Original Article

Preoperative De Ritis Ratio for the Evaluation of Recurrence and Progression in Non-muscle Invasive Bladder Cancer


  • Ramazan İnan
  • Alper Bitkin
  • Mustafa Aydın
  • Emrah Küçük
  • Mustafa Kemal Atilla
  • Lokman İrkilata

Received Date: 09.01.2022 Accepted Date: 10.04.2022 Bull Urooncol 2023;22(1):15-19


This study aimed to investigate the potential predictive value of the preoperative De Ritis ratio in patients with primary non-muscle invasive bladder cancer (NMIBC).

Materials and Methods:

Of 212 patients who underwent transurethral resection of bladder tumour surgery for primary bladder cancer at a single academic centre between 2010 and 2016, we retrospectively analysed the clinical and pathological data. Blood samples were collected 1-7 days before surgery. The De Ritis ratio’s potential prognostic value of was evaluated using receiver operating characteristic (ROC) curve analysis.


One hundred twenty-five patients (or 59%) were found to have high-risk diseases, 17 patients (or 8%) had intermediate-risk diseases, and 70 patients (or 33%) had low-risk diseases. We investigated which cut-off value for De Ritis ratio could predict NMIBC risk groups in the preoperative period. The ROC analysis showed that there was no significant cut-off value in either low-risk [area under the curve (AUC)=0.457] or high-risk (AUC=0.551) patients. According to the European Organization for Research and Treatment of Cancer risk groups, when the quantitative values were compared, it was seen that low-risk patients were younger (p=0.005) and this group’s alanine aminotransaminase (p<0.001) values were higher. De Ritis ratio was statistically similar in all patient groups.


According to our present results, the De Ritis ratio does not add any additional value to existing prognostic models. Investigating De Ritis ratio simultaneously with markers such as albumin, C-reactive protein, neutrophil-lymphocyte ratio, which are used successfully in many cancer types, may yield successful results in prospective, more comprehensive studies.

Keywords: Primary bladder cancer, De Ritis ratio, biological markers, prognosis


The seventh most prevalent cancer in men and the eleventh most common cancer overall for both sexes is bladder cancer (1). 75% of bladder cancers are non-muscle invasive bladder cancers (NMIBC) at the time of diagnosis (2). Patients with NMIBC are followed up in accordance with the disease-specific risks of recurrence and progression after transurethral resection of bladder tumour (TUR-B). NMIBC development, recurrence, and disease-related death rates vary (3). As a result, the therapy of NMIBC patients is dictated by the condition’s hazards and personal preferences. To predict oncological outcomes and pick the optimal course of treatment for each group of patients, it is critical to identify individuals with equivalent risks of recurrence and progression.

The World Health Organization (WHO) histological grade, the number of tumours, their size, the T-stage, and the presence of carcinoma in situ (CIS) are all factors that the European Organization for Research and Treatment of Cancer (EORTC) risk table uses to predict recurrence and progression (3). Numerous markers have been researched to predict the risks of progression and recurrence in routine clinical practice; however, none of them are routinely used due to their low sensitivity and specificity levels (4).

The enzymes aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), which are released from the liver cells into the bloodstream following hepatocellular injury, are frequently used to assess liver function (5). Fernando De Ritis originally studied the AST/ALT ratio in 1957; this ratio is now known as the De Ritis ratio (6). De Ritis ratio is changed in many conditions, including cirrhosis, viral hepatitis, and alcoholic hepatitis. The De Ritis ratio has a standard value of about 1.5 (7). Recent oncological studies have reported that AST and ALT act as catalysts in the synthesis of nucleotides and non-essential amino acids in tumour cells (8). AST and ALT levels become elevated with increases in anaerobic glycolysis and glucose and glutamine metabolism during adenosine triphosphate synthesis; this is called the Warburg effect (9,10). The De Ritis ratio is a helpful predictive indicator for individuals with malignant tumours of the lung, colon, pancreas, and upper urinary system, according to several recent studies (11,12,13,14).

In this context, we retrospectively analyzed data from NMIBC patients who underwent TUR-B to investigate whether the preoperative De Ritis ratio may predicts the risks of cancer recurrence and progression.

Materials and Methods

Ethical approval was obtained from our local ethics committee. The Medical Specialization Education Board of Samsun Training and Research Hospital granted clearance for this retrospective study with the number 203 dated 26.12.2017. The Dean of the Faculty of Medicine of the University of Health Sciences authorized this clearance with decision number 2018/4 dated 22.01.2018.

