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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 2310-2314 Mean volume in hepatitis A

H. ALMI , I.H. BUCAK, V. ÇELIK, M. TEKIN, F. KARAKOÇ, Ç. KONCŞA, M. TURGUT

Department of Pediatrics, Adiyaman University School of Medicine, Adiyaman, Turkey

Abstract. – OBJECTIVE : Hepatitis A virus tion, and the infection is more severe with in - (HAV) still continues to be a serious public health creasing age. Endemicity is closely linked to san - problem worldwide. Mean platelet volume (MPV) is a marker of platelet function and activation. itation, hygiene, socioeconomic status, and vac - This study aimed to evaluate the relationship be - cination. Outbreaks of HAV infection can occur, tween MPV in acute hepatitis A patients as com - although that is less common in developed coun - pared to the control group and to assess MPV as tries 5. Hepatitis A is associated with various an acute phase reactant in acute hepatitis A. hematologic abnormalities, such as autoimmune PATIENTS AND METHODS: Seventy-six pa - hemolytic anemia, leukopenia, leukocytosis, tients were enrolled in this study. The control 6-8 group consisted of 41 healthy age- and sex- , and thrombocytosis . matched individuals. Alanine aminotransferase play a critical role in the inflammato - (ALT), aspartate aminotransferase (AST), bilirubin, ry process. Many cytokines with different func - (PT), platelet count (PC), serum tions are secreted by platelets in inflammation 9,10 . albumin (ALB), and mean platelet volume (MPV) Platelet volume is an indicator of platelet func - levels were recorded. The diagnosis of HAV infec - tion was based on anti-HAV Ig M positivity. tion and activation. Mean platelet volume (MPV) RESULTS: The mean levels of MPV in the study is readily measured by clinical ana - group were significantly statistically lower than lyzers using sodium citrate as the anticoagulant 11 . in the control group ( p < 0.001). The MPV levels Mean platelet volume and changes in the activity revealed no correlation with the ALT, AST, ALP, and function of platelets affect many diseases, and GGT levels ( p > 0.05), but the MPV levels such as acute pancreatitis, acute appendicitis, correlated with the platelet counts ( p < 0.05). A 9.75 fL [area under the curve (AUC: 0.756)] opti - neonatal respiratory distress syndrome, retinal mal cutoff level of MPV with a sensitivity of vein occlusion, inflammatory bowel disease, 69.7% and specificity of 68.3% was determined Crimean-Congo hemorrhagic fever, chronic he - in the children with acute hepatitis A. patitis C and pulmonary tuberculosis 12-19 . CONCLUSIONS: MPV levels were significantly This study aimed to evaluate the relationship lower in the patients with acute hepatitis A as compared to the healthy control group. This between mean platelet volume in hepatitis A pa - study demonstrated that MPV may be a negative tients as compared to a healthy control group. acute phase reactant for acute hepatitis A. Fur - ther studies will explain the role that MPV plays in inflammation and other viral infections. Patients and Methods Key Words: Mean platelet volume, Hepatitis A, Child. This study was conducted at the Outpatient Clinic of the Department of Pediatrics at Adiya - man University Hospital in Adiyaman City, Introduction Turkey. The study was approved by the Institu - tional Review Board. Seventy-six patients were Hepatitis A virus (HAV) is a non-enveloped enrolled in this study. The control group consist - RNA virus, with an icosahedral structure, that is ed of 41 healthy age- and sex-matched individu - in the genus of Hepatovirus in the family of Pi - als. The data were obtained from patient records cornaviridae 1. HAV is usually caused by self-lim - accessed from a computerized database system. ited acute hepatitis and is transmitted via the fe - The alanine aminotransferase (ALT), aspartate cal oral route 2. Although the course of HAV in - aminotransferase (AST), bilirubin, prothrombin fection is usually asymptomatic it rarely develops time (PT), platelet count (PC), serum albumin into fulminant hepatitis 3,4 . Age is the main factor (ALB), and MPV laboratory findings of those that determines the clinical course of HAV infec - patients were recorded.

