Abstract
Background
The clinical implications of metabolic profiles in patients with chronic hepatitis C remain controversial. To study the association of metabolic abnormalities with chronic hepatitis C, we conducted a case–control study with special emphasis on serum lipid pattern, fasting blood glucose, and adiponectin.
Methods
We enrolled 500 patients with chronic hepatitis C and 536 sex and age-matched controls. Unadjusted and adjusted associations of demographic and metabolic variables were estimated.
Results
Chronic hepatitis C patients had higher alanine aminotransferase (ALT) and high-density lipoprotein-cholesterol levels, but lower total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol levels than controls. Stratifying ALT level according to its upper limit of normal, HCV infection was associated with younger age, female gender, and higher TC levels in chronic hepatitis C patients with normal ALT levels, but with lower TC and lower TG levels in those with abnormal ALT levels. By using multiple linear regression analyses for subjects with available adiponectin data, presence of HCV infection was independently associated with higher serum adiponectin levels.
Conclusions
Metabolic profiles of chronic hepatitis C patients are affected by age, gender, serum adiponectin, and ALT levels. Further longitudinal studies are needed to clarify the complex interplay between HCV infection and metabolic profiles.
Keywords: Hepatitis C virus, ALT, Adiponectin, Lipid profile, Blood glucose
Introduction
The liver plays a pivotal role in nutrient and hormone metabolism; therefore, several metabolic abnormalities are common in liver disease. Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis, liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide [1]. However, clinical manifestations of HCV infection are heterogeneous and factors affecting liver disease progression remain to be fully elucidated.
Recently, there is increasing interest in the impact of chronic HCV infection on metabolic abnormalities, including glucose, lipid, cytokines, insulin resistance, and adipokines. Although a body of experimental data from in vitro cell cultures and in vivo transgenic mice support the existence of interaction between HCV and host metabolic factors, the results from clinical and epidemiological studies remained controversial [2–16]. The inconsistencies may be due to small sample size, the selection of patients only from hospitals or limited to hepatitis patients with cirrhosis, with diabetes, or to post-liver-transplant. Although large population-based studies have been performed [17–19], the results still lack consistency and are limited to some metabolic factors.
Adiponectin, an adipokine, has been implicated in the pathogenesis of type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), and appears to have many favorable effects on glucose and lipid metabolism [20, 21]. It is positively correlated with insulin sensitivity and is decreased in obese and type 2 diabetic patients [22]. Adiponectin also antagonizes tumor necrosis factor-alpha (TNF-α) and modulates inflammatory responses [23]. In addition, adiponectin might have hepatic cytoprotective properties such as improving hepatic steatosis and injury in animal models of NAFLD [23]. Our recent data further showed that adiponectin may correlate with hepatitis C viral factors at both serum and liver tissue levels [24, 25].
To examine the influence of adiponectin, glucose and lipid metabolism on chronic hepatitis C patients, we therefore conducted a large case–control study with 500 HCV-infected index patients and 536 sex- and age-matched controls.
Patients and methods
Study population
HCV infected cases
There were more than 1,000 HCV-infected patients followed at National Taiwan University Hospital (NTUH), a tertiary medical center in Taiwan. Among them, a total of 533 patients aged 15 years or older diagnosed with chronic HCV infection who were regularly followed at the gastroenterology clinics of this hospital between 1999 and 2005 were consecutively included. After excluding the patients who had incomplete data or without informed consent, finally there were 500 patients enrolled into this study. Chronic HCV infection was defined as positivity of anti-HCV and serum HCV RNA for more than 6 months. All of them were infected with HCV genotype 1 or 2, and were negative for hepatitis B surface antigen or HIV antibody, naïve to antiviral treatment, and none had a known history or serological evidence of autoimmune liver disease, inheritable disorders such as hemochromatosis or Wilson’s disease, renal insufficiency, a history of excess alcohol intake (daily alcohol consumption greater than 20 g) or drug abuse and a record of diabetes mellitus or dyslipidemia.
