Updates in Nonalcoholic Fatty Liver Disease (NAFLD) Danielle - PowerPoint PPT Presentation

Updates in Nonalcoholic Fatty Liver Disease (NAFLD) Danielle Brandman, MD, MAS Program Director, Transplant Hepatology Fellowship Director, UCSF Fatty liver clinic Associate Professor of Medicine

Disclosures  Allergan, Gilead, NGM, Grifols: Research funding, clinical trials

Questions  When should I suspect NAFLD?  How do I diagnose NAFLD?  What do I have to worry about in patients with NAFLD?  What are the treatment options for NAFLD?  Should I screen patients for NAFLD?

Questions  When should I suspect NAFLD?  How do I diagnose NAFLD?  What do I have to worry about in patients with NAFLD?  What are the treatment options for NAFLD?  Should I screen patients for NAFLD?

NAFLD: worldwide epidemic Younossi, Nat Rev Gastroenterol Hepatol, 2017.

Epidemiology  Prevalence of NAFLD: ~30% US population  Prevalence of NASH: 3-5% US population Farrell, Hepatology , 2006. Younoussi, Hepatology , 2015.

Epidemiology  Prevalence of NAFLD: ~30% US population  Prevalence of NASH: 3-5% US population Farrell, Hepatology , 2006. Younoussi, Hepatology , 2015.

NAFLD: Non-Alcoholic Fatty Liver Spectrum of disease NAFL Steatosis without inflammation Cirrhosis NAFLD NASH + fibrosis NASH HCC Steatosis + inflammation

Questions  When should I suspect NAFLD?  How do I diagnose NAFLD?  What do I have to worry about in patients with NAFLD?  What are the treatment options for NAFLD?  Should I screen patients for NAFLD?

Case  54yo woman with MetS with mild, dull RUQ pain x several months  PMH: PreDM, dyslipidemia, HTN  Meds: atorvastatin, lisinopril  SocHx: Glass of champagne on special occasions  FamHx: Parents with diabetes  Labs: AST 38, ALT 71, albumin 4.1, INR 1.0, platelets 200  Upon review of prior lab results, she has largely had AST 20s-40s and ALT 40s-80s since 2015

What further work-up is needed? Liver biopsy A. Counsel her on lifestyle modification to try to lose weight and B. repeat liver tests again in 6 months Evaluate for other causes of chronic liver disease C. Transient elastography (Fibroscan) D.

What further work-up is needed? Liver biopsy A. Counsel her on lifestyle modification to try to lose weight and B. repeat liver tests again in 6 months Evaluate for other causes of chronic liver disease C. Transient elastography (Fibroscan ) D.

Evaluation of Suspected NAFLD  Liver tests  Abdominal ultrasound  Other serologic evaluation: - HBsAg, sAb, cAb - HCV Ab - [AMA, IgM (for PBC if alkaline phosphatase elevated)] - ASMA, ANA, IgG - A1AT phenotype - Iron, Tsat, ferritin - Ceruloplasmin age < 45 or neuropsychiatric symptoms - HAV Ab (for vaccination status)

NAFLD Diagnostic Criteria  Diagnostic criteria - Hepatic steatosis on imaging or liver biopsy - No “significant” alcohol intake - Absence of other causes of liver disease - No medications known to cause hepatic steatosis

NAFLD Diagnostic Criteria  Diagnostic criteria - Hepatic steatosis on imaging or liver biopsy - No “significant” alcohol intake - Absence of other causes of liver disease - No medications known to cause hepatic steatosis NAFLD is a diagnosis of exclusion

NAFLD A Clinically Silent Disease Symptoms: • – None: 20 - 77% – Right upper quadrant pain: 25 - 48% – Fatigue: 50 - 75% (Obstructive sleep apnea in 40%) Signs: • – Overweight/Obese: 85 - 95% – Acanthosis nigricans: 10 -15% – Hepatomegaly: 25 - 50% Laboratory: • – ALT, AST - modest elevation – “Normal enzymes” – Normal ALT <19-25 for women, <30-35 for men

Fibrosis progression

Fibrosis progression is different in NASH vs NAFL NASH 7 years per 1 stage ~28 years 0  cirrhosis

Fibrosis progression is different in NASH vs NAFL NASH 7 years per 1 stage ~28 years 0  cirrhosis NAFL 14 years per 1 stage ~56 years 0  cirrhosis

What is the best way to classify patients with NAFLD? Liver biopsy A. Fibroscan (transient elastography) B. MR elastography C. FIB-4 D.

What is the best way to classify patients with NAFLD? Liver biopsy A. Fibroscan (transient elastography) B. MR elastography C. FIB-4 D.

Liver biopsy

The liver biopsy is alive and kicking Liver biopsy

Indications for Liver Biopsy  Suspicious for NASH - Significant liver enzyme elevation - Diabetes  Suspicious for advanced fibrosis or NASH cirrhosis Advanced - Thrombocytopenia fibrosis - Imaging (e.g., splenomegaly) - Noninvasive assessment: FIB-4, Fibroscan - Diabetes - Older age  Unable to rule out other diseases Chalassani, Hepatology 2017. Chalassani, Hepatology 2012.

