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Discussion
The rates of development of cirrhosis and HCC in CHB patients in this first ever prospective study in Singapore are 1.6% per annum and 0.8% per annum, respectively. In cirrhotic patients, the incidence of HCC development is 3% per annum. These results are comparable with rates reported worldwide, in Asia, America, and Europe 9–14.
HCC surveillance comprising 6-monthly surveillance serum AFP and abdominal ultrasound has been shown in a large randomized-controlled trial of 18 816 patients to reduce HCC-related mortality by 37% 15. The decision to subject a patient to HCC surveillance is determined by the individual’s risk for HCC, which is related to the incidence of HCC in that particular population. Cost-effectiveness models suggest that an intervention is considered cost-effective if it provides gains of life expectancy of more than 3 months at a cost of less than US$50 000 per year of life saved 16. A cost-effectiveness study in Child–Pugh’s A CHB cirrhosis patients suggests that HCC incidence of 1.5% per annum or greater would justify HCC surveillance 17. Similar rates are also proposed for HCV-related cirrhosis and stage-4 primary biliary cirrhosis 18. As CHB patients are at risk of HCC development even in the absence of cirrhosis, major associations such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) recommend that the threshold incidence for efficacy of HCC surveillance should be 0.2% per year in select CHB populations such as Asian men older than 40 years of age, Asian women older than 50 years of age, African/North American blacks, and CHB patients with a family history of HCC 18,19. Compared with the incidence of HCC in western populations of about 0.1–0.4% per annum 6,20, our HCC development rate of 0.8% per annum is higher. The results of our study justify HCC surveillance in our CHB patients.
In our study, HCC rates were highest within the first year of diagnosis of cirrhosis because of seven cases of HCC being detected within a year of diagnosis of cirrhosis. Of these seven cases, four were diagnosed concomitantly with both HCC and cirrhosis on CT/MRI. The remaining three patients who were diagnosed to have cirrhosis 2, 5, and 8 months after HCC were most likely missed because of inaccuracy before the HCC diagnosis.
The high rate of HCC development in the first year may be because of prevalent cancers in patients who were not under routine HCC surveillance as cirrhosis may not have been diagnosed previously. This can also be explained by the limited sensitivity of early detection of cirrhosis or poor detection of early cirrhosis on routine US surveillance. Cirrhotic changes could have also been misinterpreted as fatty infiltration, leading to a false diagnosis of fatty liver disease coexisting with CHB. With the increasing availability and sensitivity of noninvasive liver stiffness measurement techniques, cirrhosis may be detected earlier and with greater sensitivity and accuracy.
It is traditionally believed that HBeAg-positive status is associated with an increased risk of HCC 21. Our observation of the lack of effect of HBeAg status on HCC development is similar to a Hong Kong study that reported similar findings 22. In that study by Yuen and colleagues of 820 patients followed up for a mean of 76.8 months, there was no difference in the overall risk of HCC between patients who were positive for HBeAg (n=356) compared with those positive for anti-HBe (n=464) at presentation (P=0.54). Out of 356 patients, 144 underwent HBeAg seroconversion, but there was again no difference in the overall risk of HCC development in this subgroup compared with the initial two groups.
In our study, patients aged 55 years or older were at a significantly higher risk of developing cirrhosis over 10 years (P=0.001). Thus, as expected, the overall HCC rate was significantly higher in patients aged 55 years or older. In patients who were cirrhotic, age did not influence the risk of developing HCC.
Our data also showed that patients with a baseline AFP of 4.1 µg/l or more have a significantly higher risk of developing HCC. This is an important finding because although an AFP level of 4.1 µg/l is within the normal range, a baseline AFP level of 4.1 µg/l or more has been shown in our study to carry a significant risk of developing HCC. We hope to explore whether we can combine the threshold values of the various baseline factors, including an AFP level of 4.1 µg/l or more, to predict the risk of developing HCC.
As most of the patients were started on antiviral treatment only after they developed cirrhosis, there was a huge imbalance in the number of patients with cirrhosis (and a higher risk of developing HCC) in the treatment compared with the nontreatment groups. Thus, it was not possible for us to conclude whether antiviral treatment had any impact on the rates of cirrhosis or HCC development. In addition, those who received antiviral treatment were started on treatment at various time points of their follow-up as lamivudine, entecavir, and tenofovir were available in our pharmacy only after 2004, 2006, and 2011, respectively. We could not implement a standardized protocol for hepatitis B treatment as the medications are costly and totally self-funded.
Similar to several other longitudinal studies, male sex was also found to be associated with an increased risk of HCC development both in cirrhotics and in the overall cohort 23,24. It, however, had no effect on the development of cirrhosis.
The strengths of our study are the relatively large sample size and the long duration of prospective follow-up. However, there are several limitations in this study. The diagnosis of liver cirrhosis should ideally be made by liver biopsy. However, in this clinical study, a clinical diagnosis of cirrhosis was made on the basis of imaging evidence with concomitant clinical evidence. Furthermore, many patients refused diagnostic liver biopsy in view of the risks associated with the invasive procedure. Being an academic tertiary institution, there could also have been a referral bias in this study cohort. Risk factors for HCC development such as family history, obesity, and smoking have not been adjusted for as these data were unfortunately not collected. Nonetheless, these limitations notwithstanding, the results of our study do provide additional data on cirrhosis and HCC in CHB patients in Singapore, a country that is endemic for hepatitis B with a relatively high prevalence of CHB infection. With potent antiviral agents such as entecavir and tenofovir showing ability to lower the incidence of HCC and reverse fibrosis and cirrhosis, these rates are expected to decrease in the coming years as the effects of antiviral therapy start to bear fruit 25–27.
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Conclusion
The rate of cirrhosis in HBV-infected patients in Singapore is about 1.6% per annum and the overall rate of development of HCC in HBV-infected patients in Singapore is about 0.8% per annum. The rate of development of HCC in patients with HBV cirrhosis in Singapore is about 3.0% per annum. Our rates of development of HCC justify HCC surveillance in our patients with CHB infection.
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发表于 2015-5-14 10:57
