Rare Disease Report

Lipoprotein-X Does Not Increase Atherosclerosis Risk In Child With Primary Sclerosing Cholangitis

JUNE 12, 2015
Lorraine L. Janeczko, MPH

In children with primary sclerosing cholangitis (PSC), the abnormal lipoprotein-X (LP-X) may lead to marked hypercholesterolemia, considered to be a risk factor for atherosclerosis.
The role of LP-X in atherogenesis is unclear, but it does not appear to increase the risk of atherosclerosis and, according to some researchers, elevated LP-X may reduce that risk1 and remove the need for lipid-lowering therapy. 
Primary sclerosing cholangitis is a rare, chronic, autoimmune hepatobiliary disease with cholestasis and diffuse inflammation and fibrosis of the intra- and extra-hepatic bile ducts. In PCS, the backflow of cholesterol, normally excreted by the liver with bile acids, joins with albumin to become LP-X. LP-X has a density range similar to that of low-density lipoprotein cholesterol (LDL-C), and helps elevate hypercholesterolemia in patients with cholestasis.
Patients with PSC often have ulcerative colitis that progresses to cirrhosis. Immune suppressive and modulating therapies may slow the progression but most patients eventually require a liver transplant.
While LP-X and hypercholesterolemia have mainly been reported in association with primary biliary cirrhosis in adults, lead study author Amol Patel, a student at the Texas College of Osteopathic Medicine in Fort Worth, and colleagues studied a 3-year-old boy with LP-X and severe hypercholesterolemia associated with PSC. The authors presented their case study in a poster at the National Lipid Association Scientific Sessions, June 10-14, 2015, in Chicago, Illinois.  
In an interview with Rare Disease Report, senior author Don P. Wilson, MD, of Cook Children's Medical Center in Fort Worth, said:
“Few, if any, children with PSC have been reported with severe hypercholesterolemia. We hope that our study will increase awareness of this disorder. Once the mechanisms of the disease are understood, the finding of hypercholesterolemia is not surprising. The proposed lack of atherogenicity, however, is surprising and, as yet, unproven in humans.”
The boy was being seen in the clinic for hypercholesterolemia. He was alert and developmentally normal, but his height and weight were below average for his age and sex. He did not seem to be in acute distress, but within the past 2 months he had developed xanthomas on his elbows and knees. His abdomen had been distended for the past 1.5 years, but he was eating normally and was otherwise healthy.
His stools had recently become pale, and he was feeling itchy. An initial fasting lipid profile showed normal triglycerides (47 mg/dL) but severely elevated total (>650 mg/dL) and LDL (510 mg/dL) cholesterol. He had hepatomegaly and mild scleral icterus.
The boy’s clinical, laboratory, and histology results indicated that he had primary sclerosing cholangitis. His liver function studies were greatly elevated: alanine aminotransferase (ALT) 810 U/L; aspartate aminotransferase (AST) 820 U/L; gamma-glutamyltransferase (GGT) 606 U/L; and alkaline phosphatase 1373 U/L. His total and direct bilirubin were high (2.9 mg/dL and 2.3 mg/dL, respectively).
Hepatitis A, B, and C antibodies were negative; an autoimmune panel was positive for antinuclear antibody (ANA), human epithelial type 2 (HEp-2), filamentous actin (F-actin) immunoglobulin G (IgG) antibody, liver/spleen microsomal antibodies, and inflammatory bowel disease serology.
The boy’s smooth muscle IgA antibody and thyrotropin (TSH) receptor antibodies were negative; an abdominal ultrasound showed nonspecific hepatosplenomegaly without a mass or fatty infiltration.
A liver biopsy showed advanced fibrosis, regenerative nodules, and periductal “onion skin” fibrosis around the bile ducts. A colon biopsy indicated ulcerative colitis.
According to Dr. Wilson:
“It was important to do this study to create awareness among health care professionals and to explore the need for treatment. The proposed lack of atherogenicity avoids the need for lipid-lowering medications and any potential costs and side effects associated with their use, especially in young children.” 

Because this is a very rare condition, obtaining enough patients within a single center is unlikely. Based upon our report, hopefully others who encounter this disease can help advance our knowledge and improve outcomes.”
“Unfortunately, PSC most often advances to liver failure and the need for a liver transplant. Although the procedure saves lives, long-term transplantation is associated with increased risk of premature cardiovascular disease. Therefore, patients with successful transplantation need to be followed with this risk in mind.”
The abstract of this poster won the first-place Young Investigator Award.

Clinical Pearls:
LP-X Properties That Indicate Possible Anti-Atherogenesis:2 

  • LP-X inhibits LDL-C particle oxidation and prevents oxidized LDL from altering homeostatic mechanisms in vascular endothelial cells.
  • LP-X lacks apolipoprotein B, the ligand that binds to LDL receptors to deliver cholesterol to tissues.


1. Chang P-Y, Lu S-C, Su T-C, et al. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation [published online August 16, 20014]. J Lipid Res. 2004;45(11):2116-2122. doi: 10.1194/jlr.M400229-JLR200.  http://www.jlr.org/content/45/11/2116.long
2. Patel AM, Wilson DP, de laTorre A, Brautbar A.  A 3-year-old with severe hypercholesterolemia. Presented at: the National Lipid Association Scientific Sessions 2015; June 11-14, 2015; Chicago, IL. Abstract 143.

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