Journal of Natural Science, Biology and Medicine

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 10  |  Issue : 3  |  Page : 11--15

Prothrombin time, albumin, and fibrinogen values of the liver cirrhosis stages based on the aspartate aminotransferase-to-platelet ratio index


Yusra Yusra, Claudio Agustino 
 Department of Clinical Pathology, Faculty of Medicine, Universitas Indonesia — Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Correspondence Address:
Yusra Yusra
Dr. Cipto Mangunkusumo Hospital, CMU 1 Building, 6th Floor, Jalan Diponegoro No. 71, Jakarta Pusat, 10430
Indonesia

Abstract

Introduction: Liver cirrhosis can be classified into three groups using the aspartate aminotransferase-to-platelet ratio index (APRI) score, which is a noninvasive technique. This study was designed to determine the differences between the albumin levels, prothrombin time (PT), and fibrinogen levels of the cirrhosis stages based on the APRI scores. Materials and Methods: This cross-sectional study included 60 patients who met the inclusion criteria based on their records from the Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia. The study analysis included the Kolmogorov–Smirnov test for the un—normalized data, including the albumin level (median = 2.91 g/dL) and PT (median = 1.8 s), and the normalized fibrinogen level (mean = 273.7117 mg/dL). Results: The analysis of variance (ANOVA) and Kruskal–Wallis test results showed significant differences between these three components based on the APRI score (all P < 0.05). The post hoc tests (Bonferroni for the ANOVA and Mann–Whitney U for the Kruskal–Wallis test) of the albumin levels showed a significant difference in the comparison between the APRI score of <0.5 group and >2 group. The post hoc tests of the PT showed significant differences in all the comparisons. The post hoc tests of the fibrinogen levels showed significant differences for the comparisons between the APRI score of <0.5 group and >2 group and between the APRI score = 0.5–2 group and >2 group. Conclusion: PT is the optimal biomarker to distinguish between each stage of liver cirrhosis compared to serum albumin or fibrinogen levels.



How to cite this article:
Yusra Y, Agustino C. Prothrombin time, albumin, and fibrinogen values of the liver cirrhosis stages based on the aspartate aminotransferase-to-platelet ratio index.J Nat Sc Biol Med 2019;10:11-15


How to cite this URL:
Yusra Y, Agustino C. Prothrombin time, albumin, and fibrinogen values of the liver cirrhosis stages based on the aspartate aminotransferase-to-platelet ratio index. J Nat Sc Biol Med [serial online] 2019 [cited 2020 Feb 26 ];10:11-15
Available from: http://www.jnsbm.org/text.asp?2019/10/3/11/275595


Full Text



 Introduction



Liver cirrhosis is a process characterized by the massive, chronic formation of fibrous tissue and collagen in the liver.[1] In Indonesia, liver cirrhosis is ranked as the 6th main cause of death, with a total of 489,000 individuals per year in 2016.[2] Liver cirrhosis begins with an asymptomatic period, but it will develop various systemic complications as it progresses.[3] However, the development of liver cirrhosis can be prevented with an early diagnosis. At present, the clinical standard for establishing a cirrhosis diagnosis is a liver biopsy; however, this is a high-cost invasive approach that is offered at a limited number of facilities.[4],[5] Therefore, the aspartate aminotransferase-to-platelet ratio index (APRI) score was developed, and it is correlated with liver fibrosis progression. The APRI score does have some disadvantages in terms of its low positive predictive values and the specificity does not reach a maximum value. However, correlations can be made between the liver tissue damage and the albumin, prothrombin, and fibrinogen synthesized by the cells that are affected.[5] Based on the above-mentioned background information, this study was designed to compare the albumin, prothrombin, and fibrinogen values with the development of liver damage classified using the APRI score. This research could provide a foundation for the development of new diagnostic techniques for measuring liver damage (such as the APRI score) that are both efficient and readily available.

