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Maya Balakrishnan, MD, MPH Metabolic-dysfunction Associated Steatotic Liver Disease: Recognizing who is at risk for adverse outcomes2 Patient Cases 40 yo woman with abnormal liver 55 year old man with type 2 diabetes enzymes • Normal liver enzymes forever: • Abnormal liver enzymes for 10 years: ALT 29, AST 25, ALT 90, AST 60, alkaline phosphatase 130, alkaline phosphatase 130, platelets 190 platelets 190 • Obesity (BMI 30), hypertension • Obesity (BMI 30), prediabetes • No alcohol drinking • No alcohol drinkingMetabolic-dysfunction Associated Steatotic Liver Disease (MASLD): Hepatic complication of the Metabolic Syndrome Chronic liver disease defined by the presence of fat (triglycerides) in >5% of hepatocytes caused by obesity and insulin resistance. Absence of significant alcohol drinking: <14 drinks/week in women <21 drinks/week in men Rinella M et al, A multi-society Delphiconsensusstatement onnew fatty liver nomenclature. Hepatology, 2023. MASLD is highly prevalent Global pooled prevalence of MASLD General Population 30% Populations with obesity* 75% Populations with type 2 diabetes* 65% *New guidelines recommend screening for high risk MASLD in these populations BalakrishnanMaya, ClinicalGastroenterology &Hepatology 2020. Quek J et al, Global prevalence of NAFLD and NASH overweight and obese population, Lancet 2023. Younossi ZM et al, The global epi of NAFLD & NASH in patientswith type 2 DM: systematic review and meta-analysis, J of Hepatology 2019MASLD does not cause significant clinical manifestations during early stages of disease • Asymptomatic or associated with nonspecific symptoms until people develop advanced cirrhosis • none pathognomonic: fatigue, abdominal pain, etc. • Overt symptoms (variceal bleeding, jaundice, ascites, hepatic encephalopathy) develop at late stage disease • Caveats regarding liver enzymes: • Frequently normal in patients with type 2 diabetes. • Liver enzymes do not correlate with presence or severity of disease. • MASLD is diagnosed in 3 main scenarios • Abnormal liver enzymes (hepatocellular pattern). • Incidental finding of steatosis on imaging. • Case finding among patients with prediabetes/type 2 diabetes, obesity, ≥2 metabolic syndrome criteria* (per new guidelines)Diagnosing MASLD *Cardio-metabolic Criteria (need at least 1 out of 5 metabolic syndrome features) Criteria Evaluation & Abnormal threshold Overweight/Obesity BMI≥25kg/m2 (23kg/m2 in Asian popl) ? Prior diagnosis or ongoing treatment Prediabetes or Hemoglobin A1c ≥ 5.7% diabetes? 2 hour glucose tolerance test ≥ 140mg/dL Fasting glucose ≥ 100 Existing diagnosis or ongoing treatment Hypertension? BP>130/85mmHg High triglycerides? Ongoing treatment (statin, fibrate) Fasting triglycerides ≥ 150mg/dL Ongoing treatment (statin) Low HDL? HDL <40mg/dL in men; <50mg/dL in women Rinella M et al, A multi-society Delphiconsensusstatement onnew fatty liver nomenclature. Hepatology, 2023.Patients with MASLD have are at risk for developing multiple systemic complications Type 2 Diabetes (HR 2.56, CI 2.10-3.13) Chronic Kidney Disease Hypertension HR 1.38, CI 1.27-1.50) (HR 1.75, CI 2.10-3.13) MASLD Cardiovascular Liver (cirrhosis) Disease complications (HR 1.43, CI 1.27-1.60) (HR 3.92, CI 2.05-7.49) Malignancy (HR 1.54, CI 1.35-1.50) Chan KE et al, Longitudinal outcomes associated with MASLD: A meta-analysis of 129 studies,Clin Gastro & Hepatology 2024.Leading causes of death: CV disease, malignancy, liver complications Type 2 Diabetes (HR 2.56, CI 2.10-3.13) Chronic Kidney Hypertension Disease (HR 1.75, CI 2.10-3.13) HR 1.38, CI 1.27-1.50) MASLD Cardiovascular Disease Liver (cirrhosis) (HR 1.43, CI 1.27-1.60) complications (HR 3.92, CI 2.05-7.49) 13% of deaths Malignancy 7% of deaths (HR 1.54, CI 1.35-1.50) 8% of deaths Rafiq N, Long-term follow-up of patients with NAFLD, ClinGastro & hepatology2009.Anticipating liver related complications in patients with MASLD Adverse Liver Complications Cirrhosis related Decompensation, Liver Failure, Hepatocellular carcinoma, Death MASLD Who will progress? Answer: People with severe hepatic fibrosis Clinical Implication: Need to identify and treat patients