Metabolic Syndrome

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Copyright 2013 by MediaLab, Inc. All rights reserved.

Metabolic Syndrome

Author: Mary Ellen Koenn, MS, MT(ASCP), CLS(NCA) Reviewer: Leslie Lovett, MS, MT(ASCP)

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Course Instructions

Please proceed through the course by clicking on the blue arrows or text links. Use the table of contents to monitor your progress. Your progress will be saved automatically as you proceed through the course, and you may later continue where you left off even if you use a different computer. You may encounter practice questions within the course, which are not graded or recorded.

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Course Info

This course carries the following continuing education credits:

● P.A.C.E. Contact Hours: 1.00 hour(s) Course Number: 578-009-10

● Florida Board of Clinical Laboratory Science CE - General (Clinical Chemistry/UA/Toxicology): 1.00 hour(s)

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Metabolic Syndrome: Introduction

Metabolic Syndrome

Metabolic syndrome is a designation for metabolic risk factors that, if occurring together, increase a person's risk for developing heart disease, stroke, and/or diabetes. An individual diagnosed with metabolic syndrome has an increased risk of diabetes that is five times greater than an individual without these metabolic factors and an increased risk of cardiovascular disease that is two times greater.


Other Names for Metabolic Syndrome

In scientific literature other names are sometimes used for this syndrome:

● Reaven's Syndrome - Gerald Reaven, MD, first scientist to cluster risks factors for atherosclerosis and cardiovascular disease

● Insulin Resistance Syndrome ● Syndrome X ● Deadly Quartet - abdominal obesity, glucose intolerance, hypertension, hyperlipidemia ● Obesity-Dyslipidemia Syndrome ● Dysmetabolic Syndrome ● Obesity Syndrome ● Hypertriglyceridemic Waist


Medical Complications of Metabolic Syndrome

In addition to cardiovascular disease, stroke, and diabetes, that are closely associated with metabolic syndrome, there are several medical complications and conditions that could also potentially occur. An individual with metabolic syndrome is susceptible to:

● Fatty liver disease ● Other liver diseases ● Cholesterol gallstones ● Asthma ● Sleep apnea ● Osteoarthritis ● Pulmonary disease ● Renal disease ● Ocular complications ● Polycystic ovary syndrome ● Colon, endometrial, and breast cancers

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The Importance of Diagnosing Metabolic Syndrome

Diagnosis of metabolic syndrome does not necessarily correlate directly to a diagnosis of a specific disease. This diagnosis links several health risks with obesity and the other syndrome criteria. It is not a prediction of a short-term risk for cardiovascular disease and diabetes. Those with this syndrome have a high lifetime risk for these diseases. The American Heart Association reports that the individual's short-term risk (approximately 10 years) is in the low to moderate range. The metabolic syndrome diagnosis urges patients to work with their physicians and other professionals to take steps to decrease their risk for cardiovascular disease and type 2 diabetes.


Ungraded Practice Question

An individual diagnosed with metabolic syndrome has an increased risk for developing cardiovascular disease and/or type 2 diabetes.

Select true or false



An individual diagnosed with metabolic syndrome has an increased risk for developing cardiovascular disease and/or type 2 diabetes.

nmlkj True

nmlkj False


Feedback

Metabolic syndrome increases the risk of cardiovascular disease two-fold and increases the risk of type 2 diabetes five-fold.

nmlkj True

nmlkj False

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Which of the following are possible medical complications for an individual diagnosed with metabolic syndrome?

More than one answer is correct. Please select all correct answers



Which of the following are possible medical complications for an individual diagnosed with metabolic syndrome?

gfedc Fatty liver disease

gfedc Renal disease

gfedc Brain tumor

gfedc Sleep apnea

gfedc Leukemia

gfedc Muscular dystrophy

More than one answer is correct. Please select all correct answers

Feedback

Medical complications and conditions that can occur in metabolic syndrome: fatty liver disease, cholesterol gallstones, asthma, sleep apnea, osteoarthritis, pulmonary disease, renal disease, liver disease, ocular diseases, polycystic ovary syndrome, colon, endometrial, and breast cancer.

gfedc Fatty liver disease

gfedc Renal disease

gfedc Brain tumor

gfedc Sleep apnea

gfedc Leukemia

gfedc Muscular dystrophy

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Metabolic Syndrome: Risk Factors for Metabolic Syndrome

Risk Factors

According to the American Heart Association, the risk factors for metabolic syndrome include:

● Abdominal obesity (excessive fat tissue in and around the abdomen) ● Atherogenic dyslipidemia (blood fat disorders – high triglycerides, low HDL cholesterol and high LDL cholesterol –

that foster plaque buildups in artery walls) ● Elevated blood pressure ● Insulin resistance or glucose intolerance (the body can't properly use insulin or blood sugar) ● Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor–1 in the blood) ● Proinflammatory state (e.g., elevated high sensitivity C-reactive protein in the blood)

Reference: Metabolic syndrome.The American Heart Association website. Available at:http://www.heart.org/HEARTORG/Conditions/More/MetabolicSyndrome/Metabolic-Syndrome_UCM_002080_SubHomePage.jsp#. Accessed December 5, 2011.


