Case Study: Childhood Adiposopathy Unmasks Type III Hyperlipoproteinemia

We report the case of a young girl who presented with classic type III hyperlipoproteinemia to emphasize the importance of clarifying the lipid diagnoses, to illustrate the key features of this uncommon condition, and to demonstrate the potency of non-pharmacologic therapy in improving both lipoprotein parameters and body morphology.

Case Presentation
JF was referred to our preventive cardiology clinic by a dermatologist at neighboring Children’s Hospital of Philadelphia. On presentation, she was a previously healthy 9-year-old who developed a progressive rash, prompting a biopsy and subsequent lipid profile. The rash was characterized by eruptive xanthomas on her torso, buttocks, popliteal and antecubital fossae, as well as orange creases on her palms. Biopsy confirmed the presence of xanthoma, and laboratory analysis demonstrated severe combined hyperlipidemia (Table 1, 3/26/09). Lipid levels had started to improve with a very restrictive diet prior to her presentation in our clinic. (Table 1, 5/22/2009). Of note, she attended clinic with her mother and maternal grandmother, both of whom expressed feeling terribly guilty about "causing" the girl's problem and then having to restrict her diet differently from that of her friends.. JF’s diet consisted of mostly high-fat, processed foods and more than 1 liter of soda daily. The family was counseled on a “heart healthy” diet that limits total and saturated fat as well as refined sugars and starches. She was advised to choose whole grain starches, to increase her daily servings of fruits and vegetables, and to eliminate sugar-sweetened beverages.

A clinical diagnosis of type III hyperlipoproteinemia was made, despite the uncharacteristic age of presentation. Given the physical exam findings and lipid testing, evaluation for a "second hit" was undertaken. Directly measured very lowdensity lipoprotein cholesterol (VLDL-C): triglyceride ratio was well more than 0.3, and apolipoprotein E2/E2 phenotype was later documented, confirming the diagnosis. However, no obvious second hit could be found other than her highly processed/ junk food diet. There was no precipitous weight gain, change in diet/activity level, kidney/liver dysfunction or thyroid disorder. She had normal glycemic control and no evidence of other endocrine disorders. She had not reached menarche, and she had normal features of maturation. However, at the time of her first evaluation, she was at or above the 95^th percentile for body mass index (BMI) for her age. She also was above the 95th percentile for height for her age, although abdominal adiposity was noted by several clinicians.

JF returned to our clinic after 3 months with a weight loss of 7 pounds and continued improvements in her lipid profile (Table 1, 8/6/2009). Over time, she has had gradual improvements in body morphology and lipid parameters with continued dietary counseling from our dietitian (author Fran Burke, MS, RD). Now 13, JF has been able to maintain normal lipid levels with fairly minimal restriction and without pharmacotherapy (Table 1, Overall, her cardiometabolic status has improved, though we have counseled the family about the expected challenges as she enters her adolescent years and begins to exert her independence.

Discussion
Type III hyperlipoproteinemia, also known as dysbetalipoproteinemia or remnant removal disease, is a rare disorder (prevalence ~1/10,000) characterized by significant increases in cholesteryl-ester-enriched VLDL, intermediate density lipoprotein (IDL) and chylomicron remnants, with relatively low levels of low-density lipoprotein (LDL). The diagnosis should be suspected when there are high levels of both total cholesterol (TC) and triglycerides (TG), typically >300 mg/ dL. Directly measured VLDL-C: TG ratio should exceed 0.3 (normal <0.15). In addition, direct LDL-C will be significantly lower than calculated LDL-C because of generalized assumptions about VLDL built into the Friedewald formula that do not hold in this condition.

The disorder usually is caused by a pairing of variant apoE alleles that affect normal catabolism of TG-rich lipoproteins. There are three common alleles in the population, with a frequency of ε3 > e4 > ε2; the most common apoE phenotype is E3/E3. The E2/E2 combination is most commonly associated with type III hyperlipoproteinemia. The E2/E2 phenotype leads to an apoE that has a lower affinity for the triglyceride-rich lipoprotein receptors, which results in the accumulation of partially catabolized cholesteryl-ester-enriched remnant particles. In addition, there is enhanced clearance of LDL particles. This background apoE phenotype is felt to be necessary, but not sufficient, to manifest type III, and a second hit is considered necessary to trigger the clinical presentation. The second hit generally results in increased production of TG-rich lipoproteins, which then overwhelm the catabolic mechanisms. Weight gain, hypothyroidism, pregnancy, diabetes and particular medications are common triggers (Table 2). Accumulation of highly atherogenic remnant particles predisposes a patient to the development of atherosclerosis, and these individuals have a higher-than-expected risk of developing atherosclerotic cardiovascular disease, especially peripheral arterial disease. Dermatologic manifestations are not uncommon and often herald the condition. While cutaneous xanthomas are orange creases in the palms are considered to be pathognomonic. In most cases, type III does not present clinically until the end of the second decade and tends to be present in men earlier than women, often not until after menopause in women.

