Hepatocellular
Carcinoma: Epidemiology
and Prevention
Hashem B El-Serag, MD, MPH
Dan L Duncan Professor of Medicine
Chief, Gastroenterology and Hepatology
Baylor College of Medicine
Houston, Texas
USA
The Incidence and 5-Year Survival of
HCC in United States
16.0%
14.0%
5
AIR
Survival
4
12.0%
10.0%
3
8.0%
6.0%
2
4.0%
1
2.0%
0
0.0%
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
Year of HCC Diagnosis
El-Serag HB. N Engl J Med 2011
5 -y e a r S u r v iv a l
In c id e n c e r a te p e r 1 0 0 ,0 0 0
6
Temporal Trends in Age-Adjusted
Incidence Rates of HCC by Race
12.0
1975-77
1993-95
2005-07
Rate per 100,000
10.0
8.0
6.0
4.0
2.0
0.0
White
Black
Asian
Hispanic
HCC Incidence Rates are Higher in Latinos > non Latinos
Among Latinos, HCC is highest in Texas esp southern counties
Ramirez AG, et al PLoS One. 2012
Age Distribution of HCC in Latinos: A Shift to the Left
Ramirez AG, et al PLoS One. 2012
Overall age adjusted incidence rate
8.9 cases per 100,000 (95% 8.5-9.3)
HCV Cirrhosis and HCC
Cirrhosis and HCC
Multiple small
foci of HCC
HCV is the Dominant Risk Factors for
HCC in the United States
• HBV most frequent
in Asians
• HCV most frequent
in whites and blacks
(N=691)
HCV to HCC Pyramid
HCC
1%
(1%-3%/year)
Cirrhosis
15%
(10%- 30%)
Chronic Hepatitis
HCV Infection
Goodgame B, et al., Am J Gastroenterol 2003
25
years
90%
(60%- 95%)
100
HCV-related Cirrhosis by Cohort
Number of Persons
1,200,000
Cirrhosis
Cirrhosis
Cirrhosis
Cirrhosis
Cirrhosis
Cirrhosis
1,000,000
800,000
600,000
400,000
200,000
0
1950 1960 1970 1980 1990 2000 2010 2020 2030
Year
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings L (submitted for publication).
Male >50
Male 31-50
Male <30
Female >50
Female 31-50
Female <30
Risk Factors for HCC in
Chronic HCV










Older age
Duration of HCV infection
Male sex
Race
Alcoholism
Obesity
Diabetes
HBV co-infection
HIV co-infection
ABSENCE OF TREATMENT
Highly Efficacious Treatments
Are Not Enough
All HCV
patients
Diagnosis
and treatment
Cure
PEG-IFN/RBV
95% SVR
95% SVR and higher rates
of diagnosis/treatment
100%
100%
100%
20%
20%
90%
10%
19%
85%
Sustained Response to Interferon Therapy:
HCCs still occur In Whom?
• Age
• Cirrhosis
Non‐SVR
SVR
? Role:
• Etoh
• MetSynd
Veldt, Heathcote, Wedemeyer et al., Ann Inn Med 2007
CDC and USPSTF Recommendations
for HCV Screening
• Regardless of risk factors, one-time testing for HCV of
adults born between 1945–19651,2
– Testing of persons of all ages at risk for HCV infection
• CDC also recommends for those identified with
HCV infection1
– Brief alcohol screening and intervention as clinically indicated
– Referral to appropriate care and treatment services for HCV
infection and related conditions
Centers for Disease Control and Prevention (CDC). MMWR. 2012;61(4):1-18
Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.
Globesity
2006
High BP
High TG
Low HDL
Diet
Insulin
Resistance
NAFLD
Obesity
NASH
Diabetes
Cirrhosis
Relative Risk of Malignancies in individuals
with BMI > 35 (compared to BMI < 25)
RR = 4.52
Liver
Pancrease
Stomach
Esophagus
Colon
MM
Kidney
All Cancers
0
1
2
3
4
5
Calle EE, et al. NEJM 2003 (data basd on 900,000+ Men and Women)
Obesity and Risk of HCC: A Critical Look
• Most—but not all—studies suggest a modest
increase in the relative risk of HCC in obese persons
• Systematic review of 10 cohort studies
– positive association between BMI and risk of HCC in 7
studies (relative risks ranging from 1.4 to 4.1)
– no association in 2 studies
– inverse association in 1 study
• Limitations: small number of HCC cases,
misclassification, inconsistent adjustment for
confounders
Saunders D, et al. APT 2010
Distal vs. Proximal Associations
Obesity
Diabetes
HCC
Abdominal Fat
Humoral Mechanisms
NAFLD?NASH
• Proximal associations
• Understand cancer pathogenesis in
general
• May help in diagnosis, prevention
and treatment
A high waist-to-hip ratio (WHR) conferred a 3-fold higher
HCC risk to subjects in the upper tertile of WHR > those in
the lowest tertile. (Aleksandrova K et al Hepatology 2014)
Does it make “epidemiological” sense?
