Abstract
Background:
The aspartate transaminase (AST)/alanine transaminase (ALT) ratio, also termed the De Ritis ratio, has been demonstrated to have an association with poor prognosis in several cancer types. However, its prognostic value in patients with myelodysplastic syndrome (MDS) remains unclear.
Methods:
A total of 265 MDS patients were divided into two groups by R. The clinical, laboratory, and follow-up data of patients with MDS were collected, while the relationship between AST/ALT ratio and overall survival (OS) and leukemia-free survival (LFS) were also analyzed.
Results:
The results showed that higher AST/ALT ratio was associated with higher age, β2-microglobulin level, and number of co-mutations (>4). Moreover, the high AST/ALT group had a significantly shorter OS and LFS than the low AST/ALT group. Multivariate analysis involving the Revised International Prognostic Scoring System (IPSS-R) showed that a higher AST/ALT ratio was an independent adverse factor for OS or LFS; however, the same was not noted in the multivariate analysis involving the new Molecular International Prognostic Scoring System (IPSS-M).
Conclusions:
Our study suggests that the AST/ALT ratio could be a simple and economic prognostic indicator for MDS and be used as a supplement to IPSS-R, especially when lacking of karyotype or mutation data.
Introduction
Myelodysplastic syndromes (MDS) are a group of myeloid clonal diseases derived from hematopoietic stem cells characterized by dysplasia, ineffective hematopoiesis in the bone marrow, and a high risk of transformation to acute myeloid leukemia (AML) (Platzbecker et al. Citation2021). The prognosis of patients with MDS is highly heterogeneous, and its assessment systems, such as the International Prognostic Scoring System (IPSS), World Health Organization (WHO) Classification-based Prognostic Scoring System, MD Anderson Risk Model Score, Revised IPSS (IPSS-R), and recent IPSS-M, are being updated (Greenberg et al. Citation1997; Bernard et al. Citation2022). However, there are still new prognostic factors that are independent of these evaluation systems, such as micromegakaryocytes in the bone morrow (BM) (Saumell et al. Citation2022) and inflammatory indices in the peripheral blood (Shi et al. Citation2022).
Aminotransaminases, including aspartate transaminase (AST) and alanine aminotransferase (ALT), are the biomarkers of liver injury. The AST/ALT ratio, also termed the De Ritis ratio, is initially proposed for discriminating viral hepatitis from other icteric diseases (De Ritis et al. Citation1957) and is also used as an indicator for predicting non-liver diseases, such as the risk of gestational diabetes mellitus (An et al. Citation2022), prognosis of acute ischemic stroke (Ahmadabad et al. Citation2022), and occurrence of Kawasaki disease (Cao et al. Citation2021). Interestingly, the AST/ALT ratio is also associated with the progression of some cancers. Knittelfelder O, et al. (Knittelfelder et al. Citation2020) reported that the AST/ALT ratio is an independent prognostic factor for cancer-specific survival (CSS) in oral and oropharyngeal cancer. A recent study demonstrated that an elevated AST/ALT ratio predicts a shorter disease-free survival in patients with stages II and III non-metastatic colorectal cancer (Scheipner et al. Citation2021). In addition, a higher AST/ALT ratio is associated with worse overall survival (OS) and a higher 90-day mortality rate after surgery for bladder cancer (Ghahari et al. Citation2022). However, whether the AST/ALT ratio is associated with the prognosis of MDS remains unclear. Hence, in our study, 265 MDS patients were retrospectively to determine whether the AST/ALT ratio played a role in the progression of MDS.
