Lysosomal acid lipase deficiency (LALD) is an inherited condition that affects how the body breaks down fats and cholesterols. Those with LALD have large harmful amounts of fats (lipids) in their cells and tissues which can cause liver disease.
There are 2 types of lysosomal acid lipase deficiency. Causes of LALD
Lysosomal acid lipase deficiency is an autosomal recessive disorder. This means, to develop LALD, you must have two copies of an abnormal gene present. Therefore, this condition is a rare, genetic condition. Approximately only 1 in 40,000 to 300,000 individuals are diagnosed with LALD.
LALD is caused by mutations in the LIPA gene. In unaffected healthy individuals, the LIPA gene helps to produce an enzyme known as lysosomal acid lipase (LAL). This enzyme is important for generating free fatty acids and cholesterol from cholesteryl esters and triglycerides (type of fat in the blood). However, for those with LALD, there is a reduced amount of lysosomal acid lipase.1 Therefore, fat buildup occurs in multiple tissues of the body because cholesteryl esters and triglycerides cannot be broken down properly.
The body tries to remove the excess fat particles (lipids) from the body by transferring the accumulated cholesteryl esters and triglycerides to the liver to be broken down. However, as these lipids are not previously properly broken down they cannot be removed, and instead can lead to problems in the liver, and oftentimes lead to liver disease.
Signs and symptoms of LALD
Those affected with LALD often show symptoms before the age of 5.2 LALD present in infants is also known as Wolman disease and is often associated with symptoms, such as:1
- Feeding difficulties (e.g., vomiting, diarrhoea, failure to gain weight)
- Abdominal bloating
Untreated LALD may lead to further signs and symptoms of liver disease in infants, including yellowing of the skin and whites of the eyes (jaundice), and a persistent low-grade fever. Wolman’s disease can be particularly dangerous with a high premature mortality rate for those under 12 months of age.
Older children and adults have another type of LALD known as cholesterol ester storage disease, and this disease may present with a variety of signs and symptoms. These may include:3
- Abnormal enlargement of the liver (hepatomegaly )
- Abnormal enlargement of the spleen (splenomegaly)
- Gastrointestinal issues (e.g., gastrointestinal bleeding, abdominal pain, vomiting, diarrhoea)
- Elevation of cholesterol levels
- Imbalance of lipids (dyslipidemia)
LALD in adolescence and adulthood has a slower progression than for those with infancy LALD.
Management and treatment for LALD
Recently, there has been more research on medications that are effective for treating LALD. A medication known as sebelipase alfa, a human enzyme replacement therapy, has been approved by the FDA for the treatment of LALD. Research has shown this medication is beneficial in managing symptoms of lipid imbalances and liver-related issues in both children and adults.4 Prior to this medical advancement, many individuals with LALD tried lipid-lowering medications, liver transplants, and stem cell transplants. However, such medications and procedures have drawbacks including:
- There is no long-term research on the effectiveness of liver transplants for the treatment of LALD5
- Both stem cell transplants and liver transplants do not address the multifactorial issues of the disease, and rather focus on a particularly affected organ
- Certain medications like HMG-CoA reductase inhibitors may not help liver disease in patients with LALD. 5 Other lipid-lowering medications (lovostatin) have shown to not improve lipid imbalances or liver issues6
Diagnosis of LALD
Diagnosis relies on looking at the enzyme activity of LAL. This is done by taking dried blood spots. The process of dried blood spotting involves taking blood from your finger(s) and blotting it against filter paper. These dried samples are sent to a lab where they are analysed using various methods.
LADL blood results may look similar to other conditions like:1
- Heterozygous familial hypercholesterolemia (genetic disorder leading to high cholesterol)
- Non-alcoholic fatty liver disease (excess fat surrounding liver)
- Familial combined hypercholesterolemia (increases fat in the blood)
Therefore, your doctor may also need to look at your family history to determine whether the condition is LALD.
In addition, LIPA gene analysis may be used to determine whether there is a gene mutation causing LALD. With over 100 LIPA gene mutations having been identified in those with LALD, this method can prove useful for providing a LALD diagnosis even when clinical awareness is low.
How can I prevent LALD
There is no way of preventing LALD. LALD is an autosomal recessive disorder which means an affected individual inherit two copies of the abnormal LIPA gene. Although there is no way of preventing LALD, management techniques can improve your quality of life and reduce the severity of symptoms.
How common is LALD
LALD is a rare condition, affecting approximately 1 in 40,000 to 300,000 individuals in the world. As a result, many affected individuals may go underdiagnosed due to limited clinical awareness of the disease.
When should I see a doctor
If you or your child are experiencing symptoms that may indicate LALD, it is important to seek medical help. These symptoms may look like abdominal bloating, diarrhoea, failure to thrive, and difficulty gaining weight. LALD is often rapidly progressive in infants, therefore it is important you seek your doctor’s advice immediately
LALD is a rare, genetic disease that affects the metabolism of lipids within your body. LALD is caused by a specific gene mutation that affects how your body breaks down cholesteryl esters and triglycerides. Liver disease is often seen in affected individuals, and this may make the diagnosis of LALD more difficult. Therefore, diagnosis may examine a family history of LALD, enzyme activity using dried blood spots, and genetic testing. Sebelipase alfa, a type of enzyme replacement medication, is routinely prescribed for the treatment of LALD. Other types of treatment (liver transplant, stem cell transplant, and other medications) may prove less effective for the treatment of LALD.
- Witeck C da R, Schmitz AC, de Oliveira JMD, Porporatti AL, De Luca Canto G, Pires MM de S. Lysosomal acid lipase deficiency in pediatric patients: a scoping review. J Pediatr (Rio J). 2022;98(1):4–14.
- Zhang B, Porto AF. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr. 2013 Jun;56(6):682–5.
- Wilson DP, Patni N. Lysosomal acid lipase deficiency. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 [cited 2023 May 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK395569/
- Burton BK, Balwani M, Feillet F, Barić I, Burrow TA, Camarena Grande C, et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med [Internet]. 2015 Sep 10 [cited 2023 May 30];373(11):1010–20. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1501365
- Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013 Jun;58(6):1230–43.
- Di Bisceglie AM, Ishak KG, Rabin L, Hoeg JM. Cholesteryl ester storage disease: hepatopathology and effects of therapy with lovastatin. Hepatology. 1990 May;11(5):764–72.