Xanthomas: A clue to undiagnosed lipid disorders

XANTHOMAS AND FAMILIAL LIPID DISORDERS

Familial chylomicronemia syndrome is a rare autosomal recessive genetic disorder that typically involves impaired activity of the lipoprotein lipase enzyme.⁴ It dramatically increases the risk of recurrent hypertriglyceridemia-induced acute pancreatitis. Accurate and timely recognition of familial chylomicronemia syndrome is crucial as it allows the clinician to start treatment to lower triglyceride levels, decreasing the risk of acute pancreatitis, and to recommend cascade screening to look for the disorder in close family members. In the present case,³ the patient’s history of obesity and uncontrolled diabetes mellitus may have contributed to their hypertriglyceridemia, but the extreme nature of triglyceride elevation coupled with a history of acute pancreatitis makes familial chylomicronemia syndrome a strong consideration. This patient received multiple therapies to lower their triglycerides, ultimately undergoing plasmapheresis to reduce triglyceride levels and resolve their acute pancreatitis.

Familial chylomicronemia syndrome is not the only condition associated with xanthomas. Familial hypercholesterolemia is an autosomal dominant genetic condition characterized by very high plasma levels of low-density lipoprotein cholesterol and a risk of atherosclerotic cardiovascular disease up to 20 times higher than that of the general population.^5,6 The heterozygous form of familial hypercholesterolemia (HeFH), in which an individual carries a pathogenic mutation in 1 allele, may be present in about 1 in 250 individuals in the United States, yet may be underdiagnosed in 90% or more cases in many countries.⁷ Tendon xanthomas, particularly in the Achilles tendons, are strongly associated with familial hypercholesterolemia and are part of the Dutch Lipid Clinic Network criteria used to diagnose this condition.

A rarer condition associated with xanthomas is cerebrotendinous xanthomatosis, a lipid storage disease that is associated with progressive neurologic issues.¹

XANTHOMAS—STILL A VALUABLE CLINICAL FINDING

Whether a working knowledge of xanthomas still matters for trainees and clinicians in the modern era of widely available direct-to-consumer laboratory testing is a reasonable question. Also, at a time when statin therapy is widely used for primary prevention, xanthomas may not be common even in those with an underlying lipid disorder. In the CASCADE-FH (Cascade Screening for Awareness and Detection of Familial Hypercholesterolemia) registry, only 19% of those with HeFH had tendon xanthomas.⁸

When present, however, xanthomas are sometimes nearly pathognomonic for the presence of lipid disorders, which are underdiagnosed at the population level, and thus finding xanthomas during an examination offers an opportunity to identify these disorders early. At a routine primary care visit, urgent care visit, or emergency department visit, the astute clinician who notes the presence of cutaneous xanthomas in a young patient may be prompted to undertake a dedicated evaluation for genetic disorders of lipid metabolism, which should generally include both a fasting lipid panel that evaluates total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol and a targeted family history focused on hyperlipidemia, cardiovascular disease, and pancreatitis.

For families with previously undiagnosed HeFH or familial hypercholesterolemia syndrome, an index diagnosis of one of these genetically inherited diseases, triggered by the presence of cutaneous xanthomas, can encourage genetic testing to identify affected relatives at early ages, and potentially allow early treatment and modification of the natural history of these conditions and their associated morbidity and mortality risks. The possibility of early treatment is particularly salient, given the availability in modern practice of multiple therapies for lowering low-density lipoprotein cholesterol and triglycerides levels. For example, olezarsen (an antisense oligonucleotide) and plozasiran (a small interfering RNA therapy) target apolipoprotein C-III and were recently approved by the US Food and Drug Administration for reducing triglyceride levels in individuals with familial chylomicronemia syndrome.^9,10

It remains of value for general clinicians to be familiar with xanthomas and what they may represent: a potential window into an individual’s disease, genetics, and future morbidity and mortality risks.

DISCLOSURES

Dr. Sarraju reports no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.