From the editor’s desk… – journal of hepatology anoxic brain injury mri

Acetaminophen (APAP)-induced liver injury is the most common cause of ALF worldwide. APAP metabolism gives rise to metabolites NAPQI, which bind to cellular and mitochondrial proteins to form APAP protein adducts (APAP-AD). Mitochondrial APAP-AD trigger mitochondrial damage which may result in necrotic cell death and subsequent liver injury. Little is known about how hepatocytes can remove APAP-AD. Using elegant approaches ( in vivo mouse model and in vitro experiments), ni et al. Show that APAP-AD are removed through selective autophagy. The autophagy receptor protein p62 is recruited to APAP-AD, which could facilitate APAP-AD transition to the detergent insoluble form and allow their recognition and entrapment by autophagosomes.Anoxic brain injury mri

pharmacological induction of autophagy (torin 1) or inhibition of autophagy (leu or CQ) improves or impairs autophagic removal of APAP-AD and results in protection or exacerbation of APAP-induced necrosis and liver injury, respectively. Ni et al. Suggest that pharmacological induction of autophagy may be a novel approach for treating APAP-induced liver injury.

Interleukin (IL)-15 binds with high affinity to IL-15 receptor subunit alpha (IL-15RA) to activate janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways. IL-15 (as well as IL-2) stimulates the proliferation of T cells; induces the generation of cytotoxic T lymphocytes; facilitates the proliferation of, and the synthesis of immunoglobulin, by B cells; and induces the generation and persistence of natural killer (NK) cells.Anoxic brain injury mri IL-15 is important for the maintenance of long-lasting, high-avidity T-cell responses to invading pathogens, and it achieves this by supporting the survival of CD8 + memory T cells. IL-15RA is expressed in immune cells and hepatic resident cells. Jiao and ooka et al. Hypothesized that IL-15RA engagement by its agonist may result in anti-fibrotic actions. They show that in mice IL-15RA activation results in anti-fibrotic effects through direct effects on hepatic stellate cells (HSC), independently of any action on NK homeostasis. They suggest that future studies should explore the anti-fibrotic potential of enhancing IL-15 signaling in HSC.

The respiratory complex III, which has 11 structural subunits and requires several assembly factors, plays an important role in liver homeostasis.Anoxic brain injury mri kremer et al. Report the case of a child with complex III defect and acute liver dysfunction with lactic acidosis, hypoglycemia, and hyperammonemia. Homozygous, truncating, mutations were found in LYRM7 and MTO1. The protein encoded by LYRM7 is a nuclear-encoded mitochondrial matrix protein that stabilizes rieske fe-S protein (known as UQCRFS1) and chaperones it to the inner mitochondrial membrane complex III (CIII, which is the main enzyme complex in the mitochondrial respiratory chain). MTO1 encodes a mitochondrial protein thought to be involved in mitochondrial trna modification. Comparison of the patient’s clinical history to previously reported patients with a complex III defect due to nuclear DNA mutations showed striking similarities.Anoxic brain injury mri this intriguing study demonstrates that profound complex III defect in the liver impedes liver adaptation to prolonged fasting leading to severe lactic acidosis, hypoglycemia.

As curing chronic hepatitis C virus (HCV) infection can be now effectively achieved in nearly all patients, strategies to bring patients into medical care is of upmost importance. Many, however, are unaware of their infection but treatment is vital in order to reduce the future population-based HCV-related disease burden. To achieve this goal, the centers for disease control and the united states preventive services task force recommended a universal one-time anti-HCV test. This applied to americans born 1945–1965, as more than 70% of all HCV infections in the U.S.Anoxic brain injury mri belong to this birth cohort. Sarkar et al. Studied patterns and predictors of HCV testing across the U.S. Within this birth cohort utilizing data from the national corporate data warehouse of the U.S. Veterans administration health system. From the more than 4.2 million birth cohort veterans in medical care, only 51% had HCV tests, with significant variations in testing among the different centers (range: 7–83%). Hence, further improvement in HCV screening is needed and the current work may provide an important basis in order to optimize future national HCV screening strategies.

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Spontaneous clearance of chronic HCV infection is believed only to occur in exceptional cases but valid estimates about its true incidence are missing.Anoxic brain injury mri to elucidate the true spontaneous clearance rate in chronically infected patients, bulteel et al. Used retrospective data obtained on HCV testing between 1994 and 2013 in the west of scotland and defined spontaneous HCV clearance as ⩾2 sequential samples positive for HCV RNA ⩾6 months apart followed by ⩾1 negative test. The incidence rate of spontaneous HCV clearance was surprisingly high with 0.36/100 person-years follow-up among 10,318 untreated patients with chronic HCV infection, and female gender, younger age at infection, lower HCV RNA load and co-infection with hepatitis B virus were positively associated with this event. This important study highlights that spontaneous clearance may occur in certain subgroups even after a prolonged duration of chronic infection more frequently as expected.Anoxic brain injury mri further work is required to identify the mechanisms underlying spontaneous clearance.

Viral host interactions involving regulators of the innate and adaptive immune system play an important role in viral escape mechanisms, and in this process the level of interaction is also driven by both, host but also viral genetic variants. The study by lunemann et al. Provides new insights as to how HCV type-specific viral peptides influence NK cell function by targeting the killer cell immunoglobulin like receptors. These interact mainly with HLA class I molecules on the surfaces of other cells. The authors show that the HCV core-derived viral epitope YIPLVGAPL increases binding of the inhibitory KIR2DL3-encoded protein to the respective HLA C∗03:04/peptide complex, leading to a significant inhibition of KIR2DL3 + NK cell function.Anoxic brain injury mri they provide first evidence of a novel pathway by which HCV might be able to evade NK cell-mediated recognition.

Two translational studies published in this issue of the journal provide new perspectives in the development of biomarkers in patients with HCC. Ogle et al. Investigated blood in patients with HCC and controls, using an imaging flow cytometry method (with immunofluorescence of cytokeratin, epcam, AFP, glypican-3 and DNA-PK) together with analysis of size, morphology and DNA content. They show that in patients with HCC, the use of multiple parameters enhances detection sensitivity of circulating tumor cells, revealing biological associations and predictive biomarker potential that may guide future research.Anoxic brain injury mri zhu et al. Investigated whether baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial (a randomized phase 3 study of everolimus in HCC) were associated with prognosis, etiology or ethnicity. They find that the higher plasma levels of two proteins, vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 (both known to be involved in the angiogenesis process), the poorer the prognosis. Moreover, their results reveal potential differences in cmet (hepatocyte growth factor receptor) and mtor (mammalian target of rapamycin) pathway activation between asian and non-asian patients. This suggests that these differences should be considered in future clinical trials.Anoxic brain injury mri

Bitzer et al. Enrolled patients with HCC and radiologically confirmed progression on sorafenib in a phase I/II trial. This trial aimed to investigate safety, pharmacokinetics (PK) and potential biomarkers of the histone deacetylase (HDAC) inhibitor resminostat and a combination therapy with resminostat and sorafenib. They show that the combination of sorafenib and resminostat is safe and may have early efficacy. Sorafenib does not alter the PK profile of resminostat or its HDAC inhibitory activity in vivo. Moreover, they find that baseline levels of zinc finger protein 64 levels in blood cells may be a predictor of overall survival in HCC.