Re: Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study
The extensively studied cohort from the Third National Health and Nutrition Examination Survey has yielded a unique population-based study on non-alcoholic fatty liver disease (NAFLD) and its effects on mortality. Interestingly, Lazo and colleagues found no link between NAFLD and all cause, cardiovascular-, cancer-, or liver-related mortality. Numerous other studies have found such links, especially when the advanced stages of the disease (bridging fibrosis/cirrhosis) are considered (1). The authors explain how these differences could have arisen due to different study designs, settings and patient selection. They also identify three studies that have used similar methods and study population to themselves, but reached different conclusions as the definition of NAFLD varied between each. The current gold-standard for diagnosis and staging of NAFLD remains liver biopsy, but due to multiple factors (cost, safety, sampling error) cannot be justified in the vast majority of these patients. Therefore, research studies and, by extension, physicians use a combination of demographic, biochemical and ultrasonic factors. It is this eclectic use of known indicators that results in very different conclusions being drawn by similar studies. To aid diagnosis in primary and secondary care, and to synchronise research, a firm definition of NAFLD is long overdue.
Further explanations for their reduced estimate of mortality are the limitations of ultrasound scanning (USS) and the fact that advanced liver fibrosis was not considered in the analysis, which is a key correlate with mortality in previous studies (2). Although USS is the most readily available/cost-effective imaging tool available in population-based studies, the difficulty in detecting the presence of fatty liver with this modality is well reported in the morbidly obese (24% of Lazo cohort) and when the degree of fat infiltration is less than 33% of the hepatic content (3). Furthermore, biopsy reports have shown that liver fat content is lost towards the more advanced stages of NAFLD, with the resultant fibrotic tissue being undetectable on USS (3). In addition, advanced fibrosis can be associated with normal transaminases (4). It would be fascinating to see a repeat analysis that used an accepted algorithm for estimating fibrosis (i.e. NAFLD Fibrosis Score (2)) or the simpler proxy of AST:ALT ratio >0.8 (5), with subsequent mortality estimates of no liver fat versus advanced NAFLD Fibrosis. Previous prospective population-based studies, which have utilised non-invasive techniques (transient elastography (6), NAFLD Fibrosis Score (7)) and biopsy (8), have highlighted a prevalence of advanced fibrosis of 3.7% to 7.6% in image-confirmed NAFLD from community-based populations. If such rates were estimated in the Lazo cohort, this would enable a unique comparison of mortality rate between the presence and absence of advanced fibrosis secondary to NAFLD in the community.
David Arnold*
Matthew Armstrong**
Diarmaid Houlihan**
* Final Year Medical Student at Cardiff University Medical School, UK
** Wellcome Trust Clinical Research Fellow at Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, UK
1. Sanyal AJ. NASH: A global health problem. Hepatol Res. 2011 Jul;41(7):670-4.
2. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54.
3. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002 Sep;123(3):745-50.
4. Fracanzani, A. L., Valenti, L., Bugianesi, E., Andreoletti, M., Colli, A., Vanni, E., Bertelli, C., Fatta, E., Bignamini, D., Marchesini, G. and Fargion, S. (2008), Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes. Hepatology, 48: 792–798. doi: 10.1002/hep.22429
5. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010 Sep;59(9):1265-9.
6. Wong VW, Chu WC, Wong GL, Chan RS, Chim AM, Ong A, et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut. 2011 Aug 16.
7. Armstrong MJ, Houlihan DD, Bentham L, Shaw JC, Cramb R, Olliff S, et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J Hepatol. 2011 May 18.
8. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
Gastroenterology. 2011 Jan;140(1):124-31.
Rapid Response:
Re: Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study
The extensively studied cohort from the Third National Health and Nutrition Examination Survey has yielded a unique population-based study on non-alcoholic fatty liver disease (NAFLD) and its effects on mortality. Interestingly, Lazo and colleagues found no link between NAFLD and all cause, cardiovascular-, cancer-, or liver-related mortality. Numerous other studies have found such links, especially when the advanced stages of the disease (bridging fibrosis/cirrhosis) are considered (1). The authors explain how these differences could have arisen due to different study designs, settings and patient selection. They also identify three studies that have used similar methods and study population to themselves, but reached different conclusions as the definition of NAFLD varied between each. The current gold-standard for diagnosis and staging of NAFLD remains liver biopsy, but due to multiple factors (cost, safety, sampling error) cannot be justified in the vast majority of these patients. Therefore, research studies and, by extension, physicians use a combination of demographic, biochemical and ultrasonic factors. It is this eclectic use of known indicators that results in very different conclusions being drawn by similar studies. To aid diagnosis in primary and secondary care, and to synchronise research, a firm definition of NAFLD is long overdue.
Further explanations for their reduced estimate of mortality are the limitations of ultrasound scanning (USS) and the fact that advanced liver fibrosis was not considered in the analysis, which is a key correlate with mortality in previous studies (2). Although USS is the most readily available/cost-effective imaging tool available in population-based studies, the difficulty in detecting the presence of fatty liver with this modality is well reported in the morbidly obese (24% of Lazo cohort) and when the degree of fat infiltration is less than 33% of the hepatic content (3). Furthermore, biopsy reports have shown that liver fat content is lost towards the more advanced stages of NAFLD, with the resultant fibrotic tissue being undetectable on USS (3). In addition, advanced fibrosis can be associated with normal transaminases (4). It would be fascinating to see a repeat analysis that used an accepted algorithm for estimating fibrosis (i.e. NAFLD Fibrosis Score (2)) or the simpler proxy of AST:ALT ratio >0.8 (5), with subsequent mortality estimates of no liver fat versus advanced NAFLD Fibrosis. Previous prospective population-based studies, which have utilised non-invasive techniques (transient elastography (6), NAFLD Fibrosis Score (7)) and biopsy (8), have highlighted a prevalence of advanced fibrosis of 3.7% to 7.6% in image-confirmed NAFLD from community-based populations. If such rates were estimated in the Lazo cohort, this would enable a unique comparison of mortality rate between the presence and absence of advanced fibrosis secondary to NAFLD in the community.
David Arnold*
Matthew Armstrong**
Diarmaid Houlihan**
* Final Year Medical Student at Cardiff University Medical School, UK
** Wellcome Trust Clinical Research Fellow at Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, UK
Correspondence to arnolddt@cardiff.ac.uk
1. Sanyal AJ. NASH: A global health problem. Hepatol Res. 2011 Jul;41(7):670-4.
2. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54.
3. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002 Sep;123(3):745-50.
4. Fracanzani, A. L., Valenti, L., Bugianesi, E., Andreoletti, M., Colli, A., Vanni, E., Bertelli, C., Fatta, E., Bignamini, D., Marchesini, G. and Fargion, S. (2008), Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes. Hepatology, 48: 792–798. doi: 10.1002/hep.22429
5. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010 Sep;59(9):1265-9.
6. Wong VW, Chu WC, Wong GL, Chan RS, Chim AM, Ong A, et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut. 2011 Aug 16.
7. Armstrong MJ, Houlihan DD, Bentham L, Shaw JC, Cramb R, Olliff S, et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J Hepatol. 2011 May 18.
8. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
Gastroenterology. 2011 Jan;140(1):124-31.
Competing interests: No competing interests