Diagnosis and Management of Fatty LiverHemant Shah MD MScCH HPTE

University Health Network, University of Toronto

Hemant Shah Financial Disclosures (over past 24 months)

Speaker Advisory Research Consultant

Abbvie √ √ √

Boehringer-

Ingelheim

√

Gilead √ √ √

Intercept √ √

Lupin √ √ √

Merck √ √ √

• Affiliation with a not-for-profit organization:• Freeport Physicians’ Education Fund Honorarium

Mitigating Potential Bias

• Recommendations for Drug Therapy will be based on peer reviewed journal articles and published guidelines

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify current guidelines for screening for fatty liver disease

2. Determine a management plan for incidental findings of fatty liver disease

3. Identify and determine a management plan for low-risk patients

4. Define lifestyle changes for low-risk patients

5. Identify patients who should be referred for further investigation

6. Formulate the options for treatment for fatty liver disease

Case of Patient ND

• 56F new to your practice

• PMH: Severe obesity (BMI 47), PCOS, OSA, Depression

• Meds: Cymbalta

• SocHx: No significant alcohol, Non-smoker, Desk job (taxi dispatch)

• Labs: Hb 117, WBC 7.1, Plt 180, ALT 128, AST 96, ALP 75, INR 0.9, Bilirubin 12, Albumin 39

• Abdo U/S: Liver 23.1cm, Spleen 17.1cm, Fatty liver

• Initial workup: Hep B, Hep C, Iron all normal

Case of Patient ND

• 56F new to your practice

• PMH: Severe obesity (BMI 47), PCOS, OSA, Depression

• Meds: Cymbalta

• SocHx: No significant alcohol, Non-smoker, Desk job (taxi dispatch)

• Labs: Hb 117, WBC 7.1, Plt 180, ALT 128, AST 96, ALP 75, INR 0.9, Bilirubin 12, Albumin 39

• Abdo U/S: Liver 23.1cm, Spleen 17.1cm, Fatty liver

• Initial workup: Hep B, Hep C, Iron all normal

What’s the Diagnosis?What’s the Severity of the Liver Disease?What’s the Prognosis?What treatments should I recommend?

Definition of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of fat in the liver (hepatic steatosis) either on imaging or on liver histology after the exclusion of secondary causes of fat accumulation in the liver (e.g., significant alcohol consumption, certain medications, and other medical conditions).

Puri and Sanyal. Clinical Liver Disease. Aug 2012

NAFLD – The emerging liver epidemic

Steatosis

(NAFL)

Normal Steatohepatitis

(NASH)

Cirrhosis

NAFLD is a spectrum

Banini & Sanyal Am J Gastroenterol 2017

10-15% normal70-80% obese

2-3% normal15-20% in severely obese(BMI > 35)

<1% normal3-5% obese

**Emerging Terminology

MAFLD: Metabolic-Associated Fatty Liver Disease

BAFLD: Both Alcoholic and Nonalcoholic Fatty Liver Disease

NAFLD – A Diagnosis of Exclusion

• Labs• ALT>AST (usually AST:ALT<1 unless cirrhotic, never>2)• May have GGT elevation, ALP elevation (1/3)• Ferritin often high – (50-62%)

• Exclude ALWAYS: • Viral hepatitis (HBV/HCV)• Hemochromatosis• Drug• Alcohol (<2/day)

• Exclude if relevant:• Autoimmune hepatitis (IgG, ANA, SMA)• Wilsons - (ceruloplasmin, Urine Copper)• Others

Clinical Features

General Features

• Mainly asymptomatic (48-100%)

• Uncommonly:• RUQ discomfort

• Fatigue

• Malaise

Liver Specific

• Hepatomegaly (75%)

• Splenomegaly

(if cirrhosis)

• Uncommonly:• Palmar erythema

• Spider naevi

• Ascites

Epidemiology – General Population Studies

• Ultrasound ~22%• Lean 16%

• Obese 76%

• Liver tests• NHANES III 3-23%

• 11% liver tests >1.5 x ULN

• NAFLD 46% in pop’n study in US!

