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Mild form of lysosomal acid lipase deficiency mimics NAFLD

Prevalence screening for lysosomal acid lipase deficiency and its mild form that can mimic nonalcoholic fatty liver disease showed that it is an “ultra-rare” disorder but may warrant investigation in second-line metabolic screening.

“Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutations in LIPA that manifest as a spectrum of liver disease and dyslipidemia,” Anna Carter, from the Manchester University Foundation Trust, and colleagues wrote. “It is regarded as a rare disorder however recognition of more mild forms of the condition have led to the suggestion that it may represent a significant proportion of patients presenting with nonalcoholic fatty liver disease (NAFLD).”

According to the researchers, the mild form of LAL-D known as cholesteryl ester storage disease (CESD) mimics NAFLD and may affect up to one in 40,000 but is often underdiagnosed in NAFLD clinics. To estimate the prevalence of LAL-D, they focused on genetic variations in LIPA.

The systematic review comprised 194 studies. All genetic studies used sequencing for c.894G>A in LIPA to generate a pathogenic allele frequency.

Meta-analysis of these studies showed a pooled allele frequency of 0.0015 (95% CI, 0.001-0.002). The researchers assumed that c.894G>A accounted for 60% of all CESD mutations in this case, which would correspond with a prevalence for CESD of one per 160,000 (95% CI, 65.025-761,652) and a carrier frequency of one per 400 (95% CI, 255-873).

After the researchers pooled previously reported disease variants with identified unreported variants, they found a global mutant allele frequency of 0.0024 (95% CI, 0.0022-0.0026) for a LAL-D prevalence at birth of one per 177,452 (95% CI, 149,467-210,683) and a heterozygous carrier rate of one per 421 (95% CI, 387-459).

Analysis of ethnicity showed a higher prevalence in individuals of non-Finnish European ancestry with one per 103,286, whereas the lowest prevalence of LAL-D was in East Asia, Finland, South Asia, and those of Ashkenazi Jewish ancestry.

“Through comprehensive analysis of genetic variation in LIPA we have expanded our recognition of disease-causing mutants to 120 variants. LAL-D is an ultrarare disease, even in its late-onset form as CESD, and these data can help reassure clinicians that LAL-D is unlikely to represent a significant proportion of patients presenting with NAFLD,” Carter and colleagues wrote. “A consensus is needed for when testing LAL activity should be performed in patients with dyslipidemia or hepatic steatosis.” – by Talitha Bennett

Disclosure: The authors report no relevant financial disclosures.