|MINI SYMPOSIUM: SUPPORTIVE CARE
|Year : 2012 | Volume
| Issue : 1 | Page : 125-136
The liver function test enzymes and glucose level are positively correlated in gallbladder cancer: A cancer registry data analysis from north central India
TD Singh1, MA Barbhuiya1, S Poojary1, BR Shrivastav2, PK Tiwari1
1 Centre for Genomics, Molecular and Human Genetics, Jiwaji University, India
2 Cancer Hospital and Research Institute, Gwalior, India
|Date of Web Publication||25-Jul-2012|
P K Tiwari
Centre for Genomics, Molecular and Human Genetics, Jiwaji University
Source of Support: None, Conflict of Interest: None
Aim of Study: To investigate the trend of expression of liver function test enzymes and other biochemical changes during gallbladder carcinogenesis. Materials and Methods: Eight hundred and seventy-eight gallbladder disease patients were selected to study the liver function test enzymes and routine blood biochemical changes in the last five years (2004-08). Statistical analysis was performed using Graph Pad prism® 5.02 software. Results: The liver function test enzymes showed significant correlations among themselves, and with glucose in gallbladder cancer and gallstone disease patients (N = 878). Out of 878 gallbladder cases, 46 (5.24%) showed significantly higher glucose level of 216.66 mg/dL (P < 0.0001). All the three pathological conditions of gallbladder, gallbladder cancer with stones (GBCS), gallbladder cancer without stones (GBC) and calculus cholecystitis (CC), showed highly significant positive correlation (Pearson) between Serum Glutamic Oxaloactetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT) [P < 0.0001, (GBCS); P < 0.0001, (GBC), and P < 0.0001, (CC)]. SGOT and SGPT also showed positive correlation with higher glucose level independently, in both GBCS and CC (P < 0.0001 and P < 0.0001), respectively. Conclusion: Simultaneous elevation of glucose and liver function test enzymes in GBC makes the diagnosis complex. Any patient of gallbladder diseases with higher level of glucose may have the possibility of developing gallbladder cancer.
Keywords: Gallbladder cancer, glucose, liver function tests
|How to cite this article:|
Singh T D, Barbhuiya M A, Poojary S, Shrivastav B R, Tiwari P K. The liver function test enzymes and glucose level are positively correlated in gallbladder cancer: A cancer registry data analysis from north central India. Indian J Cancer 2012;49:125-36
|How to cite this URL:|
Singh T D, Barbhuiya M A, Poojary S, Shrivastav B R, Tiwari P K. The liver function test enzymes and glucose level are positively correlated in gallbladder cancer: A cancer registry data analysis from north central India. Indian J Cancer [serial online] 2012 [cited 2018 Apr 19];49:125-36. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/125/98938
| » Introduction|| |
Gallbladder cancer is one of the most common cancers of the biliary tract, and the sixth most common cancer of the gastrointestinal tract (GITC), with a high rate of mortality. , Countries like Chile, India, Korea, Japan, Czech Republic, Slovakia, Spain, Columbia, Peru, Bolivia and Ecuador have the highest incidence rates of gallbladder cancer.  Gallbladder cancer is also one of the most common causes of cancer-related mortality in women in the northern and north-eastern states of India.  The incidence ranges from 10/1,00,000 in Delhi to 2-3/1,00,000 in South India. As in case of cholangiocarcinoma and hepatocellular cancer, the routine blood biochemical parameters were significantly elevated in gallbladder cancer . ,,, However, a systematic review of clinical investigations emphasizing the significance of routine biochemical parameters is lacking. In a recent study, a significant increase in the level of lactate dehydrogenase (LDH) isozymes was observed in the blood serum of gallbladder cancer.  Even though there are reports on the elevated values of different parameters like Alkaline phosphatase (ALP), Serum Glutamic Pyruvic Transaminase (SGPT), Serum Glutamic Oxaloactetic Transaminase (SGOT) and Total Bilirubin (TBIL) in different cancers, no correlation study has yet been made in gallbladder cancer or calculus cholecystitis, which is a potential risk factor of gallbladder cancer.