with have severe fibrosis INCIDENCE* Cumulative incidence: 9% over 13 years Rate: 6 per 1000 person-years *MACE, Gut 2022. Sanyal A et al, Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease, NEJM 2021.Current approach to stratifying patients’ risk of liver complications is grounded in our understanding of MASH pathogenesis & natural history Important principles: • Steatohepatitis (MASH) drives fibrosis • Fibrosis is associated with mortality • Treatment targets: steatohepatitis resolution and fibrosis regression drives drives Steatohepatitis Fibrosis Adverse Liver Outcomes Liver decompensations, transplant, death Natural History of MASLD Visceral Obesity Insulin-Resistance Normal Liver Steatosis Rafiq N, Long-term follow-up of patients with NAFLD, Clin Gastro & hepatology 2009. Natural History of MASLD Visceral Obesity Insulin-Resistance ⁓30% Normal Liver Steatosis Steatohepatitis (MASH) ⁓ 70% Steatosis Hepatocyte Ballooning (circle) Low risk of cirrhosis Lobular inflammation Mallory Denk Body (arrow) Rafiq N, Long-term follow-up of patients with NAFLD, Clin Gastro & hepatology 2009. Natural History of MASLD Visceral Obesity Insulin-Resistance Steatohepatitis drives fibrosis ⁓ 20% experience progressive liver fibrosis ⁓30% Early fibrosis Significant Fibrosis Cirrhosis (F0-F1) (F2-3) (F4) Normal Liver Steatosis Steatohepatitis (MASH) ⁓ 70% Low risk of cirrhosis Rafiq N, Long-term follow-up of patients with NAFLD, Clin Gastro & hepatology 2009. Natural History of MASLD Insulin-Resistance Steatohepatitis drives fibrosis ⁓30% ⁓ 20% experience fibrosis progression Early fibrosis Significant Fibrosis Cirrhosis (F0-F1) (F2-3) (F4) Normal Liver Steatosis Steatohepatitis (MASH) ⁓ 70% Decompensated Cirrhosis: • Portal hypertension Low risk of cirrhosis • Liver Failure • Death Rafiq N, Long-term follow-up of patients with NAFLD, Clin Gastro & hepatology 2009. MASH Fibrosis Progression to Cirrhosis: Unfolds Through 5 Stages of Fibrosis No Fibrosis Mild Fibrosis Moderate Fibrosis Severe Fibrosis Cirrhosis Image from: Petitclerc L et al. Liver fibrosis: review of current imaging and MRI quantification techniques. J Magn Reson Imaging. 2017 Sanyal A et al. Natural history of advanced fibrosis due to NASH. Hepatology.2019 Dec;70(6):1913-1927. SinghS et al. Fibrosis progression in NAFLD v NASH. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54. MASH Fibrosis Progresses at an Average Rate of 1 Stage Every 7 Years No Fibrosis Mild Fibrosis Moderate Fibrosis Severe Fibrosis Cirrhosis Clinical risk factors for progressive MASH fibrosis: • Type 2 diabetes • BMI • Age ≥50 • Alcohol drinking • Genetics Image from: Petitclerc L et al. Liver fibrosis: review of current imaging and MRI quantification techniques. J Magn Reson Imaging. 2017 Sanyal A et al. Natural history of advanced fibrosis due to NASH. Hepatology.2019 Dec;70(6):1913-1927. SinghS et al. Fibrosis progression in NAFLD v NASH. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54. Significant fibrosis (≥ F2) on Liver Biopsy is the strongest independent predictor of liver related mortality Dulai P et al, increased risk of mortality by fibrosis stage in NAFLD, Hepatology2017. Natural History of MASLD Visceral Obesity Insulin-Resistance ⁓30% Early fibrosis Significant Fibrosis Cirrhosis (F0-F1) (F2-3) (F4) Normal Liver Steatosis Steatohepatitis (MASH) Summary: Patients who have developed severe fibrosis by the time of evaluation are a risk for continued fibrotic progression to cirrhosis and related complications. So, the goal is to identify patients with severe fibrosis in ⁓ 70% Decompensated Cirrhosis: order to intervene and prevent progression to decompensated • Portal hypertension cirrhosis. Low risk of cirrhosis • Liver Failure • Death Rafiq N, Long-term follow-up of patients with NAFLD, Clin Gastro & hepatology2009. MASH and fibrosis are two important histologic targets for clinical trials testing medications for MASLD MASH resolution Fibrosis regression ↓ risk of adverse liver outcomes Correlates with associated with Liver decompensations, liver failure, liver transplant, death Keliner et al, JAMA Network Open 2019. Sanyal AJ, cirrhosis regression isasst with improved clinical