Nonalcoholic Fatty Liver Disease: Epidemiology, Natural History,

and Prognosis

Wing-Kin SynMD PhD FEBGH FACP FRCP (Edin) FRCP (Lond)

Professor of Medicine & Attending PhysicianMedical University of South Carolina & Ralph H Johnson VAMC

Professor, Department of PhysiologyUniversity of Basque Country UPV/EHU

Conflict of Interests

No relevant disclosures

Outline of Presentation

1. Epidemiology• What is NAFLD

• Burden of NAFLD

2. Natural History• Clinical Significance (i.e. why worry about NAFLD?)• Extrahepatic disease

3. Prognosis • Risk factors

Will not be presenting on Pathogenic Mechanisms, Diagnostic / Stratification Methods or Treatment

• Fatty infiltration of the liver (by imaging or histology)

• Associated with metabolic risk factors– Obesity (BMI, Waist: Hip circumference)– T2DM– Hypertension– Hyperlipidemia (hypertriglyceridemia)– OSA / PCOS / Gout / Hypothyroidism

• ‘Hepatic manifestation of the Metabolic syndrome’

Nonalcoholic Fatty Liver Disease (NAFLD): Metabolic Fatty Liver Disease

NAFLD Spectrum: Clinico-Pathological States

Prevalence: 25 to 40%

20% to 30%

Steatosis/ Simple fat NonalcoholicSteatohepatitis (NASH)

NASH Fibrosis NASH Cirrhosis

1. Kleiner DE, Hepatology. 2005; 2. McPherson S, . J Hepatol. 2015; 3 Singh S, Clin Gastro Hepatol. 2015

20% to 30%

Healthy

Fibrosis Stage 1 to 3 Fibrosis Stage 4

Prevalence Obesity Among U.S. Adults 2018

Obesity prevalence

In patients undergoing Bariatric surgery,

prevalence of NAFLD> 90%

http://www.cdc.gov/obesity/data/prevalence-maps.html

Diabetes Prevalence in Adults

United States Diabetes Surveillance System. https://www.cdc.gov/diabetes/atlas/countydata/atlas.html

Percentage in Quintiles0-7.837.84-8.808.81-9.969.97-11.65≥ 11.66

US adult population(300 million)

Steatosis25-40%

NASH8-13%

Cirrhosis2-3%

HCV infection 2%

Colorectal cancer 0.3%

Type 2 Diabetes 8%

HCV cirrhosis 0.5%

6-10 million people withNASH-cirrhosis*

Burden of Disease

Annual direct medical cost ~$103 billion

Natural History / Clinical Significance

Mortality associated with NAFLD

Adams LA, et al. Gastroenterology 2005; Ekstedt M, et al. Hepatology 2006

Population-based cohort studies of the natural history of patients with NAFLD• Follow-up at least 10 years• Survival of NAFLD patients was

significantly lower than of the general population

Top 3 causes of death: Cardiovascular disease Liver disease (cirrhosis)Malignancy

Minnesota Study

NAFLD and Liver Cancer • Hepatocellular carcinoma (HCC) complicates NASH-cirrhosis

• Cumulative incidence: 2.4% over 3 years to 12.8% over 7 years (Systematic Review)

• HCC may develop in Non-Cirrhotic NASH• 41.7% had no cirrhosis (our study – 162 patients with HCC)• 40.2% had HCC in the absence of cirrhosis (Review of 25 studies)

*T2DM is independent risk factor for HCC by 2-3 fold

White DL et al. Clin Gastroenterol Hepatol 2012; Duan XY et al. Hepatobiliary Pancreat Dis Int 2012; Ertle J et al. Int J Cancer 2011; Guzman G et al. Arch Pathol Lab Med 2008

Comparison of cirrhotic and non-cirrhotic NAFLD HCC: SEER-

Medicare database 1993-2007

* P value <0.01; NAFLD, Nonalcoholic fatty liver disease; HCC, Hepatocellular carcinoma;Fav., Favorable; USW, US Whites; Hisp, Hispanic; PI, Pacific Islander.

NAFLD HCC(2,863)

N(%)

Sex(M/F)

%

Race EarlyStage(I/II)

Fav. Grade (I/II)USW Black Hisp Asian/

PI

With Cirrhosis 1,832(64%)

68/32 65% 14% 6% 12% 44% 56%

Without Cirrhosis

Total 1,031(36%)

61/39 63% 15% 7% 11% 62%* 76%*

Steatosis Only

186(18%)

59/41 59% 20% 6% 11% 64% 77%

Rahman, R. M., et al. Abstract 97; AASLD2012Kanwal F, et al. Gastroenterology 2018 (VHA STUDY)

Comparison of cirrhotic and non-cirrhotic NAFLD HCC: SEER-

Medicare database 1993-2007

* P value <0.01; NAFLD, Nonalcoholic fatty liver disease; HCC, Hepatocellular carcinoma;Fav., Favorable; USW, US Whites; Hisp, Hispanic; PI, Pacific Islander.

