1. Hepatocellular Carcinoma
Thomas Hargrave M.D.
January 16, 2009
Slide 4
Epidemiology of Hepatocellular Carcinoma 1

2. HCC Is Common and Increasing
662,000 deaths from liver cancer yearly worldwide
Age-adjusted US incidence has increased 2-fold:
American Cancer Society statistics for liver cancer in 2008
Estimation of new cases: 21,370
Estimation of deaths: 18,410
5th leading cause of cancer deaths in males
HCC, hepatocellular carcinoma; US, ultrasound.
World Health Organization. Available at: Accessed October 6, American Cancer Society. Cancer facts & figures Atlanta: American Cancer Society; 2008.

3. Worldwide Incidence of Hepatocellular Carcinoma
HCC Epidemiology
Worldwide Incidence of Hepatocellular Carcinoma
Slide 5
Worldwide Incidence of Hepatocellular Carcinoma
The incidence of HCC varies considerably around the world with the highest rates in Southeast Asia and sub-Saharan Africa (areas where HBV infection is endemic and high). The United States have recently moved into the intermediate incidence areas (age-adjusted incidence rates close to 4 per 100,000 person-years).
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology Nov;127(5 Suppl 1):S27-34.
High (> 30:100,000)
El-Serag HB,
Gastroenterology
2004
Intermediate (3-30:100,000)
Low or data unavailable (< 3:100,000)

4. Recent Changes in the Incidence of HCC
HCC Epidemiology
Changes in the Incidence of HCC
Singapore, Chinese
-30
Spain, Zaragoza
-24
India, Bombay
-20
China, Shanghai
-18
Switzerland, Geneva 10
Hong Kong 12
NewZealand, Maori 14
NewZealand, Non-Maori 21
Japan, Osaka 46
UK, So. Thames
Slide 6
Recent Changes in the Incidence of HCC
The incidence of HCC has been declining in some “high-incidence” areas, such as China and Hong Kong. This is partly related to HBV vaccination of children, and to reduction of aflatoxin exposure in grains.
On the other, HCC incidence in several “low and intermediate incidence” areas, have been increasing. For example, hepatitis C related HCC has been responsible for most the observed recent rise in the United States.
McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF Jr. International trends and patterns of primary liver cancer. Int J Cancer Oct 15;94(2):290-6.
Lok AS. Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology Nov;127(5 Suppl 1):S Review. PMID:
Chang MH, Shau WY, Chen CJ, Wu TC, Kong MS, Liang DC, Hsu HM, Chen HL, Hsu HY, Chen DS; Taiwan Childhood Hepatoma Study Group. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA Dec 20;284(23): 50
Canada, Alberta 71
Italy, Varese 83
France, Bas-Rhin 90
Australia, NSW
108
-40
-20 20 40 60 80
100
120
McGlynn K, et al, Int J Cancer 2001

5. Age-Adjusted Incidence Rates For HCC (1976-2002)
HCC Epidemiology
Age-Adjusted Incidence Rates For HCC ( )
3.5
3.3
3.1 3
2.7
2.5
2.3
per 100,000
Rate
2.0 2
1.8
1.6
1.4
1.4
1.5
Slide 8
Age-Adjusted Incidence Rates For HCC ( )
The age-adjusted incidence rates (per 100,000 person years in the underlying general population) of HCC diagnosed between 1975 and The rates shown above the bars represent the average annual rates (not the sum) during each three-year period. Cases were confirmed with histology or cytology, which is likely to underestimate the true count of HCC cases. The data source is Surveillance, Epidemiology, and End Results (SEER) Population-based registries, which included information from 12 registries (14% of the US population).
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med Nov 18;139(10): Erratum in: Ann Intern Med Jan 20;140(2):151.
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med Mar 11;340(10): 1
0.5
76-78
79-81
82-84
85-87
88-90
91-93
94-96
97-99
Year
El-Serag HB, Mason A, N Engl J Med 1999
El-Serag HB et al, Ann Intern Med 2003

6. Racial Distribution of HCC in the United States
HCC Epidemiology
Racial Distribution of HCC in the United States
3000
Asian
2500
Black
2000
White
Number of Cases
1500
1000
Slide 11
Racial Distribution of HCC in the United States
The case counts (instead of age adjusted incidence rates) highlights the point that most cases of HCC are detected in Whites (non Hispanic as well as Hispanic). Asians constituted 23% of cases, Blacks 12%, and 65% White both Hispanic and non Hispanic.
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med Mar 11;340(10):
500
75-77
78-80
81-83
84-86
87-89
90-92
93-95
96-98
Year
El-Serag HB, Mason A, N Engl J Med 1999

7. Racial Incidence Rates For HCC In The United States
HCC Epidemiology
Racial Incidence Rates For HCC In The United States 9 8 7 6 5 4 3 2 1
White
Black
Other (Asian)
8.4
7.9 8
7.2
7.2
6.6
6.3 6
5.2 5
Age-Adjusted Incidence Rate
per 100,000
4.6
3.7
3.9
3.4
2.9
Slide 9
Racial Incidence Rates For HCC In The United States
The average annual age-adjusted incidence rates for HCC shown for three-periods between 1976 and 2002 and broken down by racial groups (source: SEER: Surveillance Epidemiology and End Results). Although the highest incidence rates are observed in Asians, the highest proportional increase was observed among Whites (non Hispanic as well Hispanic). Black African Americans have intermediate rates.
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med Nov 18;139(10):
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med Mar 11;340(10):
2.5
2.5
2.6
2.5
2.3
1.9
1.7
1.3
1.4 1
1.1
1.1
76-78
79-81
82-84
85-87
88-90
91-93
94-96
97-99
Year
El-Serag HB et al, Ann Intern Med 2003

