Metabolic syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]

Metabolic syndrome is characterized by a cluster of conditions that greatly increases the risk of a person to develop heart diseases, diabetes and stroke. By definition one is said to have a metabolic syndrome if they have 3 of the following 5 conditions: high blood pressure (>130/85), abnormal fasting blood glucose > 100 mg/dl, increased weight around the waist (women > 35 inches, male > 40 inches), triglycerides > 150 mg/dl and a low HDL (female < 50, male < 40). The pathophysiology of metabolic syndrome is extremely complex and has only been partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Metabolic syndrome can be defined as a chronic state of low-grade inflammation. Common causes of metabolic syndrome include insulin resistance/hyperinsulinemia, hypertension, hypertriglyceridemia, and obesity. The diagnosis of metabolic syndrome is mostly based on physical examination and lab tests. The symptoms seen in metabolic syndrome are indicative of the component disorder like hypertension, diabetes, dyslipidemia and polycystic ovarian syndrome. The prevalence of metabolic syndrome varies depending on the age and ethnicity of the population studied. Dietary modifications are the first step in the management of metabolic syndrome. Medical therapy is indicated for the treatment of complications (diabetes, stroke, angina, myocardial infarction) associated with these conditions. Surgical therapy is not routinely performed for metabolic syndrome. However, in cases of morbid obesity and unresponsiveness of medical therapy, bariatric surgery can be performed.

The term “metabolic syndrome” dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes. In 1977, Haller coined the term “metabolic syndrome” for the first time when describing the additive effects of risk factors on atherosclerosis.

There is no established system for the classification of metabolic syndrome.

The pathophysiology of metabolic syndrome is extremely complex and has only been partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Metabolic syndrome can be defined as a chronic state of low-grade inflammation. Numerous factors which are believed to play a key role in the pathogenesis of metabolic syndrome includes:

• Insulin resistance
• Visceral adiposity
• Atherogenic dyslipidemia
• Endothelial dysfunction
• Genetic susceptibility
• Elevated blood pressure(Hypertension)
• Hypercoagulable state
• Chronic stress

Common causes of metabolic syndrome include insulin resistance/hyperinsulinemia, hypertension, hypertriglyceridemia, and obesity.

Metabolic syndrome occurs in the presence of insulin resistance and accompanying obesity. It increases the risk for coronary heart disease, diabetes, fatty liver, stroke and some cancers. It may manifests as hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol. The differential diagnosis includes chronic liver disease, Cushing syndrome and congenital adrenal hyperplasia with overlapping presentations.

The prevalence of metabolic syndrome varies depending on the age and ethnicity of the population studied. But over the past few decades prevalence has increased many fold. It is higher in western countries, with increasing ages and in certain races like Mexican-Americans and African-Americans.

Common risk factors in the development of metabolic syndrome include insulin resistance, aging, positive family history, lack of physical exercise, postmenopause, smoking, low economic status, high carbohydrate diet, atypical antipsychotics like clozapine, and soft drink consumption.

Metabolic syndrome occurs in the presence of insulin resistance and accompanying obesity. It increases the risk for coronary heart disease, type II diabetes, fatty liver, stroke and some cancers. It may manifest as hypertension, hyperglycemia, hypertriglyceridemia, reduced high density lipoprotein cholesterol and abdominal obesity. It affects a large number of people in a clustered fashion. In some studies, the prevalence in the USA is calculated as being up to 25% of the population.

There are currently two major definitions for metabolic syndrome provided by International Diabetes Federation (IDF) and the revised National Cholesterol Education Program (NECP), respectively. The revised National Cholesterol Education Program (NECP) and International Diabetes Federation (IDF) definitions of metabolic syndrome are very similar and it can be expected that they will identify many of the same individuals as having metabolic syndrome. The two differences are that IDF excludes any subject without increased waist circumference, while in the NCEP definition metabolic syndrome can be diagnosed based on other criteria and the IDF uses geographic-specific cut off points for waist circumference, while NCEP uses only one set of cut off points for waist circumference regardless of geography. These two definitions are much closer to each other than the original NCEP and WHO definitions.

The diagnosis of metabolic syndrome is mostly based on physical examination and lab tests. The symptoms seen in metabolic syndrome are indicative of the component disorder like hypertension, diabetes, dyslipidemia and polycystic ovarian syndrome. Also, dietary, family, social and medical history are important tools in the diagnosis.

