Hyperlipidemia (Dyslipidemia)

A 52 year old male with obesity, hypertension, and type 2 diabetes mellitus presents for routine evaluation. Laboratory investigations reveal total cholesterol of 290 mg/dL, LDL cholesterol of 195 mg/dL, triglycerides of 240 mg/dL, and HDL cholesterol of 34 mg/dL. Physical examination demonstrates tendon xanthomas over the Achilles tendon. Family history is significant for premature myocardial infarction in his father at age 45 years. Diagnosis?

Diagnosis is severe hypercholesterolemia, likely familial hypercholesterolemia (FH).

1. Definition

Hyperlipidemia refers to abnormal elevation of plasma lipids or lipoproteins, including increased LDL cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B (ApoB), and/or lipoprotein(a) [Lp(a)], or reduced HDL cholesterol. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, ischemic stroke, and peripheral arterial disease.

Hyperlipidemia is characterized by abnormal elevation of:

1. LDL cholesterol (LDL-C)
2. Triglycerides (TG)
3. Non-HDL cholesterol
4. ApoB-containing lipoproteins
5. Lipoprotein(a) [Lp(a)]

or reduction in:

1. HDL cholesterol (HDL-C)

Dyslipidemia includes:

1. Hypercholesterolemia
2. Hypertriglyceridemia
3. Mixed dyslipidemia
4. Elevated Lp(a)

2. Lipoprotein Physiology

Chylomicrons

1. Transport dietary triglycerides
2. Synthesized in intestine
3. Contain ApoB-48

VLDL

1. Transport endogenous triglycerides
2. Produced by liver
3. Contain ApoB-100

LDL

1. Deliver cholesterol to peripheral tissues
2. Major atherogenic lipoprotein
3. Elevated LDL strongly associated with ASCVD

HDL

1. Mediates reverse cholesterol transport
2. Low HDL is associated with increased ASCVD risk

3. Classification

3.1 Primary (Genetic) Dyslipidemia

Familial Hypercholesterolemia (FH)

1. Most commonly due to LDL receptor mutation (~85–90%)
2. Markedly elevated LDL cholesterol
3. Tendon xanthomas
4. Premature ASCVD
5. Heterozygous FH occurs in approximately 1 in 250–300 individuals

Familial Combined Hyperlipidemia

1. Elevated LDL and triglycerides
2. Increased ApoB levels
3. Common inherited dyslipidemia

Familial Hypertriglyceridemia

1. Elevated triglycerides
2. Increased pancreatitis risk

Familial Chylomicronemia Syndrome

1. Severe hypertriglyceridemia
2. Recurrent pancreatitis
3. Lipoprotein lipase pathway defects

3.2 Secondary Dyslipidemia

Endocrine Causes

1. Diabetes mellitus
2. Hypothyroidism
3. Cushing syndrome

Renal Causes

1. Nephrotic syndrome
2. Chronic kidney disease

Hepatic Causes

1. Cholestatic liver disease

Lifestyle Causes

1. Obesity
2. Sedentary lifestyle
3. Alcohol use
4. Diet high in saturated fats

Drug Causes

1. Corticosteroids
2. Thiazide diuretics
3. Beta-blockers
4. Retinoids
5. Protease inhibitors

4. Pathophysiology

1. ApoB-containing lipoproteins promote atherosclerosis
2. Oxidized LDL causes endothelial dysfunction and foam cell formation
3. Progressive plaque formation leads to ASCVD
4. Severe hypertriglyceridemia predisposes to acute pancreatitis
5. Low HDL impairs reverse cholesterol transport

5. Clinical Features

Most patients are asymptomatic until complications develop

Physical Findings

Xanthelasma

1. Yellow cholesterol-rich plaques around eyelids

Tendon Xanthomas

1. Strongly suggest familial hypercholesterolemia
2. Commonly involve Achilles and extensor tendons

Eruptive Xanthomas

1. Associated with severe hypertriglyceridemia
2. Small yellow papules over extensor surfaces

Lipemia Retinalis

1. Milky retinal vessels in severe hypertriglyceridemia

6. Complications

Atherosclerotic Cardiovascular Disease (ASCVD)

1. Coronary artery disease
2. Myocardial infarction
3. Ischemic stroke
4. Peripheral arterial disease

Acute Pancreatitis

1. Risk increases significantly when triglycerides ≥500 mg/dL
2. Risk is particularly high when triglycerides ≥1000 mg/dL

7. Diagnosis

7.1 Lipid Profile

Measures:

1. Total cholesterol
2. LDL cholesterol
3. HDL cholesterol
4. Triglycerides
5. Non-HDL cholesterol

Current guidelines prefer use of:

