ACLS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vecchiet, J.
Right arrow Articles by Guagnano, M. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vecchiet, J.
Right arrow Articles by Guagnano, M. T.
Annals of Clinical & Laboratory Science 35:415-422 (2005)
© 2005 Association of Clinical Scientists

Association between Plasma Interleukin-18 Levels and Liver Injury in Chronic Hepatitis C Virus Infection and Non-Alcoholic Fatty Liver Disease

Jacopo Vecchiet1,2, Katia Falasca1,2, Pierluigi Cacciatore3, Pompea Zingariello1,2, Margherita Dalessandro1,2, Marina Marinopiccoli1, Emilio D’Amico3, Carlo Palazzi3, Claudia Petrarca4, Pio Conti4, Eligio Pizzigallo1 and Maria Teresa Guagnano1
1 Department of Medicine and Aging, and 2 Centre of Excellence on Aging, G. d’Annunzio University, School of Medicine, Chieti; 3 Unit of Hepatology, Santo Spirito Hospital, Pescara; and 4 Departiment of Oncology and Neuroscience, G. d’Annunzio University, School of Medicine, Chieti, Italy

Address correspondence to Jacopo Vecchiet, M.D., Dept. of Medicine and Science of Aging, School of Medicine, G. d’Annunzio University, Via dei Vestini, 66013 Chieti, Italy; tel 39 0871 355 5293; fax 39 0871 561 635; e-mail jvecchiet{at}unich.it.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
There is significant upregulation of interleukin-18 (IL-18) expression in viral infectious diseases and in some chronic hepatic diseases, especially (i) hepatitis C virus (HCV) infection, (ii) HCV infection with persistently normal ALT levels (PNAL), and (iii) non-alcoholic fatty liver disease (NAFLD). The aim of this study was a better understanding of the implications of plasma IL-18 levels in the above-mentioned liver diseases. Thirty-four patients with HCV infection, 13 with NAFLD, and 10 controls were enrolled. The HCV-RNA and HCV-genotypes and the serum or plasma levels of IL-18, aspartate aminotransferase (AST), alanine aminotransferase (ALT), {gamma}-glutamyltranspeptidase ({gamma}-GT), alkaline phosphatase, total cholesterol, triglycerides, {alpha}1-fetoprotein, and ferritin were evaluated. Patients with HCV showed higher levels of IL-18 than the NAFLD patients (p <0.01) and the controls (p <0.005). Patients with NAFLD showed higher values of body mass index and liver disease parameters, compared to HCV-infected subjects or controls. These data confirm previous reports of enhanced expression of IL-18 in patients with HCV and NAFLD, compared to healthy subjects, and suggest that IL-18 is important as a marker of liver diseases.

Keywords: interleukin-18, HCV-infection, viral hepatitis, non-alcoholic fatty liver disease


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hepatitis C virus (HCV) infection induces chronic hepatitis with fluctuating serum aminotransferase (ALT) levels and detectable HCV-RNA [1–3], identifying chronic active HCV hepatitis (CAH-C). About 20% of chronically infected patients develop cirrhosis with enhanced risk of hepatocellular carcinoma [4–5], because of the difficulty in eradicating HCV [6].

Approximately 30% of patients with HCV have persistently normal ALT level (PNAL) HCV infection [7–8], characterized by (i) presence of anti-HCV antibody, (ii) positive assay for HCV-RNA by RT-PCR, and (iii) normal transaminases in at least 3 evaluations at intervals of 2 mo, for a period of 6 mo [9–10]. These patients tend to have lower degrees of inflammation and fibrosis in liver biopsies [11–14]. Previous studies suggested that these patients have slower disease progression [15–16]. It is now recognized that not all HCV-infected patients with normal serum ALT levels have mild liver disease with slower progression. In fact, up to 14–20% of these patients have advanced fibrosis or cirrhosis on liver biopsy and the degree of liver injury may not differ from matched controls with elevated serum ALT levels [17–19]. Other studies provide evidence that patients with HCV infection and PNAL have progressive liver disease that can be identified in liver biopsies [20].

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease in developed countries [21]. It is currently defined as fat accumulation in liver that exceeds 5% to 10% by weight, and is practically estimated as the percent of fat-laden hepatocytes observed by light microscopy [22]. No proven treatment is currently available for patients with NAFLD. It is unclear why steatosis is stable in some patients, whereas in others it progresses to fibrosis and cirrhosis [23].

Poynard et al [3] studied the natural history of liver fibrosis in HCV patients and identified the factors associated with its progression, suggesting that host factors, rather than virologic factors, play key roles. Helper T-cell subsets are polarized by some cytokines and are believed to govern, at least in part, the immune response to viral infection [24–25]. Helper T-cells fall into subsets depending on the production of either interferon-{gamma} (IFN-{gamma}) or interleukin 4 (IL-4), in combination with other cytokines. Helper T-cell subsets and the cytokines they produce are believed to play a pivotal role in the defense against HCV [26].

In fact, viral infections and some chronic injuries are known to suppress the immune system. In this context, interleukin-18 (IL-18), or interferon-{gamma}-inducing factor, is a 18-kD cytokine synthesized by Kupffer cells and by activated macrophages with proinflammatory activity at a very early step in the immune response. IL-18 generates cell-mediated immune responses via activation of Th1 T-helper cell sub-populations primarly through the induction of interferon-{gamma} [27,28]. There are few data on IL-18 in relation to infectious diseases, but it plays a prominent role in chronic HCV infection [29].

In chronic hepatitis C virus infection, a significant upregulation of IL-18 occurs in the inflammatory infiltrate, suggesting a role of this cytokine in the chronic cellular immune response to hepatocytes in the course of the disease. In particular, it has been shown that the administration of IFN-{gamma} exerts an anti-inflammatory action in vivo by induction of IL-18 binding protein and late suppression of IL-18 [30–31].

While the pathogenesis of chronic HCV infection has not been clearly defined, many researchers believe that cytokines play an important role in both immunoregulation and immune impairment. The aim of this study was to clarify the significance of IL-18 in regard to the degree of inflammation in viral liver disease and NAFLD by comparing serum IL-18 levels with various markers of liver disease.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thirty-four caucasian patients with chronic hepatitis C-virus (HCV) infection and 13 subjects with non-alcoholic fatty liver disease (NAFLD) were recruited at the time of first examination at the Infectious Diseases Division of the G. D’Annunzio University of Chieti. In addition, 10 non-obese, uninfected healthy subjects, matched for ethnicity and age, were included as a control group. All subjects gave written informed consent; the study was approved by the Medical Ethics Committee of our Medical School.

All patients underwent an extensive medical and laboratory evaluation, including a liver ultrasound scan and biopsy, the results of which were used to assign the patients into 2 groups on the basis of the presence of chronic hepatitis (1st group: HCV) or steatosis (2nd group: NAFLD). The liver biopsies were at least 15 mm long. Slides were routinely stained with H&E. Liver biopsies were read by a single liver pathologist who was unaware of each patient’s clinical and laboratory data. Biopsies from patients with chronic hepatitis C were graded by hepatitis activity index scores, according to Knodell et al [32]. All of the patients were afflicted with mild to moderate degrees of chronic hepatitis C infection. Diagnosis of non-alcoholic steatohepatitis was defined histologically by a combination of macrovescicular steatosis and lobular inflammation, plus either balloooning of hepatocytes or abnormal fibrosis [23].

The HCV group was then divided into subgroups of subjects with chronic active HCV hepatitis (CAH-C) and subjects with persistently normal ALT level (PNAL) HCV infection. Finally, 14 patients with CAH-C were classified as genotype 1 HCV-infected (n = 9) or genotype non-1 HCV-infected (n = 5). The diagnosis of HCV infection was defined by the usual biochemical and histological data and by detection of anti-HCV antibodies (Abbot Axsym HCV-3 and Ortho HCV 3.0 ELISA), plus HCV RNA in serum by polymerase chain reaction (PCR) (Amplicor method, Roche Molecular Diagnostics, Milan, Italy), with a detection limit <600 HCV RNA copies/ml of plasma. HCV genotyping was performed by PCR and patients were screened for viral 1 or non-1 genotypes. The entire study population was negative for other forms of viral hepatitis and human immunodeficiency virus (HIV) infection. Other conditions known to cause liver dysfunction were excluded on the basis of clinical evaluation.

