Continuing Education Activity

Metabolic syndrome is an accumulation of several disorders, which together raise the risk of an individual developing atherosclerotic cardiovascular disease, insulin resistance, and diabetes mellitus, and vascular and neurological complications such as a cerebrovascular accident. This activity reviews the cause, pathophysiology, and complications of the metabolic syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Review the causes of metabolic syndrome.
• Describe the evaluation of a patient with metabolic syndrome.
• Summarize the treatment of metabolic syndrome.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by metabolic syndrome.

Introduction

Metabolic syndrome is an accumulation of several disorders, which together raise the risk of an individual developing atherosclerotic cardiovascular disease, insulin resistance, and diabetes mellitus, and vascular and neurological complications such as a cerebrovascular accident. Metabolic disarrangement becomes a syndrome if the patient has any three of the following:

• Waist circumference more than 40 inches in men and 35 inches in women
• Elevated triglycerides 150 milligrams per deciliter of blood (mg/dL) or greater
• Reduced high-density lipoprotein cholesterol (HDL) less than 40 mg/dL in men or less than 50 mg/dL in women
• Elevated fasting glucose of l00 mg/dL or greater
• Blood pressure values of systolic 130 mmHg or higher and/or diastolic 85 mmHg or higher

Metabolic syndrome has serious implications on an individual’s health and healthcare costs. It is necessary to recognize the rising prevalence of metabolic syndrome in America as through intervention the progression of the syndrome can be halted and potentially reversed.[1][2][3]

Etiology

The underlying etiology of metabolic syndrome is extra weight, obesity, lack of physical activity, and genetic predisposition. The crux of the syndrome is a buildup of adipose tissue and tissue dysfunction that in turn leads to insulin resistance. Proinflammatory cytokines such as tumor necrosis factor, leptin, adiponectin, plasminogen activator inhibitor, and resistin, are released from the enlarged adipose tissue, which alters and impacts insulin handling adversely. Insulin resistance can be acquired or may be due to genetic disposition. Impairment of the signaling pathway, insulin receptor defects, and defective insulin secretion can all contribute towards insulin resistance. Over time, the culmination of this cause development of metabolic syndrome that presents as vascular and autonomic damage.[4][5][6]

The distribution of body fat is also important, and it is known that upper body fat plays a strong role in developing insulin resistance. Fat accumulation can be intraperitoneal (visceral fat) or subcutaneous.  Visceral fat may contribute to insulin resistance more strongly than subcutaneous fat. However, both are known to play a role in the development of the metabolic syndrome. In upper body obesity, high levels of nonesterified fatty acids are released from the adipose tissue causing lipid to accumulate in other parts of the body such as liver and muscle, further perpetuating insulin resistance.

Epidemiology

In the United States, the prevalence of metabolic syndrome in adults 18 years and older is continuing to be significant. Data shows that the prevalence of this disease process increased from the 1980s to 2012 by 35%. In the 1980s, the incidence was noted to be 25.3% and increased to 34.2% in 2012. However, the most recent data from the National Health and Nutrition Examination Survey (NHANES) shows the prevalence is on a decline with 24% in men and 22% in women.[7][8]

Pathophysiology

Metabolic syndrome adversely influences several body systems.  Insulin resistance causes microvascular damage, which predisposes a patient to endothelial dysfunction, vascular resistance, hypertension, and vessel wall inflammation. Endothelial damage can impact the homeostasis of the body causing atherosclerotic disease and the development of hypertension. Furthermore, hypertension adversely affects several body functions including increased vascular resistance and stiffness causing peripheral vascular disease, structural heart disease comprising of left ventricular hypertrophy and cardiomyopathy, and leading to renal impairment.

Accumulated effects of endothelial dysfunction and hypertension due to metabolic syndrome can further result in ischemic heart disease. Endothelial dysfunction due to increased levels of plasminogen activator type 1 and adipokine levels can cause thrombogenicity of the blood and hypertension causes vascular resistance through which coronary artery disease can develop. Also, dyslipidemia associated with metabolic syndrome can drive the atherosclerotic process leading to symptomatic ischemic heart disease.[9][10]

Histopathology

The proinflammatory cytokines released from the adipose tissue are responsible for the development of atherosclerosis and coronary artery disease. Specifically, at low levels, adiponectin is associated with the formation of coronary artery disease in addition to causing insulin resistance and inflammation. Metabolic syndrome can also trigger a spectrum of liver damage by causing steatosis that can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Histologically, non-alcoholic steatohepatitis presents as steatosis, hepatocyte ballooning, lobular inflammation, Mallory bodies, and pericellular fibrosis. The exact mechanism of developing non-alcoholic steatohepatitis is unknown however it has been linked to metabolic syndrome and specifically insulin resistance and a proinflammatory state.

