Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis. Ann Int Med 2012;156:841-847. (Reprinted with permission.)
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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.
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.
This article in the Annals of Internal Medicine1 raises questions about who requires hepatocellular carcinoma (HCC) screening. The ultimate objective of a cancer screening program is reduction in mortality from that cancer. This can only be definitively demonstrated by a randomized controlled trial. Studies relying on surrogate endpoints (duration of survival, stage migration, or ability to apply potentially curative treatment) cannot provide conclusive evidence that screening saves lives. Despite this, it would seem obvious that early diagnosis of HCC should result in decreased mortality. This is because, unlike other cancers for which screening programs are in place, treatment of any but the earliest stages of HCC is usually ineffective. Other cancers that we screen for (breast, colon, prostate, cervix) have effective treatment for even moderately advanced cases. Death from the underlying liver disease complicates assessing the benefits of screening for HCC. Therefore, knowing that a patient is at increased risk of HCC is not in itself sufficient to warrant screening. Other potential considerations include that the risk has to be sufficiently high, and screening and treatment of screen-detected lesions sufficiently effective, that mortality is reduced. There is no benefit to screening if the likelihood of cure is small.
The benefit of HCC screening has been evaluated in two randomized controlled trials in patients with chronic hepatitis B.2, 3 The first was inconclusive because patients diagnosed with HCC frequently did not receive appropriate treatment.2 The second trial has some methodological flaws, but did show a benefit to HCC screening.3 There is also indirect evidence that supports that screening is beneficial, and so screening is recommended for specific groups with defined risk.4 However, one of the major unresolved issues is still who is at sufficiently high risk of HCC that they should be screened. The only practical method to determine this is by modeling studies, since it is not possible to undertake randomized controlled trials in each subgroup of potentially at-risk subjects. Most modeling studies demonstrate that the efficacy of screening depends on disease incidence. In general, screening becomes effective at an HCC incidence of somewhere above 1.5%-2%/year for cirrhosis. The only categories of liver disease that clearly exceed this threshold are cirrhosis from chronic hepatitis B or C and stage 4 primary biliary cirrhosis.5-7 In other causes of cirrhosis, including alcoholic liver disease, the incidence of HCC is not as well documented.
In the Jepsen et al. study1 the authors used administrative databases in Denmark to demonstrate that the incidence of HCC in patients with alcoholic cirrhosis at about 1% over 5 years is too low to warrant screening using the 1.5% annual incidence cutoff suggested in the American Association for the Study of Liver Diseases (AASLD) guidelines. There are some questions about the study. The diagnosis of cirrhosis was not confirmed by biopsy, but is nonetheless likely to be accurate. A more detailed review of medical records in a subcohort confirmed the accuracy of the discharge diagnoses obtained from the database. We cannot be sure, however, whether confounders such as alcoholic hepatitis were accounted for. The diagnoses of HCC were taken from the Danish Cancer registry, which is apparently 100% accurate, i.e., all diagnosed HCCs were captured, but it is not certain that this represents all HCCs. We are not told what follow-up was provided to the patients with cirrhosis, or whether all patients underwent screening subsequent to the diagnosis of cirrhosis. If follow-up did not include HCC screening it is possible that some of the deaths attributed to cirrhosis were actually related to HCC. In the absence of imaging it is impossible to separate death from progressive liver disease from death from HCC. The authors found that the incidence of HCC was higher in the subcohort where detailed chart analysis was performed, suggesting that such a possibility of misdiagnosis in the remaining cohort cannot be ruled out.
The incidence of HCC is at the lower end of reported rates.8-10 Second, there is a very high death rate overall. Sixty-seven percent of the patients died within about 7 years of diagnosis, presumably of their liver disease or other causes of death associated with alcohol excess. Therefore, death from advanced liver disease was a competing cause that may have reduced the overall HCC incidence. Most patients with alcoholic hepatitis and cirrhosis present late in the course of their disease, with the ascites or with jaundice. What happens after the initial presentation depends on whether the patient continues to drink, and whether there is a reversible component of their disease. For those who present with alcoholic hepatitis and who stop drinking enough recovery may occur to allow prolonged survival. However, if drinking continues or if there is no recovery, death ensues (assuming no transplant).
Recommendations for HCC screening generally include that if HCC were found the patient would be a candidate for some form of treatment. Patients with advanced alcoholic liver disease (Child-Pugh B or C) are seldom candidates for treatment of their cancer; it is unlikely that there will be a reduction in mortality. Screening has to find cancers that can be treated with intent to cure. Resection is seldom possible for patients with Child-Pugh B or C status. Patients who continue to drink are not transplant candidates, and even local ablation is not feasible in patients with Child-Pugh C status. Therefore, many of these patients with alcoholic cirrhosis may not have been candidates for screening in the first place.
However, the other category of patient with alcoholic cirrhosis, i.e., those who stop drinking and in whom liver function recovers, have a different outcome. These patients are left with a cirrhotic liver and are at risk for the development of HCC, but the degree of risk is unknown. This issue was addressed by the authors. They argue that if the low incidence of HCC was related to early death before HCC had time to develop, then in the later years of follow-up, after the initial acute phase, in the patients who survived there should be a higher incidence of HCC because advanced liver disease was no longer a competing cause of death. The fact that there was no increase in HCC incidence over the whole follow-up period suggested to the authors that HCC incidence in alcoholic cirrhosis does not at any stage reach an incidence high enough to warrant screening.
Therefore, what take home points can be drawn from this study? First, since other studies have found higher HCC incidence in alcoholic cirrhosis, mostly in other geographic regions, it suggests that risk has to be assessed locally. In some geographic regions the incidence of HCC in alcoholic cirrhosis may be too low to warrant HCC screening, whereas in other regions with a higher incidence screening may be worthwhile. These data require confirmation before we scratch alcoholic cirrhosis off the list of screening candidates. For now we should move alcoholic cirrhosis from the “definite” to “possible” category, together with treated hepatitis C, autoimmune hepatitis, diabetes, and nonalcoholic fatty liver disease. The “possible” category includes those patients for whom the risk of HCC has not been accurately assessed, and for whom no recommendation for or against screening can be made.