nonalcoholic fatty liver disease: epidemiology, natural ... · epidemiology, natural history, and...
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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
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