Insulin Resistance

Insulin is a pancreatic hormone that plays a vital role in carbohydrate and lipid metabolism. Insulin regulates glucose concentrations by:

● Promoting glycolysis - the uptake of glucose by cells for energy ● Stimulating glycogenesis - the conversion of excess blood glucose to glycogen storage in the liver ● Inhibiting glycogenolysis - the conversion of glycogen back to glucose ● Inhibiting gluconeogenesis - the formation of glucose from noncarbohydrates

Insulin increases lipid synthesis in the liver and fat cells and inhibits lipolysis, the release of non-esterified fatty acids (NEFAs) from triglycerides in fat and muscle cells. Insulin also promotes protein synthesis.

If insulin resistance occurs, carbohydrate and lipid metabolism are impaired. Insulin resistance ordinarily results in increased insulin levels as the body senses a need for more insulin action. The impaired insulin action results in elevated plasma glucose levels. The increase in lipolysis increases blood concentrations of NEFAs and causes abnormal blood lipid levels.


Obesity

Obesity is another major risk factor for the metabolic syndrome. Obesity and insulin resistance are interrelated and the effects of obesity are the cause of some of the ensuing resistance to insulin.

Those at risk for metabolic syndrome generally have an abnormal fat distribution. The excess adipose tissue is located in the upper body, resulting in an increased waist circumference. The greater the upper body fat, the greater the insulin

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resistance.


Other Contributing Factors

Lack of physical activity, aging, and genetics may also be contributing factors for metabolic syndrome. Physical inactivity greatly increases the risk of metabolic syndrome by enhancing weight gain and lowering metabolic rate. Diminished ability to maintain normal metabolic balance in aging accounts for the increased occurrence of metabolic syndrome with age.

An individual's gene structure does play a role in obesity. Many inherit a tendency towards obesity. So far, it is believed that this inherited tendency is not a single genetic defect but polygenic. So called "obesity genes" create only small differences in obesity. Genetic differences and polymorphisms change feedback mechanisms resulting in poor appetite control and impaired metabolism.

Adipose tissue and metabolic syndrome

Adipose Tissue as an Endocrine System

Adipose tissue is no longer considered just a storage area for fat for future energy needs or a provider of body insulation. Recent discovery that adipose tissue secretes a large number of bioactive peptides known as adipokines classifies adipose tissue as an endocrine system. Besides adipocytes (fat cells), adipose tissue also contains connective tissue, nerve tissue, stromovascular cells, and immune cells.

Each adipocyte can synthesize and secrete into systemic circulation a large number of adipokines. Additionally, the nonadipocyte fraction of adipose tissue secretes proteins.


Role of Adipokines

Over twenty adipokines have been identified. Some adipokines are secreted solely by adipocytes; several are secreted

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by adipocytes and other body cells. Their role is very widespread as they integrate with various body organs and tissues: skeletal muscle, adrenal cortex, brain and sympathetic nervous system. Adipokines function in:

● Energy balance ● Immune reactions ● Insulin sensitivity ● Angiogenesis ● Blood pressure maintenance ● Lipid metabolism ● Hemostasis


Adipokines Significant to Metabolic Syndrome

The adipokines that will be discussed on the following pages include:

● Tumor necrosis factor-alpha (TNF-α) ● Interleukin 6 (IL-6) ● Plasminogen activator inhibitor-1 (PAI-1) ● Adiponectin ● Angiotensinogen ● Leptin ● Resistin


TNF-alpha

TNF-alpha (TNF-α) produces different effects as it is secreted; many of these effects are immunological and result in increased inflammation. The original name for TNF, tumor necrosis factor, came from its first discovered activity, tumor regression. TNF-α is synthesized and secreted by adipocytes, macrophages, lymphoid cells, endothelial cells and other body cells.

Adipocyte-secreted TNF-α stimulates adipocytes to increase their release of NEFAs and decrease adiponectin synthesis. TNF-α also inhibits insulin activity, leading to insulin resistance. Adipocyte TNF-α secretion is increased in obesity causing an increased insulin resistance in obesity.


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IL-6

IL-6 responds to tissue injury. IL-6 is synthesized and secreted by many different cells in addition to adipocytes including immune cells, fibroblasts, endothelial cells and skeletal muscle.

IL-6 is increased in obesity and insulin resistance and those with elevated levels are at higher risk for type 2 diabetes and myocardial infarction. Similar to TNF-α, IL-6 increases NEFA release and reduces adiponectin secretion. IL-6 increases insulin resistance by inhibiting insulin receptor signal transduction in liver cells. It also increases other inflammatory cytokines, interleukin-1 (IL-1) and TNF-α, and stimulates the liver to produce C-reactive protein (CRP), an important protein marker of inflammation.


