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Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Hepatocellular Carcinoma | Research article

Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts

Authors: Myriam Alexander, A. Katrina Loomis, Johan van der Lei, Talita Duarte-Salles, Daniel Prieto-Alhambra, David Ansell, Alessandro Pasqua, Francesco Lapi, Peter Rijnbeek, Mees Mosseveld, Dawn M. Waterworth, Stuart Kendrick, Naveed Sattar, William Alazawi

Published in: BMC Medicine | Issue 1/2019

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Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls.

Methods

Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 “non-NAFLD” patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses.

Results

Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43–9.19) and for HCC, 3.51 (95% CI 1.72–7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes.

Conclusions

Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk.
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Literature
1.
go back to reference Friedman SL, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22.CrossRef Friedman SL, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22.CrossRef
2.
go back to reference Dyson J, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110–7.CrossRef Dyson J, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110–7.CrossRef
3.
go back to reference Mittal S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31 e1.CrossRef Mittal S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31 e1.CrossRef
4.
go back to reference Wong RJ, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55.CrossRef Wong RJ, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55.CrossRef
5.
go back to reference Koehler EM, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol. 2012;57(6):1305–11.CrossRef Koehler EM, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol. 2012;57(6):1305–11.CrossRef
6.
go back to reference Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595–602.CrossRef Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595–602.CrossRef
7.
go back to reference Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.CrossRef Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.CrossRef
8.
go back to reference Nunez, D.J., et al., Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol. 2019;316(3):G372–86. Nunez, D.J., et al., Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol. 2019;316(3):G372–86.
9.
go back to reference McPherson S, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.CrossRef McPherson S, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.CrossRef
10.
go back to reference Alexander M, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16(1):130.CrossRef Alexander M, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16(1):130.CrossRef
11.
go back to reference Vargas-Santos AB, et al. Association of Chronic Kidney Disease with Allopurinol use in gout treatment. JAMA Intern Med. 2018;178(11):1526–33.CrossRef Vargas-Santos AB, et al. Association of Chronic Kidney Disease with Allopurinol use in gout treatment. JAMA Intern Med. 2018;178(11):1526–33.CrossRef
12.
go back to reference Kringos D, et al. The strength of primary care in Europe: an international comparative study. Br J Gen Pract. 2013;63(616):e742–50.CrossRef Kringos D, et al. The strength of primary care in Europe: an international comparative study. Br J Gen Pract. 2013;63(616):e742–50.CrossRef
13.
go back to reference Gini R, et al. Chronic disease prevalence from Italian administrative databases in the VALORE project: a validation through comparison of population estimates with general practice databases and national survey. BMC Public Health. 2013;13:15.CrossRef Gini R, et al. Chronic disease prevalence from Italian administrative databases in the VALORE project: a validation through comparison of population estimates with general practice databases and national survey. BMC Public Health. 2013;13:15.CrossRef
14.
go back to reference Vlug AE, et al. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med. 1999;38(4–5):339–44.PubMed Vlug AE, et al. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med. 1999;38(4–5):339–44.PubMed
15.
go back to reference Garcia-Gil Mdel M, et al. Construction and validation of a scoring system for the selection of high-quality data in a Spanish population primary care database (SIDIAP). Inform Prim Care. 2011;19(3):135–45.PubMed Garcia-Gil Mdel M, et al. Construction and validation of a scoring system for the selection of high-quality data in a Spanish population primary care database (SIDIAP). Inform Prim Care. 2011;19(3):135–45.PubMed
16.
go back to reference Blak BT, et al. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care. 2011;19(4):251–5.PubMed Blak BT, et al. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care. 2011;19(4):251–5.PubMed
17.
go back to reference Filippi A, et al. Computerized general practice databases provide quick and cost-effective information on the prevalence of angina pectoris. Ital Heart J. 2005;6(1):49–51.PubMed Filippi A, et al. Computerized general practice databases provide quick and cost-effective information on the prevalence of angina pectoris. Ital Heart J. 2005;6(1):49–51.PubMed
19.
go back to reference Alazawi W, et al. Ethnicity and the diagnosis gap in liver disease: a population-based study. Br J Gen Pract. 2014;64(628):e694–702.CrossRef Alazawi W, et al. Ethnicity and the diagnosis gap in liver disease: a population-based study. Br J Gen Pract. 2014;64(628):e694–702.CrossRef
20.
go back to reference Patel PJ, et al. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis. Intern Med J. 2018;48(2):144–51.CrossRef Patel PJ, et al. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis. Intern Med J. 2018;48(2):144–51.CrossRef
21.
go back to reference Standing HC, et al. GPs' experiences and perceptions of early detection of liver disease: a qualitative study in primary care. Br J Gen Pract. 2018;68(676):e743–9.CrossRef Standing HC, et al. GPs' experiences and perceptions of early detection of liver disease: a qualitative study in primary care. Br J Gen Pract. 2018;68(676):e743–9.CrossRef
22.
go back to reference Singh S, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643–54 e9.CrossRef Singh S, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643–54 e9.CrossRef
23.
go back to reference Boursier J, et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol. 2016;65(3):570–8.CrossRef Boursier J, et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol. 2016;65(3):570–8.CrossRef
24.
go back to reference Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–54.CrossRef Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–54.CrossRef
25.
go back to reference Younossi ZM, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. Hepatol Commun. 2017;1(5):421–8.CrossRef Younossi ZM, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. Hepatol Commun. 2017;1(5):421–8.CrossRef
26.
go back to reference De Silva S, et al. Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of south Asian descent. Frontline Gastroenterol. 2018;9(2):115–21. De Silva S, et al. Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of south Asian descent. Frontline Gastroenterol. 2018;9(2):115–21.
27.
go back to reference Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.CrossRef Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.CrossRef
28.
go back to reference European Association for the Study of the Liver European Association for the Study of Diabetes European Association for the Study of, O. EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402.CrossRef European Association for the Study of the Liver European Association for the Study of Diabetes European Association for the Study of, O. EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402.CrossRef
29.
go back to reference Newsome PN, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6–19.CrossRef Newsome PN, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6–19.CrossRef
30.
go back to reference Hassan MM, et al. Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma. Gastroenterology. 2015;149(1):119–29. Hassan MM, et al. Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma. Gastroenterology. 2015;149(1):119–29.
Metadata
Title
Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts
Authors
Myriam Alexander
A. Katrina Loomis
Johan van der Lei
Talita Duarte-Salles
Daniel Prieto-Alhambra
David Ansell
Alessandro Pasqua
Francesco Lapi
Peter Rijnbeek
Mees Mosseveld
Dawn M. Waterworth
Stuart Kendrick
Naveed Sattar
William Alazawi
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1321-x

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