Digestive Diseases and Sciences

, Volume 52, Issue 2, pp 570–578

Clinical Implications of Hepatic Steatosis in Patients with Chronic Hepatitis C: A Multicenter Study of U.S. Veterans

Authors

    • Contributed to this study when he was the staff hepatologist at Loma Linda VA Medical Center
    • Division of Gastroenterology/HepatologyUniversity of California, Irvine, 101 The City Drive
  • Sue L. Currie
    • Veteran Affairs Medical Center
  • Hui Shen
    • Veteran Affairs Medical Center
  • Ramsey C. Cheung
    • Veteran Affairs Medical Center
  • Samuel B. Ho
    • Veteran Affairs Medical Center
  • Edmund J. Bini
    • Veteran Affairs Medical Center
  • John D. McCracken
    • Contributed to this study when he was the staff Gastroenterologist at Loma Linda VA Medical Center
    • Kaiser Permanente 2025 Morse Avenue Sacramento
  • Tim Morgan
    • Veteran Affairs Medical Center
  • Norbert Bräu
    • Veteran Affairs Medical Center
  • Warren N. Schmidt
    • Veteran Affairs Medical Center
  • Lennox Jeffers
    • Veteran Affairs Medical Center
  • Teresa L. Wright
    • Veteran Affairs Medical Center
  • for the VA HCV-001 Study Grouptitle
Original Paper

DOI: 10.1007/s10620-006-9418-4

Cite this article as:
Hu, K., Currie, S.L., Shen, H. et al. Dig Dis Sci (2007) 52: 570. doi:10.1007/s10620-006-9418-4

Abstract

Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). To address the impact of steatosis on the clinical course of CHC and treatment response requires large multicenter studies. The present study analyzed hepatitis C virus (HCV)-infected veterans enrolled in a U.S. Veteran Administration multicenter study of the epidemiology and response to interferon α-2b and ribavirin treatment. Of the 357 patients, 97.1% were males, with a mean age of 48.7±6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3±5.2 kg/m2, including 37.1% who were obese (BMI, ≥30 kg/m2). Stage III–IV fibrosis was present in 111 of 334 (33.3%) of the patients. After adjusting for age, race, and history of alcohol use in the past 12 months, only stage III–IV fibrosis was independently and significantly associated with hepatic steatosis (P=0.03). There was a trend of association between obesity and steatosis independent of the other factors. Only HCV genotype was independently associated with a sustained virological response (SVR) to interferon α-2b and ribavirin treatment after adjusting for age, alcohol use, steatosis, BMI, stage III–IV fibrosis, serum AFP, and HCV load. In conclusion, analyses of our multicenter trial data demonstrated that the prevalence of hepatic steatosis is 51.5% in HCV-infected U.S. veterans. We found that steatosis is independently associated with stage III–IV fibrosis. However, only HCV genotype, and not steatosis, obesity, or stage III–IV fibrosis, was associated with SVR to interferon α-2b and ribavirin treatment.

Keywords

Hepatitis C virusChronic hepatitis CHepatic steatosisObesityBody mass indexHepatic fibrosis

Introduction

Chronic hepatitis C virus (HCV) infection is estimated to affect 2.7 million individuals in the United States [13]. Factors that may impact disease progression, development of cirrhosis, and treatment response have been extensively studied [310] but are not yet completely understood. Hepatic steatosis is a common histological feature of HCV infection [1125]. Although studies have indicated that hepatic steatosis may negatively impact the disease course and treatment response of chronic hepatitis C (CHC), these studies included small cohorts of patients from a single center [1125]. Thus, studies of large sample size with diverse population from multicenters are needed to better define the association of steatosis with HCV disease progression and treatment response.

Factors associated with steatosis in patients with CHC can be classified by virus or host origins [24, 25]. Obesity is probably one of the most important host risk factors reported to be associated with steatosis in CHC patients [17, 24, 25]. Although many studies have found the association of HCV genotype 3 (HCV-3) infection with steatosis [12, 22, 26, 27], this was not supported by other studies [17, 19]. Whether the presence of steatosis impacts HCV treatment response remains controversial [25]. Some [8, 18, 23], but not all [9] studies have suggested that steatosis may negatively affect HCV treatment response.

