Case Study: Not So Specific Physical Findings of an Unusual Lipid Disorder

A 37-year-old patient was referred to our lipid clinic from his primary care provider. A basic lipid panel revealed: total cholesterol (TC) 715 mg/dL, triglyceride (TG) 901 mg/dL; HDL-C 45 mg/dL, Lipoprotein(a) [Lp(a)] mass was elevated (44 mg/dL); Lp(a)- cholesterol levels were not measured. The patient, who was generally very healthy, had not seen a physician for several years. He presented with bilateral palmar xanthomas (see Photo 1). He had noticed them for approximately 2 years but did not know what they were. Flat macules were diffusely spread across his palmar surfaces and the flexor surfaces of the fingers. He sought treatment after a physician friend saw his hands and urged him to see his primary care physician and to have his cholesterol levels measured.

His medical history was unremarkable; his family history was somewhat unknown, but he reported that he thought there was early cardiac death on his mother's side, though not in his immediate family. He exercised strenuously four days a week and followed a low-carbohydrate diet that was high in vegetables and lean meats. He had never had a weight problem. He was not on any prescription medications but took omega 3 fatty acid capsules daily, exact dosage unknown. He had no drug allergies, no history of cigarette smoking and no surgeries. He denied any other physical complaints.

Vital signs: Height, 6 feet, 0 inches; weight, 148 pounds; BMI 20.1; BP 120/82; P 60.

Photo 1

We suspected type III dysbetalipoproteinemia or "remnant disease" because of the physical presentation and the levels of very high triglycerides and total cholesterol. Advanced lipoprotein testing was ordered. A secondary cause workup included urine analysis (UA), thyroid function tests (TFTs), HBA1c and a complete metabolic panel (CMP).

Planar xanthomas of the palms, as seen in the patient, are also called xanthoma striatum palmare (XSP). They are rare but considered pathognomonic of dysbetalipoproteinemia.¹ In addition, the condition is characterized by very elevated cholesterol and triglycerides, as seen in the patient’s initial laboratory findings. Dysbetalipoproteinemia reflects an accumulation of remnant lipoproteins: both intestinally produced chylomicron remnants and hepatically produced VLDL remnants. It is sporadic because most cases are recessive and two defective Apolipoprotein E (ApoE) alleles (ApoE 2/2) are required, plus additional environmental factors are necessary for full expression of the dyslipidemia.² This genetic lipid disorder is associated with premature coronary and/or peripheral vascular disease.³ It is seen when factors that increase remnant lipoprotein production overwhelm the receptor-mediated clearance pathways. Conditions such as hypothyroidism, weight gain, estrogen status or uncontrolled diabetes could precipitate the development of dysbetalipoproteinemia.^4,3 XSP develop because of lipid leakage from vessels into surrounding tissues; macrophages then phagocytize the lipids.¹

Interestingly, our patient did not have any identifiable metabolic causes of his dyslipidemia; his secondary cause work-up was negative.

His advanced lipoprotein testing showed the following notable results:

The most surprising initial finding was the very high levels of both ApoB and LDL-P in addition to the apoE 3/3 genotype; these findings are not suggestive of dysbetalipoproteinemia. In true dysbetalipoproteinemia, LDL-P will be low, which could falsely suggest low cardiovascular risk. The ApoB also will be low because of the short half-life of the IDL and VLDL particles despite their high numbers. In dysbetalipoproteinemia, risk is high because of the atherogenicity of remnant lipoproteins; one cannot rely solely on ApoB and LDL-P to predict risk.

We initiated aggressive lipid management via drug therapy and prescribed Lovaza 4 grams daily, Trilipix 135 mg daily, and Crestor 10 mg daily. Zetia 10 mg daily was added later. The patient also underwent carotid intima media thickness (CIMT) testing that revealed: left side, 0.538 mm; 20th percentile for his age and gender; carotid plaque was not visualized on either side. He also elected to initiate care with a cardiologist and went through extensive cardiac testing, including a nuclear stress test and computed tomography (CT) angiogram, both of which were negative. He met with a dietitian and, though his diet was already quite healthy, he moved toward a more vegan diet, basically eliminated all animal fats and further reduced his refined carbohydrate intake. From a scientific standpoint we were intrigued by his case, which phenotypically looked like dysbetalipoproteinemia, though ApoB levels and apoE 3/3 were not consistent with this disorder. It should be noted that the patient also was quite interested in understanding the genetic cause of his lipid disorder and was hopeful we could help him shed more light on his complex case. There are rare naturally occurring apoE mutations other than apoE 2/2 that have been associated with a dominant form of dysbetalipoproteinemia that is expressed at an early age; the genetic defect alone is sufficient to trigger dyslipidemia without requiring secondary factors.⁴ We were fortunate that the patient enrolled in a research study that provided apoE gene sequencing for research purposes only, but no mutations were found. The patient continues to be involved in a genetic research study; at this time no further results are available. Overall, this case reveals that the physical presentation of lipid disorders can sometimes be misleading: We initially presumed the patient to have dysbetalipoproteinemia, given the presence of the XSP. While his electrophoresis did "look" like dysbetalipoproteinemia, his ApoB and LDL-P levels most definitely did not and his apoE initial testing did not support this diagnosis. Further sequencing of his apoE did not reveal any other genetic abnormalities to help guide a diagnosis. There are myriad abnormal genes that can influence lipid metabolism; with this patient it could be some type of overproduction of VLDL in association with defective LDL receptors, a defect in ApoB, or PCSK9 gain of function mutation. In real-life practice situations, precise labels and detailed genetic analysis are not necessary to provide adequate treatment, though the final genetic testing results will prove very interesting. The most important service we provided for this patient—who was quite concerned about his risk and his abnormal levels—was to treat his lipoproteins and help reassure him that his risk was minimized with this proper and aggressive treatment. The treatment produced marked improvements in his lipoprotein levels as summarized in the following chart:

Considering his starting levels, these are nice improvements, though his levels remain above the most aggressive lipoprotein goals. There are new lipid drugs available and in development, and he ultimately may require them or respond better to them. His xanthomas have improved ever so slightly and we will follow the patient closely. As mentioned previously, further genetic information will be very interesting and we currently await those results.

Disclosure statement: Ms. Davila has no disclosures to report.