Medical Management of NASH

Jaideep Behari, MD, PhDUPMC Fatty Liver, Obesity and Wellness (UPMC FLOW®) ClinicUPMC Center for Liver DiseasesDivision of Gastroenterology, Hepatology, & NutritionUniversity of Pittsburgh School of Medicine

Overview of the presentation

Part 1: Background and new terminology for 2020

Part 2: Clinical challenges in management

Part 3: A practical framework for clinical management

Part 1

Background and new terminology for 2020

Clinical case

70 year old female had abdominal US for mild self-limited RUQ pain

BMI 31, no DM, dyslipidemia on statin

No alcohol

ALT 35, AST 22

US reports “echogenic liver suggestive of fatty infiltration of the liver”

= Liver

= Kidney

US at initial diagnosis 1 year later after 13% weight loss

Dunn, 2013, Liver International

Liver – spleen attenuation < -10 on noncontrast CT

Histology of nonalcoholic steatohepatitis (NASH)

NASH is characterized by chicken-wire pattern of liverfibrosis

Natural history of NASHHealthy Nonalcoholic fatty liver Nonalcoholic steatohepatitis (NASH)

NASH with fibrosis NASH Cirrhosis NASH Cirrhosis with HCC

NAFLD is closely associated with inulin resistance and the metabolic syndrome

Siegel 2009

NAFLD has a complex “multihit” pathogenesis involving genetics and multiple organ systems

Mann et al 2016

New terminology for 2020 : “Positive” diagnostic criteria for MAFLD

Eslam et al, J Hepatol, 2020

Liver biopsy not requiredfor diagnosis of “NASH”

MAFLD-associated cirrhosis

Patient with cirrhosis in the absence of typical histology who meet at least oneof the following criteria:

Past or present evidence of metabolic risk factors that meet the criteria to diagnose MAFLD

With at least one of the following:- Documentation of MAFLD on a previous liver biopsy- Historical documentation of steatosis by hepatic imaging

Eslam et al, J Hepatol, 2020

Dual etiology fatty liver disease

Meeting criteria for MAFLD

+

Any other cause of liver disease (alcoholic liver disease*, HCV, HBV etc.)

* > 3 drinks per day in males; >2 drinks per day in females;or binge drinking (>5 drinks in males or >4 drinks in females in 2 hours)

Eslam et al, J Hepatol, 2020

Clinical examples- 54 year old male with BMI 40 and US with hepatic steatosis (MAFLD)

- 34 year old female BMI 24 with dyslipidemia and prediabetes (“Lean” MAFLD) and fatty liver on CT

- 60 year old male with steatohepatitis on biopsy with BMI 33 and 4 alcoholic drinks per day (Dual etiology fatty liver MAFLD + ALD)

- 71 year old female with MRI showing steatotic, nodular liver, BMI 39, T2DM (MAFLD associated cirrhosis)

Part 2

Clinical challenges in the management of NASH (MAFLD)

Prevalence of NAFLD (MAFLD) is increasing worldwide

Younossi et al, 2017, Nat. Rev. Gastroenterol. Hepatol.

First-degree relatives of individuals with NASH-cirrhosis have increased risk of advanced fibrosis

Caussy et al, JCI, 2017

NASH is very common in certain high risk populations

Sanchez, 2015, J Clin Endocrinol Metabol

Obesity T2DM

Most patients in our population have BMI > 25 kg/m2

Dudekula, 2014, PLoS One

924 non-cirrhotic NAFLD patients in CLD

NAFLD can occur in individuals with or without obesityProportion of individuals with NAFLD stratified by country and obesity status

Younossi, Z et al, 2017, Nat. Rev. Gastroenterol. Hepatol.

Due to the high prevalence of NAFLD, the public health burden is huge

Buzzetti et al 2016

Likely low risk of progression

Likely some risk of progression High risk of progression

Liver fibrosis stage is the most important prognostic factor for liver-related outcomes

Fibrosis stage: F0 no fibrosis, F1 mild, F2 moderate, F3 severe, F4 cirrhosis

Liver fibrosis stage is the only histological feature of NASH associated with survival

UPMC Center for Liver Diseases(2007-2017)

Biopsy-proven NASHN = 899 patients

**Clinical challenge:Staging fibrosiswithout a liver biopsy**

There is no FDA approved treatment for NASH (MAFLD)

Source: Clinicaltrials.gov; Accessed August 2019

>200 ongoing clinical studies around the world

Part 3

A practical framework for clinical management

Step 1: Suspect MAFLD in the appropriate clinical setting

Obesity, DM, metabolic syndrome with or without elevated liver enzymes

NASH NASH + Fibrosis

NASH + Cirrhosis

Total NASH No NASH

N 3,820 233 3,139 7,192 11,072,655FIB-4 category

Low (%)Intermediate (%)High (%)

54.434.411.2

53.836.210.0

9.722.867.5

32.928.938.2

63.328.87.9

Is NASH underdiagnosed in the community?

