Lysosomal acid lipase deficiency (LAL-D) is a disease in which abnormal lipid accumulation is found throughout the body, including in the liver, spleen, lymph nodes, and bone marrow. This is caused by mutations in the gene encoding lysosomal acid lipase (LIPA), resulting in little to no activity of this enzyme. Lysosomal acid lipase (LAL) plays a major role in intracellular lipid metabolism.
When deficiency in the LAL enzyme is detected in children, they are often diagnosed with early-onset LAL-D, also known as Wolman disease. Patients with Wolman disease typically present with hepatomegaly, failure to thrive, diarrhea, and vomiting. This condition is exceedingly rare, with estimates of it occurring in 1 of every 500,000 live births.
LAL-D is part of a larger group of diseases known as lysosomal storage disorders (LSDs). Other diseases under this umbrella term are Gaucher disease and Niemann-Pick disease. LSDs are usually inherited in an autosomal recessive manner.
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Read more about LAL-D epidemiology
Because hepatic manifestations are so common in LAL-D, we will attempt to describe the common hepatic findings in patients with LAL-D in this article. We will reference a study on the hepatic manifestations of LSDs conducted by Kavanagh and Pastores, as well as a study on the phenotypic manifestations of LAL-D conducted by Pericleous and colleagues.
Presenting Hepatic Features
Patients with LAL-D often present with hepatomegaly, abnormal liver function tests, abdominal distention, dyslipidemia, and gastrointestinal disturbances. Because these symptoms are often vague and subtle, misdiagnosis occurs frequently.
Pericleous et al wrote, “As presenting features are not pathognomonic, patients are often misdiagnosed as having non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cryptogenic cirrhosis, heterozygous familial hypercholesterolemia, Fredrickson type 2a and 2b hyperlipoproteinemia, or other forms of hypercholesterolemia.”
Even though hepatomegaly is commonly observed in LAL-D, the disease is usually fairly low on a physician’s list of differential diagnoses. However, clinical suspicion should rise upon detailed history taking and through the exclusion of other pathologies.
Kavanaugh and Pastores stated, “Several considerations should raise one’s index of suspicion that a patient’s complaint may be caused by an LSD while screening for or after preliminary exclusion of more common disorders (eg, infection, malignancy).”
Let us take a closer look at the abnormal liver function tests that patients with LAL-D commonly present with. One of the most common findings in these tests is transaminitis. Studies have demonstrated that aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels tend to be high in LAL-D. An abnormal liver profile will usually prompt further investigation into its causes, and a liver biopsy is commonly taken for histological analysis.
However, this does not necessarily result in a correct diagnosis of LAL-D. Pericleous and colleagues wrote that “LAL-D remains under-recognized, and histological analysis can be challenging and is often misinterpreted.”
Diagnostic Procedures
Physicians do have other diagnostic tools that can aid in arriving at a correct LAL-D diagnosis. Computed tomography (CT) scans are often performed in cases of hepatomegaly.
Pericleous et al stated, “CT scans can be supportive in establishing the diagnosis of adrenal hypertrophy, hepatosplenomegaly, and portal hypertension in patients with LAL-D.” They added, “High cholesterol can correlate with reduced hepatic density on CT scans, but this observation is neither reliable nor exclusive to patients with LAL-D.”
Aside from imaging modalities, a bone marrow biopsy may also be performed if physicians have concerns about potential malignancy. Perhaps the most illuminating diagnostic test that can be performed is the measurement of LAL levels. Kavanagh and Pastores wrote that “LAL-D can be confirmed by demonstrating deficiency of the cognate enzyme (namely, LAL).” However, it should be noted that measuring enzyme activity does not reliably identify carriers of this disease.
Read more about LAL-D diagnosis
In addition, genetic LIPA sequencing can also be useful to diagnose LAL-D in a patient. A diagnosis of LAL-D can be made when pathogenic variants of the LIPA gene are detected. Pericleous and colleagues wrote that “the frequency of the causative E8SJM mutation has been estimated to be one in 242 and prevalence about 1-2 in 100,000 in white populations, and is reportedly similar in Hispanic populations.” Reports of this causative mutation are lower among Asian and African populations, possibly due to the underreporting of unidentified LIPA mutations.
Aside from an abnormal liver profile, other biomarkers of LAL-D can be observed. Kavanagh and Pastores commented that patients with LAL-D often have an abnormal lipid profile (high low-density lipoproteins [LDL], low high-density lipoproteins [HDL]), while the chitotriosidase enzyme may also be elevated.
A diagnosis of LAL-D can do more than just inform clinical decision-making for the patient involved. Kavanagh and Pastores wrote, “As inherited traits, diagnosis enables consideration of genetic counseling regarding reproductive risks and implications for relatives.”
The Big Picture
In this article, we focused on one of the most obvious signs of LAL-D, hepatomegaly, as a starting point for clinical suspicion of LAL-D. Subsequently, abnormalities in liver and lipid profiles, deficiency in the LAL enzyme, and genetic testing can help confirm the diagnosis.
Ultimately, LAL-D is a systemic disease that can affect multiple organs. Pericleous et al wrote that “patients with LAL-D, particularly cholesteryl ester storage disorder, are thought to have an increased risk of cardiovascular, cerebrovascular, and aneurysmal disease (patients with [Wolman] disease often die before they develop cardiovascular sequelae) because of their dyslipidaemic profiles.”
References
Kavanagh K, Pastores GM. Hepatic manifestations of lysosomal storage disorders: differential diagnosis, investigations, and treatment, current and upcoming. Eur Med J. Published online September 21, 2021.
Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
