Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children

Hepatology Communications · 25 authors, 16 centres

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TL;DR

This multi-center cohort study of 86 pediatric patients analyzed mitochondrial hepatopathy presentations, finding key differences between acute liver failure (ALF) and chronic disease, with higher mortality and younger age in ALF, and that liver transplant provided benefit for specific genetic causes.

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This multi-center observational cohort study analyzed 86 pediatric patients with suspected mitochondrial hepatopathy (MH) from the MITOHEP and PALFSG cohorts. ALF patients were younger and had fewer neurodevelopmental delays than Chronic patients. Comprehensive genetic/enzymatic testing was more common in Chronic cases, but an etiology was identified more often in ALF (81.3% vs 61.1%), with mtDNA depletion being the most common genetic cause. Eighteen patients (21%) underwent liver transplantation, with 3 deaths reported over 33.6 post-transplant patient-years. The findings highlight phenotypic and prognostic differences between ALF and Chronic MH and support the role of rapid genetic sequencing for optimal management.

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cohort

SPECIALTY

pediatrics

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ORIGINAL PAPER

PMC10187840

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children

Hepatology Communications

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ABSTRACT

Background: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. Methods: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. Results: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. Conclusions: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

CITATION EXPORT

James E Squires, Alexander G Miethke, C Alexander Valencia et al.. Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children. Hepatology Communications. (2023). https://doi.org/10.1097/HC9.0000000000000139

AUTHORS

25 · 16 CENTRES

James E Squires, Alexander G Miethke, C Alexander Valencia, Kieran Hawthorne, Lisa Henn, Johan LK Van Hove, Robert H Squires, Kevin Bove, Simon Horslen, Rohit Kohli, Jean P Molleston, Rene Romero, Estella M Alonso, Jorge A Bezerra, Stephen L Guthery, Evelyn Hsu, Saul J Karpen, Kathleen M Loomes, Vicky L Ng, Philip Rosenthal, Krupa Mysore, Kasper S Wang, Marisa W Friederich, John C Magee, Ronald J Sokol

1UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
2Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
3Interpath Laboratory, Pendleton, Oregon, USA
4Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA
5University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colorado, USA
6Children’s Hospital Los Angeles, Los Angeles, California, USA
7Indiana University-Riley Hospital for Children, Indianapolis, Indiana, USA
8Emory University School of Medicine, Atlanta, Georgia, USA
9Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
10University of Utah School of Medicine, Primary Children’s Hospital, Salt Lake City, Utah, USA
11University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, Washington, USA
12The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
13Hospital for Sick Children, University of Toronto, Toronto, Canada
14University of California, San Francisco, California, USA
15Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA
16University of Michigan Hospitals and Health Centers, Ann Arbor, Michigan, USA