Common mechanisms in pediatric acute liver failure

Mann, Jake; Lenz, Dominic; Stamataki, Zania; Kelly, Déirdre

doi:10.1016/j.molmed.2022.11.006

Cited by 9 publications

(4 citation statements)

References 109 publications

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“…Innate and adaptive immune cells work together to play a key part in these processes. The ratio of continued liver damage to the pace of hepatocyte regeneration determines whether a patient needs a liver transplant or heals on their own (7) . In the current study, the outcome was favorable without liver transplantation in nearly two thirds of cases, while the remaining passed the way or underwent liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

Optic Nerve Sheath Diameter Measured by Trans-Cranial Ultrasound in Children with Acute Liver Failure

2024

The Egyptian Journal of Hospital Medicine

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Background: The early diagnosis of elevated intracranial pressure (ICP) improves the prognosis of acute liver failure (ALF). Invasive monitoring (intracranial bolts) is the gold standard approach for measuring ICP, however it comes with problems. Objective: This study aimed to evaluate the role of bedside, ultrasound (US) guided measurement of optic nerve sheath diameter (ONSD) in ALF children. Methods: 36 ALF and 21 healthy children (0-18 years) were enrolled. All patients had undergone full history taking, thorough clinical examination, and routine investigations. ONSD was measured for each on admission, with any change of consciousness and at recovery in ALF, and once in controls. Results: Both groups were age-and sex-matched. The ALF group showed significant increase in ONSD than in healthy controls (P 0.008). On admission, the mean of ONSD in resolved group (4.13 ± 0.573 mm) was lower than that of died group (4.57 ± 0.64 mm) but without statistical significance (P = 0.082). ONSD before discharge significantly increased in died group 5.07 ± 0.44 mm than in living group (3.98 ± 0.354 mm, P<0.0001). ONSD was significantly higher in ALF patients with disturbed conscious level (5.16 ± 0.45 mm) than in conscious patients (4.007 ± 0.34 mm, P <0.0001). ONSD at a cut-off value of > 4.82 mm showed accuracy of 88.7% in discriminating between resolving and vanishing ALF patients (P =<0.0001). Conclusions: ONSD is a safe bedside method that may be used to serially monitor children with ALF. It is an excellent predictor of patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Optic Nerve Sheath Diameter Measured by Trans-Cranial Ultrasound in Children with Acute Liver Failure

2024

The Egyptian Journal of Hospital Medicine

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“…access to renal replacement therapies and plasma exchange), 77 should be considered to bridge WRS patients to recovery throughout the first years of life. Particularly in WRS‐associated ALF treatment with N‐acetylcysteine as a scavenger for reactive oxygen species might be considered, but systematic data is lacking 78 …”

Section: Discussionmentioning

confidence: 99%

Natural history of Wolcott‐Rallison syndrome: A systematic review and follow‐up study

Aldrian,

Bochdansky,

Kavallar

et al. 2024

Liver International

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Background and AimsTo systematically review the literature for reports on Wolcott‐Rallison syndrome, focusing on the spectrum and natural history, genotype‐phenotype correlations, patient and native liver survival, and long‐term outcomes.MethodsPubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow‐up were extracted. Survival and correlation analyses were performed.ResultsSixty‐two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver‐pancreas in one and combined liver‐pancreas‐kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One‐, five‐ and ten‐year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013).ConclusionWolcott‐Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver‐ or multi‐organ transplantation is a feasible treatment option to improve survival.

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“…Deficiencies in PERK activity induced by genetic, environmental, or aging-related factors are implicated in the onset and pathogenesis of numerous diseases (Almeida et al ., 2022). Loss-of-function mutations in EIF2AK3 , the gene that encodes PERK, are causatively associated with Wolcott-Rallison syndrome – a rare autosomal-recessive disorder that involves multi-organ failures including prominent neonatal or early-childhood insulin-dependent diabetes, kidney and liver dysfunction, and cardiac abnormalities (Delepine et al , 2000; Julier & Nicolino, 2010; Mann et al , 2022). Hypomorphic EIF2AK3 alleles are also implicated in neurodegenerative diseases including the tauopathy progressive supranuclear palsy (PSP) (Hoglinger et al , 2011; Park et al , 2022; Yuan et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Perea

Baron

Dolina

et al. 2023

Preprint

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The integrated stress response (ISR) is a network of eIF2alpha kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.

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Common mechanisms in pediatric acute liver failure

Cited by 9 publications

References 109 publications

Optic Nerve Sheath Diameter Measured by Trans-Cranial Ultrasound in Children with Acute Liver Failure

Optic Nerve Sheath Diameter Measured by Trans-Cranial Ultrasound in Children with Acute Liver Failure

Natural history of Wolcott‐Rallison syndrome: A systematic review and follow‐up study

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

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