The liver function test (LFT) enzymes play important metabolic roles in the functions of different cells and tissues of the gastrointestinal tract. Albumin (Alb), ALP, SGPT, SGOT, TBIL, Direct Bilirubin (DBIL), Gamma glutamyltransferase (GGT) are the major biochemical parameters routinely estimated in the patient's blood to assess the functional status of the liver. ALP is a nonspecific enzyme marker of gallbladder cancer. It is markedly expressed in the apical pole of hepatocytes and cholangiocytes, and is secreted in bile in large amounts. , ALP comprises a group of enzymes that catalyze the hydrolysis of phosphate esters in an alkaline environment, generating an organic radical and inorganic phosphate.  SGPT, a cytosolic enzyme, and SGOT, both cytosolic and mitochondrial, are present in the sera of all age groups. These enzymes (transaminases) catalyze the reversible transfer of α-amine group of aspartic acid, alanine and α -keto group of ketoglutaric acid to form oxaloacetic acid, pyruvic acid and glutamic acid, respectively, via a specific electron transport system. , Such a biochemical mechanism helps maintain a normal and well-coordinated liver function.
Our aim in the present report was to re-evaluate, in detail, the levels of different enzymes like liver function test enzymes, serum glucose and other blood biochemical parameters, followed by correlation analysis between any two randomly selected parameters in gallbladder cancer with stones (GBCS), without stone (GBC) and calculus cholecystitis (CC). This study has an implication in aiding the prognostic management of gallbladder cancer by the clinicians.
| » Materials and Methods|| |
About 878 gallbladder cases (565 GBCS, 193 GBC and 120 CC), registered during 2004-08 at the regional Cancer Hospital and Research Institute (CHRI), Gwalior, India were selected for the present study. The study was approved by the Institutional Ethics Committee. Those patients, whose routine blood biochemical, cytological, radiological and histopathological examinations showed positive diagnosis of gallbladder diseases were included in the study, while others having symptomatic abnormalities for diseases other than gallbladder diseases were excluded from the study. General information about various gallbladder cases included in the study is given in [Table 1]. After having well-informed consent from the subjects, about 3-5 ml of whole blood samples were collected on the first day of admission to the hospital before medication began.
About 82% of the GBC patients showed persistent pain on the lower side of the right abdomen and jaundice with fever for the last two to four months. The remaining 18% of the gallbladder cancer patients were confirmed by their history of cholecystectomy. About 87% of the gallbladder cancer patients were diagnosed following routine biochemical tests, liver function test enzymes, Ultrasonography (USG), Computer Tomography Scan (CT scan), Magnetic Resonance Imaging (MRI), and finally confirmed by Fine Needle Aspiration Cytology (FNAC) and histopathology (post-surgery), while the remaining 13% were confirmed by their past history.
About 10-15 μl of the whole blood was used for blood biochemical analysis. The counting of different lymphocytic and non-lymphocytic cells was performed using fully automated Cyto-analyzer (Sysmex Asia Pacific Pvt. Ltd., India) following manufacturer's protocol with some modifications.
Liver function test enzyme analysis
To carry out the liver function tests (LFT), the serum was analyzed in Bayer's Express Plus, auto analyzer (Bayer Diagnostics, Siemens, USA). The enzymes, such as ALP, SGPT, SGOT, TBIL and DBIL were quantitated following the method given by the manufacturer of the test kit with some modifications. ,,
Quantitation of glucose
To quantitate the glucose level, about 10 μl of serum was taken in a test tube and mixed with 1 ml of the working reagent, prepared in phosphate buffer (4 aminoantipyrine - 0.2 mmol/L, p-Hydroxy Benzoic acid- 5.9 mmol/L, glucose oxidase ≥ 5000U/L and Peroxidase ≥ 5000U/L), following manufacturer's protocol supplied along with the test kit (Siemens Healthcare Diagnostics Inc., USA). After incubation at 37°C for 15 min, it was mixed, and the absorbance was taken using Spectrophotometer at 505 nm. 