Materials and methods
Patients
The clinical and follow-up data of 265 patients diagnosed with primary MDS at the First Affiliated Hospital of Ningbo University from 2009 to 2021 were retrospectively collected. Diagnosis and classification of MDS and leukemic transformation were made according to the Revised 4th Edition and the 5th Edition of the The World Health Organization (WHO) Classification of Haematolymphoid Tumours (Arber et al. Citation2016; Khoury et al. Citation2022). Risk stratification of MDS was performed using IPSS-R or IPSS-M. A total of 127 patients received further treatment, of whom 44 (15.1%) received intensive chemotherapy, 20 (6.9%) received hematopoietic stem cell transplantation (HSCT), and 63 (21.5%) received hypomethylating agents (HMAs). The pretreatment AST and ALT levels of all patients were measured using biochemical examinations. Patients with a previous history of liver disease or an ALT level ≥40 U/L were excluded. Using R software analysis, all 265 patients with MDS were categorized into two groups by using a cutoff value of 1.19 for the AST/ALT ratio. Written informed consents were obtained at the time of clinical care from all subjects or their legal guardians for the future use of their data for research purposes. This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Ningbo University (Ningbo first hospital) and conducted in accordance with the Declaration of Helsinki.
AST/ALT ratio assay
Serum AST and ALT levels were assessed by using malate dehydrogenase and lactate dehydrogenase method, respectively. The reagents were tested using an automatic biochemical analyzer (Beckman AU5800) according to the instructions of the Kit For AST or ALT Assay (Beckman Coulter, USA). And the AST/ALT ratio was calculated automatically by Beckman AU5800.
Cytogenetic analysis and fluorescence in situ hybridization analysis
BM cells were collected and cultured in RPMI-1640 medium supplemented with 20% newborn calf serum for at least 16 hours. The R-banded karyotype was described according to the International System for Human Cytogenetic Nomenclature (Citation2020) (ISCN Citation2020). Fluorescence in situ hybridization (FISH) was performed on BM cells according to the manufacturer’s instructions for the TP53 gene probe (Guangzhou LBP Medicine Science and Technology Company, China). Signals on 200 metaphase or interphase nuclei were analyzed.
Mutational analysis
Mutational analysis was performed at the Wuhan Kangshengda Medical Laboratory (China), with an average sequencing depth of 2000×, and a variant allele frequency (VAF) > 2% was considered positive. Mutational analyses of 14 and 34 common MDS genes were performed in 20 and 87 patients, respectively. The panel of 14 common MDS genes comprised NRAS, DNMT3A, SF3B1, IDH1, TET2, EZH2, JAK2, CBL, ETV6, IDH2, TP53, SRSF2, ASXL1, and RUNX1. The panel of 34 common MDS genes comprised BCOR, BCORL1, CALR, CEBPA, CSF3R, ETNK1, FLT3, KIT, NF1, NPM1, PHF6, PIGA, PTPN11, SETBP1, STAG2, U2AF1, WT1, ZRSR2, MPL, and KRAS, in addition to the above mentioned 14 genes.
Statistical analysis
Statistical analyses were performed using SPSS 22.0 software. OS was determined from the date of initial diagnosis of MDS to the date of death, last follow-up, or receiving allogeneic HSCT (allo-HSCT), whichever occurred first. Leukemia-free survival (LFS) was defined as the period from the date of diagnosis to the date of leukemia transformation, death, last follow-up, or receiving allo-HSCT, whichever occurred first. OS and LFS were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards regression model. Differences in the distribution of continuous variables between categories were analyzed using the Mann–Whitney U test, and those for categorical variables were analyzed using the chi-square test. A P-value of <0.05 was considered statistically significant.
Results
Patient characteristics
A total of 265 patients with MDS, including 109 females and 156 males, were enrolled in this study. The median age of these patients was 63 (range: 16 to 91) years. The median OS was 28.07 (range: 0.30–126.83) months, and 31 patients (11.70%) progressed to AML. Table presents information on classification and risk stratification according to the 2016 and 2022 WHO MDS classifications, IPSS-R, and IPSS-M.
Table 1. AST/ALT ratio in relation to clinical and laboratory features in MDS patients.
Association of the AST/ALT ratio with clinical and laboratory factors
Age (P < 0.001) and β2-microglobulin (β2-MG) serum levels were significantly higher in the high AST/ALT group than in the low AST/ALT group (P < 0.001). However, no significant differences were noted in other factors such as sex, absolute neutrophil count (ANC), hemoglobin level (HB), lactate dehydrogenase (LDH) level, WHO subtype distribution, and IPSS-R and IPSS-M risk stratification (P>0.05) (Table ).
