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���+�%��+�%�%([(�����08�d�������s"B'(�+�,0-/(,�1�# �1[(�1[(����%�����%,%,�%���-�������������������������������������������������������������������������1���������� �:LIVER TISSUE LEVELS OF NEOPTERIN IN NONALCOHOLIC STEATOHEPATITIS
Subheading: Neopterin in NASH
Fatih Tangi1, Zulfikar Polat2, H. Cem Gul3, Rahsan I. Sagkan4, Ugur Musabak4, Ayhan Ozcan5, C. Oktenli6*

1Division of Internal Medicine, G�lhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey
2Department of Gastroenterology, G�lhane Military Medical Academy, Ankara, Turkey
3Department of Infectious Diseases and Clinical Microbiology, G�lhane Military Medical Academy, Ankara, Turkey
4Department of Immunology and Allergic Diseases, G�lhane Military Medical Academy, Ankara, Turkey
5Department of Pathology, G�lhane Military Medical Academy, Ankara, Turkey
6Department of Internal Medicine, Anadolu Medical Center, Kocaeli, Turkey

Corresponding author: *Prof. Cagatay Oktenli, MD.
Department of Internal Medicine, Anadolu Medical Center,  TR-41400 Kocaeli, Turkey
E-mail: cagatay.oktenli@anadolusaglik.org or coktenli@yahoo.com
Tel: +90 216 547 1122; Fax: +90 216 317 9503

Abstract

Background: It is still unclear whether neopterin a contributing agent in underlying mechanism of liver injury in nonalcoholic steatohepatitis. Therefore, we aimed to investigate tissue levels of neopterin in liver biopsy specimens of patients with nonalcoholic steatohepatitis and to compare with chronic viral hepatitis.
Patients and Methods: Thirty-two male patients with histologically proven nonalcoholic steatohepatitis and 20 male patients with chronic viral hepatitis were enrolled to the study.
Results: Neopterin in liver biopsy specimens and plasma high sensitivity C-reactive protein levels were found to be significantly higher in patients with chronic viral hepatitis when compared with the nonalcoholic steatohepatitis patients. Tissue neopterin levels did not significantly differ between the nonalcoholic steatohepatitis score 1-3 and nonalcoholic steatohepatitis score 4-6, whereas they correlated significantly in a positive manner with body mass index, age and plasma high sensitivity C-reactive protein.
Conclusions: Neopterin seems not to be one of the crucial causative agents contributing to pathophysiological mechanisms of liver damage in nonalcoholic steatohepatitis.

Key words: Nonalcoholic steatohepatitis, neopterin, liver biopsy specimens, chronic viral hepatitis

Introduction
	Nonalcoholic steatohepatitis (NASH), as a subgroup of nonalcoholic fatty liver disease, is characterized by hepatic steatosis with inflammatory infiltrate and hepatocyte ballooning and/or varying degrees of fibrosis [1-5]. Importantly, about 20% of patients with NASH, during their lifetime, will develop cirrhosis that may result in decompensated liver disease or hepatocellular carcinoma. The underlying mechanisms in this progression and pathogenesis of NASH are still unclear and involve numerous complex factors such as insulin resistance, increased oxidative stress, altered adipocytokine balance, altered immunity, and inflammatory cytokines, etc. [1,3,5-7].
	Neopterin, a pyrazino-pyrimidine compound, is synthesized from guanosine triphosphate (GTP) by GTP-cyclohydrolase I in response to pro-inflammatory cytokine interferon-gamma (IFN-�) stimulation of human monocyte-derived macrophages and dendritic cells [8-12]. In this regard, neopterin is a biochemical marker of macrophage activation and cell-mediated immunity [13]. In humans, increased concentrations of serum and urine neopterin levels are detected in a number of pathologies including viral infections, atherosclerosis, autoimmune and inflammatory diseases, diabetes, chronic liver disease and various malignant disorders [14-25]. As neopterin secreted from the inflammation-activated macrophages, it can be a marker of the inflammation in liver for chronic liver diseases [8, 26]. In this way, previous reports suggested that serum and urinary neopterin levels were found to be high in patients with NASH [27,28]. On the other hand, increased neopterin levels in patients with chronic hepatitis due to hepatitis C and B viruses have been reported in various studies [15,21,29-33]. However, it is still unclear whether neopterin a contributing agent in underlying mechanism of liver injury in NASH. Therefore, we aimed to investigate tissue levels of neopterin in liver biopsy specimens of patients with NASH and to compare with chronic viral hepatitis.