Non-HCV controls
A total of 536 sex and age-matched non-HCV controls were selected from the database of the Health Management Center in National Taiwan University Hospital, and more than 10,000 subjects received regular physical check-up at this Health Management Center each year.
We excluded subjects positive for hepatitis B surface antigen (HBsAg) or anti-HCV, and those with a known history of diabetes mellitus or dyslipidemia. Random selection without replacement was used to ensure that no non-HCV control was assigned more than once.
Informed consent was obtained from each patient and control at the time of drawing blood. The NTUH ethics committee approved the study protocol conforming to the ethical guidelines of the 1975 Declaration of Helsinki.
Laboratory assays
Venous blood samples were collected in the morning after 12 h fasting and measured by standard laboratory techniques. Hepatitis B surface antigen and anti-HCV were assayed with commercial kits (Abbott Laboratories, North Chicago, IL, USA). Plasma glucose, serum AST, ALT, total cholesterol, triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol were measured by an autoanalyzer (Hitachi 7250, Special; Hitachi, Tokyo, Japan). The remnant serum samples were stored at −80°C to test the adiponectin level. Because not all of the cases and controls had enough stored samples for testing, only 668 subjects (210 HCV patients and 458 non-HCV controls) had adiponectin data. Serum adiponectin level was determined by an ELISA assay (Human Adiponectin ELISA Kit, B-Bridge International, Inc., CA, USA) according to the manufacturer’s instructions.
Serum RNA was extracted by using a commercial kit (QIAamp RNA Blood Mini Kit; Qiagen Inc., Valencia, CA, USA). HCV RNA was assayed by a real-time polymerase chain reaction (PCR) assay, with the detection limit of 1,000 copies/ml (i.e. 370.37 IU/ml) [26, 27]. Genotyping of HCV was performed by reverse transcriptase-PCR with type-specific primers [28, 29]. The detection limit of type-specific primers genotyping method is 100 copies/ml (i.e. 37 IU/ml). All samples were tested in duplicate. Serum samples from anti-HCV-positive patients with undetectable HCV RNA by real-time PCR assay were re-checked by the qualitative type-specific primers genotyping method.
Metabolic and demographic features
We collected information on sex, age, body weight, body height, body mass index, adiponectin, fasting blood glucose, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), high-density lipoprotein-cholesterol (HDL), and low-density lipoprotein-cholesterol (LDL).
Fasting plasma glucose (FPG) levels ≧100 mg/dl (5.6 mmol/l) but <126 mg/dl (7.0 mmol/l) was considered as impaired fasting glucose (IFG) according to the latest American Diabetes Association criteria [30]. Upper limit of normal (ULN) of serum ALT level was set at 30 U/l for men and 20 U/l for women [31, 32].
Statistical analysis
Demographic features and metabolic factors were compared between chronic hepatitis C patients and non-HCV control using chi-square test for categorical variables and t-test for continuous variables. Odds ratio (OR) and 95% confidence interval (CI) as well as P-values were estimated for each variable by logistic regression. Stepwise approaches were performed to examine the association between fasting blood glucose, triglyceride, adiponectin, total cholesterol, ALT levels, and risk of HCV infection, after adjusting for sex, age, and body mass index. Parameters of metabolic profiles and the presence of HCV infection were estimated by multiple linear regression analysis. ANOVA was used to examine the relationship between HCV infection and various metabolic profiles. All analyses were performed with Stata statistical software (version 8.0, Stata Corp., College Station, TX, USA) and all tests were 2-sided and P < 0.05 was considered statistically significant.
Results
Demographic features
Serum ALT and HDL were significantly higher in chronic hepatitis C patients compared with controls. In contrast, serum TC, TG, and LDL levels were significantly lower in chronic hepatitis C patients than controls (Table 1).
Table 1.
