Red Cell Distribution Width to Platelet Ratio is not Inferior than Aspartate Aminotransferase to Platelet Ratio Index Score in Predicting Liver Fibrosis in Chronic Hepatitis B Patients at Sanglah General Hospital Denpasar

Background: Red cell distribution width to platelet ratio (RPR) is known to be associated with a degree of liver fibrosis in patients with hepatitis B. This study aims to compare the under curve area, sensitivity, specificity, positive predictive value, and negative predictive value between RPR and aspartate aminotransferase to platelet ratio index (APRI) score with degree of fibrosis. Method: This study is a retrospective study, data taken from medical records of all chronic hepatitis B patients examined by Fibroscan at Sanglah General Hospital Denpasar, Bali from January 2016 to February 2018. Results: Ninety eight (98) patients with chronic hepatitis B, 81 patients were recovered after exclusion of patients with chronic kidney disease, malignancy, and dengue haemorrhagic fever (DHF). In receiver operating characteristic (ROC) analysis, obtained area under the ROC curve (AUC) at RPR of 0.816, and at APRI score 0.797. In RPR with cut off 0.066 the sensitivity was 76.9%, specificity 78.6%, PPV 79.5%, NPV 73.8%. While APRI score with cut off 0.85 got 69.2% sensitivity, specificity 76.2%, positive predictive value (PPV) 73.0%, and negative predictive value (NPV) 72.7%. According to Kappa test, we found kappa coefficient 0.653 (p < 0.05). Conclusion: In predicting severe liver fibrosis in chronic hepatitis B patients, RPR is not inferior than APRI score, and may be used as a diagnostic marker, with 65.3% conformity.


Kata kunci: skor aspartate aminotransferase to platelet ratio index (APRI), red cell distribution width to platelet ratio (RPR), hepatitis B kronis, fibrosis hati
specificity. 7In terms of cost, RPR is cheaper than APRI because it only requires one panel of routine blood examination.However, its performance when compared with APRI is still not much studied.In this study we will investigate the accuracy of diagnosis of liver fibrosis by using RPR and APRI and compare the two methods.

METHOD
This study was conducted retrospectively, from January 2016 to February 2018.Data were taken from medical record and Fibroscan register Sanglah General Hospital Bali which fulfilled the inclusion criteria ; all chronic hepatitis B patients aged > 12 years with HBsAg positivity for 6 months or more, who came to Sanglah General Hospital and performed Fibroscan examination.Exclusion criteria in this study were the presence of HIV and hepatitis C coinfection, hepatocellular carcinoma (HCC), chronic renal disease, idiopathic thrombocytopenia purpura and dengue hemorrhagic fever.
In subjects meeting the inclusion criteria, RPR and APRI were evaluated with medical record tracking, and compared with Fibroscan examination results.RDW, platelet, aspartate aminotransferase (AST), and Fibroscan data were taken at the same or the longest period within 30 days.RPR is calculated by the formula = RDW(%)/Plt(10 9 /L), whereas APRI = AST(/ULN) x 100/Plt(10 9 /L).Fibroscan examination results were classified into 2 groups; mild-moderate fibrosis (metavir F0-2) and severe fibrosis (metavir F3-4).Then the data was analysed using receiver operating characteristic (ROC) curve to determine the area under the ROC curve (AUC), cut-off point, sensitivity, specificity, positive

INTRODUCTION
Liver fibrosis is a chronic complication of hepatitis B infection.This condition remains silent until the patient falls to decompensated cirrhosis, which is the third leading cause of death after cardiovascular disease and cancer. 1 Early detection is very important in the management of chronic hepatitis B, in order to determine therapy and also improves prognosis. 2istopathological examination of liver tissue is still a gold standard of the diagnosis of fibrosis and cirrhosis of the liver.However, this method is an invasive procedure and tends to be abandoned lately.Various non-invasive methods were developed as an attempt to replace liver biopsy tests, such as ultrasonography, transient elastography (TE), and biochemical markers, such as aspartate aminotransferase to platelet ratio index (APRI), gamma glutamyl transpeptidase to platelet ratio (GPR), and fibrosis-4 (FIB-4). 3ccording to the World Health Organization (WHO) guidelines in 2015, APRI has recommended as a non-invasive method to predict liver cirrhosis in areas with limited resources, whereas TE is recommended in areas with adequate facilities. 2 APRI with a value of ≥ 2 has been validated to detect liver cirrhosis.While TE is an examination using low frequency shear waves to assess liver stiffness. 4,5Red cell distribution width to platelet ratio (RPR) is currently under investigation because it is thought to be associated with a degree of liver fibrosis.The RPR was first proposed by Chen et al in 2013, a prediction model consisting of red cell distribution width (RDW) and platelet components known to be associated with a degree of liver fibrosis in a multivariate analysis. 6In another study, RPR can also predict liver fibrosis in Primary Biliary Cirrhosis populations with 46.7% sensitivity and 96.4%

