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Original Research |

Risk for Hepatocellular Carcinoma in Patients With Alcoholic Cirrhosis: A Danish Nationwide Cohort Study

Peter Jepsen, MD, PhD; Peter Ott, MD, DMSc; Per Kragh Andersen, PhD, DMSc; Henrik Toft Sørensen, MD, PhD, DMSc; and Hendrik Vilstrup, MD, DSc
[+] Article, Author, and Disclosure Information

From Aarhus University Hospital, Aarhus, and the University of Copenhagen, Copenhagen, Denmark.

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2633.

Reproducible Research Statement:Study protocol: Not available. Statistical code: Available from Dr. Jepsen (e-mail, mailto:pj@dce.au.dk). Data set: The Danish National Board of Health (www.sst.dk) extracts data from Denmark's publicly available health care registries on request. The instructions given to the Board of Health to identify the nationwide cohort are available from Dr. Jepsen. Data for the Aarhus cohort are not available.

Requests for Single Reprints: Peter Jepsen, MD, PhD, Aarhus University Hospital, Department of Hepato-Gastroenterology, Nørrebrogade 44, Aarhus 8000 C, Denmark; e-mail, mailto:pj@dce.au.dk.

Current Author Addresses: Drs. Jepsen, Ott, and Vilstrup: Aarhus University Hospital, Nørrebrogade 44, Aarhus 8000 C, Denmark.

Dr. Andersen: University of Copenhagen, O. Farimagsgade 5, PB 2099, Copenhagen K 1014, Denmark.

Dr. Sørensen: Aarhus University Hospital, Olof Palmes Alle 43-45, Aarhus N 8200, Denmark.

Author Contributions: Conception and design: P. Jepsen, P. Ott, H.T. Sørensen, H. Vilstrup.

Analysis and interpretation of the data: P. Jepsen, P. Ott, P.K. Andersen, H.T. Sørensen, H. Vilstrup.

Drafting of the article: P. Jepsen, H. Vilstrup.

Critical revision of the article for important intellectual content: P. Jepsen, P. Ott, P.K. Andersen, H.T. Sørensen, H. Vilstrup.

Final approval of the article: P. Jepsen, P. Ott, P.K. Andersen, H.T. Sørensen, H. Vilstrup.

Statistical expertise: P.K. Andersen.

Administrative, technical, or logistic support: P. Ott, H. Vilstrup.

Collection and assembly of data: P. Jepsen.

Ann Intern Med. 2012;156(12):841-847. doi:10.7326/0003-4819-156-12-201206190-00004
Text Size: A A A

Background: Patients with alcoholic cirrhosis are at higher risk for hepatocellular carcinoma (HCC). The role of HCC surveillance for these patients is undefined.

Objective: To provide population-based estimates of HCC incidence and comparisons of HCC-related mortality and total mortality among patients with alcoholic cirrhosis as a basis for assessing the role of HCC surveillance.

Design: Nationwide, registry-based, historical cohort study.

Setting: Denmark.

Patients: All Danish citizens with a first-time hospital diagnosis of alcoholic cirrhosis from 1993 to 2005.

Measurements: Hepatocellular carcinoma incidence and mortality starting 1 year after diagnosis of alcoholic cirrhosis through 2009; ratio of HCC-related mortality to total mortality.

Results: Among 8482 patients, 169 developed HCC. A total of 5734 patients died, 151 of whom had developed HCC. Five-year cumulative HCC risk was 1.0% (95% CI, 0.8% to 1.3%), and 5-year cumulative mortality was 43.7% (CI, 42.6% to 44.7%). Only 1.8% of all deaths were HCC-related. In sensitivity analyses that included all possible HCC diagnoses and a subpopulation of patients who were followed by hepatologists, the highest 5-year HCC risk was 1.9% (CI, 0.8% to 3.9%). These patients did not have higher mortality than patients in the nationwide cohort.

Limitation: Cirrhosis and HCC diagnoses were made by hospital physicians without uniform clinical criteria, and use of registry data precluded detailed information on clinical care of patients, including HCC surveillance.

Conclusion: Danish patients with alcoholic cirrhosis have a low risk for HCC, and HCC contributes little to their high mortality. On the basis of these data, HCC surveillance would be expected to have a minimal effect on mortality and is unlikely to be cost-effective.

Primary Funding Source: None.


Grahic Jump Location
Figure 1.

Cumulative HCC risk (top) and cumulative mortality for patients with localized or nonlocalized HCC (bottom) in the nationwide alcoholic cirrhosis cohort.

The vertical bars show 95% CIs. Follow-up began 1 y after diagnosis of alcoholic cirrhosis. HCC = hepatocellular carcinoma.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Cumulative mortality in the nationwide alcoholic cirrhosis cohort, by cause of death.

We defined the HCC burden as the ratio of HCC-related mortality to total mortality. Follow-up began 1 y after diagnosis of alcoholic cirrhosis. HCC = hepatocellular carcinoma.