outcomes in NASH, Hepatology2022.How to identify which patient has severe fibrosis: • Liver biopsy is the referent standard for evaluating fibrosis, but impossible to offer all patients. • Liver enzymes are not reliable for this purpose. • Noninvasive fibrosis tests (NITs) have been developed that help to predict who is most likely to have severe fibrosis • If someone has signs of portal hypertension or decompensated cirrhosis, do not use NITs. Refer to hepatologist. How to use NIT s to evaluate risk and need for hepatology referral Enhanced Liver Fibrosis FIB-4 Fibroscan Test (first line test) (second line test) (second line test) Anyone with MASLD or If FIB 4 indeterminate If FIB 4 indeterminate When to use at risk for MASLD (1.3 to 2.67) (1.3 to 2.67) Clinical risk score Ultrasound based elastography Proprietary Blood Test What it is What it means: Significant fibrosis unlikely, reassess in 1-2 years Score<1.3 Liver stiffness < 8kPa Value <7.7 Significant fibrosis possible (Refer patient to hepatology) Score>2.67 Liver stiffness > 8kPa Value >7.7 American Association of Clinical Endocrinology Guidelines 2022 17% prevalence of ≥F2 in populations with T2DM 21% prevalence of ≥F2 in popl with obesity Patient with diabetes: repeat testing 1 year Aprevalence of NAFLD and NASH overweight and obese population, Lancet 2023.; Younossilobal ZM et al, The global epi of NAFLD & NASH in patients with type 2 DM: systematic review Otherwise: repeat in 2 years and meta-analysis, J of Hepatology 20192 Patient Cases 40 yo woman with abnormal liver 55 year old man with type 2 diabetes enzymes • Normal liver enzymes forever: • Abnormal liver enzymes for 10 years: ALT 29, AST 25, ALT 90, AST 60, alkaline phosphatase 130, alkaline phosphatase 130, platelets 190 platelets 190 Whose liver you should worry about? Which patient needs a hepatologist? What can be done to reduce the risk of liver related morbidity and mortality? 40yo woman with abnormal liver enzymes: Diagnose the cause of abnormal liver enzymes Other causes of liver disease Initial Diagnostic Workup: Tests and Thresholds Hepatitis C Hepatitis C antibody positive → should trigger HCV viral load Hepatitis B Hepatitis B surface antigen positive Ferritin >200 ng/L in women and >300 ng/L in men; iron saturation >45% → Hemochromatosis Triggers testing HFE genotype Autoimmune Hepatitis Antinuclear antibody positive with titer >1:320, smooth muscle antibody detected Wilson’s Disease Cerruloplasmin <20 mg/dL Alpha-1 antitrypsin deficiency Alpha 1 Antitrypsin level < 100 mg/dL Drug-Induced Liver Injury Prednisone, methotrexate, protease inhibitors, tamoxifen Look for hepatic steatosis, esp if all of above negative B-mode ultrasound, transient elastographyDiagnosing MASLD 40 yo woman w/ abnormal liver enzymes • Labs ALT 90, AST 60, alkaline phosphatase 130, platelets 190 • Negative serologic workup • Steatosis on liver ultrasound • Obesity (BMI 30), prediabetes • No alcohol drinkingRisk Stratify MASLD 40 yo woman w/ abnormal liver enzymes • Labs ALT 90, AST 60, alkaline phosphatase 130, FIB4 = 1.15 platelets 190 Unlikely to have severe fibrosis • Negative serologic workup • Steatosis on liver ultrasound Follow in primary care clinic, reassess in 2 years. • Obesity (BMI 30), prediabetes • No alcohol drinkingCase #2: Screening for severe fibrosis in patient at risk 55 year old man with type 2 diabetes Normal liver enzymes > no need for liver disease workup Normal liver enzymes forever: Has MASLD risk factors > Proceed ALT 29, AST 25, alkaline phosphatase 130, platelets 190 directly to risk stratification FIB4 = 1.34 (indeterminate) Obesity (BMI 30), Hypertension No alcohol drinking VCTE: unreliable measurements ELF = 10 Refer to hepatologistWhat happens at the hepatologist’s office? • Rule out possibility of concomitant liver disease etiologies. • Repeat noninvasive testing • Indeterminate testing or high risk testing – use liver biopsy or MR elastography to confirm presence of severe fibrosis. • If stage 2 or 3 fibrosis > offer MASH modifying treatments • If cirrhosis – then screen for hepatocellular carcinoma, prevent portal htn complications.MASH Treatments MASH Fibrosis ↓ Adverse liver • Weight Loss