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LIVER, PANCREAS & BILIARY TRACT: Original Articles

Alcohol-associated Cirrhosis and Alcoholic Hepatitis Hospitalization Trends in the United States

Shirazi, Farah MD*; Singal, Ashwani K. MD; Wong, Robert J. MD, MS

Author Information
Journal of Clinical Gastroenterology: February 2021 - Volume 55 - Issue 2 - p 174-179
doi: 10.1097/MCG.0000000000001378
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Abstract

Alcohol-associated liver disease (ALD) is a major driver of liver-related morbidity and mortality in the United States.1–5 ALD disease spectrum ranges from alcoholic fatty liver disease to advanced ALD (ie, alcoholic hepatitis and alcoholic cirrhosis), and the development of cirrhosis-related complications.6 Alcohol use disorder (AUD) is a major public health concern, and it is estimated that 2.4 billion people worldwide actively use alcohol, and alcohol use contributes to the seventh leading cause of premature death and disability, accounting for nearly 10% of global deaths among populations aged 15 to 49 years.7–9 AUD is a substantial health care problem in the Western World and is a leading cause of mortality in the United States, accounting for nearly 250,000 deaths in 2010.1,10 The prevalence of alcohol use, high-risk drinking, and AUD is increasing at a rapid rate.11 In fact, ALD is responsible for 48% of liver-related deaths and has now become the leading indication for liver transplantation in the United States.12 Furthermore, the increased prevalence of ALD has been linked to significant health care burden, including increases in ALD hospitalizations and health care costs.13 The present study focuses on understanding the clinical burden of ALD by evaluating overall trends in alcoholic cirrhosis and alcoholic hepatitis hospitalizations and in-hospital mortality in the United States. Understanding trends in ALD-related hospitalizations and mortality in specific subgroups can inform how to best allocate resources and to improve long-term outcomes in this group.

METHODS

We retrospectively evaluated US adults (age 18 y and older) hospitalized with a primary diagnosis of alcoholic hepatitis or alcoholic cirrhosis using the 2007-2014 National Inpatient Sample (NIS). The NIS is the largest all-payer inpatient database of hospital discharges in the United States maintained as part of the Healthcare Cost and Utilization Project (HCUP) by the Agency for Healthcare Research and Quality (AHRQ). The NIS contains de-identified information regarding each patient, with participating hospitals sampled based on characteristics such as size, location (rural/urban), geographic region, ownership, and teaching status. Between 2007 and 2011, the NIS comprised all inpatient discharges (100%) from a random 20% sample of acute-care hospitals in the United States Starting in 2012, NIS modified its method of data acquisition to include a systematic sampling of 20% of discharges from all (100%) hospitals stratified by hospital, census division, ownership status, urban versus rural location, teaching status, and bed size, as well as patient diagnosis–related group and admission month. In addition, to facilitate trends analysis spanning NIS data before 2012, new discharge weights called “trend weights” were developed for years before 2012 to replace the original NIS discharge weights. We used the newly provided trend weights for 2007-2011 data, and the provided discharge weights for 2012-2014 data for patient-level analyses.

NIS does not provide data on laboratory values, imaging data, or pathology data from biopsies, and thus disease states were based on International Classification of Diseases, Ninth Revision (ICD-9) codes. Our identification of alcoholic hepatitis or alcoholic cirrhosis–related hospitalizations followed previously validated ICD-based methods for isolating ALD from large claims databases.6,14 Specifically, we first identified all hospitalizations with cirrhosis listed as a primary diagnosis {ICD-9 codes: 571.2 [cirrhosis with alcoholism], 571.5 [cirrhosis no mention of alcohol], 456.0-456.21 [esophageal varices with or without bleeding (EV)], 567.23 [spontaneous bacterial peritonitis], 572.2 [hepatic encephalopathy (HE)], and 572.4 [hepatorenal syndrome (HRS)]}. From this cirrhosis cohort, we excluded patients with hepatitis B virus, hepatitis C virus, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. From this remaining cohort, we then identified individuals with alcoholic cirrhosis, defined as those patients who had diagnosis codes associated with alcoholic liver disease or AUD (ICD-9 codes: 305.00-305.03, 303.90-303.93, 291.9, 291.8, 303.0, 357, 425.5, 577, 571.1×, 571.3×). This stepwise method isolated our alcoholic cirrhosis cohort, which we combined with an alcoholic hepatitis cohort (ICD-9 code: 571.1×) to create our total ALD cohort.

