Can the biochemical profile predict the etiology of the obstructive jaundice early?

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38 Mediterranean Journal of Medical Sciences V2, I1 February 2015: 37-46

ISSN 2385-2712, EISSN 2385-2453 http://journal.mcmscience.org

1. Introduction Obstructive jaundice results from failure of passage of bile to the intestine caused by any pathology obstructing the biliary tree [1]. Symptoms and signs that may accompany the obstructive jaundice include: pain, nausea and vomiting, darkening of urine, itching, fever and weight loss. Nature of these clinical symptoms and signs usually depends on the original etiology and the progress of the disease process [1] [2]. Early detection of obstructive jaundice etiology can facilitate clinicians on the right and accuracy treatment and consequently will improve quality of life of patient and particularly the survival rates among the patients with malign pathology. Recently, some studies have assessed on how the value of the routine biochemical test can help on defining the etiology of the obstructive jaundice prior to the use of the invasive test. Nazli at al [3] in his study has concluded that high value of CA19-9 is a strong predictor on the early detection of malign etiology in the obstructive jaundice. In addition, the study of Kasapidis at al [4] emphasizes on the significant prediction ability of the same of widespread and inexpensive biochemical markers such as ALT, ASP, ɣGT

on the early detection of the etiology of the obstructive jaundice. Meanwhile , in the other hand Verma at al. does not conclude that the biochemical profile can predict the etiology of the obstructive jaundice[5]. The aim of our study consist to bring the experience of our hospital on the possibility of use of the routine biochemical profile as a predictor on determining the obstructive jaundice etiology

2. Methods The study has been designed as an analytic cross-sectional study and was carried out on the University Hospital Center “Mother Teresa” during the 2014.The participant included in the study had been presented with sign of obstructive jaundice at the admission and had had the final diagnosis of extra hepatic obstructive of biliary tree (malign or benign). The diagnosis was defined based on the clinical and biochemical data, and noninvasive or invasive test (ultrasound, computed tomography or magnetic resonance). The exclusion criteria were the age less than 18 years old and pregnancy status at the admission. The data were collected retrospectively. The record file of the patient was used as the source of the data on routine blood biochemical markers such as Hb, RBC, WBC, Hematocrit, azotemia

Klerida Shehu et. al. 39

©2015 Mediterranean Center of Medical Sciences.

and glycaemia, creatinemia, total and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum alkaline phosphatase (ASP), gamma glutamiltransferase (ɣGT) and tumor marker carbohydrate antigen (CA 19-9), measured at the point of admission. The patients were divided on the base of the etiology of the obstructive jaundice into two groups. The first group which had a benign etiology and the second group has the malign etiology.. The statistical analysis has included using of some test. The characteristic distribution of two groups is performed by using Chi square test. To investigate the difference in median among two study groups regarding the biochemical markers, it was used the Mann Whitney U test. Each of the biochemical markers, resulted with a significant difference among groups in the Mann Whitney U test, was further investigated through receiver operating characteristic curve (ROC), which allowed the calculating the marker’s discriminate ability and cut off value based on the trade-off between sensitivity and specificity [6]. For each of the markers with a discriminate ability, it was created a new variable based on the value of the cut off, which follows the binominal distribution i.e. it

[variable] indicated if the subject is above or below the cut off value. To measure the predictive ability (in term of odds ratio) of the marker’s value above the cut off on the early diagnosis of the obstructive jaundice, it was used the logistic regression. The SPSS 16 was used on performing the mentioned above technique A p value less than 0.05 is considered significant.

3. Results 56 subjects, who met the criteria of study, were included in the study. Most of the participants were male sex. The benign etiology group was 29 and malign etiology group was 27. The mean age was 65.2 with a CI 95 %] 62-68.3[(Table1). Table 2 shows the median and interquartile range for the biochemical markers included in the study regarding two study groups. The value of CA19-9,ASP ,ALP, ɣGT, total and indirect bilirubin are significantly more elevated among the patient diagnosed with the malign group as it is investigated by the Mann Whitney U test. For biochemical markers resulted significantly higher in the Mann Whitney U test, a ROC curves was constructed in order to evaluate their discriminate ability (figure 1). The area under the curve was more than 0.63 for all biochemical



markers, which mean that these markers have the ability to share the group in two subgroup. Based on the tradeoff between the sensitivity and specificity, it was find the cut off value for the each of the biochemical markers (table 3). Later, based on the cut off calculated through the ROC, were created a new variable for each of the biochemical marker of the table 3. Through the new variable, the patient were classified either a patient with higher value than cut off or patient with value less than cut off (table 4). As it seen on the table 4, most of the patients belong to the group with the value of markers above the cut off. Table 5 shows the odd rates and its 95% CI for the prediction ability of each of the new variable of biochemical marker on the malignancy of the obstructive jaundice. All the patient with a value of biochemical markers at the admission more than cut off value are more likely to be diagnosed with malign obstructive jaundice. The likelihood is higher for the ɣGT and the total bilirubin, that indicate that both of them are strong predictor indicators of the malign etiology of obstructive jaundice (table 5)

