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Mortality among Persons in Care with Hepatitis C Virus Infection--The Chronic Hepatitis Cohort Study (CHeCS), 2006-2010: liver disease deaths 12 times higher
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"The age-adjusted mortality rate for liver disease in CHeCS was twelve times higher than the MCOD rate......mean age of death was 59 years, 15 years younger than MCOD deaths......only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates.....This effect was seen with extra-hepatic causes as well"
Reena Mahajan1, Jian Xing1, Stephen J. Liu1, Kathleen N. Ly1, Anne C. Moorman1, Loralee Rupp2, Fujie Xu1, Scott D. Holmberg1, for the Chronic Hepatitis Cohort Study (CHeCS) Investigators*
1Centers for Disease Control and Prevention, Atlanta, Georgia
2Henry Ford Health System, Detroit, Michigan, USA
Summary: Using US health system data from an observational cohort study, HCV is under-documented on death certificates. Only 19% of those with known HCV infection had HCV listed on their death certificate although two-thirds had pre-mortem indications of chronic liver disease......Disease-specific, liver- and non-liver-related, mortality for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at four US health care systems, were compared with Multiple Cause of Death (MCOD) data in 12 million death certificates in 2006-2010......The age-adjusted mortality rate for liver disease in CHeCS was twelve times higher than the MCOD rate......only 19% of all CHeCS
decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates.
"In Table 4 just below you can see a 15 year difference in age at death between those in this study with HCV & the general population 59 vs 74 yrs old......The mortality rate estimated from this analysis was twelve times higher than the general population; this is much higher than the two-to-five times higher mortality rates in HCV-infected vs uninfected persons seen in other studies...... This effect was seen with extra-hepatic causes as well.....In summary, our analysis of a known HCV-infected cohort demonstrates that less than one-fifth of deaths in HCV-infected persons are coded as having HCV; this indicates a significant underestimation of the number of deaths among people with HCV and the true medical and public health impact of HCV. In this analysis, we have tried to be clear about the difference between dying with HCV and dying from HCV, but both represent a substantial public health burden. For purposes of public health, policy planning, disease modeling, and medical care, this is a huge burden that should be reported and hopefully spur public health action as curative, all-oral therapies are becoming available to treat HCV. Addressing the true impact of HCV, including of those chronically infected with HCV who are not utilizing health services, will be essential to appropriately respond to this epidemic. 35"
"whether the death was considered HCV or non-HCV-related, mean age of death in HCV-infected persons (59 years) was 15 years younger than for all cause mortality in the general population (74 years), a finding similar to previous research. 28......Despite confirmed chronic HCV infection, only 19% (306/1,590) had HCV infection listed on the death certificate."
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Mortality among Persons in Care with Hepatitis C Virus Infection--The Chronic Hepatitis Cohort Study (CHeCS), 2006-2010
Abstract
Background. Numbers of deaths in hepatitis C virus (HCV)-infected persons recorded on US death certificates have been increasing, but actual rates and causes of death in them have not been well elucidated.
Methods. Disease-specific, liver- and non-liver-related, mortality for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at four US health care systems, were compared with Multiple Cause of Death (MCOD) data in 12 million death certificates in 2006-2010. Pre-mortem diagnoses, liver biopsies, and FIB-4 scores (a non-invasive measure of liver damage) were examined.
Results. Of 2,143,369 adult patients seen at CHeCS sites in 2006-2010, 11,703 (0.5%) had diagnosed chronic HCV infection, and 1,590 (14%) died. CHeCS decedents were born from 1945-1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was twelve times higher than the MCOD rate. Before death, 63% had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and of those biopsied 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates.
Conclusions. HCV infection is greatly under-documented on death certificates. The 16,622 persons with HCV listed in 2010 may represent only one-fifth of about 80,000 HCV-infected persons dying that year, at least two-thirds of whom (53,000 patients) would have pre-mortem indications of chronic liver disease.
Excerpts
Of deaths from 1999-2007 with HCV infection listed as a primary or underlying cause of death, 57% had chronic liver disease as a cause 2 but many also had extra-hepatic manifestations.4 Presence of HCV may potentially accelerate the disease process in heart disease, 5-7 diabetes, 8,9 various malignancies, 10,11 and genitourinary conditions. 12,13
In this study, we looked at hepatic and extra-hepatic causes of death for a cohort of hepatitis C-infected patients in care in the United States.
The age-adjusted CHeCS mortality rate in these HCV-infected patients was 12,854 per 100,000 persons compared to the MCOD mortality rate of 1,046 per 100,000 persons.
The age-adjusted CHeCS mortality rate in these HCV-infected patients was 12,854 per 100,000 persons compared to the MCOD mortality rate of 1,046 per 100,000 persons. The age-adjusted mortality rate for all liver disease categories in CHeCS was higher than the national MCOD rate; for example,
alcohol-related liver disease was 6 times greater while other hepatitis was 86 times higher than the national rate (Table 2). The most frequently cited cause of death was non-alcohol related liver disease; it was listed for 32% of all deaths (513 /1,590). The CHeCS mortality rate among persons with non-alcohol related liver disease was 669 vs. 51 per 100,000 for alcohol-related liver disease. In addition, all age adjusted death rates from extra-hepatic causes were higher than the national MCOD rates; the highest rates were seen with genitourinary causes, mental/behavioral disorders, and diabetes (Table 2). Of 1,590 deaths, only 12 (1%) were due to intentional self-harm, 93 (6%) due to sepsis due to any cause, and none were due to overdose/poisonings.