History and Physical

History and physical exam are vital for disease recognition, treatment, and prevention. The patient encounter starts with vitals and general appearance, which can clue a clinician into potential diseases such as hypertension, dyslipidemia, and metabolic syndrome. Although no identified genetic group is predisposed to metabolic syndrome, there are genetic disorders that may predispose individuals to the development of the metabolic syndrome and insulin resistance. Therefore, a patient should be questioned about any such potential genetic disorders. Social and lifestyle history should also be obtained, as there are modifiable factors that can significantly impact the development of the metabolic syndrome.  A physical exam is crucial for the diagnosis of metabolic syndrome as one of the criteria involves the waist circumference. Furthermore, if suspected, the patient should be screened for physical manifestations of insulin resistance such as peripheral neuropathy, retinopathy, acanthosis nigricans. A clinician should listen for arterial bruits that could be due to atherosclerotic disease. Patients with dyslipidemia may present with xanthomas.  Thus, a thorough physical examination is vital to the diagnosis of metabolic syndrome.

Evaluation

After a thorough history and physical, the evaluation needs to be complemented with laboratory analysis. The blood work should include hemoglobin A1C to screen for insulin resistance and diabetes mellitus type 2. A lipid panel should also be drawn to assess for abnormally elevated triglyceride level, low HDL level, and elevated low-density lipoprotein level. The initial evaluation should also include a basic metabolic panel to evaluate for renal dysfunction and examine glucose level. Further studies such as C-reactive protein, liver panel, thyroid study, and uric acid can be drawn to investigate the existence of further and support the diagnosis of metabolic syndrome. Imaging studies can be ordered when appropriate. For instance, anyone suspected to have atherosclerotic coronary artery disease should have an electrocardiogram to evaluate for signs of cardiac ischemia, infarct, arrhythmias,  as well as evaluate for hypertension with structural heart disease. If warranted, patients should be evaluated further with cardiac stress testing including electrocardiogram stress test, stress echocardiography, stress single-photon emission computed tomography or myocardial perfusion imaging.[11][12]

Treatment / Management

Management should be targeted at treating the conditions contributing to metabolic syndrome and possibly reverting the risk factors. Thus, modifiable factors such as diet and exercise should be emphasized in patients with metabolic syndrome.[13][14][15]

As per the most recent Joint National Committee (JNC) guidelines, the target blood pressure in the general population should be 140/90 mmHg, and in patients with diabetes mellitus, the goal is less than 130/80 mmHg. The most recent Joint National Committee-8 guidelines have further specified that in patients aged 60 or older the goal should less than 150/90 mmHg.

Patients with hypertriglyceridemia defined as triglycerides more than 150 mg/dL should be evaluated and further workup should include checking full lipid analysis, thyroid-stimulating hormone level, urinalysis, and liver function tests. After a comprehensive analysis, patients should first be counseled for lifestyle changes including abstinence from smoking, weight loss, and diet and exercise modification. Physicians will start treating hypertriglyceridemia once the level is above 500 mg/dL, and usually, patients have mixed dyslipidemia disorder by that point. Patients are usually on a moderate to high-intensity statin therapy first; however, fibrates, niacin, and omega acids are also available for treating hypertriglyceridemia. Elevated LDL should also be aggressively managed in these patients especially if the atherosclerotic cardiovascular disease (ASCVD) risk score if more than 7.5%, which establishes a patient’s 10-year ASCVD risk. These patients should be placed on high-intensity statin therapy with a goal of dropping the LDL by 50%.

Patients with severe obesity may benefit from bariatric surgery. Bariatric surgery is considered as the most effective single therapy of metabolic syndrome. The most common procedures carried out are laparoscopic adjustable gastric banding, laparoscopic Roux-en-Y gastric bypass, and laparoscopic sleeve gastrectomy. Bariatric surgery is recommended for patients with BMI≥ 40 kg/m2 or in those with a BMI ≥ 35 kg/m2 and other comorbidities. Patients should have a long-term follow-up after surgery to avoid surgical, nutritional, and psychiatric complications. [16]

Differential Diagnosis

• Glucagonoma

• Hypertension

• Hyperlipidemia

• Hyperglycemia

• Hypothyroidism

• Obstructive sleep apnea

• Pheochromocytoma

• Type 2 DM

Pearls and Other Issues

Sleep health and hygiene should also be discussed with patients who have metabolic syndrome because sleep apnea and sleep deprivation can lead to the development of metabolic syndrome. Studies have shown that in patients with moderate to severe sleep apnea, 3 months of continuous positive airway pressure can reduce blood pressure and potentially reverse some metabolic syndrome abnormalities.