PAI-1

PAI-1 is a cytokine responsible for much of the prothrombotic state associated with metabolic syndrome. PAI-1 regulates the formation of thrombi by promoting formation of thrombin, platelet aggregation, and fibrin. PAI-1 inhibits fibrinolysis by blocking the activity of tissue-type plasminogen activator. PAI-1 is synthesized and released from the liver and adipocytes.

PAI-1 is increased in obesity, is associated with insulin resistance, and is an early inflammatory predictor of type 2 diabetes.


Adiponectin

Adiponectin is very different from TNF-α, IL-6, and PAI-1. It is synthesized and secreted almost exclusively by the adipocytes and is an anti-inflammatory cytokine. Levels of adiponectin are decreased in weight gain, obesity and in those who are insulin resistant. Secretions of TNF-α and IL-6 reduce adipocyte secretion of adiponectin.

Adiponectin is a protective adipokine. It inhibits several steps in the inflammatory process and increases insulin sensitivity by enhancing glucose transport into muscle cells. Adiponectin also decreases liver glucose production. Adiponectin slows and inhibits steps in plaque formation in blood vessels and is thus antiatherogenic.


Angiotensinogen

Adipocyte production of angiotensinogen explains the frequent occurrence of hypertension in obesity and insulin

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resistance. Adipose tissue and liver cells produce angiotensinogen, a precursor of angiotensin II. Most angiotensinogen is from liver synthesis but increased levels in obesity are likely from increased adipocyte synthesis. Besides increasing blood pressure, angiotensin II may stimulate adipose cell formation and thus increase adipose mass.


Leptin

The role of leptin in obesity and insulin resistance is sometimes confusing. Some authors refer to leptin as a hormone, not an adipokine. Leptin is synthesized and released from adipose cells in response to adipose tissue changes. It reduces intracellular lipid levels in many types of body cells and thus improves insulin sensitivity. It is an appetite suppressant and inhibitor of fatty liver formation.

Leptin is referred to as a "starvation signal" and the leptin gene, is sometimes referred to as "the obesity gene". These names refer to leptin's important function as a messenger in energy metabolism. Leptin signals the hypothalamus when there are increases in fat stores. The hypothalamus then restores metabolic balance by decreasing appetite, stimulating physical activity, and burning of excess calories. During fasting, leptin levels decrease rapidly and hypothalamus signaling results in an increase in cortisol and a decrease in thyroid, sex, and growth hormones. These actions work together to restore energy balance.

Leptin is usually increased in obesity, however, similar to increased insulin in obesity, leptin resistance develops. In obesity, appetite suppression does not take place and metabolic rates are lowered. Secreted leptin is not able to stimulate energy balance and healthy caloric intake.


Resistin

Resistin is another inflammatory cytokine that is increased in obesity. It increases insulin resistance and enhances adhesion molecules present on endothelial cells. It is synthesized and secreted by macrophages and adipocytes.



Which adipokine is synthesized and released by adipocytes and many other body cell types, is an inflammatory cytokine that stimulates the liver to produce C-reactive protein (CRP), and is increased in obesity and insulin resistance?

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Please select the single best answer



Which adipokine is synthesized and released by adipocytes and many other body cell types, is an inflammatory cytokine that stimulates the liver to produce C-reactive protein (CRP), and is increased in obesity and insulin resistance?

nmlkj Leptin

nmlkj IL-6

nmlkj Adiponectin

nmlkj Angiotensinogen


Feedback

IL-6 is synthesized and released by adipocytes and many other body cell types, is an inflammatory cytokine that stimulates the liver to produce C-reactive protein (CRP), and is increased in obesity and insulin resistance.



Which adipokine is decreased in obesity, is anti-inflammatory, and increases insulin sensitivity?

nmlkj Leptin

nmlkj IL-6

nmlkj Adiponectin



nmlkj Leptin

nmlkj Resistin

nmlkj TNF-a

nmlkj Adiponectin

nmlkj IL-6


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Which adipokine is decreased in obesity, is anti-inflammatory, and increases insulin sensitivity?


Feedback

Adiponectin is a protective cytokine. This cytokine is anti-inflammatory and increases insulin sensitivity. Adiponectin is usually decreased in obesity.

Diseases Associated with Metabolic Syndrome: Cardiovascular Disease

Adipokines and Atherosclerotic Inflammatory Process

Increased TNF-α, IL-6, PAI-1, leptin, resistin and decreased adiponectin promote insulin resistance leading to impaired glucose management and diabetes. Some of these adipokines also affect endothelial function and the coagulation system, promoting atherosclerosis. The low-grade inflammatory state created by abnormal adipokine levels is likely an important connection between metabolic syndrome and cardiovascular disease.

