Introduction
Many causes of hypertriglyceridemia are either acquired or genetic. One uncommon genetic cause is broad-beta disease, or dysbetalipoproteinemia (type III hyperlipidemia). This disease is associated with the apolipoprotein E2/E2 or, occasionally, the E2/E3 phenotype. It is characterized by an increase in intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL), and chylomicron remnants. Sometimes, an additional “hit” is needed to unmask the hyperlipidemia. The second hit is often another disease process or the side effect from a drug. We recently saw a patient at the University of Colorado lipid clinic who most likely had type III hyperlipidemia unmasked by her autoimmune liver disease. Her case required some thoughtful investigation.
Case Presentation
RC is a 47-year-old woman with primary biliary cirrhosis (PBC) who was referred to our lipid clinic for severe hyperlipidemia. One year after her diagnosis of PBC she developed a severe and progressive pruritus, refractory to ursodiol, cholestyramine, sertraline, rifampin, and steroids. She was referred to our hepatology department in 2011 for a liver transplant. Laboratory results from her initial evaluation are summarized in Table 1.
In 2012, she developed symptomatic palmar xanthomas and tuberoeruptive xanthomas of her elbows and knees. A fasting lipid panel was obtained (Table 2) and showed severe hypertriglyceridemia and hypercholesterolemia.
It was noted on our initial evaluation that the patient had no past medical history other than her severe PBC. She had been on an oral contraceptive pill (OCP) for many years. She had no known history of elevated lipids and, in fact, had a normal lipid panel documented in both 2005 and 2006 (while on an OCP). Her brother did have type 1 diabetes and a history of hypertriglyceridemia with levels in the 1,000 mg/dL range. She denied excessive alcohol consumption. On physical exam, her BMI was 26.9 kg/m2 and vital signs were all normal. She was jaundiced. Numerous palmar and tuberoeruptive xanthomas were noted, with surrounding excoriations and bleeding. Her physical exam was otherwise unremarkable. At the time of this evaluation, she was only taking ursodiol, anti-pruritics, and an OCP.
She was initially diagnosed with lipoprotein X as a consequence of her liver disease, but there was a suspicion that she also had an underlying genetic syndrome leading to her profound hypertriglyceridemia and hypercholesterolemia. Lipoprotein (a) and lysosomal acid lipase levels were both found to be normal; the latter test excluded adult cholesterol ester storage disease. Her apolipoprotein (Apo) B level was elevated at 267 (normal 55-125 mg/dL), which confirmed that her hyperlipidemia was not all the result of lipoprotein X. Low-dose bile acid sequestrants were re-initiated in addition to 4 grams of lovaza. Her OCP was held. Once the elevated Apo B level was noted, atorvastatin 20mg daily was added to her regimen. One month later in follow-up, her triglyceride level had decreased to 377 mg/ dL. Her total cholesterol level remained elevated at 1,220 mg/dL. With the improvement in her hypertriglyceridemia, we felt more comfortable aggressively treating her hypercholesterolemia with higher doses of bile acid sequestrants.
The diagnosis of type III hyperlipidemia was considered because of the patient’s palmer and tuberoeruptive xanthomas, history of normal lipid levels, and no family history of premature heart disease. Further testing showed an abnormal genotype of Apo E3/E2. A thorough evaluation showed no second “hit” to explain the hypertriglyceridemia, because thyroid and renal function were normal and she had no evidence of diabetes.
She had no recent weight gain or change in diet/activity level. She was not post- menopausal. She was on an OCP but had several normal lipid panels in the past while she was on this medication. Thus, we believe her primary biliary cirrhosis itself may have been the second hit that led to the clinical manifestation of her type III hyperlipidemia. Alternatively, it may have been the pharmacologic therapy of her severe pruritus that precipitated the hypertriglyceridemia.
At her six-month follow-up visit, a remarkable improvement in her lipid panel was noted. Her xanthomas resolved. Her total cholesterol level was measured at 208 mg/dL and triglyceride level was 119 mg/dL. Her HDL level was measurable at 80 mg/dL and her LDL was 104 mg/dL.
An Apo B level was found to be normal at 66 mg/dL. She had gained some weight and had an overall better sense of well- being. Surprisingly, her biliary cirrhosis also improved spontaneously and she had normal bilirubin levels. Her alkaline phosphate level was still elevated but was lower at 381 IU/L. A coronary calcium scan showed a calcium score of 0. The patient has recently undergone a successful live donor liver transplant and we expect that both her lipoprotein X and type III hyperlipidemia also will resolve.
