Rodrigo Tzovenos Starosta1,2,3, Suzanne Boyer4, Shawn Tahata5, Kimiyo Raymond6, Hee Eun Lee6, Lynne A Wolfe7, Christina Lam8,9, Andrew C Edmondson10, Ida Vanessa Doederlein Schwartz11,12, Eva Morava4,6,13. 1. Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. r.starosta@wustl.edu. 2. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. r.starosta@wustl.edu. 3. Department of Pediatrics, Washington University in Saint Louis, St. Louis, MO, USA. r.starosta@wustl.edu. 4. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. 5. Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. 6. Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 7. Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, MD, USA. 8. Division of Genetic Medicine, University of Washington, Seattle, WA, USA. 9. Center of Integrated Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. 10. Section of Biochemical Genetics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 11. Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 12. Service of Medical Genetics, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brazil. 13. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Abstract
BACKGROUND: The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice. METHODS: Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment. RESULTS: Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury. CONCLUSIONS: Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).
BACKGROUND: The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice. METHODS:Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment. RESULTS: Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury. CONCLUSIONS: Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).
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