One of the more pressing issues in modern medicine is how much governments should invest in screening programs, especially if they cross a threshold of efficiency in terms of the number of cases identified or the clinical benefit they confer. 

Should we implement screening programs if the disease one aims to identify is fairly common, like cervical cancer? What about rare diseases? If a screening program can identify only a handful of cases but can result in improved clinical outcomes throughout a person’s life, is it still worth the investment? 

These issues, while underpinned by clinical data and analyses, are often debated among nonclinicians and it is often they who make the call about which programs are worth spending money on. The work of physicians and medical researchers, therefore, is to study objective parameters of clinical success and present these analyses in the public domain. 


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The Slovenian Model of LAL-D Screening 

In Frontiers in Genetics, Sustar and colleagues investigated the merits of a universal familial hypercholesterolemia screening program to identify lysosomal acid lipase deficiency (LAL-D). 

LAL-D is a lysosomal storage disorder inherited in an autosomal recessive manner. The key genetic characteristic of this disease is variants in the LIPA gene that result in much reduced lysosomal acid lipase activity. Wolman disease is a subtype of the disease that has an infantile onset and is usually lethal, while the cholesteryl ester storage disease (CESD) subtype has a later onset and a milder phenotype. 

Read more about LAL-D etiology 

“Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with familial hypercholesterolemia or nonalcoholic fatty liver disease, leading to a delay in treatment or mistreatment,” Sustar et al write. “A correct diagnosis of LAL-D is critical for the appropriate clinical management of children.” 

One country that has a long history of implementing familial hypercholesterolemia screening is Slovenia, which started its program in 1995. It is one of many blood tests carried out on all 5-year-old children. Sustar and colleagues used clinical data from Slovenia to carry out their analysis. 

Just how many children were identified with LAL-D from the screening program? The researchers reported that of 669 children included in the LIPA gene analysis, 3 were positive for a homozygous disease-causing splicing variant that resulted in LAL-D. They also discovered that the mean age of diagnosis was 9.8 years. 

For the 3 children who were identified as having LAL-D, significant improvements in physical parameters were observed after treatment was initiated. Prior to diagnosis, the mean height percentile of the children was 14.3, and the mean BMI percentile was 30.4. After treatment, the mean height percentile improved to 22.6 and the mean BMI percentile increased to 45.9. 

In addition, the mean levels of total cholesterol, triglycerides, and low-density lipoproteins were significantly lower after treatment. Mean aspartate transaminase levels decreased from 1.33 to 0.73 μkat/L after treatment, and mean alanine transaminase levels decreased from 1.61 to 1.13 μkat/L. The initial treatment administered was ezetimibe. 

Getting to the Starting Point 

This study of the Slovenian LAL-D screening demonstrates that substantial clinical improvements can be expected upon diagnosis of LAL-D and initiation of treatment. Granted, LAL-D is a rare disease, and one can expect this to be reflected in terms of the percentage of positive cases identified via screening. Nevertheless, the 3 children who were diagnosed early with LAL-D because of the screening program were able to have the best possible start to life through medication and follow-up they might not have otherwise gotten. 

Is the LAL-D screening program in Slovenia a success? One can argue that any number of cases identified via screening constitutes a success, given that human life cannot be quantified and finding those with disease is difficult without screening programs. 

Without screening, children tend to present with significant liver disease before the necessary laboratory tests are carried out. Studies have shown that only 11% of patients with LAL-D become clinically apparent after 12 years of age. In addition, hepatomegaly was present in 99.3% of patients, while splenomegaly was present in 74% of patients. Liver fibrosis and cirrhosis were identified in 64% of patients upon biopsy. This means that patients often present with significant pathology before clinical suspicion is even raised. 

Read more about LAL-D prognosis 

“Due to the rarity of LAL-D, finding cases with the diagnosis is an unlikely event in any physicians’ lifetime,” Strebinger and colleagues wrote in Hepatic Medicine: Evidence and Research. 

It should also be noted that the rarity of this disease means that it is likely that many cases are missed entirely, and that any resulting pathology is viewed as so many isolated events. Regarding the elevated lipid profile typically seen in patients with LAL-D, physicians would often suspect metabolic syndrome and advise conservative measures such as diet and exercise. 

The good news is that enzyme replacement therapy has significantly improved the prognosis of patients diagnosed with LAL-D, and further work is underway to identify similarly effective therapeutic agents. However, treatment can only be initiated once a diagnosis of LAL-D has been made; the question on how best to arrive at this starting point remains a debate of policy and priorities. 

References

Sustar U, Groselj U, Trebusak Podkrajsek K, et al. Early discovery of children with lysosomal acid lipase deficiency with the universal familial hypercholesterolemia screening programFront Genet. 2022;13:936121. doi:10.3389/fgene.2022.936121

Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency — early diagnosis is the keyHepat Med. 2019;11:79-88. doi:10.2147/HMER.S201630