Disease screening is an important public health measure that has saved countless lives. Population-based screening for diseases such as breast cancer, cervical cancer, and prostate cancer has become increasingly embedded into the medical practices of the developed world, with laudable results. 

However, it is impossible to screen for all diseases; it would be a logistical nightmare and the healthcare expenditure to do so would be immense. Already, healthcare infrastructures in many parts of the world are stretched to near breaking point. Expensive, routine mass screening is simply beyond the budget of most countries. 

So, how common should a disease need to be for healthcare authorities to offer screening services for it? If a disease is rare but deadly, and can be easily picked up through population-based screening, should screening then be implemented? Or should we focus our attention on diseases that have a high prevalence in a given population? 

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These public health questions are never easy to answer, and it is perhaps unhelpful that some of the people making these decisions are not clinically trained. 

In this article, we will evaluate the usefulness of large-scale screening of one rare disease: lysosomal acid lipase deficiency (LAL-D). 

LAL-D is a rare autosomal recessive disorder that leads to the decrease or loss of lysosomal acid lipase enzyme activity, eventually causing the accumulation of enzyme substrates such as cholesterol esters and triglycerides in various organs, especially the liver, spleen, and cardiovascular system. Progressive pathology then occurs in various systems throughout the body. 

Read more about LAL-D etiology 

LAL-D is usually treated with a low-fat diet, reduction in lipids, and hematopoietic stem cell transplant or liver transplantation. Sebelipase alfa, an enzyme replacement therapy (ERT), has also been introduced in recent years and confers a significant survival benefit to patients. 

Targeted vs Large-Scale Screening 

Tebani and colleagues conducted a study to investigate the efficacy of screening a cohort of patients at risk for LAL-D, defined as those presenting with clinical signs suggestive of the condition. They analyzed 4174 dried blood spot samples obtained from individuals suspected of having LAL-D upon clinical screening. At-risk patients were: 

  • Individuals with unexplained hepatomegaly or an abnormal increase in transaminase activity (≥1.5 times the upper reference limit). 
  • Individuals with an abnormal serum lipid profile with or without gastrointestinal dysfunction or splenomegaly or hepatic microvacuolar steatosis/cirrhosis/fibrosis. 

The results from the screening exercise were that LAL activity was discovered to be lower than 0.06 nmol/punch/L in 19 patients (the cut-off being 0.12 nmol/punch/L). Molecular investigations were carried out in 17 patients, yielding 34 mutated alleles. The researchers managed to characterize 14 unique variants, 7 of which were novel. 

Tebani et al concluded, “This study allowed us to identify a series of patients and better tune the screening criteria for LAL-D in at-risk populations. Besides, our study expands the molecular spectrum knowledge of lipase acid deficiency.” 

This study demonstrated that screening for LAL-D yields some benefits; however, researchers were notably silent on recommending this as a routine practice. Their method of screening for LAL-D only in at-risk groups suggests a more targeted screening approach may be more pragmatic than population-wide screening. 

Retrospective Data Mining 

We now turn our attention to a paper written by Draijer and colleagues, in which they detailed a retrospective data mining study they carried out to evaluate the number of possibly undiagnosed or misdiagnosed LAL-D cases in a large pediatric hospital population. They also attempted to determine the accuracy of the adapted screening criteria for children in identifying pediatric LAL-D cases. 

Draijer et al evaluated all pediatric patients who visited a particular pediatric clinic in Amsterdam, the Netherlands, using a special screening algorithm adapted for children.

“According to the algorithm, children with increased [low-density lipoprotein cholesterol (LDL-C)], without a genetic cause for familial hypercholesterolemia (FH), are eligible for LAL-D testing if they meet 3 out of 5 additional criteria,“ they wrote. “These criteria include low [high-density lipoprotein cholesterol (HDL-C)] levels, high [alanine aminotransferase] levels, absence of obesity, presence of hepatomegaly and histologically proven steatosis.”

Read more about LAL-D epidemiology 

Through this methodology, the research team identified 2037 children with LDL-C >3.8 mmol/L. A total of 36 out of the 2037 children (1.8%) also met 3 or more of the screening criteria. Among the 36 children, 31 were found to have an underlying disorder other than LAL-D that could possibly explain the abnormalities observed. As for the remaining 5 children, their ALT and lipid levels normalized spontaneously, which excluded a diagnosis of LAL-D. 

The research team hence concluded that “retrospective data mining is unlikely to yield a significant number of LAL-D cases in children.” They commented, “As the majority of children who met ≥3 additional criteria had an underlying disorder and biochemical abnormalities disappeared after treatment, an obvious addition to the screening criteria would be that physicians can wait to see whether abnormalities disappear if abnormalities can be explained by another disorder that has been treated.” 

These 2 studies suggest that, at present, population-wide screening for LAL-D may not yield very useful results. However, further research into specific LAL-D risk factors may potentially change the calculus of healthcare authorities in the future. 


Tebani A, Sudrié-Arnaud B, Boudabous H, et al. Large-scale screening of lipase acid deficiency in at risk populationClin Chim Acta. 2021;519:64-69. doi:10.1016/j.cca.2021.04.005

Draijer LG, Bosch AM, Wiegman A, Sjouke B, Benninga MA, Koot BGP. Screening for lysosomal acid lipase deficiency: a retrospective data mining study and evaluation of screening criteriaAtherosclerosis. 2018;278:174-179. doi:10.1016/j.atherosclerosis.2018.09.023