8. Temporal Trends in The Age Distribution of Hepatocellular Carcinoma
HCC Epidemiology
Temporal Trends in The Age Distribution of Hepatocellular Carcinoma 2 4 6 8 10 12 14 16 18 20
1982 – 84
1991 – 93
2000 – 02
Incidence Rate
per 100,000 PY
Slide 12
Temporal Trends in The Age Distribution of Hepatocellular Carcinoma
The age specific rates are shown per 5 year age groups. HCC is rare below age 40, increases progressively thereafter. As the incidence of HCC has increased in the United States (during ), the age distribution curve has shifted to the left indicting that younger persons are becoming progressively more affected. Persons between 45 and 65 have been disproportionately affected with HCC.
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med Mar 11;340(10):
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med Nov 18;139(10):
20-24
30-34
40-44
50-54
60-64
70-74
80-84
25-29
35-39
45-49
55-59
65-69
75-79
85+
Age (years)
El-Serag HB, Mason A, N Engl J Med 1999

9. Risk Factors for HCC in US Patients
Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%)
Known Risk Factor in the US: Viral Hepatitis (N = 691)
100 80 60
Presence of Risk Factor Among HCC Patients (%)
HCC, hepatocellular carcinoma; US, United States. 47 40 33 15 20 5
HBV + HCV
HBV
HCV
Neither
Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98: El-Serag HB. Gastroenterology ;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

10. Risk Factors for HCC Cirrhosis from any cause (3-8%/yr) HCV HBV
HCC Epidemiology
Risk Factors for HCC
Cirrhosis from any cause (3-8%/yr)
HCV
HBV
Heavy alcohol consumption
Non-alcoholic fatty liver disease
HBV without cirrhosis ( %/yr)
Inherited metabolic diseases
Hemochromatosis
Alpha-1 antitrypsin deficiency
Glycogen storage disease
Porphyria cutanea tarda
Tyrosinemia
Autoimmune hepatitis
Slide 25
Risk Factors for HCC

11. HCV Cirrhosis and HCC Multiple small foci of HCC HCC Epidemiology
Slide 33
HCV Cirrhosis and HCC
Explanted liver showing features of cirrhosis and multiple small foci of HCC throughout the liver in a miliary pattern (arrows).

12. Why is HCC Incidence Rising?
Why HCC is Rising?
HCC Epidemiology
Why is HCC Incidence Rising?
Increasing prevalence of patients with cirrhosis
Rising incidence of cirrhosis
HCV (main reason)
HBV
Other (?NAFLD/insulin resistance)
Improved survival of patients with cirrhosis
Slide 21
Why is HCC Incidence Rising?
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology Nov;127(5 Suppl 1):S27-34.
El-Serag HB, Gastroenterology 2004

13. Prevalence of HCV in United States Males:1999-2002
Annals Internal Medicine 2006; 144:705

14. Projected Rates of HCV-Related Cirrhosis and HCC
Davis et al used a natural history model to project the prevalence of HCV infection and HCV-related cirrhosis, liver failure, and mortality over the next 40 years. Thes results are shown here and on the next slide.
According to this model, the prevalence of infection should gradually decline, due to aging and natural deaths among those currently infected. However, the rate of complications in the surviving pool of infected individuals is expected to increase dramatically over the next few decades.
Without identification and treatment of infected individuals, the peak of HCV morbidity and mortality will be reached in the year 2030, when there will be an estimated 880,000 individuals with cirrhosis and 146,000 with decompensated cirrhosis requiring transplantation.
Davis GL, et al. Liver Transpl. 2003;9:331. 14

15. Alcohol Intake and the Risk of HCC
HCC Epidemiology
Alcohol Intake and the Risk of HCC 20
No HCV
with HCV 15
Odds Ratios 10 5
Slide 38
Alcohol Intake and the Risk of HCC
The investigators enrolled 464 subjects (380 men) with a first diagnosis of HCC as cases and 824 subjects (686 men) unaffected by hepatic diseases as controls; all were hospitalized in Brescia, northern Italy, in Spline regression models showed a steady linear increase in the odds ratio of HCC for increasing alcohol intake, for values of >60 g of ethanol per day. The effect of alcohol drinking was evident even in the absence of hepatitis B or hepatitis C virus infection. In addition, a synergism between alcohol drinking and either infection was found, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers of >60 g per day.
Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A,Decarli A, Trevisi P, Ribero ML, Martelli C, Porru S, Nardi G. Alcohol and hepatocellular carcinoma: the effect of lifetime intake andhepatitis virus infections in men and women.Am J Epidemiol Feb 15;155(4): 20 40 60 80
100
120
140
Grams of Alcohol / Day
Donato F, et al, Am J Epidemiol 2002

16. HBV DNA Associated with Increased Risk of HCC
HBV DNA Associated with Increased Risk of HCC in Non-Cirrhotics
Likelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNA
Risk associated with increasing HBV DNA levels
These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication
Slide 53
HBV DNA Associated with Increased Risk of HCC
Similarly, infected individuals with detectable HBV DNA are more likely to develop HCC than those without, with the risk increasing with increasing HBV DNA.
Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, ChenDS, Chen CJ; Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med Jul 18;347(3):
Yang HI, et al, N Engl J Med 2002