The diagnosis of NAFLD was established according to the following criteria: (i) persistently elevated serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels; (ii) weekly ethanol consumption of less than 140 g; (iii) liver biopsy consistent with the diagnosis of NAFLD; and (iv) exclusion of other liver diseases [25]. No patients were taking steatogenic or antiviral drugs and they showed no clinical signs of advanced liver disease; the plasma prothrombin time, serum albumin, and serum total bilirubin levels were within normal limits.

Body mass index was calculated as weight (kg) divided by the square of height (m2). Fasting blood samples were drawn to measure serum levels of aspartate aminotransferases (AST), alanine aminotransferases (ALT), {gamma}-glutamyltranspeptidase ({gamma}-GT), alkaline phosphatase, total cholesterol, and triglycerides by (automated enzymatic methods (Ortho Clinical Diagnostics, Rochester, NY, USA), and serum {alpha}1-fetoprotein and ferritin (LIAISON AFP and ferritin assay kits, DiaSorin, Vercelli, Italy). Plasma IL-18 levels were assayed by an enzyme-linked immunosorbent assay (IL-18 ELISA, R & D Systems, Minneapolis, MN, USA). The minimum detection limit for IL-18, estimated by serial diluition, was 12.5 pg/ml.

Data are reported as means ± SD. Statistical significance was assessed by Student’s t-test for unpaired data. Linear regression analysis was performed to evaluate the correlations between plasma IL-18 and serum AST, ALT, {gamma}–GT, and alkaline phosphatase levels. P values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients with HCV infection and patients with NAFLD showed higher plasma IL-18 levels than the control group (p <0.005). Notably, IL-18 was higher in patients with HCV (370 ± 249 pg/ml) than in patients with NAFLD (175 ± 78 pg/ml) (p <0.01) (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Basic characteristics and analytical results in patients with chronic hepatitis C virus infection (HCV, n = 34), in patients with non-alcoholic fatty liver disease (NAFLD, n = 13), and in healthy control subjects (n = 10) (means ± SD).
 
No statistically significant differences were found between the HCV group and the NAFLD group in respect to age, AST, {gamma}-GT, {alpha}1-fetoprotein, ferritin, triglycerides, or platelet count. Patients with NAFLD showed higher values of BMI (p <0.02), ALT (p <0.001), alkaline phosphatase (p <0.001), and total cholesterol (p <0.001) than the HCV group. They also had higher values of BMI, alkaline phosphatase, {alpha}1-fetoprotein, ferritin, total cholesterol, and platelet count when compared to the controls (Table 1Go).

The plasma viral load in subjects with HCV infection was 546 ± 352 x 104 copies/ml. In regard to the 2 subgroups of HCV patients, the CAH-C group showed higher values of IL-18 (p <0.001), ALT (p <0.001), AST (p <0.001), {gamma}-GT (p <0.001), ferritin (p <0.001), alkaline phosphatase (p <0.01) and {alpha}1-fetoprotein (p <0.01), compared to the PNAL group (Table 2Go). In the HCV and CAH-C groups, linear regression analysis showed that plasma IL-18 was positively correlated with serum ALT (p <0.001 and <0.05, respectively), AST (p<0.001 and <0.01, respectively), {gamma}-GT (p<0.001 and <0.02, respectively), and alkaline phosphatase (p <0.001 and <0.005, respectively) (Table 3Go). In the PNAL group, plasma IL-18 was positively correlated only with serum alkaline phosphatase (p <0.01) (Fig. 1Go).


View this table:
[in this window]
[in a new window]
  		Table 2. Analytical results (means ± SD) in patients with chronic active HCV hepatitis (CAH-C, n = 16) and in patients with HCV infection with persistently normal ALT levels (PNAL, n = 18).
 

