The Role of Predictive Models in the Assessment of the Poor Outcomes in Pediatric Acute Liver Failure

Objectives: In children, acute liver failure (ALF) is a severe condition with high mortality. As some patients need liver transplantation (LT), it is essential to predict the fatal evolution and to refer them early for LT if needed. Our study aimed to evaluate the prognostic criteria and scores for assessing the outcome in children with ALF. Methods: Data of 161 children with ALF (54.66% female, mean age 7.66 ± 6.18 years) were analyzed based on final evolution (32.91% with fatal evolution or LT) and etiology. We calculated on the first day of hospitalization the PELD score (109 children), MELD, and MELD-Na score (52 children), and King’s College Criteria (KCC) for all patients. The Nazer prognostic index and Wilson index for predicting mortality were calculated for nine patients with ALF in Wilson’s disease (WD). Results: PELD, MELD, and MELD-Na scores were significantly higher in patients with fatal evolution (21.04 ± 13.28 vs. 13.99 ± 10.07, p = 0.0023; 36.20 ± 19.51 vs. 20.08 ± 8.57, p < 0.0001; and 33.07 ± 8.29 vs. 20.08 ± 8.47, p < 0.0001, respectively). Moreover, age, bilirubin, albumin, INR, and hemoglobin significantly differed in children with fatal evolution. Function to etiology, PELD, MELD, MELD-Na, and KCC accurately predicted fatal evolution in toxic ALF (25.33 vs. 9.90, p = 0.0032; 37.29 vs. 18.79, p < 0.0001; 34.29 vs. 19.24, p = 0.0002, respectively; with positive predicting value 100%, negative predicting value 88.52%, and accuracy 89.23% for King’s College criteria). The Wilson index for predicting mortality had an excellent predictive strength (100% sensibility and specificity), better than the Nazer prognostic index. Conclusions: Prognostic scores may be used to predict the fatal evolution of ALF in children in correlation with other parameters or criteria. Early estimation of the outcome of ALF is essential, mainly in countries where emergency LT is problematic, as the transfer to a specialized center could be delayed, affecting survival chances.

The Protective Effects of a Modified Xiaohua Funing Decoction against Acute Liver Failure in Mice Induced by D-Gal and LPS

Objective. The aim of this study was to evaluate the effects of a modified Xiaohua Funing decoction (Xfd) on acute liver failure (ALF) and determine whether the protective mechanisms are related to alterations in the gut microbiota. Methods. An animal model of ALF was induced by intraperitoneal injection of D-galactosamine (D-Gal, 0.5 g/kg) and lipopolysaccharide (LPS, 100 μg/kg). Male BALB/c mice were randomly divided into the following 4 groups: the control group (saline, Con), model group (D-Gal/LPS, Mod), silymarin pretreatment group (200 mg/kg, Sil), and modified Xfd pretreatment group (650 mg/kg, Xfd). The Sil and Xfd groups received the respective intervention orally for 14 days and 2 h before D-Gal/LPS treatment. The liver injury markers included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and liver histology. 16S rRNA gene sequencing was performed to assess the effects on the caecum content. Results. D-Gal/LPS treatment caused severe ALF, illustrating that the ALF model was successfully established. The administration of Sil and Xfd greatly reduced the serum ALT and AST levels and improved the pathological signs of liver injury. However, no significant difference was found between the two groups. In contrast to the Mod group, the Sil and Xfd groups showed a shift toward the Con group in terms of the gut microbiota structure. The abundances of Firmicutes and Bacteroidetes and the Bacteroidetes/Firmicutes ratio in the Mod group significantly differed from those in the Con group. The Sil and Xfd groups showed restoration of the disordered microbiota. Significantly increased relative abundances of Lachnospiraceae_NK4A136_group and Candidatus_Saccharimonas and a markedly decreased Muribaculaceae abundance were found in the Sil and Xfd mice compared with those in the Mod mice ( P < 0.01 , P < 0.05 ). Interestingly, a negative correlation was observed between the abundances of the gut microbiota constituents, specifically Clostridia_UCG-014, and ALT and AST levels. Conclusion. In summary, our results indicate that Xfd may protect the liver and modify the gut microbiota in ALF mice.

Acute HBV Related ALF- Successful Outcome with Oral Antiviral Treatment

Case report: We present a young female of fourteen years who was admitted to the hospital with short duration of Icterus, malaise, vomiting and diagnosed to be having acute hepatitis B. She went into acute liver failure as evidenced by development of hepatic encephalopathy and coagulopathy. She was managed on lines of hepatic encephalopathy along with oral antiviral treatment. She recovered successfully and was discharged after two weeks in heamodynamically stable condition. After a gap of six months, she became Hepatitis B surface (HbsAg) & hepatitis B e-antigen (HbeAg) negative and Hepatitis B Virus DNA (HBV DNA) was undetectable with normal liver function tests. She is on regular follow up for last one year and is absolutely normal. Conclusion: Acute hepatitis B can go into acute liver failure in 1% of cases, treatment for which includes liver transplantation and oral antiviral treatment which is especially helpful in cases who cannot afford liver transplantation, as was in our case.