2310 Corresponding Author: Habip Almi , MD; e-mail: [email protected] ş Mean platelet volume in hepatitis A

Exclusion criteria were the use of any drugs this study. The mean age for the study group was that might change platelet activity and function, 7.2 ± 3.1 and the mean age for the control group and the presence of mellitus, asthma, was 5.56 ± 2.56 years. There was no statistically peripheral and cerebrovascular disease, malig - significant difference with regard to age and gen - nancies, and chronic diseases. In this study, der between the groups ( p > 0.05). The laborato - cholestatic hepatitis was defined as serum biliru - ry findings and demographic data for the study bin levels of 10 mg/dL or serum bilirubin levels group and the control group are shown in Table I. that were high for more than 14 days. The mean levels of MPV in the study group were Blood from the study group and the healthy statistically significantly lower than in the control group was obtained by venipuncture. The pa - group ( p < 0.05). The MPV levels showed no tients were evaluated for anti-HAV Ig M and an - correlation with the ALT, AST, ALP, and GGT ti-HAV Ig G antibodies. The diagnosis of HAV levels (p > 0.05), but we detected a correlation infection was based on anti-HAV Ig M positivity. between the MPV levels and the platelet counts Each sample of whole blood was collected in (p < 0.05). We measured the CRP, leukocyte tubes containing ethylenediaminetetraacetic acid. count, and ESR levels in the acute hepatitis A pa - The Sysmex XT 2000i (Roche Diagnostics tients and we found no statistically significant GmbH, Mannheim, Germany) automated analyz - correlation between these levels and the MPV er was used for the blood counts. The reference levels (p > 0.05). range for MPV was between 7.0 fL and 11 fL. A 9.75 fL [area under the curve (AUC: 0.756)] optimal cutoff level of MPV with a sensitivity of Statistical Analysis 69.7 % and specificity of 68.3 % was determined in SPSS (Statistical Package for Social Sciences the children with acute hepatitis A (Figure 1). Statistical Software) 16.0 Version (SPSS, Inc., None of our patients developed fulminant hepati - Chicago, IL, USA) was used to assess the patient tis. Death did not occur in any of the studied cases. data. The Mann-Whitney U test was performed to compare gender distribution in both groups. The in - dependent two sample t-test was used to compare Discussion the age distribution and MPV levels in both groups. The Pearson’s test was used to evaluate the correla - The most important finding of our study tions among the MPV levels and the other laborato - showed that MPV levels significantly decreased ry parameters. The data were expressed as mean ± in patients with acute hepatitis A compared to the standard deviation (x±SD). Significance of statisti - healthy control group. This study showed that cal analysis was defined at a value of p < 0.05. To MPV may be a negative acute phase reactant in define the optimal cutoff level of MPV measured in acute hepatitis A. the acute hepatitis A, the reason why characteristic Platelets have three types of granules: α-gran - (ROC) curve analysis was used. ules, dense bodies, and lysosomes. The α-granules and the dense bodies play a role in the activation of hemostasis and in the production of inflamma - Results tion and cytokine; they are also modulators of in - flammation 20 . Platelets are not only required for Seventy-six children (42 males; 34 females) primary hemostasis, they also play an important with acute hepatitis A and 41 healthy control pro-inflammatory role 21 . Platelets are activated by subjects (22 males; 19 females) were included in different cytokines. IL-6 and TNF-a contribute to

Table I. Demographic and platelet parameters and laboratory findings of the control and acute hepatitis A groups.

Acute hepatitis A Control p value

Age (years) 7.44 ± 2.93 5.56 ± 2.56 > 0.05 Gender (male/female) 42 (55.3%)/34 (34.7%) 22 (53.7%)/19 (46.3%) > 0.05 ALT 1342.32 ± 763.24 19.24 ± 5.73 < 0.05 AST 1186.03 ± 860.6 28.53 ± 6.29 < 0.05 Platelet count (10 3 µL) 263.12 ± 80.12 249.61 ± 71.22 < 0.05 MPV (fL) 8.75 ± 1.24 10.02 ± 1.40 < 0.05