Resolution Regression outcomes • Pioglitazone • GLP1 agonist • Resmetirom Weight loss is recommended among all patients with MASLD: It improves steatosis, MASH, and fibrosis in a dose dependent manner Fibrosis regression ≥10% weight loss (45%) MASH Resolution ≥7% weight loss (64-90%) MASH Reduction ≥5% weight loss (41-100%) Steatosis reduction ≥3% weight loss (35-100%) Hannah W, Harrison S.Effect of weight loss, diet,exercise &Bariatric Surgery on NAFLD, Clinics in Liver Disease 2016.Patients with severe fibrosis need at least 7%, ideally 10%, weight loss MASH resolution Fibrosis regression/stability 100% 90% s100% n n 80% t 80% 45% 38% 50% t 64% P P o 60% 81% o 60% g e t 40% 44% t 40% e 45% 50% e 26% r 20% r 20% P 10% 18% 19% P 10% 0% <5% 5-<7% 7-<10% >=10% 0% Percentweight loss from baseline <5% 5-<7% 7-<10% >=10% Percentweight loss from baseline progressed stable regressed Vilar-Gomez et al, Weight loss improves NASH, Gastro 2015.Interventions for Weight Loss • Lifestyle changes (diet and physical activity) recommended among all patients. • Weight loss medications and bariatric surgery: Clinical guidelines recommend using these methods for existing indications but not specifically for treatment of MASH. BalakrishnanM et al, Behavioral weight loss interventions for NAFLD: systematic scopingreview, Hepatology Communications2023. Elmaleh-sachs et al, Obesity Management in Adults: A Review, JAMA 2023. AASLD NAFLD Guidelines 2023.Semaglutide: Led to MASH resolution but not fibrosis regression in phase 2 clinical trial MASH resolution Fibrosis regression 17% placebo v Effect – not significant 59% 0.4mg semaglutide subcu daily Newsome PN et al, A placebocontrolled trial of subcu semaglutide in NASH, NEJM 2021Pioglitazone: Led to MASH resolution but not fibrosis regression in RCT MASH resolution Fibrosis regression 19% placebo v Effect - not significant 51% pioglitazone MASH Resolutionwithoutworsening of fibrosis Fibrosisimprovement ≥1 stage 60% P<0.001 45% P value0.13 39% 51% 40% 50% t35% 40% i30% a 25% f25% 30% e t20% 20% 19% c15% e P10% 10% 5% 0% 0% Placebo Pioglitazone 45mgdaily Placebo Pioglitazone 45mgdaily (n=51) (n=50) (n=51) (n=50) Cusi K et al, Long-term pioglitazone treatment for patients with NASH and prediabetes or type 2 diabetes, Annals of Internal Medicine 2016Resmetirom: March 2024 - Conditional approval from FDA for treatment of MASH • Liver directed, selective thyroid hormone receptor- β agonist • THR-β receptors present in liver • Responsible for regulating metabolic pathways in the liver • Reduces hepatic fat through increased mitochondrial B oxidation Harrison S et al, A phase 3 randomized controlled trial of resmetirom in NASH withliver fibrosis, NEJM 2024.Resmetirom: Led to MASH resolution & fibrosis regression in phase 3 clinical trial MASH resolution Fibrosis regression 10% placebo v 14% placebo v 25% resmetirom 80mg 24% resmetirom 80mg daily daily Harrison S et al, A phase 3 randomized controlled trial of resmetirom in NASH withliver fibrosis, NEJM 2024.2 Patient Cases: Treatment 55 year old man with type 2 diabetes 40 yo woman with abnormal liver enzymes from MASLD FIB4 = 1.34 FIB4 = 1.20 VCTE: unreliable measurements Manage in primary care clinic ELF = 10 Hepatologist obtained Liver biopsy = MASH, stage 3 fibrosis • Target at least 5% weight loss • Already on semaglutide • Reassess FIB4 in 2 years • Consider treating with resmetiromKey Points Whose liver should you worry about? • Patients with type 2 diabetes, obesity, ≥ 2 metabolic syndrome features or MASLD who have severe liver fibrosis. • Use noninvasive testing to figure out whether a patient may have severe liver fibrosis. • Refer anyone with FIB4 >2.67, liver stiffness ≥ 8, or ELF ≥ 7.7 to a hepatologist. • If only FIB4 is available, then refer for value >1.3. What treatments can potentially reduce risk of adverse liver outcomes? • The four available treatments are: weight loss (7% from baseline), semaglutide, pioglitazone, and resmetirom. • Effect on clinical outcomes are to be determined, but data show these can reduce important histologic surrogates (steatohepatitis and/or fibrosis) of clinical outcomes.Questions? Maya.Balakrishnan@bcm.eduThank you