American 

College of Physicians 
Internal Medicine Meeting 2021: Virtual Experience

Fatty Liver: What You Need to Know Now

Faculty and Disclosure Information
Professor:
COL Dawn M. Torres, MD, MC USA
Nothing to Disclose.

Clinical questions to be addressed:
1. What is the role of noninvasive testing in nonalcoholic fatty liver disease, and when should one 
refer for a biopsy?
2. What is the optimal treatment strategy?
3. When should one consider bariatric procedures?
4. What is the approach to hepatocellular carcinoma screening in patients with nonalcoholic 
steatohepatitis?

Posted Date: March 29, 2021

©2021 American College of Physicians. All rights reserved. Reproduction of Internal Medicine Meeting 2021: Virtual Experience presentations, or 
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Any use of program content, the name of a speaker and/or program title, or the name of ACP without the written consent of ACP is prohibited. For 
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 Fatty Liver: What You Need to Know Now
Dawn Torres, MD
National Capital Consortium/Walter Reed GI Fellowship PD
Professor of Medicine, Uniformed Services University of the Health Sciences

Disclosure of Financial Relationships

Research Grants/Contracts:
• Genfit
• Gilead Pharmaceuticals
• Intercept Pharmaceuticals
• Madrigal Pharmaceuticals
• Novo Nordisk

© 2021 American College of Physicians. All rights reserved. 1

 Objectives
• Basic definitions & epidemiology
• Diagnosis including non‐invasive risk stratification techniques
• Treatments now & future
• Controversies

Non‐alcoholic fatty liver disease: Basic definitions
All pts with fatty liver
All pts with fatty liver

Liver biopsy
Non‐alcoholic 
Isolated fatty liver NASH:
steatohepatitis (NASH): 
fat + inflammation
fat + inflammation +/‐
+/- fibrosis
fibrosis

**Alcoholic steatohepatitis (ASH)  Increased risk:
Increased risk:
cannot be differentiated from  Cirrhosis & Liver 
Cirrhosis & Liver
NASH on biopsy, history is critical cancer
cancer

© 2021 American College of Physicians. All rights reserved. 2

 Epidemiology of NAFLD
• 25‐40% NAFLD
• 1.5‐6.45% NASH
• 95% bariatric surgery patients 
• 1/3‐2/3 diabetics 
1 Younossi ZM al. Hepatology 2016;64:73‐84.
2 Machado M et al.  J Hepatol 2006;45:600‐606.
3 Browning JD et al.  Hepatology 2004;40:1387‐95.
4 Szczepaniak L et al. Am J Physiol Endocrinol Metab 2005;288:462‐8.
5 Hashimoto E et al.  J Gastroenterol 2011;46:63‐69.
6 Williams CD et al. Gastroenterology 2011;140:124‐131.
7 Ogden CL et al.  JAMA 2010;303:242‐49.

Fibrosis in Chronic Liver Disease
• Fibrosis = single most important predictor of outcome1
• Fibrosis assessment stages & helps establish when to initiate 
treatment2
• Liver biopsy = “gold standard” of fibrosis assessment
• Invasive F1: Perisinusoidal F2: Perisinusoidal + Portal

• Complication risk
• Cost
• Sampling error F3: Bridging Fibrosis F4: Cirrhosis

• Specimen quality
1Ekstedt M et al.  Hepatology 2015;61:1547‐1554.
2Chin JL.  Frontiers in pharmacology 2016;7:159.

