Metabolic

Syndrome
Marion Mae Pernia MD
Level II IM Resident
Objectives:
1. Define Metabolic syndrome and discuss the constellation of
metabolic abnormalities
2. Discuss the epidemiology of Metabolic syndrome
3. Identify the risk factors contributing in Metabolic Syndrome
4. Briefly discuss the pathophysiology
5. Identify the Clinical Features
6. Discuss the diagnosis and treatment
 Metabolic Syndrome
Syndrome X , insulin resistance syndrome
consists of metabolic abnormalities that confer increased
risk of CVD and Diabetes Mellitus

Reference: Harrisons Principles of Internal Medicine 20th ed

 MAJOR FEATURES
Low levels
Central of HDL
Obesity

Hypertriglyceridemia
Hyperglycemia

Hypertension

Reference: Harrisons Principles of Internal Medicine 20th ed

 Global Health/ Epidemiology
 The most challenging feature of the metabolic syndrome to define is waist
circumference.
 Intraabdominal circumference (visceral adipose tissue) is the most
strongly related to insulin resistance and risk of diabetes and CVD
 In general, the prevalence of the metabolic syndrome increases with age
 Among Native Americans: 53% of women and 45% of men
 Prevalance and severity of obesity among children reflects features of
metabolic syndrome in a younger population now estimated to be up to
23% and >60% among obese and overweight children

Reference: Harrisons Principles of Internal Medicine 20th ed

 Metabolic Syndrome: Prevalence
 14% prevalence of metabolic
syndrome in the general population
United States 33%
using NCEP Criteria.
Women >Men
36% vs 30% 2003- 2004 33%
Race/ Ethnicity 11.9% NCEP/ATP III 2011-
criteria
2012 35%
Hispanic
 14.5% IDF Criteria
35%

Non-Hispanic Caucasians 18.6%
33% NCEP/ATP III criteria
Blacks modified bby the AHA/NHLB
Reference: Journal of ASEAN Federation of Endocrine Societies :Prevalence of Metabolic
Syndrome and its Individual features across different BMI in Tertiary Hospital in the
Philippines

Reference: Harrisons Principles of Internal Medicine 20th ed

 Metabolic Syndrome: Components

Reference: Harrisons Principles of Internal Medicine 20th ed

 RISK FACTORS
Genetics
Overweight/ Obesity Loci related to body weight and
Central adiposity is a key composition, insulin resistance, lipid
feature of the syndrome and lipoprotein metabolism

Sedentary Lifestyle
• Physical inactivity and less Aging
cardiorespiraory fitness
• components of the metabolic >60 years of ages
syndrome are associated with a (women>men)
sedentary lifestyle

Reference: Harrisons Principles of Internal Medicine 20th ed

 RISK
FACTORS
Diabetes Mellitus
Great majority (~75%) of patients with Lipodystrophy
type 2 diabetes or impaired glucose
tolerance have the metabolic • associated with the metabolic
syndrome. syndrome
• Acquired and Genetic Lipodystrophy
may give rise to severe insulin
Cardiovascular Disease resistance
• risk of an acute myocardial
infarction or stroke is threefold
higher in metabolic syndrome
• Coronary Heart Disease : 60%

Reference: Harrisons Principles of Internal Medicine 20th ed

METABOLIC SYNDROME

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Reference: Harrisons Principles of Internal Medicine 20th ed

 Etiology : Insulin Resistance
 The most accepted and unifying hypothesis to
describe the pathophysiology of the metabolic
syndrome

 onset of insulin resistance is heralded by post

prandial hyperinsulinemia, which is followed
by fasting hyperinsulinemia and ultimately by
hyperglycemia

Reference: Harrisons Principles of Internal Medicine 20th ed

 Etiology : Insulin Resistance
 When insulin resistance develops 
increased lipolysis  produces more FA
 Further decrease the anti-lipolytic
effects of insulin
 Leptin resistance also may be a
pathophysiologic mechanism to explain the
metabolic syndrome.

Reference: Harrisons Principles of Internal Medicine 20th ed

 Increased Waist circumference
 Waist circumference is an important component of
the most recent and frequently applied diagnostic
criteria for the metabolic syndrome.

 With increases in visceral adipose tissue, adipose

tissue–derived free fatty acids reach the liver.