Metabolic syndrome is a combination of medical disorders that increase one’s risk for cardiovascular disease and diabetes. It affects a large number of people in a clustered fashion. In some studies, the prevalence in the USA is calculated as being up to 25% of the population.

The diagnosis of metabolic syndrome is mostly based on physical examination and lab tests. The diagnostic criteria of different international societies also involve consideration of lab tests like lipid profile and fasting blood glucose.

Electrocardiograms are not routinely used in diagnosing metabolic syndrome. However, they can be used when patients with metabolic syndrome develops cardiovascular complications like angina, myocardial infarction or stroke.

There are no CT scan or MRI findings associated with metabolic syndrome.

There are no chest X-ray findings associated with metabolic syndrome.

There are no ultrasound findings associated with metabolic syndrome.

There are no other imaging findings associated with metabolic syndrome.

Obstructive sleep apnea is sometimes considered a risk factor for metabolic syndrome. It may present as sleep disturbances, snoring and day-time drowsiness. Polysomnography can act as an important tool in diagnosing these conditions.

Dietary modifications are the first step in the management of metabolic syndrome. It can be initiated either in isolation or along with other medications. It helps by assisting in weight loss, thus increasing insulin sensitivity. Studies support that diet, exercise, and drug therapy may inhibit the progression of metabolic syndrome to diabetes mellitus.

Regular aerobic exercises are thought to beneficial in decreasing the risks for the development of metabolic syndrome. Exercise may benefit by helping in weight reduction that in turn increases insulin sensitivity of the liver and other tissues.

Metabolic syndrome is formed by a constellation of medical disorders that increases the risk of developing cardiovascular disease and diabetes mellitus. It affects a large number of people in a clustered fashion. Management of metabolic syndrome involves dietary modifications, exercise and drug therapy for the complications (diabetes, stroke, angina, myocardial infarction) found associated with these conditions.

Metabolic syndrome occurs in the presence of insulin resistance and accompanying obesity. It increases the risk for coronary heart disease, diabetes, fatty liver, stroke and some cancers. Surgical therapy is not routinely performed for metabolic syndrome. However, in cases of morbid obesity and unresponsiveness of medical therapy, bariatric surgery can be performed. The beneficial effects of surgery is thought to be due to the weight loss after surgery that in turn decreases the insulin resistance. Also, increased secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) accompanies the surgery and thus helps in metabolic syndrome.

Primary prevention strategies intend to avoid the development of disease. Different strategies like dietary modification, increasing physical activity and weight reduction are found useful in the primary prevention (development) of metabolic syndrome.

Effective measures for the secondary prevention of metabolic syndrome in order to prevent its complication includes monitoring of lipid levels every 6 weeks, serum aminotransferase and CK levels every 6 months. Blood pressure, blood glucose, and HbA1c should be checked every 3 months.

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2] ; Aditya Ganti M.B.B.S. [3]

The term “metabolic syndrome” dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes. In 1977, Haller coined the term “metabolic syndrome” for the first time when describing the additive effects of risk factors on atherosclerosis.

• The term “metabolic syndrome” dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes.^[1][2]
• In 1947, Dr. Jean Vague proposed a theory that upper body obesity predisposed to diabetes, atherosclerosis, gout, and calculi.^[3]
• In 1967, Avogaro, Crepaldi and co-workers discovered obese patients with diabetes, hypercholesterolemia, and marked hypertriglyceridemia improved when they were put on a hypocaloric, low carbohydrate diet.^[4]
• In 1977, Haller coined the term “metabolic syndrome” for the first time when describing the additive effects of risk factors on atherosclerosis.^[5]
• In 1977, Singer coined the term hyperlipoproteinemia to describe the associations of obesity, gout, diabetes mellitus, and hypertension with metabolic syndrome.^[6]
• In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for myocardial infarction are not only associated with heart disease, but also with aging, obesity and other clinical states.^[7][8]
• In 1988, Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities as Syndrome X.^[9]

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is no established system for the classification of metabolic syndrome.

There is no established system for the classification of metabolic syndrome.