Behari, et al, 2020 Liver Meeting

11 million patients across 7 sites in the Northeast and Midwest US

Step 2: Define the etiology

MAFLD alone

Dual etiology fatty liver (MAFLD + ALD?)

Dual etiology liver disease (MAFLD + AIH?)

Triple etiology fatty liver (MAFLD + ALD + HCV?)

Concurrent etiologies to consider

1. Alcoholic liver disease (very common)

2. Viral hepatitis (common)

3. Autoimmune hepatitis (uncommon)

4. Other causes (hemochromatosis etc.)

Presence of autoantibodies (ANA/ASMA) is not associated with increased risk of NASH/fibrosis

P = ns

Vuppalanchi, Liver Int, 2011

Step 3: Perform non-invasive tests of liver fibrosis to stage disease

1. Point of care (FIB-4, NAFLD Fibrosis Score)

2. Commercial panels (NASH Fibrosure panel)

3. Imaging based (Fibroscan, US elastography, MR elastography)

Serum markers of liver fibrosis in NAFLD have high NPV but low PPV

Test Components AUROC Sensitivity(%)

Specificity(%)

Cutoff Fibrosisstage

NAFLD Fibrosis Score (NFS)

Age, IFG/DM, BMI, Plt, AST/ALT

.81 51 96 -1.45 (low)0.67 (high)

F3/4

FIB-4 Age, AST, plt, ALT .88 26-74 71-98 -1.92 (low)3.25 (high)

F3/4

APRI AST/Plt .67-.94 30 93 .45 (low)1.5 (high)

F2-4

Fibrosure Alpha2 macrogloblulin,haptoglobin, GGT, Total bili, apoliprotein

.81-.92 15-77 77-90 .3 (low)

.7 (high)

F2-4

BARD BMI, AST/ALT ratio, DM

.8 86.8 32.5 2 F3/4

Kawala et al 2016 Dig Sci

FIB-4 score can be used as a simple noninvasive fibrosis assessment tool

<1.45 = High NPV forabsence of advanced fibrosis

>3.25 = 97% specificity foradvanced fibrosis (65%PPV)

Vibration Controlled Transient Elastography (Fibroscan®) is very useful for point-of-care risk stratification

•CAP: Assessment of liver fat (dB/m)

35

Image source: Echosens

Eddowes, Gastroenterol, 2019

LSM: Assessment of liver fibrosis (kPa)

Steatosis cutoff: 274 dB/m for grade ≥1 steatosis [sensitivity

of .90 (95% CI

.87-.93)]

Fibrosis: liver stiffness

measurement cutoff values of 8.2 kPa for ≥F2, 9.7 kPa for

≥F3 and 13.6 kPa for F4.

Ultrasound Shear Wave Elastography is available for noninvasive fibrosis assessment

Image source: GE Healthcare

36

MR Elastography and proton density fat fraction (PDFF) can accurately measure liver fibrosis and steatosis

Venkatesh et al 2013 J Magn Reson Imaging

MRI-PDFF Proton density fat fraction for steatosis determination

Noninvasive approaches to fibrosis assessment can avoid liver biopsy in a large percentage of patients

Furlan, 2020, Am J Roent.

35 year old maleFIB-4: <1.45

5.7 kPa 2.35 kPa

Proposed simplified diagnostic workflow for MAFLDM: ALT>30; F > 19

Repeat labs; Risk factors

Alcohol history, HBsAg, HCV Ab, ferritin/iron sat, ANA, ASMA, ASMA, AIAT level, ceruloplasmin

Treat as appropriateAbd US echobright

Liver screen negative

Abd US normalLiver screen negative

NAFLD

NAFLD Fibrosis scoreVCTE/FibroscanLow risk:

NFS<-1.455 (NPV 93%)VCTE < 5 kPa*

IndeterminateNFS -1.455-0.676

VCTE 7-12.5*OR Discordant NFS/VCTE

High riskNFS > 0.676 (PPV 90%)VCTE > 12.5 (+/-1) kPa*

<-2.5<5 kPa

-1.45 to -2.55-7 kPa

Alternate diagnosis?Mild steatosis?

