NAFLD DIAGNOSIS AND MANAGEMENT:MOVING FROM THE DARK AGES TO THE RENAISSANCEDr. Thomas Jensen M.D., Assistant Professor Medicine Dr. Amanda Wieland M.D., Assistant Professor of Medicine

OBJECTIVES

• Recognize the Inadequacy of traditional work up for NAFLD• Discuss the Rationale for Screening for NAFLD • Review a practical approach to workup of NAFLD• Examine data on current and potential new treatments for NAFLD

DISCLOSURES

• Dr. Jensen has has no relevant financial disclosures for this talk

• Dr. Wieland has no relevant financial disclosures for this talk

“THE TRIUMPH OF DEATH”

PIETER BRUEGEL THE

ELDER

PREVELANCE• NAFLD: 10-35%

• NASH: 2-5% with some studies as high as 12.2%• NASH Cirrhosis: Possibly 4 million Americans affected

• Cirrhosis and Significant Fibrosis increased 2.5 and 2 Fold in last Decade

• Soon will replace Hepatitis C for number one indication for Liver Transplant

NAFLD SPECTRUM

Rinella ME. JAMA, 2015.

NAFLD SPECTRUM

Rinella ME. JAMA, 2015.

NASH ACTIVITY

GRADE = NAFLD Activity Score (NAS) of 0 to 10

NAFLD STAGE

QUESTION 1

• True or False: Liver enzymes are the most sensitive way for detecting presence and severity of NAFLD.

• True

• False

TRADITIONAL WORK-UP

45 YO Female with MetS• Hx of PreDM recently diagnosed,

Asthma, OSA• Lab work:

• ALT: 66 U/L (7-52 U/L)• AST: 32 U/L (12-39 U/L)• Total Bilirubin 0.8 mg/dL (0.0-1.2

mg/dL)• Platelet Count: 251x10e3/ul

66 YO Male with T2DM• Hx of DM since age 32, Rheumatoid

Arthritis, CAD, OSA• Lab Work:

• ALT: 31 U/L (7-52 U/L)• AST: 36 U/L (12-39 U/L)• Total Bilirubin 0.4 mg/dL (0.0-

1.2mg/dL)• Platelet Count 209x10e3/ul

ACP CARTOON: “RALPH’S

REACTION TO THE SUGGESTION HE

WILL NEED A LIVER BIOPSY”

LIVER ENZYMES

Mofrad, et al. Hepatology, 2003Browning, et al. Hepatology, 2004

QUESTION 1

• True or False: Liver enzymes are the most sensitive way for detecting presence and severity of NAFLD.

• True

• False

Vitruvian Man, Da Vinci

A RENAISSANCE IN THE APPROACH TO NAFLD

SCREENINGAmerican Association Study of Liver

Disease (AASLD) July 2017 Statement:

EASL-EASD-EASO 2016 Statement:

NATURAL HISTORY/PROGRESSION

Bertot LC, et al., Int J Mol Sci, 2016.

QUESTION 2• 47 yo surgical menopausal (age 43) female with history of overweight (BMI

27) with 8kg weight gain in the last year, hx of DCIS sp lumpectomy and radiation. She is on venlafaxine for hot flashes with limited benefit and takes tamoxifen. She is incidentally found to have steatosis on limited US for RUQ pain. Her ALT is 27 and AST 15, Albumin 4.1, normal bilirubin 0.8, A1c is 5.3, fasting glucose is 89. Your next step:

• A. Tell her to exercise more in order to lose weight • B. Change venlafaxine to estrogen patch since her early menopause is to

blame for weight gain• C. Get a complete ultrasound and calculate risk of fibrosis• D. Perform liver biopsy

High Risk Patients:Obese Patient

with other feature of MetS

or MetS

Screen for Steatosis

Absent*:Repeat testing

in 3-5 years

*Risk Factors:DMWeight GainFam Hx/GeneticsOSAMenopause

Present:Review or obtain

Liver EnzymesAssess for

Secondary Causes

Elevated liver Enzymes?

