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J Am Dent Assoc, Vol 138, No 2, 179-187.
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CLINICAL PRACTICE

JADA Continuing Education

Metabolic syndrome

Pathogenesis, medical care and dental implications



Arthur H. Friedlander, DMD, Jane Weinreb, MD, Ida Friedlander, RN, MS and John A. Yagiela, DDS, PhD


   ABSTRACT
TOP
 ABSTRACT
CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
 PATHOLOGY
 MEDICAL TREATMENT
 DENTAL IMPLICATIONS AND...
 CONCLUSIONS
 REFERENCES
 
Background. The dental literature contains little information about metabolic syndrome (MetS) and its dental implications.

Types of Studies Reviewed. The authors conducted a MEDLINE search for the period 2000 through 2005, using the term "metabolic syndrome" to define its pathophysiology, medical treatment and dental implications.

Results. MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke.

Clinical Implications. Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis.

Key Words: Hypertension; obesity; atherosclerosis; metabolic syndrome

Abbreviations: ACE: Angiotensin-converting enzyme • BMI: Body mass index • CYP3A4: Cytochrome P450 isoform 3A4 • FDA: Food and Drug Administration • FFAs: Free fatty acids • HDL-C: High-density lipoprotein cholesterol • IR: Insulin resistance • LDL: Low-density lipoprotein • LDL-C: Low-density lipoprotein cholesterol • MetS: Metabolic syndrome • NHANES III: Third National Health and Nutrition Examination Survey • PDGF: Platelet-derived growth factor

Societal advancement has led to improved transportation, readily available food and new devices that have permitted Americans to accomplish more while expending less energy and consuming a higher-calorie diet. This imbalance between energy intake and energy expenditure has led to the increasing prevalence of obesity and, as a consequence, the development of metabolic syndrome (MetS).


   CHARACTERISTICS OF METABOLIC SYNDROME
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 ABSTRACT
 CHARACTERISTICS OF METABOLIC...
EPIDEMIOLOGY
 PATHOLOGY
 MEDICAL TREATMENT
 DENTAL IMPLICATIONS AND...
 CONCLUSIONS
 REFERENCES
 
MetS (originally called "syndrome X" and "insulin-resistance syndrome") consists of at least three of the five following characteristics:

– abdominal obesity (as indicated by increased waist circumference or markedly increased body mass index [BMI]);
– raised triglyceride levels;
– reduced high-density lipoprotein cholesterol (HDL-C) levels;
– hypertension;
– impaired fasting glucose.

This last abnormality is believed to reflect, at least in part, insulin resistance (IR), in which insulin produces less than the expected biological effect. This results in inadequate suppression of hepatic glucose output, as well as inadequate removal of glucose from the systemic circulation via transport into fat and muscle cells, resulting in elevated fasting plasma glucose levels between 110 milligrams/ deciliter and 125 mg/dL1 (Table 1Go) (some clinicians have defined the range as between 100 mg/dL and 125 mg/dL2,3). Each of the abnormalities in MetS promotes atherosclerosis in the coronary and carotid arteries independently, but when clustered together, they are increasingly (synergistically) atherogenic and markedly enhance the risk of experiencing myocardial infarction and stroke.4,5


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  		TABLE 1 Identification of metabolic syndrome.

 
People with MetS typically also have elevations in coagulation factors such as fibrinogen and markers of inflammation such as C-reactive protein. These prothrombic and proinflammatory substances further contribute to increased cardiovascular risk. In addition, as the syndrome progresses, patients are at a greatly increased risk of developing type 2 diabetes mellitus, which, in turn, increases the cardiovascular risk even more.6


   EPIDEMIOLOGY
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 CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
PATHOLOGY
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 CONCLUSIONS
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Obesity is a major contributor to MetS, and it is well-established that obesity has increased in the United States from 1980 to 2000.7 Based on the estimates from the Third National Health and Nutrition Examination Survey (NHANES III) 1988–1994 and NHANES 1999–2000, the prevalence of obesity has increased 33 percent among adults 20 years and older.7 This pervasive increase in weight has resulted in ever-increasing numbers of Americans developing MetS. The prevalence of the disorder from 1988 to 1994 was 24 percent, but by 1999–2000, it had risen to 27 percent, due principally to a 24 percent increase in prevalence among women.8 Age-specific prevalence rates are even higher in both female and male Mexican-Ameri-cans and South Asians (that is, people from the Indian subcontinent).1,9 A diagnosis of MetS increases the likelihood (by more than 60 percent) of the person’s dying of coronary artery disease or stroke.10


