US Pharm. 2017:42(5):HS-22-HS-26.

ABSTRACT: Lysosomal acid lipase deficiency (LAL-D), also known collectively as Wolman’s disease and cholesteryl ester storage disease, is a heterogenous disease due to the absence or reduction of LAL enzyme activity. It is considered an ultrarare disease with limited prevalence data available; however, the literature suggests a prevalence of 8 to 25 per million, depending on ethnicity and geographical location. LAL-D can be characterized by the accumulation and buildup of cholesteryl esters and triglycerides in the liver, spleen, and other organs. Management of LAL-D consists of enzyme-replacement therapy, along with symptomatic treatment of associated complications and, possibly, surgery for complicated organ disease.

Lysosomal acid lipase deficiency (LAL-D), also known collectively as Wolman’s disease and cholesteryl ester storage disease (CESD), is a heterogeneous disease due to the absence or reduction of LAL enzyme activity. Wolman’s disease is an early presentation of the disease in infants, while CESD presents in children and adults.1,2 Wolman’s disease is the more severe form of LAL-D. CESD results in partial enzyme activity, whereas Wolman’s disease results in lack of enzyme activity or complete lack of enzyme.3 LAL-D is a genetic autosomal recessive condition that leads to a buildup of fats or lipids in multiple tissues and organs, along with calcium deposits in the adrenal glands. This accumulation of fats in tissues and organs ultimately leads to a variety of symptoms. In addition to accumulation of fats, calcium deposition in the adrenal glands is distinctive of Wolman’s disease.3

LAL-D is considered an ultrarare disease with limited prevalence data available; however, the literature suggests a prevalence of 8 to 25 per million, depending on ethnicity and geographical location. The prevalence data may be inaccurate because of the nonspecific signs and symptoms, which can lead to underdiagnosis and misdiagnosis.4 According to the European Parliament of Medicinal Products, an ultrarare disease is considered to be a condition that affects only one in every 50,000 patients.5 Due to the low prevalence of ultrarare diseases, effective treatments are rarely available, leading to higher rates of mortality.


This autosomal recessive disease arises from mutations in the lipase A or lysosomal acid type (LIPA) gene. LAL-D has been referred to as CESD, Wolman’s disease, type 2 acid cholesteryl ester hydrolase deficiency, acid lipase disease, cholesteryl ester hydrolase deficiency storage disease, and LIPA deficiency. LAL-D is a heterogeneous disease that presents with varying signs, symptoms, and rate of progression due to LIPA gene mutations.7,8 Clinically, LAL-D results in two major phenotypes: infantile-onset Wolman’s disease and later-onset CESD. The disease subtype and severity are based primarily on the absence or amount of residual LAL activity determined by the two LIPA mutant alleles.7 LAL plays a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes. LDL-derived neutral lipids are degraded by LAL, resulting in free cholesterol and fatty acids that interact with transcription factors sterol regulatory element–binding proteins (SREBPs) that directly modulate the expression of genes involved in the synthesis and uptake of cholesterol and lipogenesis.4

With normal LAL activity, there is an intracellular abundance of free cholesterol that leads to SREBP-2-mediated down-regulation of LDL receptors, feedback inhibition of hydroxymethyl glutaryl coenzyme A (HMG- CoA) reductase, stimulation of acyl-cholesterol acyltransferase, and intracellular fatty acid inhibition of phospholipid and triglyceride production.4,9 When LAL activity is absent or reduced, cholesteryl esters and triglycerides are not degraded and accumulate within lysosomes, causing a lack of intracellular free cholesterol and resulting in an SREBP-mediated up-regulation of endogenous cholesterol production by HMG-CoA reductase and of endocytosis via LDL receptors, as well as increased synthesis of apolipoprotein B (Apo B) and markedly increased production of very-low-density lipoproteins (vLDL). In LAL-D, the cellular uptake of LDL-C has been shown to increase in LAL-deficient fibroblasts, while the uptake of Apo B was normal in a patient with LAL-D.

In LAL-deficient hepatocytes, increases in cholesterol synthesis lead to great increases in vLDL-C production and secretion, the natural way of exporting cholesterol from the liver; this, in turn, leads to enhanced LDL-C production and, thus, may be an important contributor to hypercholesterolemia in LAL-D.4,9 LAL activity deficiency results in nonhydrolyzed cholesteryl esters and triglycerides that accumulate in various organs, as noted, in both parenchymal and Kupffer cells. The progressive lipid deposition results in hepatomegaly, splenomegaly, and liver fibrosis/cirrhosis.4,7,9,10 The abnormal progressive lipid accumulation has also been described in the adrenal glands, lymph nodes, intestinal mucosa, vascular endothelium, and skeletal muscle.9

Genetically speaking, the LIPA gene maps to chromosome 10q23.2; it has 10 exons and is approximately 45 kb in length.8,11 The LIPA gene encodes lipase A, the liposomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. More than 40 loss-of-function mutations have been identified to date, with the most severe alterations, such as nonsense mutations, frameshift defects, and point mutations, resulting in stop codons that are generally detected in affected infants.7,9 Of the 19 known mutations causing Wolman’s disease, most (37%) are small deletions/insertions, with 26% nonsense, 21% consensus splice-site mutations, 10% missense lesions, and 5% large deletions.7 Of the 32 known CESD mutations, 50% were missense, with 25% small deletions/insertions, 16% nonsense, 6% consensus splice-site mutations, and 3% large deletions.