• Abdominal obesity more
likely
–Caucasians more than
African Americans
–Men more than
women
Inflammatory and Metabolic Biomarkers
and Risk of Liver and Biliary Tract Cancer
Aleksandrova et al. Hepatology 2014
Diabetes Is Associated with a
Two-fold Increase in Risk of HCC
Diabetes Is Associated with a
Two-fold Increase in Risk of HCC:
A Cohort Study in US Veterans
HCC Rate (%)
0.25
Diabetes
N=173,643
0.20
P<0.0001
0.15
No Diabetes
N=650,620
0.10
0.05
0.00
0
2
4
6
8
Years of Follow up
El-Serag HB, et al, Gastroenterology 2004
10
12
14
Risk of HCC in Patients with Diabetes
Mellitus: a Meta-analysis of Cohort Studies
• A total of 25 cohort studies
– 18 studies showed that DM was associated
with an increased incidence of HCC
• SRRs = 2.01, 95% CI: 1.61-2.51
– Independent of geographic location, alcohol
consumption, history of cirrhosis, HBV or HCV
– Risk factors of HCC among diabetics are
unclear
Wang C et al., Int J Cancer 2012
High BP
High TG
Low HDL
Diet
Insulin
Resistance
NAFLD
Obesity
NASH
Diabetes
Cirrhosis
Steatosis
Fatty liver
+
inflammation
+
liver injury
Fibrosis and
nodular
regeneration
NAFLD Prevalence
Dallas Heart Study
Study cohort
(~1100 African Americans, 700 Caucasians, 400
Hispanics)
Assess risk factors
for fatty liver
No risk factors
(n = 375)
H1-NMR spectroscopy
Define normal
liver fat content
Assess prevalence of increased liver fat (steatosis)
in entire population & ethnic subgroups
Browning, et al., Hepatology 2004; 40:1387
Prevalence of Hepatic Steatosis: Varies with Ethnicity
Prevalence of Hepatic Steatosis
Varies with Ethnicity
45%
Fatty liver
33%
Hispanics Whites
Browning, et al., Hepatology 2004; 40:1387
24%
Blacks
NAFLD and Risk of HCC
• No evidence from population based data
• Possible increase in HCC risk in clinic based cohorts of
NASH
– ? Magnitude
– ? Risk factors
• Consistent evidence from clinic based cohorts with
NAFLD/NASH cirrhosis
– Magnitude < HCV cirrhosis
White D, Kanwal F, El-Serag. Clin Gastro Hep 2012
HCC in the Absence of Cirrhosis in
United States Veterans
• ~13% of 1500 HCC cases developed in absence of cirrhosis
• These cases were more likely than HCC in cirrhosis to have
– NAFLD or idiopathic compared to HCV or alcohol
– Co-morbidities associated with metabolic syndrome
• While a small proportion, this poses logistical problems for
HCC surveillance
El-Serag HB et al. DDW 2014
Mittal S et al DDW 2014
Prevalence, Relative Risk Estimates, and
Population Attributable Fraction
Prevalence Risk
Population
in general estimate attributable
population of HCC fraction
HBV
HCV
Alcoholic
liver
disease
Metabolic
syndrome
0.5-1%
1-2%
10-15%
20-25
20-25
2-3
5-10%
20-25%
20-30%
30-40%
1.5-2.5
30-40%
Obesity/Diabetes
Population Attributable Fraction (PAF)
PAF calculation includes excess fraction
• differences between cancer risk in obese and
non-obese irrespective of the presence of other
cofactors
PAF does not consider etiological fraction
• differences between the groups limited to cases
caused solely by obesity (which may be much
smaller)
PAF calculations do not account for time lag
between acquiring obesity/diabetes and
developing HCC
Temporal Trends of HCC by Major Risk Factors in
National VA System in the US
Mittal S et al., Clin Gastroenterol Hepatol 2015
Prevention of HCC
• HBV vaccination
• Treatment of viral hepatitis
• Screening and surveillance for
HCC
• ?? Statins, metformin, coffee,
weight loss
Metformin and Reduced Risk of HCC in
Diabetic Patients: a Meta-analysis
• Seven studies:
– Three cohort studies
– Four case-control studies
• Significantly reduced risk of HCC in metformin
users versus nonusers in diabetic patients
