Therapy for lysosomal acid lipase deficiency: Replacing a missing link


  • See Article on Page 950

  • Potential conflict of interest: Dr. Grabowski consults for and received grants from Shire HGT. He also consults for Sanofi-Gensyme and advises Synageva.

Address reprint requests to: Gregory Grabowski, M.D., The A. Graeme Mitchell Chair of Human Genetics, Professor and Director, Division and Program in Human Genetics, Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229-3039. E-mail:


cholesteryl ester storage disease


lysosomal acid lipase


low density lipoprotein receptor


peroxisome proliferator activated receptor gamma


Wolman disease

Inherent in deDuve's original concept of the lysosome was the need for intracellular mechanisms to localize, deliver, or traffic its enzymes/components to this subcellular organelle.[1] This concept also applied to extracellular materials to be broken down/digested in the lysosome to amino acids, mono- or oligosaccharides, or simple fats. This process of receptor-mediated endocytosis has evolved from the simple idea that lysosomes exist as a dead-end digestive vacuole to a highly sophisticated specialized organelle having processes for host defense and modulation of cellular metabolism. The elegant work by Brown and Goldstein and coworkers[2-4] detailed the endocytotic pathway mediated by low density lipoprotein receptors (LDLR) created a cycle for the control of cellular/body metabolism of cholesterol and, eventually, of much of neutral lipid metabolism. At the center of this cycle was the enzyme, lysosomal acid lipase (LAL), which cleaves cholesteryl esters and acylglycerides that are delivered to the lysosome to free cholesterol and fatty acids. These lipids leave the lysosome and interact with the SREBP system of many genes to modulate their metabolism and also, by way of free fatty acids, as ligands for peroxisome proliferator activated receptor gamma (PPARγ) to down-regulate cytokine production (Fig. 1).

Figure 1.

Schematic of the central role of LAL in the control of cholesterol and triglyceride metabolism in cells. LDL-cholesteryl esters (LDL-CE) and triglycerides enter cells by way of the LDL-receptor and are delivered to the endosomal system and to the lysosomes (blue) in which LAL resides. LAL cleaves the fatty acids from CE and triglycerides. The free cholesterol leaves the lysosome by the NPC 1 and 2 proteins, and modulates SREBP-2 and free fatty acids modulate SREBP-1c. The free fatty acids can also down-regulate cytokine expression through PPARγ. The SREBP-2 and 1c systems regulate many genes for enzymes in the synthesis of their respective endproducts.

The central role of LAL in these processes is poignantly made by its deficiency diseases, Wolman disease (WD) and cholesteryl ester storage disease (CESD). WD is a horrific disease of infancy leading to death by 3-8 months of age with failure to thrive, cachexia, malabsorption, hepatomegaly, adrenal calcifications, and ultimately liver failure.[5] CESD is more indolent, but in many patients it leads to progressive hepatic fibrosis and cirrhosis, liver dysfunction and failure, hypercholesterolemia, and attendant cardiovascular complications. Importantly, the central nervous system (CNS) is not directly involved in either variant. WD and CESD result from mutations in LIPA leading to total and partial deficiencies of LAL, respectively. In WD, the range of LAL substrates is highlighted by the massive accumulations of cholesteryl esters and tri-acylglycerides, di-acylglycerides, and mono-acylglycerides in lysosomes of the hepatocytes, Kupffer cells, and other macrophages throughout the body; in small intestinal macrophages, the accumulation leads to malabsorption. In comparison, CESD has some residual LAL activity that leads to the predominant accumulation of cholesteryl esters, hence the name, in many of the same tissues as in WD. In reality, WD and CESD represent a continuum of disease severity that is controlled by the amount of residual LAL activity in cells with high turnover of cholesteryl esters and acylglycerides. This continuum is the consequence of varying degrees of metabolic and inflammatory disruptions evolving from the level of LAL deficiency (Fig. 1). The florid clinical presentation and lethality of WD should lead to urgent, intensive, rapid evaluations and diagnosis, whereas the more indolent nature of CESD has led to missed diagnoses, and the misperception of it as a “benign” disease.