Discussion
Type III hyperlipidemia is a genetic disorder resulting in the accumulation of remnant particles stemming from a defective Apo E, resulting in an elevated cholesterol and triglyceride level.1 The disease is caused by defective forms of
Apo E that ineffectively bind to lipoprotein receptors, leading to accumulation of chylomicron and VLDL remnants. Normal apolipoprotein is E3/E3 and the most common mutation is E2. Interestingly, homozygotes with Apo E2/E2 do not always develop hypertriglyceridemia. This highlights the important role a “second hit” plays in the clinical manifestation of this disease. Common precipitants of hypertriglyceridemia include type 2 diabetes, hypothyroidism, renal failure, obesity, alcohol intake, and pregnancy. Many medications also are known to precipitate hypertriglyceridemia, including oral contraceptives, corticosteroids, tamoxifen, select antihypertensives, isotretinoin, bile acid binding resins, cyclophosphamide, antiretroviral regimens, and psychotropic medications.2
Our patient was on an oral contraceptive but had a previously normal lipid profile on this medication, so we do not believe it is the “second hit” that caused the clinical manifestation of her disease. To the best of our knowledge, the association between type III hyperlipidemia and primary biliary cirrhosis has never been described. The striking improvement of our patient’s lipid profile that correlated with the spontaneous improvement in her biliary cirrhosis has led us to suspect that her PBC was the factor that unmasked her type III hyperlipidemia. Severe hypertriglyceridemia has been described with systemic lupus erythematosus (SLE).3 Some speculate that systemic inflammation may lead to disordered lipolysis and hypertriglyceridemia in SLE.2
Additionally, autoimmune hyperlipidemia has been described. We postulate that the same mechanism may have precipitated the hypertriglyceridemia in our patient. Alternatively, it may have been the combination of medications used to treat her pruritus that was the “second hit” that unmasked her type III hyperlipidemia.
Our patient was heterozygous for the Apo E mutation with an E2/E3 genotype. Although a high E2/E2 genotype prevalence has been reported in patients with clinical manifestations of type III hyperlipidemia, it has been shown in certain populations that E2/E3 is the prevalent genotype and that heterozygotes also manifest the disease.4
Additionally, the hypertriglyceridemic effect of a single E2 allele has been shown in a meta-analysis in which triglyceride levels were higher in Apo E2/E3 vs. Apo E3/E3.5
We also believe our patient had an element of lipoprotein X (Lp-X). Her degree of hypercholesterolemia was out of proportion to the elevation of her Apo B level (Apo B level of 267 mg/ dL with a simultaneous total cholesterol level of 1,765 mg/dL). Unfortunately, we did not directly measure lipoprotein X levels in this patient. Lp-X is seen in patients with severe cholestasis and consists of an albumin core with Apo C on the surface. Unlike LDL, Lp-X does not contain Apo B and it is not removed by the LDL receptor (therefore, Apo B levels are usually in the normal range if Lipoprotein X is the primary abnormality). Statins are not effective in the treatment of this disease, so bile acid resins and plasmapheresis (not LDL-apheresis) are the cornerstones of therapy.6 We initiated bile acid resins in this patient but used very conservative dosing until her hypertriglyceridemia resolved. In contrast to type III hyperlipidemia, Lp-X is usually not associated with premature coronary disease and some believe it may even have anti-oxidant LDL activity. Our patient had a negative coronary calcium score and it may have been the development of Lp-X that protected against the coronary atherosclerosis usually seen with elevated Apo B levels.
In summary, we presented an interesting case of type III hyperlipidemia unmasked by biliary cirrhosis with rather severe hypertriglyceridemia and hypercholesterolemia. This case illustrates the complexities in the diagnosis and management of dual lipid disorders and the importance of the identification of a “second hit” in type III hyperlipidemia.
Disclosure statement: Dr. Maturu has no disclosures to report. Dr. Forman has no disclosures to report. Dr. Falko has received consultant fees from Kowa Pharmaceuticals, AstraZeneca, and Merck and Co. He’s received speaker honoraria from Kowa Pharmaceuticals, Merck and Co., and Aegerion. Dr. Falko was also on the advisory board for AstraZeneca.
References are listed on page 34 of the PDF.