Blood biochemical analysis of A, B, AB and O groups
The ABO antigen typing was recorded in 614 GBC patients using blood group detection kit (Himedia Laboratories Pvt. Ltd., India). The blood groups of 90,000 healthy control donors during the period 2002-07, were obtained from the Blood Bank of Gajra Raja Medical College, Gwalior. To study the correlation of blood parameters with different blood groups, a comparative profile of all the blood biochemical parameters was prepared for A, B, AB and O blood groups. The normal values of healthy controls, as mentioned in the blood biochemical profiling, were used as reference values for statistical analysis.
Different statistical calculations like mean, median, 50 th , 75 th percentiles, standard deviation and standard error were carried out from the estimated values of blood biochemical tests and LFTs in the three gallbladder cases using Graph Pad Prism® 5.02 software.  Wilcoxon Rank test and two-tailed student t-test were performed by taking the maximum value in the range of universal values of healthy controls, irrespective of different parameters. Chi square value and Relative Risk (RR) were calculated to know the level of significance of difference among the blood groups (A, B, AB and O). Correlation analysis (Pearson's) of the LFTs and biochemical parameters was performed, and the R square value was also calculated. Those results (of correlation) having 95% Confidence Interval (CI) value, from 0.5 to 1.00 and R square ≥ 0.1000, were considered significant.
| » Results|| |
Classification of gall bladder cancer
Out of 878 samples studied, 758 were gallbladder cancer (including GBCS). Among gallbladder cancer patients (N = 758), the number of gallbladder cancer grades I, II and III were 85 (9.68%), 292 (33.26%) and 381 (43.4%), respectively. The FNAC report classified the gallbladder cancer patients into benign (n = 57, or 7.52%), inflammatory (n = 19, or 2.51%), adenocarcinoma (n = 612, or 80.73%), squamous carcinoma (n = 51, or 6.73%), sarcoma (n = 09, or 1.19%) and scanty hemorrhagic cells (n = 10, or 1.32%). Of the total 878 patients, 597 patients (GBCS = 358, GBC = 149 and CC = 90; F = 67.90%) were female, and 281 patients (GBCS = 207, GBC = 44 and CC = 30; M = 32.0%) were male, with the average ages being 51.5 years and 55.5 years, respectively. A Lower Body Mass Index (< 18.00) was found to be associated with the patients (data not shown).
Blood biochemical and liver function test enzyme profiling and their correlations
The average values of ALP, SGPT, SGOT and TBIL were found to be elevated in all the three pathological conditions of gallbladder, i.e., GBC, GBCS and CC. A significant decrease in the value of hemoglobin (Hb) was observed in all the three gallbladder cases. The values of ALP, Urea, Creatinine and Neutrophils were found gradually increasing from CC to GBC Grade III [Table 2] and [Table 3] and [Figure 1]. In the Pearson's correlation analysis, significant positive correlation was found between elevated ALP and SGOT (P < 0.0001, R square = 0.1131 in GBC; P < 0.0001, R square = 0.2972 in GBCS; P < 0.0001, R square = 0.4831 in CC), ALP and TBIL (P < 0.0001, R square = 0.2646 in GBC; P < 0.0001, R square = 0.2047 in GBCS; P < 0.0001, R square = 0.4247 in CC), SGPT and SGOT (P < 0.0001, R square = 0.8049 in GBC; P < 0.0001, R square = 0.7768 in GBCS; P < 0.0001, R square = 0.6003 in CC; [Figure 2]], SGPT and TBIL (P < 0.0001, R square = 0.2049 in GBC; P < 0.0001, R square = 0.1975 in GBCS; P < 0.0001, R square = 0.4975 in CC; [Figure 3][ and SGOT and TBIL (P < 0.0001, R square = 0.1476 in GBC; P < 0.0001, R square = 0.2453 in GBCS; P < 0.0001, R square = 0.3283 in CC). In addition, similar positive correlation was also found in elevated SGPT and Glucose (P = 0.0001, R square = 0.4251) in CC, and SGOT and Glucose (P < 0.0001, R square= 0.7768 in GBCS; P < 0.0001, R square = 0.6287 in CC) [Table 4].
