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The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD.

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cam.issuedOnline2018-10-11
dc.contributor.authorCarter, Anna
dc.contributor.authorBrackley, Simon Mark
dc.contributor.authorGao, Jiali
dc.contributor.authorMann, Jake Peter
dc.contributor.orcidMann, Jake [0000-0002-4711-9215]
dc.date.accessioned2018-12-05T00:31:05Z
dc.date.available2018-12-05T00:31:05Z
dc.date.issued2019-01
dc.description.abstractBACKGROUND & AIMS: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect 1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate the prevalence of LAL-D using analysis of genetic variation in LIPA. METHODS: MEDLINE and EMBASE were systematically searched for previously reported disease variants and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D and CESD were calculated using the Hardy-Weinberg equation. RESULTS: Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per 160,000 (95% CI 1 per 65,025-761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which 32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672-366,865). Wolman disease was associated with more loss-of-function variants than CESD. When this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467-210,683) with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian, South Asian, and Finnish ancestry. CONCLUSION: Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the therapeutic capability of sebelipase alpha, investigation for LAL-D might be included in second-line metabolic screening in NAFLD. LAY SUMMARY: Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause severe liver disease, but it is difficult to diagnose and sometimes can look like simple fatty liver. It was not clear how common LAL-D was and whether many cases were being missed. To study this, we searched for all genetic mutations that could cause LAL-D, calculated how common those mutations were, and added them up. This let us estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is a very rare condition, but it is treatable so may be included in a 'second-line' of tests for causes of fatty liver.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.33632
dc.identifier.eissn1600-0641
dc.identifier.issn0168-8278
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286322
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.jhep.2018.09.028
dc.subjectDyslipidaemia
dc.subjectEpidemiology
dc.subjectHepatic steatosis
dc.subjectLysosomal storage disease
dc.subjectMeta-analysis
dc.subjectDNA Mutational Analysis
dc.subjectDiagnosis, Differential
dc.subjectGene Frequency
dc.subjectGlobal Health
dc.subjectHumans
dc.subjectLiver
dc.subjectMutation
dc.subjectNon-alcoholic Fatty Liver Disease
dc.subjectPrevalence
dc.subjectRare Diseases
dc.subjectSterol Esterase
dc.subjectWolman Disease
dc.titleThe global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD.
dc.typeArticle
dcterms.dateAccepted2018-09-27
prism.endingPage150
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameJ Hepatol
prism.startingPage142
prism.volume70
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1016/j.jhep.2018.09.028

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