The Triumph of Bacchus: The Emergence of Nonalcoholic Steatohepatitis and Alcoholic Liver Disease as the Leading Causes of Mortality From Cirrhosis
Authors: Thomas G. Cotter, Michael R. Charlton
Journal: Hepatology (2018)

Potential conflict of interest: Dr. Charlton is a Consultant for Gilead, AbbVie, Novartis, Lipocene, Metacrine, NGM Bio and Celgene. He has received research support from Gilead, Genfit, Galectin and AbbVie. See Article on Page 1064 Chronic liver disease (CLD) continues to be one of the leading causes of mortality and morbidity in the United States, accounting for 40,326 deaths per year, 1.5% of total deaths.1 From 2000 to 2015, death rates for CLD and cirrhosis increased 31%.1 Hepatitis C virus (HCV) infection, the most common indication for liver transplantation for many years, has been surpassed by nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD).2 Although it is logical to expect that a similar temporal trend has occurred in cirrhosis‐related mortality, this had not yet been established. In the current issue of Hepatology, Kim et al.3 examine temporal trends in cirrhosis‐ and hepatocellular cancer (HCC)–related mortality by etiology in U.S. adults from 2007 to 2016, using the U.S. Census and national mortality database. They report that age‐standardized cirrhosis‐related mortality rates increased to 23.67/100,000 persons in 2016, with an average annual percentage change (APC) of 2.3%, and HCC‐related mortality increased to 4.41/100,000 persons in 2016, with an average APC of 2.0%. Using death certificate data to elucidate mortality status may have led to misclassification and underestimation; thus, mortality rates may actually be higher than reported. The absolute frequency of mortality from cirrhosis and HCC was highest among males, 1.9‐fold higher than women, whereas increases in cirrhosis‐related mortality rates were higher in women (APC 2.9% vs. 2.0%). There was a 6.5% annual decrease in APC mortality rates for HCV‐cirrhosis during 2014‐2016, following the advent of direct‐acting antiviral (DAA) agents. Interestingly, age‐standardized mortality for cirrhosis from ALD (APC 4.5%) and NAFLD (APC 15.4%) increased over the same period to 8.23/100,000 persons and 0.82/100,000 persons in 2016, respectively, whereas mortality for hepatitis B virus (HBV)‐cirrhosis decreased with an average APC of ‐1.1%. The burden of HCC and liver‐related mortality varies substantially with ethnicity. Non‐Hispanic whites had the highest mortality rate for cirrhosis overall, whereas minority populations had a higher burden of HCC‐related mortality, with non‐Hispanic blacks surpassing Asians in 2016. A notable limitation of this study was the exclusion of Native Americans/Alaskan Natives, a group that disproportionately suffers from liver disease–related mortality. The findings of the study by Kim et al. are interesting from several perspectives. First, the clear demonstration of the impact of DAA agents in reducing mortality from HCV‐cirrhosis is to be celebrated as an unequivocal victory of the biological sciences and enterprise over a modern scourge, with particular credit to Harvey Alter, who characterized hepatitis C (non‐A, non‐B hepatitis) as a disease, Michael Houghton and his team of virologists at Chiron Corporation who discovered hepatitis C virus, and Michael Sofia, the medicinal chemist who invented sofosbuvir. Progress in the diagnosis and treatment of HCV, with the attendant decline in HCV‐related mortality, has proved timely with Kim et al. demonstrating that increases in ALD‐related cirrhosis and NAFLD‐cirrhosis have filled the void, resulting in net overall increases in rates of mortality from cirrhosis and HCC. The paper by Kim et al. establishes that ALD is now the leading cause of mortality from cirrhosis and HCC in the United States, with NAFLD‐cirrhosis rates also markedly increasing, a burden that is borne unequally across age groups, as evidenced by a recent study of the Vital Statistics Cooperative and U.S. Census Bureau,4 observing that during 2009‐2016, people aged 25‐34 years experienced the highest average annual increase in cirrhosis‐related mortality (10.5%) driven entirely by ALD.4 The