Lipoprotein-X Accumulation: A Mimic of Familial Hypercholesterolemia

Focus on Cardiometabolic Risk

ABSTRACT: Elevated low-density lipoprotein cholesterol in familial hypercholesterolemia represents an important cardiovascular risk factor in the pediatric population. This case demonstrates a condition that mimics homozygous familial hypercholesterolemia on a standard lipid profile yet carries none of the associated cardiovascular risk. Lipoprotein-X accumulation should be in the differential when evaluating hypercholesterolemia in children with hepatobiliary conditions.

Lipid disorders occur in 20.3% of youth aged 12 to 19 years.¹ Homozygous familial hypercholesterolemia (hoFH) is a rare but severe lipid disorder characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) of 500 to 1000 mg/dL and caused by gene mutations in both LDL receptor alleles, precluding normal clearance of circulating LDL-C.² Affected children present with planar, tuberous, and tendinous xanthomas and experience rapid progression to atherosclerosis and premature cardiovascular disease.³

We present a case of extreme cholesterol elevation attributed on a standard lipid profile to LDL-C at levels consistent with and mimicking hoFH. The presentation was atypical, however, because of coincident hyperbilirubinemia due to worsening cholestasis with hypertriglyceridemia. Discrepancy between the levels of apolipoprotein B-100 and LDL-C in the presence of acute cholestasis pointed instead to the diagnosis of lipoprotein-X (LP-X) accumulation.

CASE

A 6-year-old girl, status post liver transplantation at 8 months of age for extrahepatic biliary atresia, presented with jaundice and pruritus. Her current medications included tacrolimus, sirolimus, hydroxyzine, valganciclovir, prednisone, and ursodiol.

On examination, the child appeared jaundiced and her sclerae were icteric. She was afebrile with a heart rate of 78 beats per minute, respiration rate of 20 breaths per minute, and blood pressure of 106/70 mm Hg. Her body mass index was 18 (87th percentile). Her abdomen was soft, and the liver was palpable 1 cm below the right costal margin. The spleen was not palpable. She had no xanthomas. The remaining examination findings were normal.

Laboratory studies included: total bilirubin, 17.1 mg/dL (normal [nl], < 0.8 mg/dL); conjugated bilirubin, 14.2 mg/dL (nl, < 0.4 mg/dL); alkaline phosphatase (ALP), 491 U/L (nl, 218 to 499 U/L); g-glutamyltransferase (GGT), 467 U/L (nl, 9 to 20 U/L); aspartate aminotransferase (AST), 221 U/L (nl, 5 to 36 U/L); alanine aminotransferase (ALT), 250 U/L (nl, 24 to 49 U/L); total cholesterol, 1501 mg/dL (nl, < 170 mg/dL); LDL-C, 1419 mg/dL (nl, < 110 mg/dL); triglycerides (TG), 369 mg/dL (nl, < 75 mg/dL)²; and high-density lipoprotein cholesterol (HDL-C), 92 mg/dL (nl, > 50 mg/dL).

An ECG and an echocardiogram were normal. Although such drastic LDL-C elevation is characteristic of hoFH, the coincident hypertriglyceridemia, lack of xanthomas, and underlying hepatobiliary disease were all atypical for this condition. Treatment with lipid-lowering agents, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (atorvastatin), and a fibric acid derivative (fenofibrate) was transiently started while her evaluation proceeded.

Past medical history revealed that the child had multiple episodes of acute liver allograft rejections. Importantly, normal levels of total cholesterol (141 mg/dL) and fasting TG (54 mg/dL) were documented 7 months before this presentation of profound hypercholesterolemia. At that time, due to underlying chronic hepatic disease, some liver function enzymes were elevated (ALP, 338 U/L; AST, 131 U/L; ALT, 187 U/L; GGT, 58 U/L); however, total and conjugated bilirubin remained within normal limits at 0.4 mg/dL and 0.1 mg/dL, respectively.

The documentation of a normal lipoprotein profile in the context of hepatic inflammation but stable biliary function argued against a genetic LDL receptor defect and certainly against its homozygous presentation.

Final diagnosis. Further evaluation revealed an apolipoprotein B-100 level of 161 mg/dL (nl, < 90 mg/dL),² which highlighted a marked discrepancy between the elevated LDL-C level (1419 mg/dL) and the level of its signature apolipoprotein, confirming the suspicion that the patient’s severe cholesterol elevation was caused by LP-X accumulation, a unique condition seen with cholestatic liver disease.

