Hepatology : official journal of the American Association for the Study of Liver Diseases
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Randomized Controlled Trial
Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.
N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. ⋯ NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.
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The clinical and public health significance of nonalcoholic fatty liver disease (NAFLD) is not well established. We investigated the long-term effect of NAFLD on mortality. This analysis utilized the National Health and Nutrition Examination Survey conducted in 1988-1994 and subsequent follow-up data for mortality through December 31, 2006. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other known liver diseases. The presence and severity of hepatic fibrosis in subjects with NAFLD was determined by the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 score. Of 11,154 participants, 34.0% had NAFLD--the majority (71.7%) had NFS consistent with lack of significant fibrosis (NFS <-1.455), whereas 3.2% had a score indicative of advanced fibrosis (NFS >0.676). After a median follow-up of 14.5 years, NAFLD was not associated with higher mortality (age- and sex-adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.93-1.19). In contrast, there was a progressive increase in mortality with advancing fibrosis scores. Compared to subjects without fibrosis, those with a high probability of advanced fibrosis had a 69% increase in mortality (for NFS: HR, 1.69, 95% CI: 1.09-2.63; for APRI: HR, 1.85, 95% CI: 1.02-3.37; for FIB-4: HR, 1.66, 95% CI: 0.98-2.82) after adjustment for other known predictors of mortality. These increases in mortality were almost entirely from cardiovascular causes (for NFS: HR, 3.46, 95% CI: 1.91-6.25; for APRI: HR, 2.53, 95% CI: 1.33-4.83; for FIB-4: HR, 2.68, 95% CI: 1.44-4.99). ⋯ Ultrasonography-diagnosed NAFLD is not associated with increased mortality. However, advanced fibrosis, as determined by noninvasive fibrosis marker panels, is a significant predictor of mortality, mainly from cardiovascular causes, independent of other known factors.
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Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4's expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2). ⋯ SALL4's expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.