Reply to “Hepatocellular carcinoma and the Newcastle-upon-Tyne area”
Authors: Quentin M. Anstee, Bryan Jaques, Mark Hudson, Helen L. Reeves
Journal: Journal of Hepatology (2014)

Hepatocellular carcinoma and the Newcastle-upon-Tyne areaJournal of HepatologyVol. 60Issue 6PreviewThe cross sectional studies of hepatocellular carcinoma (HCC) in the Newcastle-upon-Tyne area may need further clarifications by the authors [1]. Full-Text PDF Open AccessHepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary teamJournal of HepatologyVol. 60Issue 1PreviewHepatocellular cancer (HCC) commonly complicates chronic liver disease and increases in incidence have been reported despite falling prevalences of viral hepatitis. Full-Text PDF We thank Dr Braillon for drawing attention to our recent study describing the increase in hepatocellular cancer (HCC) related mortality in the decade following the introduction of the National Health Service 'Cancer Plan 2000'. Firstly, the reported increase in mortality was based on factual data for our region, provided by Public Health Englands' North of England Cancer Networks Knowledge and Intelligence team (Northern and Yorkshire) (NYCRIS) (http://www.nycris.nhs.uk). This region is defined by the North East of England, Cumbria, and North Yorkshire and has a stable population of approximately 3 million. Actual deaths per annum attributed to HCC were 62 at the start of the decade, vs. 111 at the end – an increase of 1.8-fold. Dr Braillon points out this increase was higher than age-standardised incidence rates in England, which we have suggested may reflect regional differences in the prevalence of obesity and type 2 diabetes [[1]Dyson J. Jaques B. Chattopadyhay D. Lochan R. Graham J. Das D. et al.Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.J Hepatol. 2014; 60: 110-117Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar].We agree that improved means of HCC detection, as well as advances in therapeutic options, should have an impact on mortality. Earlier diagnosis is more likely for patients with known cirrhosis undergoing regular surveillance and certainly our study confirmed better outcomes for those individuals with HCC detected at an earlier stage. The majority (>70%) however, presented with symptomatic disease, staged as C or D according to the Barcelona Clinic for Liver Cancer (BCLC) system [[2]NHS Blood and Transplant Liver Advisory Group. Protocols and guidelines for adults undergoing deceased donor liver transplantation in the UK. In: NHS, editor. http://www.organdonation.nhs.uk; 2009.Google Scholar]. These patients were unsuitable for ablative therapies. Sorafenib will likely have an impact for those with BCLC – C disease (44.9% in our cohort), but this medical treatment only became available in England in 2010 [[1]Dyson J. Jaques B. Chattopadyhay D. Lochan R. Graham J. Das D. et al.Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.J Hepatol. 2014; 60: 110-117Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Any impact was not apparent in the cohort presenting between 2000 and 2010.Dr Braillon has also raised the important issue of smoking and HCC. While smoking prevalence is reportedly higher in the North of England, it should also be recognised that it has fallen in all regions, including the North, over the decade in which a rise in HCC mortality has been documented [[3]Public Health England. The prevalence of smoking in the North East. Update 2012. http://wwwnephoorguk/publications/1031/The_Prevalence_of_Smoking_in_the_North_East.Google Scholar]. However, these data are of interest and were not reported in our cohort because we did not wish to over interpret our relatively small series – a full smoking history was not prospectively collected in every case and an appropriate age and liver disease matched control population for comparison was not available. Data was collected in 425/629 cases and we are pleased to have the opportunity to share it. The smoking prevalence in our region was ∼20% in 2009–2010 [[3]Public Health England. The prevalence of smoking in the North East. Update 2012. http://wwwnephoorguk/publications/1031/The_Prevalence_of_Smoking_in_the_North_East.Google Scholar]. This was not different to that observed in our HCC cohort in the years 2009–2010 (20–21%), although this too had fallen across the decade. Of relevance, the recent 'Integrated Health Survey' reported by Public Health England [[4]Public Health England. Smoking prevalence among adults aged 18+ by region and local authority. Data from the integrated household survey on smoking prevalence, updated as at 10 October 2012. http://wwwlhoorguk/viewResourceaspx?id=16678.Google Scholar] revealed that smoking was much less common (11–12%) in those over the age of 65 years – an age more in keeping with the age of our cohort. The decline with age was attributed both to successful quitting and death. The prevalence of smoking in our entire cohort (26%, as summarised in Table 1) and in 2010 (20%) was clearly higher than this. Table 1 presents data by etiology, with additional significant