Orthotopic Liver Transplantation in an Adult with Cholesterol Ester Storage Disease

Ambler, Graeme K.; Hoare, Matthew; Brais, Rebecca; Shaw, Ashley; Butler, Andrew; Flynn, Paul F.; Deegan, Patrick; Griffiths, William J.

doi:10.1007/8904_2012_155

Cited by 24 publications

(12 citation statements)

References 21 publications

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“…The use of HMG‐CoA reductase inhibitors has been shown to decrease the total serum cholesterol and increase the HDL cholesterol minimizing cholesteryl ester accumulation and thereby cardiovascular morbidity. However, statins do not fully negate the hepatotoxic effect of cholesteryl esters leading to cirrhosis and end‐stage liver disease in those who are at the severe end of the spectrum .…”

Section: Discussionmentioning

confidence: 99%

“…Cirrhosis leading to end‐stage liver failure has been noted in some cases. Adequate pharmacological control of lipid levels may reduce the risk of vascular complications but does not halt the progression of liver disease, and to date, only a few cases of LT have been reported . There are also concerns that extrahepatic manifestations of the disease such as splenomegaly, gastrointestinal involvements, and accelerated atherosclerosis may persist and even progress post‐LT .…”

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confidence: 99%

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Successful long‐term outcome of liver transplantation in late‐onset lysosomal acid lipase deficiency

Sreekantam

Nicklaus-Wollenteit

Orr

et al. 2016

Pediatric Transplantation

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Late-onset LAL deficiency, previously referred to as cholesteryl ester storage disorder, is a rare lysosomal storage disorder characterized by accumulation of cholesteryl esters. It has a heterogeneous clinical phenotype including abdominal pain, poor growth, hyperlipidemia with vascular complications and hepatosplenomegaly. End-stage liver disease may occur, but there are few reports of successful LT. There are also concerns that systemic manifestations of the disease might persist post-LT. We report a case with excellent outcome eight yr following LT. The subject was noted to have asymptomatic hepatosplenomegaly during an intercurrent illness, and LAL deficiency was confirmed with compound heterozygosity in the LIPA. Despite dietary fat restriction, he developed signs of progressive liver disease and subsequently developed hepatopulmonary syndrome. He underwent cadaveric LT at the age of nine and a half yr and recovered with prompt resolution of hepatopulmonary syndrome. Eight yr post-transplant he has normal growth, normal lipid profile, and liver and renal function tests. Liver histology showed no evidence of disease recurrence at this stage. LT in this subject resulted in an excellent functional correction of late-onset LAL deficiency.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Successful long‐term outcome of liver transplantation in late‐onset lysosomal acid lipase deficiency

Sreekantam

Nicklaus-Wollenteit

Orr

et al. 2016

Pediatric Transplantation

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“…This presentation, historically known as cholesteryl ester storage disease, is an under-appreciated cause of liver fibrosis with frequent progression to cirrhosis [2]. LAL D is also associated with evidence of premature atherosclerosis in some cases [3–10]. Clinical diagnosis is challenging due to the prevalence (1:40,000 to 1:300,000 [3,11]) and manifestations that overlap with more common liver/lipid disorders.…”

Section: Introductionmentioning

confidence: 99%

Sebelipase alfa over 52weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

Valayannopoulos

Malinová

Honzík

et al. 2014

Journal of Hepatology

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Background and aims Lysosomal Acid Lipase Deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Methods Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. Results 216 infusions were administered to eight adult subjects through Week 52 during LAL-CL04. At Week 52, mean alanine aminotransferase and aspartate aminotransferase were normal with mean change from baseline of −58% and −40%. Mean change for low density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were −60%, −39%, −36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Conclusions Long-term dosing with sebelipase alfa in Lysosomal Acid Lipase-Deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

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“…Indeed, liver-specific LIPA deficiency is associated with dyslipidemia and increased cholesteryl ester storage [19]. Restoration of LAL activity through virusmediated transduction or transgenics in mouse models of LALD and liver-transplantation in LALD patients has proven beneficial [11,[20][21][22][23][24]. Of course, both gene replacement and liver transplantation create a sustained reservoir of LAL-producing cells, capable of widely distributing enzyme for uptake into all tissues via the mannose-6-phosphate receptor.…”

Section: Discussionmentioning

confidence: 99%

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

Pritchard

Strong

Fıçıcıoğlu

2020

Orphanet J Rare Dis

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Background: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Methods: A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. Results: Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. Conclusion: Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.

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Orthotopic Liver Transplantation in an Adult with Cholesterol Ester Storage Disease

Abstract: Cholesterol ester storage disease (CESD)

Cited by 24 publications

References 21 publications

Successful long‐term outcome of liver transplantation in late‐onset lysosomal acid lipase deficiency

Successful long‐term outcome of liver transplantation in late‐onset lysosomal acid lipase deficiency

Sebelipase alfa over 52weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

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