A very common disorder frequently associated with elevated VLDL and LDL or elevated VLDL only is termed familial combined hyperlipidemia (FCHL) (Table VIII). In order to make a diagnosis, the family of the patient must be screened. Some family members will display increases in VLDL, others in LDL, and some in both VLDL and

TABLE VIII Major Lipoprotein Disorders


Principal plasma abnormality

Clinical features a

Estimated frequency

Heterozygous familial hypercholesterolemia


Tendinous xanthomas, cornial arcus, premature CAD; family history of hypercholesterolemia

0.2% of general population; 5% of MI survivors under age 60

Familial combined hyperlipidemia


Patients usually over age 30, often overweight, usually no xanthomas or premature CAD

0.5% of general population; 15% of MI survivors under age 60

Polygenic hypercholesterolemia


Premature CAD, no xanthomas


Familial hypertriglyceridemia (200-500 mg/dl)


Patients often overweight, usually do not have xanthomas or premature CAD

1% of general population; 5% of MI survivors under age 60

Severe hypertriglyceridemia (> 1000 mg/dl)


Patients usually middle age, obese, hyperuricemic, diabetic, at risk for pancreatitis


Familial hypoalphalipoproteinemia


Premature CAD

~40% of patients with premature CAD

a CAD, Coronary artery disease; MI, myocardial infarction.

LDL. The basic defect appears to involve overproduction of apo-B100. In some cases, this is accompanied by overproduction of triglyceride. However, the molecular basis for the defect and the responsible gene(s) have not been elucidated.

Hypertriglyceridemia is commonly associated with obesity and both Type I and Type II diabetes mellitus. (Note that fasting hypertriglyceridemia is synonymous with increased VLDL levels.) This disorder is almost invariably accompanied by low HDL levels (Fig. 11) and for this reason is a risk factor for premature heart disease. (Whether high VLDL by itself is a cardiovascular risk factor is controversial.)

In Type I diabetes mellitus, there is a severe deficiency (or total absence) of insulin due to an autoimmune attack on the cells that produce insulin, pancreatic p-cells. The absence of insulin produces a deficiency in adipose tissue lipoprotein lipase. This causes sluggish catabolism of VLDL and leads to hypertriglyceridemia. Another mechanism by which insulin deficiency promotes increased VLDL levels is the failure to inhibit the activity of adipose tissue hormone-sensitive lipase. This enzyme hy-drolyzes cytoplasmic triglyceride droplets. The fatty acids then go to the liver, where they are re-esterified to form triglycerides. These triglycerides are exported on VLDL particles. Since adipose tissue-derived fatty acids are an important substrate for hepatic VLDL triglycerides, the failure to suppress adipose tissue lipolysis is an important contributor to the enhanced rate of VLDL triglyceride secretion.

Obesity is almost invariably associated with insulin resistance, a poor response of insulin’s target tissues to an appropriate physiological dose of insulin. To prevent diabetes, the pancreatic p -cells must secrete additional insulin to compensate for the poor insulin response. Thus, insulin resistance is commonly associated with chronic hyperinsulinemia. The poor response to insulin in insulin resistance is selective for some of insulin’s actions. For example, people with insulin resistance have a poor stimulation of glucose transport into muscle and adipose tissue in response to insulin. However, they retain the ability to stimulate lipogenesis in response to insulin. Thus, the hyperinsulinemia associated with insulin resistance can promote excessive lipogenesis. This can lead to increased hepatic triglyceride synthesis and secretion. In Type II diabetes mellitus, the pancreas fails to adequately compensate for insulin resistance. Thus Type II diabetics can still have high insulin levels but not high enough to achieve eu-glycemia (normal glucose levels) or they can have below-normal insulin levels due to loss of p-cells.

The hypertriglyceridemia of Type II diabetes, unlike that which is found with Type I diabetes, is not due to excessive adipocyte lipolysis. This is because only a small level of insulin action is required to suppress excessive adipose tissue hormone-sensitive lipase activity. In Type II diabetes, there is insufficient adipose tissue lipoprotein lipase and excessive hepatic triglyceride synthesis. Thus, inefficient VLDL triglyceride catabolism and excessive VLDL triglyceride secretion both contribute to the excess VLDL in Type II diabetes.

Next post:

Previous post: