Hepatitis C and hospital outcomes in patients admitted

with alcohol-related problems*

Judith I. Tsui1,†,*, Mark J. Pletcher2, Eric Vittinghoff3, Karen Seal4, Ralph Gonzales5

1Division of General Medicine, General Internal Medicine Section (111A1), San Francisco Veteran Administration Medical Center,

University of California, 4150 Clement Street, San Francisco, CA 94121, USA2Department of Epidemiology and Biostatistics, Division of General Internal Medicine, University of California, San Francisco, CA 94121, USA

3Division of Biostatistics, Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA4University of California, Veterans Administration Medical Center, San Francisco, CA, USA

5Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, CA, USA

Background/Aims: Alcohol is known to act synergistically with chronic hepatitis C virus (HCV) infection to cause liver

disease; however, their combined effect on outcomes in acutely hospitalized patients is less clear. We examined the impact

of HCV infection on hospital mortality and length of stay among hospitalized patients with alcohol abuse problems.Methods: We retrospectively identified 6354 admissions to an urban, public hospital between July 1996 and January

2002 with discharge diagnoses related to alcohol dependence or abuse. Hepatitis C diagnosis and other information

were extracted from a clinical database and tested for associations with death and length of hospital stay using

multivariable regression techniques.Results: The prevalence of diagnosed HCV infection in this sample of patients with alcohol abuse was 15%. Patients

with HCV were about twice as likely to die during hospital admission (4.4 vs. 2.4%; P-value!0.01), and there appeared

to be a trend toward increased mortality even after adjustment for demographics, medical service, homelessness and

comorbidities (fully adjusted OR 1.41; 95% CI: 0.97–2.04). Length of stay was significantly longer for patients with

HCV (19% longer; 95% CI: 12–27% after adjustment) than those without.

Conclusions: Patients admitted to the hospital with alcohol-related diagnoses have longer hospital stays and are more

likely to die in hospital if they have a diagnosis of HCV.

q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: Viral hepatitis; Alcohol; Alcohol use disorders

1. Introduction

Chronic infection with hepatitis C virus (HCV) is the

most common bloodstream infection in the US affecting

approximately 3.9 million individuals [1]. Chronic HCV is a

slowly progressive disease that causes liver fibrosis,

0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Pub

doi:10.1016/j.jhep.2005.07.027

Received 17 May 2005; received in revised form 12 July 2005; accepted 22

July 2005; available online 24 August 2005* Data presented as a poster at the Society for General Internal Medicine

National Meeting, New Orleans on May 14, 2005.* Corresponding author. Tel.: C1 415 221 4810x4849; fax: C1 415 379

5573.

E-mail address: judith.tsui@med.va.gov (J.I. Tsui).

† Dr Tsui had full access to all the data in the study and takes reponsibility

for the integrity of the data and the accuracy of the data analysis.

cirrhosis and hepatocellular cancer over the course of

decades [2–4]. How often and how rapidly the disease

progresses, however, varies by individual. One important

predictor of progression and severity of liver disease is

concurrent alcohol consumption which appears to act

synergistically with HCV [5]. Numerous studies have

shown that moderate to heavy amounts of alcohol use are

associated with more rapid progression of liver fibrosis, and

increased risk for clinical cirrhosis and hepatocellular

cancer among patients with chronic HCV [2–4,6,7].

Few studies have examined the relationship between

alcohol and HCV on outcomes among hospitalized patients.

One large study using a national sample of hospitalizations

found that among patients with a diagnosis of HCV, alcohol

abuse was associated with a forty percent increased odds of

Journal of Hepatology 44 (2006) 262–266

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J.I. Tsui et al. / Journal of Hepatology 44 (2006) 262–266 263

death [8]. However, the same study observed that among

hospitalized patients with alcohol-related liver disease, a

diagnosis of HCV infection was not associated with

increased risk of death. No study has examined whether

HCV infection is associated with adverse hospital outcomes

among patients admitted with problems related to alcohol

abuse and dependence, but who are not necessarily known

to have pre-existing liver disease. Since, alcohol abuse is

common among patients admitted to the hospital [9], and

the prevalence of HCV is higher among alcoholics than the

general population [10–13], it is important to know whether

patients with alcohol abuse who are admitted to the hospital

are at risk for adverse events so that appropriate clinical

strategies can be undertaken.

This study examines the effects of HCV among

hospitalized patients who abuse alcohol on mortality and

length of stay. We hypothesized that among patients who

were admitted with alcohol-related diagnoses, those with a

diagnosis of HCV would be more likely to die in the hospital

and have longer hospital stays.

2. Methods

2.1. Study design and sample

In order to compare outcomes among hospitalized alcohol-abusingpatients with and without HCV, we performed a retrospective cohort studyof in-hospital death and length of stay among patients hospitalized at SanFrancisco General Hospital (SFGH) with an alcohol abuse-relateddiagnosis. We began by searching all hospital admissions to the FamilyPractice or Medicine Inpatient Services at SFGH between July 1, 1996 andJanuary 15, 2002, using a clinical database maintained by the University ofCalifornia San Francisco (UCSF) General Clinical Research Center thatincluded all hospital admissions. Admissions were included if theycontained at least one of the following alcohol-related InternationalClassification of Diseases, 9th, Clinical Modification (ICD-9) codes amongtheir discharge diagnoses codes: 303 (alcohol dependence), 305.0 (alcoholabuse) and 291 (mental disorders associated with alcohol). These ICD-9codes have been used to define individuals with alcohol abuse in previousstudies.[8,14] Approval for the study was granted by the local Committee ofHuman Research.

2.2. Identifying patients with hepatitis C

Diagnosis of HCV was considered to be present if the patients’discharge diagnosis codes included any one of the following ICD-9 codesrelated to acute or chronic hepatitis C: 70.41 (acute or unspecified hepatitisC with hepatic coma), 70.44 (chronic hepatitis C with hepatic coma), 70.51(acute or unspecified hepatitis C without mention of hepatic coma), 70.54(chronic hepatitis C without mention of hepatic coma), and V2.62 (hepatitisC carrier).

2.3. Measurement of the outcome

The outcomes of interest were death during hospitalization and lengthof hospital stay. Death from any cause was included and length of stay wascalculated from admission and discharge dates. Admissions that weredischarged on the same day were counted as one day for the length of stayanalysis. Because length of stay data was skewed, the outcome was logtransformed for linear regression analysis. Beta coefficients were backtransformed so that results could be expressed as percentage increase ordecrease in length of stay.

2.4. Other measurements

Information on the following variables was also included in theanalysis: age, sex, race/ethnicity (White, Black, Hispanic, Asian, andOther), type of service (Internal Medicine or Family Practice), homelessstatus, and comorbid diagnoses. In order to capture information oncomorbidities, the Charlson comorbidity index score was calculated foreach visit based on ICD-9 codes. The Charlson index was developed topredict the risk of mortality from comorbid conditions and has been adaptedfor use with ICD-9 administrative databases.[15,16] It uses a system ofweighted scoring based on 19 comorbid conditions to assign a summaryscore that is predictive of risk. It includes ICD-9 codes for liver disease(cirrhosis, portal hypertension, hepatorenal syndrome and other sequelae ofchronic liver disease), but does not specifically include viral hepatitis. Datawere complete on all covariates.

2.5. Statistical analysis

Characteristics of patients with and without a diagnosis of HCV werecompared using a t-test for continuous variables and a chi-square test forcategorical variables. Bivariate analyses were conducted to examine theunadjusted associations between death and the other variables, includingHCV. Multivariable logistic regression analysis was used to examine theindependent relationship between hepatitis C infection and in-hospitaldeath, and linear regression was used to assess the independent relationshipbetween log-length of stay (log transformed for normality) and HCV.Variables were consecutively added to a model containing HCV to assesstheir effects on the relationship between HCV and the outcome. Statisticalanalyses were carried out with Stata version 8.2 (Stata Corporation, CollegeStation, TX), and all multivariable analyses were conducted clustering byindividual, as some individuals contributed to more than one admission inour analysis sample. A P-value of less than 0.05 was considered significantfor all statistical testing, and all P-values reported are for two-sided testing.

3. Results

3.1. Study sample

We identified 6354 hospital admissions meeting our

inclusion criteria. Fifteen percent (984/6354) of these had a

concurrent diagnosis of HCV infection. Patients with HCV

in our sample were significantly more likely to be female,

African–American, and to be between the ages of 40 and 50

years (Table 1). Patients with HCV also had more

comorbidities as reflected by a higher Charlson score

(mean Charlson score 2.2 for HCV patients vs. 1.4 for

others, P-value!0.0001).

