High-density lipoproteins are a group of particles that have a wide array of functional and physicochemical properties. Many methods have been used to sub-classify HDL, first by size and density via ultracentrifugal flotation rate in a high salt solution and then by the mass concentration of lipoprotein particles. Gel electrophoresis further sub-classified HDL into 2a, 2b, 3a, 3b, and 3c. HDL was further subcategorized, utilizing gel electrophoresis and by apolipoprotein AI composition. Nuclear magnetic resonance (NMR) spectroscopy and ion mobility have been used to quantify HDL particles or HDL-P. HDL has many antiatherogenic properties, including cholesterol efflux from arterial wall macrophages subsequent transport and removal of cholesterol via the hepatobiliary system, antioxidative properties, anti-inflammatory effects, and endothelial function.
Low HDL has been described in various forms of familial lipid disorders and as a part of metabolic syndrome. It has many causes, including medication, familial lipid disorders, and genetic defects resulting in syndromes such as Fish Eye disease and Tangier disease. Not all of the hereditary causes have an identified gene causing the low HDL. Familial hypoalphalipoproteinemia is caused by a mutation in the apolipoprotein A-I gene resulting in low HDL. Familial HDL deficiency, a common cause of low HDL, has been shown in studies to share an allelic relationship with Tangier disease. 
Tangier disease, discovered 40 years ago in siblings on Tangier Island, is an autosomal co-dominant condition in which the homozygous state has an absence of plasma HDL-C with premature coronary artery disease, peripheral neuropathy, cholesteryl ester deposition in the reticuloendothelial system leading to hepatosplenomegaly, xanthomata, xanthelasma, arcus corneae along with enlarged tonsils and lymph nodes. HDL is about 50% of normal levels in heterozygotes.
Another rare inherited lipid disorder is familial combined hypolipidemia. This disorder is defined by low LDL, triglycerides, and HDL. Cholesterol ester transfer protein (CETP) activity has been documented in men with low HDL and normal triglyceride levels. Its role is to facilitate cholesterol ester transfer from HDL to lipoproteins that are enriched with triglycerides. Studies have found that higher CETP concentrations and lower HDL concentrations reduce the risk of coronary atherosclerosis, while decreased CETP activity is associated with increased risk of CHD and some but not all studies. Studies have suggested that high CTP activity is a factor that causes low HDL cholesterol in patients with otherwise normal cholesterol levels.
Lipoprotein lipase facilitates the transfer of cholesterol to HDL from lipoproteins and triglyceride-enriched lipoprotein hydrolysis, lowering triglyceride levels. The premature coronary disease was present in 15% of those with heterozygotes of the lipoprotein lipase gene mutations in one study. Hepatic triglyceride lipase hydrolyzes phospholipids and triglycerides from HDL resulting in lower serum HDL levels. In patients with low HDL, the activity of this enzyme is increased regardless of the triglyceride levels.
Lecithin cholesterol acyltransferase (LCAT) is an enzyme that esterifies free cholesterol to cholesterol esters and HDL cholesterol. Very low serum HDL has been observed in those with homozygous mutations of the LCAT gene. Fish-eye syndrome is characterized by LCAT deficiency due to mutations of the LCAT gene with associated classic symptoms of severe corneal opacities, nephropathy, and proteinuria. Typically premature cardiovascular disease is not seen with LCAT deficiency but can occur in some mutations even in heterozygotes.
Low HDL cholesterol is a component of metabolic syndrome atherogenic lipid phenotype. Other features of the syndrome include insulin resistance, type 2 diabetes mellitus, obesity, hypertension, borderline high LDL, and elevations of triglyceride enriched remnants.
For most hereditary causes of low HDL, the case prevalence is not well established, and most are considered rare. The frequency of apo A-I gene mutation was estimated to be 6% and 0.3% in the general population.
