NON-ALCOHOLIC FATTY LIVER DISEASE: ROLE OF THE PRIMARY PROVIDER

25th Annual Southwestern Conference on Medicine

Archita P. Desai, MD Assistant Professor of Medicine University of Arizona

Outline

¨  Pathophysiology

¨  Natural History

¨  Scope of the problem

¨  Diagnosis & Staging of Disease

¨  Management

Pathophysiology: Overview

Adapted from: Marchesini G, et al. Hepatology. 2016:1-11. doi:10.1002/hep.28392. McCullough AJ. J Clin Gastro. 2006. doi:10.1097/01.mcg.0000168645.86658.22

Spectrum of Disease

NAFLD Spectrum

Non-Alcoholic Fatty Liver

• macrovesicular fat accumulation in more than 5% of hepatocytes – simple steatosis

• No inflammation

Non-Alcoholic Steatohepatitis

• Lobular inflammation, hepatocellular ballooning à hepatocyte necrosis

• No fibrosis

NASH with Fibrosis

• Chronic inflammation • Liver regeneration

• Fibrosis à cirrhosis

Natural history

Clinical progression limited to those with fibrosis

Spengler EK, Loomba R. Mayo Clin Proc. 2015. doi:10.1016/j.mayocp.2015.06.013. Angulo P, et al. Gastroenterology. 2015;149(2):389-397.e10. doi:10.1053/j.gastro.2015.04.043

Controls

F0-F2

F3-F4

Prevalence

¨  10–35% prevalence rate ¨  Wide variation with the study population and the

modality used to diagnose

Vernon G, et al. Aliment Pharmacol Ther. 2011. doi:10.1111/j.1365-2036.2011.04724.x.

Prevalence

Torres DM, et al. Clin Gastroenterol Hepatol. 2012. doi:10.1016/j.cgh.2012.03.011.

Impact on Liver Transplantation

Diagnosis

¨  Accurate Diagnosis

¨  Stage of Disease ¤ NAFLD vs. NASH ¤ Fibrosis ¤ Cirrhosis

Abnormal Liver Tests

¨  Liver Enzymes – Alk Phos, AST, ALT ¤ Do not effectively assess the actual function of the liver

¨  Liver Function – Bilirubin, Albumin, PT/INR

Normal ALT: < 30 for males

<19 for females

Diagnosis

Abnormal Liver Enzymes

Steatosis by imaging

Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016. doi:10.1038/nrgastro.2016.3.

AST/ALT ratio < 1 Obesity Diabetes

Metabolic Syndrome

Viral hepatitis Medications

Hemochromatosis Autoimmune Hepatitis

Risk Stratification

¤ NAFLD vs. NASH

¤ Stage of Fibrosis n Cirrhosis?

Non-invasive Staging

¨  Serologic markers

¨  Transient Elastography

¨  MRI +/- Elastography

Non-invasive Staging

Non-invasive Staging

Sebastiani G, et al. PLoS One. 2015;10(6):e0128774. doi:10.1371/journal.pone.0128774.

Non-invasive Staging

Transient Elastography: MR Elastography:

US probe delivers shear wave, velocity is mesaured and converted mathematically into a liver stiffness measurement (LSM), which is depicted in kiloPascals (kPa)

External vibrators are used to generate shear or compression waves – wave propagation measured for whole liver

Non-invasive Staging

Loomba R, et al. Am J Gastroenterol. 2016;(October 2015):1-9. doi:10.1038/ajg.2016.65.

MRE

vs.

Live

r bi

opsy

Risk-based Staging

Risk-based Staging

Management

¨  There are NO FDA approved therapies for NASH

¨  GI and Liver society guidelines recommend 2 pharmacologic therapies ¤  Limited impact on fibrosis

¨  Lifestyle modifications ¤ Management of other risk factors

¨  Bariatric Sugery

Weight Loss

http://www.chronicliverdisease.org/disease_focus/slide_details.cfm?topic=LIVERSUMMIT2015_NASH-NAFLD

Lifestyle Modifications

Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016. doi:10.1038/nrgastro.2016.3.

Pharmacologic therapy

PIVENS Trial (2010): Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis •  Only NON-Diabetics with

NASH

•  Pioglitazone lead to modest weight gain

•  Long term safety and efficacy of pioglitazone in patients with NASH is not established

Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685. doi:10.1056/NEJMoa0907929.

Bariatric Surgery

Mummadi RR, et al. Clin Gastroenterol Hepatol. 2008;6(12):1396-1402. doi:10.1016/j.cgh.2008.08.012.

Improvement or resolution of steatohepatitis

Bariatric Surgery

Improvement or resolution of fibrosis

Mummadi RR, et al. Clin Gastroenterol Hepatol. 2008;6(12):1396-1402. doi:10.1016/j.cgh.2008.08.012.

Future therapies

¨  Over 150 ongoing trials ¤ Several drugs in phase 2b or 3 ¤ Mostly non-cirrhotic NASH

¨  Future targets: ¤ Farsenoid receptor X agnoist - Obeticholic acid ¤ PPARα/δ agonist – Genfit, Elefibranor ¤ ASK1 Inhibitors ¤ Lysyl Oxidase-Like 2 inhibitors

Takaki A, et al. Int J Mol Sci. 2014;15(5):7352-7379. doi:10.3390/ijms15057352.

Future therapies

http://www.nashbiotechs.com/nash-biotech-analysis/biotechs-targeting-nash/RiskReward.html

Current Management

Corey KE, et al. Dig Dis Sci. 2016;61(5):1387-1397. doi:10.1007/s10620-016-4083-8.

¨  Weight loss - Exercise + Diet ¤  Sustain weight loss – Nutritionist, Weight Watchers ¤  Consider Bariatric surgery if other indications

¨  Aggressive management of metabolic risk factors ¤  Don’t stop statin ¤  Consider aspirin

¨  Vit E 800 IU/daily - α-tocopherol

¨  Caffeine?

¨  If Fibrosis, send to a center with on-going clinical trials

¨ Thank you!