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Raviteja Guddeti, M.B.B.S. [3]; Aarti Narayan, M.B.B.S [4]

Metabolic syndrome is characterized by a cluster of conditions that greatly increase the risk of developing cardiovascular diseases, diabetes and stroke. By definition one is said to have a metabolic syndrome if they have 3 of the following 5 conditions: high blood pressure (>130/85), abnormal fasting blood glucose > 100 mg/dl, increased weight around the waist (women > 35 inches, male > 40 inches), triglycerides > 150 mg/dl and a low HDL (female < 50, male < 40).

The pathophysiology of metabolic syndrome is extremely complex and has only been partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Metabolic syndrome can be defined as a chronic state of low-grade inflammation.^[1] Numerous factors which are believed to play a key role in the pathogenesis of metabolic syndrome includes:

• Insulin resistance
• Visceral adiposity
• Atherogenic dyslipidemia
• Endothelial dysfunction
• Genetic susceptibility
• Elevated blood pressure(Hypertension)
• Hypercoagulable state
• Chronic stress

Physical inactivity Smoking Energy dense food Stress

Positive energy balance resulting in Adipose tissue hyperplasia and hypertrophy

Altered FFA metabolism

Altered release of adipokines

↑ Portal FFA

Insulin resistance hyperinsulinemia

↑Leptin ↑AT-II ↑Aldosterone

↑ Factor VII ↑ Factor V ↑ PAI-I

↑ Lipoprotein synthesis ↑ Gluconeogenesis

Impairs 𝛽-cell function of pancreas

Activate RAAS and SNS

Oxidative stress endothelial dysfunction

Dyslipidemia

Hyperglycemia

↑ Sodium reabsorption Vasoconstriction

Proinflammatory state prothrombotic state

Hypertension

Hypercoagulable state

Metabolic syndrome WC,TCG,HDL Blood pressure, Fasting blood glucose

Atherosclerotic CVD

Diabetes Mellitus

• Insulin resistance is considered the most acceptable hypothesis to describe the pathophysiology of metabolic syndrome.
• Free fatty acids, released from the expanding adipose tissue in obese patients, are the major contributors for the development of insulin resistance.
• In the liver elevated levels of these free fatty acids lead to increased production of glucose, triglycerides, VLDLs and LDLs.
• Free fatty acids inhibit insulin-mediated glucose uptake in the muscles.
• Increased circulating glucose stimulates increased pancreatic insulin secretion resulting in hyperinsulinemia.
• Excessive free fatty acids down regulate signaling pathways and lead to insulin resistance.
• Hyperinsulinemic state results in enhanced sodium reabsorption and increased sympathetic nervous system activity which in turn leads to hypertension.
• Obesity is a proinflammatory state and adipocytes enhance the secretion of interleukin-6, C-reactive protein and TNF which results in more insulin resistance and lipolysis of adipose tissue to FFAs.
• TNFα has been shown to not only cause the production of inflammatory cytokines, but may also trigger cell signaling by interaction with a TNFα receptor that may lead to insulin resistance.
• Cytokines and FFAs are also known to enhance the production of fibrinogen by the liver and plasminogen activator inhibitor-1 (PAI-1) resulting in a pro-thrombotic state. An experiment with rats that were fed a diet one-third of which was sucrose has been proposed as a model for the development of the metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNFα to insulin resistance has some parallels to human development of metabolic syndrome. Adiponectin is an anti-inflammatory cytokine produced by the adipose tissue. It enhances insulin sensitivity and glucose uptake in the muscles. Its levels are reduced in metabolic syndrome.^[2][3]

• Adipose tissue is a collection of adipocytes, stromal pre-adipocytes, immune cells, and endothelium.
• Adipocytes are dynamic in nature and respond to alterations in calorie intake through hypertrophy and hyperplasia.
• Obesity occurs when there is increased consumption of calorie-dense food with reduced physical activity.
• Combined with obesity and adipocyte hypertrophy results in decreased blood supply to adipocytes and subsequently hypoxia.
• Decreased blood supply along with hypoxia leads to necrosis and macrophage infiltration into adipose tissue.
• Infiltration by macrophages also attracts various inflammatory cells such as glycerol, free fatty acids (FFA), pro-inflammatory mediators (tumor necrosis factor alpha (TNF-𝛼) and interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP).

