What are the common causes of hypercholesterolemia?

Common Causes of Elevated Cholesterol

Primary (Genetic) Causes

Familial hypercholesterolemia (FH) is the most important genetic cause to identify, affecting approximately 1 in 200-500 individuals, caused by mutations in LDLR, APOB, or PCSK9 genes that impair LDL cholesterol clearance. 1, 2 This autosomal dominant disorder presents with LDL cholesterol typically 190-250+ mg/dL, tendon xanthomas, premature coronary disease (men <55 years, women <65 years), and family history of hypercholesterolemia or early cardiovascular events. 1, 2

Monogenic Disorders

• LDLR gene mutations account for the majority of FH cases, with approximately 700 different mutations identified worldwide causing deficient or defective LDL receptors. 1, 2

• APOB gene mutations cause familial defective apolipoprotein B-100 (FDB) in approximately 3% of FH patients, producing a milder phenotype than LDLR-FH. 1, 2

• PCSK9 gene mutations cause increased degradation of LDL receptors, reducing receptor numbers on cell surfaces. 1, 2

• Familial combined hyperlipidemia (FCHL) is a genetically complex disorder affecting 1-2% of white populations, characterized by increased apolipoprotein B production with variable elevations in cholesterol, triglycerides, or both in patients and first-degree relatives. 1

Polygenic Hypercholesterolemia

• Polygenic causes account for many cases of severe hypercholesterolemia where no single-gene defect is identified, resulting from multiple genetic variants combined with environmental factors. 3, 4

• Genetically elevated remnant cholesterol shows a 2.8-fold causal risk increase for ischemic heart disease per 1-mmol/L increase. 2

Secondary (Acquired) Causes

Secondary causes must always be excluded before attributing hypercholesterolemia to genetic factors, as treating the underlying condition may normalize lipid levels. 1, 2

Endocrine and Metabolic Disorders

• Hypothyroidism is a common and reversible cause of elevated cholesterol that should be screened in all patients with hypercholesterolemia. 1

• Diabetes mellitus and glucose intolerance are associated with hypercholesterolemia in 70% of adults with diagnosed diabetes and 77% with undiagnosed diabetes. 5

• Obesity and metabolic syndrome greatly increase apolipoprotein B production, particularly in patients with FCHL, and are strongly associated with elevated cholesterol when genetic predisposition is absent. 1, 4

Medications

• Thiazide diuretics can elevate cholesterol levels. 1

• Beta-blockers (particularly atenolol) may worsen lipid profiles; carvedilol is preferred in patients with hypertriglyceridemia. 1

• Oral estrogens (but not transdermal) can elevate triglycerides and affect cholesterol metabolism. 1

• Corticosteroids are a well-recognized cause of secondary hypercholesterolemia. 1

• Atypical antipsychotics can significantly elevate lipid levels. 1

• Protease inhibitors, retinoic acid drugs, sirolimus, tamoxifen, and raloxifene are additional medication-related causes. 1

Renal and Hepatic Disorders

• Nephrotic syndrome and chronic kidney disease commonly cause secondary hypercholesterolemia. 1

• Cholestatic liver disease impairs bile acid metabolism and can elevate cholesterol. 1

Lifestyle and Dietary Factors

Dietary factors—particularly high saturated fat intake, dietary cholesterol, and obesity—clearly raise cholesterol levels and are important causes of borderline-high cholesterol in the general population. 6

• Saturated fatty acid intake >7% of total calories is a major modifiable dietary cause of elevated LDL cholesterol. 1, 7

• Excess dietary cholesterol contributes to hypercholesterolemia, particularly in genetically susceptible individuals. 6

• Physical inactivity and sedentary lifestyle contribute to unfavorable lipid profiles. 7, 4

• Excess alcohol consumption can affect lipid metabolism, particularly triglycerides. 1, 7

• Unfavorable lifestyle patterns are significantly associated with severe hypercholesterolemia in young women without genetic predisposition. 4

Age-Related and Hormonal Factors

• Age-related decline in LDL receptor activity contributes importantly to borderline-high cholesterol levels and cannot be ignored. 6

• Postmenopausal estrogen loss causes decreased LDL receptor synthesis and is an important contributor to elevated cholesterol in postmenopausal women. 6

• Pregnancy (especially third trimester) can cause marked triglyceride elevation in susceptible patients. 1

Critical Clinical Pitfalls

The most dangerous pitfall is failing to identify familial hypercholesterolemia early, as these patients require aggressive lifelong treatment starting in childhood to prevent premature cardiovascular death. 7, 8 Consider FH in any patient with LDL cholesterol ≥190 mg/dL without secondary causes, especially with family history of premature coronary disease or hypercholesterolemia. 2

• Never assume severe hypercholesterolemia is purely dietary—17% of young women with LDL ≥99th percentile have monogenic familial hypercholesterolemia requiring genetic counseling and family screening. 4

• Always screen for hypothyroidism before initiating lipid-lowering therapy, as this is a completely reversible cause. 1

• Review medication lists carefully—many commonly prescribed drugs elevate cholesterol and may be modifiable. 1

• Recognize that multiple factors often coexist—severe hypercholesterolemia typically results from at least two defects in LDL metabolism (genetic plus environmental), requiring combination drug therapy. 6, 3