High density lipoprotein

High-density lipoproteins (HDL) form a class of lipoproteins, varying somewhat in their size (8–11 nm in diameter), that carry cholesterol from the body's tissues to the liver. About thirty percent of blood cholesterol is carried by HDL.

It is hypothesised that HDL can remove cholesterol from atheroma within arteries and transport it back to the liver for excretion or re-utilization&mdash;which is the main reason why HDL-bound cholesterol is sometimes called "good cholesterol", or HDL-C. A high level of HDL-C seems to protect against cardiovascular diseases, and low HDL cholesterol levels (less than 40 mg/dL) increase the risk for heart disease. When measuring cholesterol, any contained in HDL particles is considered as protection to the body's cardiovascular health, in contrast to "bad" LDL cholesterol.

Structure and function
HDL are the smallest of the lipoproteins. They are the densest because they contain the highest proportion of protein. They contain the A class of apolipoproteins. The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol, carried internally, from cells they interact with. A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol) which is then sequestered into the core of the lipoprotein particle eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol molecules into their structure. Thus it is the concentration of large HDL particles which more accurately reflects protective action, as opposed to the concentration of total HDL particles. This ratio of large HDL to total HDL particles varies widely and is only measured by more sophisticated lipoprotein assays using either electrophoresis (the original method developed in the 1970s), or newer NMR spectroscopy, NMR spectroscopy methods, developed in the 1990s.

HDL particles are not inherently protective. It is only the HDL particles which become the largest (actually picking up and carrying cholesterol) which are protective. There is no reliable relationship between total HDL and large HDL, and more sophisticated analyses which actually measure large HDL, not just total, correlate much better with clinical outcomes.

In the stress response, serum amyloid A, which is one of the acute phase proteins and an apolipoprotein, is under the stimulation of cytokines (IL-1, IL-6) and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis.

Men tend to have noticeably lower HDL levels, with smaller size and lower cholesterol content, than women. Men also have an increased incidence of atherosclerotic heart disease.

Historically, beginning in the late 1970's cholesterol and lipid assays were promoted to estimate total HDL-cholesterol because such tests used to be far less expensive, by about 50 fold, than measured lipoprotein particle concentrations and subclass analysis. Over time, with continued research, decreasing costs, greater availability and wider acceptance of other "lipoprotein subclass analysis" assay methods, including NMR spectroscopy, human studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured large HDL-particle concentrations.

Epidemiology
Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) are a positive risk factor for these atherosclerotic diseases.

Data from the landmark Framingham Heart Study showed that for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. Conversely, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.

Recommended range
The American Heart Association, NIH and NCEP provides a set of guidelines for male fasting HDL levels and risk for heart disease.

More sophisticated laboratory methods measure not just the total HDL but also the range of HDL particles, e.g. "lipoprotein subclass analysis", typically divided into several groups by size, instead of just the total HDL concentration as listed above. The largest groups (most functional) of HDL particles have the most protective effects. The groups of smallest particles reflect HDL particles which are not actively transporting cholesterol, thus not protective.

Differential Diagnosis

 * HDL cholesterol is a positive cardiac Risk Factors
 * 'HDL < 35
 * Total cholesterol to HDL ratio in > 5.0 (in men)
 * Total cholesterol to HDL ratio in > 4.5 (in women)
 * Negative cardiac risk factor if HDL > 60

Decreased

 * Apolipoprotein deficiency
 * Diabetes Mellitus
 * Drugs
 * Liver disease
 * Menopause
 * Obesity
 * Puberty in males
 * Tangier Disease
 * Uremia

Increased

 * Drugs
 * Moderate alcohol intake
 * Regular aerobic exercise
 * Weight loss

Drugs
As of 2006, randomized clinical trials have demonstrated significant reduction of atherosclerosis progression and cardiovascular events with treatments that increase HDL-cholesterol (nicotinic acid or a fibrate).

Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrates and niacin. Consumption of niacin, an immediate release crystalline form of Vitamin B3, can increase HDL levels by 10–30%, and is the most powerful agent currently available to increase HDL-cholesterol. The use of statins is effective against high levels of LDL cholesterol, but it has little or no effect in raising HDL-cholesterol. The use of antioxidants in combination with statin and niacin therapy reduces the effectiveness of niacin by 33%. (NIH HATS).

Torcetrapib, a promising new drug developed by Pfizer to raise HDL by inhibition of cholesteryl ester transfer protein (CETP), was terminated after a greater percentage of patients treated with torcetrapib-Lipitor combination died compared with patients treated with Lipitor alone.

Diet and lifestyle
Certain changes in lifestyle can have a positive impact on raising HDL levels:
 * Aerobic exercise
 * Weight loss
 * Smoking cessation
 * Using supplements such as omega 3 fish oil
 * Limiting intake of dietary fat to 30–35% of total calories
 * Removing trans fatty acids from the diet
 * Adding monounsaturated and polyunsaturated  fats to the diet, and reducing or eliminating saturated fats.
 * Drinking 1–2 servings of alcoholic beverages per day
 * Adding soluble fiber to diet