 Materials and Methods



This cross-sectional study was designed to retrieve the data from the 2017 laboratory results and patient medical records from Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia. This research was conducted in the Clinical Pathology Department for 6 months, from March 2017 to November 2017, and has been approved by the ethics committee of the research module, Faculty of Medicine, Universitas Indonesia (No. 460/UN2.F1.D1/KBK/PDP. 01/2017).

The study population consisted of patients with complete laboratory examination results who met the inclusion and exclusion criteria. The patient inclusion criteria were as follows: a final diagnosis of cirrhosis with an APRI score of >2, liver disease with an APRI score of 0.5–2, or no liver disease with an APRI score of <0.5, and complete medical record data. These inclusion criteria were based on the APRI scores because they describe the liver tissue injury levels while preventing bias; stress conditions can increase the aspartate aminotransferase (AST) levels when measured by themselves. Patients under 17 years old were excluded from the study. The APRI score was calculated from the AST level divided by the normal upper limit of the AST value (44 U/L), divided by the number of platelets (109/L), then multiplied by 100.

The independent variable in this study was the liver cirrhosis level based on the APRI score. The dependent variables were the albumin level, prothrombin time (PT), and fibrinogen level. The sample size was calculated based on the unpaired analytical formula for numerical data, and the results showed that 18 study participants were needed for each group. A consecutive sampling method was used for this study, and all of the statistical analyses were conducted using IBM SPSS Statistics for Windows version 20.0 (IBM Corp., Armonk, NY, USA). An analysis of variance (ANOVA) was used to test for normal data distribution and the Kruskal–Wallis test was used for nonnormal data distribution. The significant general comparison values were then evaluated using post hoc tests, including the Bonferroni or Games–Howell test for the ANOVA and the Mann–Whitney U-test for the Kruskal–Wallis test.

 Results



The total number of participants included in this study was 60, with 20 participants in each APRI score group. Most of the study participants were males (63.3%), and their average age was 49 ± 15 years old. Most of the participants with APRI scores of <0.5 had nonliver neoplasms (55%), whereas most of those with APRI scores of 0.5–2.0 and >2.0 had hepatitis C (30% and 45%, respectively) [Table 1].{Table 1}

The albumin levels, PTs, and fibrinogen levels were compared according to the liver cirrhosis levels based on the APRI scores [Figure 1]. [Table 2], [Table 3], [Table 4] show the post hoc test results from the comparisons of each of the values. The comparison of the albumin levels of each APRI score group showed a significant difference (P = 0.003), with significant value for the comparison between the APRI score of <0.5 group and the APRI score of >2 group. The PTs showed a significant difference (P = 0.000004) in each APRI score group. The fibrinogen levels of each APRI score group showed a significant difference (P = 0.002) in the comparisons between the APRI score of 0.5–2 group and the APRI score of >2 group and between the APRI score of <0.5 group and the APRI score of >2 group. Based on post hoc analysis, of the three parameters above, PT was the best examination to distinguish three stages of liver cirrhosis, followed by fibrinogen, then albumin levels [Figure 2], [Table 2], [Table 3], and [Table 4].{Figure 1}{Table 2}{Table 3}{Table 4}{Figure 2}

 Discussion



The albumin level comparisons showed significant results between the APRI score of <0.5 group and the APRI score of >2 group. The PT and fibrinogen level comparisons showed significant values for every comparison between the groups. The inversely proportional results showing lower albumin levels with an increasing APRI score indicated that liver function had an important contribution to liver protein synthesis. These results were similar to those of Bernardi et al., who stated that the patients with advanced cirrhosis often exhibited hypoalbuminemia and a fluid imbalance.[6] In addition, the results from the study by Nagao andSata showed that the damage caused by high hepatitis C or hepatitis B viral loads inhibited the albumin-producing ability of liver cells, causing hypoalbuminemia.[7] Moreover, the study by Hessien et al. showed that a decreased albumin level was followed by an increased liver cirrhosis severity from the fibrosis stage to decompensated cirrhosis.[8]