Hepatitis CCeliac

HypothyroidismScreen ETOH

Labs for NormalHepatitis BAlpha 1 AT

HemochromatosisWilson’s (<45)Autoimmune

Drugs

Assess Risk for Fibrosis

YESNO

Assess Risk for Fibrosis

Medium or High Risk:Imaging

Low Risk

F0/F1 Disease

Monitor q 2-3 Years, consider

Bx

F2 Disease

Monitor q 1-2 Years, if HSM

do Bx

F3 or F4 Disease

F3: Consider Bx to Confirm or if HSMF4: Bx unless HSMMonitor q 1 year

Re-Assess Risk of Fibrosis

Yearly

LIVER BIOPSY VS FIBROSCAN

FIBROSCAN

Controlled Attenuation Parameter (CAP) Elastography

Karlas et al, 2016

QUESTION 2• 47 yo surgical menopausal (age 43) female with history of overweight (BMI

27) with 8kg weight gain in the last year, hx of DCIS sp lumpectomy and radiation. She is on venlafaxine for hot flashes with limited benefit and takes tamoxifen. She is incidentally found to have steatosis on limited US for RUQ. Her ALT is 27 and AST 15, Albumin 4.1, normal bilirubin 0.8, A1c is 5.3, fasting glucose is 89. Your next step:

• A. Tell her to exercise more in order to lose weight • B. Change venlafaxine to estrogen patch since her early menopause is to

blame for weight gain• C. Get a complete ultrasound and calculate risk of fibrosis• D. Perform liver biopsy

CASE 1: 40 YO FEMALE

Background History• PMH:

• PCOS on metformin, Pre-DM, Obesity

• Meds: Metformin 1000mg BID, Lexapro 20mg

• Soc Hx: Tob 8 years quit 2005, Rare etoh use

PE, Labs and Imaging• PE: BMI 35, silver stretch marks stomach,

no AN, few coarse hairs on face• Labs: ALT 21, AST 12, Alb 4.2, Alk phos

50, A1c 5.8, TC 135, Trigs 111, HDL 37, LDL 75, TSH 0.79, ferritin 25, Vit D 33, Celiac negative, CBC wnl PC 216

• US: Increased liver echogenicity• NAFLD FS: 1.706 High Risk (-1.455, 0676)• FIB-4: 0.485 Low Risk (1.45, 3.25)

CASE 2: 54 YO FEMALE

Background History• PMH: T2DM(12years),HTN,Obesity

• Medications;Degludec 114units,sitagliptin50mg+metformin1000mgBID,Losartan100mg,HCTZ25mg

• Soc:Notob,rareetoh use

PE, Labs and Imaging• PE: BMI 30, enlarged liver, diminished

vibrational sense, telangiectasias chest, diminished fat on arms and legs

• Labs: ALT 42, AST 41, Albumin 3.8, Platelet Count 64

• NAFLD FS: 2.268 (-1.455, 0.676)• FIB-4: 5.634 (1.45, 3.25)

• CT Scan: Showed Hepatosplenomegaly• Liver Biopsy: Stage 4 Fibrosis confirmed

CASE 3: 58 YO MALE

Background History

• PMH: T2DM since age 36, Nephropathy, OSA, HTN, HLD

• Medications: U500 140 units AM and PM, canagliflozin 100mg, metformin 1000mg BID, simvastatin 40mg, lisinopril 20mg

PE, Labs and Imaging

• PE: BMI 42, Hepatomegaly, Diminished vibrational sense and Achilles DTR

• Labs: ALT 32, AST 20, Platelet Count , A1c 8.0, Platelet Count: Not Done

• Ultrasound: Hepatomegaly with steatosis

QUESTION 3• 57 yo female with hx T2DM on metformin 1000mg BID and Glipizide 10mg BID

(7 years, A1c risen to 8.2 from 6.9), obesity (BMI 33), HTN (on Lisinopril 20mg), HLD (On Atorva 20mg), and Osteopenia (Vitamin D and Calcium) found to have ALT 68, AST 40. US revealed hepatomegaly with steatosis. Secondary workup was negative. Biopsy revealed NASH with Stage 1 fibrosis. Besides lifestyle modifications you would suggest:

• Increase Glipizide to 20mg BID and stop statin• Start Pioglitazone 45mg and stop statin• Start Vitamin E 800 IU and continue statin• Start Liraglutide, titrate to 1.8mg and continue statin

POTENTIAL THERAPEUTIC TARGETS

Sumida Y, et al. J Gastroenterol, 2017

INSULIN SENSITIZERSMedication Trial Outcomes OverallRecommendation

Metformin Metanalysis 9 RCT with 417 participants 4-12 months(LiY,BiomedRep,2013.)

Nohistologicalimprovementinsteatosis,inflammation,hepatocellularballooningorfibrosiscomparedtoplacebo

NotfortreatmentofNAFLD,butstillprimaryforT2DMandmayhavebenefitsincirrhosisandHCC.

Pioglitazone PIVENS Trial. 80 Nondiabetic patients with bx proven NASH on Pio 30mg for 96 weeks. (Sanyal A, NEJM, 2010.)

