Hepatic Involvement in Aicardi-Goutières Syndrome

Abstract

Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.

We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expression[ISG] scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.

Across the AGS cohort (n = 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test; p = 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly p = 0.0401, age onset p = 0.0355). While most subjects (n = 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.

In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS.

Keywords

Aicardi-Goutières syndrome - liver - ISGs

Publication History

Received: 03 June 2020

Accepted: 30 November 2020

Article published online:
14 January 2021

• References

• 1 Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 2015; 15 (07) 429-440
• 2 Adang LA, Frank DB, Gilani A. et al. Aicardi Goutières syndrome is associated with pulmonary hypertension. Mol Genet Metab 2018; 125 (04) 351-358
• 3 Crow YJ, Hayward BE, Parmar R. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 2006; 38 (08) 917-920
• 4 Rice GI, Bond J, Asipu A. et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 2009; 41 (07) 829-832
• 5 Rice GI, Kasher PR, Forte GM. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet 2012; 44 (11) 1243-1248
• 6 Rice GI, Del Toro Duany Y, Jenkinson EM. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet 2014; 46 (05) 503-509
• 7 Cattalini M, Galli J, Andreoli L. et al; IAGSA study group. Exploring autoimmunity in a cohort of children with genetically confirmed Aicardi-Goutières syndrome. J Clin Immunol 2016; 36 (07) 693-699
• 8 Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol 2008; 50 (06) 410-416
• 9 Ramantani G, Kohlhase J, Hertzberg C. et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum 2010; 62 (05) 1469-1477
• 10 Mieli-Vergani G, Vergani D, Czaja AJ. et al. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4: 18017 DOI: 10.1038/nrdp.2018.17.
• 11 Gilman AJ, Le AK, Zhao C. et al. Autoantibodies in chronic hepatitis C virus infection: impact on clinical outcomes and extrahepatic manifestations. BMJ Open Gastroenterol 2018; 5 (01) e000203 DOI: 10.1136/bmjgast-2018-000203.
• 12 Narkewicz MR, Horslen S, Belle SH. et al; Pediatric Acute Liver Failure Study Group. Prevalence and significance of autoantibodies in children with acute liver failure. J Pediatr Gastroenterol Nutr 2017; 64 (02) 210-217
• 13 Strassburg CP, Vogel A, Manns MP. Autoimmunity and hepatitis C. Autoimmun Rev 2003; 2 (06) 322-331
• 14 Vanderver A, Adang L, Gavazzi F. et al. Janus kinase inhibition in the Aicardi-Goutières syndrome. N Engl J Med 2020; 383 (10) 986-989
• 15 Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017 . Retrieved from Accessed December 16, 2020 https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50
• 16 Kim H, de Jesus AA, Brooks SR. et al. Development of a validated interferon score using Nanostring technology. J Interferon Cytokine Res 2018; 38 (04) 171-185
• 17 Rice GI, Forte GM, Szynkiewicz M. et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol 2013; 12 (12) 1159-1169
• 18 Armangue T, Orsini JJ, Takanohashi A. et al. Neonatal detection of Aicardi Goutières syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. Mol Genet Metab 2017; 122 (03) 134-139
• 19 Shults JRS, Leonard M. Improved generalized estimating equation analysis via xtqls for implementation of quasi-least squares in Stata. Stata J 2007; 7 (02) 147-166
• 20 Shults and Hilbe. Quasi-Least Squares Regression. Boca Raton, FL: Chapman & Hall/CRC; 2014