Lipoprotein disorders overview

# Overview
Lipoproteins, which are aggregates of proteins and lipids, allow the circulation of hydrophobic lipids in the body.  Disorders of lipids and lipoproteins metabolism have important health consequences, mainly on the cardiovascular system.  Lipoprotein disorders can be described as abnormalities in the level of the lipids, which include cholesterol and triglycerides, or as abnormalities in the levels of lipoproteins that include LDL, HDL, VLDL and chylomicrons.
Lipoprotein disorders have been initially classified in 1967 into different phenotypes by Fredrickson according to the type of lipoproteins that accumulate. However; Fredrickson's classification of hyperlipoproteinemias took into consideration the elevation in chylomicrons, LDL, VLDL but did not include abnormalities in HDL levels.  Other classifications have been suggested, one of which is the National Cholesterol Education Program (NCEP) classification of lipoprotein disorders.  NCEP classifies lipid disorders according to laboratory cut off points for the levels of total cholesterol, LDL-C and HDL.
Lipoprotein disorders can be classified according to different criteria.  First of all, lipoprotein disorders can be classified as primary disorders resulting from genetic mutations and secondary to other diseases.  Another way of classifying lipoprotein disorders is as hypolipidemia (or hypolipoproteinemia) and hyperlipidemia (hyperlipoproteinemia) where the lipoprotein levels are decreased and increased respectively.  However, the latter classification is not precise and creates some ambiguity, because some people can be labeled as having hyperlipidemia but have simultaneously high level of some lipoproteins and low levels of other lipoproteins depending on the underlying pathophysiology.  Hence, a better term to describe the constellation of abnormal lipid profiles is "disorders of lipoproteins", or dyslipoproteinemia or dyslipidemia.

# Historical Perspective

# Classification
Hyperlipidemias are classified according to the Fredrickson classification which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation. It was later adopted by the World Health Organization (WHO). It does not directly account for HDL, and it does not distinguish among the different genes that may be partially responsible for some of these conditions. It remains a popular system of classification, but is considered dated by many.
There are several ways in which lipoprotein abnormalities are classified. Lipoprotein disorders can be classified according to:
- The pattern of change in the lipoprotein levels, described as hyperlipidemia (increase in lipid levels) and hypolipidemia (decrease in lipid levels):  However, this classification is problematic because the lipids and lipoproteins levels in some situation can be elevated in some types of lipoproteins and lipids and decreased in others.
- Phenotype, or the specific type of lipid that is increased, as classified by Fredrickson: This classification is problematic because it does not include abnormalities in the level of HDL.
- Etiology, as primary (genetic) or secondary to another condition: This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. However, there are a few well defined genetic conditions that are usually easy to identify.
- Levels of measured lipids (cholesterol and triglycerides), described as hypercholesterolemia and hypocholesterolemia or hypertriglyceridimia and hypotriglyceridemia: This distinction is not specific because it does not reflect the specific lipoprotein(s) that are abnormally high or low.

## Definitions
In order to understand the different lipoprotein disorders, it is important to correctly define the keywords used to define them.
- Hyperlipidemia: Hyperlipidemia is a commonly used term that describes high level of lipids, whether cholesterol or triglycerides.  Despite being commonly used to describe abnormalities in lipid metabolism in our daily practice, this term is not very specific.  For instance, people who have metabolic syndrome have high LDL and low HDL and yet they are described to have hyperlipidemia when their HDL level is decreased.
- Hyperlipoproteinemia: Hyperlipoproteinemia is the elevation of lipoproteins, the aggregates of lipids and proteins. Hyperlipoproteinemia is the term used by Fredrickson in his classification of lipoprotein disorders.  Hyperlipoproteinemia can be used interchangeably with hyperlipidemia in some instances, however, they are not synonyms.  In fact, some lipoprotein disorders can have elevated or decreased level of lipoproteins while the toltal cholesterol level is within normal ranges.
- Dyslipoproteinemia: Dyslipoproteinemia describes abnormalities of lipoproteins.  Dyslipoproteinemia reflects the lipoprotein disorders better than hyperlipoproteinemia since is does not limited these disorders only to cases where some types of lipoproteins are elevated.
- Dyslipidemia: Dyslipidemia is the most general term that can describe lipoprotein and lipid disorders since the definition includes variation in the levels of lipoproteins, total cholesterol and triglycerides.
The lipid profile measured in daily clinical practice is a blood tests that measures the following variables:
- Total cholesterol
- Triglycerides
- HDL cholesterol
- LDL cholesterol, which is calculated by the formula: LDL = Total cholesterol - HDL - (Triglycerides/5)
Formula:  Total cholesterol= HDL + LDL + Triglycerides/5
According to the previous formula the measured level of total cholesterol reflects changes in LDL, triglycerides and HDL.
Lipoproteins are composed of a protein part, the apolipoprotein, and the lipid part which includes cholesterol, triglycerides and fatty acids.  The lipoproteins differ among each other in terms of density and size as a result of difference in the percentage of each components. While VLDL, chylomicrons and IDL are rich in triglycerides, LDL is rich in cholesterol. Hence, abnormalities in measured lipid levels can be simplified as follows:
- Hypercholesterolemia, defined as high level of measured cholesterol, is reflected by high LDL.
- Hypertriglyceridemia, defined as high level of measured triglycerides, is reflected by high VLDL and/or IDL and/or chylomicrons.
- Combined hyperlipidemia, defined as high levels of measured cholesterol and triglycerides, is due to elevation in both LDL and VLDL and/or IDL and/or chylomicrons.

