In lysosomal acid lipase deficiency (LAL-D), the activity of the lysosomal acid lipase enzyme is substantially reduced. This causes an accumulation of cholesteryl esters and triglycerides within the lysosomes of various organs, primarily the liver, spleen, and heart. 

The pathological accumulation of lipids in these organs drives various cellular damages. Splenomegaly can occur as lipids accumulate within macrophages. Liver fibrosis and cirrhosis can take place due to persistent damage. In the gastrointestinal tract, lipid accumulation can cause diarrhea and abdominal pain.

In addition, low free cholesterol levels can reduce steroid synthesis and cause adrenal insufficiency. Dyslipidemia can contribute to significant cardiovascular disease. 


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Because LAL-D is an inborn error of metabolism, it can be picked up through large-scale screening of populations. If screening is unavailable, physicians tend to suspect its early-onset form, Wolman disease, when a newborn presents with failure to thrive and persistent diarrhea. Other tell-tale signs include hepatomegaly, liver dysfunction, and an abnormal lipid profile.

Read more about LAL-D etiology 

“Diagnostic delays are frequent; unless there is relevant family history and as with other rare diseases are best explained by the association of non-specific and highly prevalent clinical manifestations,” Pastores and Hughes wrote in Drug Design, Development and Therapy. “This has prompted a search for biomarkers that can be used for screening, amongst high-risk populations.”

How Suitable Is Indiscriminate Screening? 

In Clinica Chimica Acta, Tebani and colleagues investigated the screening of at-risk patients who presented with signs consistent with LAL-D. At-risk patients were defined as those with unexplained hepatomegaly, or an increase of 1.5 times or more of the upper reference limit of transaminase activity, or an abnormal serum lipid profile with or without splenomegaly, or gastrointestinal disease with liver microvacuolar steatosis/cirrhosis/fibrosis. 

The research team managed to collect 4174 dried blood spot samples from selected participants; 60% of the them were male. The dried blood spot samples were analyzed for lysosomal acid lipase activity. 

The results revealed 19 patients with lysosomal acid lipase activity lower than 0.05 nmol/punch/hr. Among them, 6 were diagnosed with Wolman disease and 13 were diagnosed with cholesteryl ester storage disease, the later-onset form of LAL-D.

The percentage of patients eventually diagnosed with LAL-D was a mere 0.46%. This suggests that indiscriminate, population-wide screening for LAL-D may not be suitable in most cases.

Tebani and colleagues suggested a list of signs and symptoms to decide whether LAL-D screening should be conducted. The most salient of these are hepatomegaly, elevated transaminases, microvacuolar steatosis, failure to thrive, adrenal calcification, low-density lipoprotein (LDL) higher than 1.3g/L, high-density lipoprotein (HDL) less than 0.45 g/L, and diarrhea and vomiting. 

Debates Surrounding Population-Wide Screening 

The results of the study conducted by Tebani and colleagues naturally open up the question of the threshold at which population-wide screening for various diseases should be offered. 

Many healthcare centers offer routine, organized screenings for a number of diseases, with substantial results. Examples of frequently offered screening tests are colorectal and prostate cancer for men, as well as breast and cervical cancer for women. Detecting these cancers early can make a world of difference in terms of therapeutic outcomes. 

“Organized screening also offers a platform to measure and improve quality of screening, through tracking of follow-up of positive tests,” Dominitz and Levin wrote in Gastrointestinal Endoscopy Clinics of North America. 

However, population-wide screening faces 2 primary challenges: first, deciding whether the costs of the screening test are justified; and second, convincing at-risk populations to participate in screening exercises at sufficient levels to make a population-wide difference. In addition, it is a given that adequate healthcare infrastructures must be in place before any mass screening test can be offered to the public. 

Read more about LAL-D epidemiology 

Another important point to contemplate is the medical intervention that can be introduced should a disease be detected via screening. In the case of LAL-D, traditional forms of therapy involved a combination of lipid-lowering drugs and dietary manipulation. In more advanced disease, splenectomy, liver transplantation, and the ligation of esophageal varices can be carried out to deal with organ involvement. 

However, the recent introduction of enzyme replacement therapy has revolutionized LAL-D treatment and has delayed or eliminated the need for high-risk surgical intervention for the management of the disease. Enzyme replacement therapy is now prescribed for most cases of LAL-D. 

In addition, another important question in organized screening is the success rate of the screening method, ie, quality assurance. An inadequate screening test that often results in false positives or false negatives can be deeply distressing to the patient and the patient’s family. Hence, population-wide screening for certain diseases should only be offered once a threshold quality has been reached. 

Ultimately, the question of whether to implement population-wide screening is whether or not it will make a significant difference in the lives of the public, taking into consideration its costs and the need for adequate healthcare infrastructure and personnel. This requires a balanced, measured approach that puts patients first.

References

Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic optionsDrug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264

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

Dominitz JA, Levin TR. What is organized screening and what is its value? Gastrointest Endosc Clin N Am. 2020;30(3):393-411. doi:10.1016/j.giec.2020.02.002