Several mutations were found in a population study to determine the frequency of familial hypoalphalipoproteinemia. In the children with the identified mutations, apo A-I levels were reduced by roughly 50% in the heterozygotes, and homozygotes were deficient in plasma HDL and apo A-I. The deleterious mutation is believed to be autosomal dominant. ATP binding cassette transporter (ABC1) mutations were detected in both familial HDL deficiency, and Tangier disease resulting in impaired cholesterol efflux from macrophages via the cholesterol efflux regulatory protein. This impairment in cholesterol efflux leads to foam cells, which may explain the increased risk of coronary artery disease in these two conditions.
Tangier disease has also shown marked hypercatabolism of apoA-I in atypical lysosomes inside mononuclear phagocytes. In familial combined hypolipidemia, two nonsense mutations were found in a familial study of patients with hypobetalipoproteinemia. These mutations demonstrated codominant features with heterozygosity of either mutation and showed an intermediate decrease in LDL cholesterol and triglycerides. However, homozygosity with both mutations resulted in significantly low LDL and triglyceride plasma levels. These nonsense alleles appear to have recessive traits with HDL levels, members with both nonsense alleles had significantly lowered plasma HDL as compared to members with just one allele who showed no difference between members with neither mutation.
Polymorphism of the CETP gene affects the concentration and activity of CETP in the plasma. The B1 gene variant has been associated with lower HDL cholesterol and higher CETP concentration. Various genotypes were evaluated in an angiographic study of men with previously documented coronary atherosclerosis. The study compared the progression of coronary artery disease in these patients based on their CETP genotype. The B2B2 genotype had the least progression noted, the B1B1 genotype had the greatest progression, and B1B2 genotype had an intermediate progression of coronary disease. A different report evaluated two common mutations in CETP, resulting in a decreased CTP activity, comparing healthy subjects to those with coronary heart disease.
Lower HDL cholesterol concentrations were found in those who are heterozygous or homozygous for these mutations compared to the non-carriers. Despite the low HDL level associated with the mutations, women and men had a lower CHD risk. Typically, lipoprotein lipase gene mutations result in heterozygotes with impaired activity of lipoprotein lipase, hypertriglyceridemia, and low HDL levels. Meanwhile, complete LPL deficiency seen in homozygotes of the lipoprotein lipase gene mutations resulted in severe hypertriglyceridemia and chylomicronemia.
Most causes of low HDL do not have clear associated history or physical findings; however, some of the above-mentioned syndromes have classic findings that are important to look for as it will help narrow the differential quickly. Syndromes that have elevated LDL and triglycerides are prone to have xanthomas and xanthelasmas. Fish-eye disease characterized by severe corneal opacities that resulted in the name of the fish-eye disease. Tangier disease patients will complain of peripheral neuropathy. Physical exam of a patient with Tangier disease may have hepatosplenomegaly, enlarged tonsils or lymph nodes, arcus corneae due to lipid deposits in the eye, xanthomata, and xanthelasma. The insulin resistance seen in metabolic syndrome can sometimes be associated with acanthosis nigricans.
Fasting lipid panel will give you the HDL cholesterol level in the blood. NMR can be used to measure particle numbers; however, there is not a standardized way of quantifying this lab. Given the proteinuria and the nephropathy seen in the fish-eye disease, a measurement of kidney function on a basic anabolic panel and a urinalysis to evaluate for protein in the urine are reasonable if this syndrome is suspected.
Overall, any beneficial clinical impact resulting from the elevation of HDL cholesterol content is not supported by research. A meta-analysis, in 2009, evaluating 108 randomized trials with patients at risk for coronary heart events failed to find an association, after adjustment for LDL cholesterol changes, between creases and HDL cholesterol from treatment with risk ratios for cardiovascular events, deaths from coronary disease or total deaths. Of the medications that raise HDL, niacin, and gemfibrozil have the greatest effect with a 15 to 30% increase in serum HDL concentration. While niacin is very effective at raising HDL cholesterol levels in patients with no other lipid abnormalities, there is little evidence that the addition of niacin to statin therapy has any cardiovascular outcome benefit. In the AIM High trial, the addition of niacin to statins in patients with well-controlled LDL cholesterol did not show any benefit despite the significant rise in HDL cholesterol.