differences observed (p = 0.029, χ2). Current smoking was particularly high in cases with HBV related HCC (46%), as well as being higher in those individuals without underlying chronic liver disease (31%). Notably, there was no increase in those with NAFLD related HCC (11%). Similarly, while current smokers in the whole cohort did present at a younger age (63.4 years) compared to those who had never smoked (68.0) or who were ex-smokers (69.5), this was not apparent in those with NAFLD related HCC (current smokers 70.3; never smoked 68.0; ex smokers 71.9). While the published literature clearly indicates that smoking is an important risk factor for HCC, it was unlikely to have been a key contributor to the increase observed in our region. Moreover, it was not an obvious co-factor in our own small series of patients with NAFLD related HCC.Table 1The prevalence of smoking in patients with HCC in Northern England.Data are presented as percentages.CLD, chronic liver disease; ALD, alcoholic liver disease; NAFLD, non-alcoholic fatty liver disease; HCV, hepatitis C virus; HBV, hepatitis B virus; Haem, haemochromatosis; Crypt, cryptogenic cirrhosis; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis.Cases in category 'other' included 3 with α-1-antitrypsin deficiency, 1 with primary sclerosing cholangitis, and 1 with congenital heart disease/cardiac cirrhosis. Open table in a new tab Finally, Dr Braillon has also questioned NAFLD as an entity in its own right, pointing out that liver disease per se can produce insulin resistance and suggesting that obesity is not necessarily an independent cause of chronic liver disease. We agree that obesity and type 2 diabetes are likely contributors to progression of chronic liver disease irrespective of the primary underlying cause. However, contrary to some early reports, there are now a substantial number of large series presenting the evidence for NAFLD and its risk of progression [5Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (1755) Google Scholar, 6Younossi Z.M. Gramlich T. Matteoni C.A. Boparai N. McCullough A.J. Nonalcoholic fatty liver disease in patients with type 2 diabetes.Clin Gastroenterol Hepatol. 2004; 2: 262-265Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 7Musso G. Gambino R. Cassader M. Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Ann Med. 2011; 43: 617-649Crossref PubMed Scopus (887) Google Scholar], as recently reviewed [[8]Anstee Q.M. Targher G. Day C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.Nat Rev Gastroenterol Hepatol. 2013; 10: 330-344Crossref PubMed Scopus (1046) Google Scholar]. In our own cohort, patients classed as having NAFLD were men or women with evidence of a fatty liver on biopsy or imaging, with an otherwise negative liver screen, drinking <21 or 14 units of alcohol per week respectively for at least 5 years prior to their first presentation with liver disease.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We thank Dr Braillon for drawing attention to our recent study describing the increase in hepatocellular cancer (HCC) related mortality in the decade following the introduction of the National Health Service 'Cancer Plan 2000'. Firstly, the reported increase in mortality was based on factual data for our region, provided by Public Health Englands' North of England Cancer Networks Knowledge and Intelligence team (Northern and Yorkshire) (NYCRIS) (http://www.nycris.nhs.uk). This region is defined by the North East of England, Cumbria, and North Yorkshire and has a stable population of approximately 3 million. Actual deaths per annum attributed to HCC were 62 at the start of the decade, vs. 111 at the end – an increase of 1.8-fold. Dr Braillon points out this increase was higher than age-standardised incidence rates in England, which we have suggested may reflect regional differences in the prevalence of obesity and type 2 diabetes [[1]Dyson J. Jaques B. Chattopadyhay D. Lochan R. Graham J. Das D. et al.Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.J Hepatol. 2014; 60: 110-117Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. We agree that improved means of HCC detection, as well as advances in therapeutic options, should have an impact on mortality. Earlier diagnosis is more likely for patients with known cirrhosis undergoing regular surveillance and certainly our study confirmed better outcomes for those individuals with HCC detected at an earlier stage. The majority (>70%) however, presented with symptomatic disease, staged as C or D according to the Barcelona Clinic for Liver Cancer (BCLC) system [[2]NHS Blood and Transplant Liver Advisory Group. Protocols and guidelines for adults undergoing deceased donor liver transplantation in the UK. In: NHS, editor. http://www.organdonation.nhs.uk; 2009.Google Scholar]. These patients were unsuitable for ablative therapies. Sorafenib will likely have an impact for those with BCLC – C disease (44.9% in our cohort), but this medical treatment only became available in England in 2010 [[1]Dyson J. Jaques B. Chattopadyhay D. Lochan R. Graham J. Das D. et al.Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.J Hepatol. 2014; 60: 110-117Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Any impact was not apparent in the cohort presenting between 2000 and 2010. Dr Braillon has also raised the important issue of smoking and HCC. While smoking prevalence is reportedly higher in the North of England, it should also be recognised that it has fallen in all regions, including the North, over the decade in which a rise in HCC mortality has been documented [[3]Public Health England. The prevalence of smoking in the North East. Update 2012. http://wwwnephoorguk/publications/1031/The_Prevalence_of_Smoking_in_the_North_East.Google Scholar]. However, these data are of interest and were not reported in our cohort because we did not wish to over interpret our relatively small series – a full smoking history was not prospectively collected in every case and an appropriate age and liver disease matched control population for comparison was not available. Data was collected in 425/629 cases and we are pleased to have the opportunity to share it. The smoking prevalence in our region was ∼20% in 2009–2010 [[3]Public Health England. The prevalence of smoking in the North East. Update 2012. http://wwwnephoorguk/publications/1031/The_Prevalence_of_Smoking_in_the_North_East.Google Scholar]. This was not different to that observed in our HCC cohort in the years 2009–2010 (20–21%), although this too had fallen across the decade. Of relevance, the recent 'Integrated Health Survey' reported by Public Health England [[4]Public Health England. Smoking prevalence among adults aged 18+ by region and local authority. Data from the integrated household survey on smoking prevalence, updated as at 10 October 2012. http://wwwlhoorguk/viewResourceaspx?id=16678.Google Scholar] revealed that smoking was much less common (11–12%) in those over the age of 65 years – an age more in keeping with the age of our cohort. The decline with age was attributed both to successful quitting and death. The prevalence of smoking in our entire cohort (26%, as summarised in Table 1) and in 2010 (20%) was clearly higher than this. Table 1 presents data by etiology, with additional significant differences observed (p = 0.029, χ2). Current smoking was particularly high in cases with HBV related HCC (46%), as well as being higher in those individuals without underlying chronic liver disease (31%). Notably, there was no increase in those with NAFLD related HCC (11%). Similarly, while current smokers in the whole cohort did present at a younger age (63.4 years) compared to those who had never smoked (68.0) or who were ex-smokers (69.5), this was not apparent in those with NAFLD related HCC (current smokers 70.3; never smoked 68.0; ex smokers 71.9). While the published literature clearly indicates that smoking is an important risk factor for HCC, it was unlikely to have been a key contributor to the increase observed in our region. Moreover, it was not an obvious co-factor in our own small series of patients with NAFLD related HCC. Data are presented as percentages. CLD, chronic liver disease; ALD, alcoholic liver disease; NAFLD, non-alcoholic fatty liver disease; HCV, hepatitis C virus; HBV, hepatitis B virus; Haem, haemochromatosis; Crypt, cryptogenic cirrhosis; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis. Cases in category 'other' included 3 with α-1-antitrypsin deficiency, 1 with primary sclerosing cholangitis, and 1 with congenital heart disease/cardiac cirrhosis. Finally, Dr Braillon has also questioned NAFLD as an entity in its own right, pointing out that liver disease per se can produce insulin resistance and suggesting that obesity is not necessarily an independent cause of chronic liver disease. We agree that obesity and type 2 diabetes are likely contributors to progression of chronic liver disease irrespective of the primary underlying cause. However, contrary to some early reports, there are now a substantial number of large series presenting the evidence for NAFLD and its risk of progression [5Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (1755) Google Scholar, 6Younossi Z.M. Gramlich T. Matteoni C.A. Boparai N. McCullough A.J. Nonalcoholic fatty liver disease in patients with type 2 diabetes.Clin Gastroenterol Hepatol. 2004; 2: 262-265Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 7Musso G. Gambino R. Cassader M. Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Ann Med. 2011; 43: 617-649Crossref PubMed Scopus (887) Google Scholar], as recently reviewed [[8]Anstee Q.M. Targher G. Day C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.Nat Rev Gastroenterol Hepatol. 2013; 10: 330-344Crossref PubMed Scopus (1046) Google Scholar]. In our own cohort, patients classed as having NAFLD were men or women with evidence of a fatty liver on biopsy or imaging, with an otherwise negative liver screen, drinking <21 or 14 units of alcohol per week respectively for at least 5 years prior to their first presentation with liver disease. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.