The less significant difference in the albumin levels between the APRI score of <0.5 group and the APRI score of >2 group could have been affected by the variations in the patient conditions, such as trauma, neoplasms, and infections, due to the function of albumin as a negative acute-phase protein. The APRI score of <0.5 group had nonliver neoplasms as the dominant etiology, which can induce an inflammatory response. This data are supported by a study by Gupta and Lis, who reported that patients with histories of cancer, inflammation, and/or chemotherapy can experience decreased albumin levels due to the high degree of inflammation and apoptosis activities. These suppress albumin production in the liver due to the presence of the cytokine interleukin 6.[9] Prothrombin is a glycoprotein synthesized by the liver that plays a role in the body's coagulation process, and prothrombin formation is supported by various factors, such as VII, IX, and X. The prothrombin formation time is measured often, and it has become a laboratory examination standard. The PT is used to measure the extrinsic blood clotting pathways. According to Fontana, the PT can be a prognostic factor in determining patient mortality, in which it is important to assess a patient's bleeding risk. Patients with liver cirrhosis often experience complications in the form of esophageal varices and other causes of abnormal bleeding due to a decrease in the prothrombin level, which is a coagulative component.[10] Liver tissue injury has a significant effect with regard to decreasing the coagulative factors. Fibrinogen also plays a role in coagulation, and it is related to the blood clotting pathways. The analysis of the fibrinogen levels of the patients in this study showed a significant decrease in the fibrinogen levels in the comparisons between the APRI score of 0.5–2 group and the APRI score of >2 group and between the APRI score of <0.5 group and the APRI score of >2 group. However, the comparison between the APRI score of <0.5 group and the APRI score of 0.5–2 group showed insignificantly different fibrinogen levels. Decreased fibrinogen levels were shown in the comparisons between the APRI score of 0.5–2 (liver fibrosis) group and the APRI score of >2 (cirrhosis) group and between the APRI score of <0.5 (no liver damage) group and the APRI score of >2 (cirrhosis) group. These results are comparable to the results of the study by Hessien et al., who reported that the differences in the fibrinogen concentrations were related to the increasing cirrhosis severity.[8]

Increased fibrinogen levels (with insignificant results) were shown in the comparison between the first and second groups. These results could have been influenced by the original etiologies of the patients with APRI scores of <0.5, who had neoplasms and carcinomas of various organ systems for the majority of their diagnoses. Using the APRI score assesses the liver damage severity, but it does not detect other diseases, such as tumors and cancer. The study by Yu et al. showed lower fibrinogen levels from Stage T (F = 11.94, P < 0.0001) to Stage N (F = 4.93, P = 0.0021), based on the tumor, necrosis, and metastasis classification of the cancer severity.[11] However, it is not known whether the patients who were sampled experienced bleeding, trauma, or other conditions that could reduce the fibrinogen levels due to increased coagulation activities.

The most common cirrhosis etiology of the patients with APRI scores of 0.5–2 (fibrosis) and APRI scores of >2 (cirrhosis) was hepatitis C, with 6 and 9 patients, respectively, in each group. The most common etiology of the patients with APRI scores of <0.5 was neoplasia in a nonliver organ. According to the results of an epidemiological study by Mulyanto et al., the number of hepatitis C cases in the Java region was higher than the number outside of Java.[12] This etiology is also supported by data from the Riskesdas 2013, which showed an increase in the number of hepatitis B and C cases in Indonesia.[13] According to data from the Centers for Disease Control and Prevention and the WHO, 15%–25% of the hepatitis B cases and 15%–30% of the hepatitis C cases can chronically develop into chronic cirrhosis.[14] The average age of the participants in this study was 49 years old. The study conducted by Schuppan and Afdhal reported that age of 50 years old or older is one of the risk factors for the development of liver cirrhosis.[15] Most of the patients included in this study were males (63.3%), which corresponds with the dominant gender of most of the records of patients with liver cirrhosis (90%). Guy and Peters reported twice as many cases of chronic liver disease and cirrhosis in men, leading to more deaths in males than females; therefore, the males were considered to be more vulnerable.[16] The results of the study by Mulyanto et al. showed that male vulnerability was also linked to their lifestyles, work patterns, and environments.[12]