Primary End: Improvement in NAS Score, but not hepatocellular ballooningSecondary Endpoint: NASH resolution 47% vs 21%(p=0.001) and Fibrosis improvement 44% vs 31% (P=0.12)

ImprovementinNASHinbothDiabeticsandNondiabetics,thoughcautioninCHFandosteoporosis

GLP-1(Liraglutide) Phase 2 RCT 26 overweight/obese NASH on Liraglutide vs 26 on Placebo 48 weeks. (Armstrong, Lancet, 2016)

Outcome:39%resolutionofNASHvs9%Placeboand9%progressionfibrosisvs36%inplacebo.Outcomesassociatedwithweightloss.

Consider in the management of NASH in T2DM

SGLT Inhibitors E_Lift Study: Empagliflozin 10mg vs Placebo 20 weeks in T2DM (Endo Society 100th

Annual Meeting)

Primary Outcome: Reduction of liver steatosis 16.2% to 11.6% vs 16.4% to 15.6% Placebo.

LimiteddatatorecommendusespecificallyforNASH

ANTIOXIDANTS AND OTHER MEDS

Medication Trial Outcomes OverallRecommendationVitaminE PIVENS Trial. 84

Nondiabetic patients with bxproven NASH on Vit E 800IU for 96 weeks. (Sanyal A, NEJM, 2010.)

Primary Outcome: Improvement in Hepatocellular Ballooning and NAS ScoreSecondary Outcome: Resolution of NASH in 36% vs 21% placebo (p=0.05), NS improvement in fibrosis 41% vs 31% in placebo (p=0.24)

Can consider in nondiabetics

Limitations with 800IU, risk for all cause mortality, stroke, prostate cancer, consider 400IU

Statins Atorvastatin: 10 mg a day for 24 months in 17 follow up biopsies. (Hyogo et al. Metabolism 2008.)

Simvastatin: 40mg for 12 months (10) vs placebo (6) (Nelson A, et al. J ClinGastroenterol, 2009).

Atorvastatin Outcomes: Improvement in steatosis (Grade 1.6 to 0.8) and NAS (4.1 to 2.9), but 4/17 had fibrosis progression

Simvastatin Outcome: No significant improvements in steatosis, NAS score or fibrosis

Very limited data

Strongly recommend for treatment of hyperlipidemia in NAFLD to prevent CVD (If liver enzymes <3x ULN)

FUTURE DIRECTIONSMedication Trial Outcomes FutureResearchObetacholic Acid(FXRAgonist)

FLINT Trial: Phase 2 FXR Agonist 141 to OCA vs 142 placebo 72 weeks in NASH patients

Outcomes: 35% improvement in fibrosis compared to 19% Placebo, Steatosis 61% vs 38%, NS resolution of NASH 22% vs 13%SE: Itching and increase in LDL

Phase 3 Regenerate Trial

Possibility of FDA approval by 2020/2021

Elfibranor (PPAR α/δagonist)

Golden 505 Trial: Patients with bx proven NASH 93 80mg Elfibranor, 91 120mg Elfibranor and 92 to placebo for 52 weeks (Ratzui V, et al., Gastroenterology, 2016)

Outcomes: Resolution of NASH (resolution of ballooning with no or mild inflammation) 19% in120mg group vs 12% Placebo

Modest improvements in Glucose, Lipids, inflammatory markers

Phase 3 Trial RESOLVE IT

Serlonsertib (ASK1inhibitors)

Phase 2: 72 patients randomized to Serlonsertib18mg or 6mg w/wo Simtuzumab 125mg (LOXL2 inhibitor) or Simtuzumabalone for 24 weeks (Loomba R, et al. Hepatology 2017.)

Outcomes: 43% and 30% reduction in Fibrosis compared to 20% simtuzumab alone, 20% progressed to cirrhosis compared to 3% and 7% in Serlonsertib groups. Reductions in steatosis

Phase 3 Stellar 3

WEIGHT LOSS IN THE TREATMENT OF NAFLD/NASH

• Weight loss is the primary and most effective treatment to date in reversing the disease:

• Improvements in steatosis, ballooning, inflammation and fibrosis correlate with percent weight loss (Vilar-Gomez, et al., 2015):

Romero-Gomez M, et al., 2017

BARIATRIC SURGERY OUTCOMES

BEFORE AND AFTER

August 2017• 67 yo female T2DM (Lantus 40 unit

BID, metformin-A1c 8.8), HTN (Lisnopril-HCTZ, metoprolol), HLD (Atorva 20mg, Fish Oil), Morbid Obesity (BMI 40.44/243lbs)

