Hepatic Steatosis and Metabolic Syndrome Variables: Overplay on the Progression of Fibrosis among Hepatitis C Mono-Infected Patients and Human Immunodeficiency Virus Co-Infected Patients

Research Article

J Hepat Res. 2015;2(1): 1018.

Hepatic Steatosis and Metabolic Syndrome Variables: Overplay on the Progression of Fibrosis among Hepatitis C Mono-Infected Patients and Human Immunodeficiency Virus Co-Infected Patients

Rodríguez-Torres M1,2*, Bräu N3,4, Rios-Bedoya CF1,5, Hallman D1,6, Maldonado I1 and Rodríguez- Orengo JF1,7

1Department of Clinical Research, Fundacion de Investigacion, Puerto Rico, USA

2Ponce School of Medicine, Puerto Rico, USA

3Bronx Veterans Affairs Medical Center, USA

4Division of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, USA

5Department of Family Medicine, Michigan State University, USA

6Department of Medicine, UPR School of Medicine, USA

7Department of Biochemistry, UPR School of Medicine, USA

*Corresponding author: Rodríguez-Torres M, Department of Clinical Research, Fundacion de Investigacion,, Ponce School of Medicine, Puerto Rico, Ave. Muñoz Rivera #998, Río Piedras, Puerto Rico 00927, USA

Received: January 13, 2015; Accepted: February 09, 2015; Published: February 11, 2015


Background & Aims: Hepatic steatosis has been reported to be associated to increased fibrosis progression, reduced response rates to anti-HCV therapy and antiretroviral therapy for which it has clinical importance. This study was conducted to determine the impact of hepatic steatosis on the severity of liver disease progression in chronic HCV mono-infected and HIV/HCV co-infected patients.

Methods: Retrospective study of patients with chronic HCV or HIV/HCV coinfection, with liver biopsies, at the Fundación de Investigación in Puerto Rico and the Bronx Veterans Affairs Medical Center in New York from 1998 to 2005.

Results: Of the 1212 subjects, 834 (69%) were HCV mono-infected and 378 (31%) were HIV/HCV co-infected. Steatosis was more prevalent in HCV patients than HIV/HCV patients (51.2% vs. 39.7%, p=0.003). Severity of necroinflammatory grade was statistically associated to steatosis in HCV patients (p < 0.001), but not HIV/HCV patients (p=0.620). Severity of fibrosis progression rate was associated to steatosis in HCV patients (p=0.088), but not HIV/HCV patients (p=0.493). Hepatic steatosis increased the chances of fibrosis across all levels in the multivariate analysis (using a partial proportional odds model) in HCV patients, but not HIV/HCV patients.

Conclusion: Hepatic steatosis is more prevalent in HCV mono-infected patients, than in HIV/HCV co-infected patients. Presence of steatosis impacted the progression of liver disease differently; it increased the severity of necroinflammatory grade, the fibrosis progression rate and the chances of fibrosis in HCV mono-infected patients, but not in HIV/HCV co-infected patients.

Keywords: Hepatic steatosis; Co-infected; Metabolic syndrome; Chronic hepatitis; Nonalcoholic fatty liver disease; Fibrosis


ALT: Alanine Aminotransferase; ART: Antiretroviral Therapy; BMI: Body Mass Index; DM: Diabetes Mellitus; FPR: Fibrosis Progression Rate; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HDL: High-Density Lipoprotein; HIV: Human Immunodeficiency Virus; HS: Hepatic Steatosis; IR: Insulin Resistance; NAFLD: Nonalcoholic Fatty Liver Disease; NASH: Nonalcoholic Steatohepatitis; NRTI: Nucleoside Reverse Transcriptase Inhibitors


Liver disease in patients with HIV has been mostly focused on the co-infection with Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV), with less attention to other diseases such as Nonalcoholic Fatty Liver Disease (NAFLD). NAFLD represents a spectrum of liver diseases characterized mainly by macro vesicular steatosis in the absence of significant alcohol consumption, and is now recognized as a major cause of abnormal liver enzymes [1,2]. Hepatic histology can vary from isolated Hepatic Steatosis (HS) alone to Nonalcoholic Steatohepatitis (NASH) that can then progress to cirrhosis and liver failure [3,4]. HS has been reported in patients with both chronic HCV and HIV/HCV co- infection, with an overall prevalence ranging from 40% to 75% [5], which is greater than expected from the general population [6]. A reported meta-analysis, addressing a total of 1,989 HIV/HCV co-infected patients, found a prevalence of HS at 50.8%, ranging from 23% to 72%. Four of these studies included a total of 1,540 HCV mono-infected patients, finding its prevalence of HS at 48.6%, ranging from 33% to 59%. In this meta-analysis, HIV did not confer an increased risk for HS when compared to HCV monoinfection [7]. Although the exact mechanism for the development of NASH has not been fully elucidated, it appears to be associated to mitochondrial dysfunction [8], as a result of several metabolic abnormalities. The majority of patients with NAFLD have Insulin Resistance (IR) and Dyslipidemia, both of which are associated with other features of the metabolic syndrome such as central obesity, Diabetes Mellitus (DM), and hypertension [9,10]. In HIV/HCV coinfected patients, HS has been found to be associated with increased body mass index [11], diabetes [12], elevated ALT levels, HCV genotype 3 [13], necroinflammation, and fibrosis [5,7]. Also common in chronic HCV and HIV/HCV co- infection is the presence of IR. Although the IR mechanism in liver disease is unknown, it apparently is critical in HS and liver disease progression. A study found IR associated with liver fibrosis/steatosis in HCV mono-infected but not in co-infected patients [14], but another did find IR associated with liver fibrosis in co-infected patients [15].