   PATHOLOGY
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 CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
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MEDICAL TREATMENT
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The pathogenesis of MetS (FigureGo) remains unclear, although environmental factors such as excessive calorie consumption and sedentary lifestyle, coupled with still largely unknown genetic factors, clearly interact to produce the syndrome.11 The various components of MetS contribute to the development of the atherosclerotic lesions found in the coronary and carotid arteries.


Figure 1
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  		Figure. Proposed pathogenesis of metabolic syndrome. *FFAs: Free fatty acids. {dagger}HDL-C: High-density lipoprotein cholesterol.

 
IR is considered a major contributor to vascular disease via its several well-known effects. The adipocytes within the abdominal adipose tissue are insulin-resistant, thereby impairing the adipocyte’s ability to take up glucose and store free fatty acids (FFAs). Thus hampered, the adipocytes release large amounts of FFAs into the systemic circulation.12 Muscle cells take up much (but not all) of the FFAs. In healthy people, muscle is the major site of postprandial glucose disposal, but when glutted with FFAs, muscle becomes insulin-resistant as well, with resultant diminished glucose disposal, hyperglycemia and pancreatic beta cell stimulation to produce additional insulin (hyperinsulinemia).13,14 The residual FFAs (those that were unable to be absorbed by the muscle cells) are diverted to the liver via the portal vein, where they impair normal insulin-mediated suppression of hepatic glucose output and stimulate the synthesis, assembly and secretion of lipoproteins that promote atherogenesis (raised triglyceride levels, low concentrations of HDL-C, increased remnant lipoproteins, elevated apolipoprotein B levels, and small, dense low-density lipoprotein cholesterol [LDL-C]).15–17

The putative link between hyper-insulinemia and hypertension may be through stimulation of the sympathetic nervous system, causing vasoconstriction and increased renal sodium reabsorption and concomitant water retention.18,19 Hypertension disrupts the integrity of the endothelial lining of the coronary and carotid blood vessels, and lipoproteins and platelet-derived growth factor (PDGF) pass through the damaged and hyperpermeable endothelium.20 The lipoproteins lodge in the intima and the PDGFs cause proliferation of smooth muscle cells. These thickened and elevated lesions may protrude into the vessel lumen, where they alter the flow of blood, break off and embolize, causing hypoxia and cell death, with clinical manifestations of a myocardial infarct or stroke.

Intra-abdominal fat is metabolically active and secretes a number of substances that contribute to the pro-inflammatory and prothrombotic state present in MetS. Elevated proinflammatory factors include serum C-reactive protein and tumor necrosis factor-{alpha}. Elevated prothrombotic factors include plasminogen activator inhibitor-1, fibrinogen, factor VII, von Willebrand’s factor and thrombin.21,22


   MEDICAL TREATMENT
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 CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
 PATHOLOGY
 MEDICAL TREATMENT
DENTAL IMPLICATIONS AND...
 CONCLUSIONS
 REFERENCES
 
Appropriate care of patients with MetS requires simultaneous treatment of multiple risk factors instead of the traditional model of treating risk factors in isolation.23 Medical management first targets the modifiable underlying causes (imprudent diet and physical inactivity leading to excess body fat) and is aimed primarily at behavioral modification and lifestyle changes that will improve IR and dysregulation of fatty acid metabolism.24 However, insufficient numbers of patients achieve and/or maintain an adequate risk reduction with lifestyle changes alone. These patients then receive prescriptions for medications to treat the refractory obesity, dyslipidemia, hypertension and prothrombic and proinflammatory states.

