cirrhosis and liver cancer mortality in the united states · 2018. 7. 23. · cirrhosis and liver...

Confidential: For Review Only

Cirrhosis and Liver Cancer Mortality in the United States

1999-2016: An Observational Study

Journal: BMJ

Manuscript ID BMJ.2018.043691.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 27-Apr-2018

Complete List of Authors: Tapper, Elliot; University of Michigan, Parikh, Neehar; University of Michigan

Keywords: liver disease, hepatitis, falls, alcohol, hepatocellular carcinoma

https://mc.manuscriptcentral.com/bmj

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Cirrhosis and Liver Cancer Mortality in the United States 1999-2016: An

Observational Study

Elliot B. Tapper MD (1,2) and Neehar D Parikh MD MS (1,2)

1. Division of Gastroenterology and Hepatology, University of Michigan

2. Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor

Keywords: Liver disease, hepatitis, falls, alcohol, liver cancer

Word count: 3,439

Corresponding author:

Elliot B. Tapper, MD

3912 Taubman, SPC 5362

1500 E Medical Center Dr

Ann Arbor, MI 48109

T: (734) 647-9252

F: (734) 936-7392

e: [email protected]

Disclosure:

1. Elliot Tapper is the guarantor of this article

2. Roles

a. Concept: Tapper, Parikh

b. Analysis: Tapper, Parikh

c. Data acquisition: Tapper, Parikh

d. Writing: Tapper, Parikh

3. Conflicts of interest: no support from any organisation for the submitted work; no

financial relationships with any organisations that might have an interest in the submitted work

in the previous three years, no other relationships or activities that could appear to have

influenced the submitted work

4. Funding: Elliot Tapper receives funding from the National Institutes of Health through

the Michigan Institute for Clinical and Health Research (KL2TR002241).

5. The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all

forms, formats and media (whether known now or created in the future), to i) publish, reproduce,

distribute, display and store the Contribution, ii) translate the Contribution into other languages,

create adaptations, reprints, include within collections and create summaries, extracts and/or,

abstracts of the Contribution and convert or allow conversion into any format including without

limitation audio, iii) create any other derivative work(s) based in whole or part on the on the

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Contribution, iv) to exploit all subsidiary rights to exploit all subsidiary rights that currently exist

or as may exist in the future in the Contribution, v) the inclusion of electronic links from the

Contribution to third party material where-ever it may be located; and, vi) licence any third party

to do any or all of the above

6. The lead author affirms that the manuscript is an honest, accurate, and transparent account of

the study being reported; that no important aspects of the study have been omitted.

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Abstract

Objectives: Although both are often preventable, cirrhosis and hepatocellular carcinoma (HCC)

both characterized by the development of fatal, resource intensive complications. National data

regarding trends in demographics and associated causes of liver disease mortality are lacking.

We aimed to describe mortality by age-group, sex, race, and state of residence

Design: Observational cohort study

Setting: Death certificate data from the Vital Statistics Cooperative and population data from the

US Census Bureau compiled by the Center for Disease Control and Prevention’s Wide-ranging

Online Data for Epidemiologic Research (1999-2016).

Participants: US residents

Main outcome measures: Mortality. Trends evaluated using Joinpoint Regression.

Results: Deaths due to cirrhosis increased by 65% from 1999-2016 to 34,174; HCC deaths

doubled to 11,073. Only one demographic subgroup experienced improving HCC mortality, the

death-rate fell by 2.7% 95%CI(2.2-3.3,p<0.0001) per year for Asians/Pacific-Islanders. Annual

increases in cirrhosis mortality were most pronounces for American Indians (4.0% 9%CI(2.2-

5.7,p=0.002). The age-adjusted death-rate due to HCC both rose annually by 2.1% 95%CI(1.9-

2.3, p<0.0001); deaths due cirrhosis began rising in 2009 through 2016 by 3.4% 95%CI(3.1-

3.8,p<0.0001). Driven entirely by alcohol-related liver disease, persons aged 25-34 experienced

the highest average annual increase in cirrhosis mortality – 10.5% (95%CI8.9-12.2,p<0.0001) -

from 2009-2016. During this period, mortality due to peritonitis and sepsis in the setting of

cirrhosis rose substantially with respective annual increases of 6.1%(95%CI 3.9-8.2) and

7.1%(95%CI 6.1-8.4). Only one state, Maryland, had improving mortality (-1.2% (95%CI-1.7- -

0.7 per year), while many, concentrated in the South and West observed disproportionate annual

increases: Kentucky 6.8% (95%CI 5.1-8.5), New Mexico 6.0% (95%CI 4.1-7.9), Arkansas 5.7%

(95%CI 3.9-7.6), Indiana 5.0% (95%CI 3.8-6.1), and Alabama 5.0% (95% CI 3.2-6.8). No state

had improving HCC mortality while Arizona (5.1% 95%CI3.7-6.5) and Kansas (4.3%

95%CI2.8-5.8) saw the most severe annual increases.

Conclusions: Disparate changes in cirrhosis mortality by age, race, liver disease etiology, and

US region necessitate tailoring of preventative plans to inform rational public health outreach.

The rapid rise in death-rates among young persons due to alcohol highlight new challenges for

optimal care of patients with preventable liver disease.

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What this paper adds?

What is already known on this subject?

- Cirrhosis is a morbid condition that is increasing in prevalence

- Although hepatitis C is being eradicated, the burden of alcoholic liver disease and

Nonalcoholic Fatty Liver Disease is increasing

What this study adds

- Mortality due to cirrhosis is increasing in the US since 2009

- Persons aged 25-34 experienced the greatest relative increase in mortality driven by death

due to alcoholic cirrhosis.

- Specific demographic subgroups – namely Whites, American Indians and Hispanics –

have experienced the greatest increase in cirrhosis mortality.

- Cirrhosis mortality is improving in Maryland but worst in Kentucky, New Mexico, and

Arkansas

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Introduction

Cirrhosis, the end result for most chronic liver diseases,1 is characterized by fatal,

resource-intensive complications. These include hepatocellular carcinoma (HCC), hepatic

encephalopathy, gastrointestinal hemorrhage, infections, and renal failure. Compounding the

problem, the prevalence of cirrhosis in the United States (US) has doubled in the last decade.2 3

Although hepatitis C (HCV), a major cause of cirrhosis, could be eradicated given recently

widely available effective antiviral therapy, this trend is likely to continue,4 with deaths due to

cirrhosis are expected to triple by 2030.5 Projected increases in cirrhosis incidence are thought to

be driven primarily by the increasing prevalence of alcoholic liver disease and nonalcoholic fatty

liver disease (NAFLD).6-8 The impact of cirrhosis related morbidity and mortality is uneven

across the US with significant geographic and demographic variability.9 The trends in cirrhosis

related mortality in specific subgroups are important in understanding differential impact and

targets for improvement of cirrhosis related outcomes.

Cirrhosis and HCC carry personal, social, and financial burdens for patients, their

families, and society.10-12

Prevention and early management of cirrhosis is therefore cost-

effective.13-15

However, nationally representative data to guide the optimal allocation of

resources and preventive efforts are limited, particularly regarding differential mortality by

demographic subgroups or regions of the country.16 Herein, to fill this gap, we analyze the

Center for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic

Research (CDC WONDER) platform.

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Methods

All data were obtained from the CDC WONDER platform.17 For more details on CDC

Wonder please see the Supplemental Material. Our primary aim was to describe temporal

trends in death-rates attributable to cirrhosis (ICD-10 K70.3, K74.5, and K74.6) and HCC

(C22.0) as the primary/underlying cause of death for US adults. All rates obtained were age-

adjusted, in which age-specific mortality is weighted according to the age distribution in a

standard year (2000).18 Secondarily, we sought to describe how these trends differed based on

demographic subgroups; age, sex, race (Asian Pacific Islander, American Indian/Alaska Native,

black/African American, and white/Caucasian), Hispanic ethnicity, and place of residence. We

also aimed to describe trends in causes of death related to specific complications associated with

cirrhosis. Specifically, we examined death due to gastrointestinal hemorrhage (ICD-10 K25-K28,

K92.0-K92.2, I85.0), peritonitis (K65), sepsis (A41), hepatorenal syndrome (K76.7), or traumas

(V01-Y89) in patients with cirrhosis. Given the association between NAFLD and complications

of the metabolic syndrome like cerebrovascular disease and ischemic heart disease (I20-I25, I60-

I69).19 We also compared trends in deaths due to alcohol use disorder (F10).