3.2. Length of stay

Overall, the patients in our sample stayed in the hospital

between one and 162 days before discharge (meanZ6.3;

medianZ4 days, interquartile range: 2–7 days). Among

patients with a diagnosis of HCV, the mean length of stay

was 7.7 days compared to 6.0 days for non-HCV patients

(P-value !0.001). Using linear regression, we determined

that the length of stay was 24% longer among patients with

HCV (95% CI: 16–32%), and this difference remained,

attenuated slightly, after adjustment for the covariates age,

gender, race, medical service, homelessness and Charlson

score (adjusted % change: 19%; 95% CI: 12–27%)

(Table 2).

Table 1

Characteristics of patients admitted with alcohol diagnoses by hepatitis C status

No Hepatitis C Hepatitis C P-value*

(nZ5548) (nZ984)

N % N %

Gender Female 998 18 261 27 !0.01

Male 4550 82 723 73

Race White 2253 41 425 43 !0.01

Black 1792 32 371 38

Hispanic 1064 19 116 12

Asian 192 4 15 2

Unknown/other 247 4 57 6

Age !30 226 4 20 2 !0.01

30–39 1196 22 166 17

40–49 2176 39 485 49

50–59 1178 21 260 26

O60 772 14 53 5

Mean 47G11 46G8 0.02

Service Family practice 993 18 172 17 0.75

Internal medicine 4555 82 812 83

Homeless No 3656 66 633 64 0.34

Yes 1892 34 351 36

Charlson score 0 2657 48 326 33 !0.01

1–2 1830 33 320 33

R3 1061 19 338 34

Pearson’s chi-square test for all variables, except mean age which uses t-test statistic.

J.I. Tsui et al. / Journal of Hepatology 44 (2006) 262–266264

3.3. In-hospital mortality

The overall risk of death was 2.7% in our sample. Deaths

occurred in 2.4% (135/5548) of non-HCV alcohol-related

admissions, vs. 4.4% (43/984) of HCV associated alcohol-

related admissions (Pearsons c2Z11.82; P-valueZ0.001).

In a multivariable model that accounted for sex, age, race,

medical service, homeless status and comorbidities, there

remained a trend toward increased mortality associated with

a diagnosis of HCV (OR 1.41, 95% CI: 0.97–2.04)

(Table 3).

4. Discussion

In this study, we found that hospitalized patients with

alcohol abuse problems were more likely to suffer adverse

hospital outcomes (death and longer length of stay) if they

had a diagnosis of HCV. In the crude analysis, patients with

Table 2

Effect of hepatitis C on hospital length of stay, with stepwise adjustment for

b coefficient for hepatitis Ca (95%

Crude 0.21 (0.15–0.28)

Adjusted for sex/age/race 0.23 (0.17–0.30)

Adjusted for aboveCmedical service/

homelessness

0.23 (0.17–0.30)

Adjusted for above CCharlson score 0.18 (0.12–0.24)

a For models where outcome is log length of stay (log transformed because ofb For example, a patient without HCV who stayed in the hospital for 4 days, w

HCV were approximately twice as likely to die during

hospitalization, and had hospital stays that were about 25%

longer. After adjustment for age, sex, race, medical status,

and homeless status, length of stay was still significantly

longer for patients with HCV and there remained a trend

toward increased mortality.

We believe this is the first study to examine the effects of

diagnosed HCV on hospital outcomes among an unselected

group of hospitalized patients who have alcohol-related

diagnoses. Previous studies have looked at the impact of

HCV on hospital outcomes among patients with alcoholic

liver disease, and found no additional risk of death

associated with HCV.[8,17] However, patients who are

diagnosed with alcoholic liver disease may represent a

subset of patients who already have advanced liver disease/

cirrhosis, such that infection with HCV does not confer an

additional risk of death. Our study looked at patients with

alcohol-related diagnoses, not confirmed alcoholic liver

disease, among which there may have been a wider

other variables

CI) % increase in length of stay (95% CI) P-value

24% (16–32%)b !0.01

26% (19–34%) !0.01

26% (19–34%) !0.01

19% (12–27%) 0.04

non-normality of data).

ould instead stay 5 days (about 25% longer) if he/she had HCV.

