Hepatocellular Carcinoma: Epidemiology

and PreventionHashem B El-Serag, MD, MPH

Dan L Duncan Professor of MedicineChief, Gastroenterology and Hepatology

Baylor College of MedicineHouston, Texas

USA

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12.0%

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19731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004200520062007

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Year of HCC Diagnosis

AIR Survival

The Incidence and 5-Year Survival of HCC in United States

El-Serag HB. N Engl J Med 2011

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4.0

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8.0

10.0

12.0

White Black Asian Hispanic

Rat

e pe

r 100

,000

Temporal Trends in Age-Adjusted Incidence Rates of HCC by Race

1975-771993-952005-07

Ramirez AG, et al PLoS One. 2012

HCC Incidence Rates are Higher in Latinos > non LatinosAmong 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

Overall age adjusted incidence rate8.9 cases per 100,000 (95% 8.5-9.3)

Cirrhosis and HCCCirrhosis and HCC

Multiple smallfoci of HCCMultiple smallfoci of HCC

HCV Cirrhosis and 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 InfectionHCV Infection

Chronic Hepatitis Chronic Hepatitis

CirrhosisCirrhosis

HCCHCC1%1%

(1%-3%/year)(1%-3%/year)

100100

25years

25years

90%90%(60%- 95%)(60%- 95%)

15%15%(10%- 30%)(10%- 30%)

HCV to HCC PyramidHCV to HCC Pyramid

Goodgame B, et al., Am J Gastroenterol 2003Goodgame B, et al., Am J Gastroenterol 2003

HCV-related Cirrhosis by Cohort

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Cirrhosis Male >50Cirrhosis Male 31-50Cirrhosis Male <30Cirrhosis Female >50Cirrhosis Female 31-50Cirrhosis Female <30

Num

ber o

f Per

sons

Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings L (submitted for publication).

Risk Factors for HCC in Chronic HCV

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

Older age Duration of HCV infection Male sex Race Alcoholism Obesity Diabetes HBV co-infection HIV co-infection ABSENCE OF TREATMENT

100%

20%

10%

Diagnosisand treatment

Cure

All HCVpatients

PEG-IFN/RBV

100%

20%

95% SVR

19%

100%

90%

85%

95% SVR and higher rates of diagnosis/treatment

Highly Efficacious Treatments Are Not Enough

Veldt, Heathcote, Wedemeyer et al., Ann Inn Med 2007

Sustained Response to Interferon Therapy:HCCs still occur 

Non‐SVR

SVR

In Whom?• Age• Cirrhosis

? Role:• Etoh• MetSynd

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 withHCV 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):1-18Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.

Globesity

2006

Diet

Obesity

InsulinResistance

NAFLD

NASH

CirrhosisDiabetes

High BPHigh TGLow HDL

Relative Risk of Malignancies in individuals with BMI > 35 (compared to BMI < 25)

0 1 2 3 4 5

All Cancers

Kidney

MM

Colon

Esophagus

Stomach

Pancrease

Liver

RR = 4.52

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 modestincrease 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

• Proximal associations• Understand cancer pathogenesis in

general• May help in diagnosis, prevention

and treatment

ObesityDiabetes HCC

Abdominal FatHumoral MechanismsNAFLD?NASH

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

DiabetesN=173,643DiabetesN=173,643

No Diabetes N=650,620No Diabetes N=650,620

P<0.0001

Diabetes Is Associated with a Two-fold Increase in Risk of HCC: A Cohort Study in US Veterans

Diabetes Is Associated with a Two-fold Increase in Risk of HCC: A Cohort Study in US Veterans

El-Serag HB, et al, Gastroenterology 2004El-Serag HB, et al, Gastroenterology 2004

Years of Follow upYears of Follow up00 22 44 66 88 1010 1212 1414

HC

C R

ate

(%)

HC

C R

ate

(%)

0.250.25

0.200.20

0.150.15

0.100.10

0.050.05

0.000.00

Diabetes Is Associated with a Two-fold Increase in Risk of HCC

Diabetes Is Associated with a Two-fold Increase in Risk of HCC

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

Diet

Obesity

InsulinResistance

NAFLD

NASH

CirrhosisDiabetes

High BPHigh TGLow HDL

Steatosis

Fatty liver +

inflammation +

liver injury

Fibrosis and nodular

regeneration

NAFLD PrevalenceDallas Heart Study

NAFLD PrevalenceDallas Heart Study

Study cohort(~1100 African Americans, 700 Caucasians, 400

Hispanics)

Study cohort(~1100 African Americans, 700 Caucasians, 400

Hispanics)

H1-NMR spectroscopyH1-NMR spectroscopy

Assess risk factors for fatty liver

Assess risk factors for fatty liver

No risk factors(n = 375)

No risk factors(n = 375)

Define normalliver fat contentDefine normal

liver fat content

Assess prevalence of increased liver fat (steatosis)in entire population & ethnic subgroups

Assess prevalence of increased liver fat (steatosis)in entire population & ethnic subgroups

