Treatment of Severe Hypercholesterolemia in a Woman With Advanced Primary Sclerosing Cholangitis

Abstract

A 30-year-old woman was diagnosed with primary sclerosing cholangitis (PSC) during pregnancy at age 25 years. She was normocholesterolemic prior to the diagnosis of PSC (total cholesterol [TC], 188 mg/dL [to convert to millimoles per liter, multiply by 0.0259]). Following the diagnosis of PSC, she developed moderate hypercholesterolemia (representative TC, 256 mg/dL). She first noted the appearance of periorbital xanthelasmata 2 years after PSC diagnosis (Figure 1A). Approximately 6 months prior to referral, she developed marked worsening of biliary obstruction, deterioration of liver function, and clinical jaundice (aspartate aminotransferase, 145 U/L; alanine aminotransferase, 111 U/L; alkaline phosphatase, 726 U/L; and bilirubin, 6.7mg/dL), and she noted palmar xanthomata in the creases of her palms and fingers (Figure 1B).At the time of referral, she had severe hypercholesterolemia (TC, 832 mg/dL; triglycerides, 114 mg/dL [to convert to millimoles per liter, multiply by 0.0113]; and high-density lipoprotein cholesterol, 18 mg/dL; low-density lipoprotein cholesterol was not calculated). Medications at the time of referral were 1000 mg per day of ursodeoxycholic acid and 2 g of colestipol twice daily for symptomatic relief of pruritus. The majority of TC (719 mg/dL) consisted of free cholesterol (518 mg/dL) instead of the usual esterified cholesterol. Serum phospholipids levels were high (1186 mg/dL), while triglycerides were normal (97 mg/dL). Fast protein liquid chromatography analysis of serum lipoproteins, after ultracentrifugation to remove very-low-density lipoprotein, indicated the unique composition and distribution of lipid classes in a special form of dyslipidemia known as lipoprotein X (LpX), ie, high unesterified cholesterol and phospholipids in large lipid-containing particles. Based on results of analysis of genomic DNA in a custom targeted lipid gene resequencing panel, she had no rare mutations in 25 genes known to be associated with abnormal lipid traits (including LDLR, APOB, PSCK9, LDLRAP1, APOE, ABCG5, ABCG8, LIPA, and STAP1) and had APOE E3/E3 genotype. 1

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

“…We report our clinical and research experience with LipidSeq, a targeted hybrid panel designed for clinical resequencing of genomic loci known to be associated with dyslipidemia and related metabolic traits and disorders. Since 2014, the results from this panel have contributed to 39 publications reporting original scientific findings, including seven on FH [32,43,44,[46][47][48][49], seven on hypertriglyceridemia [42,45,[50][51][52][53][54], four on extremes of HDL cholesterol [39,[55][56][57], and 21 case reports [40,41,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. We have published an additional 15 reviews and methods articles related to this work [4, 5, 7, 11-13, 20, 34, 77-83].…”

“…As well, we diagnosed several patients whose severe hypertriglyceridemia was due to subclinical undiagnosed partial lipodystrophy [59], which altered monitoring and management. Other examples of positive clinical outcomes from use of LipidSeq include: 1) ending the protracted diagnostic odyssey endured by some patients [72,74,75]; 2) increasing the diagnostic yield in MODY diabetes by~6% through simultaneous screening for CNVs [40,76]; 3) switching some patients with GCK CNVs (diagnosed with MODY2) from insulin to oral hypoglycemic agents [40]; 4) diagnosing sitosterolemia in patients who were initially diagnosed with homozygous FH, resulting in a dramatic change in management [48]; and 5) ruling out genetic contributions in several patients with severe dyslipidemias due to secondary causes [52,60,65].…”

Use of therapeutic plasma exchange to remove lipoprotein X in a patient with vanishing bile duct syndrome presenting with cholestasis, pseudohyponatremia, and hypercholesterolemia: A case report and review of literature

“…[1][2][3] Lp-X can be observed in up to 45% of patients with liver dysfunction and cholestasis. 1,2,[4][5][6][7][8][9][10][11][12][13][14][15] Although rare, it can be also seen in pregnancy, 16 graft vs host disease, 15,17 or lecithincholesterol acyltransferase deficiency. [18][19][20] Lp-X is produced when extra-and/or intra-hepatic cholestasis occurs, causing bile lipoprotein to reflux into the circulation and bind to albumin to form Lp-X.…”

“…Lipoprotein X (Lp‐X) is an abnormal lipoprotein which is a spherical particle 50 to 70 nm in diameter with a high content of phospholipid (66% by weight) and unesterified cholesterol (22% by weight) 1‐3 . Lp‐X can be observed in up to 45% of patients with liver dysfunction and cholestasis 1,2,4‐15 . Although rare, it can be also seen in pregnancy, 16 graft vs host disease, 15,17 or lecithin‐cholesterol acyltransferase deficiency 18‐20 .…”