Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. NAFLD is associated with obesity and metabolic syndrome whereas ALD is associated with excessive alcohol consumption. Both diseases can progress to cirrhosis, hepatocellular carcinoma, and liver-related death. A higher proportion of patients with NAFLD die from cardiovascular disorders than patients with ALD, whereas a higher proportion of patients with ALD die from liver disease. NAFLD and ALD each are associated with significant morbidity, impairment to health-related quality of life, and economic costs to society. Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. NAFLD is associated with obesity and metabolic syndrome whereas ALD is associated with excessive alcohol consumption. Both diseases can progress to cirrhosis, hepatocellular carcinoma, and liver-related death. A higher proportion of patients with NAFLD die from cardiovascular disorders than patients with ALD, whereas a higher proportion of patients with ALD die from liver disease. NAFLD and ALD each are associated with significant morbidity, impairment to health-related quality of life, and economic costs to society. Linda HenryView Large Image Figure ViewerDownload Hi-res image Download (PPT) Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD) are among the most common causes of chronic liver disease, cirrhosis, hepatocellular carcinoma (HCC), and liver-related death.1Mishra A. Younossi Z.M. Epidemiology and natural history of non-alcoholic fatty liver disease.J Clin Exp Hepatol. 2012; 2: 135-144Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 2Trimble G. Zheng L. Mishra A. et al.Mortality associated with alcohol-related liver disease.Aliment Pharmacol Ther. 2013; 38: 596-602Crossref PubMed Scopus (16) Google Scholar, 3Rehm J. Samokhvalov A.V. 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Norland H. et al.Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease.BMC Gastroenterol. 2014; 14: 166Crossref PubMed Scopus (76) Google Scholar NAFLD and ALD not only contribute to the clinical burden of liver disease, but also can lead to significant morbidity and have a negative impact on patients’ quality of life.12Younossi Z.M. Henry L. Economic and quality-of-life implications of non-alcoholic fatty liver disease.Pharmacoeconomics. 2015; 33: 1245-1253Crossref PubMed Scopus (64) Google Scholar, 13Dan A.A. Kallman J.B. Wheeler A. et al.Health-related quality of life in patients with non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2007; 26: 815-820Crossref PubMed Scopus (83) Google Scholar, 14Afendy A. Kallman J.B. 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The prevalence of NAFLD appears to be increasing with time. An analysis of National Health and Nutrition Examination Survey (NHANES) data assessed the prevalence of different types of chronic liver diseases in the United States. During 2 decades, the prevalence rates for chronic hepatitis B, hepatitis C, and ALD remained relatively stable. On the other hand, the prevalence of NAFLD (defined by increased levels of liver enzymes and the absence of other causes of chronic liver disease) doubled. Visceral obesity, type 2 diabetes, insulin resistance, and hypertension were independent predictors of NAFLD.24Younossi Z.M. Stepanova M. Afendy M. et al.Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.Clin Gastroenterol Hepatol. 2011; 9: 524-530Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar However, defining NAFLD based on increases in liver enzyme levels underestimates the true prevalence of NAFLD. NAFLD is identified more accurately using radiologic analyses such as ultrasound. In North America, 24.13% of the general population is estimated to have NAFLD based on diagnosis by ultrasound or other radiologic modality (Figure 1).25Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.Hepatology. 2015 Dec 28; ([Epub ahead of print])http://dx.doi.org/10.1002/hep.28431Google Scholar In an analysis of the National Veterans Administration databases, the prevalence NAFLD also was found to have increased, from 6.3% in 2003 to 17.6% in 2011.26Kanwal F. Kramer J.R. Duan Z. et al.Trends in the burden of nonalcoholic fatty liver disease in a United States cohort of veterans.Clin Gastroenterol Hepatol. 2016; 14: 301-308.e2Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar In parallel to these reports on the increasing prevalence of NAFLD, the number of research articles published on NAFLD also has increased, indicating greater emphasis on NAFLD as an important liver disease captured by peer-reviewed literature.27Zhang T.S. Qin H.L. Wang T. et al.Global publication trends and research hotspots of nonalcoholic fatty liver disease: a bibliometric analysis and systematic review.Springerplus. 