Since HS is associated with increased fibrosis progression [16,17] its identification has clinical importance. In addition, the presence of HS has been reported to be associated with reduced response rates to anti-HCV therapy [18] and Antiretroviral Therapy (ART) [19, 20], for which it has therapeutic importance as well. To determine the impact of HS on the severity of liver disease progression in HCV mono-infected patients and HIV/HCV co-infected patients, this retrospective study was conducted on subjects who had liver biopsies performed as part of their evaluation for chronic HCV [21].

Patients and Methods

Study population

The present study included consecutive patients with chronic HCV infection or HIV/HCV co-infection, who had liver biopsies performed and were being treated at the Foundation de Investigation in San Juan, Puerto Rico and at the Bronx VA Medical Center in New York from 1998 to 2005. Laboratory and virological data, within two months of the liver biopsy dates, were required for inclusion. The study was performed in accordance to the Declaration of Helsinski, approved by Institutional Review Boards at each center and each patient provided a written informed consent and a data release form to use for clinical investigation purposes.

Variables examined

The personal information included: age, sex, Body Mass Index (BMI), ethnicity (Latino or non-Latino), presence of diabetes, amount of alcohol consumed (g/day) and determination of HCV risk factor (injection drug use, blood transfusion or sex). The laboratory data included: triglycerides level (mg/dL), total cholesterol (mg/ dL), High-Density Lipoprotein (HDL) level (mg/dL), total bilirubin (mg/dL) and Alanine Aminotransferase (ALT) levels (U/L). HCV genotyping and HCV RNA quantification were performed using standard commercial kits.

Liver tissue evaluation

The Percutaneous liver biopsies, performed in standard fashion, were formalin-fixed, paraffin-embedded and stained with hematoxylineosin and Masson’s trichrome. The Ishak Histologic Activity Index [22] was used to assess the degree of inflammation and fibrosis in the tissue sample. The necroinflammatory components were totaled to calculate the activity grade from 0 to 18, and the fibrosis was classified as stage 0 to 6. Steatosis was graded as in the modified Brunt scoring system [23,24], by determining the percent of hepatocytes containing fat; where <5% corresponds to grade 0, 5-33% corresponds to grade 1, 33-66% corresponds to grade 2 and >66% corresponds to grade 3. The Fibrosis Progression Rate [FPR] was determined by calculating the quotient of the liver fibrosis stage divided by the interval of time between the biopsy and the time of HCV infection, and expressed as units/year. To minimize intra-observer bias, all liver biopsies were reviewed by pathologists, with experience in liver tissue, whom were blinded to the clinical information. The liver biopsies from Fundacion de Investigation (69%) were performed by a sole invasive radiologist with 3 CT-guided passes, in separate directions; which yielded an average length of 45 cm using a tricut gauge 18 needle. These liver biopsies were analyzed by the same experienced hepatopathologist. The liver biopsies from the Bronx VA Medical Center were performed by the gastroenterology staff and interpreted by experienced pathologists.

Statistical analysis

Statistical analysis was performed using STATA® (v11) [25]. The data are presented as mean value ± standard deviation. Differences between continuous variables were compared using Analysis of Variance (ANOVA) or t-test, and categorical variables were compared using Fisher’s exact tests. A p value of <0.05 was used to determine statistically significant results. For the fibrosis multivariate analysis, associations were analyzed using a partial proportional odds model, since it was expected that at least one of the variables was not going to meet the proportional odds assumption. The partial proportional model [26,27] estimates the likelihood of being in an upper ordinal category of the response variable, conditional on the explanatory variables, and allows a group of explanatory variables to vary over the response variable categories while keeping the others constant. This model has been used in several clinical studies [28-30] but has been used scarcely in HCV research [31] even though it is particularly appropriate to studies involving fibrosis staging.


Study population

1212 subjects were studied; 834 (69%) HCV mono-infected and 378 (31%) HIV/HCV co-infected. The characteristics of each group are presented in Table 1. HCV genotyping and HCV RNA quantification were only available in 937 subjects (76.9%); 673 mono-infected (80.1%) and 264 co-infected (69.8%). There was a statistically significant difference between the groups in regards to the age, ethnicity, alcohol use, risk factors for HCV, HCV genotype, triglycerides levels, HDL levels, total bilirubin levels and BMI. The group of HCV mono-infected patients was: older, consumed more alcohol, had a higher BMI and predominantly HCV genotype 1. The group of HIV/HCV co-infected patients was: predominantly Latinos, had history of intravenous drug use, had higher triglycerides and total bilirubin levels, and lower HDL levels. The co-infected patients had in general well controlled HIV disease, with HIV RNA mean of 594 copies, (n=365 SD 13.3 ) with 80 patients or 22% with less than 50 copies. The mean CD4 was 455.2cells/ml (SD 272.2 and 23% or 87 had less than 250cells/ml. The mean duration of use of ART in 248 patients with information is 3.25 years (SD 2.15 with 79% or 195 patients with therapy for more than 1 year. Of the risk factors for steatosis, the significantly prevalent variables are: alcohol use in the HCV mono-infected group, elevated triglycerides levels in the HIV/ HCV co-infected group, and the high BMI in both groups, although it was significantly higher in the HCV mono-infected patients. The prevalence of diabetics was relatively low (12.5% and 12.9%) in both groups. Also of relevance, only 48 subjects of 937 (5.1%) were HCV genotype 3, with a higher prevalence in HIV/HCV co-infected patients (9.8%) than in HCV mono-infected individuals (3.3%).