• US: Hepatic Steatosis• NFS: 2.831 FIB-4: 0.840

March 2018• 1 month Post-Op Sleeve

gastrectomy• BMI 36.99/220 lbs• On Lantus 15 units only BS avg 135,

metoprolol for hx of SVT• NFS: 2.267 FIB4: 0.849

TREATMENT OVERVIEW

Sumida Y, et al. J Gastroenterol, 2017

QUESTION 3• 57 yo female with hx T2DM on metformin 1000mg BID and Glipizide 10mg BID

(7 years, A1c risen to 8.2 from 6.9), obesity (BMI 33), HTN (on Lisinopril 20mg), HLD (On Atorva 20mg), and Osteopenia (Vitamin D and Calcium) found to have ALT 68, AST 40. US revealed hepatomegaly with steatosis. Secondary workup was negative. Biopsy revealed NASH with Stage 1 fibrosis. Besides lifestyle modifications you would suggest:

• Increase Glipizide to 20mg BID and stop statin• Start Pioglitazone 45mg and stop statin• Start Vitamin E 800 IU and continue statin• Start Liraglutide, titrate to 1.8mg and continue statin

CONCLUSION

• Health Care Providers must recognize the advancing epidemic of NAFLD

• New tools developed in the last 5-10 years help to make screening and staging of disease more practical

• Diagnosis can help promote appropriate discussions on potential treatments especially lifestyle modifications

• New emerging therapies provide additional hope to prevent progression to End Stage Liver Disease

SENSITIVITY OF VARIOUS NONINVASIVE SCREENING TOOLS: NAFLD

Test Reference Components ResultFatty Liver Index Bedgoni G, etal.,2006. Waist Circumference, GGT,

Triglycerides, BMIAUROC 0.84; 2 cut offs <30 rule out, >60 rule in Se 87%, Sp 86%

Steatotest Poynard T, et al., 2005. Alpha-2 macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, fasting glucose, triglycerides, cholesterol, ALT, age, gender, BMI

AUROC 0.7; 2 cut offs 0.3 and 0.72 Se 90% and Sp 70%

NAFLD Liver Fat Score Kotronen A, et al., 2009 Presence of Metabolic Syndrome, Presence of Type 2 diabetes, ALT, AST

AUROC 0.87; 2 cut offs -1.413 and +1.257 Se 95% Sp 95%

Ultrasound Saadeh S, et al., 2002.Lee SS, et al., 2010.Van Werven JR, et al., 2010.De Moura Almeida A, et al., 2008.

Steatosis >30% Se 81.8-100% and Sp 98%, Any Steatosis Sen 53.3-66.6% and Sp 77.0-93.1%

CT Scan Park SH, et al., 2006. Non-contrast Liver HU/Spleen HU

At 0.8 Sensitivity 82% with Specificity 100%

MRI Lee SS, et al., 2010.Van Werven JR, et al., 2010.

Any steatosis Sen 76.7-90.0%, Sp 87.1-91%

MR Spectroscopy Lee SS, et al., 2010.Van Werven JR, et al., 2010.

Any steatosis Sen 80.0-91.0% and Sp 80.2-87.0%

SENSITIVITY OF VARIOUS NONINVASIVE SCREENING TOOLS: NAFLD VS

NASH/FIBROSIS

Test Reference Components ResultCytokeratin 18 Buzzetti E, et al.,2015. Levels varied in studies AUROC 0.65-0.83 for NASH vs

NAFLDFerritin Kowdley KV, et al., 2012. 1.5ULN NASH ≥F2 AUROC 0.57

APRI Score Tapper EB, et al., 2014 AST:Platelet Ratio*100 Score >1 had Se 30% and Sp 93% for ≥F2

NAFLD Fibrosis Score Angulo P, et al., 2007. Age, presence of DM/IR, BMI, AST, ALT, platelets, albumin

<-1.455 for No significant fibrosis Se 82% and Sp 77% NPV 93%, >0.676 for Significant fibrosis Se 51% Sp 98% PPV 90%

FIB-4 Score Sumida Y, et al., 2012. Shah AG, et al., 2009.

Age, ALT, AST, Platelets AUROC 0.88, At cutoff 1.45 Se 90% Sp 64% NP 98%, 3.25 cutoff Se 48% Sp 95% PPV 53%

Fibroscan (US Elastography)

Wong VW-S, et al., 2012.Sirli R, et al., 2014

AUROC ≥F2 0.8-0.83 ≥F3 0.85-0.87, ≥F4 0.89-0.91

MR Elastography Kim D,et al. 2013. Above kPa 4.15 For Advanced Fibrosis AUROC 0.95 with Se 85% and Sp 93%

SECONDARY CAUSES OF NAFLD

Kneeman JM, et al., Therap Adv Gastroenterol, 2012.

Lysosomal Lipase Deficiency