National Lipid Association
National Lipid Association
May 26, 2017
4 min read

Few solutions available for type III hyperlipidemia, sitosterolemia, lipoprotein X disorder

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PHILADELPHIA — Rare lipid disorders can be difficult to diagnose and treat, according to three presentations at the National Lipid Association Scientific Sessions.

Experts presented cases and challenges related to type III hyperlipidemia, sitosterolemia and lipoprotein X disorder.

Type III hyperlipidemia

Type III hyperlipidemia was present in 0.4% of men and 0.2% of women aged 20 years or older in the Lipid Research Clinics Prevalence Study, a large, national survey performed in the 1970s, whereas a more recent estimate of prevalence is 0.98% in all adults, Paul N. Hopkins, MD, MSPH, FNLA, professor in the division of cardiovascular medicine of the department of internal medicine at the University of Utah, Salt Lake City, said during a presentation, noting it is considerably more frequent than some estimates of the condition’s prevalence.

The condition is characterized by increased plasma concentrations of triglyceride-rich particles which also have abnormal composition. Confirmation is traditionally done after ultracentrifugation, Hopkins said. According to the Lipid Research Clinics criteria, type III hyperlipidemia is confirmed if beta-very LDL (beta-VLDL) is present upon electrophoresis of the density < 1.006 fraction, triglycerides are 150 mg/dL to 1,000 mg/dL and the ratio of measured VLDL to total triglycerides is ≥ 0.3 mg/dL, or if beta-VLDL is present upon electrophoresis and triglycerides are ≤ 150 mg/dL or > 1000 mg/dL; type III hyperlipidemia is possible if beta-VLDL is not present on electrophoresis but triglycerides are 150 mg/dL to 1,000 mg/dL and the ratio of measured VLDL to total triglycerides is ≥ 0.3 mg/dL.

However, Hopkins said, there is “no gold standard” for a definition of the condition.

Predisposing factors include obesity, diabetes, hypothyroidism, estrogen deficiency and other lipid disorders such as familial hypercholesterolemia, according to Hopkins, noting that it is present in approximately 25% of those with familial hypercholesterolemia with a single apolipoprotein E2 allele. Type III hyperlipidemia is more common in those with apo E2/E2 genotypes, but most patients with type III hyperlipidemia do not have the apo E2/E2 genotype, he said.

Treatment strategies center on slowing the production of or increasing the removal and processing of triglyceride-rich lipoproteins via agents such as fibrates, omega-3 fish oils, niacin, statins and, if deficient, estrogen, Hopkins said. He noted that PCSK9 inhibition, ANGPTL3 inhibition and antisense apolipoprotein C-III may also be viable strategies, but they have not been studied in this population.


Sitosterolemia is “an autosomal recessive disorder that causes increased plasma levels of sterols due to a defect in the regulatory plant sterole transporters,” Joyce L. Ross, MSN, ANP, CRNP, CLS, FNLA, immediate past president of the NLA and retired nurse practitioner in the University of Pennsylvania Health System, said during a presentation. “In patients with sitosterolemia, plasma levels of sitosterol are increased more than 50-fold.”

Joyce L. Ross

Extensive tendon xanthomas are common, as they are in familial hypercholesterolemia, she said.

“Most patients identified subsequently have had elevated levels of plasma LDL, especially in childhood, sometimes has high as more than 500 mg/dL,” Ross said. “Patients have abnormally high blood levels of sterols and a tendency to develop [CAD] and potential for premature death at an early age, often in adolescence.”

The condition is very rare, and only 80 to 100 patients have been described in the literature. “More than likely, sitosterolemia is significantly underdiagnosed and prevalence may be one in 50,000,” Ross said.

Diagnosis is confirmed with an assay of plasma sterol levels, but many patients may not receive this test because it is assumed they have familial hypercholesterolemia, according to Ross.

“The disease should be considered in individuals with xanthomatosis and hypercholesterolemia whose parents are normocholesterolemic,” she said.

Treatment goals are to lower plant sterols as much as possible, control blood cholesterol and reduce or prevent xanthomas, she said, noting it is accomplished by strict limitation of cholesterol in the diet, reduction in consumption of foods known to be rich in plant sterols and prescribing ezetimibe — which inhibits the active transport of plant sterols into the enterocyte — and cholestryramine resins.

A multidisciplinary team should treat the patient, including an internal medicine doctor to be the gatekeeper, a cardiologist to evaluate and treat CAD, a lipidologist, a dietitian or nutritionist, a genetic counselor, a rheumatologist and, if necessary, a hematologist, she said.

“Better understanding of the molecular mechanisms causing these genetic differences may contribute to the development of new and more individualized therapies for this treatment,” she said.

Lipoprotein X disorder

Lipoprotein X (LP-X) is a carrier of cholesterol in the same density range as LDL, but notably does not have any apolipoprotein B, Laurence S. Sperling, MD, FACC, FACP, FAHA, FASPC, professor of medicine (cardiology), professor of global health and director of the Center for Heart Disease Prevention at Emory University, and immediate past president of the American Society for Preventive Cardiology, said in his presentation.

The pathophysiology of LP-X disorder includes bile reflux into the plasma, decreased clearance, bile salt binding to albumin and membrane-bound enzymes aggregating with LP-X, he said.

LP-X concentrations are high in patients with the disorder, who may be confused for patients with familial hypercholesterolemia, he said. Patients usually have markedly elevated cholesterol, a falsely elevated measure of LDL and LDL particles and a discordance between ApoB and LDL, he noted.

“Complications can include pseudohyponatremia, hyperviscosity and cutaneous manifestations such as xanthomas,” Sperling said.

Oral medications such as statins and bile acid binding resins are unlikely to adequately treat the disorder, so clinicians should consider therapeutic plasma exchange via LDL apheresis and, if necessary, liver transplantation, he said.

“The disorder is most often seen in advanced liver disease and may not be atherogenic,” he said. “Consider plasma exchange as a temporizing treatment approach.” – by Erik Swain


Hopkins PN.

Ross JL.

Sperling LS. Less Common Lipid Disorders. All presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Hopkins and Sperling report no relevant financial disclosures. Ross reports speaking for Abbott/AbbVie, Amarin, Amgen, Kaneka America, Kowa and Sanofi/Regeneron and consulting for Akcea Therapeutics, Kaneka America and Kastle Therapeutics.



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