rise of ALD‐related mortality should be reflected in increasing alcohol consumption patterns in the U.S. population. This appears to be the case, with per capita alcohol consumption in the United States increasing to 2.35 gallons in 20165 from 1995's 33‐year nadir of 2.17 gallons (Fig. 1). In 2016, the percentage of adults who had at least one heavy drinking day that year was highest among adults aged 18‐24 (32.8%) and 25‐44 (35.2%), with males having increased alcohol consumption compared with females.6 Given this evidence, young people, particularly males, may benefit disproportionately from improved resources to evaluate and manage alcohol use disorder.Figure 1: Temporal changes in per capita alcohol consumption in the United States (left axis) and alcohol‐related liver mortality (right axis) between 2007 and 2016 are shown.Although the average APC of mortality from NAFLD‐related cirrhosis was 3‐fold greater than the average APC of ALD‐related cirrhosis during the study period,3 overall mortality rate was only one tenth that of ALD‐related cirrhosis in 2016, and one third that of HCV‐related mortality. Given the fact that NAFLD has clearly surpassed HCV and is close to ALD as the leading cause for liver transplant in the United States,2 the International Classification of Diseases, Tenth Revision code for NAFLD is likely to have only captured a small subset of NAFLD. The increase of APC in mortality from NAFLD‐related cirrhosis is, nonetheless, striking. Kim et al. also showed that mortality rates from HBV‐related cirrhosis are decreasing.3 Mortality rates for HBV‐related illness increased throughout the 1980s and early 1990s.7 HBV vaccination began in the United States in 1982 and expanded during the early 1990s to include all children and at‐risk adults.8 The relatively modest decline in HBV‐related mortality since the early 2000s is explained in part by the increase in immigration to the United States from 1990, which increased from 19.7 million (7.9% of the U.S. population) to 43.7 million in 2016 (13.5% of the population). In the same timeframe, Asian immigrants, who have a high prevalence of HBV infection, increased from 5 million in 1990 to 13 million in 2016 (31% of total immigrant population).9 Kim et al. report that mortality from HBV‐cirrhosis has decreased steadily, with an average APC of ‐1.1% since 2007 to current nadir of 0.26/100,000 persons. Although this can be explained, in part, by the efficacy of antiviral therapy for HBV, increasing HBV vaccination in countries that make up the largest part of the U.S. immigrant population from Asia may also be helping. Lastly, it appears that minority populations have a higher burden of HCC‐related mortality, with non‐Hispanic blacks now surpassing non‐Hispanic Asians with a 5.12/100,000 persons mortality rate. This highlights racial disparities in health, which has been established in prior studies.10 The reduction in HCC mortality among non‐Hispanic Asians is reflective of the efficacy of vaccination programs and of antiviral therapy for HBV in preventing the development of HCC. The disproportionately higher HCC‐related mortality rate among non‐Hispanic blacks may be reflective of barriers faced accessing care and DAA agents for HCV treatment. It has been established that non‐Hispanic blacks have lower rates of screening and surveillance for HCC and are more likely to present with metastatic disease. Moreover, it has been hypothesized that this disparity may be explained in part by disease biology; however, this has yet to be conclusively proved. For centuries, excessive alcohol consumption was the most common cause of liver‐related mortality. In the 17th century painting, "The Triumph of Bacchus," Cornelis De Vos depicts a corpulent and inebriated Bacchus returning to Rome from the conquest of distant lands. The study by Kim et al. demonstrates, in convincing fashion, that after several decades of primacy of HCV, Bacchus has returned in triumph once more. Considering the lack of approved therapies for nonalcoholic steatohepatitis and ALD, and a dismal record of failing to address the societal roots of alcoholism and obesity, Bacchus's reign seems likely to endure.