Cardiology > Hypercholesterolemia    

Background 

refers to elevated levels of cholesterol in the blood, particularly low-density lipoprotein cholesterol (LDL-C), which promotes atherogenesis. It is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, stroke, and peripheral artery disease.

II) Classification/Types

By Cause: 

• • Primary (Familial): 

• • • Familial hypercholesterolemia (heterozygous or homozygous) 

• • • Polygenic hypercholesterolemia 

• • Secondary: 

• • • Due to underlying conditions like hypothyroidism, nephrotic syndrome, diabetes, liver disease, medications (e.g., steroids, thiazides), or diet 

By Lipoprotein Pattern: 

• • Isolated hypercholesterolemia (↑LDL-C) 

• • Mixed hyperlipidemia (↑LDL-C and ↑triglycerides) 

• • Hyperalphalipoproteinemia (↑HDL; generally protective) 

III) Pathophysiology 

Excessive LDL cholesterol circulates in the blood and infiltrates arterial endothelium, where it is oxidized and triggers an inflammatory cascade. Macrophages engulf oxidized LDL, forming foam cells and initiating fatty streaks. Progression leads to atherosclerotic plaque formation, narrowing of vessels, and potential plaque rupture, leading to thrombosis and ischemic events. 

IV) Epidemiology

• • Affects >30% of adults in the United States 

• • Familial hypercholesterolemia (FH) affects ~1 in 250 people (heterozygous) 

• • More common with aging, obesity, diabetes, and sedentary lifestyle 

• • Major modifiable contributor to cardiovascular morbidity and mortality 

Etiology 

I) Causes

Primary: 

• • • Familial hypercholesterolemia (LDL receptor mutations, ApoB mutations) 

• • • Autosomal dominant hypercholesterolemia 

Secondary: 

• • • Hypothyroidism 

• • • Diabetes mellitus 

• • • Nephrotic syndrome 

• • • Cholestatic liver disease 

• • • Medications: corticosteroids, thiazide diuretics, antiretrovirals 

II) Risk Factors

• • High saturated fat or trans fat intake 

• • Sedentary lifestyle 

• • Obesity 

• • Family history of premature ASCVD 

• • Diabetes or insulin resistance 

• • Smoking 

• • Chronic kidney disease 

Clinical Presentation 

I) History (Symptoms)

• • Often asymptomatic until complications arise 

• • Chest pain or angina (from underlying ASCVD) 

• • Transient ischemic attacks or stroke symptoms 

• • Claudication (PAD) 

• • Family history of premature cardiovascular disease 

II) Physical Exam (Signs)

• • Xanthomas (tendon or tuberous, especially Achilles) 

• • Xanthelasma (cholesterol deposits on eyelids) 

• • Corneal arcus (white ring around cornea, premature if <50 years) 

• • Signs of ASCVD: bruits, diminished pulses, or signs of organ ischemia 

Differential Diagnosis (DDx) 

• • Familial combined hyperlipidemia 

• • Hypertriglyceridemia syndromes 

• • Hypothyroidism (as a secondary cause) 

• • Cholestatic liver disease 

• • Nephrotic syndrome 

• • Sitosterolemia (rare) 

Diagnostic Tests 

Initial Work-Up 

• • Fasting lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) 

• • Direct LDL measurement (if TG >400 mg/dL) 

• • TSH: rule out hypothyroidism 

• • HbA1c, fasting glucose: assess for diabetes 

• • Liver function tests (LFTs) 

• • Creatinine/eGFR and urine protein (if nephrotic syndrome suspected) 

• • Genetic testing (if FH suspected) 

Advanced Testing (if indicated) 

• • Lipoprotein(a) 

• • Apolipoprotein B 

• • Coronary artery calcium (CAC) scoring 

Treatment 

I) Initial Approach

• • Assess 10-year ASCVD risk (using pooled cohort equation) 

• • Lifestyle modification for all patients 

• • Treat secondary causes 

• • Initiate statin therapy based on risk stratification 

II) Medications

Patient Education, Screening, Vaccines 

Education 

• • Importance of medication adherence 

• • Heart-healthy diet (e.g., Mediterranean or DASH) 

• • Exercise ≥150 minutes/week (moderate intensity) 

• • Smoking cessation 

• • Weight loss if overweight 

Screening 

• • Lipid screening: 

• • Adults ≥20 years: every 4–6 years if low risk 

• • More frequent if risk factors present or on therapy 

• • Screen earlier in those with family history of premature ASCVD 

Vaccinations 

• • Influenza, pneumococcal, and COVID-19 (if ASCVD or diabetes present) 

Consults/Referrals 

• • Lipid specialist: familial or refractory hypercholesterolemia 

• • Dietitian: personalized dietary advice 

• • Endocrinology: if lipid abnormalities associated with diabetes or thyroid issues 

• • Cardiology: established ASCVD or high-risk profile 

Follow-Up 

Short-Term 

• • Recheck lipids 4–12 weeks after medication initiation or adjustment 

• • Monitor liver enzymes and muscle symptoms on statin therapy 

Long-Term 

• • Reassess lipid levels every 3–12 months 

• • Monitor for ASCVD events or progression 

• • Reinforce lifestyle modifications 

Prognosis 

• • Excellent with early detection and treatment 

• • Statins significantly reduce ASCVD morbidity and mortality 

• • Poor control leads to progression of atherosclerosis and cardiovascular events