 
  • High-fiber diet:
    • About ≥ 30 g/day of fiber 
    • Benefits: weight loss, lowered lipid concentrations, decreased hyperinsulinemia

Exercise:

  • ≥ 30 minutes of moderate exercise 5 days per week 
  • Improves BP
  • Helps revert insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance
  • Promotes weight loss

Pharmacologic and surgical treatment

  • ACE inhibitors and diuretics for hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins for dyslipidemia
  • Antihyperglycemic agents, including metformin, for type 2 diabetes
  • Bariatric surgery Bariatric surgery Bariatric surgery refers to a group of invasive procedures used to surgically reduce the size of the stomach to produce early satiety, decrease food intake (restrictive type) and/or alter digestion, and artificially induce malabsorption of nutrients (malabsorptive type). The ultimate goal of bariatric surgery is drastic weight loss. Bariatric Surgery:
    • May be considered for refractory obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • Sleeve gastrectomy
    • Gastric bypass

Clinical Relevance

Metabolic syndrome is associated with several obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity-related disorders, the most important of which include:

  • Type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus: chronic condition characterized by abnormally high levels of blood glucose due to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance in the body. Patients present with frequent urination, increased thirst, and increased appetite. Management includes lifestyle modifications, drugs for modulation of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance, and ultimately insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin substitution. Continued hyperglycemia commonly results in angiopathy (often manifesting as foot ulcers and impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing), neuropathy, retinopathy (vision loss), and nephropathy ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease).   
  • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease: gradual loss of kidney function over months to years, most commonly caused by diabetes, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, glomerulonephritis, and polycystic kidney disease. The majority of patients develop only nonspecific symptoms at a late stage, including confusion and tiredness, loss of appetite, and leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg swelling. Management includes ACE inhibitors and adequate blood glucose and BP control. Ultimately, dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis or kidney transplantation is required. Metabolic syndrome increases the risk of CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • Polycystic ovary syndrome ( PCOS PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome):  condition in which the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries produce an abnormal amount of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens. Patients present with irregular menstrual cycles, infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, acne and hirsutism, and metabolic syndrome. Diagnosis is based on detection of anovulation, high androgen levels, and multiple ovarian cysts Ovarian cysts Ovarian cysts are defined as collections of fluid or semiliquid material, often walled off by a membrane, located in the ovary. These cysts are broadly categorized as either functional or neoplastic. Neoplastic ovarian cysts are subcategorized as either benign or malignant. Ovarian Cysts. Management includes lifestyle modifications and antiandrogenic drugs.
  • Obstructive sleep apnea Obstructive sleep apnea Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea ( OSA OSA Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea): sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep-related breathing condition characterized by recurrent episodes of complete or partial obstruction of the upper airway. Patients present with reduced or partly absent breathing during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep that is often associated with loud snoring, headaches, and daytime sleepiness. Management includes weight loss for obese patients as well as continuous positive airway pressure (CPAP) and mandibular advancement devices.
  • Gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout: type of inflammatory arthritis that causes painful attacks of joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, most commonly at the base of the big toe. Chronic hyperuricemia leads to the deposition of uric acid crystals in joints and tendons. Prevention includes avoiding alcohol, fructose, and organ meats and seafood high in purine. Acute attacks are treated with NSAIDs, colchicine, and glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.

References

  1. Mayans, L. (2015). Metabolic syndrome: insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance and prediabetes. FP Essentials 435:11–16. Retrieved April 15, 2021, from https://pubmed.ncbi.nlm.nih.gov/26280340/
  2. Meigs, J. (2021). Metabolic syndrome ( insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance syndrome or syndrome X), UpToDate. Retrieved April 13, 2021, from https://www.uptodate.com/contents/metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-x
  3. Grundy, S.M., Brewer, H.B., Jr., Cleeman, J.I., et al. (2005). Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112:2735–2752. Retrieved April 15, 2021, from https://www.ahajournals.org/doi/10.1161/01.CIR.0000111245.75752.C6
  4. Alberti, K. G. M. M., et al. (2009). Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645. Retrieved April 15, 2021, from doi:10.1161/CIRCULATIONAHA.109.192644.https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.109.192644
  5. Ford, E.S., Giles, W.H., Dietz, W.H. (2002). Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359. doi:10.1001/jama.287.3.356 
  6. Moore, J.X., Chaudhary, N., Akinyemiju, T. (2017). Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Preventing chronic disease. Retrieved April 15, 2021, from https://www.cdc.gov/pcd/issues/2017/16_0287.htm
  7. Lakka, H.M., et al. (2002). The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716. doi:10.1001/jama.288.21.2709
  8. Kurella, M., et al. (2005). Metabolic syndrome and the risk for chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease among nondiabetic adults. Journal of the American Society of Nephrology 16:2134–2140. https://pubmed.ncbi.nlm.nih.gov/15901764/

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