Metabolic Syndrome in the United

Metabolic Syndrome

In the United States, metabolic syndrome will soon become a more significant risk factor for heart disease than cigarette smoking. Elements of insulin resistance and hyperinsulinemia are associated with glucose intolerance and eventual progression to Type 2 diabetes. Associated elements include hypertriglyceridemia, hypertension, polycystic ovary syndrome, hypercoagulability states and vascular inflammation. The cardiovascular system is the primary body system involved in metabolic syndrome. Patients with metabolic syndrome have a constellation of conditions which are defined below: (Definitions based on current World Health Organization definitions for metabolic syndrome)

Hypertension - Current antihypertensive therapy and/or BP > 140/90

Dyslipidemia - Plasma triglycerides > 1.7 mmol/L (150 mg/dL) and/or HDL 30 and/or waist/hip ratio >.90 in men and >.85 in women glucose intolerance or diabetes

Not clinically a disease, the metabolic syndrome is rather a constellation of medical conditions. The syndrome has 3 possible etiological factors - 1) obesity and disorders of adipose deposition 2) insulin resistance and 3) independent factors of hepatic, vascular and immunologic origin that mediate specific elements of the syndrome. Other factors of the syndrome like aging and hormones have been implicated in the condition as well. Obviously, the mechanism of the disease is not entirely understood. The resistance to insulin stimulated glucose appears to have an effect on biochemical responses, thereby increasing metabolic risk factors.

Obesity is considered a significant factor in metabolic syndrome, especially abdominal obesity. The adipose tissue releases factors which exacerbate the cardiovascular risk factors, such as nonesterfied fatty acids, cytokines and adiponectin. These elements overload the muscle and liver with lipid, increasing insulin resistance. Adiponectin and cytokine excess may cause a proinflammatory state and may correlate to a prothrombotic state, both of which can increase incidence of cardiovascular disease.

Insulin resistance may be even more important than obesity in the pathogenesis of metabolic syndrome. Insulin resistance rises with higher levels of body fat. Insulin resistant muscle is overloaded with lipid, thus causing a diversion of lipid to the liver and atherogenic plaque. Triglyceride levels are elevated. Insulin resistance is also thought to be associated with increased blood pressure, although the actual mechanism is not entirely clear.

Several elements have been associated with the pathogenesis of metabolic syndrome. These factors include:

Atherogenic dyslipidemia

Apolipoprotein B

Small low density lipoprotein

Low high density lipoprotein

Inflammatory cytokines also appear to play a part in the pathophysiology of metabolic syndrome. Tumor necrosis factor a (TNF-a) and interleukin (IL)-6 are both produced in large amounts by adipose tissue. Proinflammatory cytokines increase hepatic lipogensis and may also elicit a systemic acute-phase response (Manson, et al., 2005). The TNF impairs insulin stimulated glucose uptake in cells and also decreases lipoprotein lipase activity (lipoprotein lipase is an enzyme which hydrolyzes lipoproteins like chylomicrons, into smaller fat units). Acute phase reactants like fibrinogen, white blood cells and plasminogen activator inhibitor-1 levels are also found to be associated with metabolic syndrome (Juahan-Vague & Alessi, 1997).

C-reactive protein (CRP) levels correlate with Body Mass Index and other features associated with metabolic syndrome. CRP is a very sensitive acute phase reactant. These inflammatory mediators are doubly significant since inflammation appears to be associated with the generation of atherosclerotic plaque. Different pathophysiologic factors appear to be associated with different components of the syndrome. Grouping of the risk factors tend to be associated with a higher risk of development of Coronary Heart Disease (CHD) and the presence of three or more of the metabolic risk factors lead to doubled risk for heart disease in men and a five fold increase for women (Wilson, 2004).

Metabolic syndrome is significant for our patient for several reasons. As we have noted, the syndrome is associated with a higher risk of cardiovascular disease. Those patients who have metabolic syndrome tend to develop coronary atherosclerosis at a higher rate than those who have coronary risk factors alone. Obesity increases the risk of metabolic syndrome but so does pre-obesity, or BMI ranging from 25-30. Women who have been diagnosed with polycystic ovarian syndrome are noted to be at increased risk of hypertension, dylipidemia, insulin resistance, impaired glucose tolerance and Type II diabetes. Because of all these comorbidities, women with PCOS also tend to be at greater risk for patients with subclinical carotid atherosclerosis, especially in the premenopausal population (Talbot, et al., 2000). For these same reasons, women diagnosed with PCOS have a 5 fold increased risk for the development of complications of coronary and cerebrovascular atherosclerosis.

Mrs. Stiller has many concerns regarding her diagnosis, not the least of which is her ability to become pregnant. Metformin would be the drug of choice for her condition. Metformin works by decreasing intestinal glucose absorption, decreasing peripheral glucose uptake and has also been noted to induce ovulation. There is a greater risk of spontaneous abortion in patients with hypeinsulinemia, thought to be due to the effect of elevated insulin levels on endometrial function and the uterine environment. Patients who have PCOS and use metformin have shown a slightly decreased risk of miscarriage in two small scale studies (McCarthy et al., 2004; Ben-Haroush a, Yogev Y, Fisch B, 2004) but it should be noted that the drug is category B. And that there is little evidence to support the use of metformin for this purpose.

With metabolic syndrome, Mrs. Stiller is at a higher risk of development of diabetes in pregnancy. We have also noted that the higher levels of insulin may make maintaining a pregnancy more difficult. Hypertension can also increase Mrs. Stiller's chance of spontaneous abortion. It is also more common for women with metabolic syndrome to develop diabetes by their 4th decade. If Mrs. Stiller plans pregnancy, it would be best that she attempt to normalize as many elements as she can before becoming pregnant. Modest weight loss, even at 5% of total body weight, will result in significant improvement in both hyperandrogenism and ovulatory function, even in women with normal ovulatory function. The changes that Mrs. Stiller makes will have a positive effect not only on her health but on the health of her baby. Should Mrs. Stiller lose weight, it is likely to have a positive effect on her lipid profile as well as her blood pressure.