Low density lipoprotein overview

# Overview
Low-density lipoprotein (LDL) belongs to the lipoprotein particle family.  There is a direct association between high LDL and cardiovascular disease.  Environmental and genetic factors are involved in the pathophysiology of high LDL.  Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.  Prior approaches to the management of LDL aimed towards the classification of LDL concentrations and the treatment of subjects with dyslipidemia to a target LDL concentration.  In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III classified LDL concentrations into optimal, near optimal, borderline high, high, and very high.  However, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.  There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c, which is driving ongoing and future investigational therapies.

# Historical Perspective
From the early 1950s onward, Fredrickson specialized in the study of plasma lipoproteins, compounds of proteins and lipids which transport lipids in the blood.  However, the study of lipids in the blood has started early in the 1900's. In 1949, Faraday Society in Birmingham organized the first symposium on lipoproteins and separated for the first time lipoproteins into alpha and beta types.  In 1950, LDL was first isolated.  In 1973, Myant first hypothesized the role of LDL in the metabolism of cholesterol.

# Classification
Prior approaches to the management of LDL aimed towards the classification of LDL concentrations and the treatment of subjects with dyslipidemia to a target LDL concentration.  In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III classified LDL concentrations into optimal, near optimal, borderline high, high, and very high.  However, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.

# Physiology
Low-density lipoprotein (LDL) belongs to the lipoprotein particle family.  Its size is approximately 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that surrounds the fatty acids keeping them soluble in the aqueous environment.  The average composition of LDL is approximately 20% protein, 20% phospholipids, 40% cholesteryl esters, 10% unesterified cholesterol, and 5% triglycerides.

# Pathophysiology
Environmental and genetic factors are involved in the pathophysiology of high LDL.  Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.  Abnormally low LDL can occur, and they usually result from rare inherited conditions, such as familial hypobetalipoproteinemia and abetalipoproteinemia.

# Causes

## Low LDL
Low LDL levels can be caused by unusual inherited disorders of lipoprotein metabolism such as abetalipoproteinemia and hypobetalipoproteinemia.

## High LDL
High LDL can be primary or secondary to diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.  High LDL can also be caused by inherited diseases that affect the lipid metabolism.

# Epidemiology and Demographics
From 19761980 through 20072010, for U.S. adults aged 4074, a decrease was observed in the prevalence of high LDL-cholesterol (LDLC) from 59% to 28%, as well as an increase in adults using lipid-lowering medications and consuming a diet low in saturated fat. Despite recent advances in medical treatment, high LDL-C remains a significant public health problem in the United States, with more than one-quarter of adults aged 4074 having high LDLC.

# Risk Factors
Risk factors for high LDL include genetic predisposition, aging, and unhealthy life style choices.

# Screening
According to the United States Preventive Services Task Force (USPSTF), screening for high LDL-cholesterol (LDL-c), is indicated among men 35 years and older (Grade: A Recommendation), men age 20 to 35 years in case of an elevated risk for coronary heart disease (Grade: B Recommendation), women age 45 years and older for in case of an elevated risk for coronary heart disease (Grade: A Recommendation), and women age 20 to 45 years in case of an elevated risk for coronary heart disease (Grade: B Recommendation).  There is insufficient evidence to recommend for or against screening for dyslipidemia among infants, children, adolescents, or young adults less than 20 years of age (Grade: I statement).

# Natural History, Complications and Prognosis
The natural history and the prognosis of high LDL concentrations are directly associated with the complications of atherosclerosis, namely cardiovascular disease (CVD) which is the most common cause of mortality worldwide. Classically, elevated LDL concentration has been associated with significantly increased rates of coronary artery disease (CAD). However, emerging evidence has demonstrated that an elevated concentration of LDL is also strongly associated with insulin resistance as well as other forms of ischemic vascular diseases. The role of elevated levels of LDL in the development of ischemic complications, such as stroke, peripheral arterial disease, carotid atherosclerosis, and renovascular injury, has also been validated. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations.

# Diagnosis

## Laboratory Findings
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available.  However, there is increasing evidence and recognition of the value of more sophisticated measurements.  Specifically, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles.  LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high.  Alternatively, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low.  If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity and smoking, lose much of their additive predictive power.

# Treatment

## Medical Therapy
While prior approaches to the management of LDL plasma concentration aimed towards treating the subjects with dyslipidemia to a target LDL concentration, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.  The 2013 ACC/AHA guidelines identifies the following statin benefit groups: subjects with atherosclerotic cardiovascular disease, subjects with LDL  190 mg/dL, subjects with diabetes mellitus PLUS age 40-75 years PLUS LDL 10-189 mg/dL, and subjects with LDL 70-189 mg/dL PLUS estimated 10 year risk of atherosclerotic cardiovascular disease  7.5%.  The pooled cohort equation should be used to estimate the 10 year risk of atherosclerotic cardiovascular disease and guide the treatment among subjects with no diabetes mellitus or atherosclerotic cardiovascular disease.  Lifestyle changes is a critical component of the management of patients with elevated LDL whether they are administered or not lipid lowering drugs.

## Landmark Trials

## Future and Investigational Therapies
There is an association between the concentration of circulating LDL cholesterol (LDL-c) and the risk of cardiovascular disease.  There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c.  Ongoing studies are evaluating novel lipid-lowering therapeutic strategies, including anti-sense oligonucleotides (ASOs) to apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), microsomal triglyceride transfer protein (MTP), thyromimetics, squalene synthase, adenosine triphosphate-citrate lyase, AMP-activated protein kinase, and sterol regulatory element binding proteins.