Estimating the Attributable Fraction of Cirrhosis and Hepatocellular Carcinoma Due to Hepatitis B and C

Erika Duffell; Helena Cortez-Pinto; Marieta Simonova; Olav Dalgard; Elin Hoffmann Dahl; Catherine de Martel; Antons Mozalevskis; Maria Buti; Slava Pavlova; Tnaiq Hadzhilova; Carolina Simões; Krum Katzarov; Otilia Mardh


J Viral Hepat. 2021;28(8):1177-1189. 

In This Article


Viral hepatitis is a major cause of morbidity and mortality worldwide, especially those due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.[1,2] With the launch in 2015 of the World Health Organization's (WHO) Global Health Sector Strategy on Viral Hepatitis 2016–2021, the elimination of hepatitis due to HBV and HCV infection has become a key public health objective.[3] In the WHO strategy, elimination of hepatitis as a public threat was defined as a 90% reduction in the incidence of new chronic infections and a 65% reduction in the attributable mortality by 2030. The monitoring of key indicators as defined by WHO is crucial to follow-up progress towards the elimination goals.

Following decades of chronic infection, deaths related to HBV and HCV infections are mostly due to decompensated cirrhosis and hepatocellular carcinoma (HCC). However, these severe diseases may also be caused by other factors, for example alcohol; metabolic risk factors including diabetes, obesity and arterial hypertension, which together cause non-alcoholic fatty liver disease (NAFLD), and other rarer conditions. Measuring mortality attributable to chronic viral hepatitis is challenging for several reasons. Mortality data associated with chronic liver disease are prone to misclassification, under-reporting and differences in coding practices that exist between countries, and these caveats make trends and aetiological comparisons difficult to undertake.[4] Moreover, death certificates from patients with cirrhosis or HCC often do not capture the underlying disease, including viral hepatitis.[5]

Many European countries in recent years have witnessed some changes in the major aetiologies of cirrhosis and HCC. There has been an overall decrease in viral hepatitis-related cirrhosis and HCC, especially for decompensated cirrhotic patients, probably due to the availability of effective treatment of HCV and HBV, while NAFLD and alcohol-related liver disease (ALD) are increasing.[6,7] In a recent publication commissioned by EASL (HEPAHEALTH), prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in northern European countries, and viral hepatitis epidemics in eastern and southern European countries.[8] The reasons for the changes in NAFLD/ALD are complex and include various factors such as an increase in disease burden or changes in the diagnosis and treatment of these conditions, but highlight a need to accurately monitor the aetiological fractions to better understand the local situation.[9]

In recent years, WHO has suggested a simple and pragmatic approach to estimate hepatitis-related mortality, which combines the number of deaths from cirrhosis and HCC (derived from vital registration systems and cancer registries) with attributable fractions (AFs) obtained from published representative case series.[10] The Global Burden of Disease project (GBD), in the absence of robust and country-specific data on attributable fractions, uses statistical modelling with many different input variables to estimate global mortality due to chronic HBV and HCV infections worldwide and at the country level.[11,12] Both approaches require robust and up-to-date empirical data of the aetiological fractions in cirrhosis and HCC representative patient series, but these are lacking from many European countries. To address this gap, WHO developed a protocol to support countries in implementing simple studies to obtain these data.[13] The protocol provides a standardised method to be used in sentinel centres (e.g. hepatology or gastroenterology units) to estimate the proportion of patients with cirrhosis and HCC that have HBV and HCV infection.

The European Centre for Disease Prevention and Control (ECDC) and the European Association for the Study of the Liver (EASL) worked in collaboration with WHO Regional Office for Europe to adapt the protocol to the European setting and pilot the protocol in selected sites in three European Union and European Economic Area (EU/EEA) countries.

The primary aim of the pilot study is to assess the feasibility and acceptability of the methodological approach outlined in the protocol in different settings and to propose improvements in the protocol. While the protocol also allows the collection of data on other risk factors, such as metabolic factors or heavy alcohol consumption, this paper focuses on HBV and HCV results. The secondary aim of the pilot study is to discuss the validity of the aetiological fraction of cirrhosis and HCC due to HBV and HCV systematically reported in three different centres.