This study had several strengths. For example, the clinical pathology laboratory used valid and standardized measurement methods. In addition, no previous studies have compared the proteins synthesized by the liver, such as albumin, prothrombin, and fibrinogen, for each liver cirrhosis stage based on the APRI score. However, one limitation of this study was the fact that it was focused on determining exclusive factors due to the limited description of the patient characteristics in the medical record. Moreover, a random sampling method was not used to collect the subjects, and all of the laboratory examinations' data were not measured at the same time. The results of this study are significant with regard to the comparison of the laboratory parameters, and they could be used clinically for an advanced diagnostic study to create a new cirrhosis staging classification based on the APRI score.

 Conclusion



The results of this study showed significant differences in the comparisons of the albumin levels, PTs, and fibrinogen levels, with significant values for the liver cirrhosis level comparisons based on the APRI scores associated with each value. These laboratory parameters could be used to develop new noninvasive diagnostic techniques for liver cirrhosis, and they could be used as a reference for prognostic markers to determine the severity of this disease, especially for PT. In future studies, a prospective cohort with a multivariate analysis would sharpen the results.

Acknowledgments

The authors would like to express their sincere gratitude to the Clinical Pathology Department at the Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia and their research partners (Timotius, Iman, and Dannis) who gave their support and provided guidance to complete this study within the limited time frame.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Sarin S, Maiwall R. Global Burden of Liver Disease: A True Burden on Health Sciences and Economies. World Gastroenterology Organization; 2010. Available from: http://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/global-burden-of-liver-disease-a-true-burden-on-health -sciences-and-economies. [Last accessed on 2016 Nov 19].
2Indonesia Statistics Summary: Global Health Observatory Country. World Health Organization; 2016. Available from: http://who.int/gho/mortality_burden_disease/en/. [Last accessed on 2016 Nov 19].
3Wiegand J, Berg T. The etiology, diagnosis and prevention of liver cirrhosis: Part 1 of a series on liver cirrhosis. Dtsch Arztebl Int 2013;110:85-91.
4Motola DL, Caravan P, Chung RT, Fuchs BC. Noninvasive biomarkers of liver fibrosis: Clinical applications and future directions. Curr Pathobiol Rep 2014;2:245-56.
5Tenggara J, Hasan I, Sanityoso A, Abdullah M. Non-invasive markers for diagnosis of liver cirrhosis in chronic hepatitis B. Indian J Gastroenterol 2011;12:134-9.
6Bernardi M, Ricci CS, Zaccherini G. Role of human albumin in the management of complications of liver cirrhosis. J Clin Exp Hepatol 2014;4:302-11.
7Nagao Y, Sata M. Serum albumin and mortality risk in a hyperendemic area of HCV infection in Japan. Virol J 2010;7:375.
8Hessien M, Ayad M, Ibrahim WM, Ul-Arab BI. Monitoring coagulation proteins during progression of liver disease. Indian J Clin Biochem 2015;30:210-6.
9Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: A systematic review of the epidemiological literature. Nutr J 2010;9:69.
10Fontana RJ. Evaluation of the patient with chronic hepatitis B. Clin Liver Dis (Hoboken) 2013;2:1-4.
11Yu X, Hu F, Yao Q, Li C, Zhang H, Xue Y. Serum fibrinogen levels are positively correlated with advanced tumor stage and poor survival in patients with gastric cancer undergoing gastrectomy: A large cohort retrospective study. BMC Cancer 2016;16:480.
12Mulyanto. Viral hepatitis in Indonesia: Past, present, and future. Euroasian J Hepatogastroenterol 2016;6:65-9.
13Health Research and Development Agency Ministry of Health Republic of Indonesia. Basic health research 2013. Jakarta: Indonesian Ministry of Health; 2013. p. 71-3.
14HCV FAQs for Health Professionals. Division of Viral Hepatitis Centers for Disease Control and Prevention; 2017. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. [Last accessed on 2017 Sep 15].
15Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838-51.
16Guy J, Peters MG. Liver disease in women: The influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y) 2013;9:633-9.