Effects and Mechanism of Oxymatrine Combined with Compound Yinchen Granules on the Apoptosis of Hepatocytes through the Akt/FoxO3a/Bim Pathway

The aim of the present study was to investigate the effects and mechanism of oxymatrine (OMT) combined with compound yinchen granules (CYG) on the apoptosis of hepatocytes through the Akt/FoxO3a/Bim pathway in rats with acute liver failure. The rat model of acute liver failure was established using lipopolysaccharide/D-galactosamine (LPS/D-GalN). The expression of proteins in rat liver tissues was detected by western blot analysis. The mRNA expression of FoxO3a, Bim, Bax, Bcl-2, and caspase-3 in rat liver tissues was detected by RT-qPCR. The apoptosis rate of rat hepatocytes was determined by flow cytometry. Western blots showed that when compared with the normal group, the expression of p-Akt and p-FoxO3a in the model group was decreased ( P < 0.05 ), while the expression of Bim was increased ( P < 0.01 ). Compared with the model group, the expression of p-Akt and p-FoxO3a in the OMT group and the OMT combined with CYG groups was increased ( P < 0.05 or P < 0.01 ), while the expression of Bim was decreased ( P < 0.05 ). The Bax/Bcl-2 ratio and caspase-3 protein expression in the model group were significantly higher than those in the normal group ( P < 0.01 ). The Bax/Bcl-2 ratio and the expression of caspase-3 protein in the OMT group and the OMT combined with CYG groups were significantly lower than those in the model group ( P < 0.01 ). The results of RT-qPCR were consistent with those of western blot. The results of flow cytometry showed that the apoptosis rate of hepatocytes in the OMT group and the OMT combined with CYG groups was significantly lower than that in the model group ( P < 0.05 or P < 0.01 ). We concluded that LPS/D-GalN can induce apoptosis of hepatocytes in rats with acute liver failure through the Akt/FoxO3a/Bim pathway. OMT combined with CYG inhibits apoptosis of hepatocytes in rats with acute liver failure via the Akt/FoxO3a/Bim pathway.

Acute Liver Failure in Rats Induced Vasogenic Edema and Nitric Oxide Synthase-Nitric Oxide-cGMP Pathway after Differential Regulation of NMDA Receptors in Cerebral Cortex and Cerebellum

Acute liver failure (ALF) is a complication of severe liver dysfunction resulting from a wide range of factors including alcoholism, drug-abuse, improper medication, viral hepatitis etc., and present with high mortality rate among the human population. ALF led hyperammonemia (HA) induced cerebral dysfunction is considered to be the main cause of death in patients, however, the precise molecular mechanism is not completely understood. The aim of this study was to investigate the status of brain edema and modulation of N-methyl D-aspartate receptors (NMDAR)- Nitric oxide synthase (NOS)- Nitric oxide (NO)- cyclic guanosine monophosphate (cGMP) axis in the cerebral cortex and cerebellum of ALF rats. ALF was induced by intraperitoneal (IP) injection of thioacetamide (TAA). We observed significantly increased brain water content in ALF rats but absence of astrocytes swelling suggested induction of vasogenic edema. Except constant NR2B, down regulation of NR2A, 2C and 2D subunits containing NMDAR genes in cerebral cortex, however, constant NR2A-C but up-regulation of NR2D subunit in cerebellum suggested brain regions specific differential regulation of NMDAR in ALF rats. Significantly increased nNOS gene and protein level were found to be accompanied by the significantly increased level of NO and cGMP in both brain tissues; however, increased eNOS expression in cortex but increased iNOS expression and activity in cerebellum were observed in ALF rats. Together these findings suggested that ALF in rats may trigger differential regulation of NR2A-D subunits containing NMDAR, induction of NOS-NO-cGMP axis and vasogenic edema in cerebral cortex and cerebellum.

Liver Progenitor Cells in Massive Hepatic Necrosis—How Can a Patient Survive Acute Liver Failure?

Massive hepatic necrosis is the most severe lesion in acute liver failure, yet a portion of patients manage to survive and recover from this high-risk and harsh disease syndrome. The mechanisms underlying recovery remain largely unknown to date. Recent research progress highlights a key role of liver progenitor cells, the smallest biliary cells, in the maintenance of liver homeostasis and thus survival. These stem-like cells rapidly proliferate and take over crucial hepatocyte functions in a severely damaged liver. Hence, the new findings not only add to our understanding of the huge regenerative capability of the liver, but also provide potential new targets for the pharmacological management of acute liver failure in clinical practice.