To test for unmeasured secular trends, all findings were compared to death-rates due to

causes other than cirrhosis. Specifically, we examined the trends in deaths due to infections

(ICD-10 A00-B99), neoplasia (C00-C48, not including HCC, C22), cardiovascular disease (I00-

I99), and respiratory disease (J00-J98). Finally, we assessed overall trends in several states that

were observed to have the greatest increase or highest death-rates due to cirrhosis and HCC (e.g.

Arizona, New Mexico, and Wyoming).

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We performed several sensitivity analyses. First, we evaluated trends when the cause of

death was labelled as any liver disease with or without cirrhosis (e.g. viral hepatitis, ICD-10

K70-K76). Second, we evaluated trends when the death certificate included any mention

cirrhosis as a primary or contributory cause. A death certificate can have a primary/underlying

cause and up to 20 contributing causes. Third, we repeated trend analysis that included age-

adjusted death-rate estimates by standardizing rates to different years (2000, 2009, and 2010) and

gender (men/women).

Data Analysis

Trends in death-rates were then evaluated using the National Cancer Institute’s Joinpoint

program (version 4.6.0; available: http://surveillance.cancer.gov/joinpoint). This technique

allows us to identify if there were years in the study period where the rate of change in the death-

rate was significantly different. It, which uses a piecewise linear regression approach to

determine whether rates over time are best described by a straight line (0 joinpoints) or by

multiple linear segments (>1 joinpoints).20 21

The software detects the joinpoints in the trends

using grid search method of observe the joinpoints at any point in the time trend,22 fitting a linear

regression between consecutive joinpoints using the least squares approach. To simplify the

model, we specified modeling procedures to keep a maximum of 3 joinpoints (changes in slope)

with a minimum of 3 years per segment. Using validated methodology, we obtained the annual

percentage change (APC) in death-rates over each linear segment as well as the average annual

percentage change (AAPC) with 95% confidence intervals (CI) from 1999-2016 for each

model.23 24

The APC was obtained using a Monte-Carlo permutation analysis. Given the

uncertainty (within the confidence intervals) of each year’s mortality rate, this analytic approach

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fits a line through 4,500 different samples of each year’s rate in order to estimate the APC. The

permutation test provides a p-value reflecting the probability that the original sample based on

the calculated mortality estimates were due to chance. The software selects a final model based

on the minimum number of joinpoints (within the set limits) to explain the mortality trends. All

p-values were adjusted through a Bonferroni correction. The AAPC is a weighted average of the

segmented annual percent change (APC) over a specified time interval, providing a valid

summary statistic to compare rate changes across groups. We found one Joinpoint in the trends

of cirrhosis mortality at 2009. To further understand demographic trends, we analyzed our data

from 2009-2016.

When comparing the trends in mortality due to cirrhosis with control conditions, we

evaluated the differences using a test for parallelism.25 This test evaluates whether curves of

differing absolute values are parallel over multiple (in this case 4,500) permutations of each

model. Patients were not involved in the study design. As this is a publically available dataset of

de-identified data, no ethics approval was obtained.

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Results

Burden of Mortality Due to Cirrhosis and HCC

During the study period, cirrhosis caused a total of 460,760 deaths (20,661 in 1999 and

34,174 in 2016) and 136,442 were attributed to HCC (5,112 in 1999 and 11,073 in 2016).(Table

1) Males had a higher burden of age-adjusted cirrhosis mortality when compared to females by a

2:1 ratio and a higher burden of HCC related deaths by a nearly 4:1 ratio. The highest burden of

age-adjusted cirrhosis mortality was seen in American Indians (25.8/100,000 people), followed

by whites (12.7/100,000 people). Age-adjusted HCC death-rates were highest in Asian/Pacific

Islander patients. Compared to non-Hispanic persons, Hispanics had relatively high age-adjusted

mortality from both cirrhosis (19.3 vs 11.5/100,000) and HCC (5.7 vs 3.4/100,000). The

Southern and Western regions of the US had the highest age-adjusted mortality from cirrhosis

(13.5/100,000 and 13.3/100,000, respectively) while the Western US alone had the highest age

adjusted mortality related to HCC (4.2/100,000). In Supplementary Tables 1a-1b we provide

death rates due to all liver disease codes (1a) and deaths where cirrhosis was noted in any of the

up-to-twenty positions on the death certificate (1b). While these sensitivity tests accounted for

more deaths (742,800 and 800,344 respectively), the trends were the same with statistically

parallel annual trends for each subgroup. In Supplementary Table 1c, we provide death-rates

for persons with both cirrhosis and HCC on the same death certificate. Although the number of

deaths are lower, the relative burden by subgroup is similar to HCC overall with the exception

that American Indians have a relatively higher burden of HCC and cirrhosis.

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Demographic Trends in Mortality Due to Cirrhosis and HCC

Cirrhosis

We evaluated trends in cirrhosis death-rates in demographic subgroups with several

significant findings.(Table 2) First, there was an inflection point at 2009 where cirrhosis-related

mortality increased significantly through to 2016. Several subgroups had significant declines in

cirrhosis-related mortality from 1999-2008, however these trends reversed in nearly every

demographic subgroup beginning in 2009. Second, although more men are dying from (or with)

cirrhosis and HCC, both sexes experienced similar rates of increased mortality over time. Third,

whites and American Indians had rapid increases in cirrhosis mortality after 2009 with AAPC of

3.3%(95%CI 2.8-3.7) and 4.0%(95%CI 2.2-5.7) compared to African Americans. Fourth, non-

Hispanic patients experienced a slower rise in cirrhosis related mortality than Hispanic patients.

Fifth, in recent years, the Northeast US had the slowest rise (AAPC 1.6% 95%CI 1.1-2.1) while

the south had the fastest (3.5% 95%CI 2.8-4.2).

Hepatocellular Carcinoma

The demographic trends in mortality from HCC are markedly different from cirrhosis.

First, overall, there was a 2.1% (95%CI:1.9-2.3) increase in HCC mortality nationally over the

study period. Second, females experienced a consistent increase in HCC mortality, while HCC

death-rates for males slowed beginning in 2011. Third, Asian/Pacific Islanders were the only

subgroup with an improvement in HCC mortality, experiencing a consistent decrease of 2.7%

(95%CI 2.2-3.3) per year. Third, all US regions except for the Northeast experienced significant

increases HCC mortality over the study period.

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Age-Related Trends in Cirrhosis and HCC Mortality

We performed several analyses in order to better delineate the populations affected by

worsening trends in cirrhosis mortality during the period of worsening death-rates (2009-2016).

First, we examined changing death-rates by age-group.(Figure 1) Persons aged 25-34

experienced the highest AAPC in cirrhosis mortality; 3.7% (95%CI2.4-5.1) over the whole

period and 10.5% (95%CI8.9-12.2) from 2009-2016.(Figure 1) Whites and American Indians

had the most rapid increase in this age group. Increased death-rates in the 25-34 age group were

driven by alcoholic cirrhosis, where the average AAPC from 2009-2016 was 10.5% (95%CI 9.2-

11.8). These findings are reinforced by parallel changes mortality due to alcohol use disorder and

all alcohol-related liver diseases (Panel D). In Supplementary Tables 2a-2b, we show the

proportion of all-cause mortality has varied by age group and race 2009-2016. Notably, we show

that by 2016, cirrhosis accounts for 6.3% (up from 4.3% in 2009) and 7.0% (from 5.8% in 2009)

of deaths for American Indians aged 25-34 and >35 respectively. Cirrhosis accounted for 1.4%

(up from 0.9%) and 2.3% (up from 1.8%) of deaths for persons age 25-34 and >35 respectively.

Finally, as seen in Figure 1A, there is an opposite age relationship with respect to HCC-related

mortality; it has decreased in younger patients (<55 years) since 2009, and increased among

those >55 years-old from 2009-2016. In a sensitivity test, we evaluated patients with both HCC

and cirrhosis on the same death certificate. A formal trend analysis of young persons was not

possible as 80% of cirrhosis-HCC deaths occurred in persons older than 55. Only 58 deaths were

recorded for this combination of causes for persons aged 25-34.