HCV infection is more common in U.S. veterans than the general population [28, 29]. Other potential confounding factors of steatosis such as type 2 diabetes mellitus and obesity are also common among veterans, as is alcohol use. It remains unknown whether the prevalence of hepatic steatosis in veterans is comparable to nonveterans and how steatosis affects HCV disease progression and treatment response. More than 4000 patients with CHC were enrolled in a prospective multicenter study between 1999 and 2000 at 24 Veterans Administration (VA) Medical Centers in the United States [10, 30, 31]. The aims of the current study were to determine the prevalence of and the risk factors for hepatic steatosis and to evaluate the association between steatosis and HCV treatment response in U.S. veterans with CHC.

Patients and methods

Patient population

The present study was conducted through analysis of a multicenter prospective study conducted between December 1999 and December 2000 that assessed epidemiology, treatment eligibility, and interferon α-2b and ribavirin treatment response of U.S. veterans. A total of 4084 patients were recruited into the study from the gastroenterology, hepatology, and infectious disease clinics at 24 VA medical centers throughout the United States [10, 30, 31]. The study was approved by the local Institutional Review Board at each participating medical center and all subjects signed informed consent to participate.

The inclusion criteria for the present study were (1) positive HCV RNA by reverse transcription polymerase chain reaction (RT-PCR) for at least 6 months; (2) negative serology for HBsAg and anti-HIV; (3) a liver biopsy to stage CHC; (4) documented report for presence or absence of hepatic steatosis; and (5) absence of hepatic decompensation defined as the presence of ascites, jaundice (total bilirubin >3 mg/dl or 51 μmol/L), variceal bleeding, or hepatic encephalopathy [6]. Three hundred fifty-seven of the 4084 patients met all these criteria and were included in the present study.

Data collection

The original study consisted of two phases. The first phase of the study (screening phase) evaluated the epidemiology of HCV and treatment candidacy among U.S. veterans. The second phase of the study (treatment phase) determined the response to therapy in those who were subsequently treated with interferon α-2b and ribavirin [30]. At the time of enrollment, all patients received comprehensive counseling regarding HCV disease, risk of transmission, lifestyle changes, medical prognosis, and treatment options. Patients were interviewed by trained research coordinators who obtained detailed demographic and risk factor information. Data collected on each patient included age, gender, ethnicity, era of military service, level of education, annual household income, use of alcohol, and risk factors for HCV, including blood contact during combat, blood transfusions, injection drug use, needle stick injuries, acupuncture, tattoo, body piercing, incarceration for more than 48 hr, intranasal cocaine use, and sexual history. Information on patients’ height and weight were also recorded to determine the body mass index (BMI). In accordance with the National Institutes of Health criteria, patients with a BMI between 25 and 29.9 kg/m2 were categorized as overweight, and patients with a BMI ≥30 kg/m2 were categorized as obese [32].

In addition, results of standard laboratory testing (complete blood count, hepatic panel, prothrombin time, electrolytes, and α-fetoprotein [AFP]), HCV RNA level, and HCV genotype were recorded on standardized data collection sheets. The presence of HCV RNA was determined using the COBAS Amplicor HCV Monitor Test version 2.0 or the COBAS Amplicor HCV Test version 2.0 (Roche Diagnostics, Branchburg, NJ), while HCV genotyping was performed using the Inno-LiPA HCV II assay (Innogenetics, Gent, Belgium). All data were entered on case report forms and faxed to a central location (Therapeias Health Management, Claremont, CA) for review and processing.

A standard course of interferon α-2b and ribavirin treatment was prescribed according to the VA Treatment Recommendations at the time of the study, which was 24 weeks for HCV genotype 2 or 3 infection and 48 weeks for all other genotypes of HCV infection. To assess the association of treatment response with steatosis, an intent-to-treat analysis (ITT) was conducted for sustained virological response (SVR), which was defined as undetectable HCV RNA 24 weeks after a full course of HCV treatment is accomplished [10, 30, 31].