 Increases in abdominal SC fat release lipolysis

products into the systemic circulation and therefore
have fewer effects on hepatic metabolism

Reference: Harrisons Principles of Internal Medicine 20th ed

 DYSLIPIDEMIA
 Hypertriglyceridemia is an excellent marker of the insulin-resistant condition.
 Elevated levels of apoC-III carried on VLDLs and other lipoproteins.
 This increase in apoC-III is inhibitory to lipoprotein lipase, further
contributing to hypertriglyceridemia, and confers more risk for
atherosclerotic cardiovascular disease (ASCVD).
 Reduction in HDL cholesterol
 Hypertriglyceridemia: decrease in cholesterol content of HDL (due to reduced
cholesteryl ester content of the lipoprotein core in combination with cholesteryl
ester transfer protein-mediated alterations in triglycerides) increased
clearance of HDL from the circulation
 changes in HDL have a relationship to insulin resistance

Reference: Harrisons Principles of Internal Medicine 20th ed

 DYSLIPIDEMI
A
 Low-density lipoproteins (LDLs) have alterations in composition
 fasting serum triglycerides at >2.0 mM (~180 mg/dL)
 predominance of small, dense LDL
 Hypertriglyceridemia: increases in cholesterol content of both
VLDL1 and VLDL2 sub-fractions and in LDL particle number
 these lipoprotein changes may contribute to atherogenic risk

Reference: Harrisons Principles of Internal Medicine 20th ed

 Glucose Intolerance
 Impaired suppression of glucose production by
the liver (and kidney) and reduced glucose
uptake and metabolism in insulin-sensitive
tissues—i.e., muscle and adipose tissue.
 compensatory mechanism fails because of
defects in insulin secretion, resulting in
progression from impaired fasting glucose and/or
impaired glucose tolerance to type 2 diabetes
mellitus.

Reference: Harrisons Principles of Internal Medicine 20th ed

 HYPERTENSION
 Increase insulin resistance  (-) Insulin vasodilatory effect (+) sodium
reabsorption
 inc. activity of sympathetic nervous
system
 Impaired pathyway-specific phosphatidyl-2-
kinase signaling
 In endothelium: impairment may cause an
imbalance between production of nitric
oxide and secretion of endothelin 1  dec
blood flow
 Increases angiotensinogen gene expression  inc. circulating
angiotensin II and vasocontriction
Reference: Harrisons Principles of Internal Medicine 20th ed
 HYPERTENSION
 Reactive oxygen species released by NADPH oxidase impair endothelial
function and result in local vasoconstriction.
 Leptin or other pro-inflammatory cytokines released from adipose tissue,
such as TNF-α
 Hyperuricemia: reduction of uric acid normalizes blood pressure in
hyperuricemic adolescents with hypertension
 adverse effect of uric acid on nitric acid synthase in the macula densa
of the kidney
 stimulation of the renin-angiotensin aldosterone system.

Reference: Harrisons Principles of Internal Medicine 20th ed

 Pro-Inflammatory
Cytokines Adiponectin
 Increases pro-inflammatory
cytokines (IL1,IL6,1L18, resistin,  anti-inflammatory cytokine produced
TNF-a, CRP) exclusively by adipocytes
 reflect overproduction by  enhances insulin sensitivity and inhibits
the expanded adipose tissue many steps in the inflammatory process
mass  Reductions in adiponectin levels are
common in the metabolic syndrome

Reference: Harrisons Principles of Internal Medicine 20th ed

Clinical Features
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 Associated Diseases
Cardiovascular Diseases
 Relative risk: 1.5-3 fold
Type II Diabetes
 Associated with increases in the risk of
stroke, peripheral vascular disease and
Mellitus
 Increased three-to fivefold risk of
Alzheimer’s disease
 metabolic syndrome was associated with patients with Metabolic syndrome for
increases in high sensitivity C-reactive T2DM
 Patients developing DMT2 : 62%
protein (hsCRP) 1.34 relative risk
men 47% in women