Cause-Specific Mortality Trends

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Second, we sought to determine whether specific common causes of death in patients

with cirrhosis were changing over the study period. Supplementary Table 3 depicts the time

trends in comorbid causes of death for patients who died from cirrhosis. The AAPC for

cirrhosis-related deaths due to peritonitis (1.5% 95%CI0.2-2.8) and sepsis (3.7% 95%CI3.2-4.2)

increased significantly while no significant changes were observed for comorbid upper

gastrointestinal hemorrhage, hepatorenal syndrome, cerebrovascular and ischemic heart disease,

and trauma. However, since 2009, the mortality associated with each condition increased save

for trauma. Notably, from 2009-2016 the magnitude of increased death-rate due to peritonitis and

sepsis rose substantially with respective AAPC of 6.1%(95%CI 3.9-8.2) and 7.1%(95%CI 6.1-

8.4). Most (60%) of the 47,290 patients with sepsis or peritonitis were aged 45-64. All groups

had increasing mortality, but the rate of change was not statistically parallel. For example,

persons aged 25-34 and 35-44 experienced sharp increases in sepsis/peritonitis related mortality

beginning in 2009; the AAPC (2009-2016) for these groups were 13.5% 95%CI(9.4–17.4) and

7.4% 95%CI(4.3–10.6). Persons aged 75-84 experienced a later joinpoint with an increase in

sepsis/peritonitis mortality from 2013-2016, APC 12.4% 95%CI(3.8-21.8) and persons aged >85

years had a linear increase from 1999-2016 of 3.3% 95%CI(2.0-4.6).

State-Level Variation in Mortality

We next examined geographic changes in cirrhosis and HCC-related mortality since

2009. The fastest rise in cirrhosis and HCC related mortality occurred in the Western and

Southern US. In Supplementary Tables 4-5, we detail the state-level changes in mortality from

2009-2016; In Figure 2 we show in a series of heat-maps how the death-rate due to cirrhosis and

HCC has changed over time.

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In Figure 3A, we focus on the states with the largest increases in mortality due to

cirrhosis. The states with the greatest AAPC in cirrhosis related mortality include Kentucky

6.8% (95%CI 5.1-8.5), New Mexico 6.0% (95%CI 4.1-7.9), Arkansas 5.7% (95%CI 3.9-7.6),

Indiana 5.0% (95%CI 3.8-6.1), and Alabama 5.0% (95% CI 3.2-6.8). One state, Maryland,

experienced a significant annual decrease in cirrhosis related deaths, -1.2% (95%CI-1.7- -0.7).

No state experienced a significantly decreasing mortality due to HCC (Figure 3B). Many

of the same states with worsening cirrhosis mortality also experienced worsening HCC mortality

(e.g. Oregon, Iowa). However, some states experienced increased HCC-related deaths out-of-

sync with cirrhosis trends. These include Arizona (5.1% 95%CI3.7-6.5), Kansas (4.3%

95%CI2.8-5.8), Kentucky (4.0% 95%CI3.1-5.0), and Washington (3.9% 95%CI3.1-4.6).

State-Level Variation in Mortality Due to Alcohol-Related Diseases

In Figure 4, we evaluated the state-level trends in alcohol-related mortality. In 4A, we

show that the AAPC for deaths due to alcoholic cirrhosis increased most rapidly in Louisiana

(13.1% 95%CI 7.7-18.9), California (12.9% 95%CI6.7-19.5), Kentucky (12.8% 95%CI9.8-15.8),

Delaware (9.8% 95%CI5.1-14.7), and New Mexico (9.3% 95%CI6.3-12.4). Conversely, the

District of Columbia and Maryland had the only improvements in mortality. In 4B, we show

trends in the AAPC for deaths due to alcohol use disorder. None of the state-level trends in

deaths due to alcohol use disorder are statistically parallel with those of alcohol-related cirrhosis,

however many are qualitatively similar. In Supplementary Table 6, we show the age-adjusted

mortality and annual changes in mortality for alcohol use disorder for each state.

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Secular Trends in Non-cirrhotic death-rates (1999-2016)

We examined overall death-rates in each state. Age-adjusted mortality is uniformly

decreasing across the states with the exception of Utah, where the AAPC 2009-2016 was 0.6%

95%CI(0.3 – 0.8). A sample of states (chosen for their significant changes in cirrhosis mortality)

are shown in Supplementary Table 7. None of the state-wide all-cause mortality trends were

statistically parallel with those of cirrhosis or HCC. For example, where cirrhosis-related

mortality improved in Maryland beginning in 2009, all-cause mortality improved in Maryland

until 2010 when it plateaued.

We then evaluated trends in deaths due to other causes over the study period. In

Supplementary Table 8, we compared trends in cirrhosis-related mortality to deaths due to

infections, neoplasia, cardiovascular disease, and respiratory diseases to assess for the presence

of unmeasured secular trends. First, all other disease categories were associated with

improvements in mortality while cirrhosis worsened. Second, although each category improved,

the trends observed for the other causes were not statistically parallel. Third, each category was

associated with continuous (linear) improvement except infections, which began to improve most

after 2009.

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Discussion

Cirrhosis and HCC are deadly conditions, each with increasing footprints in American

public health. As death is one outcome from advanced liver disease among others including

caregiver burden and disability, increasing mortality due to cirrhosis and HCC speak to the

broadening socioeconomic impact of liver disease. Adverse trends in liver-related mortality are

particularly unfortunate given that in most cases the liver disease is preventable. Understanding

the factors associated with mortality due to these conditions will inform how best to allocate

resources. In this study of national data from 1999-2016, we find several major trends in

cirrhosis and HCC mortality in the US.

Worsening Cirrhosis and HCC Mortality

Mortality due to cirrhosis has been rising since 2009. Asrani et al previously

demonstrated unchanged age-and-sex-adjusted death-rates due to liver disease from 1979

(25.8/100,000) to 2008 (25.7/100,000) in Olmstead county.26 Our analysis demonstrates

increased mortality from 1999-2016 in the context of declining mortality due to other causes

such as cardiovascular disease, neoplasia, respiratory disease, and infectious diseases.

Specific Demographics Are Disproportionately Affected

Increases in cirrhosis mortality disproportionately affects young persons aged 25-34,

White, American Indian, and Hispanic Americans. These changes appear to be driven by

alcohol-related liver disease and alcohol-use disorder, which are largely preventable causes of

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death in this age group. Previous estimates of alcohol-related diseases (prior to 2010) show that

mortality was concentrated in persons aged >65 years.27 This study extends such data by

showing the rate-of-change is greatest for the young. The impact of these preventable deaths is

compounded by their economic impact, measured in decades per person of lost productivity and

outsized healthcare costs (twice that of nonalcoholic cirrhosis8). Conversely, mortality due to

HCC continues to increase in older Americans, it is decreasing in younger people and Asians.

These trends also parallel those observed for the incidence of HCC.9 Potential explanations

supported by these data include increasing early detection of HCC, application of

curative/locoregional therapies, and, because hepatitis B is the principal cause of HCC

worldwide and among Asian-Americans, effectiveness of vaccination programs and efficacy in

antiviral therapy for hepatitis B in preventing development of HCC.28-31

Infections Are a Target for Prevention

The causes of death associated with cirrhosis that had the most consistent and substantial

increases over the study period were peritonitis and sepsis. Patients with cirrhosis are at

increased risk of infections due to impaired immunity and propensity for bacterial translocation,

especially in the setting of portal hypertension.10 32-34

Infections, particularly spontaneous

bacterial peritonitis (SBP), are a major cause of death in cirrhosis patients and are major

contributors to our observed rise in cirrhosis related mortality. Proton pump inhibitors, both

over-prescribed and associated with SBP as well as increased susceptibility to antibiotic resistant

bacterial organisms, may contribute to the observed trends.35

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State-Level Variations in Mortality

Specific states in the South and West experienced the worst trends for cirrhosis and HCC

mortality. Only Maryland claimed consistent reductions in cirrhosis mortality. Adverse trends in

Kentucky, New Mexico, Arizona, and Oregon in particular require further study for explanation.

In seeking explanations, given that worsening trends began after 2008, the global financial crisis

and the subsequent economic recession in the US is a possible candidate which may in part

explain the outsized impact in some states. This dovetails with trends affecting younger men:

becoming unemployed is linked with alcohol abuse in young men but not older persons or

women.36

Clinical and Health-Policy Implications

Cirrhosis is morbid and costly to treat and therefore efforts to prevent progression of all

liver diseases are cost-effective.14 15 37 38

Our data highlight several modifiable sources of

mortality. First, young persons, particularly American Indians and Whites, may benefit from

intensified resources for screening for and treatment of alcohol use disorders. Second, quality

improvement efforts are needed optimize the identification and early-goal directed therapy of

SBP and decrease the overuse of proton pump inhibitors;39 additional data are needed to identify

the optimal preventative strategies for SBP in the era of multidrug resistant organisms. Third,

research and outreach are required to understand and contextualize the factors associated with

the adverse trends identified in many states. In addition to resources for alcohol-related disease,

the role of state-level policy instruments such as increased alcohol taxes (which have been linked

with decreased alcohol-related disease40 41

) deserve attention.