© 2021 American College of Physicians. All rights reserved. 3

 Histologic Features Associated with Disease Progression and Mortality

Mortality/Liver Transplant Risk by

Heirarchy of Mortality Risk Fibrosis Stage (95% CI of HR)
Stage 1 1.18–2.81
1. Fibrosis Stage 2 1.20–3.03
Stage 3 1.16–3.12
2. Portal inflammation
Stage 4 3.35–12.04

Liver-Related Events Risk by

3. Diagnosis of NASH Fibrosis Stage (95% CI of HR)
Stage 1 0.63–8.91
Stage 2 2.26–24.94
4. Ballooning degeneration
Stage 3 4.35–43.65
Loomba R, et al. Gastroenterology. 2015;149:278-281. Stage 4 11.94–188.61

Criteria for non‐invasive surrogates
• Readily available
• Affordable (repeat annually?)
• Accurate  Area under receiver 
operating curve (AUROCs) 1
• <0.7 poor
• 0.7‐0.8 fair
• 0.8‐0.9 good
• >0.9 excellent
1Ekstedt M et al. Hepatology 2015;61:1547-1554.

© 2021 American College of Physicians. All rights reserved. 4

 Predictive Value of Liver Aminotransferases in NAFLD

Serum ALT can be normal in nearly 60% of NAFLD patients with NASH1

Serum ALT can be increased in ~53% of NAFLD patients with no NASH2,3

Serum ALT level alone is not predictive of NASH or fibrosis level1-3

• Normal ALT cannot rule out progression or NASH
• Increased ALT cannot predict NASH

1. Fracanzani AL, et al. Hepatology. 2008;48:792-798. 2. Verma S, et al. Liver Int. 2013;33:1398-1405.
3. Torres DM, et al. Nat Rev Gastroenterol Hepatol. 2013;10:510-511.

Noninvasive Tests for Liver Fibrosis 
• Clinical or laboratory tests
• NAFLD Fibrosis Score
• FIB‐4 index
• BARD
• AST/ALT ratio
• Fibrosure (commercial panels)

• Imaging modalities for Fibrosis assessment
• Transient elastography
• MR elastography
• 2‐Dimensional Shear Wave elastography
• Acoustic Radiation Force Impulse Imaging or Point Shear Wave Elastography

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© 2021 American College of Physicians. All rights reserved. 5

 NAFLD Fibrosis Score
• Derivation and validation of the scoring system
• 733 NAFLD patients: 480 derivation; 253 validation
• Multivariate analysis
• Age, hyperglycemia, BMI, platelet count, albumin, AST/ALT ratio are independent 
predictors of advanced fibrosis
Predictive Value for Advanced 
Cutoff Point Group
Fibrosis
Low cutoff point:  Derivation NPV 93%
<–1.455  Validation NPV 88%
High cutoff point: >0.676  Derivation PPV 90%
Validation PPV 82%

Angulo P, et al. Hepatology. 2007;45:846-854.

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http://nafldscore.com

Angulo P, et al. Hepatology. 2007;45:846-854.

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© 2021 American College of Physicians. All rights reserved. 6

 FIB‐4 Index
• Originally developed to predict advanced fibrosis in HIV/HCV coinfection1
• Subsequently studied in 541 patients with NAFLD2
• AUROC 0.80
Predictive Value for 
Cutoff Point Interpretation
Advanced Fibrosis
Low cutoff point:  PPV 43% Absence of 
<1.30  NPV 90% advanced fibrosis: F0–1
High cutoff point:  PPV 80% Presence of 
>2.67 NPV 83% advanced fibrosis: F3–4

1. Sterling RK, et al. Hepatology. 2006;43:1317-1325. 2. Shah AG, et al. Clin Gastroenterol Hepatol. 2009;7:1104-1112.

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http://www.hepatitisc.uw.edu/page/clinical‐calculators/fib‐4

Sterling RK, et al. Hepatology. 2006;43:1317-1325.

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© 2021 American College of Physicians. All rights reserved. 7

 Comparison of Noninvasive Tests
• 145 patients with NAFLD

• Compared ability to identify stage 3‐4 fibrosis

AUROC NPV PPV

• FIB‐4 0.86 • FIB‐4 95% • FIB‐4 75%
• AST/ALT ratio 0.83 • AST/ALT ratio 93% • AST/ALT ratio 55%
• NAFLD Fibrosis Score  • NAFLD Fibrosis Score  • NAFLD Fibrosis Score 
0.81 92% 79%

McPherson S, et al. Gut. 2010;59:1265‐1269. 