Hepatic histology

All liver tissue were fixed and stained with hematoxylin–eosin and trichrome. The liver biopsy slides were reviewed by experienced pathologists at each study site using a modified Knodell scoring system to stage hepatic fibrosis [17, 33]. While stage 0 represented the absence of hepatic fibrosis, stages III–IV represented advanced hepatic fibrosis. Steatosis was reported as a dichotomous variable indicating its presence or absence.

Statistical analysis

The descriptive data were presented as percentage or mean with standard deviation or range. Median HCV RNA viral load was provided and stratified as a dichotomous variable due to variation in viral load reporting between centers. Medians for other categorical variables were also provided. Either chi-square test, Student t test, or ANOVA was used to compare frequencies or means, respectively. Univariate analyses were conducted for associations between clinical, biochemical, and virological parameters and steatosis and SVR. Multivariate analyses were then conducted using factors that were significant in the univariate analyses or that had been identified as significant in previous studies. Odds ratios and 95% confidence interval ranges were calculated using logistic regression models [17, 35, 36] to identify the clinical and biochemical/virologic parameters associated with steatosis and sustained virologic response to interferon α-2b and ribavirin treatment. A P value ≤0.05 was considered statistically significant. All statistical analyses were conducted using SAS and SPSS statistical software.

Results

Baseline demographic findings

The baseline demographic data are summarized in Table 1. The mean age in this cohort of veterans was 48.7 ± 6.4 (19–72) years, and 97.1% were male patients. Of the cohort, 62.5% were Caucasian, 22.8% were African American, and 11.2% were Hispanic. Information on the BMI was available for 307 (86%) of the 357 veterans. The mean BMI was 29.3 ± 5.2 (18.6–51.0) kg/m2, with 124 of 267 (46.4%) considered overweight based on BMI and 99 of 267 (37.1%) considered obese. Of 335 patients with documented histories of alcohol use, 73.4% reported a history of alcohol use ≥3 drinks/day, and 29.1% admitted to alcohol use in the 12 months prior to enrollment.
Table 1

Baseline demographics of the 357 enrolled patients

Variable

Cases

Mean ± SD (%)

Median (range)

Mean age at entry

339

48.7 ± 6.4

49.0 (19.0–72.0) yr

Male:female

349

339:10 (97.1%:2.9%)

 

Ethnicity

355

  

 African American

81

22.8%

 

 Caucasian

222

62.5%

 

 Hispanic

40

11.2%

 

 Other

12

 3.4%

 

History of regular alcohol

335

  

 <3 drinks/day

89

26.6%

 

 ≥3 drinks/day

246

73.4%

 

Alcohol in the past 12 months

351

  

 No

249

70.9%

 

 Yes

102

29.1%

 

BMI

267

29.3 ± 5.2

28.6 (18.6–51.0) kg/m2

Fibrosis staging

334

  

 0

50

15.0%

 

 I

88

26.4%

 

 II

85

25.5%

 

 III

72

21.6%

 

 IV

39

11.7%

 

Hepatic steatosis

357

  

 No

173

48.5%

 

 Yes

184

51.5%

 

HCV genotyping

340

  

 1

230

67.7%

 

 2

43

12.7%

 

 3

36

10.6%

 

 4

 3

 0.9%

 

 Mix

28

 8.2%

 

HCV RNA

339

 1.6×106 ± 1.5×106

 1×106 (1×103–5×106) copies/ml

Biochemistry

   

 ALT

346

95.9 ± 53.2

80.5 (15.0–296.0) IU/L

 AST

349

73.6 ± 45.9

59.0 (20.0–288.0) IU/L

 Platelets

350

199.5 ± 56.7

200.0 (79.0–361.0)×109/L

 AFP

294

 7.3 ± 7.2

 5.0 (0.0–44.2) ng/L

Sustained virologic response

254

  

 No

196

77.2%

 

 Yes

58

22.8%

 

The liver biopsy showed stage 0–II fibrosis in 223 (66.4%), while 72 (21.6%) and 39 (11.7%) had stage III and IV fibrosis, respectively. In the present study, patients with stage III and IV fibrosis were combined into a group defined as having advanced fibrosis (33.6%). Of the 357 patients with histological reports on steatosis, 184 (51.5%) cases recorded the presence of hepatic steatosis.

