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

J Hepatol. 2019 Jan;70(1):142-150. doi: 10.1016/j.jhep.2018.09.028. Epub 2018 Oct 11.


Background & 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.

Keywords: Dyslipidaemia; Epidemiology; Hepatic steatosis; Lysosomal storage disease; Meta-analysis.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Gene Frequency
  • Global Health
  • Humans
  • Liver / metabolism
  • Liver / pathology*
  • Mutation
  • Non-alcoholic Fatty Liver Disease
  • Prevalence
  • Rare Diseases
  • Sterol Esterase / genetics*
  • Sterol Esterase / metabolism
  • Wolman Disease / diagnosis
  • Wolman Disease / epidemiology
  • Wolman Disease / genetics*


  • LIPA protein, human
  • Sterol Esterase

Supplementary concepts

  • Lysosomal acid lipase deficiency