Comparison of clinical and metabolic characteristics between HCV patients and non-HCV controls
| Characteristics | HCV patients (N = 500) | Non-HCV controls (N = 536) | P-value |
|---|---|---|---|
| Age (years) | 52.77 ± 0.56 | 52.61 ± 0.56 | 0.84 |
| Male (%) | 279 (55.8) | 312 (58.2) | 0.43 |
| Body mass index (kg/m2) | 25.91 ± 0.95 | 25.18 ± 0.17 | 0.43 |
| Fasting blood glucose (mg/dl) | 102.05 ± 1.46 | 100.45 ± 1.41 | 0.43 |
| ALT (U/l) | 103.75 ± 5.42 | 29.54 ± 1.42 | <0.01 |
| Triglyceride (mg/dl) | 112.53 ± 2.87 | 138.92 ± 5.53 | <0.01 |
| Total cholesterol (mg/dl) | 184.20 ± 1.87 | 195.45 ± 1.49 | <0.01 |
| LDL (mg/dl) | 116.87 ± 1.89 | 124.54 ± 1.48 | <0.01 |
| HDL (mg/dl) | 47.99 ± 0.68 | 46.20 ± 0.53 | 0.04 |
Data are shown by mean ± standard error
Abbreviations: ALT, alanine aminotransferase; LDL, low-density lipoprotein-cholesterol; HDL, high-density lipoprotein-cholesterol
It is known that patients with advanced liver diseases have hyperinsulinemia and impaired glucose tolerance. In order to know the severity of liver dysfunction in the cases of present study, we also collected available data from the medical records of enrolled CHC cases. About 461 cases had available platelet (PLT) data (Table 2). If we use the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) more than 1 as a cutoff level of significant fibrosis, about 51% enrolled cases might have significant fibrosis or cirrhosis.
Table 2.
The characteristics of 461 HCV patients with available PLT data
| Characteristics | N (%) | Mean ± SE | 95% CI |
|---|---|---|---|
| PLT (K/μl) | 461 | 171.3 ± 2.7 | 166.0–176.5 |
| Albumin (g/dl) | 401 | 4.2 ± 0.0 | 4.2–4.2 |
| T-bilirubin (mg/dl) | 417 | 0.9 ± 0.0 | 0.8–1.0 |
| D-bilirubin (mg/dl) | 394 | 0.2 ± 0.0 | 0.2–0.3 |
| AST (U/l) | 456 | 87.6 ± 3.4 | 81.0–94.2 |
| APRI | 459 | 1.5 ± 1.1 | 1.4–1.7 |
| APRI ≦ 0.5 | 97 (21.1) | ||
| 0.5 < APRI ≦ 1 | 128 (27.9) | ||
| 1.0 < APRI ≦ 1.5 | 93 (20.3) | ||
| 1.5 < APRI ≦ 2 | 39 (8.5) | ||
| APRI > 2 | 102 (22.2) |
Data are shown by mean ± standard error (mean ± SE)
N represents the number of enrollers with available PLT data in each character. The values in the parentheses represent the proportion of enrollers with available data to the total enrollers of each group
Abbreviations: AST, aspartate aminotransferase; PLT, platelet count; T-bilirubin, total bilirubin; D-bilirubin, direct bilirubin; APRI, Aspartate Aminotransferase-to-Platelet Ratio Index
Metabolic profiles in HCV infection
To further clarify the association between HCV infection and metabolic profiles, categorized metabolic data were included in multiple linear regression models after adjustment for age, sex, and body mass index. We found that the presence of HCV infection was positively associated with the categorized ALT levels, but negatively associated with categorized TG levels and TC levels (Table 3).
Table 3.
