Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Atypical squamous cells of undetermined significance in liquid-based cytologic specimens: results of reflex human papillomavirus testing and histologic follow-up in routine practice with comparison of interpretive and probabilistic reporting methods.

BACKGROUND: Human papillomavirus (HPV) DNA testing for high-risk types after Papanicolaou (Pap) smear interpretations of atypical squamous cells of undetermined significance (ASCUS) is a sensitive method for identifying women who harbor underlying high-grade squamous intraepithelial lesions (HSIL). To the authors' knowledge, the application of HPV testing to ASCUS smears in routine practice with comparison of probabilistic and interpretive models of cytologic reporting has not been reported. METHODS: HPV DNA testing was performed reflexively on 216 liquid-based Pap smears that initially were interpreted as ASCUS. According to the interpretive model, ASCUS interpretations were modified and reported as either low-grade squamous intraepithelial lesions (LSIL) or squamous intraepithelial lesions (SIL) when HPV positive and as reactive when HPV negative. Using the probabilistic model, ASCUS interpretations were maintained and simply reported with the HPV test result. Histologic follow-up data were obtained. RESULTS: Of the 216 women with ASCUS cytology, 142 (65.7%) were positive for high-risk HPV types. Of the 142 HPV-positive ASCUS smears, 101 (71.1%) were modified to an interpretation of LSIL (96 cases) or SIL (5 cases). Histologic follow-up of 55 of the 101 HPV-positive smears in the interpretive group and 26 of the 41 HPV-positive smears in the probabilistic group yielded similar percentages of lesions (18 lesions [32.7%] and 9 lesions [34.6%], respectively). However, there was a preponderance of low-grade lesions in the interpretive group (89%) but a nearly equal distribution of low-grade and high-grade lesions in the probabilistic group (56% and 44%, respectively); overall, 22% of the lesions were high-grade. Of the 74 HPV-negative ASCUS smears, 71 (96%) were modified to reactive and all 5 with histologic follow-up were judged as negative. CONCLUSIONS: Colposcopy with tissue studies was virtually restricted to HPV-positive cases, regardless of the reporting model used, suggesting that clinicians are basing colposcopy triage on the HPV test result rather than the definitiveness of the cytologic interpretation. This observation, the similar yield of lesions in both groups, and the significant risk of high-grade lesions argue against application of the interpretive model to HPV-tested ASCUS cases.

Transplantation for cystic fibrosis: outcome following early liver transplantation.

BACKGROUND AND AIM: Life expectancy in patients with cystic fibrosis (CF) has recently improved due to numerous factors, including a multidisciplinary approach to their management. Prolonged survival may have led to an increasing impact of liver disease on the prognosis of CF patients. The aim of this study was to assess the role of liver transplantation in patients with CF. METHODS: The factors influencing outcome in 24 patients (15 adults and nine children) with CF who have received single liver transplantation, triple heart-lung-liver transplantation (tx) or died while being assessed for triple grafting, were analyzed. RESULTS: Median age at tx in single liver recipients (13 years) was lower than in triple graft recipients (21 years) and those who died (23 years). All patients who received single liver tx made an excellent recovery, including significant improvement of their respiratory function (mean forced vital capacity (FVC) increased from 61% before transplantation to 82% of expected, 6-9 months after tx). Four out of five patients who received triple tx died (0-2 months) after operation. On the basis of our retrospective review, we propose modifications to an existing scoring system for liver tx assessment in CF by scoring additional points for elevated white blood count, bilirubin, and impaired pulmonary function. These changes will need to be evaluated prospectively to confirm their predictive value. CONCLUSIONS: Liver transplantation is effective therapy in young patients with cystic fibrosis, portal hypertension and hepatic dysfunction, and is indicated before a critical stage of deteriorating lung function is reached. In patients with both end-stage liver and lung disease, triple tx has a poor prognosis. Pre-emptive liver tx in younger patients with CF not only has a better outcome but improves lung function.