NAFLD HCC(2,863)

N(%)

Sex(M/F)

%

Race EarlyStage(I/II)

Fav. Grade (I/II)USW Black Hisp Asian/

PI

With Cirrhosis 1,832(64%)

68/32 65% 14% 6% 12% 44% 56%

Without Cirrhosis

Total 1,031(36%)

61/39 63% 15% 7% 11% 62%* 76%*

Steatosis Only

186(18%)

59/41 59% 20% 6% 11% 64% 77%

Rahman, R. M., et al. Abstract 97; AASLD2012Kanwal F, et al. Gastroenterology 2018 (VHA STUDY)

Total Liver Transplants by Diagnosis• NASH is now the leading

indication for LT• Particularly among

those < 50 yo

Wong RJ, Hepatology 2014; Banini B, Am J Gastroenterol2016; Kim WR Am J Transplant 2019

OPTN/SRTR 2017 Annual Data Report:Liver

Association with Extrahepatic diseases

• Risk of CVD increases with NAFLD severity• Odds ratio 5-fold higher in NASH than matched

controls• ‘Metabolic NAFLD’ may even be a better predictor of CVD

as it measures more directly abnormal metabolism than metabolic syndrome.

• Chronic renal disease (including FSGN)• Cancers (non-liver: colorectal)• *T2DM (incident)

Armstrong MJ …Syn WK . Hepatology 2014; Armstrong MJ …Syn WK . HBSN 2018

What is the Prognosis for an Individual with NAFLD / NASH

a) Can we identify who is likely to progress? b) What are the risk factors?

Younossi et al, Hepatology 2011; Dulai et al. Hepatology 2017; Pais et al. J Hep 2013; Ekstedt et al, Hepatology 2015; Nasr et al. Hep Comm 2017; McPherson et al. J Hep 2015; Singh et al. Clin Gastro Hep 2015

Fibrosis Predicts Liver Mortality209 Biopsy proven NAFLD patients

Median follow-up 12.2 years

Liver Death or OLT free survival Liver-Related Mortality252015105

0

Mor

talit

y Ra

te(p

er 1

000

PYFU

)

0 1 2 3 4(Cirrhosis)Fibrosis Stage

Meta-analysis of 5 cohort studies with N = 149 patients with NAFLD

followed for 17,452 patient-yrs

NAFLD Progression

1. McPherson S, et al. J Hepatol. 2015;62:1148-1155.2. Singh S, et al. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54

Regression:18%-22%

Stable:40%-43%

Progression:34-42%

N = 108 pts with NAFL/NASH and median 6.6 yrs follow-up

(data from serial biopsies).

Change in Fibrosis

Rates of Progression

Sanyal et al. Hepatology 2019

N = 475 pts with NASH and F3 or F4- Patients from 2 phase 2 clinical trials

of Simtuzumab- Paired biopsies

- HVPG if cirrhosis

Progression in F3/F4 disease

F3 Cirrhosis Decompensation

2 YEARS 2 YEARS

~20% progress ~20% progress

Slow vs. Rapid Progressors subsets

Constitutive Risk Factors

• Ethnicity• Hispanics higher prevalence than non-Hispanic whites• African-American lower prevalence• Asians vulnerable at lower BMI*Hispanic > Asians / White > African-American

• Gender• Men > Women (Pre-Menopausal)• Post-Menopausal (no HRT) > Pre-Menopausal

Diabetes is a Risk Factor for Liver Fibrosis• Transient Elastography (Fibroscan):

• 81 subjects; No known liver disease• 26 / 81 (35%) had increased liver stiffness (i.e. fibrosis

present)• 12/16 had ≥ F2 fibrosis, including 2 with cirrhosis

• MR Elastography:• 100 subjects; No known liver disease• Prevalence of NAFLD 65%• Prevalence of Advanced fibrosis (i.e. F3) 7.1%• Only 26% had elevated ALT

Casey SP et al. Scan J Gastro 2012; Doycheva I et al. APT 2016

Genetic Risks for NAFLD

• PNPLA3, TM6SF2, MBOAT7, others

• Likely many other genes as hepatic steatosis and hepatic fibrosis are heritable traits– Family history of diabetes, even among people

without diabetes, is associated with NASH and NAFLD fibrosis

– Increased odds of advanced cirrhosis in first-degree relatives of patients with NAFLD cirrhosis

Caussy. J Clin Invest. 2017; Loomba. Hepatology. 2012; Anstee Clin Med 2018

Summary 1

• NAFLD is a common and costly disease

• NAFLD is associated with metabolic risk factors

• NAFLD is not always benign– Those with NASH are particularly at risk of non-

liver complications (including cardiac, renal, diabetes, cancer)

– Risk of disease progression to advanced fibrosis or cirrhosis

Summary 2

• (Liver) Prognosis:• Difficult to predict individual outcomes because of

the heterogeneity of disease (i.e. NAFL vs. NASH vs. NASH fibrosis)

• Those with significant or advanced fibrosis are likely to develop liver complications (morbidity and mortality)

Identifying Those at Risk for NASH and Advanced Fibrosis

AASLD Recommendation[1]

In type 2 diabetes, suspect NAFLD and

NASH and determine patient’s risk of

advanced fibrosis Increasing number of metabolic diseases =

increasing risk of progressive liver

disease

EASL-EASD-EASO Recommendation[2]

NAFLD screening recommended

in persons at high CVD risk, including type 2

diabetes or metabolic syndrome

Chalasani. Hepatology. 2018; EASL, EASD, EASO. J Hepatol. 2016

Thank You

END….QUESTIONS?