RESULTS
In January 2016 up to February 2018 there were 98 chronic hepatitis B patients examined by Fibroscan.After exclusion of patients with chronic kidney disease, malignancy, and DHF, 81 samples were obtained in the study.The subjects consisted of 59 men and 22 women, aged 15-72 years with an average age of 43 years.The results of Fibroscan examination were 42 persons with mild-moderate fibrosis (metavir F0-2) and 39 severe fibrosis (metavir F3-4).The average RDW value of the study subjects was 13.78% ± 2.69.The average platelet count was 187.429/mm³ ± 101.601.The ratio of RDW/platelet obtained an average of 0.16 ± 0.45.In ROC analysis in Figure 1, we can see that both RPR and APRI curves are on the left side of the diagonal line.The AUC of RPR in predicting severe fibrosis was found 0,816 (p < 0,05) which tends to be no different than APRI with AUC 0,797 (p < 0.05) (Figure 2).In RPR with the cut off 0.063 the sensitivity was 76.9%, specificity 78.6%, PPV 79.5%, NPV 73.8% for predicting severe liver fibrosis.While APRI with the cut off 0.85 obtained 69.2% sensitivity, specificity 76.2%, PPV 73.0%, and NPV 72.7%.Furthermore, in Kappa test, the coefficient of Kappa 0.653 (p < 0.05) as shown in Figure 3, which means the match between RPR and APRI in predicting severe fibrosis is 65.3%.

DISCUSSION
Some non-invasive markers to assess the degree of liver fibrosis in chronic hepatitis B patients are widely proposed and validated. 3This is due to the importance of in the use of non-invasive blood markers such as APRI, GRP, FIB-4, or RPR for determining treatment and prognosis in limited area setting.APRI was first proposed by Wai et al in 2003 to predict liver fibrosis and cirrhosis in chronic hepatitis C patients. 8This simple examination is preferred because it is cheap and easy to apply especially as an early screening of cirrhosis in areas with limited resources.Then several studies on its use in chronic hepatitis B infection were done, until finally APRI had recommended its use by WHO in 2015.However, when compared with other non-invasive markers, APRI is more inferior than the markers FIB-4 and GPR. 3 A study conducted by Chen et al in 2013 stated that RDW and platelet levels correlated with the degree of liver fibrosis in chronic hepatitis B patients, which then made a prediction model of RPR. 6 In another study, there was also an increase in RDW in chronic renal disease, systemic lupus erythematosus (LES), and acute myocardial infarction. 9RDW also plays a prognostic factor, which the increase in RDW is positively correlated with cirrhosis based on Child-Pugh score and increased mortality of patients with coronary heart disease, with an unexplained mechanism. 10,11

Figure 1. Receiver operating characteristic (ROC) curve
Several previous studies have suggested that RPR is superior to APRI in predicting significant liver fibrosis. 3,6Comparing to FIB-4 and GPR, RPR has a comparable AUC in predicting significant fibrosis (metavir F ≥ 2). 3 While in this study obtained AUC of RPR and APRI did not significantly different Jemi Tubung, I Ketut Mariadi, IDN Wibawa in predicting liver fibrosis in chronic hepatitis B patients.The AUC stated that both APRI and RPR have moderate accuracy in diagnosing severe fibrosis (metavir F3-4).So these two predictive models can both be used as a diagnostic tool.
The differences of sample characteristics, differences of cut off used, and some weaknesses in this study may be the cause of different results obtained from previous research.The weaknesses in this study were retrospective study design, no direct interviews on the subjects, and no histopathological examination of the liver as a gold standard diagnosis of liver fibrosis which allowed less representative results.Evaluation based on HBV DNA and HBeAg virus counts was also not done because of the limited data available.However, RPR is comparable to APRI in predicting severe liver fibrosis in chronic hepatitis B patients and may be used as a non-invasive marker with moderate accuracy.

CONCLUSION
In predicting severe liver fibrosis in chronic hepatitis B patients, RPR is not less inferior than APRI and can be used as one of the non-invasive methods in areas with limited resources.

Figure 3 .Figure 2 .
Figure 3. Kappa test result for RDW platelet ratio (RPR) and aminotransferase to platelet ratio index (APRI) Red Cell Distribution Width to Platelet Rasio is not inferior than Aspartate Aminotransferase to Platelet Ratio Index Score in Predicting Liver Fibrosis in Chronic Hepatitis B Patients at Sanglah General Hospital Denpasar predictive value (PPV), and negative predictive value (NPV) between APRI and RPR.There were also Kappa tests to determine the suitability between RPR and APRI in diagnosing severe fibrosis.Analysis was performed using SPSS Statistics version 23 (IBM Corporation, New York, NY).

Test result variable (s) Area Std.error a Asymptotic Sig. b
b Using the asymptotic standard error assuming the null hypothesis