Grahic Jump Location




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Submit a Comment/Letter
To the Editor
Posted on July 10, 2012
Hans L. Tillman MD, Steve Choi MD
Duke University, VA Durham Medical Center
Conflict of Interest: None Declared

Health care budgets need to be streamlined; it is not only important to consider the potential benefit that screening has in preventing and controlling future costs but to also critically reevaluate screening practices which might not be cost-effective. [ ] The paper by Jepsen et al highlight that screening for hepatocellular carcinoma (HCC) might be unnecessary in patients with alcoholic liver cirrhosis.[ ] “Anti-HBc positivity” is a marker for occult hepatitis, which has been associated with increased risk of HCC development in the range of 1.4 to 10 (relative risk). One study in alcoholic cirrhosis suggested an odds ratio of 3.1 if anti-HBc is positive. Thus, can the authors provide the annual risk of HCC development in anti-HBc positive and/or anti-HCV positive individuals with alcoholic cirrhosis; those patients were excluded from the initial analysis. The high 5-year mortality might suggest that a substantial number of patients were unable to maintain abstinence and died before HCC could develop. Therefore, information on the role of abstinence might be important, as there could be a risk for HCC development limited to those who live long enough due to withstanding from alcohol. Though low risk for HCC in patients with alcohol-induced cirrhosis would be welcomed news in this population, a better understanding of individual risk for HCC would be required to successfully individualize screening strategies,[ ] and thereby reduce cost and angst among low risk patients.

1. Laine C. High-value testing begins with a few simple questions. Ann Intern Med. 2012 Jan 17;156(2):162-3.

2. Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a danish nationwide cohort study. Ann Intern Med. 2012 Jun 19;156(12):841-7.

3. Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int. 2012 Feb;32(2):231-40.

4. Kwon OS, Jung YK, Bae KS, Kim JH, Kim SG, Kim YS, Lee JI, Lee JW, Kim YS. Anti-hepatitis B core positivity as a risk factor for hepatocellular carcinoma in alcoholic cirrhosis: A case-control study. Alcohol. 2012 May 7. [Epub ahead of print] PMID: 22572059

5. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012 May;142(6):1264-1273.e1.

Hepatocellular cancer in Danish patients with Alcoholic Cirrhosis
Posted on July 18, 2012
Ayokunle T Abegunde MBBS, DTM&H, MSc
John .H. Stroger Jr Hospital of Cook County
Conflict of Interest: None Declared

TO THE EDITOR,I read with interest the article by Jepsen and colleagues on the risk of HCC in Danish patients with Alcoholic cirrhosis (1). Their results are thought provoking and clearly present evidence that argues against the necessity and cost effectiveness of routine HCC surveillance of patients with alcoholic cirrhosis in Denmark. Their study was a retrospective analysis of a national dataset with the dependence on ICD coding on discharge to identify cases. This type of study is often limited by under ascertainment or misclassification of cases and lacks the clinical or temporal detail necessary to define what other factors might increase or decrease the risk of developing HCC among the cohort of patients studied. This potential limitation of misclassification is borne out by the fact that no uniform criteria for diagnosis of Alcoholic cirrhosis was used in their study. Additionally, the incidence of HCC among patients with Alcoholic cirrhosis in the Aarhus group was higher than the incidence in the study cohort probably reflecting an enhanced effect of specialist diagnosis on the incidence of HCC. The mechanism of carcinogenesis in HCC is dependent on risk factors with established carcinogenic potential such as alcohol and interactions with other risk factors. A classic example of such interaction was demonstrated by Qian and colleagues in their landmark paper which showed near doubling of the incidence of HCC in patients with HBV infection who were exposed to Aflatoxin (2). Thus, the clear difference between the results of their study and other reported studies from southern Europe deserves a closer look. Apart from the fact that most of the studies from southern Europe were hospital based, with the tendency to overestimate the incidence of HCC. There may actually be population based differences yet unidentified which may contribute to the reported higher incidence of HCC among patients with Alcoholic cirrhosis in southern Europe. In the United States, the incidence of HCC in alcoholic cirrhosis is not accurately known and HCC surveillance among high risk populations with cirrhosis is sub-optimal at best (3). Against this backdrop the results of Jepsen and colleague’s study is timely and adds to the body of knowledge on the risk of HCC in patients with Alcoholic cirrhosis.


1. Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a danish nationwide cohort study. Ann Intern Med. 2012 Jun 19;156(12):841-7

2. Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):3-10.

3. Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, El-Serag HB. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011 Jan 18;154(2):85-93.

Author's Response
Posted on August 6, 2012
Peter Jepsen, MD, PhD, Peter Ott, MD, DMSc, Hendrik Vilstrup, MD, DSc
Conflict of Interest: None Declared
We thank Mr. Abegunde and Drs. Tillman and Choi for the interest in our research. In their responses to our article they provide strong arguments for studying risk factors for HCC development in patients with alcoholic cirrhosis. Drs. Tillman and Choi add examples of candidate risk factors, namely anti-HBc or anti-HCV positivity and alcohol abstinence. At present we are unable to provide estimates of HCC risk for alcoholic cirrhosis patients with or without these possible risk factors for HCC development, but we fully agree that identification of such risk factors and interactions between them is an important next step towards identifying those patients that will benefit the most from HCC surveillance. This goal provides additional arguments for establishing an international cohort of patients followed from diagnosis of alcoholic cirrhosis. Sincerely,Jepsen P, Ott P, Vilstrup H.
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