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Fibrosis Assessments
Imaging
• Transient Elastography=VCTE
• MR Elastography 
• Acoustic radiation force impulse imaging
• Supersonic shear wave elastography

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© 2021 American College of Physicians. All rights reserved. 8

 FibroScan® = Vibration Controlled Transient Elastography
(VCTE)
 Two quantitative parameters:
 Liver stiffness (kPa)Liver fibrosis
 Controlled Attenuation Parameter Liver steatosis
 2 probes ~$150K, add‐on for existing US machine ~30K 
 2019 CPT Code 91200 
 Hospital outpatient medicare payment ~$135.95
 3cm3 liver tissue (100x > liver biopsy)

1. Friedrich Rust et al., Gastroenterology 2008

2. Sasso et al., Journal of Viral Hepatitis 2011

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Discrimination of NASH using VCTE in patients with NAFLD

• 183 pts, mean age 40.6 years

• male predominance (60.7%)
• 89(48.6%) non-NASH & 94(51.4%) NASH

Lee HW et al, Plos One, 2016

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19

MR Elastography in NAFLD
AUROC 0.924 for diagnosis of advanced
fibrosis

Loomba R et al Hepatology 2014 60 1920-8 Meng Y et al Clin Gastroenterol Hepatol 2007 10 1207-1213

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© 2021 American College of Physicians. All rights reserved. 10

 Who to biopsy?
• Diagnostic dilemma
• High risk
• Non‐invasive risk stratification 
• NAFLD fibrosis score, BARD score, etc
• VCTE, MR Elastography, etc
• Failed lifestyle modification 
• Would effect treatment choice, duration, or timing of 
therapy

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↑ serum aminotransferase levels, fa y liver on imaging, or hepatomegaly
Proposed approach to patient
with Fatty Liver
Exclude excessive alcohol use and other forms of liver disease by history 
and laboratory tests

Non‐invasive risk stratification with clinical scoring system (BARD, NAFLD fibrosis score, FIB‐4)
Refer to GI

Intermediate or High risk by non‐invasive 
scoring system = VCTE or other method to 
Low risk by non‐invasive scoring system= evaluate for advanced fibrosis
Manage Metabolic syndrome

VCTE>7.5 kpascals or other testing suggests 
advanced fibrosis
Annual follow‐up for reassessment

Consider liver biopsy to stage the disease & 
Torres DM. S&F 2019 Edition. define the risk of progression

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© 2021 American College of Physicians. All rights reserved. 11

 Treatment
• NAFLD
• Lifestyle modification 
• Management of metabolic syndrome
• What is the optimal treatment for biopsy proven NASH 
patients?
• Diet/exercise
• Surgical
• Pharmacotherapy
• Limited to NASH patients

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NAFLD: Dietary Characteristics
• Higher in saturated fat/cholesterol and lower in 
polyunsaturated fat, fiber and antioxidant vitamins C 
and E1
• Higher intake of soft drinks and meat; less omega ‐3 
fatty acids 2
• Overall energy intake significantly higher3
• High fructose diets4
1. Musso G et al, Hepatology. 2003; 2. Zelber-Sagi S, J Hepatol 2007; 3. Capristo E, Euro Rev Med Pharmacol Sci. 2005; 4. Ackerman Z et al,
Hypertension. 2005

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© 2021 American College of Physicians. All rights reserved. 12

 Weight Loss
• Effective
• 9‐10% body weight loss
• improved insulin sensitivity, liver enzymes, visceral adiposity, and histology: 
steatosis, ballooning degeneration, and lobular inflammation
• Sustainability difficult
• 1310 patients who lost 10% body weight in 1999‐2002 NHANES 
• 66.5% maintained or reduced weight
• Factors assoc with weight increase 
• Mexican‐American and Sedentary lifestyle