Inflammatory mediators	Productionction
Free Fatty Acids (FFA)	Produced by upper body subcutaneous adipocytes.	Acute exposure results in decreased glucose intake by smooth muscles Chronic exposure results in impairment of pancreatic 𝛽-cell function
Tumor necrosis factor alpha (TNF-𝛼)	Paracrine mediator in adipocytes	Reduce the insulin sensitivity of adipocytes Induces adipocytes apoptosis Inhibits insulin receptor substrate 1 signaling pathway
Interleukin-6 (IL-6)	Released by both adipose tissue and skeletal muscle	Systemic adipokine impairs insulin sensitivity by suppressing lipoprotein lipase activity. Major determinant of the hepatic production of CRP
CRP	Produced mainly by liver	Elevated levels of CRP are associated with an increased waist circumference, insulin resistance, BMI, and hyperglycemia.
Adiponectin	Adiponectin is inversely associated with CVD risk factors.	Increases glucose transport in muscles and enhances fatty acid oxidation. It inhibits hepatic gluconeogenic enzymes and the rate of an endogenous glucose production in the liver.
Leptin	Adipokine involved in the regulation of satiety and energy intake. Leptin receptors are located mostly in the hypothalamus and the brain stem Controls satiety, energy expenditure	Levels increase during the development of obesity and decline during the weight loss. Leptin resistance sets in obesity (no control over eating).

Defects in the mitochondrial oxidative phosphorylation lead to an accumulation of TGs and lipid molecules in the muscles have been identified in elderly patients with type II diabetes or obesity. Accumulation of these lipids in the muscles is associated with insulin resistance. Some have pointed to oxidative stress due to a variety of causes including dietary fructose mediated increased uric acid levels.^[4][5][6]

• Dyslipidemia is characterized by a spectrum of qualitative lipid abnormalities reflecting perturbations in the structure, metabolism, and biological activities of both atherogenic lipoproteins and antiatherogenic HDL-C which includes an elevation of lipoproteins containing apolipoprotein B (apoB), elevated TGs, increased levels of small particles of LDL, and low levels of HDL-C.
• Insulin resistance leads to an atherogenic dyslipidemia in several ways.^[7][8]
• First, insulin normally suppresses lipolysis in adipocytes, so an impaired insulin signaling increases lipolysis, resulting in increased FFA levels.
• In the liver, FFAs serve as a substrate for the synthesis of TGs.
• FFAs also stabilize the production of apoB, the major lipoprotein of very low density lipoprotein (VLDL) particles, resulting in a more VLDL production. Second, insulin normally degrades apoB through PI3K-dependent pathways, so an insulin resistance directly increases VLDL production.
• Third, insulin regulates the activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance.
• Thus, hypertriglyceridemia in insulin resistance is the result of both an increase in VLDL production and a decrease in VLDL clearance.
• VLDL is metabolized to remnant lipoproteins and small dense LDL, both of which can promote an atheroma formation.
• The TGs in VLDL are transferred to HDL by the Cholesterylester transferring protein (CETP) in exchange for cholesteryl esters, resulting in the TG-enriched HDL and cholesteryl ester enriched VLDL particles.
• Further, the TG-enriched HDL is a better substrate for hepatic lipase, so it is cleared rapidly from the circulation, leaving a fewer HDL particles to participate in a reverse cholesterol transport from the vasculature.
• Thus, in the liver of insulin-resistant patients, FFA flux is high, TGs synthesis and storage are increased, and excess TG is secreted as VLDL.
• For the most part, it is believed that the dyslipidemia associated with insulin resistance is a direct consequence of increased VLDL secretion by the liver.
• These anomalies are closely associatedwith an increased oxidative stress and an endothelial dysfunction, thereby reinforcing the proinflammatory nature of macrovascular atherosclerotic disease.

Insulin is a vasodilator under normal physiologic conditions with secondary effects on sodium reabsorption. In hyperinsulinemia and insulin resistance this vasodilatory effect of insulin is lost but the sodium reabsorption effect on the kidney is preserved. In caucasians this reabsorptive effect is increased in metabolic syndrome. Insulin also increases sympathetic nervous system activity and this effect is preserved in insulin resistance. Impairment of phosphatidylinositol-3-kinase signaling pathway causes imbalance between the production of NO and endothelin-1 resulting in reduced blood flow. ^[9]

Due to defects in insulin, Glucose intolerance leads to increased production of insulin to maintain normal glucose levels. When this compensatory mechanism fails, the result is progression from glucose intolerance to diabetes.

