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


This pilot study demonstrates for the first time the feasibility of implementing the WHO protocol to obtain empirical data on HBV and HCV aetiological fractions among patients with cirrhosis and/or HCC. This was achieved in three volunteering sites (clinics/hospitals) located in three European countries. The pilot clearly highlighted that the process is more complex than it initially appears, consuming significant time and human resources, as mentioned by each specific site. In order to implement the protocol more broadly, there is therefore a need for simplification and also for a better standardisation of procedures.

Interestingly, some of the findings were not very different from the estimates published in GBD, despite of differences in the ICD-10 codes used to define cirrhosis and/or HCC. However, a key limitation of the results presented here is that these represent a simple descriptive analysis of the data where the proportion of HCV and HBV infection in consecutive cirrhotic and HCC patients would be used as estimates of attributable fraction of mortality from these diseases. This simple method might be easier to justify for HCC (where the survival is very low) than for cirrhotic patients, as many cirrhotic patients (mainly those with compensated cirrhosis) do not die at the cirrhotic stage and may slowly progress to HCC. To infer the mortality attributable fractions from cirrhosis attributable fractions, further analysis is needed, for example to differentiate between compensated and decompensated patients, and to take into account interactions between multiple risk factors, such as the strong interaction of alcohol with viral hepatitis. It should be noted, that the IARC 2018 HCC estimates[4] are the results of a meta-analysis of representative studies published from 2000 to 2014 and rely on studies of variable quality, with limited data in many countries. Future collection of data using an updated protocol that minimises bias would increase the accuracy of pooled estimates, point out important differences between countries and better inform incidence and mortality modelling. The results obtained from the current pilot study—and future comparable studies—provide empirical data that are important to monitor the burden of mortality from viral hepatitis sequelae in a given country and help better calibrate mortality modelling by the GBD.

The prevalence distribution of HBV and HCV among cases of cirrhosis showed that in Norway and Portugal, HCV was responsible for about one-quarter of the cases, whereas in Bulgaria, HBV was more common. Similar results were observed for HCC, where HCV was responsible for more than one-third of cases in Norway and Portugal, while in Bulgaria HBV was more frequent. The differences observed between the countries may be due to many country-specific factors: for example the main routes of transmission, history of the HBV and HCV epidemics, time and scope of HBV vaccine implementation or age distribution of the chronically infected patients susceptible to evolve towards sequalae. The predominance of HBV seen for both cirrhosis and HCC in Bulgaria relates to the high levels of prevalence of HBV in the general population compared to HCV[18] (see Table 2). Interestingly, in Portugal, prevalence of HBV was also higher than HCV,[19] but less prevalent than in Bulgaria. Differences between the countries in alcohol consumption and obesity (see Table 2) are also likely to have an impact on AFs.

As expected, the contribution of viral hepatitis as aetiological factor was more significant in HCC than in cirrhosis. In fact, previous studies have shown that heavy alcohol consumption is frequent at the cirrhotic stage, especially in Europe,[20] which could explain the low proportion of other aetiologies, in particular HBV and HCV. Previous studies have also shown that compared to other aetiologies, cirrhosis associated with viral hepatitis increases the risk for the development of HCC, and among them, HBV has the higher risk.[21]

During the pilot study, each of the sites adapted the protocol to fit their local setting and this led to some differences in the methodological approaches. This provides an opportunity to assess these differences and to learn lessons to help refine and simplify the protocol.

  1. One of the main differences relates to the data collection including either exclusively hospitalised patients, or hospitalised plus ambulatory patients, as was the case in Portugal, and in Norway/Bulgaria, respectively. A previous study has found that patients who are admitted to hospital often have different aetiological and severity profile compared to ambulatory patients.[23] In fact, countries may have differences in the policies of referral to specialised ambulatory care of patients with liver disease; for example, ALD patients tend to be followed by the general practitioner, while viral hepatitis patients are more frequently referred to hospital care, due to the availability of specific treatments. This of course may result in significant bias, and the interpretation of the findings should take this potential bias into account based on a local assessment of the referral patterns for patients. As the main aim is to evaluate what is the attributable fraction of viral hepatitis in patients dying from cirrhosis and HCC, the hospitalised patients represent the more reliable source of data. In fact, decompensated cases are likely to provide a closer proxy to the aetiological factors for deaths from cirrhosis and should be used where local numbers allow. To harmonise practice and enable comparison across countries, the inclusion of patients who are admitted to hospital only should be preferred, a separate analysis of compensated and decompensated patients is encouraged.

  2. A further source of bias could be the selection of the pilot site itself, with likely differences in the populations presenting to the different types of centres. Although this was not formally assessed during the pilot study, the investigators in one site based at a tertiary centre considered the sample of patients included as potentially not representative of the population of patients with cirrhosis or HCC. The future selection of sentinel sites should include a prior assessment of the underlying characteristics of patients attending the site through discussion with local clinicians to understand whether there is likely to be any major source of bias and consideration given to collecting data from all hospital departments and across different clinical sites, including for example, patients from a tertiary and a secondary hospital. The selection of patients in hospitals from specialties other than hepatology and gastroenterology is important as patients with cirrhosis or HCC may present with a range of other non-hepatitis complications.