|Table 2: Quantitative distribution of different biochemical parameters in gallbladder cases|
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|Table 3: Comparative profile of blood biochemical parameters in different age groups of GB cases|
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|Table 4: Correlation analysis among different parameters in gallbladder cases|
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|Figure 1: Comparison of ALP, SGPT and SGOT concentrations in GBCS, GBC, CC and Controls|
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High Glucose level
The mean and median values of glucose levels were 99.66 and 88.00 (mg/dL) (SD = 44.71, SE = 2.62) in GBC, 100.80 and 88.50 (mg/dL) (SD = 50.57, SE = 4.157) in GBCS and 97.64 and 87.00 (mg/dL) (SD = 38.18, SE = 5.57) in CC. Significantly high values of glucose (average 216.66 mg/dL) were noted in 46 (5.24%) of 878 gallbladder cases. Wilcoxon Rank test and students t-test for glucose were found to be significant in GBC, GBCS and CC (P ≤ 0.0001; [Figure 4]).
|Figure 4: Profile of elevated glucose levels in gallbladder cancer cases|
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ABO antigens grouping and biochemical analysis
Among the patients studied, 221 (35.99%) were blood group B, 195 (35.75%) were O, 107 (17.42%) were A and 91 (14.82%) were AB blood group. Statistical analysis showed a positive association of AB blood group (Chi square value = 24.41 at d.f. = 1 with P < 0.0001) with gallbladder cancer, followed by A blood group (Chi-square value = 9.347 at d.f. = 1 with P = 0.0022). The Relative Risk (RR) of AB blood group with gallbladder cancer was found to be significant (RR = 1.75 with 95% confidence interval of 1.40 to 2.18, Woolf's approximation). The RR of Rh-positive patients being affected was also very high (RR = 8.52, non-significant at 95% CI = 4.04 to 17.9) in comparison to Rh-negative patients, but both were positively associated with the occurrence of gallbladder cancer (P < 0.0001; see [Table 5]a and b. The data suggests the AB blood group to be at the highest risk of gallbladder cancer, followed by the A blood group. Among the blood groups A, B, AB and O in gallbladder cancer patients, blood group A showed the highest mean values of ALP (718.5 IU/L), TBIL (9.604 mg/dL), Urea (37.13 mg/dL) and WBC (12221 per mm 3 ), and also shown to be associated with gallbladder cancer [RR (CI 95%) = 0.72 (0.58 to 0.88); Chi-square value = 9.347 at d.f. = 1 with P = 0.0022), after AB blood group [RR (CI 95%) = 1.75 (1.40 to 2.18); Chi-square value = 24.41 at d.f. = 1 with P < 0.0001] [Table 5] and [Table 6].
|Table 5: Association of blood group antigen with gallbladder cancer a) Chi square distribution of blood group antigens in total in gallbladder cancer (GBC+GBCS; N=614) and controls (N=90,000)|
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|Table 6: Blood biochemistry profile of A, B, AB and O blood groups of gallbladder cancer cases|
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| » Discussion|| |
Our analysis revealed the average values of ALP, SGOT, SGPT, TBIL and neutrophils to be significantly elevated in all the three cases of gall bladder, viz., GBC, GBCS and CC. This indicates an increase in the tissue-specific cellular physiology, most likely due to malignancy, presence of gall stone or long-term tissue inflammation. The lower counts of lymphocytes, i.e., 18.15% and 20.52% in GBC and GBCS, respectively, denote that the optimum body immunity level of the patients goes down as the tumorigenesis advances. The decrease in the values of Hb 11.12%, 10.65% and 11.26% in GBC, GBCS and CC , respectively shows the anemic condition of the patients. Such a condition may ultimately decrease the supply of oxygenated metabolites to cancerous as well as neighboring non-cancerous tissues. However, the sequence of events (from anemia to cancer or vice versa) remains to be determined.
