Skill Checkup: A 43-Year-Old Man With a History of Smoking and Current Pressure in the Middle of the Chest and Dyspnea

Romesh Khardori, MD, PhD, FACP


January 12, 2022

Diagnosis of familial hypercholesterolemia (FH) can be confirmed via pathogenic genetic testing. Genetic diagnosis of FH may involve testing for known pathogenic variants in the genes (LDL receptor [LDLR], APOB, and PCSK9 ) or whole‐gene sequencing. Genetic testing may also offer insight into cardiac risk and diagnosis, allowing for risk stratification and informing treatment decisions. Critically, however, a diagnosis of FH cannot be excluded if a mutation is not identified; many patients with a definitive clinical diagnosis of FH do not have a causative mutation, like the patient in the current case.

FLDB causes a syndrome nearly indistinguishable from heterozygous FH. But a key consideration in this case is the fact that the patient is already on statin therapy and was still not able to achieve target LDL-C levels. Although genetic testing did not identify a causative gene, it can be surmised from the clinical picture, together with the patient's history, that the condition in question is heterozygous autosomal recessive hypercholesterolemia. FH is an autosomal dominant disorder that leads to significantly elevated LDL‐C levels from birth and results in early‐onset CAD. Extensor tendon xanthomas (primarily Achilles, subpatellar, and hand extensor tendons) with significantly high LDL‐C levels are specific for FH, though a family history of CAD and elevated LDL‐C levels are often the only evidence available.

It also appears that this patient has a severe form of disease. The International Atherosclerosis Society defines severe disease on the basis of LDL‐C level and presence of known clinical risk factors for atherosclerotic CVD (ASCVD). These risk factors are age > 40 years without treatment, male sex, smoking, lipoprotein(a) level > 50 mg/dL (75 nmol/L), history of early CAD in first‐degree relatives, BMI > 30, and history of diabetes or chronic kidney disease. Patients with FH with clinical ASCVD or evidence of advanced subclinical ASCVD are also considered to have severe FH.

The most common causes of FH are pathogenic variants of the LDLR gene, which are responsible for 85%-90% of genetically confirmed FH. Early diagnosis in childhood and initiation of therapy is thought to reduce mortality and morbidity. With many causes of hypercholesterolemia and early-onset CAD clouding the differential diagnosis, the condition remains underrecognized; only an estimated 10% of the 1.3 million Americans living with FH have received a diagnosis. Consequently, FH is usually diagnosed in adults after a cardiac event.

Dysbetalipoproteinemia (type III hyperlipidemia) is a rare condition in which patients typically have elevated total cholesterol (300-600 mg/dL) and triglyceride levels (> 400 mg/dL, but may be > 1000 mg/dL). It is unlikely in this case because these patients usually have a metabolic disorder, such as diabetes, obesity, or hypothyroidism.

Homozygous autosomal recessive hypercholesterolemia is another molecular defect that causes severely elevated LDL-C. It is a rare form of FH. Seeing as this patient only has one parent with a relevant disease history, it would appear he has heterozygous FH.


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