Atherosclerosis is an inflammatory process in arterial walls. It probably begins when monocytes adhere to damaged endothelium, move to subendothelial places and transform into foam cell while incorporating lipids. Gradually atherosclerotic plaque is formed. The vessell wall shape and integrity is distorted also. Metalloproteinases produced by the foam cells digest the plaque. The plaque fibrous cap and/or portions of the plaque can then rupture and be released into circulation. Myocardial infarction and stroke can result

nmlkj Leptin

nmlkj Resistin

nmlkj TNF-a

nmlkj Adiponectin

nmlkj IL-6


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Adipokines and Atherosclerotic Inflammatory Process Continued

Adipokines play several roles in the atherosclerotic inflammatory process:

● TNF-α activity produces inflammatory changes in vascular tissue and adhesion molecules. This increases the ability of monocytes to adhere to vessel walls.

● Resistin also promotes cell adhesion. ● Angiotensin II from angiotensinogen enhances the adhesion process of monocytes and platelets to vessel walls. ● When glucose levels are increased, leptin assists in the incorporation of lipids by enhancing uptake of cholesterol by

macrophages. ● IL-6 enhances the inflammatory process and increases CRP. ● If there are ruptured atherosclerotic plaques, PAI-1 increases probability of thrombus formation and inhibits fibrin clot

lysis.


Endothelial Dysfunction

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The endothelium is the thin layer of cells at the inner lining of blood vessels. Endothelial dysfunction is a pathological state where the balance of vasodilating and vasoconstricting is lost. Endothelial dysfunction is also a preclinical stage of atherosclerosis and precursor of future cardiovascular disease. Inflammation from increased levels of inflammatory adipokines are one factor in the development of endothelial dysfunction.



Which adipokines advance atherosclerosis by enhancing cell adhesion in vessel walls?




Which adipokines advance atherosclerosis by enhancing cell adhesion in vessel walls?

nmlkj Resistin, TNF-alpha, PAI-l

nmlkj PAI-1, angiotensinogen, TNF-alpha

nmlkj TNF-alpha, angiotensinogen, resistin

nmlkj Leptin, IL-6, adiponectin


nmlkj Resistin, TNF-alpha, PAI-l

nmlkj PAI-1, angiotensinogen, TNF-alpha

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Feedback

The changes produced by TNF-α and angiotensin II from angiotensinogen enhance ability of moncytes to adhere to the vessel wall. Angiotensin II also enhances platelet adhesion and resistin promotes cell adhesion.

Diseases Associated with Metabolic Syndrome: Dyslipidemia

Dyslipidemia and Metabolic Syndrome

Those diagnosed with metabolic syndrome are at risk for atherogenic dyslipidemia, a state of abnormal lipids and lipid levels. A state of atherogenic dyslipidemia also enhances the development of atherosclerosis and cardiovascular disease. The increased release of NEFAs and their infiltration of the liver initiate the dyslipidemia process.

Increased NEFAs in the liver result in a fatty liver and increased liver triglyceride synthesis. Increased liver synthesis and secretion of very low density lipoprotein (VLDL) follow. VLDL is the lipoprotein that transports triglycerides in circulation. Blood triglyceride concentration then increases.

A fatty liver also increases low density lipoprotein-cholesterol (LDL-C) circulating in blood. The predominant lipid in LDL molecules is cholesterol. LDL molecules in the dyslipidemia state are described as small dense LDLs. The increased triglyceride presence causes depletion of the cholesterol and phospholipid content in LDL, making the molecules smaller and denser.

Decreased high density lipoprotein-cholesterol (HDL-C) also results. Most researchers believe this is also caused by the increased production of triglyceride-rich VLDL. Decreasing the concentration of HDL molecules is atherogenic in that HDL is the helpful lipoprotein transporting excess cholesterol to the liver and decreasing total blood cholesterol. Higher levels of HDL-C aid in preventing atherosclerosis and cardiovascular disease.


Small Dense LDL Molecules

Small dense LDL molecules may be more atherogenic and harmful to the endothelium because they can more easily move through the basement membrane of the endothelium and into the arterial wall. They may also adhere to glucoproteins more readily and more easily bind to monocytes and macrophages in plaque formation. Thus, small dense LDL molecules would enhance the incorporation of lipid into the plaque.


nmlkj TNF-alpha, angiotensinogen, resistin

nmlkj Leptin, IL-6, adiponectin

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Atherogenic Dyslipidemia

Abnormal lipid levels are often associated with metabolic syndrome, as shown in the table below:



Which lipid group in increased concentrations probably decreases HDL-C and causes the formation of small dense LDL molecules?

Abnormal Lipid or Lipoprotein Variation from Normal Levels

High density lipoprotein (HDL) Decreased

Low density lipoprotein (LDL) Increased

(Small dense LDL molcules)

Very low density lipoprotein (VLDL) Increased

Triglycerides Increased




Which lipid group in increased concentrations probably decreases HDL-C and causes the formation of small dense LDL molecules?

nmlkj Phospholipids

nmlkj Triglycerides

nmlkj Cholesterol

nmlkj Terpenes


nmlkj Phospholipids

nmlkj Triglycerides

nmlkj Cholesterol

nmlkj Terpenes

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Feedback

Increased NEFAs infiltrate the liver and result in increased VLDL synthesis and blood triglycerides. Increased concentrations of triglycerides in the blood cause depletion of cholesterol in LDL particles and results in small dense LDL molecules. Concentration of HDL-C is also decreased by triglyceride-rich VLDL in the blood.



