Alpha-foetoprotein or liver ultrasonography, or both, for liver cancer screening in patients with chronic hepatitis B

Liver cancer is a leading cause of death among people with chronic hepatitis B infection. Screening such patients with ultrasound of the liver or alpha-foetoprotein in the blood, or both, is widely performed to detect liver cancer at an early stage. The hope is that early stages of liver cancer can be treated by resection or transplantation, or both, with improved outcomes. Only three trials could be included in this review. One of these trials was conducted in Shanghai, China. It compared screening twice yearly with ultrasound and alpha-foetoprotein against no screening. The trial has a high risk of systematic errors (bias) and several published reports of the trial provide different results. Another trial was conducted in Toronto, Canada. It compared screening with alpha-foetoprotein and ultrasound versus screening with alpha-foetoprotein alone. This trial had too few participants. As there were no participants who were not screened, we cannot assess whether screening is effective in reducing mortality. The remaining trial was published as an abstract only. It was designed to determine the optimal time interval for screening using alpha fetoprotein and ultrasound. The cumulative four-year survival was not significantly different between the two studied screening intervals of four months and 12 months. Thus, to date, there is insufficient evidence regarding screening for liver cancer among patients with chronic hepatitis B infection.

Authors' conclusions: 

There is not enough evidence to support or refute the value of alpha-foetoprotein or ultrasound screening, or both, of hepatitis B surface antigen (HBsAg) positive patients for hepatocellular carcinoma. More and better designed randomised trials are required to compare screening against no screening.

Read the full abstract...

Chronic hepatitis B virus infection is a risk factor for development of hepatocellular carcinoma. Alpha-foetoprotein and liver ultrasonography are used to screen patients with chronic hepatitis B for hepatocellular carcinoma. It is uncertain whether screening is worthwhile.


To determine the beneficial and harmful effects of alpha-foetoprotein or ultrasound, or both, for screening of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.

Search strategy: 

Electronic searches were performed until December 2011 in the Cochrane Hepato-Biliary Group Controlled Trials Register (December 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 4) in The Cochrane Library, MEDLINE (1948 to 2011), EMBASE (1980 to 2011), Science Citation Index Expanded (1900 to 2011), Chinese Medical Literature Electronic Database (WanFang Data 1998 to 2011), and Chinese Knowledge Resource Integrated Database (1994 to 2011).

Selection criteria: 

All published reports of randomised trials on screening for liver cancer were eligible for inclusion, irrespective of language of publication. Studies were excluded when the hepatitis B status was uncertain, the screening tests were not sensitive or widely-used, or when the test was used for diagnosis of hepatocellular carcinoma rather than screening.

Data collection and analysis: 

We independently analysed all the trials considered for inclusion. We wrote to the authors of one of the trials to obtain further information.

Main results: 

Three randomised clinical trials were included in this review. All of them had a high risk of bias. One trial was conducted in Shanghai, China. There are several published reports on this trial, in which data were presented differently. According to the 2004 trial report, participants were randomised to screening every six months with alpha-foetoprotein and ultrasonography (n = 9373) versus no screening (n = 9443). We could not draw any definite conclusions from it. A second trial was conducted in Toronto, Canada. In this trial, there were 1069 participants with chronic hepatitis B. The trial compared screening every six months with alpha-foetoprotein alone (n = 532) versus alpha-foetoprotein and ultrasound (n = 538) over a period of five years. This trial was designed as a pilot trial; the small number of participants and the rare events did not allow an effective comparison between the two modes of screening that were studied. The remaining trial, conducted in Taiwan and published as an abstract, was designed as a cluster randomised trial to determine the optimal interval for screening using alpha foetoprotein and ultrasound. Screening intervals of four months and 12 months were compared in the two groups. Further details about the screening strategy were not available. The trial reported on cumulative four-year survival, cumulative three-year incidence of hepatocellular carcinoma, and mean tumour size. The cumulative four-year survival was not significantly different between the two screening intervals. The incidence of hepatocellular cancer was higher in the four-monthly screening group. The included trials did not report on adverse events. It appears that the sensitivity and specificity of the screening modes were poor, accounting for a substantial number of false-positive and false-negative screening results.