Lysosomal acid lipase (LAL) deficiency is an ultra-rare, progressive, autosomal recessive disorder resulting from an inborn error of lipid metabolism at the lysosomal level. It is characterised by the accumulation of cholesteryl esters and triglycerides in different tissues (liver, spleen, intestine, adrenal glands and mononuclear phagocyte system cells).1–3 We describe 2 cases of LAL deficiency diagnosed in childhood with different clinical presentations.

The first case corresponded to a boy aged 22 months referred to the metabolic disorder clinic for evaluation of hepatomegaly, splenomegaly and hypercholesterolaemia with normal liver enzyme levels. The key finding of the abdominal ultrasound scan was hepatomegaly due to fat accumulation and moderate splenomegaly. The evaluation for lysosomal storage disorders did not yield relevant results. Clinical suspicion of LAL deficiency led to performance of a LAL assay in a skin biopsy sample, which revealed substantially reduced enzymatic activity in fibroblasts. Genetic testing confirmed the diagnosis of LAL deficiency with the finding of 2 heterozygous mutations in the LIPA gene. At age 2 years, the patient started treatment with bile acid binding resins, switching to statins 6 months later due to the persistence of marked hypercholesterolaemia, which improved the lipid profile without achieving normalisation. From age 3 years, the patient experienced elevation of liver enzymes. An elastography performed during the follow-up revealed stage 2 liver fibrosis. At age 12 years, the patient started enzyme replacement therapy with a recombinant human lysosomal acid lipase, which achieved normalisation of liver enzyme levels and the lipid profile despite discontinuation of statin therapy.

The second case corresponded to a boy aged 10 years referred to the metabolic disorder clinic for evaluation of persistent hypertransaminasaemia and hypercholesterolaemia from age 3 years that was currently in treatment with statins. The examination of a liver biopsy sample revealed unspecified chronic hepatitis with moderate intraportal and portoportal fibrosis. Clinical suspicion of LAL deficiency motivated performance of a LAL activity assay in dry blood, in which enzymatic activity was undetectable. Genetic testing confirmed the diagnosis of LAL deficiency with detection of a homozygous mutation in the LIPA gene. The patient started enzyme replacement therapy with recombinant human LAL at age 11 years, which achieved normalisation of liver enzyme levels and the lipid profile that was sustained after discontinuing treatment with statins.

Lysosomal acid lipase deficiency is due to a reduction or complete absence of enzymatic activity due to mutations in the LIPA gene.4 This lack of activity results in the intralysosomal accumulation of cholesteryl esters and triglycerides, leading to microvesicular steatosis, progressive liver disease and dyslipidaemia associated with rapidly progressing atherosclerosis, which are the characteristic features of this disease. A lack of clinical suspicion may lead to misdiagnosis, delaying initiation of appropriate treatment and follow-up. Generally speaking, the possibility of LAL deficiency should be contemplated in patients with unexplained persistent abnormalities in liver function tests or the lipid profile.1–3

In the first case, the diagnosis was reached through the measurement of LAL activity in fibroblasts through obtention of a skin biopsy. Advances in diagnostic techniques that have made it possible to study enzymatic activity in dry blood possible allows the assessment of this disease with considerably less invasive and more accessible methods, as demonstrated by the second case. If enzymatic activity is found to be nearly undetectable, genetic analysis of the LIPA gene should be considered with the purpose of identifying the causative mutation and confirm the diagnosis.1,4

Traditionally, the management of LAL deficiency was based on the control of dyslipidaemia through a low-fat diet and lipid-lowering drugs.1,2 However, the use of lipid-lowering drugs is not always effective and does not correct the enzymatic defect or prevent lipid accumulation.1,3 In 2015, the use of sebelipase alfa (a recombinant human lysosomal acid lipase) was approved in Europe for enzyme replacement therapy. This drug is used with the aim of restoring a LAL activity nearing physiological levels through the administration of exogenous enzyme, thus halting disease progression.1,2,5 The fact that enzyme replacement therapy is now available makes awareness of LAL deficiency in health care professionals all the more relevant for the purpose of early diagnosis and treatment of the disease.