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

Abstract and Introduction


Background: We describe the differential diagnosis of an obese 12-year-old boy of Mexican origin who presented with a 6-year history of abnormal lipid profile and elevated liver transaminase levels.

Methods: The patient underwent routine clinical testing, an abdominal ultrasound and, ultimately, a liver biopsy. Based on the histologic findings, a serum leukocyte lysosomal acid lipase (LAL) assay and DNA sequencing of the lipase A (LIPA) gene were performed.

Results: Liver biopsy revealed diffuse microvesicular steatosis with clusters of foamy histiocytes in the lobules and portal areas. Our differential diagnosis included nonalcoholic fatty liver disease; medication-induced hepatotoxicity; glycogenic hepatopathy; medium-chain acyl coenzyme A dehydrogenase or long-chain acyl coenzyme A dehydrogenase deficiency; and lysosomal storage disorders, including Niemann-Pick disease and lysosomal acid lipase deficiency (LAL-D). Serum LAL activity was absent, and DNA sequencing confirmed homozygous mutation in LIPA.

Conclusions: Although it occurs rarely, LAL-D should be considered in the differential diagnosis of microvesicular steatosis for a timely diagnosis.


Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States, with an overall prevalence of 31% in adults and approximately 10% in the pediatric population.[1,2] NAFLD is associated with obesity, insulin resistance, metabolic syndrome, and cardiovascular disease; it is soon expected to be the most common indication for liver transplantation.[3–5]

NAFLD can present as liver injury ranging from steatosis to steatohepatitis, with or without fibrosis.[4] A large cross-sectional study noted that the results of approximately 10% of the liver biopsies from patients with NAFLD show a variable degree of microvesicular steatosis and that the presence of NAFLD correlates with severe (ie, increased lobular inflammation) and advanced (ie, increased fibrosis) disease.[6] Small-droplet steatosis refers to the presence of several microscopically separable lipid droplets that exist within a single hepatocyte but do not fill the entire hepatocyte.[7] In contrast, true microvesicular steatosis consists of much smaller (ie, submicroscopic), uniform fat droplets dispersed throughout the hepatocyte, giving a reticulated appearance and often requiring special stains (eg, Oil Red O) or electron microscopy for detection.[6,7] As a result, it may be easy to overlook microvesicular steatosis when admixed with large-droplet steatosis, especially given the relative frequency of NAFLD compared to other etiologies.[6]

In the population we serve in Bronx County, New York, nearly 1 in 3 children in Head Start programs and 1 in 4 children in public elementary schools are obese.[8] Many of the children with obesity have abnormal serum lipid profiles and elevated aminotransferase levels, suggesting underlying metabolic liver disease.[3,9] Liver biopsy, the criterion standard for diagnosing NAFLD,[10,11] is performed in our practice when obese children with elevated serum lipids and aminotransferases fail to improve after approximately 6 months of dietary and/or lifestyle changes. Although most of these biopsies reveal NAFLD or nonalcoholic steatohepatitis, there is a risk that rare metabolic disorders may go unrecognized due to overlapping histologic features. The surgical pathologist is therefore in a unique position to recognize subtle morphologic clues to these rare metabolic diseases, including glycogenic hepatopathy, medium-chain acyl coenzyme A dehydrogenase (MCAD), and long-chain acyl coenzyme A dehydrogenase (LCAD) deficiency, Wilson disease, Niemann-Pick disease, and lysosomal acid lipase deficiency (LAL-D).

Herein, we report the case of a 12-year-old boy of Mexican origin who was found to have diffuse microvesicular steatosis after a liver biopsy due to an abnormal lipid profile and elevated liver transaminase levels.