Interpretation
The negative correlation between the preoperative serum ALT level and postoperative mortality may be contrary to most clinicians’ expectations and seems paradoxical. ALT is a liver-specific enzyme, so serum ALT elevation is a predominant marker of liver cell damage, which has been postulated to have a negative impact on postoperative outcome. Surprisingly, our results suggest that postoperative survival was not worse in patients with high preoperative ALT, but was worse in those with low ALT. This is consistent with the results of previous studies of the general population. The inverse relationship between serum ALT and mortality was first reported in 2006 by Elinav et al. [10], and subsequent studies validated this concept in different cohorts [4, 11, 12, 17–19]. Meta-analyses also confirmed that low serum ALT levels were associated with increased overall and cardiovascular mortality in older populations [2, 3]. Similar results were reported in patients with heart failure [20], diabetes [21], and previous myocardial infarction or stroke [4]. The exact mechanism involved in the relationship between low serum ALT levels and increased mortality has not yet been elucidated. However, previous researchers have postulated that low ALT levels might be a marker of hepatic aging and frailty, since low ALT is more strongly associated with risk of death in the elderly [2, 3]. Serum ALT was substantially lower in older patients, and low ALT may reflect hepatic aging, which accompanies a decrease in liver volume and functional liver cells [10, 11, 22]. Furthermore, decreased ALT levels were associated with frailty as defined by Fried’s frailty criteria and a frailty questionnaire score (FRAIL scale: Fatigue, Resistance, Ambulation, Illnesses, and Loss of Weight) [11, 12, 23]. A recent study also showed that low ALT levels were linked with sarcopenia, a common condition in frail patients [12]. Our results showed the association of ALT with postoperative mortality was more significant in older patients. Hence, it may be plausible that low ALT could be a marker of frailty and liver aging. Another possible explanation is that low ALT may represent poor nutritional status [10, 12, 20]. Vitamin B6 deficiency, which is commonly accompanied by malnutrition, decreases serum ALT levels by reducing hepatic ALT synthesis [24]. In addition, vitamin B6 deficiency results in further lowering the detected level of serum ALT, as the serum ALT assay requires sufficient vitamin B6 in the patient’s serum as a cofactor [24]. Another noteworthy result from our study was that low ALT predicted postoperative mortality, despite the lack of significant associations with other specific major adverse events. Thus, low ALT levels may reflect a diminished physiological reserve to recover from postoperative insults, rather than predicting certain complications.
Similarly, AST appears to have an inverse association with postoperative mortality at low levels. Although the available literature related to ALT is more extensive, the relationship between low AST and increased mortality has been reported in previous studies [4, 18]. Decreased survival may be due to hepatic aging and patient vulnerability, as observed in patients with low ALT. Conversely, high AST levels showed a positive association with postoperative mortality. Considering the low liver specificity of AST and the low mortality rate in the high ALT group from our results, hepatic disease may not be the cause of the increased mortality observed in the high AST level group. Indeed, AST is one of the cardiac markers [25], and elevated AST levels may indicate a hypoperfusion state due to cardiac dysfunction [8, 20]. Thus, the increased mortality associated with high AST levels may result from underlying cardiac dysfunction and myocardial damage. The increased number of major adverse cardiovascular events in the high AST group may support this explanation. However, the U-shaped relationship between preoperative AST and postoperative mortality was not significant after adjustment with possible confounders. Other known risk factors in cardiovascular surgery may act as confounders due to the organ non-specificity of AST. Therefore, given AST’s lack of organ specificity and the availability of more specific markers, such as troponin I, creatine kinase-muscle/brain, and ALT, the usefulness of AST alone as a predictor of postoperative mortality in cardiovascular surgery may be inadequate.
Finally, the De Ritis ratio showed a positive independent association with postoperative mortality. It seems plausible because ALT has a negative correlation with postoperative mortality and the increasing trend of mortality was observed in the high AST group. This result is in line with previous studies reporting the De Ritis ratio as a predictor of mortality after urologic cancer surgery [13, 14]. However, previous studies have only focused on the numerator of the ratio and explained that the increased De Ritis ratio reflects increased AST activity resulting from anaerobic metabolism of cancer cells. Considering the previously described importance of low ALT, the De Ritis ratio should also be interpreted with regard to the denominator. Taken together, the De Ritis ratio may be a composite marker that reflects cardiac status for a given patient’s vulnerability and may be a useful predictor of postoperative mortality and morbidity in cardiovascular surgery.
Clinical implications
First, our results suggest new insights into the preoperative serum aminotransferase levels in cardiovascular surgery. Most perioperative clinical interest has focused on elevated serum aminotransferase levels. Nearly all clinicians often consider normal serum aminotransferase levels to reflect a healthy liver, but this may not be true. Our results suggest that clinicians should pay closer attention to low ALT levels and high De Ritis ratios in patients requiring cardiovascular surgery, particularly in the elderly. As the number of elderly individuals requiring cardiovascular surgery increases, determining the most appropriate intervention for older patients has become a critical clinical issue. To gain further insight into this issue, interest in biological age, rather than chronologic age, and frailty of the elderly has been increasing. Several scoring systems and assessment tools have been proposed, but the expense of time and resources makes it difficult to utilize these methods with all surgical procedure candidates [26]. Thus, there has been a demand to develop a simple method to assess frailty, such as using ICD-10 codes [27]. In this respect, the use of serum aminotransferase levels has the advantage of being easy to evaluate at a low cost; it may become a relevant risk factor that reflects hepatic aging and overall frailty in cardiovascular surgery. However, this concept should be validated in further studies under different settings.
Second, mild serum aminotransferase elevation appears to have a limited association with poor postoperative prognosis in cardiovascular surgery. Thus, delaying surgery to perform an additional evaluation of the liver may be not necessary for patients asymptomatic of liver disease. Indeed, it has been recommended that patients can proceed to surgery without additional tests if AST and ALT levels are less than twice the upper normal limit [28]. However, this recommendation was not based on high-quality evidence [5]. Others have recommended postponing elective surgery until the determination of the etiology or resolution of the elevated aminotransferase [29]. The results of our study, the comparable prognosis of high ALT with that of normal range, may assist clinicians in determining patients’ prognosis and reduce wasted resources, overspending, and patient anxiety. However, careful review of medical history and physical examinations should always be a requirement in patients with elevated aminotransferase.
Limitations
First, we cannot provide a precise mechanism for the relationship between preoperative serum aminotransferase and postoperative mortality due to the retrospective study design. Although we used nearly 30 variables available in our database for adjustment, some possible confounders, including liver volume, vitamin B6 level, nutritional status, and sarcopenia, could not be collected. Therefore, further studies are required to explore underlying mechanisms, especially modifiable ones, such as vitamin B6 deficiency and poor nutritional status.
Second, it is unclear whether our results may be generalized for patients whose preoperative serum aminotransferase levels are more than twice the upper normal limit. Indeed, we anticipated performing additional sensitivity analyses for aminotransferase levels more than twice the upper normal limit. However, even after the inclusion of 6264 patients, the number of patients with such high preoperative serum aminotransferase levels was less than 100 (1.6%). Thus, it was difficult to precisely analyze risk in these groups, and the confidence interval in the continuous analysis was also very wide in this range. Furthermore, not all patients with aminotransferase levels more than twice the upper normal limit proceeded to surgery, and some patients underwent the procedure only after normalization of aminotransferase levels. This may represent a selection bias. Therefore, our results should be interpreted with caution for preoperative serum aminotransferase levels above twice the upper normal limit.