Why are small dense LDL molecules more atherogenic?




Why are small dense LDL molecules more atherogenic?

nmlkj Small dense LDL molecules contain less cholesterol and phospholipid

nmlkj Small dense LDL molecules increase the concentration of HDL-C in the blood

nmlkj Small dense LDL molecules increase the concentration of adoponectin and inflammatory cytokines

nmlkj Small dense LDL molecules have greater mobility in the endothelium and arterial wall


Feedback

Most researchers believe that the small size and increased density of LDL molecules found in atherogenic dyslipidemia enable the molecules to more easily invade the endothelium and arterial wall of vessels.

nmlkj Small dense LDL molecules contain less cholesterol and phospholipid

nmlkj Small dense LDL molecules increase the concentration of HDL-C in the blood

nmlkj Small dense LDL molecules increase the concentration of adoponectin and inflammatory cytokines

nmlkj Small dense LDL molecules have greater mobility in the endothelium and arterial wall

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Diseases Associated with Metabolic Syndrome: Type 2 Diabetes

Hyperglycemia

It was noted at beginning of this unit that the risk of type 2 diabetes is five times greater than normal for those diagnosed with metabolic syndrome. The insulin resistance state impairs carbohydrate metabolism and elevates blood glucose levels. However, diabetes is often diagnosed before a patient is evaluated for metabolic syndrome.

Diseases Associated with Metabolic Syndrome: Hypertension

Hypertension

Frequently elevated blood pressure accompanies the diagnosis of metabolic syndrome. As previously discussed, angiotensinogen secreted by the adipocytes is one cause of hypertension. Increased NEFAs released from breakdown of triglycerides in adipose tissue elevates blood pressure. Hypertension increases the risk of stroke in these individuals.

Diseases Associated with Metabolic Syndrome: Prothrombotic State

Prothrombotic State

Liver synthesis of fibrinogen and other coagulation factors is often increased in metabolic syndrome and these elevated factor levels along with PAI-1 increase the risk of clot formation.

Diseases Associated with Metabolic Syndrome: Proinflammatory State

C-Reactive Protein (CRP)

CRP is an important acute phase reactant protein synthesized and released by the liver. In obesity, increased secretion of cytokines results in increased stimulation of the liver and increased CRP.

Elevated CRP levels are a marker of inflammation. In metabolic syndrome and obesity, CRP levels can be used to identify a proinflammatory state. Increased CRP levels are correlated with an increased risk for cardiovascular disease, particularly myocardial infarction and stroke.

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CRP Measurement

Elevated CRP levels were a marker for non-specific inflammation and were used to monitor acute inflammatory diseases. Recently, highly sensitive measurements of CRP have been developed that detect this protein in lower levels. This measurement known as high sensitivity-CRP (hs-CRP) detects levels seen in chronic and non-acute inflammation. Hs-CRP levels are reported as low, moderate, or high risk for future cardiovascular disease. Hs-CRP concentrations > 3 mg/L indicate a proinflammatory state.



Insulin resistance places an individual with metabolic syndrome at greatest risk for




Insulin resistance places an individual with metabolic syndrome at greatest risk for

nmlkj type 2 diabetes

nmlkj hypertension

nmlkj proinflammatory state

nmlkj prothrombotic state


Feedback

nmlkj type 2 diabetes

nmlkj hypertension

nmlkj proinflammatory state

nmlkj prothrombotic state

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An individual diagnosed with metabolic syndrome is at risk for all four conditions or diseases but at greatest risk of diabetes because of insulin resistance.



Which of the following most likely causes the hypertension that often occurs in metabolic syndrome?




Which of the following most likely causes the hypertension that often occurs in metabolic syndrome?

nmlkj Increased C-Reactive protein (CRP) and increased adiponectin

nmlkj Increased angiotensinogen and increased NEFAs

nmlkj Decreased adiponectin and increased PAI-1

nmlkj Decreased HDL-C and small dense LDL molecules


Feedback

Angiotensin II from adipocyte-secreted angiotensinogen increases blood pressure. Also the increase in NEFAs from lipolysis of triglycerides in fat cells elevates blood pressure.


nmlkj Increased C-Reactive protein (CRP) and increased adiponectin

nmlkj Increased angiotensinogen and increased NEFAs

nmlkj Decreased adiponectin and increased PAI-1

nmlkj Decreased HDL-C and small dense LDL molecules

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Which condition is caused by the increased PAI-1 and fibrinogen often present in metabolic syndrome?




Which condition is caused by the increased PAI-1 and fibrinogen often present in metabolic syndrome?

nmlkj Hyperglycemia

nmlkj Proinflammatory state

nmlkj Prothrombotic State

nmlkj Atherogenic dyslipidemia


Feedback

Elevations of PAI-1 and fibrinogen increase the risk of thrombus formation. Both of these proteins are often increased in metabolic syndrome.