• Type II diabetes
  • The risk of developing diabetes mellitus in patients with metabolic syndrome is very high.^[10]
• Polycystic ovarian syndrome (PCOS)
  • Women with PCOS are more likely to have metabolic syndrome than women without PCOS.^[11][12]
• Hemochromatosis (iron overload)
  • The dysmetabolic iron overload syndrome seen very commonly in metabolic syndrome can result in hemochromatosis.^[13]
• Obstructive sleep apnea
  • This condition is associated with obesity, hypertension, insulin resistance, glucose intolerance and increase in circulating inflammatory cytokines. Insulin resistance is greater in patients with obstructive sleep apnea in comparison to weight matched controls.
• Hyperuricemia
  • Increase in serum uric acid levels is a result of defective action of insulin on the renal tubular cells. An increase in asymmetric methylarginine signifies endothelial dysfunction secondary to an insulin resistant state.
• Gout
• Nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
  • Inflammation and triglyceride accumulation coexists in this condition. This condition can result in fibrosis or cirrhosis of the liver, ultimately causing hepatic failure.^[14]

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Common causes of metabolic syndrome include insulin resistance/hyperinsulinemia, hypertension, hypertriglyceridemia, and obesity.

Common causes of metabolic syndrome include:

• Insulin resistance/hyperinsulinemia
• Hypertension
• Hypertriglyceridemia
• Obesity

Less common causes of metabolic syndrome include:

• Fatty liver
• Polycystic ovarian syndrome
• Gallstones
• Sleep apnea
• Secondary hyperparathyroidism^[1]

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Metabolic syndrome syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as Cushing’s syndrome and pseudo-Cushing’s syndrome.

The table below summarizes the findings that differentiate pseudo-Cushing’s disease from other conditions that may cause hypertension, hyperandrogenism, obesity, facial plethora, skin changes, osteoporosis, nephrolithiasis and neuropsychiatric conditions.^[1][2][3][4]

Conditions Causes Associated features Diagnostic approach Metabolic syndrome X Familial/genetic Obesity Insulin resistance Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Dyslipidemia Diabetes/Glucose intolerance Waist circumference Low-density lipoproteins High-density lipoproteins Glucose tolerance test Fasting blood sugar HbA1c Cushing’s syndrome Iatrogenic Pituitary adenoma Adrenal tumor Adrenal hyperplasia Ectopic ACTH secretion Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Osteoporosis Myopathy/cutaneous wasting Neuropsychiatric problems Kidney stones 24-hour urine cortisol Midnight salivary cortisol Low dose dexamethasone challenge test CRH stimulation High dose dexamethasone test MRI brain CT/MRI adrenals Pseudo-Cushing’s syndrome Obesity Alcoholism Depression HIV Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Urinary free cortisol Midnight salivary cortisol Low dose dexamethasone challenge test Glucose tolerance test Loperamide test References ↑ Boscaro M, Barzon L, Fallo F, Sonino N (2001). “Cushing’s syndrome”. Lancet. 357 (9258): 783–91. doi:10.1016/S0140-6736(00)04172-6. PMID 11253984. ↑ Findling JW, Raff H (2001). “Diagnosis and differential diagnosis of Cushing’s syndrome”. Endocrinol. Metab. Clin. North Am. 30 (3): 729–47. PMID 11571938. ↑ Newell-Price J, Trainer P, Besser M, Grossman A (1998). “The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states”. Endocr. Rev. 19 (5): 647–72. doi:10.1210/edrv.19.5.0346. PMID 9793762. ↑ “How Is Metabolic Syndrome Diagnosed? – NHLBI, NIH”. Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]

The prevalence of metabolic syndrome varies depending on the age and ethnicity of the population studied. But over the past few decades prevalence has increased many folds. It is higher in western countries, with advanced age and in certain races like Mexican Americans and African Americans.

• According to a 1999 – 2000 survey, prevalence of metabolic syndrome among adults aged 20 years or older was found to be 32,000 per 100,000 compared to 22,000 per 100,000 in a survey done during year 1988 – 1994 ^[1].
• There is a constant increase in prevalence of metabolic syndrome and more than 25% of US population meets the diagnostic criteria for metabolic syndrome.