Characteristics of alcoholic cirrhosis and alcoholic hepatitis–related hospitalizations were presented as proportions (%) and frequencies (N) for categorical variables or mean and SD for continuous variables. Comparison across groups utilized χ2 methods for categorical variables and Student t test for continuous variables. National estimates of hospitalizations were obtained by calendar year using individual discharge sampling weights, and sampling strata (used in the NIS to sample hospitals based on geographic region, control, location/teaching status, and bed size) accounted for the survey design effects using Taylor series linearization. Comparisons of hospitalization rates between groups utilized standardized incidence rate ratios (IRRs), which were calculated by dividing the hospitalization rate of the comparator group with the hospitalization rate of the reference group. Annual changes in alcoholic cirrhosis and alcoholic hepatitis hospitalization rates were calculated as the percent change in the number of hospitalizations using 2007 as the reference year. Crude unadjusted in-hospital mortality rates in patients with alcoholic cirrhosis and alcoholic hepatitis were stratified by sex and race/ethnicity, and comparisons between groups utilized χ2 testing. Adjusted multivariate logistic regression models evaluated predictors of in-hospital mortality among alcoholic cirrhosis and alcoholic hepatitis patients, and included adjustments by sex, age, race/ethnicity, primary insurance, year, All Patient-Refined Diagnosis Related Group illness severity, and All Patient-Refined Diagnosis Related Group risk of mortality. All statistical analyses were performed using STATA statistical software package (version 14.0; StataCorp LP, College Station, TX), and statistical significance was met with a 2-tailed P-value <0.05. This study was granted exempt status from Alameda Health System Institutional Review Board.

RESULTS

From 2007 to 2014, there were 159,973 hospitalizations among patients with ALD, 133,929 (83.7%) had a primary diagnosis of alcoholic cirrhosis, and 29,509 (18.4%) had a primary diagnosis of alcoholic hepatitis (Table 1). Of those with alcoholic cirrhosis, 95,692 (71.45%) were male, and predominantly non-Hispanic white (80,092, 59.80%). Among patients with alcoholic hepatitis, 18,984 (64.33%) were male, and 18,533 (71.56%) were non-Hispanic white. When stratified by age, 38,750 (28.94%) individuals in the alcoholic cirrhosis cohort was aged 60 years and over, whereas 3447 (11.68%) individuals in the alcoholic hepatitis cohort was aged 60 years and over.

TABLE 1 - Characteristics of Alcoholic Cirrhosis and Alcoholic Hepatitis Hospitalizations in the United States
n (%)
Variables Total Alcoholic Cirrhosis Alcoholic Hepatitis
Total hospitalizations 159,973 133,929 29,509
 Male 112,479 (70.31) 95,692 (71.45) 18,984 (64.33)
 Female 47,497 (29.69) 38,237 (28.55) 10,525 (35.67)
 Age (y) 52.83 (11.44) 54.16 (10.96) 46.33 (11.36)
 Length of stay (d) 5.95 (7.11) 6.13 (7.29) 5.50 (6.49)
 Total charges ($) 45,077 (74,805) 47,655 (77,690) 34,874 (59,277)
Ethnicity
 Non-Hispanic white 96,395 (60.26) 80,092 (59.80) 18,533 (71.56)
 African American 12,913 (8.07) 10,380 (7.75) 2729 (10.54)
 Hispanic 24,823 (15.52) 22,004 (16.43) 3196 (12.34)
 Asian/Pacific Islander 1427 (0.89) 1174 (0.88) 281 (1.09)
 Native American 3034 (1.90) 2698 (2.01) 395 (1.53)
Age (y)
 <50 58,809 (36.76) 42,804 (31.96) 17,836 (60.44)
 50-59 59,443 (37.16) 52,375 (39.11) 8226 (27.88)
 60-69 30,052 (18.79) 27,704 (20.69) 2756 (9.34)
 ≥70 11,669 (7.29) 11,046 (8.25) 691 (2.34)

When comparing hospitalization rates using IRR, significant differences in hospitalization rates were observed (Table 2). Compared with females, significantly higher hospitalization rates were seen among males with alcoholic hepatitis [IRR=3.71, 95% confidence interval (CI): 3.47-4.01, P<0.01], and alcoholic cirrhosis (IRR=2.68, 95% CI: 2.21-3.71, P<0.01) (Table 2). Compared with non-Hispanic whites, significantly lower hospitalization rates were observed among African Americans and Asian/Pacific Islanders, whereas significantly higher hospitalization rates were observed in Hispanics and Native Americans. These trends were consistent for both alcoholic cirrhosis–related hospitalizations and alcoholic hepatitis–related hospitalizations (Table 2). Significant insurance-specific differences in hospitalization rates were also observed for both alcoholic cirrhosis and alcoholic hepatitis. When compared with patients age younger than 50 years with alcoholic cirrhosis, significantly higher hospitalization rates were observed in patients age 50 to 59 and 60 to 69 years but were lower for age 70 years and over. For alcoholic hepatitis, patients aged 50 to 59 years had slightly higher hospitalization rates than that aged younger than 50 years, whereas lower hospitalization rates were observed in those aged 60 years and over (Table 2).

