Citrin deficiency presenting as acute liver failure in an eight-month-old infant

Citrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy.Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile.Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation(IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate-glutamate carrier protein. The infant was immediately put on a lactosefree,medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid-soluble vitamins.However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo,two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection,and may require liver transplantation.

Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes

BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed,or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase(AKR1 D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid(CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration(FDA) approved drug cholic acid, which is currently unavailable in China.AIM To evaluate the therapeutic responses of patients with AKR1 D1 deficiency to oral bile acid therapy, specifically CDCA.METHODS Twelve patients with AKR1 D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1 D1, were treated with differing doses of CDCA or ursodeoxycholic acid(UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters,notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.RESULTS Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.CONCLUSION The primary bile acid CDCA is effective in treating AKR1 D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.

Recurrent acute liver failure associated with novel SCYL1 mutation:A case report

BACKGROUND Pediatric recurrent acute liver failure(RALF) with recovery between episodes is rare. Causes include autoimmune disease, which may flare and subside;intermittent exposure to toxins, as with ingestions; and metabolic disorders,among them the fever-associated crises ascribed to biallelic mutations in SCYL1,with RALF beginning in infancy. SCYL1 disease manifest with RALF, as known to date, includes central and peripheral neurologic and muscular morbidity(hepatocerebellar neuropathy syndrome). Primary ventilatory and skeletal diseases also have been noted in some reports.CASE SUMMARY We describe a Han Chinese boy in whom fever-associated RALF began at age 14 mo. Bilateral femoral head abnormalities and mild impairment of neurologic function were first noted aged 8 years 6 mo. Liver biopsy after the third RALF episode(7 years) and during resolution of the fourth RALF episode(8 years 6 mo) found abnormal architecture and hepatic fibrosis, respectively. Whole-exome sequencing revealed homozygosity for the novel frameshift mutation c.92_93 insGGGCCCT, p.(H32 Gfs~*20) in SCYL1(parental heterozygosity confirmed).CONCLUSION Our findings expand the mutational and clinical spectrum of SCYL1 disease. In our patient a substantial neurologic component was lacking and skeletal disease was identified relatively late.

Continuous tracheal gas insufflation during protective mechanical ventilation in juvenile piglets with acute lung injury induced by endotoxin

Low tidal volume mechanical ventilation is difficult to correct hypoxemia, and prolonged inhalation of pure oxygen can lead to oxygen poisoning. We suggest that continuous tracheal gas insufflation （TGI） during protective mechanical ventilation could improve cardiopulmonary function in acute lung injury. Totally 12 healthy juvenile piglets were anesthetized and mechanically ventilated at PEEP of 2 cmH2O with a peak inspiratory pressure of 10 cmH2O. The piglets were challenged with lipopolysaccharide and randomly assigned into two groups （n=6 each group）： mechanical ventilation （MV） alone and TGI with continuous airway flow 2 I/min. FIO2 was set at 0.4 to avoid oxygen toxicity and continuously monitored with an oxygen analyzer. Tidal volume, ventilation efficacy index and mean airway resistant pressure were significantly improved in the TGI group （P〈0.01 or P〈0.05）. At 4 hours post ALl, pH decreased to below 7.20 in the MV group, and improved in the TGI group （P〈0.01）. Similarly, PaCO2 was stable and was significantly lower in the TGI group than in the MV group （P〈0.01）. PaO2 and PaO2/FIO2 increased also in the TGI group （P〈0.05）. There was no significant difference in heart rate, respiratory rate, mean artery pressure, central venous pressure, dynamic lung compliance and mean resistance of airway between the two groups. Lung histological examination showed reduced inflammation, reduced intra- alveolar and interstitial patchy hemorrhage, and homogenously expanded lungs in the TGI group. Continuous TGI during MV can significantly improve gas exchange and ventilation efficacy and may provide a better treatment for acute lung injury.