Shah, Vijay H.

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short‐term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol‐use disorders should be incorporated into pre‐ and post‐LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

AbstractNeutrophil extracellular traps, or NETs, are heterogenous, filamentous structures which consist of extracellular DNA, granular proteins, and histones. NETs are extruded by a neutrophil in response to various stimuli. Although NETs were initially implicated in immune defense, subsequent studies have implicated NETs in a spectrum of disease processes, including autoimmune disease, thrombosis, and cancer. NETs also contribute to the pathogenesis of several common liver diseases, including alcohol-associated liver disease and portal hypertension. Although there is much interest in the therapeutic potential of NET inhibition, future clinical applications must be balanced against potential increased risk of infection.

Disease monitoring in nonalcoholic steatohepatitis (NASH) is limited by absence of noninvasive biomarkers of disease regression or progression. We aimed to examine the role of multiparametric three‐dimensional magnetic resonance elastography (3D‐MRE) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH regression after interventions. This is a single‐center prospective clinical trial of 40 patients who underwent bariatric surgery. Imaging and liver biopsies were obtained at baseline and 1 year after surgery. The imaging protocol consisted of multifrequency 3D‐MRE to determine the shear stiffness at 60 Hz and damping ratio at 40 Hz, and MRI‐PDFF to measure the fat fraction. A logistic regression model including these three parameters was previously found to correlate with NASH. We assessed the model performance in the detection of NASH resolution after surgery by comparing the image‐predicted change in NAFLD activity score (delta NAS) to the histologic changes. A total of 38 patients (median age 43, 87% female, 30 of 38 with NAS ≥ 1, and 13 of 38 with NASH) had complete data at 1 year. The NAS decreased in all subjects with NAS ≥ 1 at index biopsy, and NASH resolved in all 13. There was a strong correlation between the predicted delta NAS by imaging and the delta NAS by histology (r = 0.73, P < 0.001). The strength of correlation between histology and the predicted delta NAS using single conventional parameters, such as the fat fraction by MRI‐PDFF or shear stiffness at 60 Hz by MRE, was r = 0.69 (P < 0.001) and r = 0.43 (P = 0.009), respectively. Conclusion: Multiparametric 3D‐MRE and MRI‐PDFF can detect histologic changes of NASH resolution after bariatric surgery. Studies in a nonbariatric setting are needed to confirm the performance as a composite noninvasive biomarker for longitudinal NASH monitoring.

Pharmacologic stimulation of a G protein–coupled receptor preferentially expressed on fibroblasts reverses experimental lung and liver fibrosis.

OBJECTIVES: Alcohol-associated liver disease is increasing, especially hospitalizations with acute on chronic liver failure and need for liver transplant. We examined trends in prevalence, inhospital mortality, and resource utilization associated with AALD and ACLF in the young. METHODS: The National Inpatient Sample (2006–2014) was queried for hospitalizations with a discharge diagnosis of cirrhosis using the International Classification of Diseases, Ninth Edition, codes. ACLF hospitalization was defined as ≥2 organ failures and stratified by age: young (≤35 years) and older (>35 years). RESULTS: Of 447,090 AALD admissions (16,126 in young) between 2006 and 2014, ACLF occurred in 29,599 (6.6%), of which 1,143 (7.1%) were in young. Compared with older, admissions in young had more women (35% vs 29%), were obese (11% vs 7.6%), were Hispanics (29% vs 18%), have alcoholic hepatitis (AH) (41% vs 17%), and have ACLF grades 2 or 3 (34% vs 25%), P < 0.001 for all. Between 2006 and 2014, ACLF in AALD among young increased from 2.8% to 5.2%, with an AH proportion from 24% to 42%, P < 0.0001 for both. Young had more complications requiring ventilation (79% vs 76%) and dialysis (32% vs 28%), P < 0.001 for both. Compared with older, ACLF admission in young had longer hospitalization (12 vs 10 days) with higher hospital charges ($127,915 vs $97,511), P < 0.0001 for both, with 20% reduced inhospital mortality (54%–45%), P < 0.001. DISCUSSION: AALD-related hospitalizations are increasing in young in the United States, mainly because of the increasing frequency of AH. Furthermore, this disease burden in young is increasing with a higher frequency of admissions with more severe ACLF and consumption of hospital resources. Studies are needed to develop preventive strategies to reduce burden related to AALD and ACLF in young.

OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.

During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF‐β). The result is an epigenetically regulated transcriptional program leading to a pro‐fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF‐β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF‐β. Ingenuity pathway analysis identified “HSC Activation” as the highly up‐regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF‐β response. EZH2 overexpression suppressed TGF‐β‐induced FN protein in vitro, suggesting FN as a direct target of EZH2‐based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2‐mediated tri‐methylation of lysine 27 on histone 3 is diminished by TGF‐β. TGF‐β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N‐recognin 4 in complex with EZH2, which was validated by western blotting in vitro. Ubiquitin mutation studies suggested K63‐based ubiquitin linkage and chain elongation on EZH2 in response to TGF‐β. A deletion mutant of EZH2, lacking its N‐terminal domain, abrogates both TGF‐β‐stimulated EZH2 degradation and FN release. In vivo, cholangiocyte‐selective knockout of EZH2 exacerbates bile duct ligation–induced fibrosis whereas MDR2‐/‐ mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF‐β regulates proteasomal degradation of EZH2 through N‐terminal, K63‐linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.