Lysosomal Acid Lipase Deficiency

Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in disease-relevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder of metabolism caused by defects of the LIPA gene, resulting in disruption of intralysosomal degradation of cholesteryl esters and triglycerides and accumulation of relevant substrates. Clinical pathology primarily involves the liver and the vascular and reticuloendothelial systems. Causal gene defects are heterogeneous, with over 100 LIPA mutations having been identified in patients with LAL deficiency.

Hepatomegaly associated with liver dysfunction and an abnormal lipid profile (elevated low-density lipoprotein [LDL] cholesterol and triglyceride levels, decreased high-density lipoprotein [HDL] cholesterol) are characteristic clinical features. The dyslipidemia has been attributed to the inability to release free (unesterified) cholesterol from lysosomes, leading to a cascade of downstream intracellular events and an associated atherogenic lipid profile. Liver biopsy demonstrates micro- or macro-vesicular steatosis involving Kupffer cells and hepatocytes, accompanied by fibrosis and cirrhosis as the pathology progresses. Chronic (untreated) dyslipidemia may lead to accelerated atherosclerosis and a high risk of cardio- (i.e., myocardial infarction, coronary heart disease) and cerebrovascular (stroke) complications.

Disease severity is related to the presence of residual LAL enzyme activity and indicated by the age of onset. In the rapidly progressive form (Wolman disease, WD), the median age at initial presentation is in the first month of life, with a median age of death in untreated patients at 3.7 months. The eponymous designation is an acknowledgment of an early case reported by Moshe Wolman. In addition to hepatosplenomegaly, adrenal calcification is a characteristic feature of WD.

In two unrelated infants the diagnosis of hemophagocytic lymphohistiocytosis (HLH) was initially considered; with WD established as a diagnosis following progression to cholestasis and liver failure. Hemophagocytic lymphohistiocytosis (HLH) is a potentially lethal condition resulting from macrophage activation; it can arise as inherited or be acquired; secondary to infections, immune deficiency, and malignancy. It has been hypothesized that cholesteryl ester-induced inflammasome activation in cells of monocytic lineage may play a role, leading to secondary HLH or a phenocopy of LAL deficiency. However, it is notable that the pattern of pathological disruption as a result of macrophage activation in HLH is similar to another reticuloendothelial storage disorder, namely Gaucher disease. Studies in the LAL gene-knockout mouse model indicate critical roles of LAL in the development, homeostasis, and function of T cells, defects of which have subsequently been shown to be corrected by myeloid-specific expression of human lysosomal acid lipase. Interestingly, a similar effect was achieved by blocking stat3 and NF-κB p65 signaling using small-molecule inhibitors in myeloid-derived suppressor cells; pointing to putative molecular pathways.

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