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


Methodological Approaches (Protocol and Data Collection)

The protocol was developed by WHO and reviewed by experts at ECDC and in the three pilot sites (in Bulgaria, Norway and Portugal). The three pilot sites were selected based on their willingness and availability to undertake the pilot rather than any formal assessment of national representativeness:

  • Bulgaria—Department of Clinic of Gastroenterology, Hepato-Biliary—Pancreatic and transplant surgery, Intensive Care Clinic, Military Medical Academy (MMA), Sofia;

  • Norway—Akershus University Hospital, Oslo; and

  • Portugal—Clínica Universitária de Gastrenterologia, Centro Hospitalar e Universitário Lisboa, Norte, Faculdade de Medicina, Universidade de Lisboa, Lisbon.

Minor adjustments were made to adapt the protocol due to the differences between the healthcare settings.

Each of the protocol sites was invited to retrospectively collect data for patients first admitted or seen as an outpatient for the first time in the reference hepatology or gastroenterology centres during the year 2016. Each centre was asked to include either[1] all cases that met the case definition during 2016, or[2] the first hundred consecutive cases diagnosed with cirrhosis (irrespective of decompensation status) and/or HCC. The local differences in the methodological approaches in the pilot sites are summarized in Appendix.

The project was approved by each of the local Ethics Committees. All patient identifiable data were anonymised.

Patients with cirrhosis or HCC were identified through various means including searching patient files using criteria defined by the WHO protocol (see text Box 1) or searching healthcare databases using ICD-10 codes. Investigators in the pilot sites selected the patient identification method that best suited the local situation. In all sites, it was agreed in advance that patients diagnosed with both cirrhosis and HCC at their first visit or admission would be classified as HCC and patients with multiple admissions would be included only once.

Information on patients was extracted following a standardised case report form (Appendix). Extracted data included demographic characteristics such as age and sex; data related to the diagnosis of cirrhosis and HCC; and data on exposure including HBV, HDV and HCV infection status, alcohol intake and metabolic syndrome components (e.g. diabetes). Other clinical and biochemical data were also collected (see, Appendix). All data were obtained from the files developed as part of the routine care of the patients with cirrhosis or HCC, with no additional data collected for the only purpose of the pilot study.

In patients with cirrhosis and/or HCC, HBsAg and anti-HCV antibodies were considered markers of HBV and HCV chronic infection, respectively. In patients with both HBV and HCV markers, HBV-DNA and HCV-RNA were used to define an active infection. In all centres, it was decided that patients that were both HBV-DNA and HCV-RNA positive would be considered to have their liver disease attributable to HCV, as this virus was considered to be more amenable to curative treatment. Information on other potential risk factors including heavy alcohol consumption (defined using local clinician criteria), diabetes and dyslipidaemia (risk factors for NAFLD) was also collected, when available. If patients were negative for HBV and HCV, these other risk factors were considered the main cause of cirrhosis or HCC. If patients were HBV and/or HCV positive, it was agreed in advance through consensus of the participating centres that viral hepatitis should be considered the main cause of cirrhosis or HCC, and any other risk factors as associated risk factors.

Electronic databases were created in each centre to collate data from each case. Aggregated results were shared with ECDC for further analysis. The proportion of patients with cirrhosis and HCC who tested positive for HBV and HCV were calculated to estimate the AF (see text Box 2). This approach replicates that described by Perz et al [15] and is considered acceptable due to the strength of the association between HBV and/or HCV infection and cirrhosis and/or HCC. If the relative risk (RR) is large, the attributable fraction among exposed (RR-1/RR) is close to 100% and the attributable fraction in the population (Pe x[RR-1/RR]) is close to the proportion of the population exposed (Pe).

Qualitative Assessment of Pilot Roll-out

After the pilot study was completed, each site was asked about the feasibility and acceptability of the protocol, and a basic reporting form was used to collect the actual methodological approaches taken by the country, —especially where they differed from the protocol (see Table A1). Collaborators in each centre were also asked about concrete measures to simplify the protocol in future studies.

Validity Assessment of AF Estimates

The results on the attributable fraction estimates obtained through the pilot were compared to data published by the GBD project[17] and results from a meta-analysis conducted by the International Agency for Research on Cancer (IARC).[4]