– RR: 0.24, 95% CI 0.13–0.46, p < 0.001
Zhang H et al. Scand J Gastroenetrol 2013
Statins and Risk of HCC
Adjusted OR for Any Statin Use was 0.63 (95% CI: 0.54,0.73)
Statins and HCC
Systematic Review
• Ten studies
– 7 observational, 3 clinical trials
• Pooled OR: 0.63 (0.52-0.76)
– Not in the 3 clinical trials
• Not other lipid lowering medications
• Unclear
– Dose, duration, type
Singh S, et al Gastroenterology 2009
Coffee and Hepatocellular Carcinoma
• Epidemiologic studies: coffee consumption
is inversely related to
– Serum liver enzyme activity
– Liver cirrhosis
– HCC
• For each additional 1 cup of coffee:
– Case-control studies
• (0.77, 0.72-0.83)
– Cohort studies
• (0.75, 0.65-0.85)
Metabolic Syndrome and HCC
Which Came First? the Chicken or the Egg
Cross Sectional Studies X
Case-Control Studies X
HCC Screening Level II- Evidence
• Several non-randomized trials and observational
cohort and case–control studies reported
• Patients who undergo HCC surveillance via US and
serum AFP tests are significantly more likely than
patients found to have symptomatic HCC
– diagnosed with early-stage HCC
– receive curative therapy
– lower cancer-specific mortality
Surveillance for HCC
• Recommendations
– Ultrasound and serum biomarker (AFP) in patients
with cirrhosis every 6 months
• Limitations
– Effectiveness not examined in US
– Poor performance of AFP esp if used alone
– Limited implementation in practice
Many at-risk patients are not identified
prior to HCC presentation
Singal et al, Cancer Prevent Research 2012
Reasons for Lack of Treatment Among
Respondents to the NHANES Hepatitis C
Follow-Up Questionnaire
Survey Reponses
N = 133
Refused treatment
Did not f/u with clinician
Received treatment
Clinician did not recommend
treatment
Unaware of
diagnosis
Abbreviation: NHANES, National Health and Nutrition Evaluation Survey.
Volk ML, et al. Hepatology. 2009;50:1750-1755.
REACH‐B Model
Variable
Data
Score
Sex
M/F
0‐2
Age
Q 5 years
over 30
0‐6
ALT
<15
15‐44
>45
0‐2
+/‐
0‐2
Und.
~104
~105
~106
>106
0‐4
HBeAg
HBV DNA
Yang HI. Lancet Oncol 2011; 12: 568–74
• 60 year‐old HBeAg+ male ALT 47, HBV DNA 50,000
• REACH‐B score=13
%
years
Alcohol and Viral Hepatitis
Source: Gastroenterology 2012; 142:1264-1273.e1
Obesity and HCC Epidemiology
Summary
• Relative risk of HCC is modestly elevated in obese and diabetic persons but the absolute risk is low.
– Weak/modest causal association • Factors influencing HCC risk among obese person are unclear.
– Abdominal obesity
– Early onset/ long duration
• Factors that influence HCC risk among diabetics are unclear
–
–
–
–
Type 2 diabetes
Long duration
Not treated with metformin
???? Alcohol
• Proximal associations include inflammatory mechanisms, NAFLD/NASH, others
– The possibility of obesity related HCC developing in non‐cirrhotic liver
• Obesity/diabetes related HCC has not translated (yet) into a large burden
Patients with NASH are Significantly Less Likely to Have Recognized Liver Disease
Variable
Viral etiology
NAFLD etiology
Hepatic decompensation
Bilirubin level
Platelet count
Adjusted Odds Ratio
3.60 (1.31 – 9.94)
0.12 (0.02 – 0.74)
2.23 (0.88 – 5.61)
1.05 (0.91 – 1.21)
1.00 (0.99 – 1.00)
18% of patients with NASH had recognized liver disease
87% of patients with viral liver disease had recognized liver disease
65% of remaining patients had recognized liver disease
Singal et al, Cancer Prevent Research 2012
The Texas Hepatocellular Carcinoma Consortium (THCCC)
Principal Investigators
ADMINISTRATIVE CORE
COHORTS & SAMPLES CORE (CSC)
STATISTICAL COORDINATING CORE (SCC)
Hashem B. El‐Serag, MD, MPH
Jorge Marrero, M.D.