TABLE 2 - Incidence Rate Ratios for Alcoholic Cirrhosis and Alcoholic Hepatitis by Race, Sex, Age, and Primary Insurance
Alcoholic Cirrhosis Alcoholic Hepatitis
Variables Incidence Rate Ratio 95% Confidence Interval Incidence Rate Ratio 95% Confidence Interval
Gender
 Female 1.00 Reference 1.00 Reference
 Male 3.71 3.47-4.01 2.68 2.21-3.71
Race/ethnicity
 Non-Hispanic white 1.00 Reference 1.00 Reference
 African American 0.61 0.60-0.61 0.70 0.69-0.70
 Hispanic 1.78 1.73-1.84 1.12 1.04-1.23
 Asian/Pacific Islander 0.42 0.40-0.43 0.43 0.39-0.48
 Native American 3.46 3.29-3.64 2.19 1.84-2.73
Age (y)
 <50 1.00 Reference 1.00 Reference
 50-59 2.90 2.81-3.01 1.09 1.07-1.12
 60-69 1.42 1.39-1.46 0.34 0.30-0.37
 ≥70 0.28 0.26-0.29 0.04 0.00-0.07
Primary insurance
 Medicare 1.00 Reference 1.00 Reference
 Medicaid 2.63 2.51-2.77 4.19 3.11-8.13
 Private/commercial 1.31 1.28-1.34 3.79 2.92-6.98
 Self-pay 3.89 3.67-4.15 15.45 10.29-34.31

When evaluating annual trends in hospitalization rates, total alcoholic cirrhosis–related hospitalizations have risen by nearly 20% from 2007 to 2014 (Fig. 1). When stratified by sex, the proportional increase in alcoholic cirrhosis–related hospitalizations was significantly greater in females compared with males (33.5% increase in females vs. 14.7% increase in males, P<0.01) (Fig. 1A). When stratified by race/ethnicity, the greatest proportional increase in alcoholic cirrhosis–related hospitalizations was observed in Native Americans (108% increase), followed by non-Hispanic whites (58.3% increase), African Americans (38.6% increase), Asian/Pacific Islanders (37.5% increase), and Hispanic patients (23.1% increase) (Fig. 2A).

FIGURE 1
FIGURE 1:
Cumulative changes in alcoholic cirrhosis (A) and alcoholic hepatitis (B) hospitalizations in men and women in the United States.
FIGURE 2
FIGURE 2:
Cumulative changes in alcoholic cirrhosis (A) and alcoholic hepatitis (B) hospitalizations by race/ethnicity in the United States.

Total alcoholic hepatitis–related hospitalizations increased by 28.3%. Females experienced significantly greater proportional increases in alcoholic hepatitis–related hospitalizations compared with males (37.6% increase vs. 22.3% increase, P<0.01) (Fig. 1B). When stratified by race/ethnicity, Native Americans demonstrating the greatest increase in hospitalizations from 2007 to 2014 (109% increase), followed by Asian/Pacific Islanders (85% increase), non-Hispanic whites (71.5% increase), African Americans (62.8% increase), and Hispanic patients (46.3%) (Fig. 2B).