2311 H. Almi , I.H. Bucak, V. Çelik, M. Tekin, F. Karakoç, Ç. Konca, M. Turgut ş

Figure 1. Mean platelet volume and differentiation between acute hepatitis A and the control group, ROC (receiver operating characteristic) curve; the optimal cutoff level of the mean platelet volume (MPV) was 9.75 fL (sensitivity, 69.7%; specificity, 68.3%; AUC, 0.756). the inflammatory process by which the platelets Ekiz et al 30 showed that increased MPV was are activated 22 . After degranulation, the size of the statistically significant in patients with chronic platelets is reduced. Anti-TNF-a agents increase hepatitis B. Karaman et al 18 demonstrated that MPV and the size of the platelets 23 . high MPV levels (especially those over 8.4 fL) Platelet size varies depending on the platelet may help predict advanced fibrosis in patients function and activity. MPV can be easily mea - with chronic hepatitis C. Turhan et al 31 demon - sured by whole blood analysis 24 . Nowadays, strated that MPV levels significantly increased in MPV is a marker widely used to detect platelet inactive HBs Ag carrier patients. function and activity and acute phase reactant 24,25 . There are a few limited studies on the MPV Many studies have shown that the MPV levels levels in hepatitis B. More recently, Hu et al 32 decreases during the acute and active inflamma - showed that MPV levels were significantly in - tory period of some diseases. Liu et al 26 showed creased in chronic hepatitis B patients compared that MPV levels decreased in Kawasaki disease. with acute hepatitis B patients and healthy con - Beyazit et al 12 demonstrated that a statistically trol group. This study suggests that high MPV significant decrease in MPV levels occurred in levels are an indicator of disease severity in he - acute pancreatitis. Kisacik et al 27 demonstrated patitis B. that MPV levels significantly decreased in anky - Previous studies have supported the findings losing spondylitis and rheumatoid arthritis pa - that MPV levels are elevated in some chronic vi - tients with active disease. Yuksel et al 28 reported ral diseases, such as chronic hepatitis B and C, that MPV levels decreased in . whereas MPV levels decrease in some acute viral Danese et al 29 detected that MPV levels de - diseases, such as rotavirus gastroenteritis, HIV, creased in active inflammatory bowel disease. and RSV 25,31-35 . MPV is inversely correlated with Mete et al 25 showed that MPV levels decreased in platelet count 10 . Therefore, MPV is usually in - children with acute rotavirus gastroenteritis and creased in patients with thrombocytopenia that study suggested that MPV could be used as caused by a viral infection. an acute phase reactant in children with rotavirus There is no specific study on MPV in acute gastroenteritis. hepatitis A. Jørgensen et al 36 demonstrated that