The mean ALT, AST, and platelet count were 95.9 ± 53.2 (15.0–296.0) IU/L, 73.6 ± 45.9 (15.0–296.0) IU/L, and 199.5 ± 56.7 (79.0–361.0)×109/L, respectively. ALTs >45 IU/L and ASTs >40 IU/L were seen in 303 of 346 (87.6%) and 284 of 349 (81.4%) patients, respectively. Platelet counts <130×109/L were seen in 43 of 350 (12.3%) patients. In 294 cases who had an AFP done, the mean AFP was 7.3 ± 7.2 (0.0–44.2) μg/L, including 46 (15.7%) who had an AFP >10 μg/L. Virologically, 230 of 340 (67.7%) had HCV genotype 1 infection. The mean HCV RNA level was 1.6×106 copies/ml, and 95 of 339 (28.0%) had HCV RNA levels >2×106 copies/ml.

Parameters associated with hepatic steatosis

First, univariate analysis was used to assess eight clinical parameters for their association with hepatic steatosis. As shown in Table 2, African Americans and obesity based on BMI were significantly associated with presence of steatosis. Stage III–IV fibrosis was more frequently seen in those with hepatic steatosis, but this did not reach statistical significance. Age, gender, and history of alcohol use, including duration, amount, and recent use, were not associated with hepatic steatosis. Multivariate analysis indicated that stage III–IV fibrosis was significantly associated with steatosis independent of age, gender, history of drinking in the past 12 months, and obesity. In addition, there was an association between obesity and steatosis independent of the other factors but this did not reach significance (Table 3, upper panel).
Table 2

Univariate analysis of clinical, biochemical, and virological factors associated with hepatic steatosis

 

Presence of steatosis

Parameters

Cases (%)

OR (95% CI)

P value

Clinical

   

Age (yr)

   

 <50

90/192 (46.9%)

1.43 (0.93–2.20)

0.1040

 ≥50

82/147 (55.8%)

  

Sex

   

 Female

6/10 (60.0%)

0.71 (0.20–2.57)

0.6029

 Male

175/339 (51.6%)

  

Race

   

 Caucasian

106/222 (47.8%)

1.77 (1.05–2.97)

0.0321

 African American

50/81 (61.7%)

  

Alcoholic drink in past 12 mo

   

 No

131/249 (52.6%)

0.90 (0.57–1.43)

0.6566

 Yes

51/102 (50.0%)

  

Drink on regular basis

   

 <3 drinks/day

55/89 (61.8%)

1.34 (0.75–2.37)

0.3184

 ≥3 drinks/day

149/294 (50.7%)

  

Duration of alcohol history

   

 <10 yr

110/200 (55.0%)

0.72 (0.47–1.11)

0.1371

 >10 yr

67/143 (46.9%)

  

Body mass index (BMI)

   

 <30 kg/m2

81/168 (48.2%)

1.96 (1.18–3.27)

0.0097

 ≥30 kg/m2

64/99 (64.7%)

  

Fibrosis

   

 Stages 0–II

105/223 (47.1%)

1.53 (0.97–2.42)

0.0694

 Stages III–IV

64/111 (57.7%)

  

Biochemical and virological

   

ALT

   

 ≤45 IU/L

15/43 (34.9%)

2.14 (1.10–4.18)

0.0249

 >45 IU/L

162/303 (53.5%)

  

AST

   

 ≤40 IU/L

25/65 (38.5%)

1.98 (1.14–3.43)

0.0154

 >40 IU/L

157/284 (55.3%)

  

Platelets

   

 >130×109/L

161/307 (52.4%)

0.72 (0.38–1.36)

0.3118

 ≤130×109/L

20/45 (44.4%)

  

AFP

   

 ≤10 ng/L

109/228 (47.8%)

2.34 (1.31–4.18)

0.0041

 >10 ng/L

45/66 (68.2%)

  

HCV RNA

   

 <2.0 million copies/ml

131/244 (53.7%)

0.68 (0.42–1.10)

0.1178

 ≥2.0 million copies/ml

42/95 (44.2%)

  

HCV genotype 3

   

 No

153/309 (49.5%)

1.80 (0.88–3.69)

0.1062

 Yes

23/36 (63.9%)

  
Table 3

Multivariate analysis of the risk factors for steatosis

 

