Differential Diagnosis of a Patient With Lysosomal Acid Lipase Deficiency

A Case Report

Ashwin S. Akki, MD, PhD; Sun M. Chung, MD; Bryan J. Rudolph, MD, MPH; Michelle R. Ewart, MD


Lab Med. 2018;49(4):377-384. 

In This Article


This case demonstrates the important role that surgical pathologists can play in identifying rare diseases. It also highlights the broad differential diagnoses that one must consider in patients with hepatic steatosis—specifically in those patients with microvesicular, small-droplet, or mixed steatosis.

LAL-D is a panethnic disorder caused by mutations in the LIPA gene. A review[20] of 135 patients with LAL-D revealed that the disease was most common in white people of European origin, followed by those of North American and Latin American origin. Disease prevalence is unknown but is estimated to be from 1:40,000 to 1:300,000 depending on the population studied. More than 100 LIPA gene mutations have been identified so far,[23] the most common of which is E8SJM. Individuals who are homozygous for E8SJM, which accounts for more than half of all patients with LAL-D, typically have slowly progressive disease that is diagnosed in early to mid-childhood.

The LAL protein plays a critical role in cholesterol metabolism. In healthy individuals, LDL-C is internalized via LDL receptors and brought into intracellular lysosomes for degradation. In patients with an LAL-enzyme defect, there is reduced or absent hydrolysis of cholesteryl esters and triglycerides, resulting in sequestration of free cholesterol and fatty acids within lysosomes of Kupffer cells and hepatocytes.[24,25] The absence of free cytoplasmic cholesterol, in turn, leads to reduced feedback inhibition of hydroxymethylglutaryl-coenzyme A reductase in hepatocytes, a rate-controlling enzyme in the cholesterol synthesis pathway.[25] As a result, HDL-C synthesis is decreased, surface LDL receptors are upregulated, and very-low-density lipoprotein (VLDL) synthesis is increased.[26–28] Together, these metabolic alterations lead to the characteristic cholesterol findings of LAL-D: increased serum LDL-C and low HDL-C levels.

Clinically, these cholesterol changes are believed to be responsible for early-onset cardiovascular disease in patients with LAL-D. In the liver, progressive lipid deposition leads to fibrosis, micronodular cirrhosis, and liver failure, although the timing of these occurrences is variable.[20,29] In the intestinal microvilli, lipid accumulation can lead to diarrhea and malabsorption, with resultant failure to thrive.[29]

Therefore, LAL deficiency should be suspected in individuals with characteristic clinical findings of hepatomegaly, elevated ALT levels, elevated LDL-C levels, low HDL-C levels, or microvesicular/mixed steatosis on histology. Experimentally, staining for cathepsin D, Lysosome-associated membrane protein 2 (LAMP-2), and lysosomal integral membrane protein 2 (LIMP-2) have been used to highlight hepatocytic lysosomes,[21] although the sensitivity of this staining has not been well established. Clinically, LAL-D can be definitively diagnosed by measuring serum enzyme activity via a commercially available dried-blood-spot test or an assay of serum leukocyte activity. Genetic testing for LIPA gene variants is often performed but is not needed for definitive diagnosis.[23]

Most of the time, LAL-D can be challenging to diagnose and requires a high degree of clinical suspicion. First, LAL-D is relatively rare,[26] especially in comparison to more-common disorder NAFLD. Second, patients with LAL-D are often asymptomatic, other than the abnormalities noted in their laboratory findings. Third, serum cholesterol values can be difficult to interpret and often fluctuate. Although patients with NAFLD often have low serum HDL-C, for example, only 21% have elevated LDL-C levels (defined as LDL ≥130 mg/dL in children or ≥160 mg/dL in adults), and values may fluctuate with time.[30] However, approximatey 64% of patients with LAL-D have abnormal LDL-C values, although values can be intermittently normal when measured serially.[22] This paradigm must shift, given the severity of LAL-D and the availability of efficacious therapy in the form of a recombinant enzyme (sebelipase alpha) that reaches the lysosomes, corrects the metabolic defects, and reduces pathological accumulation of cholesterol esters in affected tissues in patients with LAL-D.[31]