Parameter estimates gained from separate multiple linear regression identifying categorized metabolic data associated with the presence of HCV infection
| Parameter estimate | Standard error | P-value | |
|---|---|---|---|
| Fasting blood glucose (mg/dl)a | |||
| <80 | Reference | ||
| 80–120 | −0.09 | 0.08 | 0.25 |
| 120–200 | −0.04 | 0.09 | 0.70 |
| >200 | −0.06 | 0.14 | 0.65 |
| ALT (U/l)b | |||
| <20 | Reference | ||
| 20–40 | 0.07 | 0.03 | 0.03 |
| 40–80 | 0.45 | 0.04 | <0.01 |
| 80–160 | 0.73 | 0.04 | <0.01 |
| 160–400 | 0.83 | 0.05 | <0.01 |
| >400 | 0.75 | 0.13 | <0.01 |
| Triglyceride (mg/dl)c | |||
| <150 | Reference | ||
| 150–300 | −0.07 | 0.04 | 0.07 |
| >300 | −0.24 | 0.08 | <0.01 |
| Total cholesterol (mg/dl)d | |||
| <220 | Reference | ||
| ≧220 | −0.09 | 0.04 | 0.02 |
Note: Multiple linear regression models using the presence of HCV infection as the dependent variable and age, sex, and body mass index as independent variables. Categorized fasting blood glucose, ALT, triglyceride, and total cholesterol levels were separately added as independent variables
aCategorizing fasting blood glucose to 4 groups and using fasting blood glucose <80 mg/dl as reference group
bCategorizing ALT to 5 groups and using ALT <40 U/l as reference group
cCategorizing serum triglyceride to 3 groups and using serum triglyceride <150 mg/dl as reference group
dCategorizing serum total cholesterol to 2 groups and using serum total cholesterol <220 mg/dl as reference group
ALT level and metabolic profiles in chronic HCV infection
Because chronic inflammation is known to be correlated with metabolic homeostasis, and ALT serves as a surrogate marker of hepatocytes injury, we thus attempted to clarify the modifying effect of ALT on metabolic profiles in chronic hepatitis C patients. We stratified ALT level according to its upper limit of normal (ULN) (30 U/l for men and 20 U/l for women) into two subgroups, and examined the differences of the metabolic profiles between HCV patients and matched controls. In the subgroup with ALT level less than or equal to ULN, HCV infection was independently associated with younger age, female gender, and higher TC levels. However, in the subgroup with ALT levels greater than ULN, HCV infection was independently associated with lower TC and lower TG levels (Table 4). To clarify the impact of hyperglycemia and dyslipidemia on the modifying effect of ALT in CHC patients, we also analyzed our data after excluding the persons with fasting glucose levels ≥110 mg/dl, triglyceride ≥150 mg/dl, or total cholesterol ≥200 mg/dl (according to the suggestion of ATPIII). The results are similar to those shown in Table 4.
Table 4.
Multiple logistic regression analysis stratified by upper limit of normal ALT levels to examine the odds of HCV patients versus non-HCV controls
| ALT ≦ ULNa (N = 417) | ALT > ULN (N = 532) | |||
|---|---|---|---|---|
| Adjusted OR | 95% CI | Adjusted OR | 95% CI | |
| Age (years) | 0.96* | 0.94–0.99 | 1.01 | 0.99–1.02 |
| Sex (male vs. female) | 0.13* | 0.07–0.27 | 1.08 | 0.71–1.64 |
| Body mass index (kg/m2) | 1.08** | 0.99–1.18 | 1.00 | 0.99–1.01 |
| Total cholesterol (mg/dl) | 1.01* | 1.00–1.02 | 0.99* | 0.98–0.99 |
| Fasting blood glucose (mg/dl) | 1.00 | 0.99–1.01 | 1.01 | 1.00–1.01 |
| Triglyceride (mg/dl) | 1.00 | 1.00–1.00 | 0.99* | 0.99–0.99 |
OR, odds ratio; CI, confidence interval
The models adjusted for age, sex, body mass index, adiponectin, fasting blood glucose, triglyceride, and total cholesterol
aUpper limit of normal (ULN) of serum ALT level is 30 U/l for men and 20 U/l for women
* P < 0.05
** P < 0.1
Adiponectin and metabolic profiles in chronic HCV infection
A total of 668 subjects (210 HCV patients and 458 non-HCV controls) had available adiponectin data, and were subjected to further subgroup analysis. By using multiple linear regression models, HCV infection was positively correlated with serum adiponectin levels (Table 5).
