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Arun J. Sanyal M.D. How to identify patients with MASH at risk of increased mortality The MASLD life cycle – a leading cause of cirrhosis Transplantation Steatosis Outcomes Death Cirrhosis Increasing fibrosis Steatohepatitis Ludwig et al, Mayo Clin Proc 1980, Powell et al, Gastro, 1989The global burden of MASLD is increasing and linked to the pandemic of obesity Global prevalence* of MASLD is 30.1% Global prevalence of MASLD and MASH in and MASH is 5.3% 1 people living with overweight/obesity 2 • Systematic review and meta-analysis • N=101 028 Asia Pacific • MASLD 28.0% • MASH 4.5% Overweight Obesity Prevalence of MASLD (%) 70.0 75.3 Prevalence of Regionalprevalence shows some variation MASH (%) 33.5 33.7 • MASLD ranges from 25.1% (Western Europe) to 44.4% (Latin America) • MASH ranges from 4.0% (Western Europe)to7.1%(Latin America) *MASLD prevalence in general population (>20 years) from 1990 to 2019. MASH prevalence was calculated by multiplying the prevalence of MASH in MASLD patients with the prevalence of MASLD in the general population. MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; T2D, type 2 diabetes. 1. Younossi et al. Hepatology 2023;77:133; 2. Quek et al. Lancet Gastroenterol Hepatol 2023;8:20.Patients are largely missed in primary care Population at risk Symptoms or accidental finding Largely in the realm of primary care T2D Ignored Triaged for care Lifestyle Progression to HCC GLP-1 End-stage liver disease Clinical trials Death or OLT ~ 70% of patients presenting with first complication of cirrhosis were not aware they had liver disease GLP-1, glucose-like peptide-1; HCC, hepatocellular carcinoma; OLT, Orthotopic liver transplantation; T2D, type 2 diabetes. Wong RJ, et al. J Clin Gastroenterol. 2020 DOI: 10.1097/MCG.0000000000001409; Williams R, et al. The Lancet. 2014;384:1953-97Key Takeaway # 1: liver risk is linked to severity of scarringTwo key concepts in MASLD: activity and stage Disease Onset Steatohepatitis Activity Scores Histological marker Underlying mechanism - Steatosis Disease Activity - Ballooning Steatosis Metabolic perturbation Ballooning Hepatocellular injury - inflammation Inflammation Response to metabolic Fibrosis g t changes/cell injury S cirrhosis Liver-related outcomes: Death Increasing fibrosis stage is linked to hepatic outcomes and mortality Decompensation All-Cause Mortality 0.40 0.20 t t i i a 0.30 a 0.15 o o r r e 0.20 e 0.10 t t l l u 0.10 u 0.05 u u C C 0 0 0 2 4 6 8 10 0 2 4 6 8 10 Years ofFollow-Up Years ofFollow-Up No Fibrosis Fibrosis Stage 1 Fibrosis Stage 2 Fibrosis Stage 3 Fibrosis Stage 4 Adapted from Sanyal AJ, et al. N Engl J Med. 2021;385(17):1559–1569.FIB-4 has emerged as a robust initial screening tool Included Using FIB4 and/or LSM Criteria Rateper100 Person Class A Class B Class C years (n=554) (n=536) (n=846) Fib4<1.3 Fib4 1.31- Fib4 > 2.6 2.6 Deaths * 0.07 0.42 3.08 Liver events * 0.21 1.32 9.33 MACE * 0.83 1.60 2.54 HCC * 0 0.07 1.08 Shah et al, CGH, 2009, 7:1104-1112 Given FIB-4 is not very sensitive to change consider adding a secondary test that accomplishes this- refer these patients for secondary testing Sanyal et al, Clin Gastro Hep 2023FIB-4 relationship with mortality is robust despite being age-linked Sanyal et al, CGH 2023FIB-4 predicts key clinical outcomes in obese populations and/or type 2 diabetes Total study population (n= 44,481) Liver events Cardiovascular events Mortality A B C Anstee et al, Lancet Regional Health-Europe, Vol 36, Jan 2024Liver stiffness measurement by vibration controlled transient elastography is an important tool for liver risk assessment Cross- Cut-off Fibrosis Validated (kPa) Sens. Spec Cut-off Spec. Sens Stage AUROC (kPa) (95% CI) 0.74 0 vs 1-4 (0.68, 0.79) 4.9 0.90 0.31 9.4 0.90 0.46 0-1 vs 2-4 0.79 5.6 0.90 0.44 11.9 0.90 0.40 (0.74, 0.83) 0.83 0-2 vs 3-4 (0.79, 0.87) 6.5 0.90 0.47 12.1 0.90 0.52 FIB-4 <1.3 FIB-4 ≥1.3 & VCTE <8 kPa 0-3 vs 4 0.93 12.1 0.90 0.82 14.9 0.90 0.69 FIB-4 ≥1.3 & VCTE 8–12 kPa (0.90, 0.97) FIB-4 ≥1.3 & VCTE >12 kPa Siddiqui et al, Clinical Gastroenterology and Hepatology, 2018; Boursier et al, J Hepatol 2022VCTE Reproducibility and Repeatability Mean of RDC Upper 95% RC Upper 95% # subjects # obs Median SWS confidence confidence (m/s) diff-day, diff-obound same-day, same-opebound Fibroscan/VCTE 39 39 1.641 35.6% 43.9% 19.6% 24.1% Key Takeaway: Changes in shear wave speed as evaluated by VCTE >35.6% can be considered true change (with 95% confidence). Pierce et al, In press, Radiology 2024A scientifically accurate and clinically viable way to use LSM data for clinical decision making FIB4 < 1.3 Lifestyle LSM < 8 Pharma Rx Pharma Rx Cirrhosis assessment-ELF FIB4 > 2.6 HCC surveillance etc LSM > 15 FIB-4 LSMELF T est: Clinical performance claims in label F3 (Bridging Fibrosis) 100 Progression to Cirrhosis % Score n Events Risk Hazard y 80 Ratio i Data pooled from a 60 placebo arms of <9.80 10 12 11.4% 1.00 o 5 p 2 clinical trials e 40 ≥9.80 to 89 21 23.6% 2.30 - (SIM F3, STELLAR-3) n 20 <11.30 v ≥11.30 18 8 44.4% 4.58 E n = 212 0 0 6 12 18 24 30 36 42 48 Follow-up time (months) F4 (Compensated Cirrhosis) 100 Progression to Liver Related Events % y 80 Score n Events Risk Hazard i Data pooled from Ratio a 60 o placebo arms of <9.80 47 2 4.3% 1.00 p e 40 3 clinical trials ≥9.80 to 17 7 4.0% 0.93 f (SIM F4, STELLAR-4, <11.30 7 n 20 v NASH-CX) ≥11.30 81 17 21.0% 5.84 E n = 305 0 0 6 12 18 24 30 36 42 48 VS et al. Clin Gastroenterol Hepatol. 2021;19(6):1292–1293.e3 Younossi ZM et al. Gastroenterologye (months) 2021;160:1608–1619. 2D MRE is also an useful tool for prognostic assessment Optimal cut-off (kPa) AUROC Sensitivity Specificity Mild ≥F1 2.65 0.82 69% 82% • Multicentre collaboration from 8 international patient cohorts • 798 patients living 3.14 0.92 79% 89% (mean age 51.6 years) Significant ≥F2 with MASLD F0–F4 • Aim: Evaluate the diagnostic Advanced ≥F3 3.53 0.92 87% 88% accuracy of MRE in staging liver fibrosis Cirrhosis F4 4.45 0.94 88% 89% AUROC, area under the receiving operating characteristics. Liang et al. J Hepatol 2023;79:592.NITs are getting better for prognostication Lin et al, JAMA 2024,The value of NITs extends beyond predicting histological severity to predicting major adverse liver outcomes Correlation with major adverse liver outcomes NIT • Baseline FIB-4 and change in FIB-4 are independently associated with occurrence of MALOs 2 FIB-4 • Cut-off of <9.8 rules out short-termoccurrence of MALOs with a NPV of 90% 2 ELF • Cut-off of ≥11.3 is associated with a fivefold increased risk of developing a MALO 2 LSM • Baseline LSM and change in LSM are independently associated with occurrence of MALOs • Cut-off of ≥6.48 kPa is independently associated with occurrence of MALOs 2 MRE cT1 • cT1 is associated with the presence of steatohepatitis/fibrosis and cardiovascular outcomes 1,2 Several NITs have proven prognostic value for clinical liver outcomes cT1, iron-corrected T1 mapping; MALO, major adverse liver outcome; MRE, magnetic resonance elastography; NPV, negative predictive value. 1. Roca-Fernandez et al. J Hepatol 2023;79:1085; 2. Harrison et al. Nature Med 2022;29:562.Key cutoff numbers to remember Cut-offs Test Modality Likely Unlikely Strengths and limitations VCTE Imaging ≥12 kPa <8 kPa • Point of care • No added cost FIB-4 Serum ≥2.67 <1.3 • Needs age adjustment • Insufficient PPV • Blood test sent toa reference laboratory ELF Serum ≥9.8 <7.7 • Cost AASLD, American Association for the Study of Liver Diseases; CAP, controlled attenuation parameter; dB, decibels; FIB-4, Fibrosis-4 index controlled transient elastography. Rinella et al. Hepatology 2023;77:1797.t fraction; PPV, positive predictive value; VCTE, vibrationEASL-EASD-EASO Clinical Practice Guidelines MASLD 2024 *FIB-4 thresholds valid for age ≤65 years (for age >65 years: lower FIB-4 cut-off is 2.0); **e.g. lifestyles intervention, treatment of comorbidities (e.g. GLP-1RA), bariatric procedures; *** e.g. MRE, SWE, for the Study of the Liver; EASO, European Association for the Study of Obesity; ELF, Enhanced Liver Fibrosis test; GLP-1RA, glucose-like peptide-1 receptor agonist; NIT, non-invasive test; SWE, shear wave elastography; TE, transient elastography. EASL-EASD-EASO J Hepatol 2024;doi.org/10.1016/j.jhep.2024.04.031.Some tips for the advanced practitioner NIMBLE data: Elastography-based measures can identify various MASLD phenotypes Context of Use: to identify those with fibrosis in patients with NAFLD Clinically significant fibrosis (stage 2 or higher), Advanced fibrosis (stage 3 or 4), Cirrhosis (stage 4) AUROCs FIB4 FAST Agile 3+ Agile 4 (age, AST, ALT, platelets) (CAP, LSM, AST) LSM, Age, gender, T2DM, LSM, gender, T2DM, platelets, AST, ALT platelets, AST, ALT ≥ stage 2 0.78 0.85^ 0.83* 0.81** ≥ stage 3 0.79 0.79 0.85* 0.84* Stage 4 0.84 0.74 0.9* 0.91* T2DM- type 2 diabetes mellitus, CAP; continuous attenuation parameter by VCTE, LSM: liver stiffness measurement,AST: aspartateaminotransferase, ALT: alanine aminotransferase *p<0.001 for comparison to FIB4 for intended use **p< 0.05 for comparison to FIB4 for intended use ^ p< 0.01 for comparison to FIB4 for intended use All AUROCs are significantly superior to AUROC=0.5 (p< 0.001 for all) Sanyal et al, FDA workshop 2023Baveno VII criteria for diagnosis of clinically significant portal hypertension Rule out: LSM < 15, normal platelets, rule in: LSM > 25 kp Jachs et al, CGH Volume 21, Issue 7, July 2023, Pages 1854-1863.e10The rule of fives The «rule of five» to quickly estimate the risk of decompensation and liver-related death irrespective of etiology de Franchis, R. et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 76, 959-974, doi:10.1016/j.jhep.2021.12.022 (2022)Key takeaway # 2: Risk to life comes from multiple metabolic directions in patients with MASLD MASLD is part of a multi-system disorder Targher et al. Gut 2024There is a strong rationale for identification of all metabolic threats linked by common biology and targeting common pathways for therapy Diet-induced obesity Metabolic stress Systemic inflammation and fibrosis Arteries Heart Liver Pancreas Kidney (Hypertension, (HFPEF) (MASLD) (T2DM) (CKD) CVD,CAD, PVD) Competing threats to life include MASLD/MASH, T2DM, hypertension, cardiac disease, vascular disease, CKD CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cerebrovascular disease; CVS, cardiovascular system; HFPEF, heart failure with preserved ejection fraction; PVD, peripheral vascular disease; T2DM, type 2 diabetes mellitus, MASLD= metabolic dysfunction associated steatotic liver disease.Patients with MASLD have increased multiple metabolic health outcomes Chan et al CGH 2024Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in T ype 2 Diabetes Shang et al Diabetes Care 2024Impaired survival according to MASLD fibrosis and Chronic Kidney Disease status Adjusted for age, sex, cardiovascular disease, and diabetes (n = 2,024) • Observational study of people who underwent routine liver function testing in Scotland. MASLD defined as: • Increased mortality risk was observed for those with liver fibrosis (aHR = 2.30, 1.49–3.56, p = <0.001) and was higher again among people with both fibrosis and CKD (aHR = 5.07, 3.07–8.39, p = <0.014). Gurun et al PlosOne 2024The risk of cirrhosis and HCC in MASH increases with fibrosis stage Risk of liver-related death Risk of CVD-related death MASLD, metabolic dysfunction-associated steatotic liver disease;, metabolic dysfunction-associated fatty liver; MASH, metabolic dysfunction-associated steatohepatitis; 1 Rinella et al. Hepatology. 2023;77:1797There is shared biology between MASLD/MASH and cardio-renal-metabolic diseases CRM diseases e.g. ASCVD There is a shared Fatty streak Atheroma Stable plaque Unstable plaque biology between Lipid Advanced MASH and other Normal accumulation Inflammation Fibrosis disease CRM diseases Steatohepatitis Steatohepatitis Cirrhosis Red blood cMacrophage Fatty hepatocytes (MASH without (MASH with LipoproteinApoptotic cell fibrosis) fibrosis) Monocyte Smooth muscle cellxlular MASH Liver disease progression is associated with progression of disease in other organs, such as the heart ASCVD, atherosclerotic cardiovascular disease; CRM, Cardiovascular-Renal-Metabolic. Finney et al. Front Cardiovasc Med 2023;10:https://doi.org/10.3389/fcvm.2023.1116861. Assessing cardiovascular risk ASCVD risk calculator and risk management New AHA PREVENT TM risk calculator: • Good for ages 39-95 • Removes race as a MASLD as risk Risk Enhancer • Includes SDOH • Provides risk of types of cardiovascular outcomes SDOH= social determinants of health (zipcodes) AHA PREVENT TM risk calculator https://professional.heart.org/en/guidelines-and-statements/prevent-calculatorMulti-dimensional assessment of risk in the patient with MASLD Schematic representation of risk through a Precision Medicine-based approach: 1–4* eGFR % decline AHA calculator FIB-4 <1.3 LSM <8.0 kPa selected as examples. AHA, American Heartbeen FIB-4 >2.67 Association; eGFR, estimated glomerular filtration LSM >12kPa rate; FAST, FibroScan AST; HbA1c, glycosylated haemoglobin; LSM, liver steatosis measurement. 1. HbA1c FIB-4 Cen et al. Front Nutr 2022; 9:916704; 2. Khan et al. LSM 2019; 9:15; 4. Stern et al. Clin Mol Hepatol JCTH 2023;29:S196;Summary • In those with metabolic risk factors, MASLD is highly prevalent • There is bi-directional relationship of hepatic and extrahepatic risks in patients with MASLD • Liver risk is driven by fibrosis • Use the tools you have at your disposal: • FIB-4 is very robust and relates to outcomes • VCTE is an excellent secondary risk assessment tool • ELF provides an independent measure of riskThank you