Browning, et al., Hepatology 2004; 40:1387Browning, et al., Hepatology 2004; 40:1387

HispanicsHispanics WhitesWhites BlacksBlacks

45%45%

33%33%24%24%

Fatty liverFatty liver

Prevalence of Hepatic SteatosisVaries with Ethnicity

Prevalence of Hepatic SteatosisVaries with Ethnicity

Prevalence of Hepatic Steatosis: Varies with EthnicityPrevalence of Hepatic Steatosis: Varies with Ethnicity

Browning, et al., Hepatology 2004; 40:1387Browning, et al., Hepatology 2004; 40:1387

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 inUnited 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 in general population

Risk estimate of HCC

Population attributable fraction

HBV 0.5-1% 20-25 5-10%HCV 1-2% 20-25 20-25%Alcoholic liver disease

10-15% 2-3 20-30%

Metabolic syndrome

30-40% 1.5-2.5 30-40%

Prevalence, Relative Risk Estimates, and Population Attributable Fraction

Obesity/DiabetesPopulation 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

Zhang H et al. Scand J Gastroenetrol 2013

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

Statins and Risk of HCC

Adjusted OR for Any Statin Use was 0.63 (95% CI: 0.54,0.73)

Singh S, et al Gastroenterology 2009

Statins and HCCSystematic 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

• 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)

Coffee and Hepatocellular Carcinoma

Metabolic Syndrome and HCCWhich Came First? the Chicken or the Egg

Cross Sectional Studies XCase-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 2012Singal et al, Cancer Prevent Research 2012

Surv

ey R

epon

ses

Refused treatmentDid not f/u with clinician

Received treatmentClinician did not recommend

treatmentUnaware of diagnosis

Reasons for Lack of Treatment Among Respondents to the NHANES Hepatitis C

Follow-Up QuestionnaireN = 133

Abbreviation: NHANES, National Health and Nutrition Evaluation Survey.Volk ML, et al. Hepatology. 2009;50:1750-1755.

REACH‐B Model• 60 year‐old HBeAg+ male ALT 

47, HBV DNA 50,000• REACH‐B score=13

Variable Data ScoreSex M/F 0‐2

Age Q 5 yearsover 30 0‐6

ALT<1515‐44>45

0‐2

HBeAg +/‐ 0‐2

HBV DNA

Und.~104~105~106>106

0‐4

yearsYang HI. Lancet Oncol 2011; 12: 568–74

%

Source: Gastroenterology 2012; 142:1264-1273.e1

Alcohol and Viral Hepatitis

Obesity and HCC EpidemiologySummary

• 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 Adjusted Odds Ratio

Viral etiology 3.60 (1.31 – 9.94)NAFLD etiology 0.12 (0.02 – 0.74)Hepatic decompensation 2.23 (0.88 – 5.61)Bilirubin level 1.05 (0.91 – 1.21)Platelet count 1.00 (0.99 – 1.00)

Singal et al, Cancer Prevent Research 2012Singal et al, Cancer Prevent Research 2012

18% of patients with NASH had recognized liver disease87% of patients with viral liver disease had recognized liver disease65% of remaining patients had recognized liver disease

Principal InvestigatorsThe Texas Hepatocellular Carcinoma Consortium (THCCC)

ADMINISTRATIVE CORE

Hashem B. El‐Serag, MD, MPHBaylor College of Medicine 

COHORTS & SAMPLES CORE (CSC)

Jorge Marrero, M.D.UT Southwestern

STATISTICAL COORDINATING CORE (SCC)

Ziding Feng, PhDMD Anderson Cancer Center

PROJECT 1

Fasiha Kanwal, MD, MSHSBaylor College of Medicine 

PROJECT 2

Hashem B. El‐Serag, MD, MPHBaylor College of Medicine 

PROJECT 3

David Moore, PhDBaylor College of Medicine 

PROJECT 4

Laura Beretta, PhDMD Anderson Cancer Center

PROJECT 5

Amit Singal, MDUT Southerwestern

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

Overview of THCCC

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 1: Risk Factors of Hepatocellular Carcinoma in Non‐Alcoholic Fatty Liver Disease

(PI: Fasiha Kanwal)

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 2: Metabolic Syndrome and HCC Risk Stratification in Patients with Cirrhosis

(PI: Hashem El‐Serag)

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 3: Circadian Disruption and Bile Acids as HCC Risk Factors 

(PI: David Moore)

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 4: Novel Biomarkers For Hepatocellular Carcinoma (PI: Laura Beretta)

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

Project 5: A Comparative Effectiveness Randomized Controlled Trial of Strategies to Increase 

HCC Surveillance Timeline (PI: Amit Singal)

• 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)

Risk Assessment

PrimaryPrevention

Detection Diagnosis CancerTreatment

Identify at‐risk patients

Primary prevention

HCC surveillance

HCC detection

Follow‐up abnormal result

• Lou Ann Fang (Baylor)• D Bessig (Baylor)• Fred Porddad (UTSA)

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