Table 5.
Parameter estimates gained from multiple linear regression identifying factors associated with the presence of HCV infection in 668 enrollers with available adiponectin data
| Parameter estimate | Standard error | P-value | |
|---|---|---|---|
| Age (years) | −0.00 | 0.00 | 0.10 |
| Sex (male vs. female) | −0.20 | 0.04 | <0.01 |
| Body mass index (kg/m2) | 0.01 | 0.00 | 0.06 |
| Adiponectin (μg/ml)a | |||
| <4 | Reference | ||
| 4–8 | 0.09 | 0.04 | 0.04 |
| >8 | 0.09 | 0.05 | 0.04 |
Note: Multiple linear regression models using the presence of HCV infection as the dependent variable and age, sex, body mass index, and stratified adiponectin levels as independent variables
aCategorizing serum adiponectin level to 3 groups and using serum adiponectin <4 μg/ml as reference group
During stepwise addition of adiponectin and ALT levels into the regression models, we found TC and TG levels were affected by adiponectin. The negative association between TG/TC levels and HCV infection disappeared when adiponectin was added to the model. In addition, the negative association between TC levels and HCV infection also disappeared after ALT was added into the model, implying a possible interaction between TC and ALT levels.
Discussion
In this study, we enrolled greater than 1,000 subjects, including 500 cases and 536 matched controls. This large sample size ensured that we could reliably analyze-related parameters. Our findings showed the existence of a close link between HCV infection and metabolic abnormalities. We found that HCV infection was positively correlated with serum adiponectin level, which was different from previously reports on subjects with non-alcoholic steatohepatitis (NASH) [20, 33].
Our data displayed that HCV infection was associated with lower TG, TC, LDL, and higher HDL levels, which confirmed and extended previous studies [10]. Of particular note is that we found adiponectin to be highly correlated with TC and TG profiles. Several lines of evidence have indicated that HCV or its viral components are able to induce derangements of host lipid metabolism, possibly via interfering with the expression of peroxisome proliferator-activated receptor α, retinoid receptor α, and multidrug resistance 3 genes [34, 35]. These genes are not only related to lipid metabolism, but also related to the functions of adiponectin [36]. Nevertheless, most previous data were based on systems overexpressing various HCV proteins in cell cultures or transgenic mouse models. Our observations on human subjects therefore provided strong support to these experimental results.
Lipoproteins may have an intriguing interaction with HCV. Recent studies indicated that lipoprotein-associated HCV particles may infect cells via LDL receptors [37]. HDL and scavenger receptor class B type I (SR-BI) play an active role in facilitating HCV entry but oxidized LDL (oxLDL) is a potent cell entry inhibitor [38, 39]. We also found that higher TC level had a positive correlation with HCV infection while lower TC level displayed inverse correlation (data not shown). These data suggested a possible interaction between TC and HCV infection. Our speculations were supported by recent data that higher TC and LDL levels are associated with a better therapeutic outcome of chronic hepatitis C [40].
In this study, we consistently showed HCV infection was associated with a lower TG level [18]. In the transgenic mouse model, HCV core protein appears to interfere with the hepatic assembly and secretion of ApoB containing very low-density lipoproteins (VLDL) [41]. These effects cause TG to accumulate within hepatocytes, and contribute to decreased serum triglyceride, which may explain the association between HCV infection and lower TG levels. However, considering that approximately 51% of the enrolled cases may have significant fibrosis or cirrhosis, and these patients with liver cirrhosis may have impaired lipid metabolism or malnutrition. Low serum TG level in the HCV group may not only result from HCV infection but also from liver cirrhosis.