2312 Mean platelet volume in hepatitis A

MPV levels were significantly lower in patients 9) GASPARYAN AY, A YVAZYAN L, M IKHAILIDIS DP, K ITAS GD . with liver disease. According to our knowledge, Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des 2011; 17: 47- this current study is the first to assess the rela - 58. tionship between MPV and acute hepatitis A. The present study has some limitations. First 10) BATH PM, B UTTERWORTH RJ . Platelet size: measure - ment, physiology and vascular disease. Blood Co - was the absence of a group of patients with ful - agul 1996; 7: 157-161. minant hepatitis, which in our determination pre - 11) PARK Y, S CHOENE N, H ARRIS W. Mean platelet volume vented the ability to evaluate whether a relation - as an indicator of platelet activation: methodologi - ship exists between MPV and disease severity. cal issues. Platelets 2002; 13: 301-306. Another limitation is that this work is retrospec - 12) BEYAZIT Y, S AYILIR A, T ORUN S, S UVAK B, Y ESIL Y, P URNAK tive. T, O ZTAS E, K URT M, K EKILLI M, I BIS M. Mean platelet volume as an indicator of disease severity in pa - tients with acute pancreatitis. Clin Res Hepatol Conclusions Gastroenterol 2012; 36: 162-168. 13) ALBAYRAK Y, A LBAYRAK A, A LBAYRAK F, Y ILDIRIM R, A YLU MPV may be a negative acute phase reactant B, U YANIK A, K ABALAR E, G ÜZEL IC . Mean platelet vol - ume: a new predictor in confirming acute appen - for acute hepatitis A. Further studies are needed dicitis diagnosis. Clin Appl Thromb Hemost 2011; to explain the role that MPV plays in inflamma - 17: 362-366. tion and other viral infections. 14) CANPOLAT FE, Y URDAKÖK M, A RMAGANGIL D, Y IGIT S. Mean platelet volume in neonatal respiratory dis - tress syndrome. Pediatr Int 2009; 51: 314-316. –––––––––––––––– –-– –– Conflict of Interest 15) ÖRNEK N, O GUREL T, Ö RNEK K O NARAN Z. Mean The Authors declare that there are no conflicts of interest. platelet volume in retinal vein occlusion. Eur Rev Med Pharmacol Sci 2014; 18: 2778-2782. 16) ÖZTÜRK ZA, D AG MS, K UYUMCU ME, C AM H, Y ESIL Y, YILMAZ N, A YDINLI M, K ADAYIFCI A, K EPEKCI Y. Could References platelet indices be new biomarkers for inflamma - tory bowel diseases? Eur Rev Med Pharmacol 1) NAINAN OV, X IA G, V AUGHAN G, M ARGOLIS HS . Diag - Sci 2013; 17: 334-341. nosis of hepatitis A virus infection: a molecular approach. Clin Microbiol Rev 2006; 19: 63-79. 17) EKIZ F, G ÜRBÜZ Y, B ASAR Ö, A YTEKIN G, E KIZ Ö, S EN - TÜRK ÇS, A KTAS B, Y ILMAZ B, A LTINBAS A, Ç OBAN S, 2) MULYANTO WIBAWA ID, S UPARYATMO JB, A MIRUDIN R, SENCAN I. Mean platelet volume in the diagnosis OHNISHI H, T AKAHASHI M, N ISHIZAWA T, O KAMOTO H. and prognosis of Crimean-Congo hemorrhagic The complete genomes of subgenotype IA he - fever. Clin Appl Thromb Hemost 2013; 19: 441- patitis A virus strains from different islands in In - 444. donesia form a phylogenetic cluster. Arch Virol 2014; 159: 935-945. 18) KARAMAN H, K ARAKÜKCÜ Ç, K ARAMAN A, K AYMAN T, YALÇIN S, T A DEMIR AE, Z ARARSIZ G, P OYRAZOGLU OK. 3) KOFF RS. Hepatitis A . Lancet 1998; 351: 1643-1649. Mean platelet volume as a fibrosis marker in pa - 4) STAPLETON TJ, L EMON SM. Infectious diseases. In: tients with chronic hepatitis C. Turk J Med Sci Hoeprich PD, Jordan MC, Ronald AR. Hepatitis A 2013; 1: 39-45. and hepatitis E. 5. Philadelphia, 1994; pp. 790- 19) TOZKOPARAN E, D ENIZ O, U CAR E, B ILGIC H, E KIZ K. 800. Changes in platelet count and indices in pul - 5) FRANCO E, M ELELEO C, S ERINO L, S ORBARA D, Z ARATTI monary tuberculosis. Clin Chem Lab Med 2007; L. Hepatitis A: epidemiology and prevention in de - 45: 1009-1013. veloping countries. World J Hepatol 2012; 4: 68- 20) JENNE CN, U RRUTIA R, KUBES P. Platelets: bridging 73. hemostasis, inflammation, and immunity. Int J Lab 6) ÇETINKAYA B, T EZER H, Ö ZKAYA PARLAKAY A, R EVIDE Hematol 2013; 35: 254-261. SAYLI T. Evaluation of pediatric patients with he - 21) ZARBOCK A, P OLANOWSKA -G RABOWSKA RK, L EY K. patitis A. J Infect Dev Ctries 2014; 8: 326-330. Platelet-neutrophil-interactions: linking hemosta - 7) MAIGA MY, O BERTI F, R IFFLET H, I FRAH N, C ALÈS P. sis and inflammation. Blood Rev 2007; 21: 99- Hematologic manifestations related to hepatitis A 111. virus. 3 cases. Gastroenterol Clin Biol 1997; 21: 22) KASER A, B RANDACHER G, S TEURER W, K ASER S, O FFNER 327-330. FA, Z OLLER H, T HEURL I, W IDDER W, M OLNAR C, L UD - 8) KUMAR KJ, K UMAR HC, M ANJUNATH VG, A NITHA C, M A- WICZEK O, A TKINS MB, M IER JW, T ILG H. Interleukin-6 MATHA S. Hepatitis A in children- clinical course, stimulates thrombopoiesis through thrombopoi - complications and laboratory profile. Indian J Pe - etin: role in inflammatory thrombocytosis. Blood diatr 2014; 81: 15-19. 2001; 98: 2720-2725.

2313 H. Almi , I.H. Bucak, V. Çelik, M. Tekin, F. Karakoç, Ç. Konca, M. Turgut ş

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