UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Hepatol Commun. 2023 May 15;7(6). doi: 10.1097/HC9.0000000000000139. eCollection 2023 Jun 1.
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.
We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.
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.
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.
线粒体 DNA（mtDNA）和核 DNA 基因的改变会影响线粒体功能，导致一系列被称为线粒体肝疾病（MH）的肝脏疾病，可分为 mtDNA 耗竭、RNA 翻译、mtDNA 缺失和酶紊乱。我们旨在提高对 MH 发病机制和自然史的认识。
我们分析了具有 MH 表型的患者的数据，以确定遗传原因，描述临床表现谱，并确定结局。
分析了三种纳入表型，即急性肝衰竭（ALF，n=37）、慢性肝病（Chronic，n=40）和肝移植后（n=9）。ALF 患者年龄更小[中位数 0.8 岁（范围，0.0，9.4）比 3.4 岁（0.2，18.6），p<0.001]，神经发育延迟更少（40.0%比 81.3%，p<0.001）比 Chronic。Chronic 患者比 ALF 患者更常进行全面检查（90.0%比 43.2%）；然而，ALF 患者更常确定病因（81.3%比 61.1%），mtDNA 耗竭最常见（ALF：77%比 Chronic：41%）。在测序队列中（n=60），63%有明确的线粒体疾病。聚类分析发现，尽管进行了全面检查，仍有一部分患者没有潜在的遗传病因。无肝移植的 2 年生存率为 40%（ALF 比 Chronic，16%比 65%，p<0.001）。18 例（21%）接受了移植。在移植后 33 患者年的随访中，报告了 3 例死亡。
ALF 和 Chronic MH 表型之间的差异包括诊断时的年龄、系统受累、无肝移植生存率和遗传病因，这突出了在适当的临床环境中进行超快速测序的必要性。聚类分析显示了一组符合纳入标准但没有明确遗传或酶学诊断的患者，这突出了需要确定其他病因的必要性。