View this table:
[in this window]
[in a new window]
  		Table 3. Pearson’s correlation coefficients (r) of plasma IL-18 levels versus serum enzyme activities in the total group of patients with hepatitis C virus infection (n = 34) and in the subgroup of patients with chronic active HCV hepatitis (CAH-C, n = 16).
 


View larger version (20K):
[in this window]
[in a new window]
  		Fig. 1. Pearson’s correlation coefficient (r = 0.59, p <0.01) for plasma interleukin-18 levels and serum alkaline phosphatase activities in 18 cases of chronic active hepatitis infection with persistently normal serum ALT level (PNAL).

 
When the 14 subjects with CAH-C were classified in 2 groups based on their viral genotypes, plasma IL-18 levels were significantly higher in patients with viral genotype 1 (678 ± 299 pg/ml) than in patients with viral genotype non-1 (358 ± 175 pg/ml) (p <0.05). Plasma IL-18 levels were positively correlated with serum ALT, AST, and {gamma}-GT activities in patients with viral genotype 1 (Table 4Go).


View this table:
[in this window]
[in a new window]
  		Table 4. Pearson’s correlation coefficients (r) of plasma IL-18 levels versus serum enzyme activities in patients with viral genotype 1 of chronic active hepatitis C (CAH-C, n = 9).
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study we measured plasma levels of cytokine IL-18 in HCV-positive (CAH-C and PNAL) patients and NAFLD patients to obtain information about the roles of IL-18 in liver inflammation and immune response.

Several cytokines mediate hepatic processes including inflammation, apoptosis, necrosis, cholestasis, and fibrosis, but paradoxically, they are also involved in regeneration of liver tissue after injury. Evidence suggests that the immune response, and expecially the pro-inflammatory cytokines, plays an important role in liver injury induced by viral and dysmetabolic factors. Indeed, Th-1 type cytokines, such as IL-18, are crucial in enhancing cell-mediated immunity and in protecting against a number of viruses, including HCV [1].

Our data confirm previous reports of elevated plasma levels of IL-18 in HCV+ patients and in NAFLD patients, compared to healthy subjects. McGuinness et al [29], for instance, documented that IL-18 mRNA expression is significantly upregulated in HCV-associated chronic hepatitis [29].

Viral infections are known to suppress the immune system; induction of IL-18 binding protein and inhibition of IL-18 by endogenous IFN-{alpha} may contribute to the immunosuppressive state during viral infections [30].

There are indications that HCV+ patients present a Th1 type immune response, with overproduction of IFN-{gamma}. [29,33–35]. In contrast, Fan et al [36] documented a Th2 type immune response during CAH-C infection.

As IL-18 promotes the differentiation of naive T cells into Th1 cells, it may also have a negative role in the immunopathogenesis of chronic hepatitis C [30]. The different levels of IL-18 in separate compartments of the body should be dynamically evaluated in order to clarify Th1/Th2 balance in HCV infection [1]. We found strong positive correlations between plasma IL-18 levels and indices of inflammation and necrosis in patients with HCV, CAH-C, and PNAL.

In regard to an association between IL-18 and HCV-RNA, our in vivo results documented moderately higher levels of plasma IL-18 in virus genotype 1 compared to genotype non-1, in spite of the small number of patients. In contrast to these findings, possibly due to the small number of our subjects, Schvoerer et al [1] found in vitro that IL-18 levels were lower in genotype 1 HCV-infected patients than in healthy donors, while comparable IL-18 production was observed in genotype non-1 HCV-infected patients and controls. In vivo, plasma IL-18 levels tended to be lower for genotype 1 HCV-infected patients than for controls, although not significantly [1]. Lastly, Schvoerer et al [1] suggested that IL-18 levels and viral genotype should be examined together during the progression of HCV infection in order to better clarify their possible involvement in the pathogenesis. Genotype 1 HCV-infected patients are supposed to be exposed to a more severe liver disease [1,37]. Moreover, low peripheral blood production of IL-18 in genotype 1 HCV-infected patients could be sufficient to favor HCV persistence. Thus, the relationships among genotype 1 HCV, plasma IL-18 levels, and the progression of HCV disease need further study.