4. Discussion On our best knowledge this is the first attempt to define a biochemical profile that can early predict the etiology of obstructive jaundice. Early determining of the obstructive jaundice etiology is important for the clinician in order to decide for right treatment to be used. Total and indirect bilirubin are biochemical markers which are very useful on prediction of the obstructive jaundice etiology. A very high value of them (respectively, 5 and 3 fold of normal value) indicate a malign etiology of obstructive jaundice. This finding are the same with the findings of Al Mofleh at al, and Bain at al, which concluded that the high value of the bilirubin is the predictor of malignancy[7-8]. Increased ALP is a phenomenon that occurs in all extra hepatic obstructive jaundice. In our study, the high values of ALP (twice of normal value) indicate a malign obstructive jaundice. The results of our study are consistent with the study of Kasapidis et al, which define the ALP as a useful marker on the early diagnosis of the obstructive jaundice. Transaminases are at high levels in hepatic jaundice. But in front of a defined obstructive jaundice, the higher value of AST indicated a malign etiology of obstructive jaundice. On the other hand, ALT



is not a biochemical marker to indicate exactly the etiology of obstructive jaundice. Our finding concerning the transaminases predictive role are consistent with the other studies conclusion [4][7-8]. ɣGT is a very sensitive indicator of obstructive jaundice. But even within the obstructive jaundice cases, ɣGTis a marker which can orientate accurately on the obstructive jaundiceetiologyif it is malignant or benign nature .So a very high value of ɣGT (11fold of the normal value) indicate a malign obstructive jaundice. The finding of our study are consistent with the conclusion of the other study which considered the value of ɣGT as a useful marker on the early differentiate diagnosis of obstructive jaundice[4][7-8]. In our study, CA19-9 is another marker which clearly indicates the etiology of the obstructive jaundice at the point of admission. A value of CA19-9 higher than normal value (8 hold) is more likely to indicate a malign etiology of the obstructive jaundice, This finding is confirm the conclusion of the several study [3] [4] [9] but it is contrary to the other study of Lin at al [10] and Mann at al [11]which do not consider CA 19-9 as an independent predictor of malignancy. The methods of data collection and the selection of the participant can be the explanatory factors for this

inconsistency of the findings among the studies. The other elements of the routine biochemical profile do not orientate toward the etiology of the obstructive jaundice. In the end, the study conclude that a biochemical profile with bilirubin >6. 3 mg/dl, indirect bilirubin >2.15 mg/dl, CA19-9 > 307 U/mL, ALP > 207 U/L, AST > 76 ɣGT > 313 U/L indicate can clearly a malign etiology of the obstructive jaundice. The strongest predictor of the malign etiology is total bilirubin, ɣGT and CA19-9. As far as, these biochemical markers are inexpensive and widespread used, they should considered as useful predictor on the etiology of the obstructive jaundice. Abbreviations WBC=white blood cell RBC=red blood cell HCT= hematocrit Hb=hemoglobin AST=aspartate aminotransferase; ALT=alanine aminotransferase; ASP=serum alkaline phosphatase; γGT=γ-glutamyltransferase; CA19-9=carbohydrate antigen 19-9; ROC=receiver operating characteristics; Competing interest The authors report no conflict of interest for this work.



Authors’ contributions Klerida Shehu and Sonela Xinxo together with Adriana Babameto,Luljeta Cakerri, Benard Shehu, Albana Duni have contributed in the conception and design of the study, by drafting the article; Sonela Xinxo has analyzed the data. Sidorela Gjini has read the manuscript. All the authors have participated in the drafting of the paper. All authors have read and approved the manuscript. Acknowledgments The authors would like to thank staff of the statistical department near University Hospital Center “Mother Teresa” for helping on data collection. Reference [1] Klein AS, Lillemoe KD, Yeo CJ.

Physiologic Basis of Surgery. Baltimore, Williams & Wilkins publisher, 5th edition, 2005; 6: 441.

[2] Beers MH, Berkow R. Beers MH. The Merck Manual of Diagnosis and Therapy, Whitehouse Station Co. publisher, 19th edition, 2005;14: 643-49.

[3] Nazli O, Bozdag AD, Tansung T, K ir R, K aymak E: The diagnostic importance of CEA and CA 19-9 for the early diagnosis of pancreatic carcinoma. Hepato Gastroenterology 2000; 47:1750-1752.

[4] Kasapidis, L. Mironidis, A. Giannakopoulos, V. Delis, V. Balatsos, A. Konstantinidis, N.

