Adult-to-adult liver transplantation from a living donor is increasingly performed in the United States but is concentrated in a few large-volume centers. Mortality among donors is low, but complications in the donor are relatively common.

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Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.

In a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

It has recently been hypothesized that hepatocyte CHO metabolites (hexose-or triose-phosphates) might not only stimulate ChREBP and activate DNL, but might also serve as a signal to enhance HGP (17,18). This hypothesis derives in part from the counterintuitive observation that while ChREBP is known to stimulate glycolysis through transactivation of glycolytic genes (22), it may also transactivate expression of G6pc encoding the enzyme er, from skeletal muscle and adipose tissue enhances hepatic DNL (20). Additionally, siRNA-mediated knockdown of ChREBP in ob/ob mice decreases hepatic DNL in the setting of persistent hyperinsulinemia (21). Thus, hepatic DNL may be regulated by increased substrate delivery independently of insulin signaling. However, whether increasing intrahepatic CHO metabolites might also signal to increase glucose production has not been fully explored.

Background & Aims Microparticles released into the bloodstream upon activation or apoptosis of CD4+ and CD8+ T cells correlate with inflammation, determined by histologic analysis, in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatter liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver. Methods We compared profiles of circulating microparticles from patients with NAFL and NASH (n=67) to those with CHC (n=42), compared with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage, based on histologic analyses. We assessed the ability of the profiles determine the severity of inflammation and fibrosis, based on serologic and histologic analyses. Results Patients with CHC had increased levels of microparticles from CD4+ and CD8+ T cells; the levels correlated with disease severity, based on histologic analysis and levels of alanine aminotransferase (ALT). Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T (iNKT) cells and macrophages/monocytes (CD14+), which mediate pathogenesis of NASH. Microparticles from CD14+ and iNKT cells correlated with levels of ALT and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99). Conclusions Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease.

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy.

Background 30-day readmissions for hospitalized patients with cirrhosis are common, particularly for patients with hepatic encephalopathy (HE). Methods We performed a prospective pre-post study from 2010–2013 to assess the impact of a quality improvement (QI) protocol on 30-day readmissions to a transplant center’s liver unit. The intervention included a yearlong control period, a handheld checklist and an “electronic” phase incorporating checklist items into the electronic provider order entry system. The intervention included goal-directed lactulose therapy and universal rifaximin for overt HE as well as prompts for antibiotic prophylaxis of spontaneous bacterial peritonitis (SBP). 30-day readmission trends were compared to non-cirrhotic patients admitted to hospitalists and patients with decompensated cirrhosis at another center. Results 824 patients were admitted 1720 times. The average model for end-stage liver disease score on admission was 17.7 ± 7.4. The electronic phase was associated with 40% lower adjusted odds of 30-day readmission compared to control, both overall and for patients with HE. The proportion of admissions for ≥ grade 2 HE that resulted in a readmission fell from 48.9% (66/135) in the control period to 26.0% (27/104) in the electronic phase (p = 0.0003). Rifaximin use for HE and antibiotic secondary prophylaxis of SBP (on discharge) were associated with lower adjusted odds of readmission (respective OR 0.39 and 0.40). The electronic phase was associated with a lower length of stay (beta coefficient −1.34 95% CI: −2.38 – −0.32, p = 0.01). Conclusion A QI initiative using electronic decision support reduced 30-day readmissions for patients with cirrhosis.