- Clinical science
Lipid disorders encompass a broad spectrum of metabolic conditions that affect blood lipid levels. They are generally characterized by elevated levels of cholesterol, triglycerides, and/or lipoproteins in the blood in association with an increased risk of (or current) cardiovascular disease. The majority of lipid disorders are acquired through unhealthy lifestyles (obesity, inactivity, alcoholism). Congenital causes are less common; examples include familial hypertriglyceridemia, which is associated with extremely high levels of triglycerides that significantly increase the risk of pancreatitis, and familial hypercholesterolemia that results in early atherosclerotic complications. Lipid disorders are usually detected during routine laboratory testing, such as cardiovascular risk factor screening. The blood lipid profile includes total cholesterol, LDL, HDL, and triglycerides. To confirm the diagnosis, a fasting lipid profile must show pathological values on two different occasions. Dyslipidemia is diagnosed if LDL levels > 130 mg/dL and/or HDL levels < 40 mg/dL. The management of lipid disorders involves lifestyle modifications and lipid-lowering agents (primarily statins).
The following terms are often used interchangeably, as they share common causes and are all associated with an increased risk of atherosclerosis and cardiovascular disease. However, the terms have differing meanings.
- Dyslipidemia: abnormal lipoprotein levels (LDL and HDL) in association with an increased risk of cardiovascular disease or current cardiovascular disease
- Hyperlipidemia: elevated blood lipid levels (total cholesterol, LDL, triglycerides)
- Hypercholesterolemia: elevated total cholesterol> 200 mg/dL
- Hypertriglyceridemia: elevated triglyceride levels
- Hyperlipoproteinemia: elevated levels of a certain lipoprotein
Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease!
- In the US, an estimated 50% of the population has elevated cholesterol levels.
Epidemiological data refers to the US, unless otherwise specified.
Congenital (less common)
- Type I – Hyperchylomicronemia: Autosomal recessive condition that is not associated with an increased risk of atherosclerosis. Patients develop eruptive xanthomas, pancreatitis, and hepatosplenomegaly.
- Type IIa – Familial hypercholesterolemia: Autosomal dominant condition associated with mutations in the LDL receptor that lead to elevated LDL levels with early atherosclerotic complications (cardiovascular disease)
- Type III – Familial dysbetalipoproteinemia: Autosomal recessive condition associated with defective ApoE that leads to elevated LDL levels with early atherosclerotic complications (cardiovascular disease)
- Type IV – Familial hypertriglyceridemia: Autosomal dominant condition associated with an increased risk of acute pancreatitis
- Acquired (more common)
|Condition||Familial hyperchylomicronemia ||Familial hypercholesterolemia ||Familial combined hyperlipidemia ||Familial dysbetalipoproteinemia ||Familial hypertriglyceridemia ||Mixed hyperlipidemia |
|Frequency||Rare||∼ 10%||1–15%||∼ 5%||∼ 70%||∼ 5%|
|Inheritance||Autosomal recessive||Autosomal dominant||Autosomal recessive||Autosomal dominant||Autosomal dominant|
|Pathogenesis|| || || || || |
|Lipoprotein defect||Chylomicrons||LDL||LDL and VLDL||Remnants of VLDL and chylomicrons||VLDL||Chylomicrons and VLDL|
|Total cholesterol||Normal to mild ↑ ||↑↑||↑↑||↑||Normal to mild ↑||↑|
|Total triglycerides||↑↑ ||Normal||↑||↑||↑↑||↑↑|
|Overnight plasma||Creamy top layer ||Clear||Clear||Turbid||Turbid||Creamy top layer and turbid bottom layer|
Elevated LDL and reduced HDL → promote atherosclerosis → increased risk of cardiovascular events
- See for details.
- Typically no specific signs or symptoms
- Skin manifestations
Xanthoma: nodular lipid deposits in the skin and tendons
- Pathophysiology: Extremely high levels of triglycerides and/or LDL result in extravasation of plasma lipoproteins and their deposition in tissue.
- Plane xanthomas: yellow, thin plaques located over large areas of the body e.g., trunk, neck, shoulders
- Eruptive xanthomas: yellow papules with an erythematous border; located on the buttocks, back, and the extensor surfaces of the extremities
Tendinous xanthomas: firm nodules, located in tendons (typically extensor tendons of hands and the Achilles tendon)
- Occurrence: severe hypercholesterinemia, ↑ LDL levels
Palmar xanthomas: yellow plaques on the palms of the hands
- Occurrence: type III hyperlipoproteinemia, ↑ VLDL
- Xanthelasmas: nodular lipid deposits around the eyelids
- Increased incidence in
- Xanthoma: nodular lipid deposits in the skin and tendons
- Lipemia retinalis: opaque, white appearance of the retinal vessels, visible on fundoscopic exam
- hepatic steatosis) (
- Severe hypertriglyceridemia (typically > 1000 mg/dL) → pancreatitis
Atherosclerosis with secondary diseases
Fasting lipid profile : total cholesterol, HDL, and triglycerides are measured
- LDL level can be measured directly using assays or estimated using the Friedewald formula
- Pathological values from two different occasions are required to confirm the diagnosis.
- Dyslipidemia is diagnosed if LDL > 130 mg/dL. and/or if HDL levels < 40 mg/dL
- Identify underlying cause
- Fasting lipid profile : total cholesterol, HDL, and triglycerides are measured
|Parameters of fat metabolism|
|Laboratory parameter||Optimal level (mg/dL)||Pathological (mg/dL)|
|Total cholesterol|| || |
|Triglycerides|| || |
|LDL|| || |
|HDL|| || |
|LDL/HDL ratio: the ratio of LDL and HDL levels serves as a control measure of cholesterol metabolism|
- Further workup required in patients with confirmed dyslipidemia
- Assess for cardiovascular disease (CVD)
- Assess for other major risk factors of CVD
- Goal: Improve serum lipid levels to reduce the risk of cardiovascular disease.
- General measures: lifestyle modifications
- Treatment of xanthomas and xanthelasmas: Not required in most cases; Surgical removal for cosmetic reasons is possible but is associated with a high rate of recurrence.
- Management of congenital disorders: : lifestyle modifications and lipid-lowering agents (high-dose statin therapy and ezetimibe for hypercholesterolemia, fibrates for hypertriglyceridemia); LDL apheresis may be required in severe cases.
- Initiate moderate-intensity or high-intensity statin therapy.
- Clinical atherosclerotic cardiovascular disease (ASCVD); : high-intensity statin therapy (age > 75 years: moderate-intensity statin therapy)
- LDL ≥ 190: high-intensity statin therapy
- Age 40–75 years + Diabetes (if LDL 70–189) → moderate dose statin therapy (consider high-dose statin therapy if > 7.5% 10 year ASCVD risk)
- Age 40–75 years + 10 year ASCVD risk > 7.5% (if LDL 70–189)
- See for details.
ATP III guidelines (2013)
|Guidelines for lipid-lowering therapy (ATP III guidelines)|
|LDL goal (mg/dL)||Lifestyle modifications indicated (mg/dL)||Medical therapy indicated (mg/dL)|
|ASCVD or risk equivalents (high risk > 20%)||< 100 (or < 70 )||> 100||> 130|
|≥ 2 Risk factors (moderate risk)||< 130||> 130||> 160|
|0–1 Risk factors (low risk)||< 160||> 160||> 190|
- The decision to screen for hyperlipidemia primarily depends on the patient's overall risk for cardiovascular disease.
- Screening high-risk individuals (i.e., with other risk factors for cardiovascular disease): ♂ > 20–25 years; ♀ > 30–35 years
- Screening low-risk individuals: ♂ > 35 years; ♀ > 45 years
Etiology deficiency of apolipoproteins (ApoB-48, ApoB-100)
- Due to mutation in the microsomal triglyceride transfer protein (MTTP) gene
- Pathophysiology: autosomal recessive disease; deficiency of chylomicrons, VLDL, and LDL.
- Clinical features
- Extremely low levels of plasma cholesterol (< 50 mg/dL)
- Acanthocytes in the blood
- Absent LDL in the blood
- Other tests performed include: complete blood count with differential, stool studies, fasting lipid profile
- Confirmatory test: genetic testing to detect mutations in the MTTP gene.
- Intestinal biopsy: microscopic evaluation may reveal lipid-laden enterocytes