Behavioral modification aimed at developing a healthy, more active lifestyle includes stress management, adoption of leisure-time activities (patients need to recognize that physical activity is preferable to watching television), planning meals and reducing portion size, reading food labels, identifying triggers for eating and/or inactivity, self-monitoring with regard to diet and physical activity, and setting achievable goals.25 Specific lifestyle changes include a reduced-calorie diet and increased physical activity (60 minutes each day).

Clinicians usually recommend a diet that reduces the intake of calories by 500 to 1,000 per day and is low in saturated fats (that is, full-fat dairy products and meats), transfatty acids (that is, prepared baked goods and oils used at fast food restaurants), cholesterol (that is, egg yolks and shellfish) and simple sugars; the diet also should include increased consumption of fruits, vegetables and whole grains.26 In a typical patient, this produces a weight loss of 1 to 2 pounds per week, with a reduction in body weight of 7 to 10 percent within six months to one year.27–29 Weight loss of this magnitude usually is associated with lower triglyceride levels, raised HDL-C levels, lowered blood pressure and glucose levels, reduced IR and prevention of diabetes.30

Managing hypertension often requires combination therapy, including diuretics, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory obesity include the appetite suppressant sibutramine and the lipase inhibitor orlistat. Sibutramine is a selective inhibitor of the reuptake of norepinephrine and serotonin from the synaptic cleft between neurons. Alteration in the norepinephrine level results in an increase in metabolic rate and thermogenesis; alteration in the serotonin level induces the feeling of satiety after eating.31 Orli-stat decreases weight by inhibiting the gastric and pancreatic lipases that are responsible for absorption of ingested dietary fat from the stomach and small intestine.

Several classes of medications are available to treat the dyslipidemia present in patients with MetS. Fibrates (fenobrate, gemfibrozil) alter the liver’s metabolism of fatty acids and lipoproteins, resulting in a decrease (between 20 and 50 percent) in triglyceride levels and a substantial increase (between 10 and 35 percent) in levels of HDL-C (that is, the "good" cholesterol with antiatherogenic properties).32 The statin medications (fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastin) are the most effective in decreasing (between 18 and 60 percent) LDL-C levels, although an elevated LDL level is not a criterion for MetS.

LDL reduction is extremely effective in decreasing cardiovascular and cerebrovascular risk.33 Furthermore, the statins also improve endothelial function, reduce vascular inflammation, decrease platelet aggregation and thrombosis, stabilize vulnerable atheromatous plaques and promote new vessel formation. Each of these attributes further reduces the risk of experiencing adverse cardiovascular events in patients with MetS.34

Clinicians frequently add niacin (prescription-strength nicotinic acid) to the treatment regimen, because it raises HDL-C levels by 15 to 30 percent. Furthermore, it lowers triglyceride and LDL-C levels by inhibiting the flow of FFAs from peripheral tissues to the liver, thereby reducing hepatic synthesis of triglyceride and secretion of very-low-density lipoprotein cholesterol and its conversion to LDL-C. Unfortunately, the use of niacin is limited in many patients because of side effects that include cutaneous flushing and elevation of plasma glucose levels. When further lowering of LDL levels is required, physicians may prescribe ezetimibe, a compound that selectively inhibits intestinal absorption of cholesterol and related phytosterols.35

Managing hypertension often requires combination therapy, including diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.36 A minority of clinicians avoid prescribing beta blockers and diuretics because these medications can increase IR and atherogenic dyslipidemia.37 In addition, low-dose aspirin (typically 81 milligrams, but with a range of 75 to 150 mg) usually is prescribed to address the prothrombic and proinflammatory states, thereby preventing myocardial infarction and stroke by virtue of its effects on coagulation and inflammatory processes.38


   DENTAL IMPLICATIONS AND TREATMENT CONSIDERATIONS
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 CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
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CONCLUSIONS
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Maintaining the health of the natural dentition is critically important for people with MetS because of their propensity to develop vascular disease.39 As people lose teeth progressively (even more so if the loss affects pairs of posterior grinding teeth [that is, the first and second premolars and molars]), they may alter their food selection and consume a diet associated with an increased risk of cardiovascular disease. This includes a significantly higher intake of saturated fat, transfatty acids and cholesterol and a lower intake of polyunsaturated fat, fiber, carotene, vitamin C, vitamin E, vitamin B6, folate, potassium, vegetables and fruits.40–48