Overall in-hospital mortality was 6.98% among alcoholic cirrhosis–related hospitalizations and 2.97% among alcoholic hepatitis–related hospitalizations (Table 3). Compared with non-Hispanic whites with alcoholic cirrhosis, significantly lower in-hospital mortality was observed in Hispanics (5.95% vs. 7.25%, P<0.001), whereas higher mortality was observed in Asian/Pacific Islanders (8.01% vs. 7.25%, P<0.001). Among alcoholic hepatitis–related hospitalizations, African Americans had lower in-hospital mortality compared with non-Hispanic whites (1.69% vs. 3.05%, P<0.001), whereas Asian/Pacific Islanders and Native Americans had higher in-hospital mortality (Table 3). No sex-specific differences in in-hospital mortality were observed. On multivariate regression, compared with non-Hispanic whites hospitalized with alcoholic cirrhosis, significantly higher odds of in-hospital mortality was observed in African Americans [odds ratio (OR)=1.133, 95% CI: 1.04-1.24, P<0.01], whereas lower odds of in-hospital mortality was observed in Hispanics (OR=0.897, 95% CI: 0.84-0.97, P<0.01 (Table 4). Compared with alcoholic cirrhosis patients with private/commercial insurance, higher odds of in-hospital mortality was observed in those with self-pay/no insurance (OR=1.506, 95% CI: 1.39-1.64, P<0.001), whereas there was lower odds of mortality in Medicare patients (OR=0.812, 95% CI: 0.75-0.87, P<0.001). When focusing on the alcoholic hepatitis cohort, compared with non-Hispanic whites, significantly higher odds of in-hospital mortality were observed for Asian/Pacific Islanders (OR=2.019, 95% CI: 1.00-4.06, P=0.048) and Native Americans (OR=1.883, 95% CI: 1.06-3.34, P=0.030), whereas lower odds of in-hospital mortality was observed in African Americans (OR=0.680, 95% CI: 0.48-0.96, P=0.027) (Table 4). No insurance-specific differences were observed. Across both the alcoholic cirrhosis and alcoholic hepatitis cohort, no significant sex-specific differences in mortality were observed.

TABLE 3 - In-hospital Mortality Among Patients Hospitalized for Alcoholic Cirrhosis and Alcoholic Hepatitis
Variables Alcoholic Cirrhosis [n (%)] P Alcoholic Hepatitis [n (%)] P
Total deaths 9342 (6.98) 0.317 877 (2.97) 0.678
 Male 6717 (7.02) 570 (3.00)
 Female 2625 (6.87) 307 (2.92)
Ethnicity <0.001 <0.001
 Non-Hispanic white 5810 (7.25) 565 (3.05)
 African American 788 (7.59) 46 (1.69)
 Hispanic 1309 (5.95) 84 (2.63)
 Asian/Pacific Islander 94 (8.01) 13 (4.63)
 Native American 175 (6.49) 20 (5.06)

TABLE 4 - Multivariate Logistic Regression Model Evaluating Predictors of In-hospital Mortality Among Alcoholic Cirrhosis and Alcoholic Hepatitis Hospitalizations
Variables Odds Ratio 95% Confidence Interval P
Alcoholic cirrhosis
 Sex
  Female 1.000 Reference
  Male 0.977 0.92-1.03 0.418
 Race/ethnicity
  Non-Hispanic white 1.000 Reference
  African American 1.133 1.04-1.24 <0.01
  Hispanic 0.897 0.84-0.96 <0.01
  Asian/Pacific Islander 1.126 0.89-1.42 0.338
  Native American 0.903 0.76-1.07 0.245
 Primary insurance
  Private/commercial 1.000 Reference
  Medicare 0.812 0.75-0.87 < 0.001
  Medicaid 1.009 1.01-1.17 0.021
  Self-pay 1.506 1.39-1.64 < 0.001
Alcoholic hepatitis
 Sex
  Female 1.000 Reference
  Male 0.957 0.80-1.14 0.626
 Race/ethnicity
  Non-Hispanic white 1.000 Reference
  African American 0.680 0.48-0.96 0.027
  Hispanic 1.264 0.96-1.67 0.098
  Asian/Pacific Islander 2.019 1.00-4.06 0.048
  Native American 1.883 1.06-3.34 0.030
 Primary insurance
  Private/commercial 1.000 Reference
  Medicare 1.029 0.78-1.35 0.837
  Medicaid 1.217 0.96-1.53 0.094
  Self-pay 1.147 0.89-1.48 0.287

DISCUSSION

Among a large cohort of US-based hospitalization data, we observed an increasing trend in alcoholic cirrhosis and alcoholic hepatitis–related hospitalizations among adults. While we did not observe any sex-specific differences in in-hospital mortality, there were significantly higher hospitalization rates for men compared with women for both alcoholic cirrhosis and alcoholic hepatitis. In a systematic review on sex differences in alcohol use, women were found to consume less alcohol than men, to drink less frequently, and to be “less likely to be hazardous” drinkers.15 In addition, the US National Epidemiologic Survey on Alcohol and Related Conditions reported higher lifetime prevalence of ALD in men (36%) compared with women (23%).9 However, it is important to note that women who drink alcohol may develop more liver problems than men who drink alcohol, which is largely due to physiological differences including less gastric alcohol dehydrogenase and increased circulating alcohol levels due to smaller volume of distribution.16 The results of our study also support the hypothesis that men may be more prone to alcohol dependence and excess alcohol consumption.8 This hypothesis may specifically also hold true in the United States.8,17 Despite increasing rates of harmful alcohol use among women,6 our study demonstrates higher hospitalization rates for men. However, it is important to note that our current dataset is limited to inpatient hospitalizations, and thus alcoholic cirrhosis may be less frequently diagnosed in women, therefore giving the impression that more men are hospitalized for alcoholic cirrhosis.18