ALP is positively correlated with SGOT and TBIL in GBC, GBCS and Calculus cholecystitis
The transformed cells (after development of tumor) become malfunctional for most of the cellular pathways. As a consequence of advancement in the process of tumorigenesis, the functional levels of enzymes released become elevated in gallbladder cancer cells. The ALP, SGOT and TBIL secreted are available in the circulation when blood passes through the affected cells. On an average, the level of ALP is higher in female patients than in male patients of GBCS, GBC and CC, which is contrary to Klaassen's report showing normal value of ALP to be more in males than in females of less than 50 years of age.  The increased levels of ALP, SGOT and TBIL may be due to the increased cell membrane permeability and leakage from inside the cells to outside into the circulation. These molecules enter and leave the cells rapidly. In normal cells, they are distributed in both plasma and interstitial fluid, and are cleared from circulation like other serum proteins. Such a mechanism may be associated with the cells of gallbladder cases also. Moreover, the positive correlation or simultaneous elevation of ALP with SGOT and TBIL are found in all the three cases, which signify its association, specifically with gallbladder cases. A clear understanding as to how the permeability of the plasma membrane is regulated, and the enzymes are released in circulation, needs an in vitro investigation through different signaling pathways with respect to LFT enzymes. The diagnosis and prognosis of gallbladder cancer can be facilitated by critical inspection of the levels of all the clinical parameters including ALP, SGOT and TBIL.
Positive correlation of SGPT with SGOT and TBIL in GBC, GBCS and Calculus Cholecystitis
Development of biochemical markers is important for early diagnosis of gallbladder cancer. Due to its inaccessibility and late detection, so far, no effective measure of treatment is yet available. The survival rate is less than five years after surgical removal in advanced cases. Being part of the gastrointestinal tract, the general mechanism of tumorigenesis of the gallbladder is expected to be similar, however, needs detailed investigation. The earlier report from our laboratory on the elevated levels of ALP, SGOT, SGPT and TBIL levels made from 464 gall bladder cases, is reproduced in this study with 878 gallbladder cases.  The increased levels of the enzymes (ALP, SGOT, SGPT and TBIL) at advanced stages of gallbladder cancer make the diagnosis and prognosis worse. The Grade III patients showed relatively higher values of enzymes than Grade I or CC patients, which seems to indicate that CC may be an early event towards gallbladder carcinogenesis. In our study, most of the late diagnosed gallbladder cancer cases showed liver metastasis (data not shown). The diagnostic utilities of SGOT and SGPT in liver metastasis become limited, since in many cases of cardiac diseases, muscle damage, prostate and lung cancers also they are elevated. ,,, The excessive release of transaminases (SGOT and SGPT) in advanced grade cancer cells may likely be due to the increased non-adaptive physiological activities in tumorigenic and stoned or inflamed tissues of the gallbladder. SGOT and SGPT showed significantly elevated values in 80.49%, 77.68% and 60.03% GBC, GBCS and CC, respectively. The extent of tumorigenesis is enhanced by a combined increase in the level of transaminases, making the prognosis more complex. Simultaneous elevation of these enzymes makes diagnosis and prognosis of GBC worse. A strong positive association between SGOT and SGPT is found in the three gallbladder cases (P < 0.0001; [Figure 2]). This association may give useful information in the diagnosis, prognosis and understanding of the molecular mechanisms involved in the progression of cancer. From the study, only the extent of tumorigenesis can be determined, but not the different grades.