Compounding these issues is the excessively high BMI noted in patients with fewer pairs of occluding posterior teeth or edentulism compared with similar dentate people. These elevated BMI levels appear to arise from the excessive ingestion of calorie-dense, soft, sweet snacks that foster obesity.49,50 These nutrient intake data also are supported by the outcomes of two large-scale cross-sectional studies (NHANES in the United States51 and the National Diet and Nutrition Surveys in the United Kingdom52). Removable partial and removable complete dentures do not appear to compensate for the chewing efficiency of lost teeth, and they do not significantly improve nutritional intake.53–57 However, some limited evidence exists of improved nutritional intake in patients who have received fixed prosthetic devices and prosthetic devices anchored to the jaws with osteointegrated dental implants.58–60

Many of the foods no longer eaten by people with a compromised dentition have been shown to afford protection against cardiovascular disease by preventing damage from free radicals, modulating cytokine production, enhancing endothelial function and preventing alteration of coagulation parameters.61–63 This is borne out by recent studies that have demonstrated an inverse association between fruit and vegetable consumption and the development of both cardiovascular and cerebrovascular disease.64–66

Dentists treating patients with medical histories and physical signs indicating possible metabolic disorder, such as an elevated BMI (≥ 27.5; calculated as weight in pounds multiplied by 703 and divided by the square of the patient’s height in inches), which can suffice in the absence of a waist circumference measurement,67–69 as well as hypertension should ask the patient if he or she has ever been evaluated for MetS or its component risk factors, because early comprehensive interventions may prevent the development of overt cardiovascular disease. If the patient is not under a physician’s care, the dentist should refer him or her for evaluation and treatment.

Patients previously diagnosed by their physicians as having MetS may have received prescriptions for medications that cause adverse systemic reactions and potentially dangerous interactions with the medications used in dentistry (Table 2Go). The medications used to treat the disorder also may cause adverse orofacial reactions; these are identified in Table 3Go.70–72


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  		TABLE 2 Drugs used commonly to treat metabolic syndrome.

 

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  		TABLE 3 Adverse orofacial reactions to medications for weight loss and dyslipidemia used in treatment of metabolic syndrome.*

 
Use of the weight control medication sibutramine in some patients has been associated with the development of hypertension, tachycardia and palpitations. The concomitant administration of sibutramine with certain opioids (that is, meperidine, tramadol, pentazocine and fentanyl) is contraindicated because of the danger of precipitating "serotonin syndrome," an acute medical emergency manifesting with one or more symptoms of excitement, agitation, confusion, loss of consciousness, motor weakness, ataxia, hyperthermia or tachycardia. Clinicians also should avoid administering erythromycin, clarithromycin and ketoconazole concomitantly with sibutramine because these medications inhibit the cytochrome P450 isoform 3A4 (CYP3A4) metabolic pathway, thereby increasing sibutramine levels and increasing the risk of toxicity.

The FDA-mandated package insert accompanying many of the ACE-inhibitor medications contains warnings of concern to dentists.70 These admonitions arise from the adverse reactions experienced by patients during the premarketing and, in some instances, postmarketing phases of the drugs’ development. On occasion, the administration of the ACE inhibitors has been associated with bone marrow depression, resulting in leukopenia (a white blood cell count of < 1,000 cubic millimeters, with a normal count being 5,000 to 10,000 mm3) and thrombocytopenia (a platelet count of < 85,000 mm3, with a normal count being 150,000 mm3 to 400,000 mm3), resulting in infection or bleeding problems.

The Physicians’ Desk Reference,70 which publishes the FDA inserts, warns of oral infection as a sign of neutropenia. Angioedema involving the face, lips, tongue, glottis and/or larynx also has been reported to occur during the first month of therapy in some patients receiving ACE inhibitors. In instances in which swelling is confined to the face and lips, the condition usually resolves by discontinuing the medication. However, in patients in whom there is involvement of the tongue, glottis or larynx that is likely to cause airway obstruction, emergency therapy includes subcutaneous administration of epinephrine solution 1:1,000 (0.3 to 0.5 milliliters).