Weiss EC et al. Am J Prev Med 2007;33:34‐40

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Dietary Treatment for NAFLD
Modality Effect Comments
Weight loss 5‐10%.  Moderate  Improves most features of  Difficult to sustain
caloric restriction (500‐750  NASH
kcal less per day)
Eliminate or reduce SFAs, high  High consumption  Prospective trials lacking
fructose corn syrup NASH and ↑ fibrosis
Consider omega‐3 fatty acid  Decreases hepatic  Lack of histologic 
replacement steatosis.  Improves serum  improvement in NASH.  
triglycerides Treats hypertriglyceridemia
Consider regular coffee Decreased risk of fibrosis Optimal amount unclear
consumption, 2‐3 cups/day

Torres DM, Harrison SA. S&F 2019 edition in press.

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© 2021 American College of Physicians. All rights reserved. 13

 Treatment for NAFLD

Modality Effect Comments

Exercise
Aerobic and/or  Improves insulin  Best results when 
resistance training 3‐4x  resistance leads to weight loss
per week with goal 400 
kcal expended

Torres DM, Harrison SA. S&F 2019 edition in press.

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Bariatric Surgery
• Duodenal switch procedure
• Older procedure
• Worsening hepatic fibrosis with rapid wt loss

• Adjustable gastric banding

• Roux‐en‐Y gastric bypass

• Gastric sleeve

• Gastric balloon

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© 2021 American College of Physicians. All rights reserved. 14

 Treatment for NAFLD

Modality Effect Comments

Bariatric surgery
RYGB, LABG, sleeve  Improves or resolves  Use only when failed 
gastrectomy NASH in 60‐80% cases  lifestyle modification & 
as well as fibrosis comorbid conditions 
justify risk of surgery

Torres DM, Harrison SA. S&F 2019 edition.

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Targeting Pathophysiological Processes

NORMAL LIVER STEATOSIS STEATOHEPATITIS CIRRHOSIS

Targets related to  Targets related to 
Targets related to  Targets related to  Targets related to 
insulin resistance  cell death 
lipotoxicity &  inflammation and  fibrogenesis & 
and/or lipid  (apoptosis and 
oxidative stress immune activation collagen turnover
metabolism necrosis)

PPARγ Pioglitazone PPARα/∂ Elafibranor ASK1  Selonsertib LOXL2  Simtuzumab

CCR2/5 Cenicriviroc
PPARα/∂/γ Lanifibranor Caspases Emricasan Galectin  GR‐MD‐02
GLP‐1 Liraglutide, Semaglutide
PPARα/γ Saroglitazar AOC3 BI 1467335
GLP‐1/GR MEDI0382
mTOT MSDC‐0602K TLR4 JKB‐121
ACC GS‐0976, PF‐05221304
OCA, GS‐9674, tropifexor,  Anti‐LPS IMM‐124E
SCD1 Aramchol FXR
LMB‐763
SGLT1/2 LIK066  TGR5 INT‐767, INT‐777
FGF21 BMS‐986036, AKR‐001 ASBT: Volixibat
THR‐β MGL‐3196, VK2809 FGF19 NGM282
FGFR1/KLB  BFKB8488A Vitamin E

Slide courtesy of Harrison SA 2019.

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© 2021 American College of Physicians. All rights reserved. 15

 Current Pharmacotherapy for NAFLD
Modality Effect Comments
Vitamin E 800‐1000 IU  Improves NASH but modest/no  Useful in non‐diabetic 
daily fibrosis benefit populations.  ? prostate 
cancer risk.
Pioglitazone 30‐45 mg  Improves NASH, possible 
Side effect profile – weight 
daily fibrosis improvement gain, osteoporosis, edema, 
CHF.  Not FDA approved for 
NASH
Incretin mimetics  Improve insulin resistance,  GI side effects.
(exenatide & liraglutide) promote weight loss, modest  Ongoing trial with 
histologic improvement small  semaglutide
trials

Torres DM, Harrison SA. S&F 2019 edition.

