Cardiometabolic Health Congress

Cardiometabolic Health Congress


Brown RJ. Rare Lipid Disorders. Presented at: Cardiometabolic Health Congress; Oct. 14-17, 2021; National Harbor, Md. (hybrid meeting).

Disclosures: Brown reports no relevant financial disclosures.
October 14, 2021
3 min read

Rarer causes of severe hypertriglyceridemia require specialized consideration


Brown RJ. Rare Lipid Disorders. Presented at: Cardiometabolic Health Congress; Oct. 14-17, 2021; National Harbor, Md. (hybrid meeting).

Disclosures: Brown reports no relevant financial disclosures.
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While rare, certain genetic and multifactorial causes of severe hypertriglyceridemia may warrant special considerations for diagnosis and treatment within their respective patient populations, a speaker reported.

“When looking at triglycerides, it's important to know that in the general population, triglycerides follow a non-normal distribution,” Rebecca J. Brown, MD, MHSc, Lasker Clinical Research Scholar at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, said during a presentation at the Cardiometabolic Health Congress.

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Brown cited data published in Frontiers in Endocrinology in 2020 showing approximately 75% of people fall within the normal range for triglycerides of less than 150 mg/dL. However, among the 99th percentile of individuals, there are those with high triglyceride levels of 450 mg/dL or more, in which the majority of circulating triglycerides, in the fasting state, is contained as VLDL or VLDL remnant particles.

In addition to VLDL or VLDL remnant particles, patients with very high triglycerides (800 mg/dL to 1,000 mg/dL) will have circulating chylomicron and chylomicron remnants particles, according to the presentation.

Brown stated that triglyceride-rich lipoprotein particles become saturated above triglyceride concentrations greater than about 500 to 700 mg/dL; therefore, patients with triglycerides above that range cannot clear chylomicrons adequately and continue to have chylomicrons present, even after an overnight fast.

According to the presentation, although the main goal of triglyceride lowering is to reduce CV risk, among patients with very high triglycerides, the primary goal is to lower the risk for pancreatitis.

Causes of severe hypertriglyceridemia can be divided into monogenic forms and multifactorial forms, according to the presentation.

One monogenic cause of hypertriglyceridemia is familial chylomicronemia syndromes, which occurs in 1 per 200,000 to 1,000,000 people or 1.1% of patients with triglycerides around 885 mg/dL.

“There are no reported causative genes for familial chylomicronemia syndromes that affect either synthesis or production of triglyceride-rich lipoproteins,” Brown said during the presentation. “Instead, all of the familial chylomicronemia syndrome genes are caused by biallelic loss-of-function variants in genes involved in hydrolysis of triglyceride-rich lipoprotein particles. Because chylomicrons carry such large quantities of triglyceride, familial chylomicronemia syndromes are characterized by increased chylomicron particle numbers and greatly increased triglyceride concentrations.”

According to the presentation, patients with familial chylomicronemia syndromes may also present with lipemia retinalis, eruptive xanthomas and pancreatitis.

Another monogenic cause of hypertriglyceridemia is lipodystrophy syndromes that are characterized by a deficiency of adipose tissue.

According to the presentation, low fat mass attributed to lipodystrophy syndromes results in low levels of adipocyte-derived hormones, including leptin, which is sensed by the hypothalamus as a starvation signal, resulting in hyperphasia.

“Because patients with lipodystrophy cannot store excess calories and adipocytes because they don't have the adipocytes,” Brown said. “They instead store these excess nutrients as ectopic lipid within tissues, such as muscle and liver, leading to insulin resistance, which has downstream health consequences, including diabetes and hypertriglyceridemia.”

According to the presentation, severe hypertriglyceridemia is present in up to 25% of patients with lipodystrophy syndromes.

The multifactorial causes of severe hypertriglyceridemia are more common compared with the monogenic causes, with a prevalence of 1 per 600 individuals.

Severe hypertriglyceridemia can be caused by the small, non-Mendelian combinatorial effects from multiple genes, such as APOC3, APOA5 and LPL, among many others.

Additional non-genetic causes of severe hypertriglyceridemia include excessive alcohol intake, pregnancy, drugs, diabetes, kidney disease and liver disease.

Brown highlighted several treatment methods for hypertriglyceridemia. Better controlling diabetes, ceasing alcohol consumption and reevaluating the patient’s medication regime may lower triglyceride levels, she said.

For patients with familial chylomicronemia syndrome, Brown stated that dietary interventions such as caloric restriction with or without medium-chain triglyceride supplementation may improve triglycerides.

For patients with lipodystrophy syndromes or multifactorial causes, such as diabetes, initiation of weight loss and a balanced macronutrient diet may benefit in the management of hypertriglyceridemia, according to the presentation.

FDA-approved drugs for the treatment of severe hypertriglyceridemia include fibrates, high-dose omega-3 fatty acids, statins and high-dose niacin, according to the presentation.