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EASL 2019 Wrap-Up Metabolic.Pptx Wrap-up session: Metabolic and alcohol related liver disease Fabio Marra Number of abstracts per category 160 140 120 100 80 60 40 20 0 Alcoholic liver NAFLD: NAFLD: NAFLD: NAFLD: disease Clinical Diagnostics Experimental Therapy aspects Alcohol: pathogenesis PS-173 Nagy Distinct functions for RIP3 and MLKL In murine models of ALD vs NAFL/NASH Ethanol-induced liver injury: • RIP3 drives injury independently of MLKL High fat diet-induced liver injury • MLKL drives injury independently RIP3 Alcohol: clinical aspects PS-057 Glyn-Owen Health Survey for England 2016 • Cross sectional survey of households • Designed to be representative of the general population of England • 7,826 adults of whom 3,791 (48%) provided a blood sample • 89.2% of sample had at least one risk factor for liver disease • 28.4% had two or more risk factors (alcohol>14 units/wk (112g/wk), BMI≥25, waist circumference high/very high, diabetes) • 13% of population are drinking above recommended alcohol (but not high risk alcohol) AND are obese or overweight • we call this group at risk of BAFLD = Both Alcohol And Fatty Liver Disease) • This group is often missed in clinical referral pathways from primary to secondary care PS-057 Glyn-Owen Proportion of the general population with high liver blood tests and fibrosis scores 100% 80% 60% 40% 20% representave sample Propor:on of the populaon 0% Male Female 18-24yrs 25-34yrs 35-44yrs 45-54yrs 55-64yrs 65-74yrs 75+ yrs High ALT High AST High Fib4 High APRI≥1.0 High AST:ALT rao • 10.9% had high ALT or AST (approx. half previous estimates) • AST:ALT ratio high in >70% of general population • Awareness of risk and testing for liver disease was low PS-171 Mueller Fibroscan (LS) predicts long-term survival in a 10-year prospective cohort of heavy drinkers Aim: Establish long-term survival data in a 10-year prospective cohort of heavy Caucasian drinkers primarily presenting for alcohol detoxification • 675 patients with mean alcohol consumption 186.5 g/d • Mean duration of heavy drinking was 14.3 years • 106 patients (15.7%) died during the observation period PS-171 Mueller Fibroscan (LS) predicts long-term survival in a 10-year prospective cohort of heavy drinkers 1 0.8 <6 kPa 0.6 6 - 12.5 kPa 0.4 ​ The cause of death could be clarified Survival >12.5 kPa 0.2 p<0.0001 in 42 patients (39%) and it was liver- related in 16 (38%) 0 0 2 4 6 8 10 12 LS was an independent predictor of Observation time (years) death in multivariate analysis (next to age, ALP, and albumin) <6 kPa 6–12.5 kPa >12.5 kPa AUROC 0.72 at 14 kPa cutoff 3-year survival rate 94% 88% 74% 5-year survival rate 90% 78% 64% LS monitoring should be mandatory for surveillance of drinkers PS-174 Tyson Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated cirrhosis Aim: determine a new non-invasive test that would distinguish SAH acute decompensation of alcohol-related cirrhosis • SAH patients had biopsy-proven steatohepatitis with MDF ≥32 • Serum BAs measured by mass spectrometry in two cohorts (89 and 105 patients) Full BA profile GCA TCA Bilirubin The entire BA profile and individual Exploratory cohort AUROC 0.93 0.90 0.87 0.79 BAs of GCA and TCA are promising 95% CI 0.87–0.99 0.83–0.97 0.77–0.97 0.67–0.91 non-invasive biomarkers for SAH, and Validaon Cohort may reduce the need for liver biopsy AUROC 0.93 0.85 0.83 0.65 95% CI 0.88–0.98 0.77–0.92 0.74–0.92 0.54–0.76 GS-011 Forrest Baseline neutrophil-to-lymphocyte ratio in alcoholic hepatitis Aim: To assess the role of neutrophil-to-lymphocyte ratio (NLR), which reflects sepsis and inflammation, in the prognosis of alcoholic hepatitis • 789 patients in the STOPAH trial • Prevalent and incident infections treated prior to randomization. Infections developing after inclusion were recorded • Prevalent and incident AKI was recorded. NLR Present (n=67) 7.5 (6.4, 8.7) Incident AKI p=0.0056 Absent (n=403) 6.0 (5.6, 6.4) Infec<on by Day Present (n=94) 7.8 (6.3, 9.2) p=0.035 7 Absent (n=695) 6.1 (5.8, 6.5) Infec<on by Day Present (n=185) 7.1 (6.3, 8.0) p=0.025 28 Absent (n=604) 6.1 (5.6, 6.5) GS-011 Forrest Baseline neutrophil-to-lymphocyte ratio in alcoholic hepatitis 100% 80% *p=0.01; OR 1.86 (1.16, 2.99) * Risk of developing infection 60% and incident AKI