What are the recommended screenings and treatments for an adult with a family history (FH) of hereditary conditions, such as hypertension, hyperlipidemia, and diabetes?

Screening and Management for Adults with Family History of Hereditary Conditions

Adults with a family history of premature cardiovascular disease, hyperlipidemia, hypertension, or diabetes require targeted screening with fasting lipid profiles and blood pressure monitoring, with specific thresholds for intervention based on the presence of familial hypercholesterolemia (FH) and other hereditary risk factors. 1

Lipid Screening for Familial Hypercholesterolemia

When to Screen

• Measure a fasting lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) if there is a family history of total cholesterol ≥240 mg/dL, premature cardiovascular disease (men <55 years, women <65 years), or known primary hypercholesterolemia. 1
• Non-fasting samples may be acceptable for initial screening, though fasting samples are preferred for diagnostic accuracy. 2
• If triglycerides exceed 400 mg/dL, repeat with a 12-hour fasting sample and use direct LDL-C measurement rather than calculated values. 2, 3

Diagnostic Thresholds for FH

• Adults with persistent LDL-C ≥190 mg/dL without secondary causes (hypothyroidism, diabetes, renal disease, nephrotic syndrome, liver disease) and at least one first-degree relative with similar elevation or premature coronary artery disease warrant strong suspicion for FH. 1
• LDL-C ≥250 mg/dL without secondary causes suggests FH even without positive family history. 1
• Measure LDL-C on at least two separate occasions to establish baseline, adjusting for any current cholesterol-lowering medications. 3

Genetic Testing Recommendations

• Offer genetic testing (LDLR, APOB, PCSK9, LDLRAP1 genes) to all adults with definite or probable FH based on phenotypic criteria. 1, 3
• Once a pathogenic variant is identified, perform cascade genetic testing of all first-degree relatives, then extend to second- and third-degree relatives. 1, 2, 3
• Refer all patients with confirmed or highly suspected FH to a lipid specialist for management planning. 3

Treatment of Familial Hypercholesterolemia

Lipid-Lowering Therapy

• Initiate statin therapy in adults with LDL-C ≥190 mg/dL after 3-6 months of intensive lifestyle modification (Step 2 American Heart Association diet with reduced saturated fat). 1
• The treatment goal is LDL-C <100 mg/dL, with consideration for more aggressive targets in those with additional cardiovascular risk factors. 1
• Start with atorvastatin 10-20 mg daily or simvastatin 20-40 mg daily, with dosage range up to atorvastatin 80 mg or simvastatin 80 mg daily as needed. 4, 5
• Consider adding ezetimibe or PCSK9 inhibitors if LDL-C goals are not achieved with maximum tolerated statin therapy. 1

Additional Lipid Considerations

• Measure lipoprotein(a) in those with family history of premature cardiovascular disease, as markedly elevated levels (>75 nmol/L) combined with elevated LDL-C increase MI risk 10-fold or higher. 2, 6
• Measure apolipoprotein B in patients with hypertriglyceridemia to better estimate atherogenic particle burden. 2

Hypertension Screening and Management

Blood Pressure Monitoring

• Screen for hypertension at every clinical encounter, as the combined presence of hypertension and hypercholesterolemia substantially increases cardiovascular risk. 7
• Hypertension is defined as systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg on multiple occasions. 1

Screening for Secondary Hypertension

• Consider screening for primary aldosteronism (plasma aldosterone:renin activity ratio) in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, incidentally discovered adrenal mass, or family history of early-onset hypertension or stroke at young age (<40 years). 1
• A positive aldosterone:renin ratio (≥30 with aldosterone ≥10 ng/dL) requires confirmatory testing and referral to a hypertension specialist or endocrinologist. 1

Treatment Goals

• Target blood pressure <140/90 mmHg in most adults, with consideration for <130/80 mmHg in those with additional cardiovascular risk factors. 1
• Select antihypertensive medications that do not adversely affect lipid profiles; ACE inhibitors are reasonable first-line agents, particularly in those with concurrent hyperlipidemia. 1, 7

Diabetes Screening

When to Screen

• Screen for diabetes in adults with family history of diabetes, particularly if other metabolic risk factors (obesity, hypertension, dyslipidemia) are present. 1
• Use fasting glucose, hemoglobin A1c, or oral glucose tolerance testing for screening. 1

Management Integration

• In adults with diabetes and family history of hypercholesterolemia (≥240 mg/dL) or premature cardiovascular disease, perform fasting lipid profile after glucose control is established. 1
• Initiate statin therapy in diabetic patients aged 40-75 years with LDL-C ≥70 mg/dL and ASCVD risk ≥7.5%, with consideration for moderate-to-high intensity statins. 1

Common Pitfalls and Caveats

• The Friedewald equation for calculating LDL-C becomes unreliable when triglycerides exceed 400 mg/dL; use direct LDL-C measurement in these cases. 2, 3
• Family history information is often incomplete or unavailable, particularly in single-parent households or when parents have not had cholesterol screening; actively encourage patients to collect comprehensive family health history. 1, 8
• Adjust LDL-C values for current statin, ezetimibe, or PCSK9 inhibitor use when phenotypically screening for FH, as treatment masks true baseline levels. 2
• Repeat lipid testing after recovery from acute illness if FH diagnosis is uncertain, as acute illness can temporarily alter lipid levels. 2
• Select antihypertensive agents carefully in patients with concurrent hyperlipidemia, avoiding those that adversely affect lipid profiles (certain beta-blockers and thiazide diuretics at high doses). 7