Which assay is a more recent marker of chronic inflammation and is used for cardiac risk assessment?

nmlkj Hyperglycemia

nmlkj Proinflammatory state

nmlkj Prothrombotic State

nmlkj Atherogenic dyslipidemia


nmlkj PAI-1

nmlkj CRP

nmlkj hs-CRP

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Which assay is a more recent marker of chronic inflammation and is used for cardiac risk assessment?

nmlkj Adiponectin

nmlkj IL-6


Feedback

The hs-CRP assay detects CRP in very low levels. It is a measurement of chronic inflammation and is used in cardiac risk assessment. The traditional CRP is a measure of inflammation present in acute inflammatory conditions.

Diagnosis of Metabolic Syndrome

Variation in Diagnostic Criteria

Metabolic syndrome may vary in definition and diagnostic criteria depending on the organization that is consulted. Health-related organizations that have developed diagnostic criteria for metabolic syndrome include:

● National Heart, Lung, and Blood Institute (NHLBI)/American Heart Association (AHA) ● World Health Organization (WHO) ● American Association of Clinical Endocrinologists (AACE) ● International Diabetes Foundation (IDF) ● European Group for Study of Insulin Resistance (EGIR)

Each organization's set of criteria is slightly different in its parameters and its details for diagnosis. All of the above organizations agree that defining glucose intolerance, obesity, hypertension, and dyslipidemia is important. However, there are varied opinions in how important each risk factor is in relation to the others.

Varied criteria to determine obesity is utilized: waist to hip ratio, BMI, and waist circumference. One organization does not include a measurement of obesity. Glucose intolerance is determined by measuring plasma insulin and/or glucose levels. Lack of standardization in insulin measurement and assay availability makes criteria using insulin levels impractical.

nmlkj PAI-1

nmlkj CRP

nmlkj hs-CRP

nmlkj Adiponectin

nmlkj IL-6

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Adult Treatment Panel III

The National Heart, Lung, and Blood Institute (NHLBI) initiated the National Cholesterol Education Program (NCEP) in 1985. The goal was to reduce the number of Americans with elevated cholesterol and thus reduce illnesses and deaths in the United States due to coronary heart disease. Three adult treatment panels have been published since then with clinical practice guidelines for managing cholesterol levels in adults.

The most recent panel, Adult Treatment Panel III (ATP III), was published in 2001 and updated in 2004. The NCEP: ATP III also includes criteria for the diagnosis of metabolic syndrome. This criteria is the most frequently used criteria in the United States.


NCEP: ATP III Diagnostic Criteria for Metabolic Syndrome

Presence of three or more of these components



At medical examination, a 50-year-old Caucasian male expressed concern regarding diabetes. There is a history of type

Component Criteria

Abdominal obesity: Increased waist circumference

Men: > 40 inches Women: > 35 inches

Elevated triglycerides> 150 mg/dL or drug treatment for elevated triglycerides

Reduced HDL-Cholesterol (HDL-C)Men: < 40 mg/dL Women: < 50 mg/dL

Elevated blood pressure> 130/85 mm Hg or drug treatment for elevated blood pressure

Elevated fasting glucose> 100 mg/dL or drug treatment for elevated glucose

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2 diabetes, hypertension, and cardiovascular disease in his family. He has gained a few pounds each year and his physician notes abdominal obesity. His physician orders laboratory tests to evalute his risk of cardiovascular disease.

Vital Signs and Pertinent Laboratoy Results:

Blood Pressure: 128/82 mm Hg Weight: 230 lbs Height: 5' 11'' Calculated BMI: 32.1 Waist Circumference: 45 inches

Fasting Blood Glucose: 120 mg/dL Triglycerides: 170 mg/dL HDL-C: 42 mg/dL

Which one of the following statements regarding this patient is true if the physician uses the guidlines of NCEP: ATP III Diagnostic Criteria for metabolic syndrome evaluation?




At medical examination, a 50-year-old Caucasian male expressed concern regarding diabetes. There is a history of type 2 diabetes, hypertension, and cardiovascular disease in his family. He has gained a few pounds each year and his physician notes abdominal obesity. His physician orders laboratory tests to evalute his risk of cardiovascular disease.

Vital Signs and Pertinent Laboratoy Results:

Blood Pressure: 128/82 mm Hg Weight: 230 lbs Height: 5' 11'' Calculated BMI: 32.1 Waist Circumference: 45 inches

Fasting Blood Glucose: 120 mg/dL Triglycerides: 170 mg/dL HDL-C: 42 mg/dL

Which one of the following statements regarding this patient is true if the physician uses the guidlines of NCEP: ATP III Diagnostic Criteria for metabolic syndrome evaluation?

nmlkj Diagnosis of metabolic syndrome; waist circumference, HDL-C, and fasting blood glucose meet the criteria

nmlkj Diagnosis of metabolic syndrome; waist circumference, triglyceride level, and fasting blood glucose meet the criteria

nmlkj Does not meet the criteria for diagnosis of metabolic syndrome because the HDL-C is not <40 mg/dL

nmlkj Cannot make conclusion regarding metabolic syndrome because the LDL-C was not assayed


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Feedback

In this scenario, waist circumference, triglyceride level, and fasting blood glucose meet the criteria for diagnosis of metabolic syndrome.

