This national population-based study compared the changes in liver-related mortality by etiology and sequelae among different age groups from 2008 to 2018 in the United States using the expanded definition (including secondary liver cancer) and according to both UCOD and MCOD data. The direction of mortality change (increasing or decreasing) was similar in UCOD and MCOD data in most etiologies and sequelae, except secondary liver cancer. However, the extent of change differed between UCOD and MCOD data. The magnitude of decreasing changes in HCV mortality was more prominent in UCOD data than MCOD, particularly for decedents aged 65–74 years (baby boomers born 1945–1965). However, the extent of increasing changes was more drastic in MCOD data than in UCOD data for esophageal varices, cirrhosis, and other diseases of the liver. The magnitude of increasing changes in UCOD and MCOD data was similar for primary liver cancer and alcoholic liver disease.
Kim et al  examined four etiology-based mortality changes according to UCOD and MCOD data. Their study indicated a mild reduction of mortality for the hepatitis C virus infection from 2007 to 2014 according to UCOD data, with an annual percentage change (APC) of − 0.4%, followed by a prominent decreasing trend in the APC of − 13.7% from 2014 to 2016. A different pattern of change was observed using MCOD data; the APC was 2.0% from 2007 to 2014 and − 6.4% from 2014 to 2016. For alcoholic liver disease, the magnitude of mortality changes was similar according to UCOD and MCOD data; the APC was 5.3% and 5.5% from 2014 to 2016, respectively. Kim et al further examined mortality changes from 2007 to 2016 for liver-related sequelae (ie, cirrhosis and liver cancer) and observed APCs of 2.3% and 2.0%, respectively .
We extended the study of Kim and colleagues to examine mortality changes by four age groups. We observed a huge increase in mortality in HCV (rate ratio was 1.75 with 95% CI 1.65–1.85) and primary liver cancer (rate ratio was 1.53 with 95% CI 1.47–1.57) according to MCOD occurred only in decedents aged 65–74 years old and not in other age group. This age specific change was mainly due to the aging of baby boomers .
Another new finding of this study is the 50% increase in the number of deaths from secondary liver cancer (liver metastasis) according to MCOD data, from 17,346 in 2008 to 31,689 in 2018. The liver is the most common site for gastrointestinal tumor metastasis because of the mesenteric venous outflow through the portal vein. The most common liver metastasis is colorectal cancer, which is the third leading cancer cause of death in the United States. Approximately 15–20% of patients with colorectal cancer have synchronous liver metastases at presentation and 50% eventually develop liver metastases. Metastatic disease in the liver is also commonly observed in lung cancer, neuroendocrine tumors, gastrointestinal stromal tumors, breast cancer, gastric cancer, melanoma, and pancreatic cancer [29, 30, 33–35]. However, no study has used mortality data to examine the changes in liver metastasis mortality. Further studies are needed to clarify the epidemiology of liver metastasis-associated mortality, including the distribution of original sites.
One of the strengths of this study is the comparison of the mortality changes using both UCOD and MCOD, which provided a more comprehensive overview of the complexity of liver-related mortality. Piffaretti et al indicated that numerous people die from more than one disease in an aging society. The exclusive use of the UCOD approach may discard useful information on the contribution of other conditions to death . A US study calculated the percentage of UCOD/MCOD deaths among 50 ranked causes of death in 2000 and 2001 and reported five causes (measles, suicide, homicide, legal intervention, and meningococcal infection) with percentages higher than 95% and six causes (certain kidney conditions [nephritis, nephrotic syndrome, nephrosis], hyperplasia of prostate, nutritional deficiencies, anemia, complications of medical and surgical care, and essential hypertension and hypertensive renal diseases) with percentages lower than 20%. The UCOD/MCOD percentage was 65% for chronic liver disease and cirrhosis and 50% for viral hepatitis . The percentage of UCOD/MCOD deaths caused by liver-related etiologies and sequelae in this study was the highest for primary liver cancer (90.8% in 2018) and was the lowest for esophageal varices and secondary liver cancer (5.8% and 6.8% in 2018, respectively). Therefore, detecting the changes in sequelae-associated mortality with a low percentage would be difficult without MCOD data. Fedeli et al had revealed the differences in mortality pattern between those according to standard statistics with those according to MCOD based on different definitions in the Veneto Region in northeastern Italy [19, 24, 27].
However, MCOD data also has limitations. Piffaretti et al indicated that the statistical unit used for MCOD is the cause of death rather than the death itself, which raises questions regarding the interpretation . For instance, the decedent in Fig. 1 would be counted as one death for hepatic failure, one death for primary liver cancer, one death for cirrhosis, and one death for HCV but only one death in overall liver-related death to avoid duplication in counting the number of death. Piffaretti et al suggested assigning weights to each cause of death reported on the death certificate with the sum of the weights for each death being 1. The cause-specific mortality rate estimated according to the MCOD weighting approach would increase for certain diagnoses (eg, 43% for alcohol abuse, 44% for rheumatoid arthritis and osteoarthrosis, and 19% for viral hepatitis) . Further studies are needed to examine the effects of using the MCOD weighting approach to investigate liver-related etiologies and sequelae.
Several limitations should be considered when interpreting the findings of this study. First, studies that have examined the information recorded on the death certificate with medical records have suggested underreporting of certain liver-related etiologies and sequelae on the death certificate [16–18]. However, as our primary aim was to examine the changes in liver-related mortality, a systemic bias between 2008 and 2018 caused by underreporting is unlikely. The recommendation of HCV screening in 2012  and the introduction of DAA in 2013 would have increased the reporting of HCV by certifying physicians on the death certificate from 2008 to 2018. Therefore, the extent of decline of recordings of comorbid HCV and liver cancer or cirrhosis among baby boomers from 2008 to 2018 estimated in this study would be underestimated. That to say, the true magnitude of decline would be larger than we estimated.
Furthermore, we argue that death certificates are not documentation recording all the diseases the decedents had, but recording only the diseases or conditions directly leading to death or contributions to the chain of events according to the certifying physician’s judgment . The certifying physician is most frequently the attending physician of the decedent and is thus in the optimal position to determine the diseases or conditions that should be recorded. The reviewers who examined the documented medical record in the retrospective study might not have been in a better position to judge which diseases or conditions should be recorded on the death certificate.
Second, to avoid complexity in presentation, we did not examine all combinations among different etiologies and sequelae. According to the study of Ly et al., there were more than 20 combinations among five etiologies, including hepatitis B and C virus, alcoholic liver disease, and nonalcoholic steatohepatitis/fatty liver disease . Including five liver-related sequelae (primary and secondary liver cancer, cirrhosis, esophageal varices, and hepatic failure) would result in just under 100 combinations. In this study, we presented only two crucial combinations (ie, HCV with liver cancer and HCV with cirrhosis). Third, to avoid the complexity of presentation, we did not analyze data for each year from 2008 to 2018, and we did not further analyze differences in sex and ethnicity. Fourth, information on the severity of sequelae is not available on the death certificate. Some people with esophageal varices or liver metastasis might have required large amounts of medical care resources, whereas others did not. There are numerous modules in the treatment of liver metastasis, with large variations in costs; thus, using mortality data alone cannot accurately estimate the healthcare resources used.