Farrell, Hepatology 2006, Williams Gastroenterology 2011

NAFLD is the commonest cause of elevated

ALT in N. America

Bril. Endocrinol Metab Clin N Am. 2016;45:765

Simple Fatty Liver vs NASH - It Matters!

Liver relatedCardiovascularOther

40

30

20

10

0

Mo

rtal

ity

(%)

No NAFLD(14.5-yr follow-up)

Nonalcoholic Fatty Liver(13.3-yr follow-up)

NASH(13.0-yr follow-up)

Patients with NASH have a significantly higher liver-related mortality than patients with simple steatosis

Major cause of death in NAFLD is cardiovascular disease

NAFLD stage correlates with hard outcomes

As stage of liver disease (fibrosis from NAFLD) increases, so does all-cause mortality and liver-related events risk

Taylor et al. Gastroenterology. May 2020

But the Challenge:

ALL THE PATIENTS

Patients with NASH

-Demographics-Labs-Special Testing

Separating Simple Steatosis from NASH

Detect Fat

• Fatty Liver Index

• Ultrasound

• CAP

• MRI-PDFF

Detect Inflammation

• Clinical Factors

• Biomarkers

Detect Fibrosis

• Clinical scores

• Elastography

• MultiparametricMRI

Separating Simple Steatosis from NASH

Detect Fat

• Fatty Liver Index

• Ultrasound

• CAP

• MRI-PDFF

Detect Inflammation

• Clinical Factors

• Biomarkers

Detect Fibrosis

• Clinical scores

• Elastography

• MultiparametricMRI

➕

Separating Simple Steatosis from NASH

Detect Fat

• Fatty Liver Index

• Ultrasound

• CAP

• MRI-PDFF

Detect Inflammation

• Clinical Factors

• Biomarkers

Detect Fibrosis

• Clinical scores

• Elastography

• MultiparametricMRI

FIB-4

• Age important factor• Well-validated in NAFLD• >3.25 – likely cirrhosis• <1.45 – very unlikely

advanced fibrosis• 1.45-3.25 – a bit less helpful

Sterling Hepatology 2006

NAFLD Score

• NAFLD Fibrosis Score• Age

• BMI

• Hyperglycemia

• Platelet count

• Albumin

• AST/ALT ratio

http://nafldscore.com

Angulo Hepatology 2007

Exclude advanced fibrosis

Sens 90%

Spec 60%

Detect advanced fibrosis

Sens 67%

Spec 97%

Before Treatment - A Diagnostic Pathway for NAFL

Identify Fatty Liver (imaging, etc)

Rule Out Advanced Fibrosis

FIB-4 <1.3NFS <-1.455

Low-Risk: Monitor Annually

FIB-4 >1.3NFS >-1.455

Intermediate to High-Risk

Rule In/Out High Risk (Advanced Fibrosis)

Fibroscan MRE

Low Score: Low Risk (Annual Monitoring)Intermediate Score: BiopsyHigh Score: Liver-focused Treatment/Trials/Biopsy

PRIMARY CARE REFERRAL CENTRE

The Management of NASH

Treatment Targets in NAFLD

Treatments targeted at the Liver- ⬇ Hepatic fat

accumulation- ⬇ Oxidative stress- Anti-fibrotics

Treatments targeted at Metabolic Syndrome

NASH and SDOH

• Even when controlling for co-morbidities…

• NASH is more common in those living below the poverty line

• NASH is more common in those living in high-density areas

• NASH is more common in blacks and hispanics (US data)

Aboubergi et al. Am J Gastro. Oct 2017

Cannot ignore the complex socioeconomic factors and system

structural inequities that contribute to NASH and make it difficult to treat

Treatment of NAFLD

Possible➢Vitamin E➢Anti-Diabetes Meds➢Anti-Cholesterol Meds➢Newer weight loss drugs➢Coffee

