|
|
|||
|
| |||
|
| |||
|
| |||
|
|
|||
|
Marcello Persico, Mario Masarone, Vincenzo La Mura, Eliana Persico, Francesco Moschella, Monica Svelto, Roberto Torella, Internal Medicine and Hepatology Unit, Second University of Naples, Naples 80122, Italy Savino Bruno, Internal Medicine and Hepatology Unit, Fatebe-nefratelli Hospital, Milan 20121, Italy Author contributions: Persico M and Masarone M analyzed data and wrote the paper; Persico M, Masarone M, La Mura V, Bruno S and Torella R designed research; Persico E and Moschella F performed research. Correspondence to: Marcello Persico, MD, Internal Medicine and Hepatology Unit, Second University of Naples, Via F. Petrarca, 101/b, Naples 80122, Italy. marcello.persico@unina2.it Telephone: +39-81-5666838 Fax: +39-81-5666838 Received: January 30, 2008 Revised: October 31, 2008 Accepted: November 7, 2008 Published online: January 28, 2009
Abstract AIM: To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB).
METHODS: We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD).
RESULTS: Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (> 30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis > 30% in CHC, whereas only age and BMI were related to steatosis in CHB.
CONCLUSION: These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Insulin resistance; Diabetes; Metabolic syndrome; Hepatitis C virus; Hepatitis B virus
Peer reviewers: Mario U Mondelli, Professor, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and University of Pavia, via Taramelli 5, Pavia 27100, Italy; Antonio Ascione, PhD, Department of Gastroenterology, Cardarelli Hospital, Via Caravaggio 89, Napoli 80126, Italy; Satoshi Yamagiwa, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi-dori 1, Chuo-ku, Niigata 951-8510, Japan
Persico M, Masarone M, La Mura V, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: Differences and similarities. World J Gastroenterol 2009; 15(4): 462-466 Available from: URL: http://www.wjgnet.com/1007-9327/15/462.asp DOI: http://dx.doi.org/10.3748/wjg.15.462
INTRODUCTION Recent years have seen numerous studies devoted to the relationship of such clinical variables as age, gender and body mass index (BMI) with metabolic alterations involving the liver in patients affected by hepatitis C virus (HCV)-related chronic hepatitis. Attention has focused on the metabolic syndrome (MS), diabetes[1-5], steatosis/steatohepatitis[6-10] and associations between these conditions[11-15]. It remains to be established whether the relationship between HCV and deranged cellular metabolic pathways is casual or whether it results from a direct effect exerted by HCV. In an attempt to shed light on this issue, we examined the prevalence of these phenomena in chronic hepatitis C (CHC) and in chronic hepatitis B (CHB) in order to distinguish between alterations due to presence of an advanced liver disease and those due to HCV[16-18]. We have investigated the prevalence of MS and/or diabetes and their effect on liver fibrosis and/or steatosis/steatohepatitis in a large cohort of patients affected by HCV- or hepatitis B virus (HBV)-related chronic hepatitis. Our aim was to look for differences and similarities between the two types of viral hepatitis and to confirm or refute the hypothesis of metabolic cofactors in HCV-related liver disease(s).