The VA HIT trial examined patients with coronary heart disease, HDL less than 40, LDL less than 140, and triglycerides less than 300. Subjects were divided randomly into two groups, gemfibrozil treatment, and placebo. After randomization, the beneficial effect first became apparent. After five years, nonfatal myocardial infarctions and cardiac death, the combined primary endpoint, was observed less often in the gemfibrozil group. Multivariable analysis of this trial found that the serum HDL concentration is achieved with gemfibrozil therapy was strongly correlated with the reduction in coronary heart disease death and nonfatal myocardial infarction independent of the changes in LDL cholesterol or triglycerides.  This analysis also revealed new interesting information that the high concentrations of total HDL particles seen in the VIA HIT trial were a better predictor of cardiovascular disease events.
Infusion of apolipoprotein A-I has been tested in multiple studies for the potential benefit. Reduced risk for cardiovascular disease events has been strongly associated with ApoA1 levels in patients on statin therapy for LDL cholesterol. In animal models, IV administration of apolipoprotein A1 demonstrated reduced macrophage content and intimal thickening following balloon injury to large arteries that were statistically significant. Based on these findings, a human trial looked at IV a blood protein A1 therapy within two weeks of an acute coronary syndrome. The small study showed a significant reduction in the portion of the coronary artery that was occupied by atheroma. A larger study looked at consecutive weekly infusions of apolipoprotein A1 versus placebo following recent myocardial infarction. Patients were randomized between infusion or placebo groups. Those who received the apolipoprotein A1 CSL 112 had an increase in cholesterol reflux capacity as well as increased apolipoprotein A1 complex. However, a properly powered phase 3 trial is needed to evaluate whether this will have a reduction in major adverse cardiovascular events.
Infusion of reconstituted HDL is examined in the erase trial were patients were randomized between placebo or dose of reconstituted human HDL. There was early study discontinuation in the higher dose HDL infusions due to increased incidence of liver function test abnormalities. However, despite this, the vascular ultrasound taken a few weeks after the last infusion did not demonstrate a statistically significant difference in the coronary atheroma volume change from baseline. Various CETP inhibitors, including torcetrapib, anacetrapib, evacetrapib, and dalcetrapib, showed significant elevation in HDL cholesterol levels.
The ILLUMINATE trial, which investigated torcetrapib, was terminated early due to the increased risk of cardiovascular events. Both major studies for evacetrapib were terminated early due to futility. Lastly, anacetrapib is currently under investigation. Relative risk reduction for vascular events patient is treated with simvastatin with similar in both high baseline HDL concentrations and low baseline HDL concentrations. Both an absolute and relative risk reduction for mortality and cardiovascular events in patients on pravastatin 40 mg were similar to the overall cohort in the postop subset analysis of the lipid study examining patients with recent myocardial infarction or unstable angina who also had LDL cholesterol of 140 or less, triglyceride level of 300 or less and HDL cholesterol level of 40. In the heart protection study, the relative risk reduction for vascular event rate in patients treated with 40 mg of simvastatin daily was similar regardless of the baseline HDL concentration. Therapy with pravastatin, in patients with CETP deficiency, slowed the progression of coronary atherosclerosis in the high-risk B1B1 carriers but not in those with B2B2.
In patients with increased cardiovascular risk with low HDL cholesterol, the evidence does support a healthy diet, regular exercise, reaching target body weight, and smoking cessation to improve HDL cholesterol and decrease cardiovascular disease risk. Of the medications previously mentioned that cause decreased HDL cholesterol, it is generally not recommended to stop these medications as they are important in the treatment of another medical condition.
