One of the challenges of clinical practice is to have the discernment to suspect a rare disease and to take appropriate steps to confirm or dismiss the suspected diagnosis. However, the rarely spoken rule in medicine is that everything runs on costs; an alarmist position for every medical case can easily cost far more than any benefit that it might bring.
Physicians are ingrained with the mantra that “common things are common”; however, it is also true that every physician’s worst nightmare is to miss something uncommon at an early stage when treatment can still be administered with comparably good clinical outcomes.
So what can physicians do about this ever-pressing dilemma? One thing is to be familiar with early warning signs of a possible rare disease. Then, clinical judgment and experience can help physicians make the best decisions for their patients.
Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disorder that is the result of mutations in the lysosomal acid lipase gene. The course of this disease is heterogeneous, but most patients are diagnosed as children and later develop liver failure and cardiovascular events. LAL-D is also known as Wolman disease, which tends to have an earlier onset, and cholesteryl ester storage disease (CESD), which tends to have a later onset.
Read more about LAL-D epidemiology
Witeck and colleagues conducted a scoping review into the occurrence of LAL-D in pediatric patients. In their study, they wrote about the challenge of diagnosing LAL-D in children:
“The relatively low number of cases diagnosed with LAL-D in comparison to its genetic prevalence is likely explained by a low degree of suspicion for the diagnosis. For this reason, raising pediatrician awareness about this condition is an essential step for identifying individuals with LAL-D, as there are means for diagnosis available after the disease is suspected.”
Strebinger et al, in their study entitled “Lysosomal acid lipase deficiency – early diagnosis is the key,” came to a similar conclusion. They commented, “It appears evident that there is a gap between the genetically estimated prevalence of LAL-D and the cases known in most countries worldwide. Due to the rarity of LAL-D, finding cases with the diagnosis is an unlikely event in any [physician’s] lifetime.”
In this article, we will be looking at some of the early warning signs that can lead physicians to confidently include LAL-D in their list of differential diagnoses.
Early Warning Signs
A study suggests that the mean onset of LAL-D is 5 years, but only 11% of patients become clinically apparent after 12 years of age. Strebinger and colleagues wrote, “All reported subjects presented with significant liver disease with elevated serum transaminases. Hepatomegaly was present in nearly all (99.3%) and splenomegaly in 74% of the patients. In 64% of the biopsied patients liver fibrosis or cirrhosis and in 29% cirrhosis was detected in the histological work-up.”
Witeck and colleagues also discovered that hepatomegaly and splenomegaly feature heavily in physical examinations of pediatric LAL-D patients. According to their literature review, “Hepatomegaly was an important sign in the physical examination, present in 93% of the early-onset patients and 88% of the patients with CESD. Splenomegaly was also frequent, occurring in 77% of the Wolman disease patients and 45% of the patients with CESD.”
Hepatomegaly and splenomegaly can be detected via a careful physical examination of the abdomen (and confirmed with imaging), serving as potent signs that the patient might have LAL-D. Strebinger et al called liver-related abnormalities, such as hepatomegaly, splenomegaly, jaundice, and gallbladder dysfunction, “red flags” for LAL-D in the presence of abdominal pain.
Read more about LAL-D diagnosis
Concurrently, liver function tests might also reveal deviations that can further strengthen a physician’s suspicion of LAL-D. These are usually present early in the course of the disease. Witeck and colleagues wrote, “ALT, AST and albumin concentrations below the normal range and elevated GGT and bilirubin levels were characteristic in the early-onset form, in agreement with a more aggressive disease spectrum.”
Another helpful sign in patients with LAL-D that can lead to an early diagnosis is dyslipidemia.This is because we know that the LAL enzyme plays an important role in cholesterol metabolism. Witeck and colleagues discovered a pattern linking dyslipidemia with LAL-D, noting it was present in most reported cases in their study.
“Elevated LDL and VLDL cholesterol are typical of CESD, and metabolic changes lead to a characteristic increase in total serum cholesterol and low HDL levels,” they commented. “There is an increase in triglyceride concentrations, a decrease in HDL cholesterol and qualitative changes in LDL, with consequent high cardiovascular risk.”
Strebinger and colleagues also noted a link between dyslipidemia and LAL-D, as well as an increase in cardiovascular risk. A study they referenced demonstrated that “hypercholesterolemia due to an increase in LDL cholesterol was present in nearly all patients, despite many of them being treated with statins, indicating an increased cardiovascular risk. There are case reports of accelerated atherosclerosis in LAL-D patients including aortic plaques in a 9-year-old and cardiovascular events at young age.”
A Race Against Time
Both of the research teams quoted in this study believe that early diagnosis of LAL-D is the best way to secure better clinical outcomes. However, finite as we are, cases may still be missed, especially if patients present with less obvious clinical features than those described in this article.
Witeck CDR, Schmitz AC, de Oliveira JMD, Porporatti AL, De Luca Canto G, Pires MMS. Lysosomal acid lipase deficiency in pediatric patients: A scoping review. J Pediatr (Rio J). Published online May 6. 2021. doi:10.1016/j.jped.2021.03.003
Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency – early diagnosis is the key. Hepat Med. 2019;11:79-88. Published online May 23, 2019. doi:10.2147/HMER.S201630