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The Frequency of Lysosomal Acid Lipase Deficiency in Children With Unexplained Liver Disease

Kuloglu, Zarife*; Kansu, Aydan*; Selbuz, Suna*; Kalaycı, Ayhan G.; Şahin, Gülseren; Kirsaclioglu, Ceyda Tuna§; Demirören, Kaan||; Dalgıç, Buket; Kasırga, Erhun#; Önal, Zerrin**; İşlek, Ali†† and National LAL-D Study Group

Journal of Pediatric Gastroenterology and Nutrition: March 2019 - Volume 68 - Issue 3 - p 371–376
doi: 10.1097/MPG.0000000000002224
Original Articles: Hepatology
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Objectives: Evidence suggests that lysosomal acid lipase deficiency (LAL-D) is often underdiagnosed because symptoms may be nonspecific. We aimed to investigate the prevalence of LAL-D in children with unexplained liver disease and to identify demographic and clinical features with a prospective, multicenter, cross-sectional study.

Methods: Patients (aged 3 months–18 years) who had unexplained transaminase elevation, unexplained hepatomegaly or hepatosplenomegaly, obesity-unrelated liver steatosis, biopsy-proven cryptogenic fibrosis and cirrhosis, or liver transplantation for cryptogenic cirrhosis were enrolled. A Web-based electronic data collection system was used. LAL activity (nmol/punch/h) was measured using the dried blood spot method and classified as LAL-D (<0.02), intermediate (0.02–0.37) or normal (> 0.37). A second dried blood spot sample was obtained from patients with intermediate LAL activity for confirmation of the result.

Results: A total of 810 children (median age 5.6 years) from 795 families were enrolled. The reasons for enrollment were unexplained transaminase elevation (62%), unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%), cryptogenic fibrosis and cirrhosis (6%), and liver transplantation for cryptogenic cirrhosis (<1%). LAL activity was normal in 634 (78%) and intermediate in 174 (21%) patients. LAL-D was identified in 2 siblings aged 15 and 6 years born to unrelated parents. Dyslipidemia, liver steatosis, and mild increase in aminotransferases were common features in these patients. Moreover, the 15-year-old patient showed growth failure and microvesicular steatosis, portal inflammation, and bridging fibrosis in the liver biopsy. Based on 795 families, 2 siblings in the same family were identified as LAL-D cases, making the prevalence of LAL-D in this study population, 0.1% (0.125%–0.606%). In the repeated measurement (76/174), LAL activity remained at the intermediate level in 38 patients.

Conclusions: Overall, the frequency of LAL-D patients in this study (0.1%) suggests that LAL-D seems to be rare even in the selected high-risk population.

*Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ankara University School of Medicine, Ankara

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ondokuz Mayıs University, School of Medicine, Samsun

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Sami Ulus Children's Hospital, Ankara

§Department of Pediatric Gastroenterology, Hepatology and Nutrition, Turkish Republic Health Ministry, Ankara Child Health Diseases, Haematology Oncology Training and Research Hospital, Ankara

||Department of of Pediatric Gastroenterology, Hepatology and Nutrition, Yuzuncu Yıl University, Faculty of Medicine, Van

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Gazi University University, Faculty of Medicine, Ankara

#Department of Pediatric Gastroenterology, Hepatology and Nutrition, Celal Bayar University Faculty of Medicine, Manisa

**Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Medical Sciences, Bakırkoy Dr Sadi Konuk Research and Training Center, İstanbul

††Department of Pediatric Gastroenterology, Hepatology and Nutrition, Atatürk University, Faculty of Medicine, Erzurum, Turkey.

Address correspondence and reprint requests to Zarife Kuloglu, MD, Ankara Üniversitesi, Tıp Fakültesi, Çocuk Hastanesi, 06643 Cebeci, Mamak/Ankara, Turkey (e-mail: zarifekuloglu@yahoo.com).