Proven➢ Lifestyle, diet and exercise➢Weight loss surgery (if BMI >35)

Unlikely to help➢Older weight loss drugs➢Anti-inflammatories➢Milk thistle, Other herbals

Investigational➢Antifibrotics➢Bile acid pathways

Comprehensivelifestyle approach

Energy restriction• Calorie restriction (500−1,000/day)• 7−10% weight loss target• Long-term maintenance approach

Macronutrient composition• Low-to-moderate fat• Moderate-to-high

carbohydrate• Low-carbohydrate ketogenic

diets or high protein

Fructose intake• Avoid fructose-containing

food and drink

Daily alcohol intake• Strictly below 30 g men

and 20 g women

Coffee consumption• No liver-related limitations

Physical activity• 150−200 min/week moderate intensity

in 3−5 sessions• Resistance training to promote

musculoskeletal fitness and improvemetabolic factors

EASL Guidelines

Which diet is effective?

Romero-Gomez et al. J Hepatol 2017.

Ontario Bariatric Network

Vitamin E – Potential Early Treatment

Consider use of Vitamin E 400IU/d for patients with earlier disease, minimal or controlled cardiac risk factors

• Glucagon-like peptide 1 reduces liver fat, ALT and insulin resistance in mice models

• RCT liraglutide vs. placebo x 48 weeks (LEAN trial)

• Resolution of NASH in 9/23 (39%) liraglutide vs. 2/22 (9%) placebo p=0.019• Secondary outcomes showed improvements in weight

and ALT

• Liraglutide well tolerated

• Being studied in Phase 3 (Semaglutide)

• Recent large GLP-1 trial showed improvements for DM and weight loss

Liraglutide – Opportunity to Synergize DM Therapy

Armstrong et al Lancet 2016

New Treatments of NASH – Many Targets

Konerman MA, et al. J Hepatol 2018

Examples of NASH Treatments in Phase II or III Investigations (as of January 2020)

Steatohepatitis (NASH) CirrhosisNormal Liver Steatosis (NAFL)

Insulin resistance and/or lipid metabolism

Lipotoxicity and oxidative stress

Inflammation and immune activation

Cell death (apoptosis and

necrosis)

Fibrogenesis and collagen turnover

PPARγ: PioglitazoneGLP-1: Liraglutide,

semaglutideSGLT: Empagliflozin,

licogliflozin, canagliflozin

DPP-4 SitagliptinACC: GS-0976, PF-05221304SCD1: AramcholASBT: Volixibat

Some agents have multiple targets

PPARα/∂: ElafibranorPPARα/γ: SaroglitazarPan-PPAR: LanifibranorFGF19: NGM282

FGF21: Pegbelferim

FXR: OCA, cilofexor,tropifexor, nidufexor

MPC: MSDC-0602KTGR-5: INT-767/777THR-β: MGL-3196, VK2809

Slide credit: clinicaloptions.com

CCR2/5: Cenicriviroc (inflammatory target but affects fibrosis)

ASK1: Selonsertib (cell death target but affects fibrosis)Caspase: Emricasan

AOC3: BI-1467335P2X7R: SGM-1019TLR-4: JKB-121/122

Galectin: GR-MD-02LOXL2: Simtuzumab

Treatment Algorithm

Confirmed NASH, Clinically or Biopsy

BMI < 35LifestyleDiet/ExerciseMedical TreatmentClinical Trials

Treat Associated Conditions

Improvement:Intermittent

Staging No Improvement: Intensive Behaviour

Medification

BMI >35LifestyleDiet/ExerciseBariatric Surgery

Consider Clinical Trials

Summary

• NAFLD is highly prevalent and intertwined with social factors

• Identifying high-risk patients important

• Look for ways to optimize therapy within the context of patient’s existing health and social situation

• Lots more therapies being studied for NASH. So far, no home runs but there never are for metabolic diseases

• Thank you for your attention!