Neopterin as an Inflammatory Biomarker in Patients
with Non-alcoholic Fatty Liver Disease
Rawa Ratha1
, Vian Ahmed Wasta Esmail1
, Fenk Bakir Maarouf2
, Hemn Abdalla Omer3
,
Marwan Al-Nimer4 & Mohammed Omer Mohammed5*
Abstract
References
1 Department of Clinical Pharmacy, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
2 Department of Biochemistry, College of Medicine, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
3 Department of Microbiology, College of Medicine, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
4 Department of Pharmacology and Toxicology, Hawler Medical University, Erbil, Iraq
5 Department of Medicine, College of Medicine, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
*Correspondence author Email: mohammad.raheem@univsul.edu.iq
Abstract
Background: Early diagnosis of non-alcoholic fatty liver diseases (NAFLD) through
detection of a new biomarker is crucial to prevent disease deterioration. Aim: To evaluate
the serum level of neopterin in NAFLD patients and to demonstrate its role as an early
biomarker of NAFLD. Methodology: This is an observational, cross-sectional study that
conducted on 71 newly diagnosed NAFLD patients and 60 healthy individuals as a control
group. Liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase
[AST]) and uric acid were determined. The serum level of neopterin was measured by
ELISA and WBC differential count by a Coulter counter analyzer. Erythrocyte
sedimentation rate (ESR) was determined by Wintrobe’s method. Results: NAFLD
patients had a significantly higher BMI, waist circumference, and body weight compared
to control, also their blood pressure was significantly higher. The serum level of ALT,
AST, and uric acid were significantly higher in NAFLD patients than the control. There is
non-significant difference between NAFLD patients and controls regarding ESR,
lymphocytes and granulocytes, while monocytes and neopterin values were significantly
higher among NAFLD patients. Conclusions: Serum neopterin level can be a predictor
inflammatory marker in NAFLD patients. Clinical Pharmacists as part of healthcare
professionals can support NAFLD patients by educating them on lifestyle modification if
the disease is diagnosed early before reaching a critical stage.
Key Words:
Nonalcoholic fatty liver
disease, pro.inflammatory cytokines,
neopterin, cross.sectional study
References
[1] Sumida Y, Yoshikawa T, Tanaka S, Taketani H, Kanemasa K, Nishimura T, et al. The ‘donations for decreased
ALT (D4D)’ prosocial behaviour incentive scheme for NAFLD patients. J Public Health (Oxf) 2014; 36: 629-
634.
[2] Pulzi FB, Cisternas R, Melo MR, Ribeiro CM, Malheiros CA, Salles JE. A new clinical score to diagnose
nonalcoholic steatohepatitis in obese patients. Diabetol Metab Syndr 2011; 3: 3.
[3] Tevar AD, Clarke C, Wang J, Rudich SM, Woodle ES, Lentsch AB, Edwards ML. Clinical review of
nonalcoholic steatohepatitis in liver surgery and transplantation. J Am Coll Surg 2010; 210: 515-526.
[4] De Hewavisenthi SJ, Dassanayaka AS, De Silva HJ. Clinical, biochemical, and histological characteristics of a
Sri Lankan population of non-alcoholic steatohepatitis (NASH) patients. Ceylon Med J 2005; 50: 113-116.
JZS-A Volume 24, Issue 1, June 2022
100
[5] Wilson S, Chalasani N. Noninvasive markers of advanced histology in nonalcoholic fatty liver disease: are we
there yet? Gastroenterology 2007; 133: 1377-1378.
[6] Scheja L, Heeren J. Metabolic interplay between white, beige, brown adipocytes and the liver. J Hepatol 2016;
64:1176–1186.
[7] Wieckowska A, Papouchado BG, Li Z, et al. Increased hepatic and circulating interleukin-6 levels in human
nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103:1372–1379.
[8] Fon Tracer K, Kuzman D, Seliskar M, Pompon D, Rozman D. TNF-alpha interferes with lipid homeostasis and
activates acute and proatherogenic processes. Physiol Genomics 2007; 31: 216-227.
[9] Feingold KR, Soued M, Serio MK, Adi S, Moser AH, Grunfeld C. The effect of diet on tumour necrosis factor
stimulation of hepatic lipogenesis. Metabolism 1990; 39: 623-632.
[10] Das SK, Balakrishnan V. Role of cytokines in the pathogenesis of non-alcoholic Fatty liver disease. Indian J
Clin Biochem 2011; 26: 202-209.
[11] Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin
administration in healthy subjects in the fed and fasting states regulation by gender and adiposity. Clin
Pharmacokinet 2008; 47: 753-764.
[12] Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Dig Dis 2010; 28: 179-185.
[13] Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D, Brandacher G. Neopterin, a prognostic marker
in human malignancies. Cancer Lett 2010; 287(1):13–22.
[14] Neurauter G, Schrocksnadel K, Scholl-Burgi S, Sperner-Unterweger B, Schubert C, Ledochowski M, et al.
Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab 2008; 9(7):622–
627.
[15] Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, et al. Pteridine biosynthesis
in human endothelial cells. Impact on the nitric oxide-mediated formation of cyclic GMP, J. Biol. Chem. 1993;
268: 1842–1846.