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Contextual Factors

Several considerations must be made in the interpretation of these findings. First, these

findings are based on data abstracted from death certificates. Death certificates may be

inaccurate (in up to 15% of cases42) and this study does not explicitly validate disease coding

with chart review. For this reason, we chose the diagnostic codes most specific to cirrhotic

complication. Still, sensitivity analyses using a variety of coding algorithms for liver disease

confirm consistency of results and comparisons of our results to other conditions imply

independence from secular trends. Second, though we have detected worsening mortality since

2009, the precise explanations for this trend and the geographic heterogeneity in our analysis

require further study. For example, we identify the most at-risk states, but granular data is needed

to determine root-causes, be they trends in healthcare access and insurance, policy (e.g. alcohol

tax-rates or laws), employment, education levels, or the differential changes in the comorbidities

(e.g. obesity) of a given state’s population.

Third, it is unclear how these trends are – or will be – affected direct-active antivirals for

HCV. We have included 3 years of data since the approval of DAAs and the observed trends

have remained consistent. Screening for HCV is recommended given the availability of highly

efficacious therapy, however hundreds of thousands of individuals in the US have undetected

HCV or do not have access to antiviral therapy.15 43

At the same time, HCV eradication will

prevent the development of cirrhosis and its complications, potentially changing these trends if

re-assessed in the next 5-10 years. However, HCV therapy cannot modify the significant trends

observed related to alcohol or the expected increase in the burden of NAFLD.5

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Conclusion

Specific demographic subgroups and states are disproportionately affected by adverse

trends in cirrhosis and HCC-related mortality. Additionally, patients with cirrhosis are more

likely to die due to specific secondary causes (i.e. infections.) These data underscore gaps in care

and opportunities for prevention.

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Table 1: Overall Demographics 1999-2016

Total

s and rates are cumulative and reflect the entire period 1999-2015.PI = pacific islander.

Cirrhosis Deaths Hepatocellular Carcinoma Deaths

Deaths Crude rate

(per 100,000) Age-adjusted (per 100,000) Deaths

Crude rate (per 100,000)

Age-adjusted (per 100,000)

Overall 460,760 12.87 12.83 12.91 12.18 12.14 12.21 136,442 3.81 3.79 3.83 3.55 3.53 3.56

Female Male

162,599 298,161

8.75 8.71 8.79 8.02 7.98 8.06 31,694 105,248

1.70 1.68 1.71 1.50 1.48 1.51

17.31 17.25 17.37 16.82 16.76 16.88 6.1 6.06 6.14 5.97 5.93 6.01

American Indian Asian/PI

African American White

9,145 6,687 40,598

404,330

23.7 23.21 24.18 25.81 25.26 26.37 1,386 11,241 21,303

103,012

3.6 3.41 3.79 4.72 4.46 4.99

3.59 3.51 3.68 4.45 4.34 4.56 6.02 5.91 6.13 7.43 7.29 7.57

9.43 9.33 9.52 9.71 9.61 9.81 4.94 4.87 5.00 5.20 5.13 5.27

13.82 13.78 13.86 12.71 12.67 12.75 3.51 3.49 3.53 3.15 3.13 3.17

Hispanic Non-Hispanic

64,001 395,128

14.18 14.07 14.29 19.27 19.11 19.42 17,288 119,250

3.82 3.76 3.88 5.74 5.65 5.83

12.63 12.59 12.67 11.51 11.47 11.54 3.80 3.78 3.82 3.37 3.35 3.39

Northeast Midwest South West

71,388 90,958

187,949 110,465

10.65 10.58 10.73 9.81 9.74 9.89 23,996 24,172 45,105 32,596

3.85 3.8 3.90 3.48 3.43 3.52

11.60 11.52 11.67 10.78 10.71 10.85 3.34 3.30 3.38 3.06 3.02 3.10

14.32 14.25 14.38 13.53 13.47 13.6 3.75 3.72 3.79 3.49 3.46 3.52

13.58 13.5 13.66 13.33 13.25 13.41 4.34 4.29 4.38 4.23 4.19 4.28

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Table 2: Trends in the Annual Percentage Change in Death-rates Due to Cirrhosis and Hepatocellular Carcinoma

Time Trends in Cirrhosis Deaths Time Trends in Hepatocellular Carcinoma Deaths

Years of

similar trend APC (95%CI) P-value Years of

similar trend APC (95%CI) P-value

Overall 1999-2008 2008-2016

-0.5 (-0.9- -0.1) 3.4 (3.1-3.8)

0.02 <0.00001 Overall 1999-2016 2.1 (1.9-2.3) <0.00001

Female Female

Male Male

1999-2008 2008-2016 1999-2009 2009-2016

-0.3 (-0.8-0.2) 3.6 (3.1-4.2)

-0.7(-1.1- -0.3) 2.6 (2.1-3.0)

0.2 <0.00001

0.003 <0.00001

Female Male Male

1999-2016 1999-2010 2010-2016

1.3 (1.9-1.7) 2.6 (2.1-3.1) 1.3 (0.4-2.3)

<0.00001 <0.0001

0.02

American Indian American Indian

Asian/PI African American African American

White White

1999-2010 2010-2016 1999-2016 1999-2008 2008-2016 1999-2008 2009-2016

-0.3(-1.2-0.5) 4.0 (2.2-5.7) 0.3 (-0.2-0.7)

-3.6 (-4.3- -3.9) 1.7 (0.9-2.4)

-0.1 (-0.5-0.3) 3.3 (2.8-3.7)

0.4 0.002

0.2 <0.00001

0.003 0.7

<0.00001



1999-2016 1999-2016 1999-2016 1999-2016

2.3 (1.1-3.5) -2.7 (-3.3- -2.2)

2.2 (1.7-2.7) 2.4 (2.2-2.8)

0.007 <0.00001 <0.00001 <0.00001

Hispanic Hispanic

Non-Hispanic Non-Hispanic

1999-2007 2008-2016 1999-2008 2009-2016

-1.7 (-2.3 - -1.0) 1.3 (0.8 – 1.7)

-0.5 (-0.9 - -0.1) 3.0 (2.5 – 3.4)

0.0003 <0.00001

0.02 <0.00001

Hispanic Non-Hispanic Non-Hispanic Non-Hispanic Non-Hispanic

1999-2016 1999-2006 2006-2010 2010-2014 2014-2016

0.7 (0.02-1.2) 2.0 (1.3-2.7) 3.3 (1.1-5.6)

0.5 (-1.5 – 2.6) 3.7 (-0.2 – 7.7)

0.009 0.0004 0.01 0.1

Northeast Northeast Midwest Midwest South South West West

1999-2007 2007-2016 1999-2008 2008-2016 1999-2009 2009-2016 1999-2008 2008-2016

-2.2 (-2.8- -1.6) 1.6 (1.1 - 2.1)

-0.4 (-0.7- -0.1) 3.1 (2.7-3.4) -0.1(-0.6-0.3) 3.5 (2.8-4.2) -0.1(-0.7-0.6) 3.0 (2.3-3.6)

0.0003 0.0008 0.01

<0.00001 0.4

<0.00001 0.8

<0.00001

Northeast Northeast Midwest South West

1999-2010 2010-2015 1999-2015 1999-2015 1999-2015

2.5 (1.6-3.4) 0.7 (-0.2-1.6) 2.5 (2.3-2.7) 2.3 (1.9-2.8) 1.8 (1.5-2.1)

0.002 0.1

<0.00001 <0.00001 <0.00001

In this table, an analysis of the trends in the changing rates of death are shown. Each segment shown is derived from a Joinpoint analysis where

the years included in the trend are chosen based on similarities in the annual rate of change. For example, if the whole study period (1999-2016)

is included, it is because there are no periods > 3 years in which the rate of change is significantly different. AI = American Indian, A/PI =

Asian/Pacific Islander, AA = African American, NE = Northeast, MW = Midwest, S = South, W = West

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Figure 1: Death-rate Trends by Age-Group 2009-2016

This graph explores changes in mortality by subgroup over the period in which there was an

overall increase in cirrhosis mortality. Each bar represents the average annual percentage change

in the death-rate due to cirrhosis and hepatocellular carcinoma (HCC) in all adult age groups

from 2009-2016. Panel A depicts changes in overall cirrhosis and HCC mortality; B shows

changes by race; C shows changes by sex; and D shows changes by alcohol-related diagnosis

codes.

