SERUM BILIRUBIN AS A PREDICTOR OF MALIGNANCY IN PATIENTS PRESENTING WITH OBSTRUCTIVE JAUNDICE

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1 ORIGINAL ARTICLE SERUM BILIRUBIN AS A PREDICTOR OF MALIGNANCY IN PATIENTS PRESENTING WITH OBSTRUCTIVE JAUNDICE SIDRA RASHEED, SABEEN FARHAN, MUHAMMAD ARIF NADEEM MUHAMMAD NAEEM AFZAL, UMBREEN ASLAM KHAN Department of Medicine III, Gastroenterology & Hepatology Services Institute of Medical Sciences/Services Hospital, Lahore. ABSTRACT Introduction: Malignant bile duct obstruction is a condition caused by blockage of the bile ducts by cancerous tumor broadly classified as pancreatico-biliary carcinomas including cholangiocarcinomas, pancreatic carcinomas and ampullary/peri-ampullary carcinomas etc. Surgery is the definite curative treatment but malignant obstructive jaundice often goes undetected until the advanced stages of cancer hence most patients are poor surgical candidates. Bilirubin is the active chemical present in the bile. Its level rises in obstructive jaundice being more marked in malignant than in the benign etiologies. Objective: To determine diagnostic accuracy of serum bilirubin levels for diagnosis of malignancy in suspected patients of malignancy presenting with obstructive jaundice by keeping histopathology as gold standard. Study Design: Cross sectional study. Setting: Medical Unit III Department of Medicine, Services Hospital, Lahore. Duration: 6 months from to Methods: A total of 200 patients fulfilling the inclusion criteria were included. After informed consent, blood sample was drawn and serum bilirubin levels were recorded. Biopsy specimen of ampullary mass or common bile duct stricture were taken during endoscopic retrograde cholangiopancreatography (ERCP) and sent for histopathology to have a record of presence or absence of malignancy. Data was analyzed by using SPSS 17.0 and data stratification was done for age, gender, duration of obstructive jaundice and size of the mass. Sensitivity, specificity and diagnostic accuracy of bilirubin levels as a predictor of malignancy was recorded keeping histopathology as gold standard. Results: Mean age was observed to be 58 ± 9.67 years. There were 40% (n = 80) males and 60% (n = 120) females. The male to female ratio was 1:1.5. Mean duration of jaundice was 5.13 ± 2.32 weeks while mean serum bilirubin level was observed to be ± 6.71 mg/dl. bilirubin level > 8.4 mg/dl was observed in 97% (n = 194) patients while < 8.4 mg/dl was seen in 3% (n=6) patients. Mean size of ampullary mass was found to be 2.93 ± 1.00cm. On histopathology malignancy was found in 98% (n = 196) cases. bilirubin levels showed sensitivity of 98.5%, specificity 75% and overall diagnostic accuracy of 98%. Data stratification showed best sensitivity, specificity and diagnostic accuracy in age group of years, in females, in patients with duration of jaundice of 9 12 weeks and mass size of < 4cm. Conclusion: It was concluded from the results of the study that serum bilirubin levels can be used to predict malignant etiology in patients presenting with obstructive jaundice. Keywords: Obstructive jaundice, serum bilirubin, malignancy, cholangiocarcinoma. INTRODUCTION Malignant biliary tract obstruction is a frequent cause of jaundice. Primary pancreatico-biliary tract cancers and other local cancers that can cause compression of the biliary tract (e.g., liver, gallbladder) account for approximately 80,000 new cancer cases and an estimated 58,000 deaths in the United States. 1,2 Despite advances in diagnosis and treatment, the 5- year survival rate of the most commonly encountered malignancies, pancreatic cancer and cholangiocarcinoma, remains dismal at less than 5%. 2 Malignant biliary tract obstruction can also arise from 41 Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar., 2014