Materials and Methods
	Thirty-two male patients with histologically proven NASH and 20 male patients with chronic viral hepatitis were enrolled to the study. All patients included in the present study underwent a percutaneous liver biopsy under ultrasonic guidance. Liver samples were divided into two groups, one group was processed for routine diagnostic histology and the other group was immediately frozen in liquid nitrogen and stored at -80�C. An independent pathologist who was unaware of the clinical data of patients made the histological diagnostic. The pathologist reviewed and scored the liver biopsy specimens according to the necroinflammatory (NIA) grading system for steatohepatitis, and defined as grade 1 (mild), grade 2 (moderate), and grade 3 (severe) steatohepatitis [34]. The liver specimens were also scored histologically with the NASH scoring system defined by the Pathology Committee of the NASH Clinical Research Network [35].
	Chronic viral hepatitis group consisted of 11 patients with type B chronic hepatitis and 9 patients with type C chronic hepatitis. Use of interferon or antiviral treatment within last one month was excluded. In patients with chronic viral hepatitis, the histopathological findings of liver biopsy specimens showed varying degrees of portal inflammation and parenchymal injury without advanced fibrosis and/or cirrhosis. Patients with chronic viral hepatitis who had > 5% steatosis in biopsy specimens were also excluded.
	All patients had normal renal and thyroid functions and they underwent detailed laboratory tests rule out other causes of liver disorders such as hemochromatosis, autoimmune hepatitis, sclerosing cholangitis or primary biliary cirrhosis, and genetic liver diseases. Patients who reported a history of gastrointestinal surgical procedures, infectious diseases, hypertension, diabetes, pancreatic, pulmonary, chronic inflammatory, malignant and vascular diseases, current smoking were excluded. None of the patients had ingested drugs such as statins, fibrate, oxacilline, tetracycline, chloroquine, sulfasalazine, methotrexate, nonsteroid anti-inflammatory drugs, corticosteroids, amiodarone, calcium channel blockers or spironolactone. Alcohol consumption (> 20 g per day) was also an exclusion criterion from the study. Each subject gave his informed consent to the study, which was previously approved by our local ethics committee and institutional review board.
	After an overnight fast, venous blood samples were obtained for laboratory analyses. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting serum glucose, total cholesterol, HDL-cholesterol and triglyceride levels were measured with a spectrophotometric technique by the Olympus AU-2700 autoanalyzer using commercial kits (Olympus, Hamburg, Germany). Low-density lipoprotein (LDL) cholesterol was calculated by Friedewald�s formula. Plasma high sensitivity C-reactive protein (hs-CRP) and insulin levels were determined with a chemiluminoassay technique by the Immulite 2000 hormone autoanalyzer using commercial kits (Bio-DPC, Los Angeles, CA, USA).
	The neopterin levels in liver biopsy specimens were measured by enzyme immunoassay (IBL International, Hamburg, Germany). Absorbance readings were carried out on Alisei Quality System (SEAC Radim Group, Pomezia, Italy). Sample concentrations of neopterin were determined from a curve obtained with the standards.
	Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. The estimate of insulin resistance by homeostasis model assessment for insulin resistance (HOMA-IR, %) was calculated from fasting plasma insulin and glucose levels as (insulin (microunits per milliter) x glucose (millimoles per liter))/22.5.


Statistical Analyses
	All statistical analyses were performed by using a package program SPSS 15.0 (SPSSFW, SPSS Inc., Chicago, IL, USA) statistical package. Descriptive statistics were given as arythmetic mean � standard deviation notation. Comparisons between the groups were made by Mann-Whitney U test. Correlations among the parameters were investigated by Spearman rank correlation coefficient (�  Rho-) and Pearson correlation procedure. P values less than or equal to 0.05 were evaluated as statistically significant.