Received 25 April, 2018

Accepted 22 November, 2018

National LAL-D Study Group: The members of the Study Group are as follows: Esra Eren (Ondokuz Mayıs University, School of Medicine, Samsun), Ferda Özbay Hoşnut (Dr Sami Ulus Children's Hospital, Ankara), Nafiye Urgancı (Şişli Etfal Training and Research Hospital, İstanbul), Aytaç Yaman (Turkish Republic Health Ministry, Ankara Child Health Diseases, Haematology Oncology Training and Research Hospital, Ankara), Tanju Özkan (Uludağ University Faculty of Medicine, Bursa), Neslihan Ekşi Bozbulut (Gazi University, Faculty of Medicine, Ankara), Güzide Doğan (Celal Bayar University Faculty of Medicine, Manisa), Özlem Durmaz Uğurcan (İstanbul University, İstanbul Faculty of Medicine, İstanbul), Ayşe Merve Usta (Şişli Etfal Training and Research Hospital, İstanbul), Duran Arslan (Erciyes University, Faculty of Medicine Kayseri), Mustafa Akçam (Süleyman Demirel University, School of Medicine, Isparta), İshak Abdurrahman Işık (Antalya Training and Research Hospital, Antalya), Çiğdem Ömür Ecevit (Dr Behçet Uz Children Disease and Surgery Training and Research Hospital, İzmir), Yusuf Usta (Mersin University, Faculty of Medicine, Mersin), Taner Özgür (Uludağ University Faculty of Medicine, Bursa), Figen Özçay (Başkent University, Faculty of Medicine, Ankara), Necati Balamtekin (Gülhane Training and Research Hospital, Ankara), Yeşim Öztürk (Dokuz Eylül University, Faculty of Medicine, İzmir), Serdar Cantez (İstanbul University, İstanbul Faculty of Medicine, İstanbul), Fulya Gülerman (Kırıkkale University, Faculty of Medicine, Kırıkkale), Gonca Handan Üstündağ (Bülent Ecevit University, Faculty of Medicine, Zonguldak), Halil Haldun Emiroğlu (Selçuk University, Faculty of Medicine, Konya), Neslihan Karacabey (Erciyes University, Faculty of Medicine Kayseri), Atakan Comba (Hitit University, Faculty of Medicine, Çorum), Gülin Erdemir (Dr.Behçet Uz Children Disease and Surgery Training and Research Hospital, İzmir), Ayşen Uncuoğlu Aydoğan (Kocaeli University, School of Medicine, Kocaeli), Selim Gökçe (Bezmialem University, Faculty of Medicine, İstanbul), Pınar Kuyum (Dokuz Eylül University, Faculty of Medicine, İzmir), Meltem Gülşan (Başkent University, Faculty of Medicine, Ankara), Mahya Sultan Tosun (Denizli State Hospital, Denizli), Yavuz Tokgöz (Adnan Menderes University, Faculty of Medicine, Aydın), Burcu Güven (Kırıkkale University, Faculty of Medicine, Kırıkkale), Hasan Yüksekkaya (Necmenttin Erbakan University, Faculty of Medicine, Ankara), Gökhan Tümgör (Çukurova University, Faculty of Medicine, Ankara), Makbule Eren (Eskişehir Osmangazi University, Faculty of Medicine, Esikişehir), Maşallah Baran (İzmir Tepecik Training and Research Hospital, İzmir), Meltem Gümüş (Konya Eğitim Konya Training and Research Hospital, Konya), Oğuz Canan (Adana Başkent University; Adana), Halil Kocamaz (Pamukkale University, Faculty of Medicine, Denizli), Nelgin Gerenli (Ümraniye Training and Research Hospital, İstanbul), Murat Çakır (Karadeniz Technical University, Faculty of Medicine, Trabzon), Mehmet Ağın (Çukurova University, Faculty of Medicine, Ankara), Şamil Hızlı (Keçiören Training and Research Hospital, Ankara), Yaşar Doğan (Fırat University, Faculty of Medicine, Elazığ), Coşkun Çeltik (Şifa University, İzmir), Uğur Deveci (Fırat University, Faculty of Medicine Elazığ), Oya Balcı Sezer (Keçiören Training and Research Hospital Ankara).

Clinical registration number: NCT02372513 https://clinicaltrials.gov/ct2/show/NCT02372513.

This investigator sponsored research was funded by Alexion Pharmaceuticals Inc.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

Z.K. and A.K. are consultants for Alexion Pharmaceuticals Inc. The remaining authors report no conflicts of interest.

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,