Deficiency of the lysosomal enzyme lysosomal acid lipase (LAL; acid cholesteryl ester hydrolase, EC 3.1.13), caused by mutations in the lysosomal acid lipase (LIPA) gene, results in storage of cholesterylesters in macrophages and hepatocytes. LAL hydrolyses cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. The disorder is extremely rare and has an autosomal recessive pattern of inheritance.
Near or complete absence of LAL activity results in the rapidly fatal infantile-onset Wolman disease (WD) (OMIM 278000). These infants have failure to thrive, diarrhea, malabsorption and massive hepatosplenomegaly and usually die before the age of 1 year. Adrenal glands are frequently involved. The more attenuated form, cholesteryl ester storage disease (CESD; OMIM 278000) has a wide spectrum of clinical phenotypes. Severe disease symptoms with gross enlargement of liver and spleen can occur during childhood, often also accompanied by involvement of the adrenal glands. On the other end of the spectrum are adults who are without any symptoms.
Pathophysiology and phenotypes
Tissues affected by the storage are mainly the liver, but also the adrenal glands, testis and gut. Adrenal glands may show calcification, particularly in the severe Wolman phenotype. These infants have a severe failure to thrive due to malabsorption that results in malnutrition, storage of cholesterol esters and triglycerides in hepatic macrophages that results in hepatomegaly and liver disease, and adrenal gland calcification that results in adrenal cortical insufficiency. Untreated, infants with classic Wolman disease do not survive beyond age one year. Children with milder forms, but severe manifestations may have gross hepatosplenomegaly, cytopenia, malnutrition and ultimately liver failure. In attenuated phenotypes, a typical pattern of type IIb dyslipidemia occurs in plasma with an increase in total cholesterol as well as LDL cholesterol, combined with low HDL cholesterol levels. This atherogenic profile may result in premature atherosclerosis, which is due to the enhanced production of cholesterol as well as decreased reverse cholesterol transport. Other complications in adults with CESD are hepatic fibrosis and eventually cirrhosis. It is not completely clear what causes the fibrotic changes. Patients with progressive liver disease will become at risk for development of cirrhosis and liver cancer.
Supportive care for patients with CESD consists of measures to treat the complications of liver disease or cardiovascular complications, according to the most up-to-date standards of care. Liver transplantation has been performed for cases with end-stage liver failure. For patients with atherosclerosis, the use of statins is part of routine treatment but has received attention as it may also more specifically target the underlying lipid disorder.
Hematopoietic stem cell transplantation has been performed in some cases of Wolman disease with variable success. This form of therapy is not applied in adult patients.
Since statins and cholestyramine can reduce the production of cholesterol and ApoB , several studies have focused on this type of treatment to reduce the lipid burden in CESD patients. However, while a favorable effect in plasma can be achieved, with some reduction in LDL-cholesterol, its effect on lysosomal accumulation in tissues is unclear. Lovastatin has been reported to have some effect, although others reported no change even in plasma levels . Ezetimibe, a cholesterol absorption inhibitor, has shown to be able to reduce liver cholesterol accumulation in LIPA knock-out mice may. Addition of ezetimibe to statins has been reported in a patient with CESD to further reduce LDL-cholesterol in plasma.
Enzyme replacement therapy
Enzyme replacement therapy with recombinant LAL (sebelipase alfa; Kanuma), has recently received marketing authorization in the EU and USA. This therapy offers great hope for children severely affected by this disorder, as they are at risk of liver failure and early death that can currently only be prevented by liver transplantation. In an ongoing study in 9 infants presenting with early-onset LALD (Wolman disease), open-label treatment with sebelipase alfa significantly improved 1-year survival compared with historical controls. The results of a placebo-controlled trial of sebelipase alfa, administered every 2 weeks at a dose of 1 mg/kg has been published in 2015. Treatment for 20 weeks in a primarily pediatric group of 66 patients with CESD resulted in normalization of alanine aminotransferase levels in 31% of patients compared with 7% in the placebo group, and improvement in the abnormal lipid profile. Interestingly, in 32 patients, liver biopsies were performed. Although sebelipase alfa undoubtedly positively affects key features of LAL deficiency, reversal of liver damage and prevention of cirrhosis or early death remain to be established. Once active screening for LAL deficiency is performed, many patients with potentially benign phenotypes are likely to be identified. For this group of patients, the natural disease progression and relevant clinical endpoints should be defined for appropriate use of sebelipase alfa.
The Amsterdam UMC is involved in the diagnosis and follow-up of patients with LALD. A protocol for follow-up of patients including criteria to start and stop sebelipase alfa therapy is currently under development in collaboration with regulators.