Figure 2: Age Adjusted Death-rates Attributable to Cirrhosis and Hepatocellular

Carcinoma over Time

The age-adjusted mortality for each condition in each state is presented in quartiles for the first,

middle and last year of the study. Quartiles for each time period are denoted by yellow (first),

light orange (second), dark orange (third), and red (fourth). Striped or shaded states imply data

that is either unreliable or suppressed to protect patient identity.

Figure 3: States with Significant changes in Death-rates Attributable to Cirrhosis and

Hepatocellular Carcinoma (HCC) 2009-2016

This graph explores the changes in cirrhosis and HCC mortality at the state level 2009-2016. The

average annual percentage change (AAPC) in mortality for each individual state is plotted

against the age-adjusted death-rate in 2009. States without significant trends were excluded from

this figure for simplicity. Panel A shows trends for cirrhosis and B shows trends for HCC.

Figure 4: Average Annual Percentage Change (AAPC) in Mortality Due to Alcohol-Related

Disease

Note: Many states were excluded from the figures for simplicity because their trends were non-

significant (no changes over the specified timeframes).

Top: The AAPC for mortality by state for alcohol-related cirrhosis (ICD-10 K70.3) is shown for

2009-2016.

Bottom: The AAPC for mortality by state for alcohol-use disorder (ICD-10 F10) is shown for

2009-2016.

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Cirrhosis and Liver Cancer Mortality in the United States 1999-2016: An

Observational Study

Supplementary Material

Elliot B. Tapper MD (1,2) and Neehar D Parikh MD MS (1,2)

1. Division of Gastroenterology and Hepatology, University of Michigan

2. Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor

Table of Contents

Page 2: Methods - Technical supplement

Page 3: Supplementary Table 1a: Deaths due to Any Liver Disease Diagnosis (1999-2016)

Supplementary Table 1b: Deaths Involving Cirrhosis at Any Position on the Death

Certificate (1999-2016)

Supplementary Table 1C: Deaths Involving Both Cirrhosis and HCC (1999-2016)

Page 5: Supplementary Table 2b: The proportion of all deaths for each racial subgroup attributed to

cirrhosis Age >35

Supplementary Table 2b: The proportion of all deaths for each racial subgroup attributed to

cirrhosis Age >35

Page 6: Supplementary Table 3: Age-Adjusted Death Rates per 100,000 Americans

Page 7: Supplementary Table 4: Average Annual Percentage Change in the rate of Cirrhosis-related

death (2009-2016)

Page 9: Supplementary Table 5: Average Annual Percentage Change in the rate of HCC-related

death (2009-2016)

Page 11: Supplementary Table 6: Average Annual Percentage Change in the rate of Alcohol Use

Disorder-related Death (2009-2016)

Page 13: Supplementary Table 7: Overall Age-Adjusted Death Rates in States with High Rates of

Liver-Related Mortality

Page 15: Supplementary Table 8: Death-Rates Due to Other Conditions

Page 16: Supplementary Figure 1: Graphical Depiction of Cirrhosis Mortality

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Methods - Technical supplement

Database

CDC WONDER provides mortality data derived from US death certificates, compiled

from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative.

These include 50 states, 5 territories (Puerto Rico, U.S. Virgin Islands, Guam, American Samoa,

and the Northern Mariana Islands), the District of Columbia, and New York City. Each

jurisdiction reports data to National Center for Health Statistics though state centralized vital

record offices and the over 6,000 local vital registrars nationwide.

The CDC WONDER platform uses the number of cases as the numerator and the

corresponding population size based on US Census Bureau data as the denominator with death

rates calculated per 100,000 persons. Each estimate is associated with a standard error and 95%

confidence interval (CI), both based on the death count and the underlying population and

provided by the CDC WONDER platform. Within the platform, we used two specific data sets.

First, we used the Detailed Mortality File (DMF), a county-level national mortality and

population data collection derived from the U.S. records of deaths (death certificates) since 1968.

Counts and rates of death can be obtained by place of residence, age, race, gender, year, and

underlying cause-of-death. Second, we used the Multiple Cause of Death (MCD) data set which

contains the same mortality and population counts as does DMF. It is only available for 1999-

2015. MCD data contains a single underlying cause of death, and up to twenty additional coded

causes of death coupled with demographic data. This allowed us to assess trends in specific

causes of death linked to cirrhosis. Beginning in 1999 through 2015, all data available was coded

according to the International Classification of Diseases (ICD)-10 system. We therefore

restricted all analyses to this timeframe.

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Supplementary Table 1a: Deaths due to Any Liver Disease Diagnosis (1999-2016)

Supplementary Table 1b: Deaths Involving Cirrhosis at Any Position on the Death Certificate (1999-2016)

Liver Disease Deaths

Deaths Crude rate

(per 100,000) Age-adjusted (per 100,000)

Overall 742,800 17.11 17.07 17.15 16.23 16.19 16.26

Female Male

278,168 464,632

12.48 12.43 12.52 11.38 11.33 11.42

21.99 21.93 22.06 21.65 21.58 21.71



16,257 11,435 70,542

644,562

32.02 31.53 32.51 37.84 37.23 38.45

5.03 4.93 5.12 6.23 6.11 6.35

12.77 12.68 12.87 13.99 13.89 14.1

18.36 18.31 18.4 16.79 16.75 16.84


95,141 645,165

15.91 15.81 16.01 23.36 23.2 23.51

17.23 17.19 17.27 15.56 15.52 15.59


119,283 149,601 292,894 181,022

14.85 14.76 14.93 13.57 13.5 13.65

15.71 15.63 15.79 14.69 14.61 14.76

18.4 18.33 18.46 17.42 17.35 17.48

18.22 18.13 18.3 18.03 17.95 18.12

Liver Disease Deaths

Deaths Crude rate


Overall 800,344 18.4 18.4 18.5 17.4 17.3 17.4

Female Male

276,676 523,668

12.4 12.4 12.5 11.2 11.2 11.3

24.8 24.7 24.9 24.3 24.3 24.4



14,383 15,892 80,485

689,584

28.3 27.9 28.8 34.1 33.5 34.6

7 6.9 7.1 8.8 8.6 8.9

14.6 14.5 14.7 15.9 15.8 16

19.6 19.6 19.7 17.8 17.8 17.9


111,480 685,901

18.6 18.5 18.8 27.9 27.7 28.1

18.3 18.3 18.4 16.4 16.4 16.4


127,885 153,093 318,664 200,702

15.9 15.8 16 14.5 14.4 14.6

16.1 16 16.2 14.9 14.9 15

20 19.9 20.1 18.9 18.8 18.9

20.2 20.1 20.3 19.9 19.8 20

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Supplementary Table 1c: Deaths Involving Both Cirrhosis and HCC (1999-2016)

Cirrhosis and Hepatocellular Carcinoma

Deaths Crude rate


Overall 37737 0.56 0.53 0.59 0.56 0.53 0.59

Female Male

7136 30601

0.32 0.31 0.33 0.28 0.28 0.29

1.45 1.43 1.46 1.37 1.35 1.38



511 2085 5169 29972

1.01 0.92 1.09 1.28 1.16 1.4

0.92 0.88 0.96 1.12 1.07 1.17

0.94 0.91 0.96 1.00 0.97 1.03

0.85 0.84 0.86 0.76 0.75 0.77


6522 31091

1.09 1.06 1.12 1.66 1.61 1.7

0.83 0.82 0.84 0.71 0.7 0.72


6131 6773 13985 10848

0.76 0.74 0.78 0.68 0.67 0.7

0.71 0.69 0.73 0.63 0.62 0.65

0.88 0.86 0.89 0.79 0.78 0.81

1.09 1.07 1.11 1.04 1.02 1.06

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Supplementary Table 2a: The proportion of all deaths for each racial subgroup attributed to cirrhosis Age 25-34

Age 25-34

American Indian

Asian / Pacific

Islander African American White

Year Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

2009 32 4.26% 8 0.75% 50 0.54% 294 0.93%

2010 33 4.15% 7 0.63% 54 0.61% 305 0.97%

2011 50 5.95% 8 0.71% 51 0.56% 337 1.03%

2012 39 4.18% 8 0.68% 44 0.48% 435 1.30%

2013 44 4.77% 17 1.38% 56 0.59% 426 1.26%

2014 51 5.41% 17 1.33% 48 0.50% 503 1.42%

2015 59 5.57% 18 1.30% 67 0.64% 568 1.47%

2016 76 6.26% 23 1.56% 64 0.54% 602 1.40%

Supplementary Table 2b: The proportion of all deaths for each racial subgroup attributed to cirrhosis Age >35

