Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis

Brandt, Eric; Regnier, S.; Leung, Edward Ky; Chou, Sharon H.; Baron, Beverly W.; Te, Helen S.; Davidson, Michael; Sargis, Robert M.

doi:10.2217/clp.15.23

Cited by 19 publications

(30 citation statements)

References 39 publications

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“…Lp‐X from cholestasis has been clearly shown to cause severe xanthomas, which can be quite disfiguring, particularly in Allagile syndrome and is due to the uptake of Lp‐X by dermal macrophages . The pathogenesis is not well understood, but Lp‐X has also been implicated in neuropathy, which can sometimes develop in patients with longstanding cholestasis . Another potential indication for developing a treatment to lower Lp‐X in cholestasis is hyperviscosity syndrome .…”

Section: Discussionmentioning

confidence: 99%

“…Oral lipid‐reducing medications, such as statins, and fibrates, have been tried to lower Lp‐X in cholestasis, but they are usually ineffective . Besides treating the underlying cause of cholestasis, the only effective treatment to lower Lp‐X is plasma exchange . It can acutely lower Lp‐X, leading to the normalization of alkaline phosphatase, total bilirubin and AST.…”

Section: Discussionmentioning

confidence: 99%

“…23 The pathogenesis is not well understood, but Lp-X has also been implicated in neuropathy, which can sometimes develop in patients with longstanding cholestasis. 8 Another potential indication for developing a treatment to lower Lp-X in cholestasis is hyperviscosity syndrome. 27 Some cholestatic patients can develop such high levels of Lp-X that it can increase the viscosity of plasma to such a degree that it impedes blood flow and can precipitate life-threating strokes.…”

Section: Discussionmentioning

confidence: 99%

“…51 Besides treating the underlying cause of cholestasis, the only effective treatment to lower Lp-X is plasma exchange. 8 It can acutely lower Lp-X, leading to the normalization of alkaline phosphatase, total bilirubin and AST. Based on the results of this study, rhLCAT, which has been shown to be safe in early stage clinical trials, 21,22 could also be a potential therapy.…”

Section: Discussionmentioning

confidence: 99%

“…3 It is most readily identified by agarose gel electrophoresis, because it migrates toward the cathode, whereas normal lipoproteins migrate toward the anode. 4,5 Lp-X has been reported in patients with both extrahepatic and intrahepatic obstructive type liver diseases, such as obstructive jaundice from gallstones, 6 primary biliary cirrhosis, 7 sclerosing cholangitis, 8 intrahepatic cholestasis of pregnancy, 9 and alcoholic hepatitis. 10 It can also occur in children with a genetic abnormality in the development of the liver, such as biliary atresia 11 and Allagile Syndrome.…”

Section: Introductionmentioning

confidence: 99%

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LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

Amar

Freeman

Nishida

et al. 2019

Pharmacology Res & Perspec

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Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp‐X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp‐X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp‐X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT‐deficient (KO), wild type (WT), and LCAT‐transgenic (Tg) mice by gavaging mice with alpha‐naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT‐Tg mice, however, prevented the formation of Lp‐X and other plasma lipid abnormalities in WT and LCAT‐KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp‐X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp‐X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp‐X in other diseases besides FLD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

Amar

Freeman

Nishida

et al. 2019

Pharmacology Res & Perspec

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

2017

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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

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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

Jung,

Nelson,

Lin

2024

J of Clinical Apheresis

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IntroductionLipoprotein X (Lp‐X) is an abnormal lipoprotein found in multiple disease conditions, including liver dysfunction and cholestasis. High Lp‐X concentrations can interfere with some laboratory testing that may result in spurious results. The detection of Lp‐X can be challenging, and there is currently a lack of consensus regarding the management of Lp‐X other than treating the underlying disease.Case PresentationA 42‐year‐old female with Hodgkin's lymphoma treated with dexamethasone, high dose cytarabine and cisplatin and vanishing bile duct syndrome confirmed by liver biopsy presented with cholestasis, pseudohyponatremia (sodium, 113 mmol/L; reference range 136–146 mmL/L; serum osmolality, 303 mOsm/kg), and hypercholesterolemia (> 2800 mg/dL, reference range < 200 mg/dL). Lp‐X was confirmed by lipoprotein electrophoresis (EP). Although she did not manifest any specific signs or symptoms, therapeutic plasma exchange (TPE) was initiated based on laboratory findings of extreme hypercholesterolemia, spuriously abnormal serum sodium, and HDL values, and the potential for short‐ and long‐term sequelae such as hyperviscosity syndrome, xanthoma, and neuropathy. During the hospitalization, she was treated with four 1.0 plasma volume TPE over 6 days using 5% albumin for replacement fluid. After the first TPE, total cholesterol (TC) decreased to 383 mg/dL and sodium was measured at 131 mmol/L. The patient was transitioned into outpatient maintenance TPE to eliminate the potential of Lp‐X reappearance while the underlying disease was treated. Serial follow‐up laboratory testing with lipoprotein EP showed the disappearance of Lp‐X after nine TPEs over a 10‐week period.Literature ReviewThere are seven and four case reports of Lp‐X treated with TPE and lipoprotein apheresis (LA), respectively. While all previous case reports showed a reduction in TC levels, none had monitored the disappearance of Lp‐X after completing a course of therapeutic apheresis.ConclusionClinicians should have a heightened suspicion for the presence of abnormal Lp‐X in patients with cholestasis, hypercholesterolemia, and pseudohyponatremia. Once Lp‐X is confirmed by lipoprotein EP, TPE should be initiated to reduce TC level and remove abnormal Lp‐X. Most LA techniques are not expected to be beneficial since Lp‐X lacks apolipoprotein B. Therefore, we suggest that inpatient course of TPE be performed every other day until serum sodium, TC and HDL levels become normalized. Outpatient maintenance TPE may also be considered to keep Lp‐X levels low while the underlying disease is treated. Serum sodium, TC, and HDL levels should be monitored while on maintenance TPE.

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Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis

Cited by 19 publications

References 39 publications

LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

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

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

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