Lysosomal acid lipase deficiency (LAL-D) is characterized by the abnormal accumulation of cholesteryl esters and triglycerides in the body. These are usually concentrated in organs such as the liver, spleen, bone marrow, and lymph nodes.

The pathological effects of this can lead to liver disease and cardiovascular complications. Liver disease in LAL-D is often initially misdiagnosed as nonalcoholic fatty liver disease or hereditary dyslipidemia. Meanwhile, cardiovascular complications such as coronary artery disease and stroke are often treated as isolated events, meaning that some patients never undergo the necessary investigations for LAL-D to be detected. 

The severity of LAL-D is largely determined by the residual amount of LAL activity. In cases of which there is a complete (<1%) loss of LAL activity, symptoms appear early in life, and death usually occurs within 6 months without enzyme replacement therapy. In patients who have a residual amount (1%-12%) of LAL activity, clinical symptoms tend to appear later in life, most notably in the form of liver and cardiovascular disease. 

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With regard to the relationship between LAL-D and atherosclerosis, many studies have identified a possible link between the 2 conditions. In patients with cholesteryl ester storage disease (CESD), one type of LAL-D, premature atherosclerosis is frequently reported. There is some evidence that sebelipase alfa, a form of enzyme replacement therapy, can ameliorate the severity of atherosclerosis. 

Read more about LAL-D etiology 

The relationship between LAL-D and liver disease has been known from the very first instance the condition was described. In the 1950s, physicians described an infant female who had cholesterol-laden foam cells throughout her liver and spleen, among other organs. It is now a known fact that patients with LAL-D typically exhibit hepatomegaly and an abnormal liver profile. 

The presence of multisystem complications upon diagnosis means that physicians must initiate enzyme replacement therapy as soon as possible to prevent further clinical deterioration.

Case Study: Liver Disease and Atherosclerosis in LAL-D 

In Case Reports in Gastroenterology, Zharkova and colleagues describe the case of a 17-year-old female who presented with varicella infection and was subsequently diagnosed with LAL-D. 

The patient was first hospitalized for the varicella infection. Laboratory investigations revealed elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. Viral hepatitis and alcohol abuse were ruled out. Nevertheless, her liver function test results continued to demonstrate the same trend over the subsequent year. 

Upon physical examination, her liver edge was palpable 4 cm below the costal margin, and her spleen edge reached the iliac crest. There was no stigmata of liver cirrhosis, which effectively ruled out intrahepatic portal hypertension. 

Although her liver function tests revealed elevated ALT and AST levels, other parameters remained within normal range. An ultrasound of the abdomen revealed hepatomegaly with signs of hyperechogenic parenchyma, as well as splenomegaly. There were no signs of portal hypertension or esophageal/gastric varices, and the portal and splenic veins were normal. 

Her physicians sought to rule out infiltrative disease. A computed tomography (CT) scan was conducted that revealed hepatomegaly, splenomegaly, and a diffuse decrease in hepatic attenuation, which were consistent with liver steatosis. The scan also revealed atherosclerotic plaques in her thoracic aorta and its branches. A Doppler ultrasound scan demonstrated a plaque with 30% stenosis in her left internal carotid artery. 

A lipid profile test revealed marked dyslipidemia, which was consistent with LAL-D, among other differential diagnoses. A liver biopsy revealed a diffuse and uniform microvesicular steatosis of more than 90% hepatocytes, as well as foci of Kupffer cells with foamy cytoplasm situated around the portal triads and central veins.

Read more about LAL-D treatment 

“These histopathologic findings, taken together with elevation of liver enzymes, dyslipidemia, and hepatosplenomegaly, enabled us to suspect LAL-D,” the authors wrote. 

This diagnosis was confirmed by additional tests. The patient was started on enzyme replacement therapy, sebelipase alfa. The initiation of treatment allowed her serum aminotransferases to normalize, and a CT scan performed at the 24th week of therapy revealed reduced fat content in the liver. An ultrasound of her carotid arteries revealed a reduction in the atherosclerotic plaque in her left carotid artery. 

Putting Two and Two Together 

In this case study, the patient presented with nonspecific clinical features. It was the presence of hepatosplenomegaly without evidence of portal hypertension that raised clinical suspicion of some form of storage disease. Other congenital storage diseases such as Niemann-Pick Type B disease, Gaucher disease, and glycogenosis were ruled out due to the lack of other corroborating signs such as cytopenia, hypoglycemia, lung disease, renal pathology, nervous system dysfunction, or skeletal dysplasia. 

Another clue to the patient’s underlying diagnosis was the presence of marked dyslipidemia in a young patient without a family history of cardiovascular disease. As mentioned, premature atherosclerosis is a sign of LAL-D. 

This case study demonstrates that unexplained liver disease and atherosclerosis could very well be signs of LAL-D. Thanks to the availability of enzyme replacement therapy, the initiation of treatment can result in rapid improvements in the matter of weeks or months. 


Besler KJ, Blanchard V, Francis GA. Lysosomal acid lipase deficiency: a rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver diseaseFront Genet. 2022;13:1013266. doi:10.3389/fgene.2022.1013266

Zharkova M, Nekrasova T, Ivashkin V, Maevskaya M, Strokova T. Fatty liver and systemic atherosclerosis in a young, lean patient: rule out lysosomal acid lipase deficiencyCase Rep Gastroenterol. 2019;13(3):498-507. doi:10.1159/000504646