Abstract. citrin is a liver-type aspartate/glutamate carrier (AGc) encoded by the gene SLc25A13. Two phenotypes for human citrin deficiency have been described, namely the adult-onset citrullinemia type II (cTLN2) and the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). However, citrin deficiency currently remains a perplexing and poorly recognized disorder. In particular, description of postNIccd clinical presentations before cTLN2 onset is rather limited. Analysis of SLC25A13 mutations, identification of dysmorphic erythrocytes, hepatobiliary scintigraphic imaging and investigation of post-NIccd clinical presentations were performed in a citrin-deficient cohort comprised of 51 cases of children diagnosed with citrin deficiency in a Chinese pediatric center. Twelve SLc25A13 mutations were detected in this cohort, including the novel V411M and G283X mutations. Among the 51 citrin-deficient subjects, 7 cases had echinocytosis, which was associated with more severe biochemical abnormalities. delayed hepatic discharge and bile duct/bowel visualization were common scintigraphic findings. Moreover, 9 of the 34 post-NIccd cases demonstrated concurrent failure to thrive and dyslipidemia, constituting a clinical phenotype different from NIccd and cTLN2. The novel mutations, echinocytosis, hepatobiliary scintigraphic features and the novel clinical phenotype in this study expanded the genotypic and phenotypic spectrum of citrin deficiency, and challenge the traditionally-assumed 'apparently healthy' period after the NIccd state for this disease entity.

Background The alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio has been considered an alternative marker for hepatic steatosis. However, few studies have investigated the association of the ALT/AST ratio with non-alcoholic fatty liver disease (NAFLD) in nonobese people. Methods A total of 12,127 nonobese participants who were free of NAFLD participated in this study. The participants were divided into quintiles of the ALT/AST ratio. Multiple Cox regression models were used to explore the association of the ALT/AST ratio with new-onset NAFLD. Results During the five-year follow-up period, 2147 individuals (17.7%) developed new-onset NAFLD. After adjusting for all non-collinear covariates, the multiple Cox regression analysis results showed that a higher ALT/AST ratio was independently associated with new-onset NAFLD in nonobese Chinese (adjusted hazard ratios [aHRs]: 2.10, 95% confidence intervals: 1.88, 2.36). The aHRs for NAFLD across increasing quintiles of the ALT/AST ratio were 1, 1.63 (1.30, 2.04), 2.07 (1.65, 2.60), 2.84 (2.33, 3.48) and 3.49 (2.78, 4.39) (P for trend< 0.001). The positive association was more significant among people with high blood pressure, high blood lipids and hyperglycaemia, as well as in men. Additionally, the regression spline showed that the saturation effect of the ALT/AST ratio on NAFLD risk was at 0.93 in this study population, which was 1.22 in males and 0.89 in females. Conclusions In nonobese Chinese individuals without NAFLD at baseline, the increase in the ALT/AST ratio is closely associated with the risk of new-onset NAFLD.

Background Low-density lipoprotein to high density lipoprotein (LDL/HDL) cholesterol ratio has been reported to predict the risk of many metabolic diseases. However, the association between the LDL/HDL cholesterol ratio and nonalcoholic fatty liver disease (NAFLD) has not been established. Methods A longitudinal cohort design was adopted in this study; 9767 non-obese subjects without NAFLD were included and analyzed. The subjects were grouped according to the quintile of LDL/HDL cholesterol ratio. The cumulative incidence of NAFLD and the independent effect of the LDL/HDL cholesterol ratio on NAFLD during 5 years of follow-up were calculated using the Kaplan-Meier method and Cox proportional-hazards regression model. Results During the 5-year follow-up period, 841 subjects were diagnosed with new-onset NAFLD, and the 1-, 2-, 3-, 4-, and 5-year cumulative incidence rates of NAFLD were 1.16, 4.65, 8.33, 12.43, and 25.14%, respectively. In the multivariable-adjusted Cox proportional-hazards regression model, the LDL/HDL cholesterol ratio was significantly associated with the risk for NAFLD (HR: 1.66, 95% CI: 1.38–1.99, P trend< 0.001), especially among young people (HR: 3.96, 95% CI: 1.50–10.46, P interaction< 0.05). Additionally, receiver operating characteristic curve analysis showed that the LDL/HDL cholesterol ratio was better than HDL cholesterol and LDL cholesterol in predicting new-onset NAFLD. Conclusions LDL/HDL cholesterol ratio is an independent predictor of NAFLD in Chinese non-obese people with normal lipids, and its predictive value is higher than that of other lipoproteins. In clinical practice, the LDL/HDL cholesterol ratio can be used to identify people at high risk of NAFLD.

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