Although both in vitro and in vivo studies revealed correlation between glucose metabolism and HCV infection, the clinical relevance of this issue remains unclear. Recently, a population-based study revealed a positive association between HCV infection and hyperglycemia [18], but the association disappeared when adjusted for age and gender. However, our analyses demonstrated that more chronic hepatitis C patients had an impaired fasting glucose compared to sex- and age-matched controls (data not shown). Before the subjects were included, we could only exclude the subjects with a known history of diabetes mellitus or dyslipidemia. All of these relevant histories were told by the subjects themselves or kept on their past medical records. In addition, we used the information told by the subjects themselves or kept on past medical records as a definition of diabetes mellitus or dyslipidemia. This means that some cases of diabetes mellitus or dyslipidemia may be enrolled into our study, and accordingly the possible association between the development of diabetes mellitus or dyslipidemia with HCV infection is weakened. Further studies are needed to solve this important issue.
As anticipated, HCV infection served as an important and independent correlate of serum ALT level. Previous studies indicated that metabolic factors influence ALT activities as well [32, 42]. However, whether ALT level affects metabolic profiles in chronic HCV infection remains unclear. We thus added ALT into the multivariate analysis models, and found an inverse association between TC with HCV infection in chronic hepatitis C patients with abnormal ALT. We also analyzed our data after excluding the persons with elevated fasting glucose, triglyceride, or total cholesterol levels to clarify the impact of hyperglycemia and dyslipidemia on the modification role of ALT in CHC patients, and we got similar results. Since ALT is a surrogate parameter of hepatocyte turnover and damage, we could infer that extent of liver injury may influence lipid and glucose metabolism and thus plays an important role in the metabolic derangement of chronic HCV infection.
Adiponectin is reported to have an inverse association with hepatic inflammation in NASH patients [23]. On the contrary, recent data revealed a positive association in chronic hepatitis C patients, and inferred that the increased adiponectin in the scenario of hepatic inflammatory activity might be secondary to the response of viral infection [43]. Our data added support to this speculation and suggested HCV might have an interaction with adiponectin.
Given the cross-sectional and case–control study design, we could not investigate the duration–response relationship between HCV infection and metabolic profiles. However, previous studies have shown a link between HCV infection and insulin resistance [44], and the presence of insulin resistance is one of the risk factors for fibrosis progression in chronic hepatitis C patients. These evidences give supports to the possible connection between HCV infection and metabolic derangements through insulin resistance. Besides, our study further indicated that HCV-related liver dysfunctions, such as ALT levels and the extent of liver injury, are important modifiers of host metabolic profiles. Further studies are needed to clarify the roles of metabolic variables in liver disease progression of chronic hepatitis C.
In summary, our results indicate that HCV infection is associated with higher alanine aminotransferase, high-density lipoprotein-cholesterol, and serum adiponectin levels, but with lower total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels. The association persists even after adjusting for sex, age, and body mass index. In addition, ALT may serve as a modifying factor affecting metabolic profiles in chronic hepatitis C patients. These findings highlight the complex pathophysiologic relationships between HCV infection and metabolic factors.
Acknowledgments
This work was supported by grants from the National Taiwan University Hospital, the Department of Heath, and the National Science Council, Executive Yuan, Taiwan. We thank Dr. Huang SP at the Health Management Center of National Taiwan University Hospital for providing data of non-HCV controls.
Abbreviations
- HCV
Hepatitis C virus
- ALT
Alanine aminotransferase
- TG
Triglyceride
- TC
Total cholesterol
- HDL
High-density lipoprotein-cholesterol
- LDL
Low-density lipoprotein-cholesterol
- ULN
Upper limit of normal
- ADN
Adiponectin
Contributor Information
Ching-Sheng Hsu, Email: d94421001@ntu.edu.tw.