2 SERUM BILIRUBIN AS A PREDICTOR OF MALIGNANCY IN PATIENTS PRESENTING WITH OBSTRUCTIVE JAUNDICE gallbladder, duodenum, ampullary cancers, metastatic cancers or malignant lymphadenopathy. 3 Pancreatico-biliary carcinomas are more prevalent than benign etiologies of obstructive jaundice. 4 One study showed their prevalence of 64% in 241 patients of obstructive jaundice. 5 Another local study revealed that 57% patients of obstructive jaundice had malignant etiologies. 6 Malignant bile duct obstruction does not usually cause signs or symptoms until later in the course of the disease, but sometimes symptoms can appear earlier and lead to an early diagnosis. These patients can present with jaundice, itching, clay colored stool/ greasy stools, dark urine, abdominal pain, fever, nausea, vomiting and weight loss. 7 To diagnose malignant bile duct obstruction certain blood tests can be performed. Liver function tests show cholestatic pattern with hyperbilirubinemia and markedly elevated alkaline phosphatase. The transaminases levels are usually normal or mildly elevated. 8 Tumor markers like carcinogen embryonic antigen (CEA) and CA19-9 can help us to diagnose the malignant etiology of obstructive jaundice. 9 Multiple invasive modalities such as ERCP, Percutaneous Trans hepatic Cholangiography (PTC) and non-invasive modalities like ultrasound abdomen, computed tomography, Magnetic Resonance Cholangiopancreatography (MRCP) are available for diagnosing etiology of obstructive jaundice. of the biopsy specimen taken through invasive modalities is considered for final diagnosis. 8 The timely diagnosis of underlying malignancy with obstructive jaundice is complex, as malignant tumors are often asymptomatic in their earlier course and thus preclude its curative resection. At the time of their presentation about 85 90% patients with malignant obstructive jaundice have surgically unresectable tumor resulting in poor survival rate. Therefore, it is necessary to identify the nature of biliary obstruction at an early stage for proper management and better prognosis of disease. 10 Different studies to date are available to use various parameters for early predicting malignant etiologies of obstructive jaundice. One study showed that serum bilirubin levels of >8.4 mg% was associated with malignant bile duct strictures at the hilum level with sensitivity of 83.3% and specificity of 70%, using histopathology as gold standard for final diagnosis. 5 Another study used bilirubin levels of 5.8mg/dl to predict malignancy as cause of obstructive jaundice with a sensitivity of 71.9% and specificity of 86.9%. 11 This local study was conducted to find out diagnostic accuracy of bilirubin level for diagnosis of malignancy in patients suffering from obstructive jaundice. bilirubin test is usually done in all the patients as first line biochemical test and is relatively cheaper than the other diagnostic tools. The findings of this study will be helpful in future to use bilirubin as predictor of malignancy as the cause of biliary obstruction in cost effective and time saving way. So far, no local study was available that had evaluated the diagnostic accuracy of bilirubin level, therefore this study was conducted. MATERIALS AND METHODS Study was carried out over a period of six months from to It was a cross sectional study. This study was carried out in Gastroenterology Department of Services Hospital, Lahore, in which 200 patients were enrolled in the study. Sampling technique was non-probability consecutive sampling. Inclusion Criteria Both genders. Patients years of age. All patients with obstructive jaundice (for at least 1 week). Suspected patients of malignancy. Exclusion Criteria Patients having jaundice because of causes other than obstructive cause. DATA COLLECTION PROCEDURE Patients fulfilling the inclusion and exclusion criteria were included after an inform consent. Blood sample was drawn from all these patients and sent to laboratory for measuring bilirubin levels. A bilirubin level 8.4 mg/dl was considered as "positive" for malignancy. All the patients were subjected to biopsy from any mass lesion and the biopsies were sent for histopathology to confirm the malignancy. The results of laboratory were recorded. Patients were labeled as positive or negative for malignancy on histopathology. Data was analyzed by using SPSS version Age and serum bilirubin level were quantitative variables and their mean and standard deviation were calculated. Gender and presence of malignancy on bilirubin