Rare lipid disorders in the real world: Improving recognition in clinical practice
Industry Buzz
Rare lipid disorders, however, are genetic conditions that occur from birth and typically impair the body’s ability to clear fat and cholesterol from the bloodstream.
—Brett A. Sealove, MD
Untreated low-lipid disorders can cause neurological, vision, and growth problems. Awareness and early recognition of rare lipid disorders is crucial for preventing devastating complications.
—Olivia Hollyer, PA-C
Disorders of lipoprotein metabolism remain central drivers of atherosclerotic cardiovascular disease (ASCVD), spanning common polygenic hypercholesterolemia to rare monogenic syndromes that profoundly disrupt lipid clearance.
In routine cardiology practice, elevated LDL-C and triglyceride-rich lipoproteins are among the most frequently managed—and undertreated—risk factors, often persisting despite guideline-directed therapy. In the United States alone, tens of millions of adults meet criteria for elevated LDL-C, with a substantial proportion either undiagnosed or not at goal on therapy.[]
“Most cases of high cholesterol in cardiology are secondary, meaning they’re influenced by diet, lifestyle, metabolism, and age,” says Brett A. Sealove, MD, Chair of Cardiology at Hackensack Meridian Jersey Shore University Medical Center. “Rare lipid disorders, however, are genetic conditions that occur from birth and typically impair the body’s ability to clear fat and cholesterol from the bloodstream.”
Homozygous familial hypercholesterolemia (HoFH)
One of these rare lipid disorders is homozygous familial hypercholesterolemia (HoFH).[] “This is caused by mutations in both copies of genes related to LDL cholesterol clearance,” says Marios Arvanitis, MD, a board-certified cardiovascular disease physician at The Ohio State University Wexner Medical Center. “The condition is associated with severe buildup of cholesterol in several tissues in our body and is associated with early plaque buildup in the arteries, leading to early heart attacks or strokes, along with cholesterol buildup in the heart, leading to narrowing of heart valves.”
Related: HoFH in children: Key diagnostic challenges and the case for early detectionOlivia Hollyer, PA-C, of Manhattan Cardiology, says HoFH is often diagnosed using cholesterol levels, physical signs, family history, and genetic testing. “These tools can also help differentiate between heterozygous and homozygous FH,” she says. Genetic testing can confirm mutations in the responsible genes, including the LDLR, APOB, or PCSK9 genes.
“Early recognition is essential,” says Dr. Sealove. “These patients typically require intensive, specialized therapies beyond standard statins. Increased education in both the general population and medical practices is needed to ensure everyone knows about these conditions.”
Low-lipid disorders
On the other end of the spectrum are the low-lipid disorders. Class II disorders in this category tend to be asymptomatic, while class I disorders (like abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease) impact LDL and triglyceride transport; this causes lipids to become trapped inside the liver and intestine, leading to steatosis and fat malabsorption. These are severe, ultra-rare, and usually discovered incidentally.[]
Tangier disease, another low-lipid disorder, is marked by very low HDL cholesterol in the blood. “These patients suffer from the consequences of cholesterol deposition in many organs, including the nervous system (nerve pain and weakness), the liver and spleen (leading to organ enlargement), the arteries (often leading to early plaque buildup), and the eyes, bone marrow, and other organs,” Dr. Arvanitis says.
Dr. Arvanitis emphasizes that these conditions stem from rare, highly penetrant genetic variants, which carry important diagnostic implications.
“Diagnosis of low-lipid disorders usually begins with a routine fasting lipid panel detecting an abnormally low LDL, usually below 50 mg/dL,” says Hollyer. “The next step is checking for secondary causes, such as hyperthyroidism, liver disease, cancer, or malabsorption.” If other causes are ruled out, genetic testing is key.
“We typically use advanced tests, including Apolipoprotein B, Lipoprotein(a), and genetic analysis, to identify the underlying genetic defect,” Dr. Sealove says.
The risk of not adequately diagnosing and treating these disorders is clear. In high-lipid disorders, that means early heart disease and peripheral artery disease. “In contrast, untreated low-lipid disorders can cause neurological, vision, and growth problems. Awareness and early recognition of rare lipid disorders is crucial for preventing devastating complications,” says Hollyer.