NCEP: ATP III criteria for diagnosis of metabolic syndrome is the presence of three or more of these components:

LDL-C is not used as a determining factor in diagnosis of metabolic syndrome with the NCEP guidelines.

Clinical Management in Metabolic Syndrome

Treatment

The primary goal in treatment of those with metabolic syndrome is reduction of risk factors for atherosclerotic disease. If the person does not already have type 2 diabetes, prevention of diabetes is another critical goal in management and treatment. Lifestyle changes and medications are utilized to meet these goals.

Lifestyle changes that reduce obesity are critical: increase physical activity, reduce the fat in the diet, and decrease calorie intake. Exercise provides benefits beyond just burning calories. Exercise stimulates anabolic metabolism, raises basal metabolism rate, decreases stress, and increases hormonal sensitivity. Cessation of smoking is also important.

Often drug therapy is needed to address the patient's hyperlipidemia, hypertension, and/or hyperglycemia. Low-dose aspirin and other antiplatelet agents may be used to prevent thrombosis.

nmlkj Diagnosis of metabolic syndrome; waist circumference, HDL-C, and fasting blood glucose meet the criteria

nmlkj Diagnosis of metabolic syndrome; waist circumference, triglyceride level, and fasting blood glucose meet the criteria

nmlkj Does not meet the criteria for diagnosis of metabolic syndrome because the HDL-C is not <40 mg/dL

nmlkj Cannot make conclusion regarding metabolic syndrome because the LDL-C was not assayed

Component Criteria

Abdominal obesity: Increased waist circumference

Men: > 40 inches Women: > 35 inches

Elevated triglycerides> 150 mg/dL or drug treatment for elevated triglycerides

Reduced HDL-Cholesterol (HDL-C)Men: < 40 mg/dL Women: < 50 mg/dL

Elevated blood pressure> 130/85 mm Hg or drug treatment for elevated blood pressure

Elevated fasting glucose> 100 mg/dL or drug treatment for elevated glucose

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Magnesium, Calcium, and Vitamin D

Several studies have shown an inverse relationship between magnesium, calcium, vitamin D intake and metabolic syndrome risks, particularly insulin resistance. When dietary intake of magnesium, calcium, and vitamin D decreases, the risk of metabolic syndrome increases.

Decreased magnesium concentrations occur in low grade inflammation. Milk and dairy products provide calcium and vitamin D while whole grains, green leafy vegetables, legumes, and nuts are rich in magnesium.



Low-dose aspirin and antiplatelet agents may reduce the risk of diabetes for those diagnosed with metabolic syndrome.




Low-dose aspirin and antiplatelet agents may reduce the risk of diabetes for those diagnosed with metabolic syndrome.

nmlkj True

nmlkj False


Feedback

Low-dose aspirin and antiplatet agents can be used to prevent thrombosis.

nmlkj True

nmlkj False

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Laboratory Role in Metabolic Syndrome

Clinical Laboratory Testing in Metabolic Syndrome

The diagnostic criteria for metabolic syndrome require laboratory testing of glucose, triglycerides, and HDL-C. Glucose may also be assayed with self-monitoring glucose meters. Several other analytes may be monitored in those diagnosed with metabolic syndrome. Important assays are LDL-C, hs-CRP, IL-6, adiponectin, and PAI-1.

Hyperinsulinemia occurs in insulin resistance and insulin levels can be quantitated in the clinical laboratory. However, lack of standardization and significant variation in results currently makes insulin testing impractical.


Analytes and Target Ranges Pertinent to Metabolic Syndrome



A 45-year-old African American female has been diagnosed and treated for type 2 diabetes for the past five years. She maintains good control of her blood glucose with medication but does not exercise and has gained 12 pounds over the past year.

At her next appointment, her physician orders hs-CRP along with blood assays to monitor her diabetes.

Analyte Reference Range

Fasting glucose 75-100 mg/dL

Total cholesterol < 200 mg/dL

HDL-C > 60 mg/dL

LDL-C < 100 mg/dL

Triglycerides < 150 mg/dL

hs-CRP Associated Risk

< 1.0 mg/L Low Cardiovascular Disease Risk

1.0-3.0 mg/L Average Risk for Cardivascular Disease

>3.0 mg/L High Risk for Future Cardiovascular Disease

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Laboratory Result:

hs-CRP 2.8 mg/L




A 45-year-old African American female has been diagnosed and treated for type 2 diabetes for the past five years. She maintains good control of her blood glucose with medication but does not exercise and has gained 12 pounds over the past year.