17. HBe Antigen and Risk of HCC
11,893 Noncirrhotic Taiwanese Males Followed 8 Yrs 12
HBsAg+, HBeAg+
(RR = 60.2) 10 8
Percent cumulative incidence 6 4
HBsAg+, HBeAg-
(RR = 9.6)
Slide 52
HBe Antigen and Risk of HCC
In 1991 and 1992, the investigators enrolled 11,893 men without evidence of hepatocellular carcinoma from seven townships in Taiwan. Serum samples obtained at the time of enrollment were tested for HBsAg and HBeAg by radioimmunoassay. The diagnosis of hepatocellular carcinoma was ascertained through data linkage with the computerized National Cancer Registry in Taiwan and with death certificates. There were 111 cases of newly diagnosed hepatocellular carcinoma during 92,359 person-years of follow-up. The incidence rate of hepatocellular carcinoma was 1169 cases per 100,000 person-years among men who were positive for both HBsAg and HBeAg, 324 per 100,000 person-years for those who were positive for HBsAg only, and 39 per 100,000 person-years for those who were negative for both. After adjustment for age, sex, the presence or absence of antibodies against hepatitis C virus, cigarette-smoking status, and use or nonuse of alcohol, the relative risk of hepatocellular carcinoma was 9.6 (95 percent confidence interval, 6.0 to 15.2) among men who were positive for HBsAg alone and 60.2 (95 percent confidence interval, 35.5 to 102.1) among those who were positive for both HBsAg and HBeAg, as compared with men who were negative for both.
Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, ChenDS, Chen CJ; Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med Jul 18;347(3): 2
HBsAg-, HBeAg- 1 2 3 4 5 6 7 8 9 10
Year
Yang HI, et al, N Engl J Med 2002

18. HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+
Template _1
4/22/2017 6:32 AM
HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+
HBV DNA (copies/mL)
3465 HBeAg (+) Non-cirrhotic Taiwanese Patients followed for a mean of 11.5years
65% had HBV DNA > 100,000,000
Incidence of HCC
Per Year (%)
This slide summarizes PAUSE…lost the line
Chen et al. JAMA. 2006;295:65-73 (B). 18

19. Risk Factors for HCC in US Patients
Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%)
Known Risk Factor in the US: Viral Hepatitis (N = 691)
100 80
(?NAFLD/insulin resistance?) 60
Presence of Risk Factor Among HCC Patients (%)
HCC, hepatocellular carcinoma; US, United States. 47 40 33 15 20 5
HBV + HCV
HBV
HCV
Neither
Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98: El-Serag HB. Gastroenterology ;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

20. Non-alcoholic Fatty Liver Disease (NAFLD) and HCC
HCC Epidemiology
Non-alcoholic Fatty Liver Disease (NAFLD) and HCC
Single center study, Univ. Michigan
105 consecutive patients with HCC
51% due to HCV-associated cirrhosis
Cryptogenic cirrhosis in 29%
Half had histologic features consistent with NASH
Estimated that 13% of HCC and cryptogenic cirrhosis may have NAFLD/NASH
Slide 63
Non-alcoholic Fatty Liver Disease (NAFLD) and HCC
In this study from the University of Michigan, 105 consecutive patients with HCC were studied. The most common etiology of liver disease was hepatitis C (51%) and cryptogenic cirrhosis (29%). Half of the patients with cryptogenic cirrhosis had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD). NAFLD accounted for at least 13% of the cases.
Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology Dec;36(6):
Marrero J, et al, Hepatology 2002

21. (Highest BMI Category)
Prospective Study Cancer Mortality in Obese US Adults (n=900,053):
Men
Prostate (>35)
1.34
Non-Hodgkin’s Lymphoma(>35)
1.49
All Cancers (>40)
1.52
All Other Cancers (>30)
1.68*
Kidney (>35)
1.70
(Highest BMI Category)
Type of Cancer
Multiple Myeloma (>35)
1.71
Gall Bladder (>30)
1.76
Colon and Rectum (>35)
1.84
Slide 65
Mortality from Cancer in Obese US Men (n=900,053)
In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the liver (in addition to the esophagus, colon and rectum, gallbladder, pancreas, and kidney).
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studiedcohort of U.S. adults.N Engl J Med Apr 24;348(17):
Esophagus (>30)
1.91*
Stomach (>35)
1.94
Pancreas (>35)
2.61*
4.52
Liver (>35) 1 2 3 4 5 6 7
Relative Risk of Death (95% Confidence Interval)
Calle EE, & et al, N Engl J Med 2003

22. Obesity and Liver Cancer
HCC Epidemiology
Obesity and Liver Cancer 8
35 to 39.9 48 6
30 to 34.5 19
BMI
Women
Men 5
20 to 29.9 10
Slide 64
Obesity and Liver Cancer
In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the liver (in addition to the esophagus, colon and rectum, gallbladder, pancreas, and kidney).
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studiedcohort of U.S. adults.N Engl J Med Apr 24;348(17): 5
18.5 to 25 9 50 40 30 20 10 60
Death Rate per 100,000
Calle, et al, NEJM 2003