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Current Pharmacotherapy for NAFLD
Modality Effect Comments
Pentoxyifylline Possible NASH & fibrosis  Small pilot trials
improvement
Statins NASH histology generally  Safe in NAFLD & reduces risk 
unchanged*  of cardiovascular disease
Ezetimibe Modest improvement in  Safe in NAFLD & can be used 
pilot trial for hyperlipidemia but not as 
NAFLD/NASH therapy

*Dongiovanni P et al.  J Hepatol 2015.  107/1021 NASH patients on statins  less steatosis, NASH and fibrosis.

Torres DM, Harrison SA. S&F 2019 edition.

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© 2021 American College of Physicians. All rights reserved. 16

 Future Treatment for NAFLD
Modality Effect Comments
FXR agonist (obetocholic Improves NASH histology Side effects: pruritus, 
acid) increased LDL, lowered HDL

Antifibrotics:   Ongoing phase 2 & phase 3  Promising but need more 

Cenicriviroc, emricasan,  studies data
selonsertib, GR‐MD‐02
PPAR α‐δ agonist: Relatively modest efficacy Side effects: ↑ crea nine
Elafibranor

Torres DM, Harrison SA. S&F 2019 edition.

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NASH: Metabolic Agents in Phase 3 Clinical Development
AGENT MoA (TARGET) TRIAL, PATIENTS AND ENDPOINT(S) METABOLIC AGENTS

RESOLVE‐IT (n=2000*, fibrosis stage 1–3) – PRO: JAN 2020, FRO: DEC 2021 1 1 1
Lipotoxicity/oxidative stress
Elafibranor (PPARα/δ agonist)
> NASH resolution without worsening of fibrosis
> Long‐term composite of all‐cause mortality, cirrhosis and liver‐related events

REVERSE (n=540*, compensated REGENERATE (n=2065*, fibrosis stage 1–3) – PRO: FEB 2019, 

Obeticholic 2 final Completion: OCT 2022 3 3 3
Lipotoxicity/oxidative stress  cirrhosis) – Q3 2020 2
Acid  (FXR agonist) > Fibrosis improvement ≥1 stage without 
> Fibrosis improvement ≥1 stage without NASH worsening 
> NASH resolution without fibrosis worsening / All‐cause mortality and 
(Ocaliva) NASH worsening liver‐related events

4 4
Resmetirom Lipotoxicity MAESTRO‐NASH (n=2000*, fibrosis stage 2–3) – PRO: JUN 2021, final Completion: MAR 2024 4
(MGL‐3196) (THR‐ß agonist) > NASH resolution without worsening of fibrosis

ARMOR (NASH and fibrosis) – PRO: JUN 2022, final Completion: DEC 2024 5 5 5
Fatty acid synthesis
Aramchol (SCD1 inhibitor)
> Histological endpoint at 52 weeks
> Composite of progression to cirrhosis, liver‐related clinical outcomes and all‐cause mortality

3 1 2 4 1 5 3 4 5
PRIMARY and FINAL READOUT

*Planned. PRO, Primary Readout;  FRO, Final Readout; FXR, farnesoid X receptor; PPAR, peroxisome proliferator‐activated receptor; SCD, stearoyl CoA desaturase; THR, thyroid hormone 
receptor. 1. ClinicalTrials.gov. NCT02704403; 2. ClinicalTrials.gov. NCT03439254; 3. ClinicalTrials.gov. NCT02548351;. 4. NCT03900429; 5. https://www.prnewswire.com/il/news‐
releases/galmed‐pharmaceuticals‐announces‐successful‐completion‐of‐end‐of‐phase‐2‐meeting‐with‐fda‐and‐plan‐for‐start‐of‐phase‐3‐300827912.html (accessed  Sept 2019). 