2015; 4: 776Crossref PubMed Scopus (18) Google Scholar Obesity is the main risk factor for NAFLD. The increasing incidence of obesity appears to be the main contributor to the increase in the prevalence of NAFLD. Globally, the prevalence of being overweight and obese, defined as a body mass index (BMI) greater than 25, has increased from 28% in 1980 to 39% in 2013.28GBD 2013 Risk Factors CollaboratorsGlobal, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2014; 384: 766-781Abstract Full Text Full Text PDF PubMed Scopus (8105) Google Scholar In parallel, the global prevalence of NAFLD is estimated to be 25.2%.25Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.Hepatology. 2015 Dec 28; ([Epub ahead of print])http://dx.doi.org/10.1002/hep.28431Google Scholar Furthermore, the prevalence of NAFLD is higher in specific populations, such as in people with components of the metabolic syndrome. In fact, the prevalence of NAFLD in patients with type 2 diabetes has been estimated to be 65%, with 7.1% of the patients having advanced fibrosis, detected by magnetic resonance elastography.29Doycheva I. Cui J. Nguyen P. et al.Non-invasive screening for NAFLD and advanced fibrosis in diabetes in primary care setting by MRI and MRE.Aliment Pharmacol Ther. 2016; 43: 83-95Crossref PubMed Scopus (137) Google Scholar If these data are extrapolated to the US population, approximately 15.5 million diabetic individuals in the United States have NAFLD and approximately 1.8 million of these patients may have significant fibrosis related to NAFLD.29Doycheva I. Cui J. Nguyen P. et al.Non-invasive screening for NAFLD and advanced fibrosis in diabetes in primary care setting by MRI and MRE.Aliment Pharmacol Ther. 2016; 43: 83-95Crossref PubMed Scopus (137) Google Scholar Because the prevalence of diabetes is increasing, these rates probably underestimate the true burden of NAFLD and NAFLD-related fibrosis in diabetics. Nevertheless, these data are alarming and indicate that the burden of NAFLD is substantial and growing, especially among individuals with diabetes. Finally, the prevalence of NAFLD in individuals who undergo weight-reduction surgery is very high. In one study, 93% of patients undergoing weight-reduction surgery had NAFLD and 26% had histologic NASH, with 9% having advanced fibrosis.30Ong J.P. Elariny H. Collantes R. et al.Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients.Obes Surg. 2005; 15: 310-315Crossref PubMed Scopus (251) Google Scholar Similarly, the prevalence of hepatic steatosis in another study of morbidly obese patients was reported to be approximately 80%.31Mathurin O. Hollebecque A. Arnalsteen L. et al.Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.Gastroenterology. 2009; 137: 532-540Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar In contrast, 2 prospective studies of morbidly obese patients undergoing weight reduction surgery have reported that the prevalence of NASH is approximately 8% and 11%.32Merriman R.B. Ferrell L.D. Patti M.G. et al.Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease.Hepatology. 2006; 44: 874-880Crossref PubMed Scopus (255) Google Scholar, 33Lassailly G. Caiazzo R. Buob D. et al.Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.Gastroenterology. 2015; 149 (quiz e15–e16): 379-388Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Despite the differences in their study designs, these data suggest that approximately 80%–90% of morbidly obese patients have NAFLD and 8%–26% have underlying NASH. Although most patients with NAFLD are overweight or obese, some are lean. The prevalence of NAFLD in lean individuals in the United States has been estimated to be approximately 7%.34Younossi Z.M. Stepanova M. Negro F. et al.Nonalcoholic fatty liver disease in lean individuals in the United States.Medicine. 2012; 91: 319-327Crossref PubMed Scopus (359) Google Scholar The presence of NAFLD in lean individuals has been associated independently with younger age, female sex, and less likelihood of having insulin resistance and hypercholesterolemia.34Younossi Z.M. Stepanova M. Negro F. et al.Nonalcoholic fatty liver disease in lean individuals in the United States.Medicine. 2012; 91: 319-327Crossref PubMed Scopus (359) Google Scholar Lean NAFLD has been reported predominantly from Asian countries. In a study from China, the prevalence of NAFLD in individuals with a BMI less than 25 was reported to be 7.27%. In this study, of the 5562 subjects who did not have NAFLD at baseline, over 5 years of follow-up evaluation there were 494 subjects (8.88%) who developed NAFLD.35Xu C. Yu C. Ma H. et al.Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study.Am J Gastroenterol. 2013; 108: 1299-1304Crossref PubMed Scopus (124) Google Scholar The risk factors associated with the development of NAFLD in this study were similar to those reported from North America and Europe.32Merriman R.B. Ferrell L.D. Patti M.G. et al.Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease.Hepatology. 2006; 44: 874-880Crossref PubMed Scopus (255) Google Scholar In contrast to prevalence data, data on the incidence of NAFLD are relatively scarce. Nevertheless, the incidence rates for NAFLD reported from Asia (China and Japan) and Israel have been estimated to be approximately 52.34 and 28.01 per 1000 person-years, respectively.25Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.Hepatology. 2015 Dec 28; ([Epub ahead of print])http://dx.doi.org/10.1002/hep.28431Google Scholar Given the growing rates of obesity and metabolic syndrome worldwide, the global burden of NAFLD likely will increase. ALD is caused by the ingestion of excessive alcohol: more than 14 drinks per week for men and 7 drinks per week for women. One alcoholic drink (1 oz liquor, 5 oz wine, or 12 oz of beer) has approximately 12–14 g of alcohol.36Substance Abuse and Mental Health Services Administration (SAMHSA). 2013 National Survey on Drug Use and Health (NSDUH). Table 2.41B—Alcohol use in lifetime, past year, and past month among persons aged 18 or older, by demographic characteristics: percentages, 2012 and 2013. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabsPDFWHTML2013/Web/HTML/NSDUH-DetTabsSect2peTabs1to42-2013.htm#tab2.41b. Accessed: October 28, 2015.Google Scholar, 37World Health Organization. Global status report on alcohol and health, p. XIV. 2014 ed. Available at: http://www.who.int/substance_abuse/publications/global_alcohol_report/msb_gsr_2014_1.pdf?ua=1. Accessed: October 28, 2015.Google Scholar The prevalence of ALD in the US population is estimated to be 2.0%–2.5%.36Substance Abuse and Mental Health Services Administration (SAMHSA). 2013 National Survey on Drug Use and Health (NSDUH). Table 2.41B—Alcohol use in lifetime, past year, and past month among persons aged 18 or older, by demographic characteristics: percentages, 2012 and 2013. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabsPDFWHTML2013/Web/HTML/NSDUH-DetTabsSect2peTabs1to42-2013.htm#tab2.41b. Accessed: October 28, 2015.Google Scholar Data from the NHANES indicate that the prevalence of ALD increased from 1.38% during the period from 1988 to 1994 to 2.21% during the period from 1999 to 2004, but then remained stable, at 2.05%, during the period from 2005 to 2008.24Younossi Z.M. Stepanova M. Afendy M. et al.Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.Clin Gastroenterol Hepatol. 2011; 9: 524-530Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar Although general population data can provide information about the overall prevalence of ALD, only biopsy studies of selected populations can provide data on the specific subtypes of ALD. A large study from France reported the histopathology findings from 1604 biopsy specimens collected from patients admitted with ALD from 1982 through 1995. The results of liver biopsy data showed that 12% of these patients had normal liver histology, 25% had steatosis without fibrosis, 18% had fibrosis with or without steatosis, 7% had acute alcoholic hepatitis (AAH) without cirrhosis, 15% had cirrhosis without AAH, and 11% had cirrhosis with AAH. The risk factors associated with the presence of alcoholic cirrhosis were age, sex, duration of drinking, total amount of alcohol in the prior 5 years, and excess weight (BMI ≥ 25 for women and BMI ≥ 27 for men). Interestingly, multivariate logistic regression analysis showed that excess weight for at least 10 years was a risk factor for cirrhosis, AAH, and steatosis.38Naveau S. Giraud V. Borotto E. et al.Excess weight risk factor for alcoholic liver disease.Hepatology. 1997; 25: 108-111Crossref PubMed Scopus (535) Google Scholar This relationship between outcome of ALD and excess weight indicated that there is a gray zone between ALD and obesity-related NAFLD, in which each contributes to the development of liver disease and cirrhosis. Data on the incidence of ALD in the general population have been reported from Europe and the United States. Based on an analysis of the Danish National Registry (1999–2008), the nationwide population-based annual incidence of ALD in Denmark increased from 37 to 46 per 1,000,000 for men and from 24 to 34 per 1,000,000 for women over a decade. These data indicate an increase in the incidence of ALD.39Kraus L. Østhus S. Amundsen E.J. et al.Changes in mortality due to major alcohol-related diseases in four Nordic countries, France and Germany between 1980 and 2009: a comparative age-period-cohort analysis.Addiction. 