During the administration of general anesthetic agents that produce hypotension, ACE inhibitors may block angiotensin II formation secondary to compensatory renin release. If hypotension develops during the procedure and the clinician considers it to be due to this mechanism, he or she should correct it via volume expansion. The concomitant administration of ACE inhibitors and either nonsteroidal anti-inflammatory agents or excessive amounts of epinephrine or levonordefrin in local anesthetic solutions may antagonize the antihypertensive effects of these agents. In addition, the concomitant administration of ACE inhibitors and either narcotic analgesics or barbiturates increases the likelihood and magnitude of orthostatic hypotension.

Niacin has been implicated in worsening the symptoms of gastroesophageal reflux.73 Therefore, clinicians should evaluate the dentition of patients receiving long-term niacin therapy for signs of erosion.

Most of the statin medications (simvastatin, atorvastatin, fluvastatin, lovastatin) are metabolized, in part or in whole, by the CYP3A4 system. Clinicians should not prescribe ketoconazole, erythromycin and clarithromycin concomitantly, because they may inhibit this metabolic pathway and increase the likelihood that the statin may cause myopathy manifesting as muscle pain or weakness associated with grossly elevated creatine phosphokinase levels or rhabdomyolysis, with acute renal failure secondary to myoglobinuria.

To minimize cutaneous flushing, clinicians usually prescribe a full-dose aspirin tablet (containing 325 mg of medication) to be taken simultaneously with niacin.74 However, an acetylsalicylic acid dosage of this magnitude may interfere with platelet function, resulting in prolonged bleeding.75–77 Elective surgical procedures are best performed when the patient is no longer receiving aspirin treatment. However, patients receiving long-term, low-dose (75 to 150 mg) aspirin therapy for prevention of stroke and myocardial infarction should not discontinue this treatment for dental and oral surgical procedures, because the increased cardiovascular risk is greater than the risks associated with platelet dysfunction and consequent bleeding.78,79 Furthermore, local measures have proven sufficient to control the bleeding that may occur in these patients during oral surgical procedures.80


   CONCLUSIONS
TOP
 ABSTRACT
 CHARACTERISTICS OF METABOLIC...
 EPIDEMIOLOGY
 PATHOLOGY
 MEDICAL TREATMENT
 DENTAL IMPLICATIONS AND...
 CONCLUSIONS
REFERENCES
 
Identification and treatment of MetS is of enormous public health importance because of the increased risk of cardiovascular disease in the United States. The convergence of the epidemic of obesity and aging of the large post–World War II generation will result in a dramatic rise in the number of dental patients with this disorder. Given the prevalence and adverse cardiovascular outcomes of the disorder, dentists need to consider MetS when formulating risk assessments for middle-aged and older patients who may undergo stress-provoking invasive dental procedures. Furthermore, dentists should develop treatment plans that preserve the natural dentition, thus ensuring maximum masticatory efficiency and affording the patient the optimum opportunity to ingest foods that will not foster atherogenesis.


   FOOTNOTES
 

Dr. Friedlander is associate chief of staff and the director of Graduate Medical Education, VA Greater Los Angeles Healthcare System, the director of Quality Assurance, Hospital Dental Service, University of California Los Angeles Medical Center, and a professor of Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".


Dr. Weinreb is chief, Diabetes Program, and residency program director for Endocrinology, Diabetes, and Metabolism, VA Greater Los Angeles Healthcare System, and an associate professor of clinical medicine, David Geffen School of Medicine at UCLA, Los Angeles.


Ms. Friedlander is a public health nurse, North Hollywood Health Center, North Hollywood, Calif.


Dr. Yagiela is a professor and chair, Diagnostic and Surgical Sciences, University of California Los Angeles School of Dentistry, and a professor of anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles.


   REFERENCES
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 EPIDEMIOLOGY
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 MEDICAL TREATMENT
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 CONCLUSIONS
 REFERENCES
 

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