after * 40% prednisolone treatment greater if NLR >8 vs ≤8: % Lille Response 20% 0% NLR <5 NLR ≥5 Prednisolone 63.7% 56.5% Untreated 64.5% 41.1% High NLR associates with prevalent AKI and infection in alcoholic hepatitis. A Lille response to prednisolone is more likely if NLR ≥5, but development of infection or AKI after prednisolone treatment is greater if NLR >8 NAFLD: basic science and pathogenesis Western diet triggers a unique MoMF III PS-004 Hundermarkt inflammatory phenotype of myeloid leukocytes in bone marrow and liver Liver Ly6Gneg non-lymphoid CD45pos cells MoMF II Normal diet Western diet MoMF I y MoMF I MoMF II MoMF III tSNE tSNE x MoMF = Monocyte derived macrophages av. FC [log] av. FC [log] av. FC [log] The diet-induced inflammatory polarization of monocytes and myeloid precursors is already stably imprinted in the bone marrow and determines pathogenic responses driving NAFLD in the liver Targets for NASH therapy derived from genetic studies Eslam et al., J Hepatol 2018 PS-006 Meroni Hepatic MBOAT7 silencing by i.p. ASO induces microvesicular steatosis in vivo 1 (AU) MBOAT7 protein 0.5 * β-actin Hepatic Scramble MPO MBOAT7 MBOAT7 0 2 1.5 * TG (%) TG 1 0.5 Scramble MPO MBOAT7 Intrahepatic 0 H&E (200X) Scramble MPO MBOAT7 *P <.005 vs Scramble n=6 n=6 PS-006 Meroni Hypothesis of mechanism: Post-prandial state/ hyperinsulinemia/MBOAT7 risk allele carriers PI3P De novo lipogenesis Saturated-PI TG FATP1 Arachidonoyl- FABP1 CoA MBOAT7 Co-A Free Arachidonic TG Acid Eicosanoids Inflammation The miR-34a/SIRT1:AMPK pathway is activated in PS-003 Simao the human NAFLD muscle steatosis patients NASH patients miR-34a AMPK SIRT1 Akt The miR-34a/SIRT1:AMPK pathway and mitochondrial dynamics dysfunction were found Drp1 Mfn2 amplified in the muscle of experimental NAFLD models and human NASH. Insulin Mitochondrial signaling dynamics Targeting of the miR-34a/SIRT1:AMPK pathway may benefit the liver and the muscle improving whole body metabolism Persistence of hepatic and adipose tissue PS-002 Van Eck alterations despite diet reversal in mice ​Although diet reversal N A S V A T T re g c e lls induced metabolic and 8 P<0.001 P<0.01 8 0 P<0.001 s * * * * * * * * l l e histological normalization c 6 6 0 + 4 D in HFHFD-fed mice, S C A 4 4 0 + N 3 alterations in hepatic D W e ig h t g a in C 2 2 0 f o Th17, VAT Tc, and VAT 6 0 % 0 0 Treg cells t t D l D D D l D D 4 0 s ie s ie C k a F F C k a F F were not reversed within D s D s r H s H s w r H s H s w e F k F k e F k F k 2 2 g v H w H w v H w H w 3 e 3 e r 0 2 r 0 2 2 3 2 3 12 weeks. 2 0 C D L iv e r T h 1 7 c e lls V A T T c c e lls D ie t re v e rs a l P<0.01 This finding challenges 2 0 * * 6 0 P<0.001 0 H F H F D s * * * l l e our current s c l 5 0 1 5 l e 0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 + c 4 understanding of D W e e k s + 4 0 3 C 1 0 D + C 3 3 0 reversibility of NAFLD- f D o C 5 f 2 0 % o related inflammation % 0 1 0 upon lifestyle t t D e l D D D s e l D D C s i a F F C i a F F modification k D s k D s r H s H s w r H s H s w e F k F k e F k F k 2 v H w H w 2 v H w H w 3 e 3 e r 0 2 r 0 2 2 3 2 3 The glucocorticoid antagonist ST-001 prevents fibrosis PS-129 Caffrey development in the DIAMOND mouse model Mouse Fibrosis (NASH CRN) Perisinusoidal fibrosis (0–2) NAS SAF ac<vity score Posi:ve control 0.67 1.00 4.56 1.78 High dose 0.00 p=0.0006 0.10 p=0.0069 4.10 1.1 Low dose 0.00 p=0.0010 0.11 p=0.0110 4.00 1.00 While ST-001’s effect on NASH development is inconclusive, improvements in measures of fibrosis and NAFLD were demonstrated. NAFLD: clinical aspects GS-08 Abeseykera Non-alcoholic fatty liver disease in young adults A previous cross-sectional analysis of the ALSPAC cohort in late teens identified a NAFLD prevalence of 2.5% by ultrasound criteria This study aimed to identify the prevalence of NAFLD in this cohort, now young adults, using TE to measure fibrosis and steatosis with CAP (4,021 participants, exclusion excessive daily alcohol intake) ! ALT, AST, and GGT all rose with F score and CAP score ! CAP associated with F score ! BMI rose with rising F score and CAP score Using TE, 1 in 5 patients had steatosis and 1 in 40 had fibrosis at 24 years, an increase on the previous estimate within the same cohort 6 years prior.
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