Increased glucose level in GBC patients
We found several gallbladder cancer patients, 5.26% (46 of 878), to be associated with increased glucose level, which supports the earlier study made in a Chinese population, where only 0.03% of GBC cases were found to have established diabetes.  Diabetes is reported to be one of the major risk factors in various cancers of the colon, breast, kidney, pancreas, endometrium, ovary and biliary tract. , Because of a decrease in the number of insulin receptors and alterations in post-reception function or in the presence of blocking antibodies, the target tissues (e.g. muscles and liver) show poor performance in the uptake and use of insulin.  The intracellular rise of glucose is also due to decreased activities of hexokinase and glycogen synthase resulting in impaired glucose transport.  Thus, the insulin and insulin-like growth factors involved in the regulation of cell growth including differentiation and apoptosis, may also have possible effects on the epithelial cells of gallbladder cancer, as observed in colon cancer. , The cause of higher glucose level in the blood serum may also be due to intake of sugary and less fibrous diets. , Basically, having similar molecular mechanisms of tumorigenesis in cancerous tissues, the gallbladder organ, being muscular in nature may likely have reduced availability of insulin molecules by any one of the modes mentioned above or by all of them together, which needs further investigation. This may possibly alter the transport mechanisms of glucose and its concentration in the tumor tissues as compared to the normal ones . So far, very few studies have described the association of diabetes with gallbladder cancer. The available literature show a relative risk of 1.3 for gallbladder cancer due to diabetes, and an Odds Ratio of 2.6 with 95% confidence interval (1.5-4.7) and 2.0 with 95% confidence interval (1.2-3.3) in cancers of the gallbladder and biliary tract, respectively. , Our analysis is relevant to those patients having any gallbladder problem with high glucose level, with a likely probability of developing gallbladder cancer.
Positive correlations of SGOT with TBIL and glucose in GBCS and calculus cholecystitis, and SGPT with glucose in GBC, GBCS and calculus cholecystitis
Our data on the frequency of gallbladder cancer with elevated glucose level is highly significant as compared to other reports on different cancers. , Since the discovery of Braunshtein and Kritzmann in 1937, transaminases (SGPT and SGOT) have been used to indicate the severity in many diseases including liver disease, hepatocyte necrosis and even hepatitis. ,,, The tumor cells of the gallbladder (after its metastasis into the liver or to even distant organs) may transform the hepatocytes and also other cells into cancerous, where different genetic, physiological, biochemical and other related mechanisms are involved. Following cellular transformation, the leakage of such enzymes from both the gallbladder and liver cells may critically increase as the tumorigenesis advances. The functional correlation of SGOT and glucose in the gallbladder cancer and its risk factor, calculus cholecystitis, needs detailed investigation . Variations in the serum transaminase levels and other related enzymes were observed in the affected muscle cells of the heart, hepatocytes, , and also in other cancers. ,, Simultaneous elevation of SGOT and serum glucose levels among the gallbladder cancer and CC cases gives a positive indication towards the increased complexity of gallbladder pathogenesis, supporting further the report of CC being a risk factor for gallbladder cancer. This can be considered as an early event leading to carcinogenesis in due course of time.
Association of ABO blood group with gallbladder cancer
The association of AB O blood group antigen with gallbladder cancer draws potential attention to investigate its genetic association with the disease. Some earlier reports have also shown the association of ABO blood group antigens with cancers including ovarian, breast and pancreatic cancers. ,,, Our data showing the highest value of ALP and TBIL in blood group A also supports the positive association of AB and A blood groups with gallbladder cancer. To the best of our knowledge, there is no such biological or population-based study yet made to investigate the association of gallbladder cancer with blood group system. Our ongoing genetic study is expected to provide significant information on this aspect.
| » Conclusion|| |
Our present study clearly shows that the major blood biochemical parameters are significantly increased during the pathogenesis of gallbladder cancer. Simultaneous elevation of serum ALP, SGOT, SGPT and glucose in both gallbladder cancer and CC, makes the pathogenesis complex. The result of the correlation study indicates the possible association between gallbladder cancer and calculus cholecystitis, suggesting calculus cholecystitis to be a potential risk factor for GBC. Such individuals may have a greater possibility of developing gallbladder cancer. The association of blood group AB with gallbladder cancer is another puzzle to be further elucidated. Our CARD (CAncer Registry Data) analysis can be further elaborated at molecular levels for better understanding on its diagnostic and prognostic potential.
| » Acknowledgment|| |
The research fellowships provided by JU, Gwalior and ICMR, New Delhi to Tekcham Dinesh Singh, and by ICMR to Mustafa Ahmed Barbhuiya and Satish Poojary are highly acknowledged.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]