As for NAFLD, it represents a potential evolution towards non-alcoholic steatohepatitis (NASH), which is a new syndrome that usually occurs in obese patients with a liver biopsy consistent with alcoholic steatohepatitis, but without a history of alcohol abuse. As documented by our NAFLD patients, who had a body mass index higher than either the HCV-infected patients or control subjects, obesity is a major risk factor for these syndromes. The magnitude of the problem is impressive, because as many as 20–25% of the general population is believed to be affected by NAFLD, and one-fourth to one-fifth of these may have NASH [38].

The etiology of NASH and NAFLD remains difficult to explain, but most investigators agree that a critical baseline of steatosis requires a second strong stimulus capable of inducing inflammation, fibrosis, or necrosis to develop NASH. The interaction of cytokines with oxidative stress [39–41] and lipid peroxidation has been postulated to play a key role in the induction of steatohepatitis [42,43]. Kugelmas et al [43] documented that plasma levels of IL-18 did not decrease with therapy in patients with NASH and suggested that the metabolic defect, which permits overproduction of cytokines in response to lipopolysaccharide (LPS) stimulation, was not corrected by short-term modest weight loss, with or without antioxidant therapy.

Our NAFLD patients showed, although not significantly, higher plasma levels of IL-18 than the controls, suggesting that IL-18 might have an important role in the prediction of worsening NAFLD. Moreover, we documented, for the first time, increased plasma levels of IL-18 in 2 HCV-subgroups (CAH-C and PNAL), with the highest IL-18 levels in CAH-C. Thus, most HCV-infected patients with persistently normal serum ALT activities will have mild disease in terms of degree of activity and fibrosis.

