We detected that the frequency of NODAT was 70% on 1st day, decreased progressively during follow-up, and it was detected in a minority of survivors on 12th month. Those without diabetes on the 1st month had almost stable normoglycemia on 12th month. We showed that pretransplant hyperglycemia increased the risk of NODAT by 4 times, but pretransplant hypoglycemia was not a predictor for NODAT.
Several pretransplant (age, family history of diabetes, obesity, prediabetes, hypertension, dyslipidemia, HCV infection) and posttransplant (immunosuppressive drugs such as calcineurin inhibitors, tacrolimus, cyclosporine, glucocorticoids, and CMV infection, cytokines or acute rejection) risk factors had been shown to be risk factor for post-transplant diabetes mellitus [19-28]. Some studies investigated these risk factors in specific population undergoing LTx [7,29,30]. However, in these studies, the indication of LTx consisted of both acute and chronic liver failure. There is no report that examine the development of NODAT only in the patients with ALF in particular. We analyzed the possible predictors of NODAT in the patients undergoing LTx due to ALF.
In ALF, hypoglycemia may be observed due to depleted glycogen stores, and a defect in glycogenolysis and gluconeogenesis [31]. Increased level of serum insulin may also contribute to the development of hypoglycemia in ALF [32-34]. The frequency of hypoglycemia was shown as high as 45% in this patient population [14-16]. We proposed that preoperative catabolic state contributing hypoglycemia might continue after LTx, and hence, might blunt possible posttransplant hyperglycemia in the patients with ALF. However, we found that preoperative hypoglycemia was not associated with posttransplant DM. The frequency of hypoglycemia was 7.6% in our study and lesser than previous studies. However, we did not analyze all the patients admitted to our clinics with ALF, but we evaluated only the patients who underwent LTx due to ALF. We analyzed the predictors of NODAT according to FBG on the 1st month, and the mortality rate on the 1st month was 30.76%. The mortality rate was higher in the patients having pretransplant hypoglycemia than in the rest of the group (42.85 vs 29.76%). Therefore, the possible effect of pretransplant hypoglycemia on the development of NODAT might be underestimated. Together with this, analysis the 1st day FBG also showed that pretransplant hypoglycemia was not a significant predictor for the development of NODAT. Multicenter studies including a large population will clearly identify this issue.
Perioperative hyperglycemia was known as a risk factor for the development of NODAT [20,35]. In one study, transplant candidates with impaired glucose tolerance which was detected by glucose load were found to have an increased risk for posttransplant diabetes [36]. We showed that pretransplant hyperglycemia increased NODAT by approximately 4-fold. However, we could not perform oral glucose tolerance test because of unstable clinical condition. We evaluated preoperative glycemic status only by random blood glucose measurement. Independent of subgroups, pretransplant RBG was positively correlated with 1st or 3rd month FBG. Moreover, none of the patients having normal FBG on the 1st month did develop NODAT until 12th month. Hence, our findings suggested that pre- and post-transplant glycemic management is so important to prevent the development of NODAT at each period of the follow-up. It should be kept in mind that constitution of stable pretransplant glucose level in such a patient with ALF might be complicated.
Timing of the test for diabetes mellitus may affect the diagnosis of NODAT and hence the frequency of NODAT in transplant patients [2]. Perioperative stress may result in acute postoperative hyperglycemia. The effect of immunosuppressive drugs on glycemic status in the postoperative period may alter during the follow-up. Spontaneous remission may be observed in some patients with NODAT, especially after tapering dose of immunosuppressive drugs [37]. In some studies, analyzing renal transplant patients, NODAT was divided as early-onset, late-onset or temporary [38]. It may be thought that evaluation of post-transplant diabetes mellitus would be done under more stable clinical conditions. If rejection or surgical complications are not observed, most of the patients recovered from transplantation at the end of the 1st month [2]. Based on these reports, we evaluated and analyzed the predictors of NODAT which was diagnosed according to the 1st month FBG. We found the frequency of NODAT as 67.03% on the 1st day, 58.75% on the 1st week, 26.98% on the 1st month. So, our findings suggested the temporary alteration of NODAT. NODAT was detected in 8.3% among the survivors on 12th month. None of the patients having normal FBG on the 1st month did develop NODAT until 12th month; therefore, normoglycemia on the 1st month might point stable FBG during follow-up. We may say that if posttransplant normoglycemia is constituted in the early postoperative period, it will be stable during the follow-up. We measured only FBG after LTx; however, we could not perform glucose load or HbA1c in our study.
Pretransplant obesity or higher age, or gender were defined as risk factors for the development of NODAT [2]. Our findings showed that obesity, gender or older age (>40) were not as significant predictors for NODAT. In one study, posttransplant 12th month BMI was also shown as an important factor for NODAT after LTx [7]. However, we could not analyze posttransplant BMI level of the patients. Sick euthyroid syndrome was frequently observed in chronic liver disease, and free T3 level was shown to be corrected after LTx in several studies [30,39]. In one study, free T3 was significantly lower in the patients with HBV related acute-on-chronic liver failure than in chronic HBV infection [40]. Systematic analysis of thyroid function tests in ALF is limited in the literature. Anastasiou et al. investigated thyroid function in ALF, and showed that the patients who recovered from ALF had higher TSH, total T4 and T3 levels than the patients undergoing LTx or died from ALF [41]. We showed that subclinical thyrotoxicosis was found in 15.38% of the patients, but according to 1st day or 1st month FBG, it was not a significant predictor for NODAT. We did not analyze the association between thyroid function and mortality; however, 8 patients with pretransplant subclinical thyrotoxicosis died in 1st month of LTx.
Strength and Limitations
There is no report that examine the development of NODAT only in the patients with ALF in particular. We analyzed the possible predictors of NODAT only in the patients undergoing LTx due to ALF. We did not analyze the patients with ALF whom LTx was unnecessary or unavailable, but we evaluated only the patients who underwent LTx due to ALF. So, the frequency of hypoglycemia, or the frequency of ALF due to acetaminophen were not predictable. We could not perform oral glucose tolerance test or HbA1c measurement because of unstable pretransplant clinical condition, we evaluated pretransplant glycemic status only by random blood glucose measurement. Based on the reports, we evaluated and analyzed the predictors of NODAT which was diagnosed according to the 1st month FBG. Our study was designed as a retrospective manner, because prospective study might be difficult in such a clinical condition of ALF. Further clinical studies analyzing the development of NODAT in a large cohort of patients with LTx for a longer period will clarify the unexplained issues.