Reference: Harrisons Principles of Internal Medicine 20th ed

 Metabolic Syndrome:
Associated Diseases
Non-Alcoholic Fatty Liver
Hyperuricemia
Disease (NAFLD)
 has become the most common liver
 reflects defects in insulin action on the
renal tubular reabsorption of uric acid
disease
 increases in free fatty acid flux, reductions  increase in asymmetric
in intrahepatic fatty acid oxidation with dimethylarginine, an endogenous
resultant increases in triglyceride inhibitor of nitric oxide synthase, also
biosynthesis and hepatocellular accu- relates to endothelial dysfunction.
mulation, with variable inflammation and  Increased urine albumin/creatinine ratio ,
oxidative stress. may relate to altered endothelial
 ~25–60% have NAFLD and up to 35%
pathophysiology in insulin-resistant state
have NASH
Reference: Harrisons Principles of Internal Medicine 20th ed
 Metabolic Syndrome:
Associated Diseases
Polycystic Ovary Obstructive Sleep
Syndrome Apnea
 Polycystic ovary syndrome is highly  commonly associated with obesity,
associated with insulin resistance (50– hypertension, increased circulat- ing
80%) cytokines, impaired glucose tolerance,
 prevalence of the syndrome between 40 and and insulin resistance.
50%.  may predict metabolic syndrome, even in
 Women with polycystic ovary syndrome are the absence of excess adiposity.
2–4 times more likely to have the metabolic  insulin resistance is found to be more
syndrome severe in those with apnea.
Reference: Harrisons Principles of Internal Medicine 20th ed
 Diagnosis
 Fulfillment of the criteria
 Medical history should include evaluation of symptoms for obstructive sleep apnea in
all patients and polycystic ovary syndrome in premenopausal women.
 Family history
 Physical Examination:
 Blood pressure
 Waist circumference measurements
 Measurement of fasting lipids and glucose
 Additional biomarkers associated with insulin resistance
 apoB, hsCRP, fibrinogen, uric acid, urinary albumin/creatinine ratio, and
liver function
 Sleep Study
 Testosterone, LH and FSH in case of PCOS
Reference: Harrisons Principles of Internal Medicine 20th ed
 Waist circumference

Journal of the ASEAN Federation of Endocrine Societies: Accuracy of Waist Circumference Measurement using the WHO versus
NIH Protocol in Predicting Visceral Adiposity , November 2021
Treatment
 LIFESTYLE
 Weight reduction is the primary approach to
the disorder
 at least a 5% and more so with 10%
weight reduction

 Caloric restriction is the most important

component

 Caloric restriction, increased physical

activity, and behavior modification

Reference: Harrisons Principles of Internal Medicine 20th ed

 DIET
 emphasize that it has taken the patient a
long time to develop an expanded fat mass
 ~3500 kcal = 1 lb. of fat, ~500-kcal
restriction daily equates to weight reduction
of 1 lb. per week.
 adherence to the diet is more important
than the chosen diet Physical Activity
 ensure that the increased activity does not
incur risk
 should undergo formal cardiovascular
evaluation before initiating an exercise program
 Although increases in physical activity can lead
to modest weight reduction, 60–90 min of daily
activity
 at least 30 min of moderate-intensity activity
daily.

Reference: Harrisons Principles of Internal Medicine 20th ed

 BEHAVIOR MODIFICATION

 recommendations for dietary restriction and more physical

activity that predicts sufficient weight loss that benefits
metabolic health.
 Improved long-term outcomes often follow a variety of
methods, such as a personal or group counselor, the
Internet, social media, and telephone follow-up to maintain
contact between providers and patients.

Reference: Harrisons Principles of Internal Medicine 20th ed

 OBESITY

 Weight-loss drugs come in two major classes: appetite

suppressants and absorption inhibitors.
 Metabolic or bariatric surgery
 BMI: >40 kg/m2 or >35 kg/m2 with co-morbidities
 Gastric bypass or vertical sleeve gastrectomy results in dramatic
weight reduction

Reference: Harrisons Principles of Internal Medicine 20th ed

Reference: Katzung – Basic and Basic Pharmacology 14TH Edition
 LDL
● a Statin should be prescribed in all patients with diabetes age 40–79 with an LDL
cholesterol between 60 and 189 mg/dL.
● patients with diabetes and known ASCVD :a high intensity-statin dose (e.g.,
atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily)
● Diets restricted in saturated fats (<6% of calories) and trans- fats (as few as
possible) should be applied aggressively.
● treatment with statins, which lower LDL cholesterol by 15–60%, is the first-choice
medication intervention
● For each doubling of the statin dose, LDL cholesterol is further lowered by only
~6%.
● cholesterol absorption inhibitor ezetimibe is well tolerated and should be the
second-choice medication intervention, Ezetimibe typically reduces LDL
cholesterol by 15–20%.