MATERIALS AND METHODS We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who underwent clinical evaluation and liver biopsy for HBV- or HCV-related hypertransaminasemia in the Internal Medicine and Hepatology Unit at the Second University of Naples from April 1999 to November 2005. The inclusion criterion was HBsAg-positive or HCV-Ab-positive chronic hepatitis. The exclusion criteria were: patients with a recent (< 6 mo) history of high alcohol consumption (> 30 g/d in females, > 40 g/d in males ) or a history of intravenous drug abuse, clinical and/or ultrasound evidence of cirrhosis, an human immunodeficiency virus (HIV)-positive test and HBV/HCV co-infection. In addition to a complete blood count, each patient underwent tests for: serum markers for hepatitis B infection determined by radioimmunoassay (Abbott Laboratories, North Chicago, IL, USA), antibodies to HCV assayed by a second-generation enzyme-linked immunoassay (ELISA; Ortho Diagnostic Systems, Raritan, NJ, USA), the presence of type 2 diabetes according to American Diabetes Association criteria[19] by assessing fasting serum glucose and/or the oral glucose tolerance test (OGTT) on two different occasions, and for the presence of MS based on NCEP-ATP Ⅲ criteria[20]. BMI (kg/m2) was recorded and the apparent disease duration [(ADD) in years] was determined by considering the exposure to major risk factors as the start of infection. Each patient underwent an echo-assisted liver biopsy performed with a 17G Menghini modified needle (Surecut, TSK Laboratory, Japan) through an intercostal entry. The liver specimens were formalin-fixed, embedded in paraffin and evaluated with the Ishak scoring system for viral liver disease[21] by skilled liver pathologists, who also evaluated the presence of liver steatosis and steato-hepatitis according to Brunt et al[22]. Statistical analysis of data was performed using the SPSS® 13.0 software for Windows®. Non-parametric tests (c2 or Fisher’s exact), Spearman’s rho test, ANOVA, linear and logistic regression tests were performed where appropriate.
RESULTS As shown in Table 1, HCV-positive patients had a significantly longer ADD (P < 0.005), a significantly older age (P < 0.0001) and a significantly higher BMI (P < 0.005) vs HBV-positive subjects. The MS was present in 76 out of 726 HCV patients (10.46%) and in only 2 of the 126 HBV subjects (P < 0.005). The prevalence of diabetes did not differ significantly between the two groups, but it was significantly higher in HCV subjects when comparing only patients with mild fibrosis (Ishak S0-S3) at liver biopsy (P < 0.005) (Figure 1). The prevalence of diabetes in mild fibrosis patients did not differ between the two groups when patients were stratified by age. No differences were found at liver biopsy as regards grading and staging, neither was there a difference in the prevalence of patients with higher degrees of steatosis. To evaluate whether age, sex, BMI, ALT, diabetes, MS and steatosis were independent risk factors for liver fibrosis we carried out a univariate and a multivariate analysis in the two groups of patients. At univariate analysis, all the variables tested were significantly related to higher degrees of fibrosis in HCV patients, whereas only age was correlated to liver fibrosis in HBV patients (Table 2). The results of the multivariate analysis confirmed these findings, namely age, sex, BMI, ALT and diabetes were independent risk factors for fibrosis in HCV subjects, whereas only age was related to fibrosis in HBV patients (Table 3). We next carried out statistical analyses to evaluate whether age, sex, BMI, ALT or diabetes were related to steatosis, which is a well known negative predictor of both disease outcome and response to therapy in HCV patients[23-26]. None of these parameters were significantly associated with degree of steatosis. However, when we did the same analysis considering only patients with steatosis > 30%, a higher BMI, diabetes and fibrosis were correlated with severe steatosis in CHC patients (Tables 4 and 5).
DISCUSSION In our cohort study, the prevalence of MS and diabetes was significantly higher in patients with HCV-related chronic hepatitis than in patients with HBV-related chronic liver disease. This suggests that insulin resistance, which is the mechanism underlying MS, might at least in part be related to HCV infection. Insulin resistance is identified with the euglycemic clamp technique[27] or with the homeostasis model assessment insulin resistance (HOMA-IR) test[28]. Neither euglycemic clamp nor the HOMA-IR test was performed in our patients. However, we used the most practical worldwide accepted definition of MS according to the ATP-Ⅲ NCEP clinical criteria[20]. Moreover, unlike other authors[16,29-32], we were able to measure, using these criteria, central obesity which is considered the fundamental condition for a clinical diagnosis of MS[33]. The association of diabetes and severe chronic liver disease is widely recognized[4,16,32,34], therefore the effect of severe liver disease on diabetes onset should be considered when comparing groups of patients affected by chronic liver disease. In our study, we were able to rule out that diabetes was related to the altered hepatic glycaemic homeostasis due to severe liver disease (i.e. cirrhosis). In fact, whereas the total prevalence of diabetes did not differ between HCV and HBV patients, the prevalence of diabetes among patients with mild chronic hepatitis was significantly higher in HCV subjects. This finding confirms reports of a higher prevalence of diabetes in HCV patients[14,29,34], and, vice versa, a report of a higher prevalence of HCV in diabetic patients[30]. Moreover, our data are in line with recent reports of a higher prevalence of diabetes in HCV patients compared with other liver diseases (e.g. HBV infection)[1]. In particular, Jan et al[17] reported a significantly higher prevalence of MS in HCV patients vs HBV patients, and an inverse ratio between HBV infection and clinical expression of MS in a population-based study carried out in Taiwan.
