Cholesteryl Ester Storage Disease (CESD) is an autosomal recessive lysosomal storage disorder (LSD) caused by mutations in the lysosomal acid lipase gene (LIPA) that markedly reduce lysosomal acid lipase (LAL) activity, leading to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types. In the liver, accumulation of lipids leads to diffuse microvesicular steatosis, which progresses to fibrosis and ultimately, to micronodular cirrhosis. Patients typically present with hepatomegaly, liver dysfunction, hepatic failure and type II hyperlipidemia. Although hepatosteatosis is a typical finding, the liver biopsy diagnosis may be misclassified as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or cryptogenic liver disease. Biopsy and radiological findings are not considered diagnostic, but help to suspicion of CESD. The definitive diagnosis is based on deficient LAL activity and/or LIPA gene mutations.

CESD is pan-ethnic, however, the disease incidence is unknown. The estimated incidence of the disease indicates that CESD should be largely underdiagnosed especially in European patients. Elevation of serum transaminases, and hepatomegaly are early indications of liver impairment. Therefore, CESD should be considered as a differential diagnosis in liver disease of unknown origin.

To data, there is no study which evaluated the frequency of CESD in children with unexplained transaminase elevation and/or organomegaly and/or chronic liver disease. The aim of this prospective, multicenter and cross-sectional study is to investigate frequency of CESD in children with unexplained transaminase elevation and/or and/or chronic liver disease and to identify demographic and clinical features of CESD.

Patients of 3 months to 18 years of age at the time of enrolment who have unexplained transaminase elevation (serum alanine aminotransferase (ALT) levels > 1.5 times the upper limit of normal) for more than 3 months and/or unexplained hepatomegaly or hepatosplenomegaly and/or obesity- unrelated hepatosteatosis and/or biopsy-proven cryptogenic fibrosis and cirrhosis and/or liver transplantation for cryptogenic cirrhosis will be included.

Potential participants will be invited for LAL enzyme analysis. Written informed consent will be obtained from the parents or guardians of the participants at the time of enrolment. Prospective and retrospective data will be collected. Complete family and medical history, physical examination and previously existing laboratory findings will be recorded on standard case reports form and up to 0.25 ml of blood will be drawn for LAL enzyme analysis. The blood obtained from participants will be spotted on filter paper, and dried blood spot sample (DBS) will be prepared. Finally, the dried blood spot sample will be sent to reference laboratory (NHS Greater Glasgow and Clyde, England) for LAL enzyme measurement within 1 week.

Inclusion Criteria:

1. A male or female of 3 months to 18 years of age at the time of enrolment
2. Patients who have unexplained transaminase elevation (serum ALT levels > 1.5 times the upper limit of normal) for more than 3 months
3. Patients who have unexplained hepatomegaly or hepatosplenomegaly
4. Patients who have obesity- unrelated hepatosteatosis
5. Patients who have biopsy-proven cryptogenic fibrosis and cirrhosis
6. Patients with liver transplantation for cryptogenic cirrhosis

Exclusion Criteria:

1. A male or female < 3 months or > 18 years old
2. Patients with obesity -related hepatosteatosis
3. Patients with drug-induced hepatosteatosis ( such as aspirin, methotrexate, amiodarone, glucocorticoid, tamoxifen, 5-fluorouracil, valproate, nucleoid revers transcriptase inhibitors)
4. Patients with organomegaly or transaminase elevation due to infectious causes (EBV, Brucella, cytomegalovirus, salmonella, malaria, leishmania etc), hæmato-oncological disease (hemolytic anemia, leukemia,lymphoma, malign or benign liver neoplasms), connective tissue disorders (SLE, RA), cardiac and vascular causes (heart failure, pericarditis, Budd-Chiari syndrome, portal vein thrombosis) and obesity.
5. Patient with definitive diagnosed chronic liver disease such as chronic viral hepatitis (B, C hepatitis), autoimmune hepatitis, alpha-1 antitrypsin deficiency, Wilson disease, metabolic disorders.

Patients of 3 months to 18 years of age at the time of enrolment who have unexplained transaminase elevation (serum ALT levels > 1.5 times the upper limit of normal) for more than 3 months and/or unexplained hepatomegaly or hepatosplenomegaly and/or obesity- unrelated hepatosteatosis and/or biopsy-proven cryptogenic fibrosis and cirrhosis and/or liver transplantation for cryptogenic cirrhosis