23. Impact of Diabetes and Overweight on Liver Cancer Occurrence in Cirrhosis
771 Compensated ETOH or HCV Cirrhotics Prospectively Screened for HCC
1.0 .8
BMI <23.9, diabetes -
BMI <23.9, diabetes +
BMI diabetes -
BMI diabetes +
BMI >27.3, diabetes -
BMI >27.3, diabetes + .6
Probability of HCC Free Survival
P<0.0001 .4
Slide 68
Impact of Diabetes and Overweight on Liver Cancer Occurrence in Cirrhosis
In this French study, a cohort of 771 patients with well-compensated alcohol- or HCV-related cirrhosis who were screened prospectively for HCC. At enrollment, the mean age was /- 10 years and 431 patients were men. Cirrhosis was caused by alcohol (n = 478), HCV (n = 220), or both factors (n = 73). The mean body mass index (BMI) was 25.4 kg/m(2) and 231 patients were diabetic. During a mean follow-up period of 4.2 +/- 3 years, 220 patients developed HCC. There was a positive linear relationship between BMI level and HCC incidence during follow-up evaluation (Kaplan Meier shown above). In multivariate analysis, predictive factors were a BMI between kg/m(2) (hazard ratio [HR], 2.0; 95% confidence interval [CI], ), BMI of 30 kg/m(2) or more (HR, 2.8; 95% CI, ), diabetes (HR, 1.6; 95% CI, ), age years (HR, 2.4; 95% CI, ), age older than 70 years (HR, 3.0; 95% CI, ), male sex (HR, 2.0; 95% CI, ), HCV (HR, 1.6; 95% CI, ), and mixed (HR, 2.6; 95% CI, ) etiology.
N'Kontchou G, Paries J, Htar MT, Ganne-Carrie N, Costentin L,Grando-Lemaire V, Trinchet JC, Beaugrand M. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral Cirrhosis.Clin Gastroenterol Hepatol Aug;4(8): .2
N = 771 2 4 6 8 10
Time (Years)
N’Kontchou G, Clin Gastro Hepatol 2005

24. Cancer and Insulin Resistance
Excess weight / adiposity
FFA , TNFa Resistin , Adiponectin
Tumor development
Insulin resistance
Insulin IR
Slide 61
Cancer and Insulin Resistance.
In obesity, increased release from adipose tissue of free fatty acids (FFA), tumour-necrosis factor-á (TNFá) and resistin, and reduced release of adiponectin lead to the development of insulin resistance and compensatory, chronic hyperinsulinaemia (BOX 4). Increased insulin levels, in turn, lead to reduced liver synthesis and blood levels of insulin-like growth factor binding protein 1 (IGFBP1), and probably also reduce IGFBP1 synthesis locally in other tissues. Increased fasting levels of insulin in the plasma are generally also associated with reduced levels of IGFBP2 in the blood. This results in increased levels of bioavailable IGF1. Insulin and IGF1 signal through the insulin receptors (IRs) and IGF1 receptor (IGF1R), respectively, to promote cellular proliferation and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis.
These tumorigenic effects of insulin could be directly mediated by insulin receptors in the (pre)neoplastic target cells, or might be due to related changes in endogenous hormone metabolism, secondary to hyperinsulinaemia.
Target cells Apoptosis Cell proliferation
Blood and tissue: IGFBP IGFBP2
IGF1R
IGF1 bioavailability

25. Screening / Surveillance for Hepatocellular Carcinoma
Slide 79
Screening / Surveillance for Hepatocellular Carcinoma

26. Cost-Effectiveness of HCC Surveillance
HCC Screening
Cost-Effectiveness of HCC Surveillance
Surveillance with bi-annual alpha-fetoprotein (AFP) and ultrasonography in Child class A cirrhotics had cost-effectiveness ratios between $26,000 and $55,000 per QALY
2 other studies show cost-benefits of HCC surveillance
Slide 86
Cost-Effectiveness of HCC Surveillance
There have been 3 studies that have evaluated whether screening for HCC is cost-effective. Two important points need to be highlighted about these studies. One, is that all of this studies have concentrated on patients with cirrhosis secondary to chronic hepatitis C. The other point is that all the studies evaluated the cost-effectiveness of the screening strategy of using alpha-fetoprotein (AFP) and hepatic ultrasonography (US).
In the study by Sarasin and colleagues (Am J Med 1996;:), they evaluated the strategy of screening patients with compensated cirrhosis secondary to hepatitis C. They showed that surveillance with biannual AFP and US in child class A cirrhosis had cost-effectiveness ratios between $26,000 and $55,000 quality adjusted life years or QALY, depending on the availability of liver transplantation. It has been established that for a strategy to be cost-effective it has to be under $55,000, which is the acceptable cost-effectiveness of dialysis.
There have been 2 other studies that have corroborated the findings.
Therefore, the strategy of surveillance for HCC seems to be a cost-effective one.
Sarasin FP, et al. Am J Med 1996;101:
Arguedas MR,et al. Am J Gastroenterol 2003;
Lin OS, et al. Aliment Pharmacol Ther 2004;19:
Sarasin FP, et al, Am J Med 1996
Arguedas MR, et al, Am J Gastroenterol 2003
Lin OS, et al, Aliment Pharmacol Ther 2004

27. Alpha-fetoprotein Cross-Sectional Studies
HCC Screening
Alpha-fetoprotein Cross-Sectional Studies
Author
Cutoff
No. of HCC
Sensitivity %
Specificity %
Peng 20
205 65 88
Trevisani 16
170 60 90
Cedrone
100 74 25 95
Soresi 30
197 65 89
Slide 91
Alpha-fetoprotein Cross-Sectional Studies
This slide reviews the largest case-controlled studies performed to evaluate the performance of AFP. All of the studies were performed in patients with cirrhosis.
As can be seen, the cutoff of AFP that would maximize the sensitivity and specificity has been highly variable in the studies.
The sensitivity has ranged from 25% to 65%, and the specificity ranges from 79% to 96%. This is considered suboptimal to be utilized as a screening test.
The problems with these studies are the variable sample size, which limits the power of the studies, and that in all studies more than 80% of the cases (i.e., patients with HCC) had advanced stage. Because the goal of surveillance is the detection of small tumors, studying patients with advanced tumors would not be helpful towards reaching the goal.
Marrero JA. Clin Liver Dis. 2005;9:
Lee
200 54 53 79
Nguyen 20
163 63 79
Marrero JA, Clin Liver Dis 2005