At her next appointment, her physician orders hs-CRP along with blood assays to monitor her diabetes.

Laboratory Result:

hs-CRP 2.8 mg/L

nmlkj At no risk for cardiovascular disease

nmlkj Low risk for cardiovascular disease

nmlkj Average risk for cardiovascular disease

nmlkj High risk for cardiovascular disease


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A hs-CRP of 2.8 mg/L indicates an average risk of cardiovascular disease (1.0-3.0 mg/L).



nmlkj At no risk for cardiovascular disease

nmlkj Low risk for cardiovascular disease

nmlkj Average risk for cardiovascular disease

nmlkj High risk for cardiovascular disease

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A physician discusses weight with an overweight 60-year-old female at her yearly physical appointment. The female exercises regularly and eats healthy most of the time. The physician suggests she decrease carbohydrate intake and decrease portion size at meals.

Review patient vital signs and laboratory assay results to decide if a diagnosis of metabolic syndrome is appropriate using the NCEP:ATP lll Diagnostic Criteria shown on the right.

Height: 5' 7' Weight: 192 lbs BMI: 30.1 Waist Circumference: 37 inches Blood Pressure: 108/70

Fasting Blood Glucose: 92 mg/dL Total Cholesterol: 172 mg/dL LDL-C: 112 mg/dL HDL-C: 46 mg/dL Triglycerides: 70 mg/dL hs-CRP: <1.0 mg/L

Which of these statements regarding this patient is true?




nmlkj This patient meets the criteria for diagnosis of metabolic syndrome.

nmlkj This patient does not meet the criteria for diagnosis of metabolic syndrome.

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A physician discusses weight with an overweight 60-year-old female at her yearly physical appointment. The female exercises regularly and eats healthy most of the time. The physician suggests she decrease carbohydrate intake and decrease portion size at meals.

Review patient vital signs and laboratory assay results to decide if a diagnosis of metabolic syndrome is appropriate using the NCEP:ATP lll Diagnostic Criteria shown on the right.

Height: 5' 7' Weight: 192 lbs BMI: 30.1 Waist Circumference: 37 inches Blood Pressure: 108/70

Fasting Blood Glucose: 92 mg/dL Total Cholesterol: 172 mg/dL LDL-C: 112 mg/dL HDL-C: 46 mg/dL Triglycerides: 70 mg/dL hs-CRP: <1.0 mg/L

Which of these statements regarding this patient is true?


Feedback

According to the NCEP: ATP III diagnostic criteria, this patient does not have metabolic syndrome. She has only two parameters outside the criteria limits: waist circumference and HDL-C.

She does need to lose weight though because she does seem to have increased upper body fat according to the waist circumference measurement. This may eventually cause an increased triglyceride, increased blood glucose, and/or hypertension and metabolic syndrome diagnosis along with an increased risk for cardiovascular disease.

References

References

nmlkj This patient meets the criteria for diagnosis of metabolic syndrome.

nmlkj This patient does not meet the criteria for diagnosis of metabolic syndrome.

Armstrong C. Practice guidelines AHA and NHLBI review diagnosis and management of the metabolic syndrome. Am Fam Physician. 2006;74:891-1062.

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D'Amore PJ. Evolution of c-reactive protein as a cardiac risk factor. Lab Med. 2005;36:234-238.

Devaraj, S, Swarbrick MM, Singh U et al. CRP and adiponectin and its oligomers in the metabolic syndrome evaluation of new laboratory-based biomarkers. Am J Clin Pathol. 2008;129:815-822.

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-1428.

Expert Panel in Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (authors). Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA.2001;285:2486-2497.

Gade W, Gade J, Collins M et al. Failures of feedback: rush hour along the highway to obesity. Clin Lab Sci. 2010;23:39-50.

Gade W, Gade J, Collins M et al. Beyond obesity: the diagnosis and pathophysiology of metabolic syndrome. Clin Lab Sci. 2010;23:51-61.

Grundy SM. Does a diagnosis of metabolic syndrome have value in clinical practice? Am J Clin Nutr. 2006;83:1248-1251.

Grundy SM, Brewer HB, Cleeman JI, et al. Definition of metabolic syndrome: report of the national heart, lung, and blood institute/american heart association conference on scientific issues related to definition. Circulation. 2004;109:433-438.

Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112:2735-2752.

Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 2004;89:2595-2600.

Mathew B, Francis L, Kayalar A, et al. Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med. 2008;21:562-568.

Metabolic Syndrome. National Heart Lung and Blood Institute. Diseases and Conditions Index. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/ms/ms_whatis.html. Accessed December 5, 2011.

Mittal S. The Metabolic Syndrome in Clinical Practice. London, England. Springer-Verlag Springer Science; 2008.

Molinaro RJ. Metabolic syndrome: an update on prevalence, criteria, and laboratory testing. MLO. 2007;39:24-27.

Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol. 2006;64:355-365.

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Metabolic Syndrome

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