Lysosomal acid lipase deficiency (Wolman disease and cholesteryl ester storage disease)

The LIPA gene instructs cells to make lysosomal acid lipase, an enzyme found inside lysosomes. It breaks down fats such as cholesteryl esters and triglycerides into cholesterol and fatty acids that the body uses or sends to the liver for removal. With too little enzyme, fats pile up in cells throughout the body, which typically causes liver disease. The severity depends on how much working enzyme remains.

LAL-D is estimated to occur in between 1 in 40,000 and 1 in 300,000 people, varying by population, and the later-onset form is more common than the infant form. Both forms are autosomal recessive.

In the severe early-onset form, fat accumulates throughout the body within the first weeks of life, especially in the liver. Typical early signs are vomiting, diarrhoea and failure to gain weight. Babies may develop an enlarged liver and spleen, jaundice, fatty stools and poor absorption of nutrients, anaemia and developmental delay, and calcium deposits can form in the adrenal glands. Scar tissue builds up quickly in the liver, leading to cirrhosis.

NICE describes Wolman disease as a rare genetic condition that presents in babies and children under 2 years old and causes fat build-up in the liver, heart, blood vessels and digestive system. Without treatment, the baby or child will not survive. Before enzyme replacement was available, standard care was palliative.

The later-onset form usually begins in mid-childhood but can appear at any age up to late adulthood. Nearly all affected individuals develop an enlarged liver, and the spleen may also be enlarged. About two-thirds develop liver fibrosis that may progress to cirrhosis, and around one-third have malabsorption, diarrhoea, vomiting and fatty stool. Blood tests often show raised liver enzymes and high cholesterol.

Because raised cholesterol and liver problems have many more common causes, LAL-D can be hard to spot. It becomes a consideration when a child or young adult has an unexplained enlarged liver, raised liver enzymes or blood fats, or early arterial disease. The MPS Society also lists coronary artery disease among the problems seen.

LAL-D can be diagnosed with a simple blood test, usually measuring enzyme activity in a dried blood spot, confirmed with genetic testing of LIPA. Hepatology and metabolic services lead the work-up, and the extent of liver damage and cardiovascular risk are assessed alongside.

Enzyme replacement therapy with sebelipase alfa replaces the missing enzyme. In January 2024 NICE recommended it as an option for long-term treatment in Wolman disease, defined as rapidly progressive LAL-D, only if people are 2 years or under when treatment starts and the company provides it under its commercial arrangement. It is used alongside a restricted diet and can allow a haematopoietic stem cell transplant to be done if appropriate. Evidence suggests it increases survival, though the size of the benefit and long-term quality of life are uncertain.

For the later-onset form the MPS Society reports that, despite best efforts, NICE was unable to make a recommendation for sebelipase alfa in non-Wolman disease. Care there centres on specialist management of liver disease and of cardiovascular risk.

Each pregnancy for two carrier parents carries a 1 in 4 chance of an affected baby. Families with an affected child can discuss early testing in pregnancy by amniocentesis or chorionic villus sampling, and carrier testing for relatives, through a regional genetics service.

Seek urgent medical help for a baby who vomits repeatedly, will not feed, has yellow skin and eyes, or a swollen abdomen. In older children and adults, call 999 for chest pain or stroke symptoms, and seek urgent care for vomiting blood, black stools or confusion, which can signal advanced liver disease.