• The prevalence of metabolic syndrome is approximately 25% in European and Latin American countries ^[2].
• Also, with westernization lifestyle and food habits there has been a constant increase in the prevalence of metabolic syndrome in the Asian countries. However, the prevalence is still less compared to the western population (approximately 8-18%).

• Prevalence increases with age.
• 2 out of 5 people above 60 years of age fall under the criteria of metabolic syndrome.
• Increased prevalence in the pediatric population is attributed to increased incidence of obesity early in childhood.

• Age adjusted prevalence in male – (24%)
• Age adjusted prevalence in female – (23%)
• However, females have an increased risk for metabolic syndrome due to association of certain factors like pregnancy, oral contraceptives pills (OCP) and polycystic ovarian syndrome (PCOS) ^[3].
• Some association is found to exist between metabolic syndrome and breast cancer, especially in postmenopausal females.

• The diagnostic criteria for metabolic syndrome were defined initially for Caucasian population. However, these definitions are not uniform among different races.
• Highest age – adjusted prevalence of metabolic syndrome in the United States was found to be in Native American patients, with nearly 60% of women and 45% of men aged 45 – 49 years met the ATP III criteria ^[4] (approximately 31.9%, 1999-2000 survey).
• High prevalence is also seen in African Americans especially women.

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Raviteja Guddeti, M.B.B.S. [3]

Common risk factors in the development of metabolic syndrome include insulin resistance, aging, positive family history, lack of physical exercise, postmenopause, smoking, low economic status, high carbohydrate diet, atypical antipsychotics like clozapine, and soft drink consumption.

Common risk factors in the development of metabolic syndrome include:^{[1][2][3][4][5]}

• Central obesity
• Insulin resistance
• Aging
• Positive family history
• Hormonal changes
• Lack of physical exercise ^[6]
• Postmenopausal status
• Smoking
• Low economic status
• High carbohydrate diet
• Atypical antipsychotics like clozapine^[7]
• Soft drink consumption ^[8]
• Coagulopathies

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Raviteja Guddeti, M.B.B.S. [3]; Aarti Narayan, M.B.B.S [4]

Metabolic syndrome occurs in the presence of insulin resistance and accompanying obesity. It increases the risk for coronary heart disease, type II diabetes, fatty liver, stroke and some cancers. It may manifest as hypertension, hyperglycemia, hypertriglyceridemia, reduced high density lipoprotein cholesterol and abdominal obesity. It affects a large number of people in a clustered fashion. In some studies, the prevalence in the USA is calculated as being up to 25% of the population.

If left untreated, consistently high levels of insulin in metabolic syndrome usually leads to type 2 diabetes. Insulin resistance is also associated with many changes in the body prior to its manifesting as disease including chronic inflammation and damage to arterial walls, decreased excretion by the kidneys, and coagulopathies.

The complications found associated with metabolic syndrome are:

• Type II diabetes mellitus: The Framingham Heart Study cohort found that metabolic syndrome is a strong predictor of new-onset diabetes in both men and women. It was also shown that obese people with metabolic syndrome have a 10-fold higher risk for developing new diabetes when compared to obese people without metabolic syndrome. Prospective studies have shown that hyper-insulinemia, body size and lipid factors are strongly associated with the development of diabetes in patients with metabolic syndrome. ^{[1][2][3][4][5][6]}
• Cardiovascular complications: The Framingham Heart Study showed that obese people with metabolic syndrome have a 2-fold higher risk for cardiovascular disease (CVD) when compared to obese people without metabolic syndrome. The increased risk for CVD can be due to either risk factor clustering or insulin resistance and obesity. Obese patients with insulin resistance have the highest risk for developing CVD.^[4][5][6][7]
  • Coronary heart disease
  • Atrial fibrillation
  • Heart failure
  • Aortic stenosis
  • Stroke: The Northern Manhattan study in 3298 stroke free subjects showed that metabolic syndrome increases the risk for ischemic stroke. The risk is greater in women compared to men and Hispanics compared to Caucasians and African-Americans.^[8] A similar study in Japan showed the increased risk of ischemic stroke in women with metabolic syndrome.^[9][10]
• Chronic kidney disease: Many prospective cross-sectional studies have shown that metabolic syndrome is strongly associated with the development of chronic kidney disease (CKD) over the years. It was also shown that the more components of metabolic syndrome the more the risk for developing CKD.^{[11][12][13][14]}
• Nonalcoholic fatty liver disease, cirrhosis: A fatty liver is insulin resistant and is directly correlated to other components of metabolic syndrome independent of obesity. Insulin resistance, oxidative stress, apoptosis and adipokines are thought to be involved in the pathogenesis of fatty liver disease in metabolic syndrome. The risk of nonalcoholic fatty liver and liver fibrosis increases with presence of elevated waist/hip ratio, impaired glucose tolerance, hypertension, and dyslipidemia. The risk of cardiovascular diseases is very high in patients with metabolic syndrome associated with nonalcoholic fatty liver disease. These patients are also more likely to have excess intra-abdominal fat and inflammatory changes in adipose tissue.^{[15][16][17][18][19][16][17][15][18]}
• Obstructive sleep apnea: Sleep apnea is seen frequently in patients with metabolic syndrome. In a study conducted in 228 patients it was shown that patients with obstructive sleep apnea (OSA) had a higher prevalence of metabolic syndrome compared with patients without OSA. ^[20][21]
• Breast cancer: Adipokines in metabolic syndrome are known to alter plasminogen activator inhibitor – 1 (PAI-1) expression to promote angiogenesis, tumor cell migration and pro-coagulant micro-particle formation from endothelial cells. The endothelial cells in turn generate thrombin and further propagates PAI-1 synthesis. Elevated levels of PAI-1 have been shown to be associated with poor prognosis in breast cancer. All these factors lead to the risk of developing chemotherapy-resistant breast cancer. Moreover hyper-insulinemia with insulin resistance is known to be associated with proliferative tissue abnormalities through IGF-1 receptor. ^{[22][23] [24]}
• Cancers of the liver, colon, gallbladder, kidney, and prostate gland: Obesity is known to be consistently associated with an increased risk for developing cancers of the liver, colon, gallbladder, kidney and prostate gland. Obesity, insulin resistance and metabolic syndrome are associated with elevated levels of inflammatory markers like leptin, interleukin-6 and TNF which are known to enhance tumor growth.^[25][26]
• Polycystic ovary syndrome: Insulin resistance and visceral obesity are two important features of polycystic ovarian syndrom (PCOS) similar to metabolic syndrome. Metabolic syndrome is much more common in women with polycystic ovarian syndrom (PCOS) that in women without polycystic ovarian syndrom (PCOS). In the USA almost 50% of PCOS patients have associated metabolic syndrome. ^[27][28]
• Hyperuricemia and gout: Data from the Third National Health and Nutrition Examination Survey (1988-1994) in 8,807 participants aged ≥20 years showed that the prevalence of metabolic syndrome is remarkably high among individuals with gout.^[29]
• Psoriasis: Multiple epidemiologic studies have shown that patients with psoriasis have a higher prevalence of metabolic syndrome. ^{[30][31][32][33]}
• Accelerated cognitive decline in the elderly: Studies have shown that compared to elderly people without metabolic syndrome, those with metabolic syndrome have a higher prevalence of cognitive impairment. ^{[34] [35]}

• SOURCE and YEAR: The American Journal of Cardiology

• OBJECTIVE: Estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome

• METHOD: Post hoc determination of placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) used to estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome.

• RESULTS: In the Scandinavian Simvastatin Survival Study and AFCAPS/TexCAPS, respectively, placebo-treated patients with the metabolic syndrome were-
  • 1.5 (95% confidence interval 1.2 to 1.8) times more likely to have MCEs than those without it in 4S
  • 1.4 (95% confidence interval 1.04 to 1.9) times more likely to have MCEs than those without it in 4S

• CONCLUSION: The following risks factors increased the relative risk for MACE
  • Low high-density lipoprotein levels were associated with elevated risk of MCEs in both studies
  • High triglycerides in the Scandinavian Simvastatin Survival Study
  • Elevated blood pressure and obesity in AFCAPS/TexCAPS were associated with a significantly increased relative risk.

Prognosis is generally good with appropriate treatment and life style modifications.

Template:WS Template:WH