# Pathophysiology
Hyperlipidemia can occur as either a primary event or secondary to some underlying disease. The primary hyperlipidemias are associated with overproduction and/or impaired removal of lipoproteins. The latter defect can be induced by an abnormality in either the lipoprotein itself or in the lipoprotein receptor.

# Causes
Hyperlipidemias are caused by primary and secondary causes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein)such as chylomicronemia, hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia, mixed hyperlipoproteinemia, and combined hyperlipoproteinemia, while secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population, and are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.

# Differentiating Hyperlipidemia from other Diseases
Several conditions, such as 27-hydroxylase, deficiency and sitosterolemia produce tendon xanthomas that are similar to those produced by several types of hyperlipidemia. However, these occur with normal cholesterol levels and, therefore, can be easily differentiated from hyperlipidemia.

# Epidemiology and Demographics
Hyperlipidemia is a common health problem that tends to more often affect the elderly population in developed countries. It is a major cause of disease burden globally as a risk factor for cardiovascular and cerebrovascular diseases.

# Risk Factors
There is an increased risk of hyperlipidemia in certain groups of patients. Some of these risks are age (males  age 45 and females  age 55), family history of premature coronary artery disease; definite myocardial infarction (MI) or sudden death before age 55 in father or other male first-degree relative, or before age 65 in mother or other female first-degree relative, cigarette smoking, hypertension, diabetes mellitus and body mass index > 30.

# Screening
Screening and treatment of lipid disorders in people at high risk for future coronary heart disease (CHD) events has been recommended by the, United States Preventive Services Task Force (USPSTF) especially for patients with known CHD. However, the role of screening in people with low to medium risk is controversial. On the basis of the effectiveness of treatment, the availability of accurate and reliable tests, and the likelihood of identifying people with abnormal lipids and increased CHD risk, screening appears to be effective in middle-aged and older adults and in young adults with additional cardiovascular risk factors.

# Natural History, Complications and Prognosis
Hyperlipidemia may be inherited or secondary to some underlying disorder. Without treatment, it progresses to cause cardiovascular and cerebrovascular diseases. However, early detection and aggressive management to lower the blood lipid levels helps prevent complications.

# Diagnosis

## History and Symptoms
Hyperlipidemia itself usually does not produce any symptoms and is often discovered during routine screening. Family history of premature coronary heart disease and severe hyperlipidemia may be present in primary hyperlipidemias. Patient may have symptoms consistent with its complications.

## Physical Examination
Hyperlipidemias, particularly familial hypercholesterolemia and familial defective apoB-100, are commonly associated with the findings of xanthoma, xanthelasma and corneal arcus on physical examination.

## Laboratory Findings
Complete fasting lipid profile should be obtained for making the diagnosis of hyperlipidemia and risk stratification for coronary heart diseases. In the absence of symptoms or signs suggestive of a particular disorder, a limited workup should also be performed to rule out secondary hyperlipidemias.

# Treatment

## Medical Therapy
Hyperlipidemia requires early detection, careful evaluation and aggressive treatment with combination of therapeutic lifestyle changes and lipid-lowering drug therapies to reduce the risk of cardiovascular and cerebrovascular complications.

# Prevention

## Future or Investigational Therapies
Gene therapy to manipulate the LDL-receptor (LDLR) gene is still at an experimental stage. Initially, expectations were high that genetic manipulation would be a less hazardous and more effective method for providing functional LDL-receptors compared with liver transplantation. However, progress in the development of gene therapy has been slow.