Steatosis presence vs. absence

Variable

Odds ratio (95% CI)

P value

Clinical

  

 Age (≥50 yr old)

1.44(0.80–2.60)

0.2272

 Race (African American)

1.35(0.70–2.61)

0.3640

 History of drinking in past 12 mo

0.73(0.38–1.41)

0.3516

 BMI (≥30 kg/m2)

1.82(0.98–3.38)

0.0564

 Stage III–IV fibrosis

2.01(1.07–3.78)

0.0305

Biochemical and virological

  

 HCV genotype 3

1.47 (0.63–3.43)

0.3800

 HCV RNA ≥2×106 copies/ml

0.77 (0.44–1.36)

0.3700

 ALT >45 IU/L

1.85 (0.76–4.47)

0.1700

 AST >40 IU/L

1.32 (0.64–2.73)

0.4500

 AFP >10 ng/L

1.48 (0.74–2.97)

0.2700

Univariate analysis was then used to assess six biochemical and virological parameters for their association with hepatic steatosis. As shown in Table 2 (lower panel), elevated ALT and AST and serum AFP, but not platelet counts, HCV RNA, or HCV genotype 3, were significantly associated with presence of steatosis. However, in multivariate analysis none of the five parameters, including elevated ALT, AST, and AFP, a higher HCV RNA load, and HCV genotype 3, were significantly and independently associated with steatosis (Table 3, lower panel).

Parameters associated with Sustained Virologic Response (SVR) to interferon alfa-2b and ribavirin treatment

Table 4 summarizes results of univariate analysis of 15 clinical and biochemical of virological parameters for their association with SVR to interferon α-2b and ribavirin treatment. Among all the factors, only African American race, AFP, and genotype 1 were significantly associated with SVR. Patients with hepatic steatosis and stage III–IV fibrosis tended to have a lower SVR, but these were not statistically significant. Age, gender, obesity, and alcohol use, including history of, duration, amount, and recent use, were not significantly associated with SVR, nor were ALT and AST, platelets, and HCV RNA viral load. Multivariate analysis revealed that HCV genotype 1 was significantly associated with a lower SVR, however, race, history of alcohol use in the past 12 months, obesity, presence of steatosis, stage III–IV fibrosis, elevated serum AFP, and higher HCV RNA level were not (Table 5).
Table 4

Univariate analysis of the factors associated with a sustained virologic response (SVR)

 

SVR

Parameter

Cases (%)

Odds ratio (95% CI)

P value

Age

   

 <50 yr

29/136 (21.3%)

1.31 (0.72–2.37)

0.3769

 ≥50 yr

28/107 (26.2%)

  

Gender

   

 Female

  1/8 (12.5%)

2.17 (0.26–18.00)

0.4735

 Male

57/241 (23.7%)

  

Ethnicity

   

 Caucasian

42/153 (27.5%)

3.34 (1.34–8.35)

0.0098

 African American

  6/59 (10.2%)

  

Alcohol use in past 12 mo

   

 No

41/189 (21.7%)

1.23 (0.63–2.39)

0.5432

 Yes

16/63 (25.4%)

  

History of ≥3 drinks/day

   

 No

14/69 (20.3%)

1.21 (0.61–2.38)

0.5877

 Yes

43/183 (23.5%)

  

Duration of drinking history

   

 <10 yr

38/143 (26.6%)

0.59 (0.31–1.10)

0.0953

 ≥10 yr

18/103 (17.5%)

  

BMI

   

 <30 kg/m2

27/114 (23.7%)

1.02 (0.51–2.02)

0.9602

 ≥30 kg/m2

18/75 (24.0%)

  

Steatosis

   

 Absent

32/114 (28.1%)

0.58 (0.32–1.05)

0.0745

 Present

26/140 (18.6%)

  

Fibrosis stages III–IV

   

 No

43/158 (27.2%)

0.52 (0.26–1.03)

0.0623

 Yes

13/80 (16.3%)

  

ALT

   

 ≤45 IU/L

 7/32 (21.9%)

1.01 (0.41–2.47)

0.9911

 >45 IU/L

47/214 (22.0%)

  

AST

   

 ≤40 IU/L

11/43 (25.6%)

0.81 (0.38–1.74)