28. Specificity of AFP Surveillance for HCC: PPV 9- 46%
Study
Specificity, %
PPV, %
Case-control studies
Trevisani 2001 91
25*
Surveillance studies
Pateron 1994 86 33
Sherman 1995 9
McMahon 2000 95 31
Bolondi 2001 82 46
Tong 2001 11
AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; PPV, positive predictive value.
*5% prevalence of HCC.
Trevisani F, et al. J Hepatol. 2001;34: Pateron D, et al. J Hepatol. 1994;20: Sherman M, et al. Hepatology. 1995;22: McMahon BJ, et al. Hepatology. 2000;32: Bolondi L, et al. Gut. 2001;48: Tong MJ, et al. J Gastroenterol Hepatol. 2001;16: 28

29. Current Serologic Surveillance Tests Not Sufficiently Sensitive/Specific
Prospective analysis of 99 patients with histologically proven, unresectable HCC
100
84.8
84.8
85.9 80
72.7
73.7
67.7
61.6 60
Sensitivity (%) 40
AFP, alpha-fetoprotein; AFP-L3, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein; DCP, des-gamma-carboxy prothrombin; HCC, hepatocellular carcinoma. 20
AFP-L3%
DCP
AFP
AFP-L3%
+ DCP
AFP-L3%
+ AFP
DCP
+ AFP
AFP-L3%
+ DCP
+ AFP
Tumor Marker
Carr BI, et al. Dig Dis Sci. 2007;52: 29

30. Ultrasound in HCC in Cohort Studies
HCC Screening
Slide 94
Ultrasound in HCC in Cohort Studies
This slide reviews the studies that have evaluated hepatic ultrasound (US) for the diagnosis of HCC.
The overall pooled estimates are a sensitivity of 60.5%, a pooled specificity of 96%, and a positive likelihood ratio, the likelihood that a positive test leads to a diagnosis of HCC, of 17.7 (greater than 10 is considered excellent).
However, only the studies by Chalasani and Tanaka were performed to evaluate the performance of US as a surveillance test. The others were to determine US as a diagnostic test.
Colli A, et al. Am J Gastro 2006;101(3):513.
Colli A, et al, Am J Gastro 2006

31. HCC Surveillance by Ultrasound: NPV 98-100%
Performance characteristics of ultrasound as a screening test
Performance Characteristic, %
Cohort 1
Years 1-5
Years 6-8
Cohort 2
Years 1-3
Sensitivity 79 87 80
Specificity 94 91
PPV 15 13 14
NPV 98
100
HCC, hepatocellular carcinoma; NPV, negative predictive value; PPV, positive predictive value.
Collier J and Sherman M. AASLD Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. 31

32. HCC Doubling Time Rationale for Surveillance Every 6 Months
HCC Screening
HCC Doubling Time Rationale for Surveillance Every 6 Months
Slide 96
HCC Doubling Time Rationale for Surveillance Every 6 Months
The interval for the performance of HCC surveillance has not been fully established.
However, it has been estimated that the best interval for surveillance of HCC is every 6 months based on tumor doubling time.
This slides shows a graph indicating the tumor doubling time of 9 patients in which the natural history was established. The observed tumor doubling time was indicated by the yellow circle, red triangle, purple x, green cross and light blue diamond. The expected doubling time is shown by the orange line and estimated to be around 180 days (ie 6 months). The observed doubling time for small tumors is shorter than larger tumors at baseline, so for diagnosing smaller tumors during surveillance an interval of 6 months seems to be the best time.
Taouli B, et al. J Comp Assist Tomogr 2005;29(4):425-9
Taouli B, et al, J Comput Assist Tomogr 2005

33. Surveillance Interval: 6 vs 12 Months
Trevisani et al[1]
Survival similar with 6-month vs 12-month surveillance
Santagostino et al[2]
Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillance
Kim et al[3]
Survival improved with 6-month vs 12-month surveillance
HCC, hepatocellular carcinoma.
1. Trevisani F, et al. Am J Gastroenterol. 2002;97: Santagostino E, et al. Blood. 2003;102: Kim DY, et al. AASLD Abstract 368. 33

34. AASLD and NCCN Surveillance Guidelines
AASLD Guidelines
Surveillance recommended in at-risk groups
Specific hepatitis B carriers
Nonhepatitis B cirrhosis
US preferred surveillance tool
AFP alone should not be used unless US unavailable
Patients should be screened at - 6 to 12-month intervals
NCCN Guidelines
US and AFP, AP, and albumin for surveillance in high-risk patients
Every 3-6 months
Continue screening every 3 months in those with high AFP but no evidence on imaging
AASLD, American Association for the Study of Liver Diseases; AFP, alpha-fetoprotein; AP, alkaline phosphatase; NCCN, National Comprehensive Cancer Network.
NCCN, National Comprehensive Cancer

35. Surveillance for HCC Improves Mortality A Randomized Controlled Trial
HCC Screening
Surveillance for HCC Improves Mortality A Randomized Controlled Trial
Screened group Control group
Person-years in study 38, ,077
HCC occurrence
Cases
Total incidence (per 100,000)
Rate ratio (95% CI) 1.37 (0.99, 1.89)
Deaths from HCC
Deaths
Total mortality (per 100,000)
Rate ratio (95% CI) 0.63 (0.41, 0.98)
Slide 98
Surveillance for HCC Improves Mortality A Randomized Controlled Trial
This slide shows the results of the randomized controlled study.
The screening group had a larger number of cases compared to the control group, as well as a higher incidence rate. The rate ratio of HCC development was not statistically significant though there was a trend for a higher development of HCC in the screening group.
There was a significant decrease in the number of HCC developed in the screening group versus the control group, with a reduced rate ratio of 0.63.
Zhang BH, et al. J Cancer Res Clin Oncol 2004;130:

36. Diagnosis of Hepatocellular Carcinoma
Slide 104
Diagnosis of Hepatocellular Carcinoma

37. Clinical Features at Presentation
HCC Diagnosis
Clinical Features at Presentation
Symptoms Percent of Patients
None 23%
Abdominal Pain 32%
Ascites %
Jaundice %
Anorexia/weight loss 10%
Malaise %
Bleeding %
Encephalopathy %
Slide 105
Clinical Features at Presentation
There are no specific symptoms associated with HCC. However, the symptoms that occur are as a result of liver disease and a space occupying mass in the right upper quadrant of the abdomen.
Gastroenterology 2002

38. Guidelines for Diagnosis of HCC
HCC Diagnosis
Guidelines for Diagnosis of HCC
Ultrasound findings
< 1 cm
1-2 cm
> 2 cm
Repeat US every 3-6 mo
Dynamic CT, contrast US or MRI
2 tests
Typical = HCC
Atypical = biopsy
1 test
Typical = HCC
Slide 112
Guidelines for Diagnosis of HCC
This slide shows the recommended algorithm endorsed by the American Association for the Study of Liver Disease (AASLD) for the diagnosis of HCC.
If the screening test in a cirrhotic patient is abnormal, then an evaluation for the diagnosis of HCC should be performed. Ultrasound and AFP are the recommended tests but the AFP should not be used alone.
If the ultrasound shows a hepatic nodule < 1 cm, then US is recommended in 3-6 months.
If the ultrasound shows a hepatic nodule between 1-2 cm, then a triple phase imaging that includes CT scan, MRI or contrast enhanced US should be performed. If 2 tests show typical features of HCC (arterially enhancing mass with washout of contrast in delayed phases), the diagnosis is confirmed. If atypical features appear on imaging, then biopsy is recommended.
If the ultrasound shows a hepatic nodule > 2 cm, then a triple phase imaging is also recommended. Only 1 test is recommended for the diagnostic evaluation. If typical features appear on the imaging, then the diagnosis of HCC is confirmed. If atypical features are seen, then biopsy is recommended.
Bruix J, et al. Hepatology 2005; 42:
Typical features of HCC = vascular nodule on arterial phase
with washout in delayed phases
Bruix J, et al, Hepatology 2005

39. Dual Blood Supply of Liver
HCC Diagnosis
Dual Blood Supply of Liver
The vascular supply of HCC arises from the hepatic artery through neovascularization.
Normal hepatocytes receive 80% of blood flow from portal vein
Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases
Slide 106
Dual Blood Supply of Liver
Imaging is the best recall test for the diagnosis of HCC.
However, t is important to remember that the liver has a dual blood supply, about 80% through the portal vein and about 20% through the hepatic artery. As the liver fibrosis progresses to cirrhosis and then towards cancer, the blood supply in the cirrhotic nodule changes from portal venous to arterial blood supply, a process called angiogenesis. (Yu JS, et al. Am J Roentgen 1999)
Therefore, when performing computerized tomography (CT) or magnetic resonance imaging (MRI) it is important for the testing to be done with an arterial phase, portal venous phase and delayed phases. The next will show an example of a triple phase imaging.
Yu JS et al. Am J Roentgenol 1999;173:
Yu JS, et al, Am J Roentgenol 1999

40. Triple Phase Imaging of Hepatocellular Carcinoma
HCC Diagnosis: MRI
Pre-contrast
Arterial Phase
Slide 107
Triple Phase Imaging of Hepatocellular Carcinoma
This is a MRI of the liver.
The left upper panel shows a precontrast examination indicating a cirrhotic-appearing liver with the presence of ascites.
The right upper panel shows the arterial phase. The arrow shows an arterially enhancing lesion in the posterior right lobe.
The left lower panel shows the portal venous phase, and at th is phase we can see the intrahepatic branches of the portal vein enhance and the enhancement of the aorta dimish. In this phase, the arterially enhancing lesion is not well visualized due lack of arterial enhacement (i.e., lack of arterial blood supply in the lesion) in this phase. If the MRI is performed without an arterial phase, this lesion would be missed.
The right lower panel shows the 5 minute delayed phase. The location that corresponds to the arterially enhancing lesion now appears darker than the surrounding liver, a process called washout. This is delayed phase hypointensity of the mass compared to the surrounding liver, and this is an important feature of HCC.
Portal Venous Phase
5-min Delayed

41. Dynamic MRI Spiral CT for Diagnosis of HCC
HCC Diagnosis
Dynamic MRI Spiral CT for Diagnosis of HCC
Variables Dynamic MRI Spiral CT
Sensitivity 76% (58/76) 61% (43/70)
Specificity 75 % (18/24) 66% (12/18)
PPV 90% (58/64) 87% (43/49)
NPV 50% (18/36) 30% (12/39)
LR positive test
Slide 108
Dynamic MRI Spiral CT for Diagnosis of HCC
There seems to be a controversy with regards to which is better: MRI or CT scans.
This slide shows compared the performance characteristics of MRI and CT in patients with cirrhosis. The authors studied 45 patients who were listed for transplantation, and a CT and MRI examinations were performed within 6 weeks of each other and within 6 months of a transplant. A total of 18 patients had HCC at the time of explant examination, which was the gold standard for which CT and MRI were compared to. MRI had a better sensitivity, specificity, positive and negative predictive values compared to CT scan.
Two other studies compared MRI versus CT, and MRI seems to be better at determining the diagnosis of HCC.
Burrel M, et al. Hepatology 2003;38:
Krinski G, et al. Radiology 2001;219:
Rode A, et al. J Comput Assist Tomogr 2001;25:
n= 55 cirrhotics (29 with HCC)
Burrel M, et al, Hepatology 2003