Skandalis. Clinical discrimination between choledocholithiasis andbiliopancreatic malignancy based on a new biochemical model Annals of gastroenterology 2008, 21(2):119-126.

[5] S Verma, S Sahai, P Gupta, A Munshi, S Verma, P Goyal. Obstructive Jaundice- Aetiological Spectrum, Clinical, Biochemical And Radiological Evaluation At A Tertiary Care Teaching Hospital. The Internet Journal of Tropical Medicine. 2010 Volume 7 Number 2.

[6] Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983; 148: 839-843

[7] Al-Mofleh IA, Aljebreen AM, Al-Amri SM, Al-Rashed RS, Al-FalehFZ, Al-Freihi HM, Abdo AA, Isnani AC. Biochemical and radiological predictors of malignant biliary strictures. World J Gastroenterol 2004; 10(10): 1504-1507

[8] Bain VG, Abraham N, Jhangri GS, Alexander TW, Henning RC, Hoskinson ME, Maguire CG, Lalor EA, Sadowski DC. Prospective study of biliary strictures to determine the predictors of malignancy. Can J Gastroenterol 2000 ; 14: 397-4029.

[9] Marrelli D, Caruso S, Pedrazzani C, Neri A, Fernandes E, Marini M, Pinto E, Roviello F. CA19-9 serum levels in obstructive jaundice: clinical value in benign and malignant conditions. Am J Surg. 2009 Sep; 198(3):333-9.

[10] Mao-Song Lin, Jun-Xing Huang, Hong Yu. Elevated serum level of carbohydrate antigen 19-9 in benign biliary stricture diseases can reduce its value as a tumor marker Int J Clin Exp Med 2014; 7(3):744-750



[11] Mann DV, Edwards R, Ho S, Lau WY and Glazer G. Elevated tumour marker CA19-9: clinical in-terpretation and influence of

obstructive jaundice. Eur J Surg Oncol 2000; 26: 474-479.

Figure 1. ROC curves for total and indirect Bilirubin, ASP, ALP,γGT and CA19-9.



Table1. Characteristic of the sample

*chi square test Table 2 Descriptive statistics of biochemical markers [median (interquartile range)] and their comparisons Biochemical marker Malign etiology

Median/interquartile Benign etiology Median/interquarte

p value*^

WBC (103/μL) 6.5(4) 6.7(4) 0.3

RBC (103/μL) 4.2(1) 4.3(1) 0.5

Hb(g/dl) 11(2) 12(2) 0.61

HCT (%) 35(6) 38(6) 0.35

Glycaemia(mg/dl) 108(46) 102(54) 0.9

Azotemia(mg/dl) 31(15) 28(11) 0.2

Creatinemia(mg/dl) 0.8 0.8 0.9

total bilirubin (mg/dl) 8.2(12) 3.7(8) 0.045

indirect bilirubin (mg/dl) 4.5(8) 2.5(8) 0.03

CA19-9 (U/mL) 124(1885) 90(140) 0.039

ALT (U/L) 137(188) 71(74) 0.114

ASP (U/L) 126(78) 58(58) 0.02

ALP (U/L) 301(231) 168(154) 0.048

ɣGT (U/L) 424(1202) 196(408) 0.02

* p value <0.05 is significant ^ p in Mann Whitney U test

n (%) p value*

Age ( mean in year) &CI 95% 65. 2 ]62-68.3[ sex <0.05 Male 38(67) Female 18(33) Etiology >0.05 Benign 29(52) Malign 27(48)



Table 3 The cut off value based on the trade-off sensitivity and specificity

Table 4. The distribution of sample according the cut off based variable

Table 5.The results of the logistic regression on the relationship between the value of the biochemical markers and malign etiology of obstructive jaundice. Biochemical marker OD CI 95%

ɣGT>313U/L 1.5 1.1-2.1

AST>76 U/L 1.3 1.1-1.9

ALP>204U/L 1.2 1.1-1.8

Total bilirubin>6.3mg/dl 1.7 1.1-2.1

Indirect bilirubin >2.15mg/dl 1.4 1.1-2.2

CA19-9>306 U/ml 1.7 1.3-2.9

Biochemical marker less than the cut off above than cut off

n (%) n(%)

AST 25 (45) 31(55)

GGT 27 (48) 29 (52)

ALP 25 (45) 31(55)

Total Bilirubin 27 (48) 29(52)

Indirect bilirubin 25(45) 31(55)

CA19-9 27 (48) 29 (52)

Biochemical marker cut off sensitivity specificity

ɣGT(U/L) 313 61 60

AST (U/L) 76 70 60

ALP (U/L) 204 63 60

Total bilirubin(mg/dl) 6.3 65 73

Indirect bilirubin( mg/dl) 2.15 73 73

CA19-9 (U/ml) 306 74 73

Can the biochemical profile predict the etiology of the obstructive jaundice early?

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