0.5939

 >40 IU/L

45/206 (21.8%)

  

Platelets

   

 >130×109/L

54/218 (24.8%)

0.47 (0.16–1.40)

0.1739

 ≥130×109/L

 4/30 (13.3%)

  

AFP

   

 ≤10 ng/L

43/162 (26.5%)

0.25 (0.09–0.74)

0.0124

 >10 ng/L

 4/48 (8.3%)

  

HCV RNA

   

 <2×106 copies/ml

44/174 (25.3%)

0.69 (0.34–1.37)

0.2867

 ≥2×106 copies/ml

13/69 (18.8%)

  

Genotype 1

   

 No

32/82 (39.0%)

0.29 (0.16–0.53)

0.0001

 Yes

26/166 (15.7%)

  
Table 5

Multivariate analysis of factors associated with SVR

 

Sustained virologic response

Variables

Odds ratio (95% CI)

P value

Race (African American)

1.81 (0.51–6.45)

0.360

Alcohol in past 12 mo

1.04 (0.30–3.56)

0.950

BMI ≥30 kg/m2

1.12 (0.40–3.19)

0.830

Presence of steatosis

0.80 (0.29–2.23)

0.670

Presence of stage III–IV fibrosis

0.72 (0.23–2.26)

0.570

AFP >10 ng/L

0.34 (0.04–3.18)

0.350

HCV genotype 1 infection

0.22 (0.08–0.59)

0.003

HCV RNA ≥2×106 copies/ml

0.60 (0.16–2.25)

0.450

Discussion

It was previously reported that the prevalence of hepatic steatosis was as high as 66% in a large cohort of U.S. patients [17]. Data also suggest that the presence of hepatic steatosis in patients with CHC varied depending on ethnicity, BMI, and other variables of the studied population [1123]. Our recent multicenter VA study on epidemiology and treatment of veterans with CHC [30, 31] provided us an opportunity to examine these issues. Among the 4084 patients enrolled in the National VA HCV study [30, 31], 357 qualified for the present retrospective study. The baseline demographics, including mean age, BMI, HCV genotype distribution, and history of alcohol use, were comparable to those in other studies of nonveterans [17, 22, 23], except that this cohort was predominantly male. The prevalence of hepatic steatosis in our study population was 51.5%, which is slightly lower than in U.S. nonveteran patients reported by previous single-center studies [17, 22]. Since the present study included patients from 24 geographically diverse VA medical centers, we believe that the reported prevalence may be more generalizable and better reflect the actual prevalence of steatosis in male patients with CHC in the United States.

Determining factors associated with hepatic steatosis in HCV infection will help us to understand the natural history of CHC. Among host factors, the association between obesity as determined by BMI and steatosis was found in many previous studies [11, 17, 22]. In the present study, univariate analysis of eight clinical variables suggested that BMI and race, but not age, gender, hepatic fibrosis, or alcohol history (duration, amount, and time of last drink), were associated with steatosis. Multivariate analysis indicated that stage III–IV fibrosis was independently associated with presence of steatosis (P = 0.03) and, although not statistically significant, a trend toward a significant association with BMI (P =0.06). Our results support previous single-center studies [11, 17, 22] reporting that obesity may serve as an important risk factor for steatosis in U.S. patients with CHC. Unlike some of the previous studies, we were unable to assess the degree of steatosis in this cohort study because data were only collected on the presence or absence of steatosis. It is also well known that hepatic steatosis in both HCV-infected and uninfected patients is associated with metabolic syndrome characterized by obesity, diabetes mellitus, and hypertriglyceridemia [37]. Because the present study did not collect data on diabetes mellitus or triglyceride levels, we were unable to assess the association of diabetes mellitus and hypertriglyceridemia with hepatic steatosis.

Several studies have found an association between steatosis and progression of hepatic fibrosis in CHC patients of various ethnicities [12, 14, 21]. However, data on this issue remain limited and controversial in U.S. patients [13, 17, 19, 20, 22]. Although univariate analysis in the current study did not find an association between steatosis and hepatic fibrosis, multivariate analysis indicated that presence of steatosis was significantly associated with stage III–IV fibrosis independent of age, race, history of alcohol use in the past 12 months, and BMI. Our results support most recent reports [17, 23] that the presence of steatosis is associated with more advanced fibrosis in U.S. patients with CHC.