Our study also demonstrated that Hispanics and Native Americans had significantly higher hospitalization rates for alcoholic cirrhosis and alcoholic hepatitis compared with non-Hispanic whites. On the basis of the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, Native Americans and Hispanics had greater alcohol consumption than other ethnic minority groups. In fact, weekly heavy drinking was highest among Native Americans.19 Possible explanations for these results may include a lack of supportive environments, fewer resources for preventive care, and minority populations being less likely to seek help for AUD. There may also be a component of ethnic/culture-related vulnerabilities, including drinkers with lower socioeconomic status often indicate a higher prevalence of problems with alcohol abuse and dependence.20 Significant differences in mortality rates were noted among Asian/Pacific Islanders, African Americans, and Native Americans. Previous data from May and colleagues using the 2008-2011 NIS data, evaluated alcoholic hepatitis hospitalizations observed the whites with alcoholic hepatitis had significantly lower hospitalization length of stay, but that blacks had significantly higher in-hospital mortality, and Hispanics had significantly higher hospitalizations costs than whites hospitalized with alcoholic hepatitis.21

In general, there are multiple socioeconomic factors associated with ethnic disparities that can contribute to alcohol-related liver disease including lower socioeconomic status, greater neighborhood alcohol availability, reduced alcohol rehabilitation programs, and neighborhood poverty.22–25 In addition, African Americans have been shown to experience negative health effects from alcohol use despite showing the later onset of use and levels of use often lower than whites.19 Thus, in addition to socioeconomic factors, biological differences related to alcohol metabolism may also be an important factor in the observed differences.

The strengths of the study include the utilization of a comprehensive hospitalization dataset, the NIS, which is the largest all-payer inpatient hospitalization discharge database in the United States, which improves the generalizability of our findings. In addition, we utilized a systematic and validated algorithm to identify alcoholic cirrhosis and alcoholic hepatitis hospitalizations, to provide a more comprehensive analysis of ALD epidemiology in the United States. However, our study has certain limitations. The NIS does not allow for patient-specific identification; therefore, we were unable to link inpatient hospital admission with outpatient medical records to determine whether outpatient factors, such as medication adherence access to subspecialty care, readmission, or implementation of quality of care guidelines. Further, given our focus on inpatient disease burden, patients with ALD in the outpatient setting who are undiagnosed or never progressed to hospitalization were not accurately captured in our analyses. In addition, this database does not include Veterans Administration hospitals, an exclusion which likely results in an underestimation of overall inpatient mortality for liver disease given the high burden of alcohol-related liver disease with the Veterans Administration population.26 Finally, it is important to note that the NIS is an observational cross-sectional database, whereby disease diagnoses and identified based on ICD-9 claims data. However, our methodology used has been previously well-validated to accurately identify the cohort of patients with alcoholic cirrhosis and alcoholic hepatitis. Furthermore, while specific details such as laboratory data or imaging data were not available for more granular assessment of disease severity, we did incorporate ICD-9 coding as detailed in the method section to account for cirrhosis-related complications and we further employed All Patient-Refined Diagnosis Related Group illness severity and All Patient-Refined Diagnosis Related Group risk of mortality variables that were provide by the NIS dataset to incorporate into our multivariate models. Yet, the potential for unmeasured confounders persist, and thus the data presented must be interpreted in light of the limitations of retrospective observational cohort studies based on claims data.

In conclusion, a comprehensive assessment of inpatient hospitalization data in the United States demonstrated increasing rates of alcoholic cirrhosis and alcoholic hepatitis hospitalizations. The highest rates were observed in men and among Native American and Hispanic ethnic minorities. The disparately higher rates of in-hospital mortality observed for ethnic minorities is also alarming. While there are no specific medical therapies for the treatment of ALD, our current study along with existing studies1,6,27 emphasizes the importance of raising awareness of unhealthy alcohol use among US adults. Particularly, the disparities observed in the present study may be helpful in steering future health care policies to curtail the negative impact of alcohol on vulnerable communities including marketing regulation, effective screening, focused addiction and abstinence counseling, support groups, rehabilitation programs, psychosocial support, and education.

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Keywords:

alcohol use disorder; alcoholic hepatitis; alcoholic cirrhosis; Nationwide Inpatient Sample; alcoholic liver disease

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