In conclusion, we showed that, in HCV (CAH-C and PNAL) and NAFLD patients, elevated plasma levels of IL-18 may have an important role as a marker of both inflammation and hepatic-biliary injury progression. In addition, we observed positive correlations between plasma IL-18 levels and cholestatic indices. Although the plasma IL-18 level is envisioned as an important marker of global liver injury, little is known about plasma IL-18 responses in HCV infection and hence further studies are needed.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Schvoerer E, Navas MC, Thumann C, Fuchs A, Meyer N, Habersetzer F, Stoll-Keller F. Production of interleukin-18 and interleukin-12 in patients suffering from chronic hepatitis C virus infection before antiviral therapy. J Med Virol 2003;70:588–593.[Medline]
  2. Bouffard P, Hayashi PH, Acevero R, Levy N, Zeldis JB. Hepatitis C virus is detected in a monocyte/macrophage subpopulation of peripheral blood mononuclear cells of infected patients. J Infect Dis 1992;166:1276–1280.[Medline]
  3. Poynard T, Bedossa P, Opolon P for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825–832.[Medline]
  4. Sharara AI, Hunt CM, Hamilton JD. Hepatitis C. Ann Intern Med 1996;125:658–668.[Abstract/Free Full Text]
  5. Tarao K, Rino Y, Takemiya S, Tamai S, Ohkawa S, Sugimasa Y, Miyakawa K, Morinaga S, Yoshida M, Shibuya A, Kokubu S, Kakita A, Endo O. Close association between ligh serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepato-cellular carcinoma. Intervirol 2000;43:20–26.[Medline]
  6. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxì A, Ling MH, Albrecht J. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. NEJM 1998;339:1493–1499.[Abstract/Free Full Text]
  7. Conry-Cantilena C, VanRaden M, Gibble J, Menpolder J, Shakil AO, Viladomiu L, Cheung L, DiBisceglie A, Hoofnagle J, Shih JW. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. NEJM 1996;334:1691–1696.[Abstract/Free Full Text]
  8. Puoti C. HCV carriers with persistently normal aminotransferase levels: normal does not always mean healthy. J Hepatol 2003;38:529–532.[Medline]
  9. National Institutes of Health Consensus Development Conference Panel. Management of hepatitis C. Hepatol 1997;26:S133–136.[Medline]
  10. EASL International Consensus Conference on Hepatitis C. Consensus statement. J Hepatol 1999;30:956–961.[Medline]
  11. Mathurin P, Moussali J, Cadranel JF, Thibault V, Charlotte F, Dumouchel P, Cazier A, Huraux JM, Devergie B, Vidaud M, Opolon P, Poynard T. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998;27: 868–872.[Medline]
  12. Alberti A, Chemello L, Noventa F, Cavalletto L, De Salvo G. Therapy of hepatitis C: re-treatment with alpha interferon. Hepatology 1997;26:137S–142S.[Medline]
  13. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26:29S–33S.[Medline]
  14. Martinot-Peignoux M, Boyer N, Cazals-Hatem D, Pham BN, Gervais A, Le Breton V, Levy S, Degott C, Valla DC, Marcellin P. Prospective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA. Hepatology 2001;34:1000–1005.[Medline]
  15. Persico M, Persico E, Suozzo R, Conte S, De Seta M, Coppola L, Palmentieri B, Sasso FC, Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000; 118:760–764.[Medline]
  16. Jamal MM, Soni A, Quinn PG, Wheeler DE, Arora S, Johnston DE. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the southwestern United States. Hepatology 1999;30:1307–1311.[Medline]
  17. Ghoulson CF, Morgan K, Catinis G, Favrot D, Taylor B, Gonzalez E, Balart L. Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study. Am J Gastroenterol 1997;92:1788–1792.[Medline]
  18. Alberti A, Noventa F, Benvegnu L, Boccato S, Gatta A. prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection. Ann Intern Med 2002;137:961–964.[Abstract/Free Full Text]
  19. Puoti C, Stati T, Magrini A, Rigato P, Romagnoli G, Rossi P, Montagnese F, Resta S. Liver histology in anti-HCV positive subjects with normal ALT levels. Ital J Gastroenterol Hepatol 1997;29:383–384.[Medline]
  20. Kyrlagkitsis I, Portmann B, Smith H, O’Grady J, Cramp M. Liver histology and progression of fibrosis in individual with chronic hepatitis C and persistently normal ALT. Am J Gastroenterol 2003;98:1588–1593.[Medline]
  21. Puoti C, Guido M, Mangia A, Persico M, Prati D. Clinical management of HCV carriers with normal aminotransferase levels. Digest Liver Dis 2003;35:362–369.
  22. Cairns W, Smith CA, McLaren AW, Wolf CR. Characterization of the human cytochrome P4502D6 promoter. A potential role for antagonistic interactions between members of the nuclear receptor family. J Biol Chem 1996;271:25269–25276.[Abstract/Free Full Text]