42. Treatment of Hepatocellular Carcinoma
Slide 104
Diagnosis of Hepatocellular Carcinoma

43. Population-based Survival Estimates in the United States
HCC Treatment
HCC Survival Estimates
in the United States
100
Median Survival 6-8 months 80
White
Hispanic 60
Black
Survival (%)
Asian 40
Slide 167
Population-based Survival Estimates in the United States
Davila JA, El-Serag HB. Racial differences in survival of hepatocellular carcinoma in the United States: a population-based study. Clin Gastroenterol Hepatol Jan;4(1): 20 1 2 3
Years Following Diagnosis
Davila J, & El-Serag HB, Clin Gastroenterol Hepatol. 2006

44. Key Concepts in the Management of Hepatocellular Cancer
HCC Treatment
Key Concepts in the Management of Hepatocellular Cancer
Potentially Curative
Liver transplantation (75% 5-year survival)
Surgical resection
Palliative
Radiofrequency ablation (RFA)
Transarterial chemoembolization (TACE)
Percutaneous ethanol or acetic acid ablation
Cryoablation
Systemic Chemotherapy
Slide 166
Key Concepts in the Management of Hepatocellular Cancer

45. Key Concepts in the Management of Hepatocellular Cancer
HCC Treatment
Key Concepts in the Management of Hepatocellular Cancer
Liver transplantation achieves the best outcome in HCC patients with decompensated cirrhosis who meet criteria
Surgical resection is most effective for non-cirrhotic patients or those with cirrhosis and preserved liver function and can be followed by salvage OLT
Patients with small tumors are best stratified for resection or OLT by the presence of clinically-significant portal hypertension and/or increased serum bilirubin
Local ablative methods are an option for small solitary nodules and those who are not surgical candidates
Transarterial chemoembolization improves survival in intermediate-advanced HCC
Slide 166
Key Concepts in the Management of Hepatocellular Cancer

46. Hepatobiliary Surgery Liver Transplant Program
HCC Treatment
Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach
Hepatobiliary Surgery
Hepatology
Oncology
Slide 234
Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach
Pathology
Radiology
Liver Transplant Program

47. Liver Transplantation for HCC: Milan Criteria (Stage 1 and 2)
Single tumor, not > 5 cm
Up to 3 tumors, none > 3 cm
HCC, hepatocellular carcinoma. +
Absence of macroscopic vascular invasion,
absence of extrahepatic spread
Mazzaferro V, et al. N Engl J Med. 1996;334:

48. Management of HCC in Patients with Cirrhosis
HCC Treatment
Slide 226
Management of HCC in Patients with Cirrhosis

49. Surgical Resection of HCC: Outcome in a US Cancer Center
HCC Treatment
Surgical Resection of HCC: Outcome in a US Cancer Center
78% with cirrhosis
Transplant Eligible
Transplant Ineligible
74 pts (80%)
Unresectable
385 pts (70%)
Resected
180 pts (30%)
HCC Pts Evaluated
1989 – 2001
611 pts
36 pts (20%)
Slide 189
Surgical Resection of HCC: Outcome in a US Cancer Center 611 pts were seen at Memorial Sloan Kettering with the diagnosis of HCC from 1990 to 2001.
180 (30%) underwent hepatectomy and from a prospective database, 36 patients eligible for transplantation were identified.
Demographic data, tumor characteristics, and patient outcome were analyzed.
The 5-year overall survival in the 36 transplant-eligible patients who underwent resection was 69%.
Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH, DeMatteo RP. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg. 2003; 238:
Ann Surg. 2003; 238:

50. Treatment of HCC in US at Non-Federal Hospitals in 2000
2 databases evaluated for trends in HCC
48,349 HCC deaths 15
11.0 10
HCC, hepatocellular carcinoma; US, United States.
Treatment (%)
5.5
4.9 5
3.5
1.8
Surgical
Resection
Liver
Transplant
Local
Ablation
Embolization
Chemotherapy
Kim WR, et al. Gastroenterology. 2005;129:

51. Treatment for HCC Often Suboptimal
Proportion of patients receiving potentially curative therapy (N = 2963)
34.0% of patients with single lesions
34.0% of patients with lesions < 3 cm
19.2% of patients with lesions > 10 cm
4.9% of patients with metastatic disease
11.5% of patients ideal for transplantation received it
12.9% of patients ideal for surgical resection received it
HCC, hepatocellular carcinoma.
El-Serag HB, et al. J Hepatol. 2006;44:

52. Outcomes of HCC Treatment: Observational Population-based study
2,963 patients with HCC diagnosed between 1992 and 1999 in SEER-Medicare datasets 1
Median Age:74
0.8
0.6
(Kaplan Meier Estimate)
Survival
Transplant
Resection
0.4
Ablation
Slide 227
Outcomes of HCC Treatment: Observational Population-based study
The cumulative 5-year survival in. 2,963 patients with HCC diagnosed between 1992 and 1999 and identified in SEER-Medicare datasets Patients were grouped into 4 groups depending on the type of therapy received. Median overall survival was 104 days following HCC diagnosis with the longest survival in the transplant group (852 days) and the shortest survival in the group with no treatment (58 days). In the survival analysis, transplantation led to the longest survival, followed by resection. Neither ablation nor TACE yielded prolonged survival (3 year survival was less than 10%).
El-Serag HB, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, McGlynn KA. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol Jan;44(1):
TACE
0.2
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
Follow up Duration (Years)
El-Serag HB, et al, J Hepatology :158