Noninvasive assessment of liver fibrosis NAFLD fibrosis score = -1.675 + 0.037*age + 0.094*BMI + 1.13*IFG/DM + 0.99*AST:ALT – 0.13*platelets – 0.66*albumin

Noninvasive staging of NAFLD AUROC ≥F2 Any fibrosis F3-4 Cirrhosis Transient 0.74-0.78 0.79-0.84 0.83-0.88 0.86-0.93 elastography MR 0.83 0.91 0.89 0.97 elastography NAFLD fibrosis 0.82 0.72-0.82 0.73-0.86 0.77-0.92 score FIB-4 0.8 0.72-0.83 0.78-0.86 0.78-0.88 Siddiqui, . . .Brandman et al. Clin Gastro Hep, 2018. Boursier, J Hepatol 2016. Imajo, Gastroenterology 2016. Hsu, Clin Gastro Hep , 2018.

Serial use of NFS/FIB-4 and TE Petta, AP&T, 2017.

Questions  When should I suspect NAFLD?  How do I diagnose NAFLD?  What do I have to worry about in patients with NAFLD?  What are the treatment options for NAFLD?  Should I screen patients for NAFLD?

Prognosis of NAFLD by fibrosis stage Steatosis 8% NASH ± 12 − 40% F1 − F2 fibrosis 13% 5 − 10% Advanced 14% F3 fibrosis 0 − 50% Death/ Cirrhosis LTx 25% 25 − 50% 7% HCC Day, J Hep, 2008.

What is the strongest predictor of outcomes in patients with NAFLD? Steatosis (fat) severity A. Liver size B. Fibrosis stage C. Number of ballooned hepatocytes on liver biopsy D.

What is the strongest predictor of outcomes in patients with NAFLD? Steatosis (fat) severity A. Liver size B. Fibrosis stage C. Number of ballooned hepatocytes on liver biopsy D.

Fibrosis is the most important predictor of death and liver-related events Liver-related event Overall mortality Hagstrom, J Hep, 2017.

Outcomes in NAFLD with F3-4 fibrosis Decompensation HCC CV events Non-HCC malignancy Vilar-Gomez, Gastro , 2018.

Increased risk of incident CV in NAFLD Hagstrom, J Hep, 2018.

NAFLD is a risk factor for CVD Fatal CVD Events OR 1.31 (95% CI 0.87-1.97) Fatal+non-fatal CVD Events OR 1.63 (95% CI 1.06-2.48) Non-fatal CVD Events OR 2.52 (95% CI 1.52-4.18) Targher, J Hepatol , 2016.

NAFLD is a risk factor for CVD NAFLD + elevated GGT or advanced fibrosis Fatal CVD Events OR 3.28 (95% CI 2.26-4.77) Fatal+non-fatal CVD Events OR 1.94 (95% CI 1.17-3.21) Targher, J Hepatol , 2016.

Association of NAFLD and HCC Younossi, Hepatology , 2015.

HCC in non-cirrhotic patients Risk of having HCC in • absence of cirrhosis  NAFLD: OR 5.4 (3.4-8.5)  MetS: OR 5.0 (3.1-7.8) Mittal, Clin Gastro Hep , 2015.

NASH is a leading indication for LT 2 Noureddin, AJG , 2018.

LT for NASH-HCC is expected to rise more steeply than NASH alone No HCC HCC Shingina, Transplantation , 2019.

LT for NASH-HCC is expected to rise more steeply than NASH alone No HCC HCC NASH HCV NASH HCV Female 36% 21% Female 51% 30% Age 62 57 Age 58 52 Shingina, Transplantation , 2019.

Questions  When should I suspect NAFLD?  How do I diagnose NAFLD?  What do I have to worry about in patients with NAFLD?  What are the treatment options for NAFLD?  Should I screen patients for NAFLD?

What treatment options are currently available to treat NAFLD? Bariatric surgery A. Vitamin E B. Ursodiol C. Lifestyle modification for weight loss D. B & D E.

What treatment options are currently available to treat NAFLD? Bariatric surgery A. Vitamin E B. Ursodiol C. Lifestyle modification for weight loss D. B & D E.

NAFLD treatment: Weight Loss Diet & Exercise •  Combination is best  Avoid fructose-sweetened beverages, added sugars  Exercise alone reduces liver fat o Aerobic >150-250 minutes per week o Resistance training 45 minutes/day x 3 days/week Harrison. Hepatology , 2009. Promrat, Hepatology , 2010 Vilar-Gomez, Gastro , 2015 Chalasani , Hepatology 2012 .

Moderate or vigorous exercise reduces visceral adiposity ** ** 68 * 44 21 * p<0.05, **p<0.01 Oh, Hepatology , 2015.

Aerobic vs resistance training Resistance exercise • 60 minutes Aerobic exercise • 3 times per week • 60 minutes • 10 whole body • 3 times per week exercises 1 st 4 weeks: 1-2 • 60-75% peak VO2 • by week 2 sets 8-12 reps 2 nd 4 weeks: 2 • sets 8-12 reps Lee, Diabetes , 2012..

Barriers to exercise Associated comorbidities  Obstructive sleep apnea: fatigue, headache  Osteoarthritis: pain, decreased mobility  Depression: decreased activity and motivation  Balance problems  Generalized weakness  Cognitive deficits Gerber, Clin Liver Dis , 2014.