The cardiometabolic killer we do not know... the lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is a rare autosomal recessive lysosomal storage disease caused by mutations in LIPA gene. The disease has two phenotypes, early-onset or infantile-onset form formerly known as Wolman disease and late-onset or childhood/adult-onset form formerly known as cholesterol ester storage disease. In normal situation, lysosomal acid lipase degrades cholesterol esters and triglycerides into free cholesterol and fatty acids. LIPA gene mutation causes lysosomal acid lipase activity to be reduced which leads to dyslipidemia and accumulation of lipids in liver and other tissues. Cardinal clinical features of lysosomal acid lipase deficiency are dyslipidemia and liver dysfunction. Infantile-onset form presents in the first days or weeks of life with gastrointestinal symptoms like diarrhea, steatorrhea and vomiting, hepatosplenomegaly and failure to thrive. These patients rapidly progress from liver steatosis to fibrosis to cirrhosis and liver failure. If untreated, infantile-onset form is fatal within 6-12 months. Childhood/adult-onset form instead can present at any age of childhood or adulthood and has slower and more variable progression. It presents with hepatomegaly, elevated serum transaminases, gradual reduction of liver function, dyslipidemia and atherosclerosis. Diagnosis is difficult since clinical features overlap with many other more common conditions like non-alcoholic fatty liver disease and more common inherited hypercholesterolemias. The disease is thought to be underdiagnosed. Diagnosis is based on demonstrating decreased lysosomal acid lipase activity on blood test and confirmed with genetic test for LIPA gene mutation. Treatment used to be based on hematopoietic stem cell transplantation, liver transplantation and lipid lowering drugs but these did not have optimal outcomes. In 2015 enzyme replacement therapy with Sebelipase alfa became available which has so far been demonstrated to be relatively safe and effective significantly improving the prognosis.