Despite confirmed chronic HCV infection, only 19% (306/1,590) had HCV infection listed on the death certificate. HCV was not listed for the majority of deaths across disease categories whether liver or non-liver related. The total number of deaths listed as liver-related was 47% (752/1,590), but of these, only 41% (306/752) had HCV listed as a cause of death. By type of liver-related death, HCV was listed for 36% (183/513) of those with non-alcohol related liver disease, 27% (13/49) of those with alcohol-related liver disease, 31% (53/169) of those with liver cancer, and only 9% (6/70) of those with ÒotherÓ hepatitis (Figure; Table 3). Even among 156 (10%) of decedents who had a liver transplant before death, HCV was only listed on 46 (29%) of death certificates.
Discussion:
Data from this study suggests a much greater role of HCV on mortality in the United States than has been previously understood based on analyses of death certificate data. The data in this paper document and contradict prevalent views that, perhaps because of its long incubation period (30 years), HCV infection is an indolent infection that is not of urgent concern. Originally intended as a study of causes of death in approximately 1,600 well characterized decedent HCV patients in the CHeCS, we found that only 19% had HCV listed on their death certificates, and only in 30% of death certificates in which liver disease had been noted. Even among the 156 HCV-infected CHeCS patients who had a liver transplant before death, only 46 (29%) had had HCV noted on their death certificate. As there were 16,622 death certificates in the US listing HCV as an underlying or contributing cause of death in 2010, we extrapolate that only one-fifth of those with HCV who die are having HCV recorded on their death certificates. Thus, our analysis suggests that at least 80,000 persons with HCV may have actually died in 2010. Given that 63% of the well-characterized CHeCS patients had medical records (ICD 9 codes) indicating pre-mortem liver disease--and 76% had FIB4 scores indicative of substantial or more liver damage-this suggests that total US deaths contributed to by HCV total at least 53,000.
Our results may be a conservative estimate as recent studies indicate that only about half of all HCV-infected persons have been diagnosed with the infection. 20-22 Further, approximately 50% of all deaths in those with known HCV had liver disease listed on their death certificates. Thus, even if we exclude other diseases associated with HCV infection such as diabetes and non-Hodgkin lymphoma, 23-26 it appears that most are dying not just with HCV but in possibly from HCV. These considerations are especially important because identifying and treating HCV patients in an era of rapidly evolving and effective, curative therapies could have a major public health impact.
Often, the high mortality and burden from HCV infection are minimized because other non-HCVrelated causes of death are considered to be more proximal or immediate reasons. For example, in a recent survey of New York resident physicians, over-documentation of cardiopulmonary causes of death and other inaccuracies-- both knowing and unavoidable--were reported; those surveyed believe that the current cause-of-death reporting system is generally inaccurate.27 This study also indicates that in the HCV-infected population over 70% had pre-mortem liver disease by ICD-9-CM electronic hospital record coding, liver biopsy, or FIB-4 score. So, in addition to under-recording HCV infection, even verified pre-mortem liver disease is also under-recorded, Further, whether the death was considered HCV or non-HCV-related, mean age of death in HCV-infected persons (59 years) was 15 years younger than for all cause mortality in the general population (74 years), a finding similar to previous research. 28
The mortality rate estimated from this analysis was twelve times higher than the general population; this is much higher than the two-to-five times higher mortality rates in HCV-infected vs uninfected persons seen in other studies. 29-32 Even with significant underreporting, persons who died in our cohort with non-alcohol related liver disease had 24 times the risk of death and those with liver cancer had almost 29 times the risk of death compared to over 12 million deaths in the age-matched general population. This effect was seen with extra-hepatic causes as well: compared to the general population, cases had three times the rate of injuries and genitourinary causes of death, ten times the rate of HIV, and twice the rate of mental/behavioral disorders. Other researchers have attributed higher rates of injuries/trauma as well as mental/behavioral disorders to lifestyle factors, including a previous history of
substance abuse. 7,33 However, results from our death certificate data show that only 1% of CHeCS patients had suicide listed, 6% had sepsis, and none died of overdose or poisoning.
Our data represent findings from four health care systems in the United States and thus have a number of limitations. While two sites have transplant centers associated with them, we cannot measure how many patients are ÒattractedÓ to these medical centers because they have tertiary care facilities vs the fact that they are in the catchment area of these large integrated health systems. However, as only a minority (10%) of the CHECS decedents were seen at the transplant centers, these patients do not affect the overall picture. Level of care provided at a particular site should not affect the low rate of death certificate recordings of HCV (29%). Due to the variability in the definition of ICD-10 mortality codes used for chronic liver disease, we compared the codes that we used for our definition of chronic liver disease with a previously established definition. We found that for both definitions, 46% of cases were identified as having liver-related causes of death.34 This concordance further substantiates our findings.
An additional limitation is the use of the FIB-4 index as a measure of chronic liver disease; although validated, changes to liver enzymes and platelet count may be affected by non-liver related conditions such as infection or malignancy. However, the overlap between liver disease defined by ICD-9-CM codes and FIB-4 scores correlates with the findings using the ICD-10 mortality codes indicating that there is truly underlying liver disease in patients dying with and from HCV.
In summary, our analysis of a known HCV-infected cohort demonstrates that less than one-fifth of deaths in HCV-infected persons are coded as having HCV; this indicates a significant underestimation of the number of deaths among people with HCV and the true medical and public health impact of HCV. In this analysis, we have tried to be clear about the difference between dying with HCV and dying from HCV, but both represent a substantial public health burden. For purposes of public health, policy planning, disease modeling, and medical care, this is a huge burden that should be reported and hopefully spur public health action as curative, all-oral therapies are becoming available to treat HCV. Addressing the true impact of HCV, including of those chronically infected with HCV who are not utilizing health services, will be essential to appropriately respond to this epidemic. 35
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