Table 3

Association between hepatitis C and in-hospital death, with stepwise

adjustment for other variables

OR (95% CI) P-value

Crude 1.83 (1.29–2.60) !0.01

Adjusted for sex/age/race 2.02 (1.41–2.90) !0.01

Adjusted for aboveCmedical

service

2.02 (1.41–2.90) !0.01

Adjusted for aboveCCharlson score 1.41 (0.97–2.04) 0.07

J.I. Tsui et al. / Journal of Hepatology 44 (2006) 262–266 265

spectrum of drinking behaviors and liver pathology. Our

findings showed that among a sample of patients admitted

with alcohol-related diagnoses, the patients with HCV were

more likely to die during the hospitalization, even after

adjusting for demographic factors, medical service, and

homelessness. Adjusting for Charlson index diminished the

strength of the association between HCV and death

somewhat; however, there remained a trend toward

increased mortality among those with a diagnosis of HCV.

Since Charlson index encompasses liver disease diagnoses,

we can hypothesize that patients with HCV were more

likely to have a higher score because of more frequent liver

disease, which would then increase their risk of mortality.

Therefore, adjusting for Charlson index should attenuate the

association between HCV and death, as we saw in our

results. Given that there was a trend toward increased

mortality among those with HCV even after adjustment for

Charlson, we cannot exclude the possibility that HCV could

be associated with more in-hospital deaths due to other non-

liver disease related conditions that associate with HCV,

such as complications of drug use or other infections.

Interestingly, a diagnosis of HCV was found to be

independently associated with longer hospital stay, even

after adjusting for Charlson index. This suggests that HCV

infection may complicate hospitalizations in ways that are

not fully accounted for by liver disease. Chronic HCV

infection can have numerous non-hepatic manifestations

(renal, autoimmune, etc.), and also is associated with

depression and fatigue, which may complicate clinical

course and lead to a longer length of stay. Another

explanation for this finding is that HCV infection may be

associated with other unmeasured confounders such as

injection drug use, more severe alcohol use, or HIV which

could in turn impact length of hospital stay.

There are a number of limitations to this study, including

lack of information on other potentially important covari-

ates, including both the patient-level (HIV, illicit drug use,

detailed information on drinking behaviors, degree of liver

disease/liver dysfunction, etc.) and provider-level (type of

treatments received, experience of provider, etc.) factors.

Another limitation of the study is imperfect measurement of

HCV status and alcohol abuse by relying on ICD-9 codes. In

particular, the use of ICD-9 codes to determine HCV

infection makes misclassification a likely phenomenon.

Many patients with the diagnosis of chronic hepatitis C may

not have had PCR testing to confirm persistent infection

(approximately 15–25% of individuals with a positive

screening EIA test will have cleared the virus[18]), and

therefore have been misclassified as being infected with

HCV. However, patients with HCV whose infection did not

directly impact their hospital admission may not have had

their diagnosis noted among discharge diagnosis codes,

resulting in being misclassified as HCV-negative. The

prevalence of HCV diagnoses in this sample was much

higher than the national estimate[1] (15 vs. 2%) and

comparable to prevalence estimates based on serum

antibody and PCR testing in similar populations (patients

with alcohol use problems)[10–13], suggesting that use of

ICD-9 codes may approximate true prevalence. Finally, we

had no information on treatments provided and limited

information on cause of death, making it impossible to

determine if death occurred because of a error of manage-

ment (e.g. over-treatment with benzodiazepines for alcohol

withdrawal of a HCV-infected patient with unrecognized

severe liver disease) or from complications of the HCV

itself (cirrhosis, end-stage liver disease, liver cancer, etc.) or

other associated conditions, such as injection drug use or

HIV-related complications.

HCV infection appears to be an important predictor of

death and longer length of stay among patients hospitalized

with alcohol-related problems. Recognition of the increased

risk for adverse hospital outcomes among this population

highlights the need for improvements in care among patients

with alcohol use disorders with HCV. Efforts to improve

care could include more aggressive screening for HCV

among patients with alcohol abuse and expedited referral for

treatment for substance abuse and chronic hepatitis C.

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