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Increasing understanding of the genetics orchestrating the many players regulating cholesterol in the body has expanded the realm of inherited hypercholesterolemias.

Millions of single nucleotide polymorphisms have been linked to cholesterol levels. Common variants that individually chip in a small contribution to risk for developing atherosclerotic cardiovascular disease have been worked into polygenic risk scores for mainly coronary heart disease, as genome-wide association studies for stroke have been less robust.

In Mendelian randomization studies, genetically determined lifetime exposure to higher low-density lipoprotein (LDL) concentrations has a stronger link to atherosclerotic cardiovascular disease (ASCVD) than LDL elevations acquired by diet and lifestyle. The opposite is also true, as have shown a bigger impact on coronary artery disease than pharmacological interventions.

Familial Hypercholesterolemia

"The justly celebrated unraveling of the LDL receptor pathway revealed that mutations in a single gene give rise to familial hypercholesterolemia (FH)," Peter Libby, MD, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, said in a chapter in .

FH, now thought to affect 1 in 250 adults, is most commonly caused by a single gene variant inherited from one parent (heterozygous FH). The three main known genetic mutations in FH impact LDLR (most common), APOB (apolipoprotein B, about 10% of FH cases), or PCSK9 (<5% of FH cases), notes . These mutations all reduce uptake of LDL cholesterol for transport back to the liver away from vessel walls, where it could deposit.

Much rarer and more serious is homozygous FH, with an LDL gene variant inherited from both parents, which has an incidence of about 1 in 315,000 individuals. With an almost total lack of LDL receptors for uptake LDL, these patients have extremely high LDL cholesterol (typically >400 mg/dL) and can die of atherosclerosis in the first decade of life. They may also have cholesterol deposits (xanthomas) visible under the skin or built up in tendons.

PCSK9 mutations can either activate or inactivate its action, raising or lowering plasma LDL levels and coronary heart disease risk accordingly.

Less Common Inherited Hypercholesterolemias

Polygenic hypercholesterolemia from the additive effect of a number of single nucleotide variants along the whole genome may represent an important proportion of severe primary hypercholesterolemia cases. A less common mutation in was also reported to be linked to FH, but later .

Lysosomal acid lipase deficiency (LAL-D) is rare, with a reported incidence of 1 in 40,000 to 300,000. These mutations in the lipase A gene keep cholesterol and triglycerides from being degraded for disposal, leading to buildup inside the lysosomes of various organs, which leads to liver dysfunction and structural injury.

Notably, LAL-D's lipid profile can be "indistinguishable from that observed in common genetic hypercholesterolemias and often masquerades as FH ... with severe long-term consequences," according to a 2023 paper. This often results in hepatomegaly with or without early ASCVD, "and should be considered in patients with poor responsiveness to statins, abdominal symptoms, transaminase elevations, and elevated triglycerides."

Screening for FH

Given that FH exposes individuals to elevated LDL levels beginning before birth and leads to early ASCVD, early identification and treatment is a priority.

Cholesterol guidelines call FH screening reasonable for children and adolescents with a family history of either early cardiovascular disease or "significant hypercholesterolemia," defined as total cholesterol of at least 240 mg/dL, LDL-C at least 190 mg/dL, non–HDL-C at least 220 mg/dL, or known primary hypercholesterolemia. To this end, the guidelines say a fasting or nonfasting lipoprotein profile (non–HDL-C) as early as age 2 years is reasonable to detect FH or rare forms of hypercholesterolemia. Children's LDL-C levels are better discriminators of FH than are adults'.

Universal screening of children at ages 9-11 is guideline recommended as reasonable for early detection of homozygous FH. Genomic-based population screening or newborn screening could also be used. However, "the best approach to detecting FH in primary care remains uncertain," states 2023 from the International Atherosclerosis Society.

Use of a (incorporating levels of triglycerides, LDL-C, and apolipoproteins along with use of statins and other clinical factors) showed promise for better detection of FH in primary care compared with LDL-C measurement alone in a U.K. Biobank study.

Whatever the age at diagnosis, cascade screening of family members is recommended as reasonable when FH is diagnosed. This group includes not just parents and siblings but also even third-degree biological relatives like grandparents, aunts, and uncles.

"Consenting family members should be offered a standard plasma lipid profile and a genetic test if the family mutation is known and DNA testing is available," noted a from the American Heart Association (AHA). All should be made aware of and understand the implications of genetic testing for certain types of insurance coverage and political discrimination."

Genetic counseling can help in this regard.

Diagnosis of FH

Homozygous FH can be diagnosed based on LDL-C plasma levels over 500 mg/dL if treated or 300 mg/dL if already on lipid-lowering therapy. Tendon xanthoma or cutaneous manifestation before the age of 10 years or in both parents is also telling.

Heterozygous FH is most commonly evaluated by the and the , which both incorporate LDL levels, presence of xanthomas, presence of a genetic mutation or family history of FH, premature cardiovascular events, tendon xanthomas, corneal arcus senilis, and elevated LDL levels at young ages.

Genetic screening for FH is not required for diagnosis but can aid in cases of uncertainty.

The National Organization for Rare Disorders cautions that 20-30% of individuals who meet clinical criteria for FH may be negative by standard clinical due to technical limitations of current technology or causal genes that have not yet been discovered. "Therefore, a negative FH genetic test result does not rule out a diagnosis of FH, but may lower the suspicion for FH in circumstances where a diagnosis of FH is unclear," the organization points out.

If a skin lesion or the diagnosis of heterozygous FH is unclear, a biopsy of the skin lesion can be performed. Both xanthelasma cholesterol deposits around the eyes and the xanthomas of FH contain accumulations of cholesterol.

However, the AHA statement cautions: "The Simon Broome criteria and Dutch Lipid Clinic Network Criteria are for diagnosing FH index cases and, because of ascertainment bias, should not be used strictly to detect new cases of FH during cascade or family screening. Plasma LDL-C thresholds, validated against FH-causing mutations, have been reported for this purpose."

In addition, the statement says, genetic testing for confirmation of FH diagnosis is controversial for less cohesive healthcare systems like that in the United States. "A reduction in costs and improved efficiency of genetic testing is likely to increase its broader application in screening families for FH."

Before confirming a diagnosis of FH, secondary causes should be excluded, such as hypothyroidism, nephrotic syndrome, obstructive liver disease, and an extremely poor diet in terms of saturated fat and cholesterol content.

Read previous installments in this series:

Part 1: Hypercholesterolemia: A Complex System

Part 2: Consequences of Hypercholesterolemia

Up next: Epidemiology of Hypercholesterolemia