Age >35

American Indian

Asian / Pacific

Islander African American White

Year Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

Cirrhosis

Deaths

Proportion

of all

deaths

2009 753 5.81% 883 1.91% 4,278 1.65% 36,763 1.83%

2010 789 5.80% 909 1.89% 4,396 1.68% 38,672 1.90%

2011 860 6.16% 949 1.89% 4,570 1.73% 41,161 1.98%

2012 917 6.36% 1,064 2.00% 4,754 1.76% 43,188 2.06%

2013 989 6.56% 1,097 1.94% 5,235 1.89% 45,665 2.13%

2014 1,052 6.60% 1,164 2.00% 5,503 1.94% 48,305 2.24%

2015 1,194 7.10% 1,181 1.87% 5,695 1.95% 50,948 2.29%

2016 1,215 7.02% 1,266 1.93% 5,532 1.83% 51,426 2.30%

The denominator for ‘all deaths’ is national all cause mortality for the specified age group

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Supplementary Table 3: Age-Adjusted Death Rates per 100,000 Americans

Deaths attributable to cirrhosis

Deaths due to

HCC

(overall)

Year

Overall

Causes listed in addition to cirrhosis

Upper

Gastrointestinal

Bleeding

Peritonitis Sepsis Hepatorenal

syndrome

Cerebro-

vascular and

ischemic

heart disease

Trauma

1999 9.58 9.45 9.71 1.63 1.58 1.68 0.29 0.26 0.31 0.72 0.68 0.76 0.91 0.87 0.96 0.49 0.46 0.52 0.21 0.19 0.23 2.85 2.77 2.93

2000 9.62 9.49 9.75 1.61 1.56 1.67 0.31 0.28 0.34 0.72 0.68 0.76 0.83 0.79 0.87 0.52 0.49 0.55 0.23 0.2 0.25 3 2.92 3.08

2001 9.58 9.45 9.71 1.59 1.53 1.64 0.28 0.26 0.3 0.73 0.7 0.77 0.84 0.8 0.88 0.49 0.47 0.52 0.2 0.18 0.22 2.95 2.87 3.03

2002 9.61 9.48 9.74 1.46 1.41 1.51 0.31 0.29 0.34 0.7 0.67 0.74 0.82 0.78 0.86 0.54 0.51 0.57 0.2 0.18 0.22 3.06 2.98 3.14

2003 9.7 9.58 9.83 1.47 1.42 1.52 0.28 0.26 0.31 0.72 0.69 0.76 0.8 0.76 0.84 0.5 0.47 0.53 0.21 0.19 0.23 3.21 3.13 3.29

2004 9.39 9.26 9.51 1.39 1.34 1.44 0.27 0.25 0.29 0.76 0.72 0.79 0.77 0.73 0.81 0.44 0.41 0.47 0.18 0.16 0.2 3.21 3.13 3.29

2005 9.42 9.3 9.54 1.25 1.21 1.3 0.27 0.24 0.29 0.79 0.76 0.83 0.71 0.67 0.75 0.47 0.44 0.5 0.21 0.19 0.23 3.27 3.19 3.35

2006 9.19 9.07 9.31 1.16 1.12 1.21 0.25 0.23 0.28 0.75 0.71 0.78 0.66 0.62 0.69 0.47 0.44 0.5 0.18 0.16 0.2 3.34 3.26 3.42

2007 9.28 9.16 9.4 1.23 1.19 1.27 0.23 0.21 0.25 0.77 0.73 0.8 0.7 0.66 0.74 0.46 0.43 0.48 0.2 0.18 0.22 3.32 3.24 3.4

2008 9.36 9.24 9.48 1.25 1.21 1.29 0.25 0.23 0.27 0.79 0.75 0.82 0.68 0.64 0.72 0.47 0.44 0.5 0.19 0.17 0.21 3.54 3.46 3.62

2009 9.36 9.25 9.48 1.25 1.21 1.3 0.28 0.25 0.3 0.82 0.78 0.85 0.64 0.61 0.68 0.44 0.42 0.47 0.18 0.16 0.2 3.66 3.58 3.75

2010 9.72 9.6 9.84 1.29 1.25 1.34 0.28 0.26 0.3 0.9 0.87 0.94 0.69 0.65 0.72 0.49 0.47 0.52 0.17 0.15 0.19 3.76 3.68 3.84

2011 10.1 9.98 10.23 1.31 1.27 1.36 0.27 0.25 0.29 0.91 0.88 0.95 0.71 0.67 0.74 0.48 0.46 0.51 0.21 0.19 0.23 3.87 3.79 3.96

2012 10.38 10.26 10.5 1.36 1.32 1.41 0.3 0.28 0.32 0.99 0.96 1.03 0.72 0.69 0.76 0.51 0.49 0.54 0.19 0.18 0.21 3.83 3.75 3.91

2013 10.65 10.53 10.77 1.43 1.39 1.48 0.31 0.28 0.33 1.03 0.99 1.06 0.72 0.68 0.75 0.52 0.49 0.55 0.18 0.17 0.2 3.9 3.82 3.98

2014 11.09 10.97 11.21 1.38 1.34 1.43 0.36 0.34 0.39 1.13 1.1 1.17 0.76 0.72 0.79 0.5 0.47 0.53 0.19 0.17 0.2 3.84 3.76 3.92

2015 11.57 11.45 11.7 1.46 1.42 1.51 0.4 0.37 0.43 1.25 1.2 1.29 0.83 0.79 0.86 0.56 0.54 0.59 0.19 0.17 0.21 3.93 3.85 4.01

2016 11.42 11.29 11.54 1.56 1.51 1.6 0.37 0.35 0.4 1.29 1.24 1.33 0.85 0.81 0.88 0.55 0.52 0.58 0.23 0.21 0.25 4.2 4.12 4.28

AAPC 1.1 (0.8-1.4) -0.5 (-1.8- -0.9) 1.5 (0.2-2.8) 3.7 (3.2-4.2) -0.6 (-1.2 – 0.1) 0.6 (-0.3 – 1.5) -0.2 (-1.1-0.6) 2.1 (1.3-3.0)

AAPC

Since

2009 3.0 (2.5-3.4) 2.6 (2.0-3.2) 6.1 (3.9-8.2) 7.1 (6.1-8.4) 3.2 (2.2 – 4.2) 2.9 (1.5-4.4) -0.2 (-1.1-0.6) 2.0 (0.2-3.7)

AAPC = Average annual percentage change. All percentage changes are presented with 95% Confidence Intervals. AAPC Intervals that do not

cross zero have p values < 0.05. Gastrointestinal bleeding is defined by the presence on the death certificate of causes inclusive of peptic ulcers,

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melena, hematemesis and bleeding varices. Peritonitis and hepatorenal syndrome are both defined by the corresponding ICD-10 codes. Trauma is

defined by V01-Y89.

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Supplementary Table 4: Average Annual Percentage Change in the rate of Cirrhosis-related

death (2009-2016)

State AAPC 95% CI Age-Adjusted Death-Rate in

2009 (95% CI)

Alabama 5 3.2 6.8 11.11 10.06 12.15

Alaska 2.3 0.7 3.9 11.18 8.19 14.91

Arizona 3.6 2.4 4.9 12.7 11.7 13.7

Arkansas 5.7 3.9 7.6 9.6 8.35 10.84

California 2.7 2.1 3.2 11.77 11.36 12.18

Colorado 2.4 2 2.9 10.52 9.48 11.56

Connecticut 3.3 1.5 5.2 8.17 7.15 9.18

Delaware 0 -1.4 1.4 10.47 8.27 13.06

District of Columbia -1.7 -3.5 0.1 9.07 6.42 12.45

Florida 2.2 1 3.3 12.19 11.65 12.72

Georgia 3.9 1.4 6.5 8.47 7.78 9.16

Hawaii 2.3 1.3 3.4 7.39 5.9 9.16

Idaho 2.4 1.6 3.3 8.6 6.91 10.29

Illinois 2.1 1.1 3.2 9.05 8.46 9.64

Indiana 5 3.8 6.1 9.08 8.26 9.91

Iowa 3.1 2.1 4.2 7.22 6.18 8.27

Kansas 1.7 1 2.3 7.77 6.61 8.93

Kentucky 6.8 5.1 8.5 9.9 8.86 10.94

Louisiana 4.5 2.2 6.9 9.19 8.19 10.2

Maine 1.4 0.5 2.2 9.2 7.51 10.9

Maryland -1.2 -1.7 -0.7 8.09 7.26 8.92

Massachusetts -0.3 -0.9 0.2 8.78 7.99 9.56

Michigan 1.6 1 2.1 10.47 9.77 11.17

Minnesota 3.3 2.2 4.4 6.93 6.14 7.73

Mississippi 3.9 2.4 5.5 11.07 9.71 12.43

Missouri 3.6 2.6 4.6 8.3 7.5 9.11

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Montana 2.2 1.3 3.1 11.25 9.09 13.77