  3. A further issue relates to the bias associated with inclusion of patients identified through liver transient elastography. Many patients with compensated cirrhosis were only identified by transient elastometry, with this method developed to assess stage of liver disease in patients with chronic hepatitis C and used presumably most often in this patient group. Thus, among those with compensated cirrhosis the frequency of HCV as aetiology is probably overestimated. Consequently, it is suggested that in order to get a more realistic picture of the distribution of the aetiological factors in the chronic liver diseases population, it might be better to include only the cases of HCC and cirrhosis that are already decompensated, or newly diagnosed cases of cirrhosis. A focus on decompensated cirrhosis patients is further justified by the aim of the study to estimate AF for mortality estimates and few patients die from compensated cirrhosis.

  4. In each of the pilot sites, the number of patients included in the sample was a pragmatic sample size and there were no local sample size calculations undertaken based on expected risk factors prevalence. One of the sites opted for a fixed number of patients and the other two included all patients over a period of time. Ideally, the sample size should be assessed in advance of the study based on a straightforward sample size calculation which needs to be considered alongside available resources. The other possibility would be to use time frames, shorter than one year, in a cyclic fashion.

  5. Challenges with inconsistent use of ICD coding with sites using different codes. The problem with coding was a particular issue for cases of HCC—many patients with metastatic cancer arising from other primary sites in the body being coded as HCC. This was not an issue in one of the sites, as all patients that did not match the EASL covering diagnostic criteria for HCC, or had concomitant malignancy or a history of malignant disease, and no substantial contraindication for liver biopsy had an image-guided liver biopsy performed. In relation to cirrhosis, the situation is also complicated as some patients with cirrhosis, for example based on the radiology description, were not coded as such and would not be included if a smaller selection of ICD coding was used. Another issue is the difficulty in obtaining detailed information on alcohol consumption (self-reported) what could lead to understatement of alcoholic component. Although we acknowledge it as a problem, most clinicians are able to identify a history of harmful alcohol consumption, that is usually reflected in the coding diagnosis.

The description and discussion of the findings of this pilot study of a standardised methodological approach to produce estimates of viral hepatitis was able to show how challenging it can be to obtain this simple information. The different methodologies used in pilot sites were useful to compare different strategies. Because of the prioritisation of aetiological causes of cirrhosis and HCC, which was decided ahead of the pilot (with viral causes placed ahead of other causes), the results should be interpreted with caution. This simple and fairly crude approach will be further complicated in the future with increasing numbers of cured HCV patients (HCV-RNA negative) still progressing to HCC.[24] We recognise that more advanced regression analyses that take into account all the different aetiological factors are preferable to our simple approach and future work will be conducted to determine the optimal analyses of such data.

Following the evaluation of the pilot study the next steps will be (1) to undertake further detailed analysis of the data to account for the interaction of other factors, (2) to revise and simplify the protocol and (3) to engage other countries to help derive more country-specific estimates of hepatitis mortality. From the results of this pilot, and in order to increase the feasibility of creating sentinel centres to support the collection of data, we propose the following:

a. Sentinel centres carefully chosen to minimise referral bias and to ensure periodical collection of data over the years in order to capture changes happening because of treatment or the course of the epidemic.

b. Revised/simplified protocol which includes details relating to the best way of collating and collecting data to avoid duplication and optimise the time of the field collaborators.

c. Prospective collection of data

d. Inclusion of the following ICD codes: K74.3, K74.5, K74.4, K.74.6, K74.0 –K74.2 for cirrhosis and C22.0 for HCC, as per WHO protocol to ensure consistency and comparability.

e. Sample size to be defined based on expected prevalence.

f. Significant reduction of the data set, to include basic variables:

   i. HCC; cirrhosis

   ii. age

   iii. sex

   iv. HCV and HBV markers antibodies, and viral load if positive

   v. Harmful alcohol consumption

   vi. Presence of obesity and diabetes

   vii. Other causes of liver disease

In conclusion, the pilot demonstrated the feasibility of collecting data on the prevalence of HBV and HCV infection among patients with cirrhosis and HCC that can be used to estimate mortality attributable to HBV and HCV for monitoring progress towards hepatitis elimination. Sentinel studies are a good way to empower countries, collectt up-to-date data and closely monitor the changes in the attributable fraction at a country level, while allowing validation of statistical models to predict future changes. Further consideration should be given to the representativeness of samples collected from reference centres, the underlying assumptions of the methodological approach, and to the relative risk of dying from HCC and cirrhosis among patients with chronic HBV and HCV infections.