The most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; also referred to as E8SJM-1), which has the potential to allow the generation of full-length transcripts and resulting in the production of low levels of residual enzyme activity.7,11,12 This specific gene mutation accounts for 60% of reported mutations among multiethnic CESD. In addition, this mutation is estimated to have a predicted prevalence of CESD in the Caucasian and Hispanic populations of ~0.8 per 100,000 cases.12

Residual enzyme activity levels are more significantly decreased in Wolman’s disease (5% of controls) compared to a generally less severe but overlapping range of loss of activity in CESD (range 2%-11% of residual activity).13 Due to Wolman’s disease, absent or <1% of normal LAL activity results in massive lysosomal accumulation of cholesterol esters and triglycerides, predominantly in the liver, spleen, adrenals, bone marrow, lymph nodes, and macrophages throughout the body, particularly the intestinal villi.7

Diagnosis/Clinical Manifestations

LAL-D can be diagnosed by measuring LAL enzymatic activity, in addition to genetic testing of the LIPA gene. Enzyme activity can be measured by testing peripheral leukocytes, cultured fibroblasts, liver tissue, or dried blood spots. LIPA gene mutations can be discovered by performing LIPA gene analysis. When deficiency in enzyme activity occurs, buildup of lipids can result. As a result of this accumulation of cholesteryl esters and triglycerides in the liver, spleen, and other organs, many complications can arise in infants and adults.4,14 Dyslipidemia is commonly found in LAL-D patients, with development of atherosclerosis, cardiovascular disease, and premature mortality.4 Liver disease is another feature of LAL-D, with patients presenting with hepatomegaly, elevated transaminases, microvesicular steatosis, and progressive liver fibrosis and cirrhosis.4,14

Hepatomegaly is the most common initial abnormality seen.15 Other manifestations include frequent diarrhea, abdominal and epigastric pain, emesis, anemia, malabsorption, cholestasis, steatorrhea, poor growth, and gallbladder dysfunction.7 LAL-D is an underrecognized disease in which many patients will receive no diagnosis or the incorrect diagnosis.4 The abnormalities hepatomegaly, elevated transaminases, and dyslipidemia also occur in other cardiovascular, liver, and metabolic diseases that are more prevalent than LAL-D.4,15 LAL-D may often be confused with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, familial combined hyperlipidemia, heterozygous familial hypercholesterolemia, metabolic syndrome, or cryptogenic cirrhosis.4,15 Therefore, timely identification and diagnosis are important.

Infants with LAL-D typically have a more acute clinical course compared with children and adults.

The most rapidly progressive presentation of LAL-D occurs in infants.4 First onset of symptoms for most infants occurs before the age of 1 month.14 Growth failure and gastrointestinal symptoms, including vomiting, diarrhea with steatorrhea, and abdominal distention, are usually the first signs to manifest, followed by liver complications.4,14 Infants develop liver fibrosis and cirrhosis due to a large accumulation of cholesteryl esters and triglycerides in the liver.4,15 Liver complications in infants resemble the abnormalities seen in children and adults, which include hepatomegaly, elevated transaminases, liver steatosis, and fibrosis.14 Multiorgan failure due to liver cirrhosis, liver failure, and adrenal failure occur later in an infant. Death typically occurs in infants within the first 6 months of life.14

The clinical course in children and adults with LAL-D is more variable than in infants.4 Onset of symptoms can range from age 5 years to age 44 years in males and age 68 years in females. Detection of LAL-D is often incidental.4 Children and adults will present initially with asymptomatic symptoms, including nausea, abdominal pain, and constipation.4 Liver dysfunction is commonly seen with hepatomegaly—the universal finding upon diagnosis.4,15 Elevated transaminases, splenomegaly, and dyslipidemia will also present in this population.15 Children and adults experience type IIa or IIb hyperlipidemia with elevated total cholesterol, triglycerides, and LDL-C, and decreased HDL-C. Dyslipidemia in these patients has been associated with atherosclerosis and premature cardiovascular disease.4 Morbidities related to liver disease in patients with LAL-D are seen more frequently than cardiovascular events in patients with LAL-D.4 Children who are affected will have a severe course of disease, which will lead to early liver failure and liver transplant.7 LAL-D patients who are diagnosed later in life have a more attenuated course during which they are normally asymptomatic until a cardiovascular event or sudden death from liver injury leads to the identification of LAL-D.7


Enzyme-Replacement Therapy

Until recently, there were no FDA-approved medications for the treatment of LAL-D. On December 8, 2015, the FDA announced the approval of sebelipase alfa (Kanuma) for the treatment of this ultrarare and devastating disease. Kanuma is IV recombinant human LAL infusion produced in the egg whites of genetically engineered chickens to support the replacement of absent or reduced LAL activity.16 LAL enzyme activity leads to reductions in liver fat content and transaminases  and enables metabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in LDL cholesterol, non-HDL cholesterol, and triglycerides, and increases in HDL cholesterol. Improvement in growth occurs as a result of substrate reduction in the intestine. Kanuma has proven beneficial in both components of LAL-D, Wolman’s disease and CESD. Studies have shown that sebelipase alfa can be lifesaving in those patients suffering from severe Wolman’s disease. In patients with CESD, sebelipase alfa has shown to be life improving, with prolonged survival.10 Dosing considerations may be different based on the component of the disease and/or presentation. Patients presenting with rapidly progressive disease within the first 6 months of life will require dosing at 1 mg/kg every week, with dose escalation up to 3 mg/kg every week. All other patients will be dosed at 1 mg/kg every other week.

