Lipid disorders

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.

• 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

• 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.

• 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.

• 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.

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.
• Types

:

Xanthelasmas

• Description: typically bilateral, yellow, flat plaques on the upper eyelids (nasal side)
• 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

• Lipemia retinalis
  • Description: opaque, white appearance of the retinal vessels, visible on fundoscopic exam
  • Associated condition: hyperlipoproteinemia type I, III, and IV
• 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:
  • Coronary heart disease
  • Myocardial infarction
  • Stroke
  • Peripheral arterial disease
  • Carotid artery stenosis
  • Cholesterol embolization syndrome

Approach ^[11]

• Screening for lipid disorders
  • 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
• 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]

Assessment for secondary causes of hyperlipidemia ^[11]

• Indications
  • Adults 20–39 years of age with hyperlipidemia
  • Consider in adults of any age with LDL > 190 mg/dL ^[11][19]
• Tests include:
  • Fasting blood glucose or HbA1c ^[20][21]
  • TSH
  • Liver function tests
  • Urine analysis and serum creatinine

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
  • 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: statin therapy (see “ASCVD” for further details)
• 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
  • 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.
• Patients 40–75 years of age with diabetes mellitus: statin therapy (see “ASCVD” for further details) ^[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]

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 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

See “Primary prevention of ASCVD” and “Secondary prevention of ASCVD.”

• Etiology
  • Deficiency of apolipoproteins (ApoB-48, ApoB-100)
  • Due to a mutation in the microsomal triglyceride transfer protein (MTTP) gene
• Pathophysiology
  • Autosomal recessive disease
  • Deficiency of chylomicrons, VLDL, and LDL (hypolipoproteinemia)
• Clinical features
  • Early
    • Steatorrhea
    • Failure to thrive
    • Fat malabsorption → fat-soluble vitamin deficiency
    • Acanthocytosis
  • Late
    • Developmental delay
    • Retinitis pigmentosa
    • Myopathy
    • Progressive ataxia
    • Spinocerebellar degeneration as a result of vitamin E deficiency
• 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.
• Treatment
  • Vitamin E supplementation (high doses)
  • Reduced long-chain fatty acids intake

1. Rosenson RS, JP Kastelein JJP. Hypertriglyceridemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/hypertriglyceridemia.Last updated: February 28, 2017. Accessed: January 14, 2018.
2. HYPERLIPOPROTEINEMIA, TYPE I. https://www.omim.org/entry/238600. Updated: September 7, 2016. Accessed: April 3, 2019.
3. HYPERLIPOPROTEINEMIA, TYPE II, AND DEAFNESS. https://www.omim.org/entry/144300. Updated: January 21, 2009. Accessed: April 3, 2019.
4. Rosenson RS, Durrington P. Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/inherited-disorders-of-ldl-cholesterol-metabolism-other-than-familial-hypercholesterolemia.Last updated: March 27, 2018. Accessed: April 3, 2019.
5. HYPERLIPOPROTEINEMIA, TYPE III. https://www.omim.org/entry/617347. Updated: March 22, 2018. Accessed: April 3, 2019.
6. HYPERLIPOPROTEINEMIA, TYPE IV. https://www.omim.org/entry/144600. Updated: November 22, 2010. Accessed: April 3, 2019.
7. HYPERLIPOPROTEINEMIA, TYPE V. https://www.omim.org/entry/144650. Updated: June 3, 2018. Accessed: April 3, 2019.
8. Bays HE, Jones PH, Orringer CE, Brown WV, Jacobson TA. National Lipid Association Annual Summary of Clinical Lipidology 2016. Journal of Clinical Lipidology. 2016; 10 (1): p.S1-S43. doi: 10.1016/j.jacl.2015.08.002 . | Open in Read by QxMD
9. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018; 139 (25). doi: 10.1161/cir.0000000000000625 . | Open in Read by QxMD
10. National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics. 2011; 128 (Supplement): p.S213-S256. doi: 10.1542/peds.2009-2107c . | Open in Read by QxMD
11. Bibbins-Domingo K, Grossman DC, et al. Screening for Lipid Disorders in Children and Adolescents. JAMA. 2016; 316 (6): p.625-33. doi: 10.1001/jama.2016.9852 . | Open in Read by QxMD
12. Sturm AC, Knowles JW, Gidding SS, et al. Clinical Genetic Testing for Familial Hypercholesterolemia. J Am Coll Cardiol. 2018; 72 (6): p.662-680. doi: 10.1016/j.jacc.2018.05.044 . | Open in Read by QxMD
13. McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia. Journal of the American Heart Association. 2019; 8 (24). doi: 10.1161/jaha.119.013225 . | Open in Read by QxMD
14. Sampson M, Ling C, Sun Q, et al. A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia. JAMA Cardiol. 2020; 5 (5): p.540-548. doi: 10.1001/jamacardio.2020.0013 . | Open in Read by QxMD
15. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. https://www.nhlbi.nih.gov/files/docs/resources/heart/atp-3-cholesterol-full-report.pdf. Updated: September 1, 2002. Accessed: May 10, 2017.
16. Millán J, Pintó X, Muñoz A, et al. Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.. Vasc Health Risk Manag. 2009; 5 : p.757-65.
17. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Journal of the American College of Cardiology. 2014; 63 (25). doi: 10.1016/j.jacc.2013.11.002 . | Open in Read by QxMD
18. Goldberg IJ. Diabetic Dyslipidemia: Causes and Consequences. J Clin Endocrinol Metab. 2001; 86 (3): p.965-971. doi: 10.1210/jcem.86.3.7304 . | Open in Read by QxMD
19. Vodnala D, Rubenfire M, Brook RD. Secondary Causes of Dyslipidemia. Am J Cardiol. 2012; 110 (6): p.823-825. doi: 10.1016/j.amjcard.2012.04.062 . | Open in Read by QxMD
20. Rohrich RJ, Janis JE, Pownell PH. Xanthelasma Palpebrarum: A Review and Current Management Principles. Plast Reconstr Surg. 2002; 110 (5): p.1310-4. doi: 10.1097/01.prs.0000025626.70065.2b . | Open in Read by QxMD
21. Sathiyakumar V; Jones SR; Martin SS. Fitzpatrick's Dermatology, Ninth Edition, 2-Volume Set. McGraw-Hill Education / Medical ; 2019
22. Karr S. Epidemiology and management of hyperlipidemia.. Am J Manag Care. 2017; 23 (9 Suppl): p.S139-S148.
23. Earl S. Ford, Wayne H. Giles, William H. Dietz. Prevalence of the Metabolic Syndrome Among US Adults. JAMA. 2002; 287 (3): p.356. doi: 10.1001/jama.287.3.356 . | Open in Read by QxMD