The association between diabetes and HCV-related chronic
hepatitis was reported to influence the clinical outcome of liver
disease[35-37].
Moreover, diabetes and/or obesity were found to be cofactors of liver
disease in that they affect liver fibrosis progress and response to
antiviral therapy[23,24,37-39].
Here we report that, besides ALT, sex and age, also diabetes and BMI
were independent risk factors for more severe liver fibrosis in HCV-positive
patients, whereas they were not associated with the severity of liver
fibrosis in HBV subjects.
This finding supports the idea that obesity and diabetes might represent
clinical epiphenomena of the pathogenesis of HCV infection.
In line with this hypothesis, using an animal model, Shintani
Steatosis has been associated with more severe liver fibrosis[23-26] as well as with a worse response to antiviral therapy. Moreover, steatosis is defined “metabolic steatosis” in non-3-genotype-infected patients as opposed to the viral steatosis typical of genotype 3 patients[11]. In our cohort of HCV patients, steatosis did not appear to be an independent risk factor for fibrosis stage. The discrepancy between our results and previous findings is apparent. Indeed, univariate and multivariate analyses vs fibrosis showed that steatosis was associated with the severity of liver fibrosis in our HCV patients if they were also affected by diabetes and/or obesity. Moreover, at multivariate analysis vs steatosis, BMI, diabetes and fibrosis were independent risk factors only for steatosis > 30%. This suggests that histological features of fibrosis, whether related to non-alcoholic steatohepatitis or to virus-associated steatohepatitis, will be found only in cases in which steatosis is > 30%. This study provides clinical evidence that HCV directly affects insulin resistance in a large Italian retrospective, single-centre, consecutive population of HCV- and HBV-infected subjects. Biological, molecular and genetic studies are required to test this hypothesis.
COMMENTS Background Glucose metabolism derangements are common in hepatitis C virus (HCV) patients but there is still a lot of deliberation as to whether the relationship between HCV and deranged cellular metabolic pathways is casual or whether it results from a direct effect exerted by HCV. Research frontiers To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). Innovations and breakthroughs A direct comparison of the prevalence of clinical features of insulin resistance in HCV and HBV infection in a large cohort of Italian patients. Applications To shed light on the association between insulin resistance and HCV infection and recommend further biological, molecular and genetic studies, and finally to suggest a careful assessment of insulin resistance status in HCV clinical care. Peer review The authors retrospectively analyzed a large cohort of consecutively-enrolled HCV (726) and HBV (126) patients undergoing liver biopsy in order to find a correlation between clinical expressions of insulin resistance (diabetes and metabolic syndrome) and HCV liver disease in comparison with HBV-related chronic hepatitis. This is an interesting paper and is of importance.
REFERENCES
1
Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, Guo L,
Jacob S, Regenstein FG, Zimmerman R, Everhart JE,
2
Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M,
Thomas DL. Prevalence of type 2 diabetes mellitus
3
Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A.
Increased risk of type 2 diabetes in noncirrhotic patients
4
Zein NN, Abdulkarim AS, Wiesner RH, Egan KS, Persing DH.
Prevalence of diabetes mellitus in patients with end-stage
5
Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan
GW, George J. Insulin resistance is associated with
6
Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in
chronic hepatitis C: relative contributions of obesity,
7
Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic fatty liver
disease. Semin Liver Dis 2004; 24: 399-413
PubMed
8
Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP.