Chun-Jen Liu, Email: cjliu@ntu.edu.tw.
Chen-Hua Liu, Email: jacque_liu@mail2000.com.tw.
Chi-Ling Chen, Email: chlnchen@ha.mc.ntu.edu.tw.
Ming-Yang Lai, Email: mylai@ha.mc.ntu.edu.tw.
Pei-Jer Chen, Email: peijer@ha.mc.ntu.edu.tw.
Ding-Shinn Chen, Email: dschen@ha.mc.ntu.edu.tw.
Jia-Horng Kao, Phone: +886-2-23123456, FAX: +886-2-23825962, Email: kaojh@ntu.edu.tw.
References
- 1.Chen DS, Wang JT, Chen PJ, Wang TH, Sung JL. Hepatitis C virus infection in Taiwan. Gastroenterol Jpn. 1991;26 Suppl 3:164–6. [DOI] [PubMed]
- 2.Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–9. [DOI] [PubMed]
- 3.Mangia A, Schiavone G, Lezzi G, et al. HCV and diabetes mellitus: evidence for a negative association. Am J Gastroenterol. 1998;93:2363–7. [DOI] [PubMed]
- 4.Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29:328–33. [DOI] [PubMed]
- 5.Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;30:1059–63. [DOI] [PubMed]
- 6.Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc. 2000;75:355–9. [DOI] [PubMed]
- 7.Thuluvath PJ, John PR. Association between hepatitis C, diabetes mellitus, and race: a case–control study. Am J Gastroenterol. 2003;98:438–41. [DOI] [PubMed]
- 8.Zein CO, Levy C, Basu A, Zein NN. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol. 2005;100:48–55. [DOI] [PubMed]
- 9.Antonelli A, Ferri C, Fallahi P, Pampana A, Ferrari SM, Goglia F, et al. Hepatitis C virus infection: evidence for an association with type 2 diabetes. Diabetes Care. 2005;28:2548–50. [DOI] [PubMed]
- 10.Jarmay K, Karacsony G, Nagy A, Schaff Z. Changes in lipid metabolism in chronic hepatitis C. World J Gastroenterol. 2005;11:6422–8. [DOI] [PMC free article] [PubMed]
- 11.Siagris D, Kouraklis-Symeonidis A, Christofidou M, et al. Serum lipid profile and hepatic steatosis of adult beta-thalassaemia patients with chronic HCV infection. Eur J Gastroenterol Hepatol. 2005;17:345–50. [DOI] [PubMed]
- 12.Siagris D, Christofidou M, Theocharis GJ, et al. Serum lipid pattern in chronic hepatitis C: histological and virological correlations. J Viral Hepat. 2006;13:56–61. [DOI] [PubMed]
- 13.Behrendt CE, Ruiz RB. Hyperglycemia among persons with hepatitis C: not the classical diabetic phenotype. Diabetes Res Clin Pract. 2006;71:68–74. [DOI] [PubMed]
- 14.Petit JM, Benichou M, Duvillard L, et al. Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis. Am J Gastroenterol. 2003;98:1150–4. [DOI] [PubMed]
- 15.Serfaty L, Andreani T, Giral P, Carbonell N, Chazouilleres O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. J Hepatol. 2001;34:428–34. [DOI] [PubMed]
- 16.Fabris C, Federico E, Soardo G, Falleti E, Pirisi M. Blood lipids of patients with chronic hepatitis: differences related to viral etiology. Clin Chim Acta. 1997;261:159–65. [DOI] [PubMed]
- 17.Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–9. [DOI] [PubMed]
- 18.Jan CF, Chen CJ, Chiu YH, et al. A population-based study investigating the association between metabolic syndrome and hepatitis B/C infection (Keelung Community-based Integrated Screening study No. 10). Int J Obes (Lond). 2006;30:794–9. [DOI] [PubMed]
- 19.Shaheen M, Echeverry D, Oblad MG, Montoya MI, Teklehaimanot S, Akhtar AJ. Hepatitis C, metabolic syndrome, and inflammatory markers: results from the Third National Health and Nutrition Examination Survey [NHANES III]. Diabetes Res Clin Pract. 2007;75:320–6. [DOI] [PubMed]