Nebraska 1.6 0.5 2.7 6.71 5.44 8.19

Nevada 0.7 -0.3 1.7 11.82 10.33 13.32

New Hampshire 1.6 0.3 2.9 9.57 7.78 11.37

New Jersey 1 0.2 1.9 8.3 7.63 8.96

New Mexico 6 4.1 7.9 16.99 14.97 19

New York 1.6 0.9 2.3 6.92 6.51 7.33

North Carolina 2.8 1.9 3.7 10.44 9.7 11.17

North Dakota 5.9 -0.7 12.8 5.7 3.84 8.13

Ohio 3.3 2.8 3.8 10.2 9.57 10.84

Oklahoma 2.6 1.8 3.5 11.4 10.18 12.63

Oregon 2.6 2.1 3 10.68 9.54 11.82

Pennsylvania 2.1 1.5 2.7 8.91 8.35 9.46

Rhode Island 0.5 -0.6 1.7 10.43 8.41 12.8

South Carolina 1.9 1.3 2.6 12.27 11.15 13.4

South Dakota 2.7 1.1 4.3 6.74 4.9 9.04

Tennessee 3.8 3 4.7 11.68 10.74 12.61

Texas 3.2 2.3 4.1 14.09 13.53 14.65

Utah 4 1.9 6.2 6.97 5.66 8.28

Vermont 1.1 -0.4 2.7 8.8 6.53 11.61

Virginia 3.2 2 4.4 9.1 8.35 9.84

Washington 2.2 1.5 3 9.83 8.99 10.68

West Virginia 2.1 1.1 3.1 12.54 10.85 14.24

Wisconsin 1.5 0.9 2.1 8.19 7.37 9.01

Wyoming 3.1 1.2 5 7.55 5.23 10.56

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Supplementary Table 5: Average Annual Percentage Change in the rate of HCC-related

death (2009-2016)

State AAPC 95% CI Age Adjusted Death-Rate in

2009 (95% CI)

Alabama -1.1 -4.4 2.3 2.93 2.39 3.47

Arizona 5.3 -4.7 16.3 2.7 2.24 3.16

Arkansas 10.9 3.5 18.9 1.84 1.34 2.47

California 0.8 0.4 1.2 4.28 4.03 4.53

Colorado 3.8 2.5 5 3.32 2.72 3.92

Connecticut 1.7 0.3 3 3.11 2.52 3.8

Delaware 2.3 0.6 4 3.47 2.26 5.08

District of Columbia 2.3 -0.6 5.3 7.0 4.72 9.99

Florida 1.1 -3.1 5.5 3.29 3.02 3.57

Georgia 2.5 1.8 3.2 2.38 2.01 2.75

Hawaii 0 -1.1 1.2 6.27 4.91 7.88

Idaho 5.5 2 9.2 1.81 1.12 2.76

Illinois 1.1 0.4 1.7 2.72 2.4 3.05

Indiana 3.1 -0.4 6.6 2.7 2.25 3.15

Iowa 4.5 3 6 2.48 1.91 3.17

Kansas 5.2 3.8 6.7 2.73 2.09 3.5

Kentucky 4.2 3.2 5.1 3.04 2.46 3.62

Louisiana 2.5 1.4 3.6 3.19 2.6 3.79

Maine 2.4 0.6 4.3 3.12 2.22 4.27

Maryland 2.6 1.9 3.4 3.18 2.66 3.71

Massachusetts -0.7 -2.8 1.5 3.87 3.34 4.39

Michigan 2.4 1.4 3.4 2.58 2.24 2.93

Minnesota 3.1 2 4.2 2.63 2.14 3.12

Mississippi 2.5 0.6 4.4 1.69 1.2 2.31

Missouri 0.2 -2 2.4 3.32 2.81 3.83

Nebraska 3.9 1.5 6.3 3.07 2.24 4.1

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Nevada 3.2 2 4.4 2.77 2.08 3.62

New Hampshire 2.4 0.8 3.9 2.35 1.53 3.44

New Jersey 0.3 -0.5 1 2.83 2.44 3.22

New Mexico 2.5 0.7 4.3 3.44 2.61 4.46

New York 1.3 0.8 1.9 3.01 2.74 3.28

North Carolina 4.2 3.4 5.1 3.7 3.26 4.14

Ohio 1.5 -0.2 3.2 3.2 2.85 3.56

Oklahoma 7.4 -1.1 16.6 2.83 2.25 3.5

Oregon 5.2 3.9 6.5 4.75 4 5.51

Pennsylvania 2.9 2.3 3.6 3.37 3.03 3.71

Rhode Island 1.2 -0.6 3.1 3.84 2.66 5.37

South Carolina 3.4 2.4 4.5 3.78 3.16 4.4

Tennessee 4.1 3.1 5.1 3.98 3.43 4.52

Texas 2.3 1.6 2.9 4.24 3.92 4.55

Utah 2.5 0.8 4.2 2.23 1.55 3.1

Vermont -5.6 -12.2 1.5 5.19 3.48 7.46

Virginia 0.5 -4.2 5.5 3.77 3.29 4.26

Washington 1.6 -1.1 4.5 4.51 3.93 5.09

West Virginia 3.1 1.1 5.1 2.05 1.44 2.84

Wisconsin 2.8 2.1 3.4 2.4 1.96 2.84

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Supplementary Table 6: Average Annual Percentage Change in the rate of Alcohol Use

Disorder-related Death (2009-2016)

State AAPC 95% CI Age Adjusted Rate in 2006

Alabama -2.3 -3.6 -1.1 1.59 1.23 2.03

Alaska -0.8 -9.5 8.7 8.89 6.26 12.25

Arizona 0.9 0 1.8 3.71 3.18 4.24

Arkansas -0.5 -2.4 1.3 1.54 1.09 2.11

California 0.7 -1 2.5 2.25 2.08 2.42

Colorado 0.4 -0.8 1.5 4.85 4.17 5.53

Connecticut 7.8 -0.5 16.9 1.79 1.35 2.33

Delaware 11.1 -7.2 33 2.75 1.7 4.2

District of Columbia -6.4 -8.5 -4.3 4.17 2.55 6.44

Florida 5.9 3.8 8 2.45 2.21 2.69

Georgia 2.3 0.8 3.9 2.68 2.31 3.04

Idaho 0.9 -1.1 2.9 2.88 2.01 4.01

Illinois 8 4.6 11.6 1.72 1.47 1.98

Indiana 8.3 4.8 11.8 2.04 1.66 2.42

Iowa 13.1 8.9 17.4 1.8 1.31 2.4

Kansas 2.9 -2.8 8.9 2.87 2.23 3.63

Kentucky 7.6 2.4 13 2.83 2.29 3.37

Louisiana -1.6 -3.5 0.4 1.37 1.01 1.81

Maine 10.8 5.8 16 2.04 1.34 3

Maryland -2.5 -3.8 -1.2 1.8 1.45 2.22

Massachusetts 7.3 4.5 10.1 2.22 1.83 2.61

Michigan -0.2 -1.3 0.9 2.6 2.26 2.95

Minnesota 4.8 -1.6 11.6 2.42 1.97 2.87

Mississippi -2.8 -4.3 -1.3 2.4 1.83 3.09

Missouri 5.7 -1.1 12.9 2.19 1.78 2.59

Montana 3.4 1.8 5.1 5.46 3.97 7.34

Nebraska 15.4 9.2 22 - 0.66 1.82

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Nevada 0.5 -0.8 1.8 4.79 3.88 5.71