The medical records of patients with primary bladder cancer who had TUR-B at the Samsun Training and Research Hospital in Turkey between 2010 and 2016 were retrospectively reviewed. 212 NMIBC patients’ individual medical records, test findings, and pathology reports were examined. Patients were excluded if they had transitional cell non-epithelial bladder cancer, concomitant tumours, chronic use of medications that elevated liver enzymes, hepatic disease, or incomplete TUR-B.

The tumour tissues had been graded using the 1973 WHO classification system (15) and staged using the 2009 tumor-node-metastasis classification system by the Union for International Cancer Control (16). The EORTC recommended using tumour size and number, recurrence rate, T-stage, concurrent CIS, and histological grade to assess the risks of progression and recurrence (3). Patients with tumours that are primary, solitary, TaG1 (low-grade, papillary urothelial neoplasm with low malignant potential), tiny (diameter 3 cm), and the absence of concomitant CIS are at low risk, according to the European Association of Urology guidelines. High-risk patients had numerous recurring TaG1/G2 tumours with diameters 3 cm, HG/G3 tumours, or CIS. Patients with tumoral characteristics, on the other hand, who range into the low- and high-risk diseases groups, are at an intermediate risk (17).

Up to one week before surgery, routine preoperative biochemical tests were conducted to evaluate the levels of AST and ALT. Automatic analyzers were used to measure the AST and ALT levels by colorimetric technique. In our biochemistry lab, the maximum standard values for AST and ALT were 40 U/L and 35 U/L, respectively. Divide AST by ALT to obtain the De Ritis ratio.

Statistical Analysis

The software program SPSS Statistics were used to examine the data (version 23; IBM Corp., Armonk, NY, USA). Using the Shapiro-Wilk test, the normality of the data distribution was evaluated. Data that weren’t normally distributed were compared using the Kruskal-Wallis and Mann-Whitney U tests. To compare qualitative data, the chi-square test was employed. The De Ritis ratio was used to classify the patients, and binary logistic regression was applied to compare the independent risk factors within and between the groups. Frequencies (percentages) are used to portray qualitative data, while medians are used to present quantitative data that did not follow a normal distribution (ranges). The p-value cut-off for statistical significance was 0.05.


The demographic, clinical, and histological characteristics of 212 NMIBC patients who underwent TUR-B are described in Table 1. Patients were divided into three risk groups: high (n=125; 59%), intermediate (n=17; 8%), and low (n=70; 33%).

We investigated the cut-off level for the pre-treatment De Ritis ratio that could predict risk in NMIBC patients. In receiver operating characteristic curve analysis, no significant differences were identified in cut-off values between low-risk [area under the curve (AUC)=0.457] and high-risk (AUC=0.551) patients (Figure 1A-B).

Quantitative differences between risk groups showed that low-risk patients were younger (p=0.005) and had higher ALT levels (p=0.001) than high-risk patients (Table 2). The De Ritis ratio, even so, was comparable across all groups.

The De Ritis ratio was unaffected by tumour features in the univariate and multivariate studies (Table 3). Additionally, no correlation between the De Ritis ratio and the EORTC recurrence and progression scores was found to be statistically significant (Table 4).


A comparison of quantitative variables between EORTC risk groups in this study revealed that low-risk patients were younger (p=0.005) and had higher ALT levels (p<0.001). Even so, preoperative the De Ritis ratio was similar across all groups.

The risks of recurrence and progression of NMIBC are determined using the EORTC risk table (3). Despite the risk stratification and use of intravesical therapy, there were high rates of recurrence (70%) and progression (30%), which poses a significant obstacle to the treatment of NMIBC (18). Pretreatment markers are required to predict the risks of recurrence and progression at the initial diagnosis and to identify misclassified or inadequately classified patients (19).

Although ALT is exclusive to the liver, AST is broadly expressed in various tissues, including the liver, brain, kidney, muscle, and even the heart (7). AST is preferentially used instead of ALT during anaerobic glycolysis; therefore, a higher De Ritis ratio is expected during periods of oxidative stress. The precise mechanism has not, however, been completely clarified (20,21,22). During frequent cell proliferation, such as in areas of tissue damage or tumours, an increase in AST is likely to increase the De Ritis ratio, which makes it an enticing potential biomarker (14). Although research on NMIBC is lacking, many recent studies have found that AST and ALT levels can help predict the development of upper urinary tract, colon, pancreatic, and lung cancers (11-14). In a study of the use of De Ritis ratio in NMIBC patients, Laukhtina et al. (23) observed a significant predictive value only in NMIBC patients with recurrence-free survival. The De Ritis ratio, according to the authors, did not influence the prognostic models.