Treatment course. Eleven months later, the patient’s cholestatic liver disease showed significant response to modulation of immune therapy. Bilirubin levels had normalized (total bilirubin to 0.4 mg/dL, conjugated bilirubin to 0.2 mg/dL), the ALP level remained in the upper limits of normal (460 U/L), and levels of GGT (97 U/L), AST (91 U/L), and ALT (142 U/L) had decreased. Her lipid profile showed improved levels of total cholesterol (178 mg/dL), LDL-C (86 mg/dL), HDL-C (69 mg/dL), and TG (124 mg/dL) (Figures 1 and 2).

Figure 1 – The lipid profile.

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
All units are mg/dL.

WHAT EXACTLY IS LP-X?

LP-X is a lipoprotein found in children with cholestatic liver disease or lecithin-cholesterol acyltransferase (LCAT) deficiency. Increased serum cholesterol levels have been noted in patients with intrahepatic or extrahepatic biliary obstruction.^4,5 Pierce and Gofman⁶ were the first to describe that the atypical lipoprotein fell within the LDL-C fraction.

The term LP-X emerged in 1969 when the elevated lipoprotein cholesterol in patients with cholestatic liver disease proved immunochemically distinct from both apolipoprotein A and B containing lipoproteins.^7,8 LP-X is characterized by a vesicular structure that consists of a lipid bilayer of 30 to 70 nm and encloses an aqueous compartment. It has an unusually high content of unesterified cholesterol and phospholipids and a low content of cholesterol esters, triglycerides, and protein—the latter being dominated by albumin with a small amount of apolipoprotein C and E but no structural apolipoprotein B.^8,9 Standard lipoprotein ultracentrifugation falsely reports LP-X as LDL-C because of their shared density.^8,9

Figure 2 – The liver enzymes.

ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT , alanine aminotransferase; GGT, g-glutamyltransferase. All units are U/L.

LP-X IN CHOLESTASIS

The pathogenesis of LP-X in cholestasis remains poorly understood. The liver normally excretes lipoprotein complexes with phospholipid and unesterified cholesterol into bile. In vitro incubation of these bile lipoproteins with serum or albumin leads to the appearance of LP-X–like particles, suggesting that bile reflux into the plasma compartment causes LP-X formation in cholestasis.¹⁰ In contrast, lipoprotein particles seen in familial LCAT deficiency are identical to LP-X in cholestasis. Reduced LCAT activity, common in patients with hepatocellular disease may also contribute to LP-X accumulation in cholestasis.^11,12 LP-X is mainly metabolized by the reticuloendothelial system.¹³

ASSOCIATED CONDITIONS

LP-X accumulation can be seen in a variety of conditions causing cholestasis. These include cirrhosis, malignancy, graft versus host disease, a-1 antitrypsin deficiency, infectious hepatitis, biliary obstruction, and drug-induced cholestasis.^14,15 To our knowledge, LP-X accumulation in patients status post liver transplantation with chronic liver allograft rejection has not been reported.

DIAGNOSIS

Elevated LDL-C in familial hypercholesterolemia represents an important cardiovascular risk factor in the pediatric population. This case demonstrates a condition that mimics hoFH on a standard lipid profile yet carries none of the associated cardiovascular risk. LP-X accumulation should be in the differential when evaluating hypercholesterolemia in children with hepatobiliary conditions.

TREATMENT

Compared with LDL-C, LP-X is not thought to be atherogenic. Some advocate treatment with lipid-lowering agents,^16,17 as was done initially in this case, or even plasma LDL-apheresis.¹⁸ Others have questioned this approach because of the absence of any associated increased risk of coronary artery disease in patients with primary biliary cirrhosis and hypercholesterolemia due to LP-X.^16,17

LP-X may even exhibit anti-atherogenic properties.^17,19 Chang and colleagues¹⁹ have suggested that LP-X reduces LDL atherogenicity by preventing LDL oxidation, which protects endothelial cell integrity. When the lipid-lowering medications were discontinued in our patient, the hypercholesterolemia resolved coincident with the resolution of biliary obstruction.n

REFERENCES:

1. Centers for Disease Control and Prevention. Prevalence of abnormal lipid levels among youths — United States, 1999-2006 [published correction appears in MMWR Morb Mortal Wkly Rep. 2010;59(3):78]. MMWR Morb Mortal Wkly Rep. 2010;59(2):29-33.