level and histopathology were qualitative variables and values were expressed as frequencies and percentage. A table of 2 2 was generated to calculate sensitivity, specificity, positive predictive value and negative predictive value for bilirubin level keeping histopathology as gold standard. Data was stratified for age, gender, duration of obstructive jaundice, size of mass to deal with effect modifiers. Poststratification chi square test was applied. P-value 0.05 was considered statistically significant. RESULTS In this study, 200 patients were included with mean age of 58 ± 9.67 years. The age and gender distribution is shown in Table 1 & 2. The mean duration of jaundice and the descriptive statistics for serum bilirubin are Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar.,

3 SIDRA RASHEED, SABEEN FARHAN, MUHAMMAD ARIF NADEEM, et al shown in Table 3 & 4. Number of patients with a serum bilirubin more than more than and less than 8.4 mg/dl is shown in Table 5, whereas the descriptive statistics of the ampullary/peri-ampullary mass is shown is Table 6. Table 7 depicts the patient who had malignancy and benign lesions on histopathology. Table 8 depicts the diagnostic accuracy of serum bilirubin levels for diagnosis of malignancy. Table 1: Age Distribution of Patients (in Years). Mean SD 9.67 Minimum age 20 Maximum age 70 Table 2: Gender Distribution of Patients. Frequency Percentage Male 80 40% Female % Total % Table 3: Descriptive Statistics for Duration of Jaundice (in Weeks). Mean 5.13 SD (standard deviation) 2.32 Minimum 1 Maximum 12 Table 4: Descriptive Statistics for Bilirubin Levels (mg/dl). Mean SD (standard deviation) 6.71 Minimum 7.9 Maximum 47.3 Data was stratified in different age groups and it was revealed that best sensitivity, specificity and diagnostic accuracy was achieved in years age group (Table 9). Data was stratified for gender of patients and it was revealed that best sensitivity, specificity and diagnostic accuracy was achieved in females group (Table 10). Stratification for duration of jaundice revealed that best sensitivity, specificity and diagnostic accuracy was found in patients who had Table 5: Bilirubin Levels of > 8.4 mg/dl. Bilirubin Level > 8.4 mg/dl Frequency Percentage % 6 3% Total % Table 6: Descriptive Statistics for Size of Mass (in cm). Size Mass-Length Mass-Size Mean SD (standard deviation) Minimum Maximum Table 7: Findings. Findings Malignancy Frequency Percentage % 4 2% Total % Table 8: Diagnostic of Bilirubin Levels for Diagnosis of Malignancy. Bilirubin Level (>8.4) mg/dl Findings Total Total Sensitivity=98.5% Specificity= 75% Positive Predictive Value (PPV) = 99.5% Negative Predictive Value (NPV) = 50% Diagnostic = 98% 43 Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar., 2014

4 SERUM BILIRUBIN AS A PREDICTOR OF MALIGNANCY IN PATIENTS PRESENTING WITH OBSTRUCTIVE JAUNDICE jaundice 9 12 weeks. (Table 11), whereas stratification for mass size revealed that best sensitivity, specificity and diagnostic accuracy was found in patients who had lesion size < 4cm (Table 12). Table 9: Diagnostic of Bilirubin Levels for Malignancy in Relation to Age of Patients. Age Groups Bilirubin Level (>8.4) mg/dl Findings Sensitivity Specificity PPV NPV Diagnostic p-value > % 0% 90.91% % NA 98.1% 100% 100% 100% 98.1% % - 100% % NA = not applicable Table 10: Diagnostic of Bilirubin Levels for Malignancy in Relation to Gender of Patients. Gender Bilirubin Level ( 8.4) mg/dl Findings Sensitivity Specificity PPV NPV Diagnostic P- value Male Female % 0% 98.7% % % 100% 100% % P-value = (Insignificant) Table 11: Diagnostic of Bilirubin Levels for Malignancy in Relation to Duration of Jaundice. Duration Bilirubin Level ( 8.4) mg/dl Findings Sensitivity Specificity PPV NPV Diagnostic P- value % 100% 100% 33.3% 98.3% % 50% 98.5% 50% 97.1% % 100% 100% % P-value = (Insignificant) P-value = (Insignificant) Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar.,