Our patient had the classic physical exam findings and lipid profile. Subsequent ultracentrifugation with direct measurement of LDL-C and VLDL-C confirmed the lipid phenotype of remnant disease and, ultimately, the E2/E2 genotype was confirmed. There was a high suspicion for this mutation in our patients and, given the concern about uncovering apoE4 (a potent risk factor for Alzheimer’s disease), family counseling was undertaken prior to this testing. In fact, the authors all agree that this possibility is an important enough concern that apoE genotyping should be reserved to confirm a strong clinical suspicion for type III hyperlipoproteinemia and not for broader screening purposes. At our center, our laboratory reports the findings as either apoE2/E2 positive or negative, to avoid providing information about E4 that is not directly related to the present condition.

Treatment of type III entails identification of the second hit and correction, if possible, as well as dietary recommendations and lipid-lowering medication. The medical literature on type III consists mostly of case series, and fibric acid derivatives have been the most commonly tested therapy, offering good results. Combination therapy with statin drugs is reasonable after dietary modification, even though the LDL-C levels can be quite low, as with our patient. Other treatment includes niacin or omega-3 fatty acids in high doses. It should be noted that the safety and efficacy of fibrates has not been evaluated in children. Cardiovascular risk should decrease with correction of the hyperlipidemia and, as we saw in JF, the cutaneous eruptions completely resolve, including the orange palmar creases.

For our young female patient, the disorder likely presented at a very early age because of adiposopathy, or excess body fat, and a nutrient-poor diet. Fortunately, diet and lifestyle interventions can lead to a dramatic improvement in type III hyperlipoproteinemia, as seen in JF. If a patient is overweight, weight loss should be recommended. From a dietary standpoint, calories derived from saturated fat should be minimized; whole foods and unprocessed diets are favored. Specific dietary intervention for high TG can be complicated by the distinction between excess chylomicron versus VLDL remnant particles. Certainly, type III can be the result of both chylomicron and VLDL remnants, and the relative response to diet and specific dietary quality may have to take into account the relative responsiveness to reduced fat versus reduced calorie/simple carbohydrate for each individual. In this case, the replacement of heavily processed "junk" food with whole foods, increased consumption of fresh fruits and vegetables, lean cuts of meat, whole grains and vegetable oils, all led to the improvements seen.

JF is a very active young girl but had significant abdominal adiposity. As a result of the combination of an inherited predisposition and unhealthy dietary habits, she developed a very uncommon hyperlipoproteinemia with potentially very serious consequences and a disfiguring skin reaction. Improvement in the quality of her diet resulted in normalization of her body morphology, improvement in the skin manifestations and normalization of her lipid parameters. She is not very verbal during our office visits, so it is difficult to gauge how committed she is as she enters adolescence. It has been a struggle convincing her mother that the entire family has to eat the same diet as a critical step in improving the family’s overall health, but also to normalize the dietary intervention for JF. We have counseled her mother that, in addition to all of the normal struggles of adolescence, this adds another layer of complexity and medical need. We will continue to see JF regularly, reinforcing the need for active engagement in a healthy lifestyle and modeling of this behavior by her mother. Hopefully, JF's rare condition can be controlled long-term without the need for pharmacotherapy by maintaining a healthy diet and normal body weight.

Disclosure statement: Dr. Soffer has received honorarium from Aegerion, Potomac CME, ACP Pier, and MD Consult. He has served as a local subinvestigator for clinical trials for Amgen, Sanofi, Regeneron and Novartis. Dr. Duffy has received honoraria from Genzyme, and research grants from Amgen and Forest Laboratories. Ms. Burke has no disclosures to report. Ms. Ross has received honoraria from Abbott Laboratories, Genzyme, Kowa Pharmaceuticals, AstraZeneca and Practice Point.