2. Kwiterovich PO Jr. Recognition and management of dyslipidemia in children and adolescents.
J Clin Endocrinol Metab. 2008;93(11):4200-4209.

3. Alves AC, Medeiros AM, Francisco V, et al. Molecular diagnosis of familial hypercholesterolemia:
an important tool for cardiovascular risk stratification. Rev Port Cardiol. 2010;29(6):907-921.

4. Ahrens EH Jr, Kunkel HG. The relationship between serum lipids and skin xanthomata in 18 patients with primary biliary cirrhosis. J Clin Invest. 1949;28(6, pt 2):1565-1574.

5. Eder HA, Russ EM, Pritchett RA, et al. Protein-lipid relationships in human plasma: in biliary cirrhosis, obstructive jaundice, and acute hepatitis. J Clin Invest. 1955;34(7, pt 1):1147-1162.

6. Pierce FT, Gofman JW. Lipoproteins, liver disease, and atherosclerosis. Circulation. 1951;4(1):
25-28.

7. Seidel D, Alaupovic P, Furman RH. A lipoprotein characterizing obstructive jaundice. I. Method
for quantitative separation and identification of lipoproteins in jaundiced subjects. J Clin Invest. 1969;48(7):1211-1223.

8. Seidel D, Alaupovic P, Furman RH, McConathy WJ. A lipoprotein characterizing obstructive jaundice. II. Isolation and partial characterization of the protein moieties of low density lipoproteins. J Clin Invest. 1970;49(12):2396-2407.

9. Narayanan S. Biochemistry and clinical relevance of lipoprotein X. Ann Clin Lab Sci. 1984;14(5):
371-374.

10. Manzato E, Fellin R, Baggio G, et al. Formation of lipoprotein-X. Its relationship to bile compounds. J Clin Invest. 1976;57(5):1248-1260.

11. Zhu X, Herzenberg AM, Eskandarian M, et al. A novel in vivo lecithin-cholesterol acyltransferase (LCAT)-deficient mouse expressing predominantly LpX is associated with spontaneous glomerulopathy. Am J Pathol. 2004;165(4):1269-1278.

12. Seidel D, Gjone E, Blomhoff JP, Geisen HP. Plasma lipoproteins in patients with familial plasma lecithin: cholesterol acyltransferase (LCAT) deficiency—studies on the apolipoprotein composition of isolated fractions with identification of LP-X. Horm Metab Res. 1974;suppl 4:6-11.

13. Walli AK, Seidel D. Role of lipoprotein-X in the pathogenesis of cholestatic hypercholesterolemia. Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat. J Clin Invest. 1984;74(3):867-879.

14. Zidan H, Lo S, Wiebe D, et al. Severe hypercholesterolemia mediated by lipoprotein X in a
pediatric patient with chronic graft-versus-host disease of the liver. Pediatr Blood Cancer. 2008;50(6):1280-1281.

15. Diliberti JH, McMurry MP, Connor WE, Alaupovic P. Hypercholesterolemia associated with alpha-1 antitrypsin deficiency and hepatitis: lipoprotein and apoprotein determinations, sterol balance and treatment. Am J Med Sci. 1984;288(2):81-85.

16. Sorokin A, Brown JL, Thompson PD. Primary biliary cirrhosis, hyperlipidemia, and atherosclerotic risk: a systematic review. Atherosclerosis. 2007;194(2):293-299.

17. Allocca M, Crosignani A, Gritti A, et al. Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis. Gut. 2006;55(12):1795-1800.

18. Franceschini G, Busnach G, Chiesa G, Sirtori CR. Management of lipoprotein-X accumulation in severe cholestasis by semi-selective LDL-apheresis. Am J Med. 1991;90(5):633-638.

19. Chang PY, Lu SC, Su TC, et al. Lipoprotein-X reduces LDL atherogenicity in primary biliary
cirrhosis by preventing LDL oxidation. J Lipid Res. 2004;45(11):2116-2122.

Authors’ note: Drs Yinn Khurn Ooi, Clarivet Torres, and Ashraf Harahsheh were involved in acquisition of data and drafting of the manuscript. Drs Michele Mietus-Snyder and Parvathi Mohan provided critical revision of the manuscript for important intellectual content.

Disclosure: The authors received no funding for this article and have no institutional or corporate affiliations. They report no conflicts of interest.