5 SIDRA RASHEED, SABEEN FARHAN, MUHAMMAD ARIF NADEEM, et al Table 12: Diagnostic of Bilirubin Levels for Malignancy in Relation to Size of Mass. Size of Mass Bilirubin Level (>8.4) mg/dl Findings Sensitivity Specificity PPV NPV Diagnostic p- value < % 75% 99.4% 50% 97.6% % - 100% - 100% NA NA = not applicable DISCUSSION The malignancies of gastrointestinal tract and the accessory organs of digestion (pancreas, liver, gall bladder) are more common and are responsible for more deaths than cancers from any other system in the body. 12,13 Jaundice is the symptom seen in gastrointestinal malignancies of pancreaticobiliary origin. The jaundice thus produced is termed as obstructive jaundice. 14 These malignancies have poor prognosis with 5 year survival rate of usually less than 5%. 15 This can be in part attributable to late presentation of these patients due to asymptomatic nature of the disease in earlier stages and delay in diagnosis. So, it is emphasized that earlier diagnosis of malignant obstructive jaundice and its various etiologies can make patient a suitable candidate for curative surgical resection. 9 Various non-invasive (ultrasound, CT scan and MRCP) and invasive (ERCP, PTC, and Cholangioscopy) modalities are used to diagnose these patients 8 but these diagnostic tools are not only very expensive but also not freely available, thus making early diagnosis difficult. Different studies have used various parameters like CA 19-9, USG abdomen 16 and Bilirubin 17 for the early detection of malignant obstructive jaundice. In our study bilirubin was used as parameter to predict the malignancy. bilirubin is simple, inexpensive and easily available test that can be used in patients of obstructive jaundice to help diagnose the malignancy as its cause. Bilirubin is the chemical found in the bile. Clinically obvious jaundice develops when bilirubin levels are mg/dl. In obstructive jaundice, composition of bile and cholesterol metabolism changes drastically with growing severity towards malignancy. 10 Literature describes malignant bile duct obstruction as a disease of older age group. About two third of patients are more than 65 years of age. 18 In our study mean age of presentation was 58 ± 6 year. Al- Mofleh IA et al from Saudi Arabia found mean age of 62.4±11.7 years for malignant bile duct strictures which is almost the same as was in our study. 19 In this study malignancy was found to be more in females (60%) as compared to males (40%) with male to female ratio of 1: 1.5. Another study by Khurram et al also showed increased presentation among females with male to female ratio of 1: In our study, sensitivity of serum bilirubin level for predicting malignant etiology of obstructive jaundice was 98.5% but specificity was 75%. The positive and negative predictive values were 99.5% and 50% respectively. The overall diagnostic accuracy of serum bilirubin level was 98%. These results were obtained by using cut off bilirubin levels of 8.4mg/dl. This study showed better sensitivity and specificity of serum bilirubin levels for predicting malignancy as compared to the study by Singh Saluja et al which showed sensitivity of 83.3% and specificity of 70% by using same cut off value of 8.4mg/dl for bilirubin. 5 The role of bilirubin as a predictor is further supported by Gracea et al. They used bilirubin levels of 100µmol/l (5.8 mg/dl) to detect sensitivity and specificity of bilirubin for predicting malignancy and found it to be 71.9% sensitive and 86.9% specific for malignancy. 21 The difference in sensitivities and specificities from that of our study might be due to use of different cut off value for serum bilirubin. Another study used serum bilirubin levels of 84µmol/l and found sensitivity of 98.6% and specificity of 59.3%. The specificity in our study was more as compared to this study although sensitivity was almost the same. Again different cut off values of serum bilirubin can be responsible for the difference and showed that specificity of bilirubin to predict malignancy increases with use of higher bilirubin levels. This showed that chances of malignancy to be the cause of obstructive jaundice will be higher with high serum bilirubin levels. 45 Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar., 2014