[16] D'agostino LE, Ventimiglia F, Verna JA, Colina Ade L, Aguirre Y, Arturi A, et al. Correlation between DAS.28 and neopterin as a biochemical marker of immune system activation in early rheumatoid arthritis,
Autoimmunity 2013; 46: 44–49.
[17] Viaccoz A, Ducray F, Tholance Y, Barcelos GK, Thomas-Maisonneuve L, Ghesquières H, et al. CSF neopterin
level as a diagnostic marker in primary central nervous system lymphoma, Neuro-Oncology 2015;17: 1497–
1503.
[18] Bansil S, Mithen FA, Singhal BS, Cook SD, Rohowsky-Kochan C. Elevated neopterin levels in Guillain-Barré
syndrome. Further evidence of immune activation, Arch. Neurol. 1992; 49: 1277–1280.
[19] Ipekci SH, Kebapcilar AG, Yilmaz SA, Ilhan TT, Pekin AT, Abusoglu S, et al. Serum levels of neopterin in
gestational diabetes mellitus: the relationship with Apgar scores, Arch Gynecol Obstet. 2015; 292: 103–109.
[20] Marwan A, Rawa R, Taha M. Utility of Tetrahydrobiopterin Pathway in the Assessment of Diabetic Foot
Ulcer: Significant and Complex Interrelations. Journal of Diabetes Research, Volume 2019, Article ID
3426878, 7 pages.
[21] Daito K, Suou T, Kawasaki H. Clinical significance of serum and urinary neopterin levels in patients with
various liver diseases. Am J Gastroenterol 1992; 87: 471–476.
[22] Ahmet U, Abdurrahman K, Ugur M, Nuri E, Yildirim K, Bulent D, et al. Serum neopterin levels in patients
with non-alcoholic steatohepatitis. Hepatology Research 2008; 38: 904–908.
[23] Kaneki M, Shimizu N, Yamada D. Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox
Signal. 2007; 9: 319-329.
[24] Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev
Pathol 2010;5: 145-171.
[25] Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK. Nonalcoholic steatohepatitis:
association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120:1183-1192.
JZS-A Volume 24, Issue 1, June 2022
101
[26] Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and
clinical implications. HEPATOLOGY 2010;51: 679-689.
[27] Sun K, Kusminski CM, Scherer PE. Adipose tissue remodelling and obesity. J Clin Invest 2011; 121:2094–
2101.
[28] Moschen AR, Molnar C, Geiger S, et al. Anti-inflammatory effects of excessive weight loss: potent suppression
of adipose interleukin 6 and tumour necrosis factor-alpha expression. Gut 2010; 59:1259–1264.
[29] Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression
and secretion. J Clin Endocrinol Metab 2007; 92:1023–1033.
[30] Stojsavljevic S, Gomercic Palcic M, Virovic Jukic L. Adipokines and proinflammatory cytokines, the key
mediators in the pathogenesis of the nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070–
18091.
[31] Stoner L, Lucero AA, Palmer BR. Inflammatory biomarkers for predicting cardiovascular disease. Clin
Biochem 2013; 46:1353–1371.
[32] Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, et al. Independent predictors of fibrosis in
patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009; 7: 1224-1229, 1229e1-e2.
[33] Wilfred de Alwis NM, Day CP. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease. Semin
Liver Dis 2007; 27: 44-54.
[34] Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006; 44:
466-471.
[35] Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for
nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005; 42: 44-52.
[36] Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP. Nonalcoholic fatty liver disease in severely
obese subjects. Am J Gastroenterol 2007; 102: 399-408.
[37] Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI. Elevated serum uric acid levels are
associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United
States: liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 2013;
62(3): 392–399.
[38] Yong-Jae Lee, Hye-Ree Lee, Jung-Hyun Lee, Youn-Ho Shin, and Jae-Yong Shim. Association between serum
uric acid and non-alcoholic fatty liver disease in Korean adults. Clin Chem Lab Med 2010;48(2):175–180.
[39] Park SH, Kim BI, Yun JW. Insulin resistance and C-reactive protein as independent risk factors for
nonalcoholic fatty liver disease in non-obese Asian men. Journal of Gastroenterology and Hepatology 2004;
19(6): 694–698.
[40] Hack-Lyoung K, Goh EC, In YP, Jin MC, Se-Min H, Jeong-Hoon L, et al. Elevated Peripheral Blood Monocyte
Fraction in Nonalcoholic Fatty Liver Disease. Tohoku J Exp Med 2011;223: 227-233.
[41] Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM 2010; 103:
71-83.
[42] Byrne CD. Fatty liver: role of inflammation and fatty acid nutrition. Prostaglandins Leukot. Essent. Fatty Acids
2010; 82: 265-271.
[43] Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev
Pathol 2010; 5: 145-171.
[44] Siebler J, Galle PR, Weber MM. The gut-liver-axis: endotoxemia, inflammation, insulin resistance and NASH.
J Hepatol 2008; 48: 1032-1034.
[45] Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, et al. Adipokines and cytokines in
non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 27: 412-421.
[46] Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, Nagaoka S, et al. Serum cytokine and soluble
cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int 2006; 26: 39-45