Reviews of the reported cases of CESD indicate a different clinical picture. Progressive liver fibrosis leading to cirrhosis is not uncommon, nor is liver transplantation. Indeed, many of the patients who received liver transplantation were children,[5] indicating an unappreciated severity of CESD. Nearly all CESD patients receive pharmacologic therapy for their significant hypercholesterolemia (250-500 mg/dL), but this has little if any effect on the tissue involvement and progression. CESD patients have persistent elevations of serum transaminases, indicating continuous liver disease processes and elevated acute phase reactants, e.g., ferritin and cytokines, as evidence of ongoing inflammation. Clearly, there is a need to define the spectrum of CESD, or late onset LAL deficiency, in a broader population.

Because of CESD's more slowly progressive disease, the frequencies and the clinical spectrum have been underappreciated in the general population. Based on molecular screening for LIPA mutations, studies in Germany and the Czech Republic estimated a frequency of 1/40,000-1/80,000 for CESD.[6] A similar study of patients in a large USA cardiovascular risk group produced frequency estimates of ∼1/160,000.5 The screened populations bias these estimates and suggest that there could be significant frequency variations, but are in the range of other lysosomal storage diseases. It would be informative to screen the nonalcoholic fatty liver disease (NAFLD) population with normal body mass index (BMI) for LIPA mutations. However, an awareness and ease of diagnosis of CESD, e.g., molecular testing or LAL assays in dried blood spots, and its listing in the differential diagnosis of NAFLD or hypercholesterolemia is essential for more accurate frequency estimates and the true spectrum of LAL deficiency phenotypes. WD appears to be more rare.

As implied by Balwani et al.[7] in this issue, defining the involved populations and developing an awareness for rapid diagnosis of WD and CESD is becoming more pressing, since LAL treatment seems on the horizon. Proof-of-principle studies in rodents, using human recombinant LAL made in several different eukaryotic systems, show that enzyme replacement therapy with LAL can correct the majority of the biochemical, histological, and inflammatory consequences of LAL deficiency, except for those in the adrenal gland.[8, 9] Balwani et al. used human recombinant LAL produced in chicken eggs by selective expression in the oviduct with accumulation of human LAL in egg white. The enzyme is then purified for administration. The results show that the biopharmaceutical is safe and many of the parameters of CESD, e.g., elevated transaminases, ferritins, and serum cholesterol levels, respond rapidly, and upon withdrawal of LAL they partially return to pretreatment levels.

Although liver biopsies were not a part of this study, several patients had evidence of cholesterol mobilization with transient increases in serum cholesterol following LAL administration. This result varied between patients and may be related to the degree of liver involvement, e.g., fibrosis. The exact mechanism of this effect is unknown, but likely relates to the delivery of LAL to lysosomes in hepatocytes and Kupffer cells since in rodents this is where most of the enzyme localizes. In future studies, the relationships between the serum cholesterol levels and hepatic histology could be important, as the peak of the cholesterol elevation following LAL administration might serve as a biomarker of excess cholesteryl esters in the hepatocytes and other cell types. Similarly, the extent of reversibility of tissue lesions and residual damage will need to be assessed.

Although not part of this safety study, a role of LAL therapy in WD appears clear since, except for one case, the effects of HSCT have been uniformly poor. However, the lethality of WD will make early and rapid diagnosis essential. The degree of recovery in WD, or CESD, is not known, but based on other rapidly progressive lysosomal storage diseases, e.g., Infantile Pompe disease, earlier therapy leads to better outcomes.

As with the other lysosomal storage diseases for which enzyme replacement therapies are available, there remain many questions and issues to address as this therapy for LAL deficiency states moves forward: how soon to treat, how to predict the disease severity, how much is reversible, what are the long-term effects, are all tissues treated equally, and the list goes on. Importantly, there are and will be many basic and applied issues that arise from this promising treatment. As with the other lysosomal storage diseases, LAL therapy should stimulate much basic and clinical research into these neglected diseases that will lead to enhanced overall care and improved health of afflicted patients.

  • Gregory Grabowski, M.D.

  • Division and Program in Human Genetics, Children's Hospital Research Foundation, Cincinnati OH