- 20.Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54. [DOI] [PubMed]
- 21.Fumeron F, Aubert R, Siddiq A, et al. Adiponectin gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3-year period: the epidemiologic data on the insulin resistance syndrome prospective study. Diabetes. 2004;53:1150–7. [DOI] [PubMed]
- 22.Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13:84–9. [DOI] [PubMed]
- 23.Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40:177–84. [DOI] [PubMed]
- 24.Liu CJ, Chen PJ, Jeng YM, et al. Serum adiponectin correlates with viral characteristics but not histologic features in patients with chronic hepatitis C. J Hepatol. 2005;43:235–42. [DOI] [PubMed]
- 25.Liu CJ, Jeng YM, Chen PJ, et al. Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C. Antivir Ther. 2005;10:405–15. [PubMed]
- 26.Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol. 2004;41:659–66. [DOI] [PubMed]
- 27.Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–71. [DOI] [PubMed]
- 28.Kao JH, Lin HH, Chen PJ, Lai MY, Wang TH, Mizokami M, et al. Serotyping of hepatitis C virus in chronic type C hepatitis in Taiwan: correlation with genotypes. J Gastroenterol. 1996;31:224–7. [DOI] [PubMed]
- 29.Ohno O, Mizokami M, Wu RR, et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol. 1997;35:201–7. [DOI] [PMC free article] [PubMed]
- 30.Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29 Suppl 1:S43–8. [PubMed]
- 31.Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983. [DOI] [PMC free article] [PubMed]
- 32.Prati D, Shiffman ML, Diago M, et al. Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C. J Hepatol. 2006;44:679–85. [DOI] [PubMed]
- 33.Kaser S, Moschen A, Cayon A, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54:117–21. [DOI] [PMC free article] [PubMed]
- 34.Yamaguchi A, Tazuma S, Nishioka T, Ohishi W, Hyogo H, Nomura S, et al. Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci. 2005;50:1361–71. [DOI] [PubMed]
- 35.Tsutsumi T, Suzuki T, Shimoike T, et al. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002;35:937–46. [DOI] [PubMed]
- 36.Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat? J Hepatol. 2006;44:253–61. [DOI] [PubMed]
- 37.Favre D, Muellhaupt B. Potential cellular receptors involved in hepatitis C virus entry into cells. Lipids Health Dis. 2005;4:9. [DOI] [PMC free article] [PubMed]
- 38.Voisset C, Callens N, Blanchard E, Op De Beeck A, Dubuisson J, Vu-Dac N. High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I. J Biol Chem. 2005;280:7793–9. [DOI] [PubMed]
- 39.von Hahn T, Lindenbach BD, Boullier A, Quehenberger O, Paulson M, Rice CM, et al. Oxidized low-density lipoprotein inhibits hepatitis C virus cell entry in human hepatoma cells. Hepatology. 2006;43:932–42. [DOI] [PubMed]
- 40.Gopal K, Johnson TC, Gopal S, et al. Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment. Hepatology. 2006;44:335–40. [DOI] [PubMed]
- 41.Barba G, Harper F, Harada T, et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA. 1997;94:1200–5. [DOI] [PMC free article] [PubMed]
- 42.Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23. [DOI] [PubMed]
- 43.Jonsson JR, Moschen AR, Hickman IJ, et al. Adiponectin and its receptors in patients with chronic hepatitis C. J Hepatol. 2005;43:929–36. [DOI] [PubMed]
- 44.Hsu C-S, Liu C-J, Liu C-H, et al. High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int. 2008;28:271–277. [DOI] [PubMed]