In our study, no De Ritis ratio cut-off value could be identified that predicted a high risk. However, recent studies have reported different cut-offs for the prognosis of various types of cancer types. Patients with gastric cancer and a De Ritis ratio of greater than 0.8 have a better prognosis, according to Chen et al. (24). According to Tan et al. (13), individuals with distal cholangiocarcinoma should have a De Ritis ratio of >2.0 as a useful indicator of long-term survival. Additionally, the De Ritis ratio cut-off value that indicated survival in patients with urological malignancies ranged from 1.26 to 1.6. (25-27). Age (p=0.001), T-stage (p=0.001), and De Ritis ratio (cut-off value: 1.3) were thought to be independent predictive markers for the overall survival of patients with muscle-invasive bladder cancer after radical cystectomy by Gorgel et al. (28). In patients who underwent surgery for upper urinary tract urothelial carcinomas, Lee et al. (25) found that the De Ritis ratio (cut-off value: 1.5), age, T-stage, and lymph node involvement were related to cancer-specific survival and overall survival. Previous studies have shown that the De Ritis ratio correlated with lymph node involvement and recurrence-free survival in upper urinary tract malignancies, although we did not find correlations between the De Ritis ratio and tumour characteristics, recurrence, or progression scores (29,30). Tumour parameter analyses in our study, both univariate and multivariate, revealed that tumour parameters had no effect on the De Ritis ratio. Furthermore, no correlation was found between the EORTC recurrence and progression scores and the preoperative de RITIS ratio. Considering these findings, we conclude that the De Ritis ratio does not predict risk beyond the data provided by common clinical factors.

Study Limitations

The retrospective analysis of the prospectively acquired data and the lack of follow-up information regarding the specific recurrence and progression rates were the study’s limitations. Moreover, undetected liver or other diseases may have affected the AST and ALT levels. The lack of additional systemic inflammatory indicators in our investigation, such as the neutrophil-lymphocyte ratio (NLR) or platelet-lymphocyte ratio, is a significant limitation. The primary goal of this study was to investigate the correlation between De Ritis ratio and NMIBC, although we discovered that the NLR value of the high-risk group was significantly higher (p=0.001) than that of the intermediate and low-risk groups.

Finally, variability in the skills of surgeons (i.e., quality of surgery) and pathologists (i.e., determination of T-staging, histological grading, and CIS evaluation) may have affected the results. Despite these limitations, our study is one of the few to look at the correlation among preoperative De Ritis ratio, disease risk categories, and tumour characteristics in NMIBC patients.


In NMIBC patients, the preoperative De Ritis ratio is not significantly correlated with disease risk categories, tumour characteristics, or recurrence or progression scores. As a result, the De Ritis ratio falls short of outperforms existing prognostic models. More robust results may be obtained from prospective studies with longer follow-up durations that also evaluate routine biochemical markers, such as albumin, C-reactive protein, and NLR, in various cancer types.


Publication: The results of the study were not published in full or in part in form of abstracts.

Contribution: There is not any contributors who may not be listed as authors.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.


Ethics Committee Approval: The Medical Specialization Education Board of Samsun Training and Research Hospital granted clearance for this retrospective study with the number 203 dated 26.12.2017. The Dean of the Faculty of Medicine of the University of Health Sciences authorized this clearance with decision number 2018/4 dated 22.01.2018.

Informed Consent: Retrospective study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: R.İ., Design: R.İ., A.B., Supervision: A.B., M.A., Data Collection-Processing: E.K., Analysis-Interpretation: M.A., Literature Review: M.K.A., L.İ., Writing: R.İ., Critical Review: M.K.A., L.İ.