1. Martin/Hopkins equation
2. Sampson/NIH equation

over Friedewald equation for LDL estimation

7.2 ApoB Measurement

ApoB better reflects total atherogenic particle burden and is useful in:

1. Elevated triglycerides
2. Diabetes mellitus
3. Low achieved LDL-C
4. Residual ASCVD risk assessment

7.3 Lipoprotein(a) [Lp(a)]

1. Should be measured at least once in all adults
2. Elevated Lp(a) is a major ASCVD risk-enhancing factor

Elevated levels:

1. ≥50 mg/dL or ≥125 nmol/L increase ASCVD risk

7.4 Evaluation for Secondary Causes

1. TSH for hypothyroidism
2. HbA1c or fasting glucose for diabetes mellitus
3. Liver function tests
4. Renal function tests
5. Urinalysis for nephrotic syndrome

8. Severe Hypercholesterolemia / Familial Hypercholesterolemia

Suspect FH in:

1. LDL ≥190 mg/dL
2. Tendon xanthomas
3. Premature ASCVD
4. Strong family history

Genetic Defects

1. LDL receptor mutation
2. ApoB mutation
3. PCSK9 gain-of-function mutation

Panel-based genetic testing may help confirm FH and identify higher ASCVD risk patients

9. Management

9.1 Lifestyle Modification

1. Weight reduction
2. Regular aerobic exercise
3. Smoking cessation
4. Reduced saturated and trans fat intake
5. Increased dietary fiber
6. Limit alcohol intake

Lifestyle optimization should begin early to reduce cumulative exposure to atherogenic lipoproteins

9.2 Statins (First-Line Therapy)

Mechanism:

1. HMG-CoA reductase inhibition
2. Increased hepatic LDL receptor expression
3. Reduced LDL cholesterol

High-Intensity Statins

1. Atorvastatin
2. Rosuvastatin

Indications

1. Clinical ASCVD
2. LDL ≥190 mg/dL
3. Diabetes mellitus age 40–75 years
4. Elevated ASCVD risk

LDL Goals

Primary Prevention High Risk

1. LDL goal <70 mg/dL
2. Non-HDL goal <100 mg/dL

Secondary Prevention / Very High Risk ASCVD

1. LDL goal <55 mg/dL
2. Non-HDL goal <85 mg/dL

9.3 Ezetimibe

1. Inhibits intestinal cholesterol absorption
2. Added if LDL goals are not achieved with statins

9.4 PCSK9 Inhibitors

1. Evolocumab
2. Alirocumab

Used in:

1. Familial hypercholesterolemia
2. Very high-risk ASCVD
3. Persistent LDL elevation despite statin therapy

9.5 Inclisiran

1. Small interfering RNA against PCSK9
2. Used in persistent LDL elevation despite maximally tolerated therapy

9.6 Bempedoic Acid

1. ATP citrate lyase inhibitor
2. Useful in statin intolerance or for additional LDL lowering

9.7 Fibrates

1. Fenofibrate
2. Gemfibrozil

Primarily lower triglycerides and reduce pancreatitis risk

9.8 Omega-3 Fatty Acids / Icosapent Ethyl

1. Lower triglycerides
2. Reduce ASCVD risk in selected high-risk patients

10. Statin Adverse Effects

1. Myalgia
2. Myopathy
3. Rare rhabdomyolysis
4. Elevated liver enzymes
5. Mild increase in diabetes risk

True statin intolerance is less common than perceived

11. Monitoring

1. Repeat lipid profile after therapy initiation
2. Monitor adherence and lifestyle changes
3. CK only if muscle symptoms occur
4. Liver enzymes only if clinically indicated

12. Prognosis

1. Early lipid lowering significantly reduces ASCVD risk
2. Untreated familial hypercholesterolemia markedly increases premature cardiovascular disease risk

13. Key Clinical Insight

Patient with markedly elevated LDL cholesterol, tendon xanthomas, and premature family history of myocardial infarction strongly suggests familial hypercholesterolemia

14. Key Exam Points

1. LDL is the primary atherogenic lipoprotein
2. ApoB-containing lipoproteins drive ASCVD risk
3. Familial hypercholesterolemia is most commonly due to LDL receptor mutation
4. Tendon xanthomas strongly suggest familial hypercholesterolemia
5. Severe hypertriglyceridemia markedly increases pancreatitis risk
6. Statins are first-line therapy for elevated LDL cholesterol
7. PCSK9 inhibitors and inclisiran are used for persistent LDL elevation
8. Lp(a) should be measured at least once in all adults
9. LDL ≥190 mg/dL strongly suggests severe hypercholesterolemia/FH
10. Early aggressive lipid lowering reduces cardiovascular morbidity and mortality