Ziding Feng, PhD
Baylor College of Medicine UT Southwestern
MD Anderson Cancer Center
PROJECT 1
PROJECT 2
PROJECT 3
PROJECT 4
PROJECT 5
Fasiha Kanwal, MD, MSHS
Hashem B. El‐Serag, MD, MPH
David Moore, PhD
Laura Beretta, PhD
Amit Singal, MD
Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine MD Anderson Cancer Center
UT Southerwestern
Overview of THCCC
Our overarching goal is to reduce the burden and mortality of HCC in Texas. • multidisciplinary group of investigators with vast experience and expertise in HCC research. • researchers from UT Southwestern Medical Center and Parkland Health and Hospital System in Dallas, Baylor College of Medicine and MD Anderson in Houston, and UT San Antonio • inclusion of sites all across Texas will enrich the diversity and representativeness of our patients, ensuring a racially and ethnically diverse cohort with a wide range of socioeconomic status. • critical gaps and needs in the HCC prevention process and appropriate ways to address them
Project 1: Risk Factors of Hepatocellular Carcinoma in Non‐Alcoholic Fatty Liver Disease
(PI: Fasiha Kanwal)
Aim 1: To examine the risk of HCC in NAFLD patients in all Texas VA centers
Aim 2: To identify predictors of HCC in NAFLD. We will assess the role of demographic (e.g., age, race) and metabolic traits (e.g., diabetes, obesity, dyslipidemia, hypertension diagnoses and biomarkers like hemoglobin A1c) in the development of HCC in NAFLD patients.
Aim 3: To determine the chemopreventive effect of common treatments in NAFLD including metformin and statins and the risk of HCC among patients with NAFLD.
Project 2: Metabolic Syndrome and HCC Risk Stratification in Patients with Cirrhosis
(PI: Hashem El‐Serag)
Aim 1: Examine the Association between Metabolic Syndrome and HCC Risk in Cirrhosis.
Gross and molecular phenotype, genotype
Aim 2: Develop and optimize an index for predicting the risk of progression from cirrhosis to HCC using a set of candidate factors derived from the literature, Aim 1 or uncovered by other THCCC projects.
Project 3: Circadian Disruption and Bile Acids as HCC Risk Factors (PI: David Moore)
Aim 1: Test the ability of the CAR inverse agonist androstanol to prevent tumorigenesis in wild type mice in response to chronically elevated bile acids and jet lag.
Aim 2: Test the ability of human specific CAR activators to promote hepatocarcinogenesis in humanized mice.
Aim 3: Determine whether elevated serum bile acids or circadian disruption increase risk of human HCC.
Project 4: Novel Biomarkers For Hepatocellular Carcinoma (PI: Laura Beretta)
Aim 1: To evaluate the ability of novel HCC biomarkers to distinguish between patients with cirrhosis but no HCC and patients with cirrhosis and HCC in a surveillance setting
Aim 2: To evaluate the performance of AFP, AFP‐L3, DCP, OPN and selected panel from Aim 1 in detecting HCC during surveillance: A Phase‐3 Validation Study
Aim 3: Genomic classification of the incident HCC tumors and association between novel biomarkers, somatic mutations and HCC subtypes
Project 5: A Comparative Effectiveness Randomized Controlled Trial of Strategies to Increase HCC Surveillance Timeline (PI: Amit Singal)
Aim 1: Compare the clinical effectiveness of the intervention strategies to increase completion of the HCC surveillance process
Aim 2: Compare patient‐reported satisfaction and acceptability of the HCC surveillance strategies
Aim 3: Evaluate whether intervention effects are moderated by patient sex, race/ethnicity, socioeconomic status, health care utilization, and documented vs. unrecognized cirrhosis
Risk Assessment
Identify at‐risk patients
•
•
•
•
•
•
•
Primary
Prevention
Diagnosis
Detection
Primary HCC HCC prevention surveillance detection
Hashem El‐Serag, MD, MPH (Baylor)
Laura Beretta, PhD (MDACC)
Ziding Feng, PhD (MDACC)
David Moore, MD (Baylor)
Jorge Marrero, MD (UTSW)
Amit Singal, MD (UTSW)
Fasiha Kanwal, MD (Baylor)
•
•
•
Follow‐up abnormal result
Lou Ann Fang (Baylor)
D Bessig (Baylor)
Fred Porddad (UTSA)
Cancer
Treatment
Summary
• HCC is the fastest rising cause of cancer related deaths in the US
• Hispanics are the group most affected with the increase in HCC
• Hepatitis C (and possibly NAFLD) are the main reasons for HCC in Hispanics
• Texas has one of the highest HCC incidence rates in US, and high prevalence of people with HCC risk factors