  1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-386.
  2. Compérat E, Larré S, Roupret M, et al. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. Virchows Arch 2015;466:589-594.
  3. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. Eur Urol 2006;49:466-477.
  4. van Rhijn BWG, van der Poel HG, van der Kwast TH. Urine Markers for Bladder Cancer Surveillance: A Systematic Review. Eur Urol 2005;47:736-748.
  5. Ozer J, Ratner M, Shaw M, et al. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008;245:194-205.
  6. De Ritis F, Coltorti M, Giusti G. An enzymic test for the diagnosis of viral hepatitis: The transaminase serum activities. Clin Chim Acta 1957;2:70-74.
  7. Botros M, Sikaris KA. The De Ritis Ratio: The Test of Time. Clin Biochem Rev 2013;34:117-130.
  8. DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 2007;104:19345-19350.
  9. House SW, Warburg O, Burk D, Schade AL. On Respiratory Impairment in Cancer Cells. Science 1956;124:267-272.
  10. Chang SG, Lee JH, Hong DH, et al. Comparison of glucose-consumption and thymidine-incorporation endpoints in histocultured human superficial bladder tumors. Anticancer Res 1994;14:77-83.
  11. Rawson NS, Peto J. An overview of prognostic factors in small cell lung cancer. A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br J Cancer 1990;61:597-604.
  12. Stocken DD, Hassan AB, Altman DG, et al. Modelling prognostic factors in advanced pancreatic cancer. Br J Cancer 2008;99:883-893.
  13. Tan X, Xiao K, Liu W, et al. Prognostic factors of distal cholangiocarcinoma after curative surgery: a series of 84 cases. Hepatogastroenterology 2013;60:1892-1895.
  14. Angelika B, Edvin M, Daniel K, et al. The Preoperative AST/ALT (De Ritis) Ratio Represents a Poor Prognostic Factor in a Cohort of Patients with Nonmetastatic Renal Cell Carcinoma. J Urol 2015;194:30-35.
  15. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998;22:1435-1448.
  16. Brierley JD, Gospodarowicz MK, Wittekind C, Eds. TNM Classification of Malignant Tumours. 8th Edition, Hoboken: Wiley-Blackwell; 2016.
  17. Babjuk M, Burger M, Compérat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol 2019;76:639-657.
  18. Xylinas E, Kent M, Kluth L, et al. Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. Br J Cancer 2013;109:1460-1466.
  19. Kamat AM, Vlahou A, Taylor JA, et al. Considerations on the use of urine markers in the management of patients with high-grade non-muscle-invasive bladder cancer. Urol Oncol 2014;32:1069-1077.
  20. Hsu PP, Sabatini DM. Cancer Cell Metabolism: Warburg and Beyond. Cell 2008;134:703-707.
  21. Heiden MG Vander, Cantley LC, Thompson CB. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 2009;324:1029-1033.
  22. Sookoian S, Pirola CJ. Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine. World J Gastroenterol 2015;21:711-725.
  23. Laukhtina E, Mostafaei H, D’Andrea D, et al. Association of De Ritis ratio with oncological outcomes in patients with non-muscle invasive bladder cancer (NMIBC). World J Urol 2020;39:1961-1968.
  24. Chen SL, Li JP, Li LF, et al. Elevated Preoperative Serum Alanine Aminotransferase/Aspartate Aminotransferase (ALT/AST) Ratio Is Associated with Better Prognosis in Patients Undergoing Curative Treatment for Gastric Adenocarcinoma. Int J Mol Sci 2016;17:911.
  25. Lee H, Choi YH, Sung HH, et al. De Ritis Ratio (AST/ALT) as a Significant Prognostic Factor in Patients With Upper Tract Urothelial Cancer Treated With Surgery. Clin Genitourin Cancer 2017;15:e379-385.
  26. Cho YH, Hwang JE, Chung HS, et al. The De Ritis (aspartate transaminase/alanine transaminase) ratio as a predictor of oncological outcomes in patients after surgery for upper urinary tract urothelial carcinoma. Int Urol Nephrol 2017;49:1383-1390.
  27. Wang H, Fang K, Zhang J, et al. The significance of De Ritis (aspartate transaminase/alanine transaminase) ratio in predicting pathological outcomes and prognosis in localized prostate cancer patients. Int Urol Nephrol 2017;49:1391-1398.
  28. Gorgel SN, Kose O, Koc EM, et al. The prognostic significance of preoperatively assessed AST/ALT (De Ritis) ratio on survival in patients underwent radical cystectomy. Int Urol Nephrol 2017;49:1577-1583.
  29. Nishikawa M, Miyake H, Kurahashi T, Fujisawa M. Significance of multiple preoperative laboratory abnormalities as prognostic indicators in patients with urothelial carcinoma of the upper urinary tract following radical nephroureterectomy. Int J Clin Oncol 2017;23:151-157.
  30. Nishikawa M, Miyake H, Fujisawa M. De Ritis (aspartate transaminase/alanine transaminase) ratio as a significant predictor of recurrence-free survival in patients with upper urinary tract urothelial carcinoma following nephroureterectomy. Urol Oncol Semin Orig Investig 2016;34:417.e9-417.e15.