To recognize the development of metabolic syndrome is crucial to treatment, prevention, and reversal of the disease process. Through history and physical exam, patient education, and workup of the contributing factors appropriately, physicians can not only treat the metabolic syndrome but also potentially alter the trajectory of disease development.

Enhancing Healthcare Team Outcomes

The management of metabolic syndrome is best done with an interprofessional team that includes a dietitian, physical therapist, pharmacist, cardiologist, internist, neurologist, bariatric surgeon, nurse practitioner, an endocrinologist, and a social worker. The key to this disorder is the prevention and education of the patient. The patient must be told of the importance of changes in lifestyle and weight loss. The dietitian should educate the patient on a Mediterranean-style diet and the importance of exercise. The patient should be urged to stop smoking and abstaining from alcohol. The pharmacist must ensure that the patient is compliant with the medications. Probably the most important intervention is an exercise because it can lower body weight, cholesterol, blood pressure, and blood glucose at the same time. Finally, patients with metabolic syndrome should be educated on good sleep hygiene. [17][18](Level V)

Outcomes

Patients with metabolic complications can develop a wide range of complications including heart disease, aortic stenosis, atrial fibrillation, stroke, and even thromboembolic disease. Today evidence seems to indicate that the risk of an ischemic stroke is much higher in patients with metabolic syndrome than previously thought. In addition, other problems associated with metabolic syndrome include a risk for malignancies of the kidney, gallbladder, colon and even the prostate gland. Further, the metabolic syndrome may also increase the risk of eclampsia and affect cognitive performance. Finally, patients with metabolic syndrome also face higher medical bills, are more likely to be poor and may find access to good quality healthcare difficult. [19][20](Level V)

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

van der Pal KC, Koopman ADM, Lakerveld J, van der Heijden AA, Elders PJ, Beulens JW, Rutters F. The association between multiple sleep-related characteristics and the metabolic syndrome in the general population: the New Hoorn study. Sleep Med. 2018 Dec;52:51-57. [PubMed: 30278295]

2.

Burrage E, Marshall KL, Santanam N, Chantler PD. Cerebrovascular dysfunction with stress and depression. Brain Circ. 2018 Apr-Jun;4(2):43-53. [PMC free article: PMC6126243] [PubMed: 30276336]

3.

Kim JY, Yi ES. Analysis of the relationship between physical activity and metabolic syndrome risk factors in adults with intellectual disabilities. J Exerc Rehabil. 2018 Aug;14(4):592-597. [PMC free article: PMC6165970] [PubMed: 30276179]

4.

White LS, Van den Bogaerde J, Kamm M. The gut microbiota: cause and cure of gut diseases. Med J Aust. 2018 Sep 01;209(7):312-317. [PubMed: 30257633]

5.

Catharina AS, Modolo R, Ritter AMV, Sabbatini AR, Lopes HF, Moreno Junior H, Faria AP. Metabolic Syndrome-Related Features in Controlled and Resistant Hypertensive Subjects. Arq Bras Cardiol. 2018 Jun;110(6):514-521. [PMC free article: PMC6023630] [PubMed: 30226908]

6.

Cozma A, Sitar-Taut A, Orăşan O, Leucuta D, Alexescu T, Stan A, Negrean V, Sampelean D, Pop D, Zdrenghea D, Vulturar R, Fodor A. Determining Factors of Arterial Stiffness in Subjects with Metabolic Syndrome. Metab Syndr Relat Disord. 2018 Nov;16(9):490-496. [PubMed: 30183523]

7.

Fietze I, Laharnar N, Obst A, Ewert R, Felix SB, Garcia C, Gläser S, Glos M, Schmidt CO, Stubbe B, Völzke H, Zimmermann S, Penzel T. Prevalence and association analysis of obstructive sleep apnea with gender and age differences - Results of SHIP-Trend. J Sleep Res. 2019 Oct;28(5):e12770. [PubMed: 30272383]

8.

Hooijschuur MCE, Ghossein-Doha C, Kroon AA, De Leeuw PW, Zandbergen AAM, Van Kuijk SMJ, Spaanderman MEA. Metabolic syndrome and pre-eclampsia. Ultrasound Obstet Gynecol. 2019 Jul;54(1):64-71. [PubMed: 30246464]

9.