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© 2021 American College of Physicians. All rights reserved. 17

 ANTI‐INFLAMMATORY AGENTS
NASH Phase 3 clinical development
ANTI‐FIBROTIC AGENTS

AGENT MoA (TARGET) TRIAL, PATIENTS AND ENDPOINT(S)

1
STELLAR‐3 (n=808, fibrosis stage 3) – Q2 2019 2 2
STELLAR‐4 (n=883, compensated cirrhosis) – Q1 2019 1
Apoptosis/necrosis  > Fibrosis improvement ≥1 stage without NASH 
Selonsertib > Fibrosis improvement ≥1 stage without NASH worsening 
(ASK1 inhibitor) worsening 
> Event‐free survival
> Event‐free survival

3
Belapectin Fibrosis NASH‐RX (n=500*, compensated NASH cirrhosis) – Q4 2022 3
(GR‐MD‐02) (Galectin‐3 inhibitor) > NASH resolution without worsening of fibrosis

AURORA (n=2000*, fibrosis stage 2–3) – PRO: OCT 2021, final Completion: 2028 4  4 4
Inflammation/fibrosis 
Cenicriviroc (CCR2/5 antagonist)
> Fibrosis improvement ≥1 stage without NASH worsening 
> Composite of progression to cirrhosis, liver‐related clinical outcomes and all‐cause mortality

1 2 4 3 4
PRIMARY and FINAL READOUT

*Planned. PRO, Primary Readout;  FRO, Final Readout; ASK, apoptosis signal‐regulating kinase; CCR, CC chemokine receptor; PPAR, peroxisome proliferator‐activated receptor; 
FXR, farnesoid X receptor; THR, thyroid hormone receptor. 1. ClinicalTrials.gov. NCT03053063; 2. ClinicalTrials.gov. NCT03053050; 4. ClinicalTrials.gov. NCT02704403; 

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Hepatocellular Carcinoma and NAFLD
• HCC reported increasingly in non‐cirrhotic NAFLD 
• Obesity and diabetes  increased rates of HCC in NAFLD
• Not feasible to screen all NAFLD with serial imaging, 
although recommended for NASH cirrhosis.  
• Stage 3 NASH patients or those with NAFLD and a strong 
family history of liver cancer can be considered for serial 
imaging.

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© 2021 American College of Physicians. All rights reserved. 18

 Alcohol Use in NAFLD
• EtOH = calories & carbohydrates
• Conflicting data on modest intake
• Avoid heavy EtOH intake
• NHANES III 4264 pts >3 men/>1.5 women drinks daily  1.79 HR death, 2.46 HR death in 
subgroup with MS 1

• FINRISK study (8345 pts)  
• Even low alcohol  increased risks of advanced liver disease & cancer
• Low to moderate EtOH associated w/reduced mortality & CVD in never smokers2

1 Younossi ZM et al.  Nonalcoholic and alcoholic‐related fatty liver disease.  Clin Gastro Hepatol 2018.

2 Aberg F et al.  Risks of light and moderate alcohol use in fatty liver disease.  Hepatology 2019. 

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MAFLD  (Metabolic dysfunction‐associated liver disease)
• “Positive instead of Negative criteria to diagnose” by a panel of liver experts from 22 
countries

• Hepatic steatosis plus one of the following:
• Overweight/obesity
• Type 2 Diabetes
• Evidence of metabolic dysregulation

• Dual etiology fatty liver disease – MAFLD + any other cause of liver disease (example 
alcohol, viral hepatitis, autoimmune, etc.)

• Currently being debated on utility of this nomenclature change, more to come…..

Eslam M et al.  A new definition for metabolic dysfunction‐associated fatty liver disease: an 
international expert consensus statement.  J Hepatol 2020. 73:202‐209.
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 Conclusions
• NAFLD is the most common chronic liver disease 
• NASH most clinically relevant subset
• Non‐invasive scoring systems useful screening tools
• Lifestyle modification remains mainstay of therapy
• 7‐10% gradual & sustained weight loss
• Many meds in the research pipeline for NASH 
• Metabolic, anti‐inflammatory, anti‐fibrotic
• NAFLD patients have increased risk of liver cancer
• HCC screening in cirrhosis +/‐ stage 3 fibrosis or family history liver cancer

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© 2021 American College of Physicians. All rights reserved. 20