  23. Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol 2004;42: 943–949.
  24. Schirren CA, Jung MC, Gerlach JT, Worzfeld T, Baretton G, Mamin M, Hubert Gruener N, Houghton M, Pape GR. Liver-derived hepatitis C virus-specific CD4+ T cells recognize multiple HCV epitopes and produce interferon gamma. Hepatology 2000;32:597–603.[Medline]
  25. Marinos G, Rossol S, Carucci P, Wong PY, Donaldson P, Hussain MJ, Vergani D, Portmann BC, Williams R, Naoumov NV. Immunopathogenesis of hepatitis B virus recurrence after liver transplantation. Transplantation 2000;69:559–568.[Medline]
  26. Woitas RP, Rockstroh JK, Beier I, Jung G, Kochan B, Matz B, Brackmann HH, Sauerbruch T, Spengler U. Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients. AIDS 1999;13:1313–1322.[Medline]
  27. Lebel-Binay S, Berger A, Zinzindohoue F, Cugnenc P, Thiounn N, Fridman WH, Pages F. Interleukin-18: biological properties and clinical implications. Eur Cytokine Netw 2000;11:15–26.[Medline]
  28. Dinarello CA. Interleukin-18, a proinflammatory cytokine. Eur Cytokine Netw 2000;11:483–486.[Medline]
  29. McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokine (particularly interleukin 18) in chronic hepatitis C infection. Gut 2000;46:260–269.[Abstract/Free Full Text]
  30. Kaser A, Novick D, Rubinstein T, Siegmund B, Enrich B, Koch RO, Vogel W, Kim SH, Dinarello CA, Tilg H. Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients. Clin Exp Immunol 2002;129:332–336.[Medline]
  31. Jia H, Du J, Zhu S, Ma Y, Cai H. Clinical observation of serum IL-18, IL-10 and sIL-2R levels in patients with chronic hepatitis C pre-and post antiviral treatment. Clin Med J 2003;116:605–608.
  32. Knodell RG, Ishak KG, Black WC, Craig R, Kaplowitz N, Kiernan TW, Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.[Medline]
  33. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding of hepatitis C virus to CD81. Science 1998;282:938–941.[Abstract/Free Full Text]
  34. Bertoletti A, D’Elios MM, Boni C, De Carli M, Zignego AL, Durazzo M, Missale G, Penna A, Fiaccadori F, Del Prete G, Ferrari C. Different cytokine profile of intrahepatic T cells in chronic hepatitis B and hepatitis C virus infection. Gastroenterology 1997;112:193–199.[Medline]
  35. Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, Joh Titoh M, KaKumu S. Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. J Gastroenterol 2001;36:544–551.[Medline]
  36. Fan XG, Liu WE, Li CZ, Wang ZC, Luo LX, Tan DM, Hu GL, Zhang Z. Circulating Th1 and Th2 cytokines in patients with hepatitis C virus infection. Mediators Inflamm 1998;7:295–297.[Medline]
  37. Boni C, Amadei A, Urbani S, Fisicaro P, Zerbini A, Mori C, Missale G, Bertoni R, Azzurri A, Del Prete G, Ferrari C. Antiviral CD8-mediated responses in chronic HCV carriers with HBV superinfection. Hepatology 2004;40:289–299.[Medline]
  38. Zhang Y, Wang Y, Gilmore X, Xu K, Mbawuike IN. Independent and synergistic effects of interleukin-18 and interleukin-12 in augmenting cytotoxin T lymphocyte responses and IFN-gamma production in aging. J Interferon Cytokine Res 2001;21:843–850.[Medline]
  39. Kempuraj D, Frydas S, Karagouni E, Hatzstilianou M, Boscolo P, Ferro F, Di Giannantonio M, Conti CMV, Merlitti D, Doyle R, Petrarca C, Castellani M, Theoharides TC. Cytokines and the brain. Int J Immunopathol Pharmacol 2004;17:229–232.[Medline]
  40. De Lutiis MA, Felaco M, Gizzi F, Patruno A, Sperana L, Di Giulio C, Conti P, Castellani ML, Grilli A. A scavenger role of nitric oxide in the aged rat kidney. Int J Immunopathol Pharmacol 2004;17:265–271.[Medline]
  41. Kempraj D, Donelan J, Frydas S, Iezzi T, Conti P, Boucher W, Papadoopoulou NG, Madhappan B, Letourneau L, Sabatino G, Riccioni G, Theoharides TC. Interleukin-28 and 29 (IL-28 and IL-29): new cytokines with antiviral activities. Int J Immunopathol Pharmacol 2004;17:103–106.
  42. Marra F. NASH: are genes blowing the hits? J Hepatol 2004;40:853–856.[Medline]
  43. Kugelmas M, Hill DB, Vivian B., Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003; 38:413–419.[Medline]



This article has been cited by other articles:


Home page
 Annals of Clinical & Laboratory ScienceHome page
K. Falasca, C. Ucciferri, M. Dalessandro, P. Zingariello, P. Mancino, C. Petrarca, E. Pizzigallo, P. Conti, and J. Vecchiet
Cytokine Patterns Correlate with Liver Damage in Patients with Chronic Hepatitis B and C.
Ann. Clin. Lab. Sci., March 1, 2006; 36(2): 144 - 150.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vecchiet, J.
Right arrow Articles by Guagnano, M. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vecchiet, J.
Right arrow Articles by Guagnano, M. T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS