Summary
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 (hyperlipoproteinemias), which are often associated with an increased risk of (or current) cardiovascular disease. Hyperlipoproteinemias are most commonly caused by lifestyle factors (diet, lack of activity, alcohol consumption). However, they may also be congenital, as is the case with familial hypertriglyceridemia, which is associated with extremely high levels of triglycerides that significantly increase the risk of pancreatitis, and familial hypercholesterolemia, which 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. Treatment of hyperlipidemia is indicated to reduce the risk of cardiovascular disease in patients with LDL > 190 mg/dL, diabetes mellitus, and clinical ASCVD, and should be considered for other patients with a 10-year ASCVD risk score ≥ 7.5% after discussion of the risks and benefits. Lifestyle modifications and lipid-lowering agents (primarily statins) are the main treatment modalities. Abetalipoproteinemia is a congenital lipid disorder characterized by a deficiency of apolipoproteins (hypolipoproteinemia), which leads to impaired intestinal absorption of fats and fat-soluble vitamins. Symptoms, which usually appear early, mainly consist of failure to thrive, steatorrhea, and signs of vitamin E deficiency. The treatment includes supplementation of vitamin E.
Definition
- Dyslipidemia: an abnormal concentration of lipids in the blood (e.g., high LDL, low HDL)
- Hyperlipidemia: elevated blood lipid levels (total cholesterol, LDL, triglycerides)
- Hypercholesterolemia: total cholesterol > 200 mg/dL
- Hypertriglyceridemia: triglyceride levels > 150 mg/dL
- Hyperlipoproteinemia: elevated levels of certain lipoproteins
Epidemiology
- In the US, the prevalence of lipid disorders is estimated as follows:
- Hypercholesterolemia: ∼ 50% [1]
- Hypertriglyceridemia: ∼ 35% in men and ∼ 25% in women [2]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
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Acquired (more common)
- Obesity
- Diabetes mellitus
- Physical inactivity
- Heavy consumption of alcohol
- Hypothyroidism
- Nephrotic syndrome
- Cholestatic liver disease
- Cushing disease
- Drugs: antipsychotics, beta blockers (e.g., metoprolol), oral contraceptive pill, high-dose diuretic use
- Inherited (less common): See “Frederickson classification of inherited hyperlipidemias” below.
Classification
Frederickson classification of inherited hyperlipoproteinemias [3] | ||||||
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I | Type II hyperlipoproteinemia | III | Type IV hyperlipoproteinemia | V | ||
IIa | IIb | |||||
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Pathogenesis |
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Clinical manifestations |
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Lipoprotein defect |
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Total cholesterol |
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Elevated serum lipoproteins | ||||||
Total triglycerides |
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Overnight plasma |
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Pathophysiology
- Elevated LDL and reduced HDL → promote atherosclerosis → increased risk of cardiovascular events
- See “Pathogenesis of atherosclerosis.”
Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease.
Clinical features
There are typically no specific signs or symptoms.
Skin manifestations
Xanthomas
- Description: 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.
- Histology: large perivascular infiltrates with foam cells (lipid-laden macrophages) and multinucleated histiocytes called Touton giant cells.
- Types
Types of xanthomas | |||
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Description | Location | Associated condition | |
Eruptive xanthoma |
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Tuberous xanthoma |
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Tendinous xanthoma |
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Palmar xanthoma |
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Plane xanthoma |
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Xanthelasmas
- Description: typically bilateral, yellow, flat plaques on the upper eyelids (nasal side)
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Etiology
- Idiopathic
- Increased incidence in
- Patients with diabetes mellitus
- Patients with increased lipoproteins in plasma
- Usually affects postmenopausal women
- Associated conditions: hypercholesterolemia (e.g., primary biliary cholangitis), hyperapobetalipoproteinemia, ↑ LDL levels
Eye manifestations
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Lipemia retinalis
- Description: opaque, white appearance of the retinal vessels, visible on fundoscopic exam
- Associated condition: hyperlipoproteinemia type I, III, and IV
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Arcus lipoides corneae
- Associated with hyperlipoproteinemia type II
- Not pathological in advanced age
Gastrointestinal manifestations
- Fatty liver (hepatic steatosis): associated conditions include abetalipoproteinemia, metabolic syndrome, heavy consumption of alcohol
- Pancreatitis in severe hypertriglyceridemia (typically > 1,000 mg/dL): associated conditions include hyperlipoproteinemia type I and IV, hypertriglyceridemia
Premature atherosclerosis
- Associated conditions: hyperlipoproteinemia type II, III, and IV
- Manifests with secondary diseases such as:
Diagnostics
Approach [11]
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Screening for lipid disorders
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Indications
- All individuals 40–75 years of age [12][13]
- Patients with a family history of familial hypercholesterolemia or premature ASCVD: consider earlier screening
- Tests
- Adequate in most cases: nonfasting lipid profiles
- Nonfasting triglycerides > 400 mg/dL or if evaluating for familial lipid disorders: fasting lipid profile
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Indications
- Further testing
- Patients 20–39 years of age: consider testing for secondary causes of hyperlipidemia
- Presence of risk factors (e.g., persistently high LDL levels, premature ASCVD, and/or positive family history): consider testing for familial hypercholesterolemia [14][15]
- Assess ASCVD risk to guide treatment decisions, e.g., via the 2013 ACC/AHA pooled cohort equation
Lipid profile [11]
- Includes total cholesterol, HDL, LDL, and triglycerides
- LDL can be measured directly or estimated using the Friedewald formula (LDL = total cholesterol – HDL – (triglycerides/5) [11][16]
Parameters of fat metabolism [17] | ||
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Laboratory parameter | Optimal level | Abnormal levels |
Total cholesterol |
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Triglycerides |
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LDL |
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HDL |
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LDL/HDL ratio [18] | ||
Total cholesterol/HDL ratio [18] |
Assessment for secondary causes of hyperlipidemia [11]
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Indications
- Adults 20–39 years of age with hyperlipidemia
- Consider in adults of any age with LDL > 190 mg/dL [11][19]
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Tests include:
- Fasting blood glucose or HbA1c [20][21]
- TSH
- Liver function tests
- Urine analysis and serum creatinine
Treatment
Approach [11]
- Encourage all patients to make lifestyle modifications (see “Primary prevention of ASCVD”).
- Initiate pharmacologic therapy based on the patient's age, LDL level, and ASCVD risk.
- Statins: first-line
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Nonstatin lipid-lowering agents: may be added to statins if treatment goals are not met.
- If treatment goals are not reached with maximally tolerated statin treatment, consider adding ezetimibe.
- If goals are still not reached, a bile-acid sequestrant or PCSK9 inhibitor may be added.
- Patients with familial lipid disorders [15]
- Consider specialist referral.
- Treatment should involve lifestyle modifications and pharmacologic therapy with individualized treatment goals.
- Xanthomas and xanthelasmas can be treated for cosmetic reasons, but recurrence is common. [22][23]
The goal of treatment is to reduce the risk of cardiovascular diseases. Therefore, the decision to treat hypercholesterolemia should be based on a patient's 10-year ASCVD risk.
In severe hypercholesterolemia (LDL ≥ 190 mg/dL) that is not adequately controlled with medical therapy, LDL apheresis may be used in consultation with a lipid specialist. [11]
Treatment of hypercholesterolemia in adults [11]
Indications for treatment [11]
- Patients ≥ 20 years of age with clinical ASCVD: Consider high-intensity statin therapy.
- Patients 20–75 years of age and LDL ≥ 190 mg/dL: high-intensity statin therapy
- Patients 40–75 years of age and LDL 70–189 mg/dL: Treatment is based on the 10-year ASCVD risk.
- High (≥ 20%): high-intensity statin therapy
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Borderline to intermediate (5–20%)
- Review ASCVD risk-enhancing factors and consider moderate-intensity statin therapy depending on result.
- If the benefit of treatment is unclear in patients with intermediate-risk, consider coronary artery calcium scoring.
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Patients 40–75 years of age with diabetes mellitus
- Initiate moderate-intensity statin therapy.
- Consider high-intensity statin therapy in patients with several ASCVD risk factors. [11]
- Patients 20–39 years of age if LDL ≥ 160 mg/dL and family history positive for premature ASCVD: Consider statin therapy.
If high-intensity statin therapy is indicated but not tolerated, consider moderate-intensity statins or low-intensity statins. [11]
Statins [11]
Statins used for lipid-lowering therapy in adults [11] | ||
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Statin intensity | Expected reduction in LDL level | Agents |
High-intensity statin therapy |
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Moderate-intensity statin therapy |
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Low-intensity statin therapy |
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Nonstatin lipid-lowering agents [11]
- Ezetimibe
- Bile-acid sequestrants, e.g., colesevelam
- PCSK9 inhibitors, e.g., evolocumab or alirocumab
Treatment of hypertriglyceridemia in adults
In patients with intermediate to high ASCVD risk, the risk-benefit assessment should take hypertriglyceridemia into account. Moderate to severe hypertriglyceridemia is generally a factor that favors statin therapy. [11]
Treatment of hypertriglyceridemia in adults [11] | ||
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Definition | Treatment | |
Moderate hypertriglyceridemia |
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Severe hypertriglyceridemia |
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Treatment of dyslipidemia in children [12]
Base treatment decisions on average of ≥ 2 fasting lipid panels taken within 2 weeks to 3 months of each other. The goal of medical therapy is to lower LDL to ≤ 130 mg/dL.
- Children with LDL ≥ 130 mg/dL or elevated triglycerides : lifestyle modifications
- Children ≥ 10 years
- Consider medical therapy if fasting lipids remain elevated after 6 months despite lifestyle modifications.
- Base treatment decision on LDL levels, traditional ASCVD risk factors, family history of premature ASCVD , and the presence of high- or medium-risk conditions.
- Children < 10 years: medical therapy not generally recommended, except in the following situations:
- Clinical ASCVD in patients ≤ 20 years or cardiac transplantation
- Severe primary hyperlipidemia: LDL ≥ 400 mg/dL and/or TG ≥ 500 mg/dL
- Consult a lipid specialist for treatment of:
- Triglycerides > 500 mg/dL: Consider pharmacotherapy to reduce the risk of acute pancreatitis.
- LDL ≥ 250 mg/dL
Prevention
See “Primary prevention of ASCVD” and “Secondary prevention of ASCVD.”
Abetalipoproteinemia
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Etiology
- Deficiency of apolipoproteins (ApoB-48, ApoB-100)
- Due to a mutation in the microsomal triglyceride transfer protein (MTTP) gene
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Pathophysiology
- Autosomal recessive disease
- Deficiency of chylomicrons, VLDL, and LDL (hypolipoproteinemia)
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Clinical features
- Early
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Late
- Developmental delay
- Retinitis pigmentosa
- Myopathy
- Progressive ataxia
- Spinocerebellar degeneration as a result of vitamin E deficiency
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Diagnostics
- Extremely low levels of plasma cholesterol (< 50 mg/dL)
- Acanthocytes in the blood
- Other tests performed include complete blood count with differential, stool studies, and fasting lipid profile.
- Confirmatory test: genetic testing to detect mutations in the MTTP gene
- Intestinal biopsy: Histology may reveal lipid-laden enterocytes.
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Treatment
- Vitamin E supplementation (high doses)
- Reduced long-chain fatty acids intake