Reference: Harrisons Principles of Internal Medicine 20th ed

 LDL
● Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent LDL
cholesterol lowering drugs (~45–60%)
○ if these patients also have familial hypercholesterolemia, or insufficient LDL
cholesterol lowering on statins ± ezetimibe, a PCSK9 inhibitor should be considered

● Bile acid sequestrants : cholestyramine, colestipol, and colesevalam may be

more effective than ezetimibe
○ with caution in patients with the metabolic syndrome when fasting triglycerides are
>300 mg/ dL.
○ SE: gastrointestinal symptoms (palatability, bloating, belching, constipation, anal
irritation).

• Nicotinic acid has similar LDL cholesterol–lowering capabilities (<20%).

• Fibrates are best employed to lower LDL cholesterol when triglycerides are not elevated.
• Fenofibrate may be more effective than gemfibrozil in this setting.

Reference: Harrisons Principles of Internal Medicine 20th ed

 Triglyceride
● fasting triglycerides >500 mg/dL should be treated to prevent more serious
hypertriglyceridemia and pancreatitis.
● A fibrate (gemfibrozil or fenofibrate) is the drug of choice to lower fasting triglyceride
levels, which are typically reduced by 30–45%.
● Other drugs that lower triglyceride levels include statins, nicotinic acid, and prescription
omega-3 fatty acids.
○ intermediate or high dose of the “more potent” statins (atorvastatin, rosuvastatin) is needed
○ Effect of nicotinic acid on fasting triglyerides is dose related and ~20–35%, an effect that is
less pronounced than that of fibrates.
○ Prescriptions of omega-3 fatty acid preparations that include high doses of eicosapentaenoic
acid ± docosahexaenoic acid (~1.5– 4.5 g/d) lower fasting triglyceride levels by ~25–40%.

Reference: Harrisons Principles of Internal Medicine 20th ed

 HDL Cholesterol
● Very few lipid-modifying compounds increase HDL
cholesterol levels.
● Statins, fibrates, and bile acid sequestrants

Reference: Harrisons Principles of Internal Medicine 20th ed

 Blood Pressure
● Direct relationship between blood pressure and all-cause mortality rate has
been well established in studies comparing patients with hypertension
(>140/90 mmHg)
● The best choice for the initial antihypertensive medication is an angiotensin-
converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker
● Sodium-restricted dietary pattern enriched in fruits and vegetables, whole
grains, and low-fat dairy products should be advocated.
● Home monitoring of blood pressure

Reference: Harrisons Principles of Internal Medicine 20th ed

 Impaired Glucose
● Aggressive glycemic control may favorably modify fasting levels of
triglycerides and/or HDL cholesterol.
● a lifestyle intervention that includes weight reduction, dietary saturated
fat restriction, and increased physical activity has been shown to reduce
the incidence of type 2 diabetes.
● Metformin also reduces the incidence of diabetes, although the effect is
less pronounced than that of lifestyle intervention.

Reference: Harrisons Principles of Internal Medicine 20th ed

 Insulin Resistance
● Several drug classes (biguanides, thiazolidinediones [TZDs]) increase insulin
sensitivity.
● Both metformin and TZDs enhance insulin action in the liver and suppress
endogenous glucose production.
● TZDs, but not metformin, also improve insulin-mediated glucose uptake in muscle
and adipose tissue.
● Adverse effects including weight gain, bone fracture, and congestive heart failure
with/or without edema were seen.
● TZDs has been seen in patients with NAFLD, and with metformin in women with
poly- cystic ovary syndrome, and both drug classes have been shown to reduce
markers of inflammation.

Reference: Harrisons Principles of Internal Medicine 20th ed

Summary
Risk factors:

• Obesity Associated Diseases

• Sedentary • CVD
Lifestyle • Type 2 DM
• Genetics • NAFLD
• Aging • Hyperuricemia
• Diabetes Mellitus • PCOS
• Cardiovascular • Obstructive Apnea
• Lifestyle
Disease • Diet Modification
• Lipodystrophy • Physical Activity
• Behavior Modification
• Pharmacotherapy
 suppressants and absorption
inhibitors
 Statins
 cholesterol absorption inhibitor
 Fibrates
 Anti-hypertensive drugs
 Hypoglycemic drugs
 References:

● Harrisons Principle of Internal Medicine 20th edition

● Katzung – Basic and Basic Pharmacology 14TH Edition
● Journal of the ASEAN Federation of Endocrine Societies: Accuracy of Waist
Circumference Measurement using the WHO versus NIH Protocol in Predicting Visceral
Adiposity , November 2021
Thank you for your kind
attention doctors