6 SERUM BILIRUBIN AS A PREDICTOR OF MALIGNANCY IN PATIENTS PRESENTING WITH OBSTRUCTIVE JAUNDICE CONCLUSION It was concluded from the results of this study that bilirubin levels are an early indicator of malignant obstructive jaundice. Bilirubin levels are always measured as a first test in a jaundiced patient. It is a cheaper test and easily available. So, in countries like Pakistan it can be helpful to diagnose the malignant obstructive jaundice in economical and time saving way and thus cannot only reduce the morbidity and mortality of patients but can also help to reduce the expenses required to correctly diagnose such patients. Further local studies are required to strengthen the role of serum bilirubin levels as predictor of malignant obstructive jaundice. Address for Correspondence: Dr. Sidra Rasheed Senior Registrar, Medical Unit III Services Hospital, Lahore sidsrashed5@gmail.com REFERENCES 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, CA: a cancer journal for clinicians, 2009; 59 (4): David Chu MDGA, MD. Malignant Biliary Tract Obstruction: Evaluation and Therapy. Journal of the National Comprehensive Cancer Network, 2010; 8 (9): Lokich J, Kane R, Harrison D, McDermott W. Biliary tract obstruction secondary to cancer: management guidelines and selected literature review. Journal of Clinical Oncology, 1987; 5 (6): Nguyen NQ. Pancreato-Biliary Cancers Diagnosis and Management. 5. Singh Saluja S, Sharma R, Pal S, Sahni P, Kanti Chattopadhyay T. Differentiation between benign and malignant hilar obstructions using laboratory and radiological investigations: a prospective study. HPB. 2007; 9 (5): Khanzada TW, Samad A, Memon W, Kumar B. Etiological spectrum of obstructive jaundice. Journal of Postgraduate Medical Institute (Peshawar-Pakistan), 2011; 22 (2). 7. Bile Duct (Cholangiocarcinoma) Cancer Signs and symptoms of bile duct cancer. [online] 2014 [updated ; cited 2015]; Available from: guide/bile-duct-cancer-diagnosis. 8. Siddique K, Ali Q, Mirza S, Jamil A, Ehsan A, Latif S, et al. Evaluation of the aetiological spectrum of obstructive jaundice. J Ayub Med Coll Abbottabad, 2008; 20 (4): Bile Duct (Cholangiocarcinoma) Cancer. [online] 2015 [updated 11/01/2014; cited 2015]; Available from: guide/bile-duct-cancer-diagnosis. 10. Ssrrskhog, Dsjkkac, Sonkar AA. Cholesterol and its esters as serum biomarkers in malignant obstructive jaundice: a single step 1H NMR metabolomic approach. Metabolomics, 2013; 9 (3): Garcea G, Ngu W, Neal CP, Dennison AR, Berry DP. Bilirubin levels predict malignancy in patients with obstructive jaundice. HPB. 2011; 13 (6): Gastrointestinal cancer. [online] 2015 [updated 31 August 2015; cited 2015]; Available from: a TYDHAe. Textbook of gastroenterology [online]: Chichester, West Sussex ; Hoboken, NJ : Blackwell Pub.,; [cited Available from: Nelson Awori AB, Alan Beasley, James Boland, Michael Crawford, Frits Driessen, Allen Foster, Wendy Graham, Brian Hancock, Branwen Hancock, Gerald Hankins, Neville Harrison, Ian Kennedy, Julius Kyambi, Samiran Nundy, Joe Sheperd, John Stewart, Grace Warren, Michael Wood. :Primary Surgery:n Trauma [online] [cited Available from: Ries L, Harkins D, Krapcho M, Mariotto A, Miller B, Feuer E. Seer Cancer Statistics Review National Cancer Institute, Available from: h ttp. seer cancer gov/csr/1975_2003 (Access ed vember 2005) Akhtar S, Mufti T. Diagnosti c accuracy of obstructive jaundice on ultrasonography at Ayub Hospital complex. J Ayub Med Coll Abottabad. 1999;11: Bain VG, Abraham N, Jhangri GS, Alexander TW, Henning RC, Hoskinson ME, et al. Prospective study of biliary strictures to determine the predictors of malignancy. Canadian journal of gastroenterology= Journal canadien de gastroenterologie, 2000; 14 (5): Malignant Bile Duct Obstruction [cited 2015]; Available from: Al-Mofleh IA, Aljebreen AM, Al-Amri SM, Al-Rashed RS, Al-Faleh FZ, Al-Freihi HM, et al. Biochemical and radiological predictors of malignant biliary strictures. World Journal of Gastroenterology, 2004; 10 (10): Khurram S QA, Shirin M, Aiza J, Aisha E, Sarmad L, Asif ZM:. Evaluation of the aetiological spectrum of obstructive jaundice. J Ayub Med Coll Abbottabad, 2008; 20: Roche SP KR. Jaundice in the Adult Patient. Am Fam Physician, 2004; 69 (2): Pakistan J. of Gastroenterology, Vol. 29, Biannual Mar.,