Of medications, many anti-hypertensive medications alter serum HDL levels. Diuretics cause an increase in all cholesterol and triglycerides proportionate to the dose. This effect is more pronounced in African Americans. The one exception is the reduction of HDL in diabetics on diuretics. Beta-blockers cause a decrease in HDL secondary to increased triglycerides. Cardioselective beta-blockers, especially in diabetics, have a smaller increasing effect on triglycerides. Alpha-blockers have an opposite effect compared to beta-blockers resulting in decreased triglycerides and increased HDL. HDL and other cholesterol are decreased with central sympathomimetics. Vasodilators increase HDL while reducing LDL and total cholesterol.
Myocardial infarction, according to data from Framingham heart study, increases by about 25% for every 5 mg/dL decrease in HDL cholesterol serum levels below median values. Studies since have found that a low level of HDL cholesterol, once other known risk factors have been adjusted for, is an independent risk predictor. In patients with established cardiovascular disease, follow-up studies found that HDL cholesterol is protective for future events while being treated with statin therapy, as evidenced in the SMART study.
Elevation of HDL cholesterol without a substantial increase in HDL particle can result in cholesterol overloaded HDL particles, which in one community-based cohort study showed an increased progression towards carotid atherosclerosis as measured by carotid intimal medial thickening in asymptomatic patients with no underlying atherosclerotic disease. CETP inhibitors and niacin both raise HDLC levels without having any effect on HDL function or number of particles and therefore tend to increase cholesterol overloaded particles.
As discussed previously, a healthy diet is recommended in the treatment of low HDL. The Mediterranean diet in observational studies has shown a decrease in cardiovascular and overall mortality. In a meta-analysis of the PREDIMED trial, no reduction in cardiovascular or overall mortality was observed. It is important to counsel patients on the types of fat they consume as these affect their HDL levels. A meta-analysis of randomized controlled feeding studies compared fat sources by replacing just 1% of energy consumption, trans fatty acids in place of saturated fats, monounsaturated fats, or polyunsaturated fats, respectively, increased the ratio of total cholesterol to HDL by 0.31, 0.54 and 0.67; apolipoprotein (Apo)-B/ApoAI ratio was increased by 0.007, 0.010 and 0.011; and increased lipoprotein (Lp)(a) by 3.76, 1.39 and 1.11 mg/L.
Further counseling on weight loss and exercise is warranted as well. Amongst the saturated fatty acids, the carbon chain length affects the change in serum cholesterol. For instance, those with carbon chain lengths of 14 (myristic) and 16 (palmitic) increase LDL and HDL cholesterol while decreasing triglyceride-rich lipoproteins. These smaller saturated fats can be found mostly in dairy products and red meats. On the other hand, stearic acid (18 carbons) has less of an effect on LDL and HDL cholesterol and can be found in beef and cocoa butter.
While there is no consensus on monounsaturated fats effect on HDL replacing polyunsaturated fats with monounsaturated fats in patients with type 2 diabetes mellitus reduces insulin resistance. Insulin resistance and diabetes are important causes of low HDL and should be addressed during patient education. Omega 6 fatty acids have been shown to increase HDL cholesterol while lowering serum triglycerides and LDL cholesterol. This polyunsaturated fat can be found in plant oils such as soybean, safflower, sunflower, and corn oils.
In an analysis, evaluating obese individuals with pre-diabetes and diabetes, many reported a lack of lifestyle counseling from their primary care provider on exercise, diet, and weight-loss strategies. Referrals to weight loss programs were also reported at low levels.
A survey found the average primary care provider median visit length was 10 minutes. There are many capable members of the health care team that could assist in counseling our patients and supporting them over multiple visits to help make the lifestyle modifications recommended to improve their HDL levels.
Licensed therapists have been shown to help with behavior modification strategies, including smoking cessation as well as overeating or binge eating. Personal trainers with guidance from the clinician or for patients with cardiovascular disease cardiac rehab specialists can help with exercise programs tailored to each individual. Dieticians can help not only with one on one consultation but also classes on healthier cooking mechanisms.
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