Preoperative aspartate transaminase/alanine transaminase ratio as a prognostic biomarker in primary non-muscle-invasive bladder cancer: a propensity score-matched study

Bladder cancer is one of the most prevalent cancers in the urinary tract and the seventh most common tumor in the male population worldwide, while it drops to the 11th if both genders are considered [1, 2]. Approximately 75% of patients with bladder cancer present with disease confined to the mucosa or submucosa, which is referred to as non-muscle-invasive bladder cancer (NMIBC) and this proportion is even higher in younger patients (< 40 years) [3]. The standard treatment for NMIBC is transurethral resection of bladder tumor (TURBT), eventually followed by adjuvant intravesical therapy based on risk stratification [4]. However, the high recurrence rate of NMIBC patients is as high as 50–70% and one-third of recurrent patients will develop into muscle-invasive bladder cancer (MIBC) and eventually succumb to the disease [5, 6]. To better predict the recurrence and progression of NMIBC, several biomarkers, such as serum cholinesterase, neutrophil-to-lymphocyte ratio, plasma fibrinogen, and D-dimer, have been studied [7‐9]. Nevertheless, our knowledge of plasma prognostic factors assessed preoperatively in NMIBC remains limited.

Aspartate transaminase (AST) and alanine transaminase (ALT) are found in the liver, heart, skeletal muscle, brain, kidney, and red blood cells, which are widely used to reflect hepatocellular damage in clinical practice. In 1957, the ratio of the serum activities of AST to ALT was first described as an important indicator for differentiating the etiology of acute hepatitis by De Ritis et al., which was also called the De Ritis ratio [10]. The AST/ALT ratio was widely used to identify various liver diseases such as viral hepatitis and alcoholic hepatitis. Meanwhile, the latest research shows that this ratio has been reported as a prognostic biomarker in several malignancies, such as renal cell carcinoma, lung cancer, pancreatic cancer, and colorectal cancer [11‐15]. Similarly, this ratio has been demonstrated as a significant prognostic biomarker in patients undergoing radical cystectomy with bladder cancer [16‐18]. Although their study was valuable for proposing the AST/ALT ratio as a new prognostic factor in BC, the molecular features and clinical outcomes between NMIBC and MIBC are highly distinct [19]. The prognostic predictive value of the AST/ALT ratio in primary NMIBC needs to be further clarified.

The purpose of this study was to evaluate the prognostic predictive value of the AST/ALT ratio on the survival prognosis of patients with primary NMIBC. A propensity score-matching (PSM) methodology was performed to minimize the interference of other confounding factors.

The serum levels of AST and ALT are biochemical markers widely used in clinical treatment to determine the liver function and to identify liver diseases such as viral hepatitis and alcoholic hepatitis. The AST is widely expressed in several organs, but ALT is s considered more liver-specific and enriched [21]. Thus, pathological conditions leading to a higher proliferative state, tissue damage, and high tumor cell turnover are likely to elevate AST rather than ALT, at least not to the same extent, making the AST/ALT ratio a novel potential biomarker in tumors.

In the present study, we find that the high AST/ALT ratio has independent predicting early disease relapse and progression value in primary NIMBC after PSM. In fact, several recent studies about the AST/ALT ratio all demonstrated that it could be considered as a significant prognostic biomarker in renal cell carcinoma, lung cancer, pancreatic cancer, and colorectal cancer. [11‐15]. Lee et al. indicated that the AST/ALT ratio (≥ 1.5) is an independent prognostic factor associated with a worse prognosis of disease progression, overall mortality, and cancer-specific mortality in patients with nonmetastatic renal cell carcinoma [12]. Moreover, Nishikawa et al. also first reported that the AST/ALT ratio was considered as an independent prognostic factor in upper tract urothelial cancer [22]. Similarly, Gorgel et al. [16] Ha et al. [17] and Yuk et al. [18] all concluded that the AST/ALT ratio was an independent prognostic predictor in patients undergoing radical cystectomy with bladder urothelial carcinoma. These findings are consistent with the results of our study. On the contrary, Cho et al. showed that the AST/ALT ratio was not significantly associated with RFS in upper urinary tract urothelial carcinoma [23]. This might be related to different diseases, different pathological states, as well as the selected population.

This study describes the AST/ALT ratio as a novel significant biomarker for predicting recurrence and progression in patients with primary NMIBC. However, the mechanism behind the relationship between NMIBC and AST/ALT ratio remains obscure and requires further research. Several hypotheses have been presented to explain this mechanism. The most famous of these hypotheses is the “Warburg effect.” In tumor cell metabolism, it produces enough adenosine triphosphatase (ATP) by increasing glucose uptake and anaerobic glycolysis to promote the multiplying of cancer cells [24]. Meanwhile, the accelerated glycolysis will promote the secretion of lactate. The study suggested that increased lactate plays an important role in maintaining glycolysis, affecting the ratio of lactate dehydrogenase and nicotinamide adenine dinucleotide (NADH)/NAD⁺ as well as the glucose transporter. [25]. It is known that AST plays an essential role in glycolysis by relocating NADH into the mitochondria by the malate-aspartate shuttle pathway. Consequently, cancer cell metabolism might be connected with the AST/ALT ratio in many glucose-using malignancies. Bladder cancer is considered as a glucose-reliant malignant tumor [26, 27]. Whyard et al. used fluorescence microscopy to investigate the uptake of fluorescent glucose by bladder cancer cells and found that there was a big difference in glucose consumption between normal urothelial and malignant urothelial cells [26]. Therefore, it is highly likely that the AST/ALT ratio is correlated with the prognosis of patients with primary NMIBC after TURBT, but our understanding of the mechanism behind it is so far limited.

Despite the current study showed novel findings, it has some limitations. First, this study was a retrospective analysis. Although all included patients received alike treatment, there were inevitably various inherent biases. Second, the AST/ALT rate was performed only once on the patient before TURBT and no comparative analysis was conducted at the interval of follow-up. Finally, it has the disadvantage of a single-center study and a small sample size. The results of this study need prospective larger studies to further consolidate, but this finding also would help clinicians in clinical decision making.

This study has shown that the high AST/ALT ratio group tended to have poorer RFS and PFS than the low AST/ALT ratio group. Meanwhile, our results also indicated that the elevated preoperative AST/ALT ratio could be regarded as a significant prognostic biomarker for predicting early disease recurrence and progression of patients with primary NMIBC after TURBT. The findings would further help clinicians in making clinical decisions.