Alcohol use can cause hepatic steatosis. Although it was reported that a history of alcohol use may not be associated with hepatic steatosis in HCV-infected patients [11, 17, 21, 22], these data were generated from smaller, single-center cohorts. This multicenter national VA study prospectively collected detailed information regarding past and recent alcohol use [30, 31]. Thus, we were able to assess whether alcohol use serves as a risk factor for steatosis in patients with CHC. This cohort of patients included 50.7% who drank ≥3 drinks per day and almost 55.0% who had been drinking for more than 10 years. Interestingly, our data did not reveal an association between any of the alcohol factors such as a history of moderate alcohol use (≥3 drinks/day), duration (regular alcohol use for more than 10 years), or recent use (drinking in the past 12 months) with hepatic steatosis. These results confirm previous findings [11, 17, 21, 22] that a history of alcohol use may not be associated with hepatic steatosis in HCV-infected patients.

In transgenic mice, expression of HCV proteins has been associated with hepatic steatosis [38, 39]. Recent studies suggested that both HCV core and nonstructural proteins play a pathogenic role in hepatic steatosis [40, 41]. Some [12, 22, 26, 27], but not all [17, 19] studies have revealed a higher frequency and grade of hepatic steatosis in patients with HCV genotype 3 infection. A recent study indicated that effective HCV treatment is associated with reduced steatosis in patients with HCV-3 infection [18]. Similar to the genotype distribution in the general population in the United States, we have a relatively small percentage of genotype 3 patients in our study. Based on our data, it does appear that there may be a trend (49.5% vs. 63.9%; P = 0.11) suggesting that steatosis is more common in genotype 3 patients, however, this was not statistically significant, likely due to the small sample size. There may also be other explanations. A recent in vitro study demonstrated that expression of HCV core protein derived from different patients with HCV genotype 3 infection resulted in variable degrees of steatosis in human hepatoma cells [42]. This indicated that, besides genotype 3 infection, other factors might also play important roles in HCV-related steatosis. Additional studies will be required to elucidate the association of HCV genotype 3 infection with steatosis.

The impact of steatosis on HCV treatment response remains controversial. Some studies reported that its presence may reduce SVRs to antiviral treatment [8, 25]. Other studies did not support this notion [9]. In our cohort, 254 patients completed a full course of HCV antiviral treatment with posttreatment follow-up to determine treatment outcome. The SVR rate (22.8%) was lower than previously reported [43]. Univariate analysis revealed that African American race, elevated AFP, and genotype 1 infection were associated with a lower SVR rate. However, after adjusting for race, alcohol use in the past 12 months, BMI, presence of steatosis, stage III–IV fibrosis, elevated AFP, and HCV RNA load, only HCV genotype-1 was independently associated with a lower SVR rate. Thus, steatosis was not independently associated with lower SVR in our cohort of patients. It was reported that mild elevation of AFP is associated with advanced stage of fibrosis and active liver injury in HCV-infected patients [36]. In the present study, univariate analysis suggested an association of elevated AFP with a low SVR rate. Failure to confirm this association by multivariate analysis indicated that it might be confounded by other clinical and/or biochemical variables. However, large sample studies are necessary to further elucidate this issue.

In conclusion, this study reveals a high prevalence of hepatic steatosis in HCV-infected U.S. veterans that is significantly associated with stage III–IV fibrosis and trends toward statistical significance with obesity. However, neither presence of steatosis, stage III–IV fibrosis, nor obesity was independently associated with a lower SVR to interferon α-2b and ribavirin treatment other than genotype 1 infection.

Acknowledgments

Part of this work was published as an abstract in Hepatology, Volume 38 (Supplement 1), 445A, 2003, and presented at the 54th AASLD annual meeting, November 2003, in Boston. This work was funded in part by a grant from Schering-Plough Corporation and the VA National HIV/Hepatitis C Program. We would also like to thank Roche Molecular Systems, Inc., for providing Amplicor HCV Monitor Test Kits for the study of HCV RNA testing.

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© Springer Science&#x002B;Business Media, Inc. 2007