Hyperglycemia is defined as any glucose value > 140mg/dl.1 It occurs in 32 to 38% of all hospitalized patients, 41% of all the critically ill, 44% of patients with heart failure, and up to 80% of patients after cardiac surgery; between 30 and 80% of those individuals have no history of diabetes.2 Stress hyperglycemia is that which presents in patients with no history of diabetes and is usually transitory. It is caused by counterregulatory hormones (such as cortisol and adrenaline) and by the increase in insulin resistance,3,4 but the most important factor appears to be hepatic gluconeogenesis.5 Hyperglycemia in the hospitalized patient, especially those that have undergone transplantation, can also be the consequence of the use of different types of medication, such as glucocorticoids and other immunosuppressant drugs.6,7

The long-term deleterious effects of hyperglycemia are well-known, especially those related to micro and macrovascular damage.8,9 In the context of the acute patient, hyperglycemia produces changes in the immune system10 and coagulation.11 In addition, fluctuations in glucose levels induce apoptosis in the endothelial cells, causing endothelial dysfunction. 12

In the patient with no history of diabetes, hyperglycemia is a mortality marker, especially in those patients in intensive care units (ICUs). It is also associated with longer periods of hospital stay and a greater risk for postoperative infection.13–15 Hyperglycemia has additionally been associated with adverse events in patients with acute myocardial infarction16–19 and with cerebrovascular disease (CVD).20,21

On the other hand, diabetes is a frequent comorbidity in patients on the liver transplantation waiting list, presenting in 65% of them.22 Despite this fact, there is scant evidence that hyperglycemia is a risk factor for negative outcomes in patients that have undergone transplantations, even though, in general, diabetes is associated with a worse outcome in liver transplantation patients. The prevalence of post-transplantation diabetes is as high as 31-38%,23 and these patients are at a higher risk for cardiovascular complications, such as high blood pressure and coronary disease, as well as a higher mortality rate, compared with those patients that do not develop diabetes.24,25 Likewise, patients that develop post-transplantation diabetes have a higher number of acute rejection episodes, and infectious and neurologic complications.26–28

Different mechanisms have been proposed by which hyperglycemia could produce graft damage and increase the risk for rejection. Hyperglycemia increases the co-stimulation and presentation of antigens, and increases ischemic damage29 and the inflammatory reaction associated with reperfusion;30 it increases cytokine production and adhesion molecule expression, as well as dendritic cell activation.31,32

Some observational studies have evaluated the impact of diabetes on patient survival and the risk for complications in the immediate post-transplantation period,26,33 whereas others have reported an association between hyperglycemia during the intraoperative period and the risk for postoperative infection and mortality at the first year follow-up.34,35 However, none of the studies took metabolic control into account during the immediate post-transplantation period; that has only been evaluated in patients that underwent bone marrow or kidney transplantation.36–39

Based on the above, we decided to conduct an observational study to determine whether there was an association between the increased glucose values during the first 48h after liver transplantation and the risk for early rejection, bacterial infection, or longer hospital stay. Our hypothesis was that the presence of sustained hyperglycemia during that period of time was associated with a greater risk for early rejection, a higher risk for nosocomial infection, and longer hospital stay.

The data of 316 patients that underwent liver transplantation were collected; 152 patients were excluded from the analysis due to a lack of glucose results at 48h after transplantation (n=142) and to death during the procedure or in the immediate postoperative period (n=10). The proportion of rejections in the excluded patients was 10.5% (n=16). Of the 164 patients analyzed, 108 (66%) were men and the mean age was 51±12.3 years. Table 1 shows the general population information.

According to the established definitions, 94% of the patients analyzed presented with at least one form of hyperglycemia: a minimum of one value above 140mg/dl in 154 patients and the mean of all the measurements > 140mg/dl in 140 patients. The mean glucose level at the time of ICU admission was 182±55mg/dl and the patients analyzed had glucose levels above 140mg/dl for an average 30% of the first 48h. In the bivariate analysis, hyperglycemia was not associated with a greater risk for rejection, infection, or longer hospital stay, regardless of its definition (table 2). The results did not vary in the analysis of those patients with no history of diabetes or those that had more than one glucose measurement in the first 48h (tables 3 and 4). None of the factors regarded as potential confounding variables (late commencement of calcineurin inhibitors, HLA histocompatibility, the reason for transplantation, sex, age, the need for transfusion, the use of total parenteral nutrition [TPN], or length of stay in the ICU) were associated with the risk for rejection or infection (data not shown).