He Y, Wu W, Wu S, Zheng HM, Li P, Sheng HF, Chen MX, Chen ZH, Ji GY, Zheng ZD, Mujagond P, Chen XJ, Rong ZH, Chen P, Lyu LY, Wang X, Xu JB, Wu CB, Yu N, Xu YJ, Yin J, Raes J, Ma WJ, Zhou HW. Linking gut microbiota, metabolic syndrome and economic status based on a population-level analysis. Microbiome. 2018 Sep 24;6(1):172. [PMC free article: PMC6154942] [PubMed: 30249275]

10.

Cӑtoi AF, Pârvu AE, Andreicuț AD, Mironiuc A, Crӑciun A, Cӑtoi C, Pop ID. Metabolically Healthy versus Unhealthy Morbidly Obese: Chronic Inflammation, Nitro-Oxidative Stress, and Insulin Resistance. Nutrients. 2018 Sep 01;10(9) [PMC free article: PMC6164113] [PubMed: 30200422]

11.

Klimova B, Kuca K, Maresova P. Global View on Alzheimer's Disease and Diabetes Mellitus: Threats, Risks and Treatment Alzheimer's Disease and Diabetes Mellitus. Curr Alzheimer Res. 2018;15(14):1277-1282. [PubMed: 30251605]

12.

Chiarelli F, Mohn A. Early diagnosis of metabolic syndrome in children. Lancet Child Adolesc Health. 2017 Oct;1(2):86-88. [PubMed: 30169210]

13.

Chambers JH, Zerofsky M, Lustig RH, Rosenthal P, Perito ER. Diet and Exercise in Pediatric Liver Transplant Recipients: Behaviors and Association With Metabolic Syndrome. J Pediatr Gastroenterol Nutr. 2019 Jan;68(1):81-88. [PMC free article: PMC6758561] [PubMed: 30234760]

14.

Kelley E, Imboden MT, Harber MP, Finch H, Kaminsky LA, Whaley MH. Cardiorespiratory Fitness Is Inversely Associated With Clustering of Metabolic Syndrome Risk Factors: The Ball State Adult Fitness Program Longitudinal Lifestyle Study. Mayo Clin Proc Innov Qual Outcomes. 2018 Jun;2(2):155-164. [PMC free article: PMC6124330] [PubMed: 30225445]

15.

Hohenester S, Christiansen S, Nagel J, Wimmer R, Artmann R, Denk G, Bischoff M, Bischoff G, Rust C. Lifestyle intervention for morbid obesity: effects on liver steatosis, inflammation, and fibrosis. Am J Physiol Gastrointest Liver Physiol. 2018 Sep 01;315(3):G329-G338. [PubMed: 29878845]

16.

Cordero P, Li J, Oben JA. Bariatric surgery as a treatment for metabolic syndrome. J R Coll Physicians Edinb. 2017 Dec;47(4):364-368. [PubMed: 29537411]

17.

Carson C, Lawson HA. Epigenetics of metabolic syndrome. Physiol Genomics. 2018 Nov 01;50(11):947-955. [PMC free article: PMC6293117] [PubMed: 30240346]

18.

Albert Pérez E, Mateu Olivares V, Martínez-Espinosa RM, Molina Vila MD, Reig García-Galbis M. New Insights about How to Make an Intervention in Children and Adolescents with Metabolic Syndrome: Diet, Exercise vs. Changes in Body Composition. A Systematic Review of RCT. Nutrients. 2018 Jul 06;10(7) [PMC free article: PMC6073719] [PubMed: 29986479]

19.

Cichos KH, Churchill JL, Phillips SG, Watson SL, McGwin G, Ghanem ES, Ponce BA. Metabolic syndrome and hip fracture: Epidemiology and perioperative outcomes. Injury. 2018 Nov;49(11):2036-2041. [PubMed: 30236796]

20.

Chen YY, Fang WH, Wang CC, Kao TW, Chang YW, Yang HF, Wu CJ, Sun YS, Chen WL. Association of Percentage Body Fat and Metabolic Health in Offspring of Patients with Cardiovascular Diseases. Sci Rep. 2018 Sep 14;8(1):13831. [PMC free article: PMC6138631] [PubMed: 30218093]

Disclosure: Supreeya Swarup declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Yulia Grigorova declares no relevant financial relationships with ineligible companies.

Disclosure: Roman Zeltser declares no relevant financial relationships with ineligible companies.