Currently, the prescribing information does not include guidelines on whether dosage adjustments are needed in patients with hepatic or renal disease. Sebelipase alfa is available only through a restricted-distribution program in the United States. Infusion usually lasts about 2 hours, but the drug can be given at a faster rate over 1 hour for patients tolerating infusion on lower doses (1 mg/kg). This medication is available in a 20-mg/10-mL single-use vial, and a volume of 0.9% sodium chloride is used for dilution. According to the prescribing information, the infusion volume should be based on the prescribed dose and prepared to a final concentration of 0.1 mg/mL to 1.5 mg/mL. The final product should be immediately used after dilution but may be refrigerated up to 24 hours if immediate use is not possible. For those who may experience hypersensitivity reactions and/or are using higher doses (3 mg/kg), healthcare providers should consider prolonging the infusion time.

Common adverse reactions that may be experienced while a patient is receiving enzyme-replacement therapy with Kanuma include diarrhea, vomiting, fever, anemia, nasopharyngitis, and headache. Those with known hypersensitivity reactions to egg, egg products, or excipients should be cautious about using this drug. Hypersensitivity reactions may occur from as early as the sixth infusion to as late as 1 year after treatment initiation. In clinical trials, about 3% to 20% of patients treated experienced a reaction that may or may not be related to hypersensitivity. Most cases of hypersensitivity reactions occurred during or within 4 hours of infusion completion. If anaphylaxis does occur, immediate discontinuation of infusion along with appropriate medical support should be initiated. Pretreatment with antihistamines, antipyretics, and corticosteroids may be necessary for future infusions or to prevent possible anaphylactic episodes. Another potential concern is the development of antibodies to Kanuma, although there is not a clear association between antibody development and efficacy of therapy in the pediatric and adult populations.17 The annual cost of Kanuma in the U.S. is expected to be about $700,000.18

Treating Symptoms/Complications

Many patients with CESD may have hypercholesterolemia. In particular, elevations in total cholesterol and LDL may occur. As a result, lipid-lowering therapy may be needed to treat these high levels and prevent atherosclerotic events. Statins, cholestyramine, ezetimibe, and a diet low in triglycerides and cholesterol may be recommended.10 In addition, every effort should be made to reduce cardiovascular risks and complications. Malabsorption and malnutrition can occur in LAL-D patients and may necessitate involving a nutritional specialist and possible parenteral nutrition therapy in severe cases due to weight loss and failure to thrive. Those with severe liver disease (i.e., cirrhosis or liver failure) may eventually require a liver transplant. Hematopoietic stem cell transplants have limited utility in managing the multiorgan disease process but has been performed in some infants with LAL-D, although high rates of toxicity and problems with maintaining engraftment may occur. Adrenal insufficiency may be treated with corticosteroids as needed. Beta blockers are beneficial and may be recommended for those individuals found to have esophageal varices, although they have not proven to be helpful in preventing esophageal varices. Nonsteroidal anti-inflammatory drugs should be avoided in patients with thrombocytopenia.4,10

Conclusion and Pharmacist’s Role

When treating a complex and rare genetic disorder like LAL-D, an interdisciplinary team approach is always beneficial and provides the best outcomes for patients due to the collaborative expertise of all disciplines involved. This team should comprise primary care physicians, mid-level practitioners, geneticists, nutritionist/dieticians, clinical pharmacists, and other specialists as necessary based on clinical disease manifestations. Pharmacists have a unique role because they are one of the most respected and accessible healthcare professionals. Providing insight into therapeutic considerations when it comes to the utilization of enzyme-replacement therapy, lipid-lowering therapy, and diet will be valuable input in the decision making for each patient. Pharmacists are in a key position to provide education to providers and patients on proper storage, handling, administration, and management of infusion-related reactions when it comes to enzyme-replacement therapy.

In addition, clinical pharmacists can help identify  individuals who may be at high risk for cardiovascular complications associated with this disease or with comorbid disease states. Identification of these unique patients are imperative so that preventative measures, whether medication therapy or nonpharmacologic therapies, are recommended and/or employed. Also, these patients (in particular, adult patients) commonly may have co-occurring health conditions that may need to be managed in conjunction with LAL-D and that potentially can make medication-therapy recommendations more complicated. Therefore, although LAL-D is a rare disorder, pharmacists knowledgeable on this subject can provide much insight in efforts to augment positive outcomes along with the rest of the interdisciplinary team.


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