PCP follow up/3 years

Reassess in 1 yearLifestyle mod.

Manage as cirrhosis

Liver biopsyTreat if F2-3 fibrosis

Simplified algorithm for risk stratification in NASH

NAFLD

FIB-4 VCTE or SWE+

BOTH CONCORDANT FOR LOW RISK<1.45 / < 7 kPa

BOTH CONCORDANT FOR HIGH RISK>3.25 / >15 kPa

MRE + PDFF

DISCORDANT RESULTS OR BOTH CONCORDANT FOR MODERATE RISK

1.5-3 / 7-15 kPa

Liver biopsy

Step 4: Manage based on risk stratified MAFLD disease stage

Adapted from Rinella and Sanyal, Nat Rev Gastroenterol Hep, 2016

Step 5: Focus on lifestyle modification for all MAFLD disease stages

• Diet quality

• Smoking cessation

• Alcohol cessation

• Physical activity

• Weight management

There is limited data on optimal dietary advice for patients with MAFLD

Zivkovic, 2007, Am J Clin Nutr; Musso, 2009, Am J Clin Nutr; Ryan, 2013, J Hepatol;Harrison, 2009, Hepatology; Molloy, 2012, Hepatology

• The best diet to treat NAFLD is unknown (high protein diet?)• >5% weight loss improves steatosis• >7-9% weight loss improves histology in NASH• Avoid saturated fats, sugary drinks, simple carbohydrates

(fructose)• A Mediterranean diet (monounsaturated fatty acids-rich) improves

hepatic steatosis and insulin sensitivity• Coffee consumption is associated with reduced risk of fibrosis in

NASH patients

Coffee consumption is associated with reduction in risk of fibrosis in MAFLD patients

Molloy et al, Hepatology, 2011

Weight loss is an effective treatment for MAFLD but difficult to achieve for most patients

Romero-Gomez, J Hepatol, 2017

Weight loss is associated with improved liver histology in MAFLD

Promrat, 2010, Hepatology

Bariatric surgery can improve fat, inflammation and fibrosis in patients with severe obesity

Lassailly, 2015, Gastroenterology

NASH grade Fibrosis stage

82 patients at 1 year after surgery

Premature to consider weight loss surgery solely for NASH but can be considered if otherwise indicated (caution if cirrhosis/portal hypertension)

250 min/week of moderate exercise with weight loss may be optimal for improvement of MAFLD

Oh, 2015, Hepatology

Lifestyle modification is effective for MAFLD at any disease stage

10/2017 8/2019

Step 6: Consider liver-directed pharmacotherapy for moderate to severe fibrosis

Cusi, 2018, Ann Int MedSanyal, 2010, NEJM

Vitamin E800 I.U. daily

Pioglitazone45 mg daily

Non-diabeticNon-cirrhotic

Non-diabetic or diabeticNon-cirrhotic

GLP-1 RA?SGLT2 inhibitors?

There are over 200 ongoing clinical trials for MAFLD around the world

Source: Clinicaltrials.gov; Accessed August 2019

Clinical trials are taking three main approaches to treating MAFLD

Fat accumulation → Liver cell injury → Cell death → Fibrosis

UPMC FLOW clinic =9 MAFLD clinical trialsF1 to F4 fibrosis

Step 7: Manage MAFLD associated comorbid metabolic problems

• T2DM

• Hypertension

• Dyslipidemia

• OSA

• Cardiovascular risk reduction

Statins are safe and should not be withheld if indicated in MAFLD

- MAFLD patients are at high risk for CVS morbidity and mortality

- Aggressive CVD risk modification should be considered for all MAFLD patients

- MAFLD patient are not at high risk from statins and they can be used for dyslipidemia

- Avoid in decompensated cirrhosis

AASLD NAFLD Guidance

Patients with NASH-cirrhosis and diabetes should continue metformin after cirrhosis diagnosis

Zhang, 2014, Hepatology

Step 8: Screen for HCC and varices in MAFLD-associated cirrhosis / advanced fibrosis

Mittal et al, Clin Gastroenterol Hepatol, 2019

Proportion of HCC patients with or without evidence of cirrhosis by risk factor

Summary and conclusions• NAFLD/NASH is very commonly encountered in

clinical practice• The new definition of MAFLD enables a “positive”

diagnosis of fatty liver• Diagnosis, staging and management of MAFLD

remains challenging• A step-wise approach to risk stratification and

management can enable effective management