No greater risk for infection (OR 2.3; 95% CI=0.48-10.9) or difference in the length of hospital stay (20.7 days vs 19 days) was found in the diabetic patients when compared with the non-diabetic ones. The proportion of diabetic patients on the transplantation waiting list was high (28%), and the quantity of patients that developed diabetes after transplantation was considerable (30%).

In our study, we attempted to clarify whether hyperglycemia, defined either as an isolated, mean, or time-weighted value, was associated with a greater risk for rejection, infection, or longer hospital stay. Our results showed that a large proportion of patients that underwent liver transplantation presented with some degree of hyperglycemia during the first 48h after transplantation and that an important number of those patients had elevated glucose values for the majority of that period. However, those high glucose values, whether isolated, mean, or weighted, were not associated with a higher risk for infection, rejection, or longer hospital stay. In addition, when a history of diabetes was taken into consideration, no greater risk for infection during the postoperative period was found.

According to previous studies on animal models and some clinical observations, hyperglycemia is associated with immune and non-immune alterations that could increase the risk for rejection or infection in transplantation patients. These include a greater inflammatory response associated with reperfusion-related ischemia, which appears to be mediated by an exaggerated adhesion of leukocytes to the endothelium.30,44 Furthermore, hyperglycemia in the postoperative period reflects an insulin-resistant state, which is associated with higher alpha tumor necrosis factor and interleukin 1, 6, and 12 values; all of this favors a state of systemic inflammation that could increase the immunologic response against the graft.45 Finally, the elevated glucose levels increase the expression of the major histocompatibility complex class I and class II molecules, with the subsequent potential increase of the innate immune response activation mechanisms.46 From the clinical viewpoint, in an analysis carried out on 184 patients that evaluated intraoperative glucose levels,34 the authors reported that values above 150mg/dl were associated with a greater risk for infection at 30 days following surgery, as well as with a higher mortality rate at one year.

Multiple studies have also been conducted evaluating the impact that hyperglycemia has on hospitalized patients. In a published study by Umpierrez et al.13 in which hyperglycemia was defined according to its isolated values, it was associated with longer hospital stay. In another study14 that also considered the isolated values in the immediate postoperative period, hyperglycemia was associated with a 5-fold greater risk for presenting with nosocomial infections. When the outcomes of critically ill hospitalized patients have been evaluated, taking into account the length of time glucose levels remained high, it was found that there could be a benefit in relation to mortality if the values stayed within a 144-200mg/dl range.40 The proportion of diabetic patients on the transplantation waiting list was high in our study, a result that has also been described in other case series.22 Our results showed that a considerable number of nondiabetic patients developed diabetes mellitus after transplantation, which was also similar to data described in other studies.23

The majority of studies that have evaluated glycemia in hospitalized patients usually define it as one or several values that are altered at one period of time. However, it is important to consider not only isolated or mean values, but also the length of time during which the patient presents with the elevated glucose levels; such differences in the type of measurement could partially explain the contradictory results of studies that have included glycemic control.40,47–51

One of the important limitations of our study was the high number of patients that were excluded for not having an adequate register of glucose measurement during the first 48h after transplantation and the subsequent reduction in the sample size necessary for detecting differences. Nevertheless, all the hyperglycemia measurements appeared to favor it as a «protective factor» in relation to adverse events and the proportion of rejections was even lower in the patients not included in the analysis (10% vs 20%). An important strength of our study was the detailed exploration of the exposure variable, with the different manners in which hyperglycemia was defined; not only did we look for an association with isolated values, but we also took into account the length of time the glucose values remained high.

Despite the limitations that correspond to an observational study in terms of residual confounding and population type, this analysis showed that hyperglycemia is most likely a frequent phenomenon in the immediate postoperative period of patients that undergo liver transplantation, and that complications like those of rejection and infection essentially depend on other factors, such as the use of immunosuppressant drugs, histocompatibility, and age, among others. A clinical trial could confirm whether carrying out some form of metabolic control in liver transplantation patients would provide any benefit in relation to rejection or infection. However, in patients that underwent kidney transplantation and had strict glycemic control, the risks appear to be greater than the benefits,39 and in critically ill patients in the ICU, kidney transplantation appears to bring about a high risk for hypoglycemia and a higher mortality rate.51 Previous findings and the results of our study suggest that glycemic control contributes very little in relation to complications in liver transplantation patients.

No financial support was received in relation to this article.

The authors declare that there is no conflict of interest.