Steatosis and hepatitis C virus: mechanisms and
9
Koike K, Moriya K. Metabolic aspects of hepatitis C viral
infection: steatohepatitis resembling but distinct from NASH. J
10
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R,
Ruggiero G. Steatosis accelerates the progression of liver
11
Ong JP, Younossi ZM, Speer C, Olano A, Gramlich T, Boparai N.
Chronic hepatitis C and superimposed nonalcoholic fatty
12
Younossi ZM, McCullough AJ, Ong JP, Barnes DS, Post A, Tavill A,
Bringman D, Martin LM, Assmann J, Gramlich T,
13
Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML,
Stravitz RT, Mills AS. Nonalcoholic fatty liver disease in
14 Chitturi S, George J. Interaction of iron, insulin
resistance, and nonalcoholic steatohepatitis. Curr Gastroenterol Rep
15
Clouston AD, Powell EE. Interaction of non-alcoholic fatty liver
disease with other liver diseases. Best Pract Res Clin
16 Papatheodoridis GV, Chrysanthos N, Savvas S, Sevastianos V,
Kafiri G, Petraki K, Manesis EK. Diabetes mellitus in
17
Jan CF, Chen CJ, Chiu YH, Chen LS, Wu HM, Huang CC, Yen MF, Chen
TH. A population-based study investigating the
18
Sangiorgio L, Attardo T, Gangemi R, Rubino C, Barone M, Lunetta
M. Increased frequency of HCV and HBV infection in 19 Diagnosis and classification of diabetes mellitus. Diabetes Care 2006; 29 Suppl 1: S43-S48 PubMed
20
Executive Summary of The Third Report of The National Cholesterol
Education Program (NCEP) Expert Panel
21
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F,
Denk H, Desmet V, Korb G, MacSween RN. Histological 22 Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004; 24: 3-20 PubMed DOI
23
Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C,
Clouston A, Powell EE. Fibrosis in chronic hepatitis C
24
Castera L, Hezode C, Roudot-Thoraval F, Bastie A, Zafrani ES,
Pawlotsky JM, Dhumeaux D. Worsening of steatosis is an
25
Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo
G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A,
26 Ratziu V, Trabut JB, Poynard T. Fat, diabetes, and liver
injury in chronic hepatitis C. Curr Gastroenterol Rep 2004; 6:
27 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a
method for quantifying insulin secretion and resistance.
28 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher
DF, Turner RC. Homeostasis model assessment: insulin
29 Lecube A, Hernandez C, Genesca J, Esteban JI, Jardi R, Simo
R. High prevalence of glucose abnormalities in patients
30 Chen HF, Li CY, Chen P, See TT, Lee HY. Seroprevalence of
hepatitis B and C in type 2 diabetic patients. J Chin Med
31 Mangia A, Schiavone G, Lezzi G, Marmo R, Bruno F, Villani
MR, Cascavilla I, Fantasia L, Andriulli A. HCV and diabetes
32 Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence
for a link between hepatitis C virus infection and diabetes 33 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366: 1059-1062
34 Zein CO, Levy C, Basu A, Zein NN. Chronic hepatitis C
and type II diabetes mellitus: a prospective cross-sectional study.
35 Prati D, Shiffman ML, Diago M, Gane E, Rajender Reddy K,
Pockros P, Farci P, O’Brien CB, Lardelli P, Blotner S,
36 Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB.
Diabetes increases the risk of hepatocellular carcinoma in the
37 Tarantino G, Conca P, Sorrentino P, Ariello M. Metabolic
factors involved in the therapeutic response of patients with
38 D'Souza R, Sabin CA, Foster GR. Insulin resistance plays a
significant role in liver fibrosis in chronic hepatitis C and in
39 Sanyal AJ, Chand N, Comar K, Mirshahi F. Hyperinsulinemia
blocks the inhibition of hepatitis C virus (HCV) replication by
40 Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K,
Kimura S, Moriya K, Koike K. Hepatitis C virus infection and
41
Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T,
Taniguchi E, Kumemura H, Hanada S, Maeyama M,
S- Editor Li DL L- Editor Logan S E- Editor Ma WH
| |||
|
|