New Hampshire 2.1 0.6 3.6 3.1 2.19 4.28

New Jersey -1.8 -3.4 -0.2 1.22 0.99 1.49

New Mexico 7.3 3 11.8 8.25 6.84 9.65

New York 3.3 0.4 6.3 2.06 1.85 2.28

North Carolina 5.1 2.1 8.2 2.29 1.95 2.62

North Dakota -3.7 -12.3 5.8 - 1.94 5.33

Ohio 10.2 6.1 14.5 1.37 1.14 1.6

Oklahoma 4.3 2.3 6.2 2.4 1.88 3.01

Oregon 6.8 2.2 11.5 4.4 3.68 5.12

Pennsylvania 3.9 2.5 5.2 1.63 1.39 1.88

Rhode Island 7.8 0.7 15.4 1.99 1.2 3.1

South Carolina 4.1 -4.2 13.1 2.39 1.92 2.87

South Dakota 3.2 -9.3 17.4 3.91 2.53 5.77

Tennessee 7.3 3.7 11 2.16 1.77 2.55

Texas -0.8 -1.8 0.3 1.66 1.47 1.84

Utah 0.8 -0.5 2.2 3.1 2.32 4.05

Vermont 8.5 -1.3 19.3 - 1.45 4.27

Virginia 5.8 2.6 9.1 2.01 1.67 2.35

Washington 0.9 -0.4 2.2 2.12 1.73 2.51

West Virginia 12.3 4.7 20.5 1.85 1.27 2.6

Wisconsin 5.1 0.7 9.7 2.87 2.4 3.34

Wyoming 10.6 -0.8 23.4 - 2.03 5.78

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Supplementary Table 7: Overall Age-Adjusted Death Rates in States with High Rates of Liver-Related Mortality

Alabama Arizona California Kansas Louisiana Maryland New Mexico

Oregon Texas

1999 1575.13 1284.53 1056.49 1336.62 1337.65 1420.2 1310.48 1322.71 1397.74

2000 1572.77 1268.36 1036.79 1338.39 1320.42 1426.56 1255.16 1311.03 1404.93

2001 1570.87 1243.73 1031.74 1326.52 1326.40 1390.96 1297.52 1314.37 1403.18

2002 1587.94 1269.77 1013.31 1336.7 1317.31 1365.93 1282.98 1325.37 1399.6

2003 1602.18 1248.12 1011.31 1306.71 1328.39 1350.22 1296.66 1289.92 1361.31

2004 1563.01 1205.73 966.22 1252.34 1290.91 1285.56 1223.48 1237.8 1316.14

2005 1570.39 1230.14 961.39 1283.9 1339.91 1282.8 1245.50 1242.79 1309.44

2006 1529.44 1196.42 945.22 1260.32 1251.52 1243.26 1236.37 1218.78 1271.30

2007 1494.87 1140.84 910.00 1235.33 1224.84 1223.52 1211.42 1193.24 1264.45

2008 1505.97 1121.34 893.43 1247.24 1239.18 1203.17 1228.56 1189.28 1267.14

2009 1478.56 1089.00 863.54 1191.93 1187.98 1178.37 1168.50 1155.11 1217.51

2010 1476.99 1092.21 854.09 1201.38 1186.41 1146.33 1170.96 1147.54 1220.59

2011 1469.05 1085.20 846.92 1210.45 1163.76 1125.39 1172.05 1146.91 1189.67

2012 1458.72 1076.35 833.93 1198.99 1179.60 1116.41 1162.72 1120.65 1192.09

2013 1456.80 1064.19 833.05 1195.96 1178.60 1119.41 1150.01 1139.97 1189.38

2014 1430.24 1043.43 801.77 1200.42 1175.71 1101.90 1172.83 1122.19 1179.28

2015 1455.28 1061.53 823.11 1225.52 1148.29 1108.99 1156.97 1148.22 1178.86

2016 1442.28 1067.18 817.04 1195.24 1144.04 1125.17 1177.12 1122.11 1155.76

AAPC 2009-2016

-0.4 (-0.7 – 0.01)

-0.5 (-1.0 – 0.0)

-1.0 (-1.2 - -0.9)

-0.1 (-0.6–0.4)

-1.0 (-1.5 – -0.6)

-0.7 (-1.2 - -0.3)

-0.7 (-0.9 - -0.6)

-0.5 (-1.1 – 0.2)

-0.8 (-1.3 - -0.3)

AAPC = average annual percentage change

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Supplementary Table 8: Death-Rates Due to Other Conditions

Cirrhosis Infections Neoplasia Cardiovascular Disease

Respiratory Disease

Age-adjusted Rate

Total Deaths

Age-adjusted Rate

Total Deaths

Age-adjusted Rate

Total Deaths

Age-adjusted Rate

Total Deaths

Age-adjusted Rate

Total Deaths

1999 9.58 20,661 32.94 58,447 301.72 534,316 540.97 951,686 129.37 227,985

2000 9.62 21,003 32.1 57,611 299.75 537,000 526.41 938,843 128.52 229,285

2001 9.58 21,390 32.22 58,805 294.82 537,278 509.62 924,331 125.9 228,203

2002 9.61 21,835 33.8 62,526 291.3 540,015 500.17 920,716 126.67 232,826

2003 9.7 22,496 33.68 63,291 285.75 539,069 482.85 904,465 125.19 233,938

2004 9.39 22,166 33.18 63,312 279.24 535,440 453.9 863,280 118.89 225,342

2005 9.42 22,808 33.53 65,151 276.45 540,134 441.79 858,251 123.15 237,950

2006 9.19 22,717 33.1 65,664 271.39 540,415 415.53 825,146 114.19 224,931

2007 9.28 23,473 32.42 65,578 267.38 542,761 397.93 807,609 112.23 225,547

2008 9.36 24,140 32.55 67,222 262.61 544,306 388.65 805,912 118.66 243,365

2009 9.36 24,736 32.32 68,090 257.88 545,370 369.49 782,260 113.08 236,444

2010 9.72 26,045 30.87 66,178 256.54 551,580 363.02 782,081 110.96 235,777

2011 10.1 27,614 30.67 67,575 250.33 552,251 352.3 781,117 112.94 246,951

2012 10.38 28,971 29.84 67,193 246.12 556,760 345.67 785,154 109.18 244,817

2013 10.65 30,293 30.16 69,444 240.96 558,122 343.61 798,743 112.75 259,381

2014 11.09 32,142 29.33 69,208 237.85 564,249 338.93 805,554 108.96 256,642

2015 11.57 33,968 29.43 70,856 233.52 567,484 343.32 834,308 111.64 269,543

2016 11.42 34,174 28.07 68,791 229.16 568,787 338.26 838,482 107.23 264,353

Average

Annual

Percentage

Change

1999-2016

1.1 (0.8 – 1.4) -0.8 (-1.1 - -0.4) -1.6 (-1.7 - -1.6) -2.7 (-3.2 - -2.3) -1.1 (-1.3 – -0.8)

The absolute number of deaths and age-adjusted death-rate (per 100,000 people) is shown for each year 1999-2016 for cirrhosis, infections (ICD-

10 A00-B99), neoplasia (C00-C48, not including HCC, C22), cardiovascular disease (I00-I99), and Respiratory Disease (J00-J98). The

average annual percentage change is calculated for the whole study period and shown as percentage (95% confidence interval).

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Supplementary Figure 1: Graphical Depiction of Cirrhosis Mortality

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Figure 1: Death-rate Trends by Age-Group 2009-2016 This graph explores changes in mortality by subgroup over the period in which there was an overall increase in cirrhosis mortality. Each bar represents the average annual percentage change in the death-rate due to

cirrhosis and hepatocellular carcinoma (HCC) in all adult age groups from 2009-2016. Panel A depicts changes in overall cirrhosis and HCC mortality; B shows changes by race; C shows changes by sex; and D

shows changes by alcohol-related diagnosis codes.

176x114mm (300 x 300 DPI)

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Figure 2: Age Adjusted Death-rates Attributable to Cirrhosis and Hepatocellular Carcinoma over Time The age-adjusted mortality for each condition in each state is presented in quartiles for the first, middle and last year of the study. Quartiles for each time period are denoted by yellow (first), light orange (second), dark orange (third), and red (fourth). Striped or shaded states imply data that is either unreliable or

suppressed to protect patient identity.

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Figure 3: States with Significant changes in Death-rates Attributable to Cirrhosis and Hepatocellular Carcinoma (HCC) 2009-2016

This graph explores the changes in cirrhosis and HCC mortality at the state level 2009-2016. The average annual percentage change (AAPC) in mortality for each individual state is plotted against the age-adjusted death-rate in 2009. States without significant trends were excluded from this figure for simplicity. Panel A

shows trends for cirrhosis and B shows trends for HCC.

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Figure 4: Average Annual Percentage Change (AAPC) in Mortality Due to Alcohol-Related Disease Note: Many states were excluded from the figures for simplicity because their trends were non-significant

(no changes over the specified timeframes).

Top: The AAPC for mortality by state for alcohol-related cirrhosis (ICD-10 K70.3) is shown for 2009-2016. Bottom: The AAPC for mortality by state for alcohol-use disorder (ICD-10 F10) is shown for 2009-2016.

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cirrhosis and liver cancer mortality in the united states · 2018. 7. 23. · cirrhosis and liver...

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