Association between the AST/ALT ratio and mutations
Mutations were detected in 107 patients, and 84 (78.51%) of these patients harbored at least one mutation. The most common mutation was ASXL1 mutation (27.1%), followed by RUNX1 (15.89%), U2AF1 (14.94%), TET2 (14.02%), TP53 (11.93%), STAG2 (9.20%), SF3B1 (8.41%), ZRSR2 (8.05%), and NF1 (8.05%) mutations. The high AST/ALT group had a lower U2F1 mutation rate than the low AST/ALT group (1.28% vs. 10.09%, P = 0.001). However, no significant differences were noted in other mutations between the groups (P > 0.05) (Figure A). A previous study has demonstrated that the number of mutations is closely associated with the prognosis of MDS (Bejar Citation2014). In our study, the proportion of co-mutations (in >4 genes) was significantly higher in the high AST/ALT group than in the low AST/ALT group (10.71% vs. 0.00%, P = 0.028).
Figure 1. Gene mutation distribution and survival analysis. (A) Common genes carrying mutations in MDS patients. (B) Overall survival of 265 patients with primary MDS stratified by AST/ALT ratio ≤1.19 vs AST/ALT ratio >1.19 (P = 0.013). (C) Leukemia-free survival of 265 patients with primary MDS stratified by AST/ALT ratio ≤1.19 vs AST/ALT ratio >1.19 (P = 0.044).
Association between high AST/ALT ratio and worse prognosis
The median OS was 22.67 months (95% confidence interval [CI] 15.47–29.87) in the high AST/ALT group, which was significantly shorter than that in the low AST/ALT group (82.83 months, 95% CI 22.21–143.45, P = 0.013; Figure B). Furthermore, the high AST/ALT group had a shorter LFS (median: 20.43 months, 95% CI 6.57–34.29) than the low AST/ALT group (median: 45.57 months, 95% CI 0.00–92.94, P = 0.044; Figure C).
In the multivariate analysis involving IPSS-R, besides sex (male), age (>60 years), higher-risk IPSS-R, β2-MG level (>3 μg/L), and LDH level (>250/U/L), a high AST/ALT ratio (>1.19) was identified as an independent adverse prognostic factor (P = 0.016). For LFS, a high AST/ALT ratio (>1.19; P = 0.029), sex (male; P = 0.013), age (>60 years; P = 0.016), higher-risk IPSS-R (P < 0.001), and high LDH level (>250/U; P = 0.002) were associated with poor prognosis (Table ). In multivariate analysis involving IPSS-M, higher-risk IPSS-M and high LDH level (>250U/L) were found to be significant prognostic factors for worse OS and LFS (Table ).
Table 2. Multivariate analyses involving IPSS-R for overall survival and leukemia-free survival in primary MDS patients.
Table 3. Multivariate analyses involving IPSS-M for overall survival and leukemia-free survival in primary MDS patients.
Discussion
In our cohort, a higher AST/ALT ratio was associated with older age, a higher β2-MG level, and a higher number of co-mutations (>4). Age is an important prognostic predictor that has been included in the recent IPSS-M (Bernard 2022). Elderly patients with MDS harbor a higher number of gene mutations than younger patients (Wu et al. Citation2022). Moreover, the higher the number of mutations present in patients with MDS, the worse their prognosis is (Bejar Citation2014). Hence, these findings indicate that a high AST/ALT ratio may predict poor prognosis in MDS.
MDS has a vast genetic and biological heterogeneity that affects the disease survival (Hellström-Lindberg et al. Citation2020). IPSS-R was widely adopted for the evaluation of MDS risk stratification for a decade. However, recently, new prognostic factors, such as fetal hemoglobin, erythroferrone, and micromegakaryocytes, have been identified (Riabov et al. Citation2021; Hara et al. Citation2022; Saumell et al. Citation2022). In this study, a high AST/ALT ratio was found to be an adverse indicator for OS and LFS. To the best of our knowledge, no previous report has described an association between the AST/ALT ratio and prognosis of MDS.