53. Summary of NCCN Treatment Guidelines
Potentially resectable, inoperable mass
Unresectable/ Denies Surgery
Inoperable by PS, comorbidity (local disease)
Metastatic
Not transplant candidate/has cancer-related symptoms
Transplant if appropriate candidate
Surgical eval/ biopsy
No cancer-related symptoms
Cancer-related symptoms
Extensive/ no cancer-related symptoms
Sorafenib
Chemo-embolization
Clinical trial
Ablation
Chemo + RT RT
Radio-embolization
Supportive care
Systemic/intra-arterial chemo
NCCN, National Comprehensive Cancer Network; PS, performance status; RT, radiotherapy.
Resectable
Sorafenib
Ablation
Clinical trial
Chemo-embolization RT
Radio-embolization
Supportive care
Sorafenib
Clinical trial
Sorafenib
Clinical trial
Supportive care
Sorafenib
Ablation
Clinical trial
Ablation
Transplant
Transplant
NCCN. Available at: Accessed October 23, 2008.

54. HCC: Summary HCC is one the most rapidly increasing cancers in the US
The 5-year survival is 8-12%
Less than 20% are candidates for surgery/transplant at diagnosis
Treatment is mainly palliative
Referral to a tertiary center indicated
Screening to detect early HCC is the main priority of primary care physicians

55. Hepatitis B Carriers Suitable for HCC Surveillance
Asian males > ~ 40 years (incidence ~ 0.4% to 0.6% per year)
Asian females > ~ 50 years (incidence ~ 0.2% per year)
Africans older than 20 years of age (incidence unknown but likely > 0.2% per year)
Cirrhosis (HCC incidence: 3% to 5%/year)
Family history of HCC: Screen from the time of diagnosis (mainly Asian and African)
HCC, hepatocellular carcinoma. 55

56. AASLD and NCCN Surveillance Guidelines
AASLD Guidelines
Surveillance recommended in at-risk groups
Specific hepatitis B carriers
Nonhepatitis B cirrhosis
US preferred surveillance tool
AFP alone should not be used unless US unavailable
Patients should be screened at - 6 to 12-month intervals
NCCN Guidelines
US and AFP, AP, and albumin for surveillance in high-risk patients
Every 3-6 months
Continue screening every 3 months in those with high AFP but no evidence on imaging
AASLD, American Association for the Study of Liver Diseases; AFP, alpha-fetoprotein; AP, alkaline phosphatase; NCCN, National Comprehensive Cancer Network.
NCCN, National Comprehensive Cancer

57. Focus Screening Efforts on Patients Under Age 652 4 6 8 10 12 14 16 18 20
1982 – 84
1991 – 93
2000 – 02
Incidence Rate
per 100,000 PY
Slide 12
Temporal Trends in The Age Distribution of Hepatocellular Carcinoma
The age specific rates are shown per 5 year age groups. HCC is rare below age 40, increases progressively thereafter. As the incidence of HCC has increased in the United States (during ), the age distribution curve has shifted to the left indicting that younger persons are becoming progressively more affected. Persons between 45 and 65 have been disproportionately affected with HCC.
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med Mar 11;340(10):
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med Nov 18;139(10):
20-24
30-34
40-44
50-54
60-64
70-74
80-84
25-29
35-39
45-49
55-59
65-69
75-79
85+
Age (years)
El-Serag HB, Mason A, N Engl J Med 1999

58. HCC: Preventative Measures?
Although unproven, data suggest that maximal suppression of HBV DNA may reduce the annual incidence of HCC
Obscenely expensive
Eradication of HCV significantly reduces the risk of HCC
Minimize ETOH
Minimize risk factors for hyperinsulinemia
Statins?
Coffee

59. HCC After IFN Therapy for HCV
HCC Epidemiology
HCC After IFN Therapy for HCV 30 25 20
No Response
Cumulative Incidence
of HCC (%) 15 10
Slide 41
HCC After IFN Therapy for HCV
In this Japanese retrospective cohort study, 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls.
SR: Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment.
NR: Nonresponse included all other ALT patterns.
Imai Y, Kawata S, Tamura S, Yabuuchi I, Noda S, Inada M, Maeda Y, Shirai Y,Fukuzaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y. Relation of interferon therapy and hepatocellular carcinoma in patients withchronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group.Ann Intern Med Jul 15;129(2):94-9.
Relapse 5
Sustained
Response 1 2 3 4 5 6 7
Follow-up (yr)
Imai Y, et al, Ann Intern Med 1998

60. Statins vs HCC Retrospective, case-controlled study
VA database >1, veterans
14,021 HVC positive
34% on statins
HCC diagnosed in 409
After controlling for age, genotype, statin use was associated with a significant reduction in risk for HCC
V. Khurana et al. “Statins Are Protective Against HCC in HCV Infection”DDW May Abstract S1535

61. Don’t Forget Your Coffee
Meta-analysis of published studies on HCC that included quantitative information on coffee consumption
Ten studies were retrieved: 2,260 HCC cases
The overall summary RR for low or moderate coffee drinkers was 0.70 (95% CI ), and that for high drinkers was 0.45 (95% CI )
Hepatology 2007 Aug;46(2):430-5