Results
	
The mean age of patients with NASH was 36.72 � 5.84 years; (range 30-49), while it was 22.25 � 1.41 years; (range 20-25) in patients with chronic viral hepatitis. The mean levels and comparisons of parameters between the groups were shown in Table 1. The mean levels of BMI, HOMA-IR, LDL and triglyceride were significantly higher in patients with NASH than chronic viral hepatitis. However, tissue neopterin and plasma hs-CRP levels were found to be significantly high in patients with chronic viral hepatitis when compared with the NASH patients. The mean levels of ALT and AST did not significantly differ between the groups.
	According to the NIA grading system, histopathologic examination of liver biopsies revealed that 29 of the patients with NASH (91%) had grade 1 and 3 patients (9%) had grade 2 steatohepatitis. There is no patient in grade 3. Neopterin levels in liver biopsy specimens in NASH patients according to NASH scoring system were given in Table 2. Tissue neopterin levels did not significantly differ between the NASH score 1-3 and NASH score 4-6 (z = 0.898; P = 0.369).
	Tissue neopterin levels correlated significantly in a positive manner with BMI, age and plasma hs-CRP (� = 0.385, P = 0.005; � = 0.438, P = 0.001; and � = 0.915, P < 0.001, respectively).




Discussion
	
To our knowledge, the present results are the first observation of comparison of neopterin levels in liver biopsy specimens between chronic viral hepatitis and NASH. Liver tissue neopterin levels were found to be significantly high in patients with chronic viral hepatitis when compared with the NASH patients in the current study. As mention above, IFN-� is produced by the stimulation of T-lymphocytes by several specific antigens like viral antigens, and it is an effective inducer of neopterin release by monocytes/macrophages [8]. Neopterin is synthesized in macrophage/Kupffer cells in response to IFN-� and other cytokines [36]. Our results are in line the previous observations that the neopterin levels were found to be high in chronic hepatitis due to hepatitis C and B viruses [15,21,29-33]. In contrast to our findings, Yaman et al. reported urinary neopterin levels did not significantly differ between the NASH patients and patients with chronic viral hepatitis [28]. In another study, it has been demonstrated that serum neopterin levels in patients with NASH was higher than healthy controls [27]. Uygun et al. also reported a gradual increase in serum neopterin levels with the severity of liver damage according to the NASH scoring system [27]. However, as suggested in a previous study, neopterin levels were not significantly correlated with the histopathological stage of disease in our study.
	Not surprisingly, the mean levels of HOMA-IR, LDL, and triglyceride were higher in patients with NASH than patients with chronic viral hepatitis in the present study. All of these markers are the metabolic hallmarks of NASH [37,38]. We found also, plasma hs-CRP, an inflammatory marker, significantly correlated with neopterin levels in liver tissue. This may support the concept that neopterin is a marker of IFN-�-inducible inflammation cascade of some infectious and inflammatory diseases [39]. In consistent with previous reports [40,41], liver neopterin levels positively correlated with BMI and age. It is well known that elevated BMI is related with altered cytokines and a pro-inflammatory state [42].
	In conclusion, liver tissue neopterin levels were found to be significantly higher in patients with chronic viral hepatitis than NASH patients. Neopterin seems not to be one of the crucial causative agents contributing to pathophysiological mechanisms of liver damage in NASH. Since all patients were men in the present study, whether these conclusions can be extended to women awaits confirmation in sex-matched studies.

Acknowledgements
	This study was supported by grant from the Research Center of G�lhane Military Medical Academy.

Disclosure Statement
	Authors of this study have no interest which might be perceived as posing a conflict or bias.





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CJOJQJaJmH	sH	2002) Nonalcoholic steatohepatitis: what we know in the new millennium. Am J Gastroenterol 97: 2714-2724.
Willner IR, Waters B, Patil SR, Reuben A, Morelli J, et al. (2001) Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 96: 2957-2961.
Hoffmann G, Wirleitner B, Fuchs D. (2003) Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm Res 52: 313-321.
Ledochowski M, Murr C, Widner B, Fuchs D. (1999) Association between insulin resistance, body mass and neopterin concentrations. Clin Chim Acta  282: 115-123.
Spencer ME, Jain A, Matteini A, Beamer BA, Wang N, et al. (2010) Serum levels of the immune activation marker neopterin change with age and gender and are modified by race, BMI, and percentage of body fat. J Gerontol A Biol Sci Med Sci 65: 858-865.
Festa A, D�Agostino R Jr, Williams K, Karter AJ, Mayer-Davis EJ, et al. (2001) The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25: 1407-1415.








Tables
Table 1. The Mean Levels and Comparisons Results of Parameters Between the Groups

Table 2. Neopterin levels in liver biopsy specimens in patients with nonalcoholic steatohepatitis (NASH) according to NASH scoring system.
















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