The most widely used IPSS-R has five assessment factors: neutrophil, platelet, and hemoglobin levels in the peripheral blood; percentage of BM blasts; and type and number of chromosomal abnormalities (Schanz et al. Citation2012). IPSS-M includes age, VAF and number of TP53 mutations, status of MLL partial tandem duplication (MLL-PTD), FLT3 internal tandem duplication (ITD) or mutation in the tyrosine kinase domain (TKD), and status of other 28 gene mutations, in addition to the five factors in IPSS-R (Bernard 2022). A study comparing the two prognostic scoring systems reported an advantage for IPSS-M over IPSS-R in patients with MDS aged ≥60 years, whereas the opposite result was noted in patients aged <60 years (Wu et al. Citation2022), indicating that both prognostic scoring systems are complementary to each other in clinical practice. Although IPSS-M was developed using data from a large scale patients from 24 centers, in some specific subsets of patients, such as those treated with HMAs, IPSS-M has not been verified yet (Garcia-Manero Citation2023).
In our study, multivariate analyses showed that the AST/ALT ratio was an independent indicator for OS or LFS when IPSS-R was involved but not when IPSS-M was involved. Hence, a multicenter study with a larger sample and perfect mutation panel sequencing is warranted to assess the independent prognostic value of the AST/ALT ratio using IPSS-M. Nevertheless, the AST/ALT ratio is a simple and useful indicator for the prognosis of MDS when IPSS-M cannot be used because TP53 deletion using FISH or mutation analysis is not performed.
Although the AST/ALT ratio is associated with the prognosis of a variety of malignancies (Knittelfelder et al. Citation2020; Riedl et al. Citation2020; Durhan et al. Citation2021; Ghahari et al. Citation2022), the exact mechanism underlying this association remains unclear. ALT and AST are primarily present in the liver and commonly used as biomarkers of liver damage. Moreover, AST is expressed in other tissues such as cardiac and skeletal muscles (Levey et al. Citation1999; Schindhelm et al. Citation2006). Recently, researches on energy metabolism in cancer has become popular, which has revealed that glycolytic metabolites increase in order to generate more ATP for cell growth in several malignant cells (Abbaszadeh et al. Citation2020). Increased extra-mitochondrial glucose catabolism has also been identified in patients with MDS and leukemia (Song et al. Citation2020; Balaian et al. Citation2021). In addition to glycolytic metabolites, glutaminolysis plays a critical role in the survival and growth of cancer cells (Yang et al. Citation2017), and AST is an important enzyme in glutaminolysis (Otto-Ślusarczyk et al. Citation2016). A study by Lu et al. (Lu et al. Citation2019) on diffuse large B-cell lymphoma (DLBCL) showed that higher AST levels were closely associated with advanced-stage DLBCL and indicated a shorter OS.
The present study has several limitations. First, in our cohort, more than half of the patients lacked mutation data mainly because gene mutation analysis was not performed before 2015. Second, this was a single-center, retrospective observational study, and further multicenter, prospective studies are warranted.
In summary, high AST/ALT ratio could be an independent adverse prognostic factor in MDS patients. The AST/ALT ratio is a simple and economic indicator for the prognosis measure of MDS patients and a useful supplement to IPSS-R, especially when patients with MDS lack karyotype or mutation data.
Author contributions
YC and YW were involved in the conception and design. Data acquisition was performed by TC. Analysis and interpretation of the data was performed by DZ, CS, and NW. The drafting of the paper was revised critically for intellectual content by QM and GO. LS carried out additional analyses and finalized this paper. All authors agree to be accountable for all aspects of the work.
Ethics approval and consent to participate
The project was approved by the Ethics Committee of the First Affiliated Hospital of Ningbo University (2023RS017) and was in accordance with the Declaration of Helsinki. All co-authors were included in this authorization request to have access to the data. All methods were carried out in accordance with relevant guidelines and regulations and all experimental protocols were approved by the First Affiliated Hospital of Ningbo University. Written informed consents were obtained at the time of clinical care from all subjects or their legal guardians for the future use of their data for research purposes. The ethics committee waived the need for additional informed consent due to the retrospective nature of the study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available at https://doi.org/10.17632/ntvnbvnznm.2.
Additional information
Funding
References
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