Ira J Goldberg MD and Phillip Bukberg MD

Contents

Case #1: Diabetes with Familial Combined Hyperlipidemia

Case #2: Low Cholesterol Syndrome

Case #3: Familial Hypercholesterolemia

Case #4 and #5: Unusual Levels of HDL Cholesterol

CASE #1: DIABETES WITH FAMILIAL COMBINED HYPERLIPIDEMIA

Case Description

A 59-yr-old man presented with the diagnosis of type 2 diabetes. He was in good health until 5 yr ago when he presented to the emergency room (ER) with an episode of chest pain and numbness in his jaw that occurred as he was walking up stairs. He was admitted to the hospital, and although an acute myocardial infarction (MI) was ruled out, an exercise stress test was positive. Coronary angiography revealed triple-vessel disease, and a coronary bypass operation was performed. Risk factors for coronary disease included the following: family history—his father died of an MI at age 52, mild hypertension -145/88, cigarette smoking—1 pack per day x 20 yr. He works as a bus driver and is 5 ft 9 in and 180 lbs. A lipid profile taken 2 mo postoperatively was as follows: cholesterol 250 mg/dL, triglyceride 180 mg/dL, HDL 30 mg/dL, and LDL 184 mg/dL. Liver, renal, and thyroid functions were normal.

The patient was begun on a ß-blocker, aspirin, and 20 mg/d of simvastatin. A subsequent evaluation one month later included cholesterol 210 mg/dL, triglyceride 240 mg/dL, HDL 28 mg/dL, LDL 144 mg/dL.

His primary care physician followed the patient for the next 3 yr with no change in his medications and no new symptoms. Two weeks prior to his visit, he was seen for a routine evaluation. He now weighs 210 lbs. His cholesterol was 240 mg/dL, triglycerides 600 mg/ dL, HDL 25 mg/dL, and LDL was not estimated. You order several additional tests including Lp(a), small dense LDL measurement, glucose and HA1c. Lp(a) was less than 30, LDL was pattern B (more small dense LDL), fasting glucose was 160, and HbA1c was 8.0%.

From: Contemporary Endocrinology: Challenging Cases in Endocrinology Edited by: M. E. Molitch © Humana Press Inc., Totowa, NJ

Discussion

As is not uncommon, patients with prediabetes often present first with clinical evidence of coronary artery disease. These patients often have a constellation of risk factors that include low HDL, small dense LDL, hypertension, and insulin resistance (1). Although this latter finding was not assessed in this patient, insulin levels are often elevated in this situation.

In the course of treatment for his anginal syndrome, this man was appropriately given P-blockers and a cholesterol-lowering medication, simvastatin. Although P-blockers have been reported in one study to be associated with increased development of diabetes (2), their positive effects to reduce cardiac death make their usage in this situation appropriate. It should also be noted that, as in this patient, P-blockers can increase triglyceride and reduce HDL levels (3).

Another issue is the measurement of cardiac risk factors other than a lipid profile. A number of other blood tests have been associated with increased risk in several studies. These include homocysteine, Lp(a) in Caucasians, but not blacks, and measurements of inflammation such as C-reactive protein, tumor necrosis factor, and Interleukin-6 (IL-6). A number of investigations have suggested that LDL particle size is associated with greater cardiovascular risk; however, this effect seemed to be limited to subjects who also had increased apoB levels—owing to either increased LDL or hypertriglyceridemia—or reduced HDL (4,5). In other studies this measurement did not seem to add additional information (6). In addition to hypertriglyceridemia, other predictors of small dense LDL include abdominal obesity and, presumably, insulin resistance (7). Therefore, clinical assessment might be as informative as direct measurement of this LDL subfraction in this patient.

The current problem is hypertriglyceridemia. Although the P-blocker may have contributed to this, the likelihood is that the diabetes is the primary reason for the triglyceride elevation. Occasional patients with mild hypertriglyceridemia will become severely hyper-triglyceridemic with the onset of diabetes mellitus; some of these patients have a heterozygous defect in lipoprotein lipase, the rate-limiting enzyme for triglyceride removal (8). This may be the case in this patient. Although that enzyme can be measured in the blood after a heparin injection and the patient's gene can be sequenced, neither evaluation will alter the clinical approach to the disorder.

The role of hypertriglyceridemia as a risk factor for cardiovascular disease has been debated for several decades (9). Except for hypertriglyceridemia associated with estrogens or alcohol, these patients invariably have reduced HDL owing to transfer of VLDL triglyceride for HDL cholesterol, a reaction mediated by the cholesteryl ester transfer protein (10). Although a primary prevention trial of triglyceride-lowering agents has not been done, a recent study in VA patients with established cardiovascular disease and low HDL demonstrated that gemfibrozil reduces the incidence of recurrent events in a lower HDL population (11). Gemfibrozil reduced triglycerides 25% and increased HDL 7%— the lipid change responsible for the beneficial effect of the drug cannot be ascertained because both changes occurred. Although the subjects in this VA study were not as hyper-triglyceridemic as our patient, it is likely that triglyceride reduction would be of benefit. Moreover, because triglyceride levels over 500 mg/dL are at a level associated with saturation of lipoprotein lipase, there is concern that dietary indiscretion or worsening diabetes might lead to an acute, rapid increase in triglyceride leading to pancreatitis.

The primary approach to this patient is life-style modification and diabetes management. Without control of his diabetes, the hypertriglyceridemia is unlikely to resolve.

Weight reduction and exercise can sometimes lead to dramatic reductions in triglyceride; this alone may well correct the problem. Diets should avoid alcohol completely, free sugars and simple carbohydrates should be reduced, and fats that will exacerbate postprandial lipemia should be limited. After introduction of diabetes therapy, triglyceride-lowering medications should be considered. In this situation, fibric acids—gemfibrozil and fenofibrate—are probably the first line therapy. Occasionally, the improved glycemic control will fully correct the triglycerides; sometimes the LDL will increase and the patients may then benefit most by a statin. Alternatively, combination therapy may be needed, however, with the patient's statin therapy there is an increased the risk of development of myositis. The patient needs to be warned to stop his medications and inform his physician if he develops myalgias. Niacin in low dose may be effective, but it may exacerbate glucose intolerance. High-dose statins and fish oil also may be useful.

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