Hypercholesterolemia is a tricky disease to manage, not least because there is still debate about the threshold at which active intervention is needed. This is especially true when the lipid profile is only slightly elevated. We know that high cholesterol levels can eventually lead to health conditions such as cardiovascular disease, but how much attention should we spend on it, especially when there are other comorbidities that demand more urgent attention? 

The evidence points us as physicians to at least counsel patients on the virtues of exercise, dietary modifications, and smoking cessation in addressing the issue. There is still no broad consensus with regards to if and when a statin should be started. Opinions range from it being an appropriate prophylactic drug even in healthy individuals, to suggestions that it only be started in high-risk patients.

In practice, if we are to admit it, we as physicians rarely investigate the causes of hypercholesterolemia; most of the time, we are content to assume that it is due to lifestyle factors, which is often the case. If the patient has a family history of hypercholesterolemia, we consider it likely to be a contributing factor. Rare causes such as lysosomal acid lipase deficiency (LAL-D) rarely cross our minds. 

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Needless to say, this may mean missed opportunities for an early diagnosis to be made and for appropriate medical intervention to follow. Physicians from the Driscoll Children’s Hospital in Corpus Christi, Texas published a case study elucidating this difficulty in the ACG Case Report Journal. The study involves a 2-year-old boy who presented with hypercholesterolemia and elevated liver enzymes who was initially diagnosed with familial hypercholesterolemia but later corrected to cholesteryl ester storage disease (CESD), a form of LAL-D. 

A Worsening Picture 

Let us now visit in detail the case study as presented. The boy presented with hepatomegaly upon physical examination and an abnormal lipid profile: 

  • Total cholesterol (TC): 280 mg/dL (elevated)
  • Triglyceride (TG): 255 mg/dL (elevated)
  • Low-density lipoprotein cholesterol (LDL-C): 200 mg/dL (elevated)
  • High-density lipoprotein cholesterol (HDL-C): 40 mg/dL (normal) 

As expected, he also had an abnormal liver profile: 

  • Alanine aminotransferase (ALT): 73 U/L (elevated)
  • Aspartate aminotransferase (AST): 68 U/L (elevated) 

He also had an abnormal full blood count that displayed microcytic anemia: 

  • Hemoglobin (Hb): 10.4 g/dL (low)
  • Mean corpuscular volume (MCV): 68 fL (low)

He had a 65th weight percentile and a 76th height percentile. Blood results from his first-degree relatives were taken and did not display hyperlipidemia. Nevertheless, the boy was diagnosed with familial hypercholesteremia and the decision was made to manage his symptoms conservatively (abstaining from fatty foods). 

A year later, he was seen on follow-up and was found to have a worsening lipid profile: 

  • TC: 295 mg/dL (higher) 
  • TG: 96 mg/dL (normal)
  •  LDL-C: 241 mg/dL (higher) 
  •  HDL-C: 41 mg/dL (normal) 

His liver profile also showed a worsening picture. Something wasn’t adding up. There were a few key points that made doctors suspect that the initial diagnosis was incorrect: no family history of hyperlipidemia, worsening hyperlipidemia, and worsening liver enzymes. The boy’s atypical presentation and course prompted a referral to the gastroenterology department for further investigation. 

Read more about LAL-D epidemiology

A few investigations were carried out and led to the CESD diagnosis. First, doctors carried out a test to check lysosomal acid lipase enzyme activity on a dried blood sample, which returned an abnormal result of 0 nmol/punch/hour. Subsequently, LIPA gene sequencing was carried out, which showed compound heterozygosity at c.894G>A, the mutation most commonly associated with LAL-D, and heterozygosity for the c.599T>C mutation, which has been previously reported in LAL-D. This confirmed a diagnosis of CESD. 

With the revised diagnosis, the boy was started on sebelipase alfa, an enzyme replacement therapy. He showed interval improvement in both his lipid profile and his liver enzymes: 

  • TC: 264 U/L (lower)
  • LDL-C: 195 U/L (lower)
  • ALT: 38 U/L (lower) 
  • AST: 46 U/L (lower) 

Diagnostic Difficulties

In the case of this young patient, the main challenge of identifying the cause of his deranged lipid profile was his atypical presentation; typically, LAL-D presents in infancy as Wolman disease with the main symptoms being malabsorption, failure to thrive, and liver failure. Therefore, the patient’s normal height and weight threw off suspicion of this diagnosis. 

LAL-D is also rare in pediatrics as it typically presents later in life. “Moreover, this is the first patient where complete LAL enzyme deficiency presents outside of infancy with a less severe phenotype,” the authors of the study wrote. Therefore, it is unclear why the patient had CESD, which has a milder phenotype, compared to Wolman disease, which has a more severe presentation, given that he had complete enzyme deficiency. 

Read more about LAL-D prognosis

This case study represents an exception to the rule and not the rule itself. However, even in typical presentations of hypercholesterolemia, uncovering the underlying cause can still be challenging. This is partly because it has so many differential diagnoses, and physicians always need to weigh the benefits and costs of pursuing a thorough investigation. Most of the time, we adopt a “wait and see” approach, advising lifestyle changes and testing the lipid profile again at a later follow-up. 

Perhaps we will eventually discover tests that can uncover the cause of hypercholesterolemia more accurately early. Until then, physicians need to use their best judgment in deciding the threshold to pursue a more thorough investigation of its causes, keeping in mind that atypical presentations do occur.  


Saad M, Syed S. The emerging battle: lysosomal acid lipase deficiency vs familial hypercholesterolemia in children. ACG Case Rep J. Published online January 13, 2021. doi:10.14309/crj.0000000000000516

Burton BK, Deegan PB, Enns GM, et al. Clinical features of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr. Published online November 24, 2015. doi:10.1097/MPG.0000000000000935