Hypercholesterolemia

Aka: Hypercholesterolemia, Hyperlipidemia, Familial Hypercholesterolemia, Familial Hyperlipidemia

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II. Causes: Familial Hypercholesterolemia

  1. General Findings
    1. LDL Cholesterol >190 mg/dl
    2. Premature, early onset coronary event (age <50 years)
      1. Coronary events may occur as early as age 17 years in males, and 25 years in females
  2. Homozygous Familial Hypercholesterolemia
    1. Corneal arcus senilis
    2. Xanthomas
  3. Heterozygous Familial Hypercholesterolemia
    1. Worldwide Prevalence: 1 in 250 to 350
    2. Silent severe Hyperlipidemia (LDL Cholesterol >190 mg/dl)
    3. No physical findings until premature cardiovascular events occur
  4. References
    1. Hu (2020) Circulation 141(22): 1742-59 [PubMed]

III. Causes: Other Secondary Causes of Hypercholesterolemia

  1. Genetic Cholesterol disorder findings
    1. See Familial Hypercholesterolemia as above
    2. LDL Cholesterol >190-200 mg/dl
    3. Serum Triglycerides > 1000 mg/dl
    4. HDL Cholesterol < 30 mg/dl
  2. Hypothyroidism
  3. Nephrotic Syndrome
  4. Chronic Liver Disease (Primary Biliary Cirrhosis)
  5. Dysglobulinemia
  6. Cushing's Syndrome
  7. Hyperparathyroidism
  8. Acute Intermittent Porphyria
  9. Medications
    1. Protease Inhibitors

IV. Screening: Guidelines

  1. General counseling for all patients
    1. Low Fat Diet
    2. Exercise Program
  2. Criteria for age to start screening
    1. NIH as of 2011 recommends screening all ages 9-11 and again at 17-21 years
      1. Treat patients only with significant LDL increase (e.g. >190)
      2. Goal to identify Familial Hypercholesterolemia
      3. Early lowering of LDL Cholesterol with prevention and lifestyle change significantly decreases ASCVD risk
    2. Age over 20 years (ATP III Guidelines)
      1. Screen at age 20 and then every 5 years
      2. Prior guidelines for age to start screening
        1. Age >34 years in men
        2. Age >44 years in women
    3. Ages 2 to 20 years
      1. Family History of Total Cholesterol >300 mg/dl
      2. Family History Premature Coronary Artery Disease
        1. Age under 56 years in men
        2. Age under 66 years in women
  3. Screening protocol (repeated every 5 years)
    1. Full Fasting lipid profile preferred (ATP III guide)
    2. Alternative protocol: Non-Fasting lipid screening
      1. NCEP reasoning for non-Fasting lipid screening
        1. Non-Fasting screening improves compliance
        2. Postprandial Triglyceride rise can be evaluated
          1. Related to atherosclerosis risk
      2. Protocol
        1. Obtain non-Fasting Total Cholesterol with HDL
      3. Criteria to perform Fasting full lipid panel
        1. No Cardiac Risk Factors: Cholesterol >240 mg/dl
        2. Cardiac Risk Factors: Cholesterol >200 mg/dl
        3. HDL Cholesterol <40 mg/dl
    3. Alternative protocol: Non-Fasting Non-HDL Cholesterol
      1. Non-HDL Cholesterol = VLDL + IDL + LDL
      2. Correlates very well with outcomes
      3. Convenient (Patient does not need to fast)
      4. Goal Non-HDL Cholesterol is 30 higher than LDL goal

V. Evaluation: Cardiac Risk Factors

  1. See Cardiac Risk
  2. Framingham calculator is replaced with more predictive calculators
    1. PREVENT-ASCVD, AHA Calculator (preferred in 2026 to guide Hyperlipidemia Management)
      1. https://professional.heart.org/en/guidelines-and-statements/prevent-calculator
    2. Pooled Cohort Equation (ACC/AHA Guideline)
      1. https://tools.acc.org/CVD-Risk-Estimator-Plus/#!/calculate/estimate/
      2. Newer 10 year Cardiovascular Risk calculator to help risk stratify (including Statin dosing)
    3. QRisk3 (NICE Guideline)
      1. https://qrisk.org/
      2. Includes Renal Function in risk calculation
  3. Results of lowering LDL Cholesterol
    1. Relative CAD risk reduced 1% per 1% LDL decrease
  4. Other markers
    1. Lipoprotein A (LpA)
      1. Recommended to check at least once in adults
      2. LpA >=125 nmol/L is associated with 40% increased ASCVD risk
    2. Apolipoprotein B (apoB)
    3. High sensitivity C-Reactive Protein (hsCRP)
    4. Coronary ArteryCalcium Score (CAC Score)
      1. Consider in men age >=40 years, women >=45 years with borderline risk
      2. CAC Score >= 1000 AU
        1. CAD risk extensive
        2. Indicates high intensity Statin and LDL target <55 mg/dl
      3. CAC Score 300 to 999 AU (or moderate to severe Coronary ArteryCalcium incidental on non-cardiac CT)
        1. CAD Risk Severe
        2. Indicates high intensity Statin and LDL target <70 mg/dl
      4. CAC Score 100 to 299 AU (or mild Coronary ArteryCalcium incidental on non-cardiac CT)
        1. CAD Risk >75th percentile
        2. Indicates moderate intensity Statin and LDL target <100 mg/dl