2015; 110: 1443-1452Crossref PubMed Scopus (23) Google Scholar Although the incidence of ALD in the US general population may be increasing owing to higher alcohol consumption by women, these rates may be countered by reduced rates in other segments of the population.20Centers for Disease Control and Prevention. Excessive drinking costs U.S. $223.5 billion. Available at: http://www.cdc.gov/features/alcoholconsumption. 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Amundsen E.J. et al.Changes in mortality due to major alcohol-related diseases in four Nordic countries, France and Germany between 1980 and 2009: a comparative age-period-cohort analysis.Addiction. 2015; 110: 1443-1452Crossref PubMed Scopus (23) Google Scholar Health care utilization data from the United States also have shown an increase in the number of ALD-related hospitalizations, from 249,884 in 2002 (0.66% of total admissions) to 326,403 in 2010 (0.83% of total admissions).19Jinjuvadia R. Liangpunsakul S. Translational research and evolving alcoholic hepatitis treatment consortium. Trends in alcoholic hepatitis-related hospitalizations, financial burden, and mortality in the United States.J Clin Gastroenterol. 2015; 49: 506-511Crossref PubMed Scopus (76) Google Scholar The worldwide prevalence of ALD is determined by the availability and amount of alcohol consumed, which vary among regions. Although the prevalence of ALD seems stable, the incidence of ALD, especially in women, appears to be increasing. Therefore, ALD will remain an important cause of liver disease that contributes to the burden of liver disease worldwide. NAFLD and ALD each range from steatosis only to steatohepatitis, which can lead to cirrhosis, HCC, liver transplantation, and/or death. Most patients with NAFLD have histologic evidence for steatosis that does not appear to progress.1Mishra A. Younossi Z.M. Epidemiology and natural history of non-alcoholic fatty liver disease.J Clin Exp Hepatol. 2012; 2: 135-144Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 7Clark J.M. The epidemiology of nonalcoholic fatty liver disease in adults.J Clin Gastroenterol. 2006; 40: S5-S10PubMed Google Scholar, 10Beste L.A. Leipertz S.L. Green P.K. et al.Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013.Gastroenterology. 2015; 149: 1471-1482Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar A recent meta-analysis reported that approximately 9% of NASH patients will progress to cirrhosis annually (6%–12%), with 2.6% of this group progressing to HCC.25Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.Hepatology. 2015 Dec 28; ([Epub ahead of print])http://dx.doi.org/10.1002/hep.28431Google Scholar It is important to note that in patients with NAFLD and diabetes or metabolic syndrome, liver disease progresses more rapidly.40Younossi Z.M. Gramlich T. 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Gores G.J. et al.Alcoholic hepatitis: current challenges and future directions.Clin Gastroenterol Hepatol. 2014; 12: 555-564Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Nevertheless, liver disease progresses more rapidly in patients with ALD than in patients with NAFLD. Of patients with ALD, 1.0%–3.1% progress from simple steatosis to steatohepatitis per year, whereas 3.2%–12.2% of patients with alcoholic hepatitis progress to cirrhosis each year.50Dam-Larsen S. Becker U. Franzmann M.B. et al.Final results of a long-term, clinical follow-up in fatty liver patients.Scand J Gastroenterol. 2009; 44: 1236-1243Crossref PubMed Scopus (159) Google Scholar, 51Mathurin P. Beuzin F. 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In fact, in a study using the NHANES data, only 7% of NAFLD patients as compared with 20% of ALD patients progressed to cirrhosis in a median follow-up time of 178.27 months.48Kwon H.K. Greenson J.K. Conjeevaram H.S. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease.Liver Int. 2013; 34: 129-135Crossref PubMed Scopus (71) Google Scholar There are no clear explanations for why NAFLD or ALD progress in some patients but not others; however, potential contributing factors include high BMI, female sex, dietary habits, alterations in the intestinal microbiome (dysbiosis), and genetic factors (PNPLA3 genotype).43Younossi Z.M. Otgonsuren M. Venkatesan C. et al.In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not.Metabolism. 2013; 62: 352-360Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 53Dunn W. 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