Lysosomal Acid Lipase Dificiency (LAL-D) in adults: Epidemiologic Multi-Center Study Underway

A multi-center, investigator-initiated epidemiologic study is underway [clinical trial: NCT01633489] aiming to determine the proportion of adults affected by late-onset lysosomal acid lipase deficiency (LAL-D) using definitive genetic testing.

LAL-D is an autosomal recessive disease caused by mutations in the Iipase gene that lead to decreased or absent enzyme activity. Lack of such activity causes lysosomal accumulation of cholesteryl ester in various organs, including the liver, spleen and adrenals, which leads to morbidity and mortality.1 Transplant hepatologist Karen L. Krok, M.D., Penn State Hershey Gastroenterology and Hepatology, explains, “At Penn State Hershey and other study centers in Pennsylvania, adults with cryptogenic cirrhosis or nonalcoholic steatohepatitis [NASH] who are awaiting liver transplant will have the opportunity to be tested for LAL-D. The signs and symptoms of LAL-D are similar to other common conditions; however, 10 to 15 percent of patients have no comorbid condition like hepatitis, obesity, diabetes or alcohol use to explain the disease. (Learn more about clinical features of LAL-D in adults.)

“Although LAL-D is considered rare, [one out of every 40,000 to 300,000 patients], no large-scale study has systematically conducted genetic testing in patients with unexplained fatty liver disease. LAL-D incidence could potentially be much higher once we start to actually look for it in patients with signs and symptoms.”

For qualifying patients, testing for the LAL-D mutation will be performed by a simple blood test developed by Synageva (Athens, GA), which has sebelipase alfa, a potential enzyme replacement treatment for LAL-D, in phase 3 development. Krok notes, “Although the blood test is not yet commercially available, it has the potential to be widely used to screen for LAL-D mutations in patients with unexplained fatty liver disease.”

The current trial may help to lay the ground work for properly selecting patients for the test and interpreting its results. The availability of such a blood test may reduce the use of biopsy to investigate symptoms. Accurate diagnosis of the genetic LAL-D mutation, in turn, may help to guide more efficient management of symptoms.

LAL-D presents along a clinical spectrum. Neonatal cases (Wolman’s disease) represent the most severe LAL deficiency, often leading to death within months. Many adults with LAL-D have some remaining LAL enzyme activity; symptoms may not become clinically evident until they are older. Such patients are often misdiagnosed as having non-alcoholic fatty liver disease or steatohepatitis, or cryptogenic liver disease¹, which is managed symptomatically; patients face a poor prognosis often culminating in liver failure and death.

Karen L. Krok, M.D. Karen L. Krok, M.D.
Associate Professor of Medicine
Penn State Hershey Gastroenterology and Hepatology
Phone: 717-531-1017 | E-mail:
Fellowships: Transplant Hepatology, Gastroenterology, Johns Hopkins Hospital, Baltimore, Maryland
Residency: Internal Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
Medical School: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania


  1. Bernstein DL, Hulkova H, Bialer MG, Desnick RJ. 2013. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 58:1230-1243.

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