VI. Management: General

  1. See Hyperlipidemia Management
  2. Coronary Artery Disease Risk Factors
    1. Positive Risk Factors
      1. See Cardiac Risk Factors
    2. Negative Risk Factors (Protective)
      1. HDL Cholesterol over 60 mg/dl
  3. Available lipid lowering modalities
    1. Dietary changes
      1. Low Fat Diet
      2. Phytosterols (Plant Stanols) lower LDL Cholesterol
    2. Weight loss for Obesity
      1. Lowers LDL Cholesterol
      2. Improves Insulin sensitivity
    3. Aerobic Exercise
      1. Raises HDL Cholesterol
      2. Lowers Triglycerides
    4. Anti-hyperlipidemic Medications
    5. Tobacco Cessation (Increases HDL by 30%)

VII. Management: Low Risk Patients

  1. Indications
    1. PREVENT-ASCVD <3%
    2. Previously defined as <2 Cardiac Risk Factors
  2. Goals
    1. LDL Cholesterol <160 mg/dl
  3. Cholesterol Management
    1. Lifestyle interventions
    2. Anti-hyperlipidemic: moderate intensity Statin (consider)
      1. See Hyperlipidemia Management
      2. Indications
        1. LDL Cholesterol >160 mg/dl OR
        2. Thirty year risk >10%
      3. Targets
        1. LDL Cholesterol <100 mg/dl (and >=30% reduction) OR
        2. Non-HDL Cholesterol <=130 mg/dl
  4. Lipid Profile frequency
    1. Obtain every 5 years if LDL Cholesterol <160 mg/dl AND Thirty year risk <10%
    2. Obtain at more often if LDL Cholesterol >160 mg/dl OR Thirty year risk >10%

VIII. Management: Borderline Risk Patients

  1. Indications
    1. PREVENT-ASCVD 3-5%
  2. Goals
    1. LDL Cholesterol <100 to 160 mg/dl (depending on additional risk assessment)
  3. Cholesterol Management
    1. Lifestyle interventions
    2. Anti-hyperlipidemic: moderate intensity Statin (consider)
      1. See Hyperlipidemia Management
      2. Indications
        1. LDL Cholesterol >160 mg/dl OR
        2. Thirty year risk >10% OR
        3. Coronary ArteryCalcium Score (CAC Score) or other elevated risk markers
      3. Targets
        1. LDL Cholesterol <100 mg/dl (and >=30% reduction) OR
        2. Non-HDL Cholesterol <=130 mg/dl
  4. Monitoring
    1. Desirable lipids: Repeat Lipid panel in 1-2 years
    2. Borderline lipids: Repeat lipid panel in 6 months
    3. Elevated lipids: Repeat lipid panel in 2-3 months

IX. Management: Intermediate Risk Patients

  1. Indications
    1. PREVENT-ASCVD 5-10%
    2. Previously defined as >=2 Cardiac Risk Factors
  2. Goals
    1. LDL Cholesterol <100 mg/dl
  3. Cholesterol Management
    1. Lifestyle interventions
    2. Anti-hyperlipidemic: moderate to high intensity Statin
      1. See Hyperlipidemia Management
      2. Statins are recommended in all intermediate risk patients
      3. Targets
        1. LDL Cholesterol <100 mg/dl (and >=30% reduction) OR
        2. Non-HDL Cholesterol <=130 mg/dl
  4. Monitoring
    1. Desirable lipids: Repeat Lipid panel in 1-2 years
    2. Borderline lipids: Repeat lipid panel in 6 months
    3. Elevated lipids: Repeat lipid panel in 2-3 months

X. Management: High Risk Patients

  1. Indications
    1. PREVENT-ASCVD >10%
    2. Previously defined as Coronary Artery Disease or equivalent
      1. Diabetes Mellitus and age 40-75 years old and 10 year Cardiovascular Risk >7.5%
      2. Known cardiovascular disease or other serious risk factors (10 year Cardiovascular Risk >20%) OR
      3. Abdominal Aortic Aneurysm
      4. Peripheral Vascular Disease (e.g. Claudication)
      5. Symptomatic Carotid Artery disease
  2. Goals
    1. LDL Cholesterol <70 mg/dl
  3. Cholesterol Management
    1. Lifestyle interventions
    2. Anti-hyperlipidemic: high intensity Statin
      1. Statins are recommended in all high risk patients (may add adjunctive agents as needed)
      2. Targets
        1. LDL Cholesterol <70 mg/dl (and >=50% reduction) OR
        2. Non-HDL Cholesterol <=100 mg/dl
  4. Monitoring
    1. Desirable lipids: Repeat Lipid panel in 6-12 months
    2. Borderline lipids: Repeat lipid panel in 2-3 months
    3. Elevated lipids: Repeat lipid panel in 6 weeks

XI. References

  1. (2026) Presc Lett 33(5): 4-5
  2. (2001) JAMA 285:2486-97 [PubMed]
  3. Ahmed (1998) Am Fam Physician 57(9):2192-203 [PubMed]
  4. Blumenthal (2026) J Am Coll Cardiol S0735-1097(25)10254-4 +PMID: 41824590 [PubMed]
  5. Grundy (1997) Circulation 95:2329-31 [PubMed]
  6. Grundy (1997) Am Fam Physician 55(6): 2250-8 [PubMed]
  7. Mosca (2002) Am Fam Physician 65(2):217-26 [PubMed]
  8. Safeer (2002) Am Fam Physician 65(5):871-80 [PubMed]
  9. Yeshuran (1995) South Med J 88:379-91 [PubMed]

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