EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: New onset diabetes mellitus after transplant is one of the major metabolic complications after liver transplant. Development of impaired fasting glucose after liver transplant is thought to be associated with increased risk of cardiovascular mortality and has not been well studied before. The aim of this study was to evaluate incidence and risk factors of new onset diabetes mellitus after transplant and impaired fasting glucose in liver transplant patients.

Materials and Methods: In a cross-sectional study, all adult patients (aged ≥ 18 years) who were transplanted because of chronic liver diseases from June 2002 to September 2010 at Shiraz Liver Transplant Center were evaluated for developing diabetes and impaired fasting glucose.

Results: Totally, 86 patients (18.81%) were found to have diabetes after liver transplant. Forty patients (27 men and 13 women; 8.75%) developed new onset diabetes mellitus after transplant and 36 patients (7.87%) developed impaired fasting glucose after liver transplant. The mean age of patients with new onset diabetes mellitus after transplant was higher than that of nondiabetic patients (P = .001). Mean fasting plasma glucose before liver transplant was significantly higher in diabetic patients compared with nondiabetic patients (P = .002)
(5.20 ± 0.93 mmol/L vs 4.44 ± 0.56 mmol/L)
(93.86 ± 16.80 mg/dL vs 80 ± 10.14 mg/dL). Patients with new onset diabetes mellitus after transplant received higher doses of tacrolimus as immunosuppressive medication than nondiabetic patients (P = .001).

Conclusions: Fasting plasma glucose before transplant can predict development of new onset diabetes mellitus after transplant. Age and tacrolimus dosage are independent risk factors for new onset diabetes mellitus after transplant in our patients.

Key words : Liver transplant, New onset diabetes, Fasting plasma glucose

New onset diabetes mellitus after transplant (NODAT) is a major metabolic complication after liver transplant. Development of NODAT after a liver transplant has been associated with increased risk of cardiovascular morbidity and mortality, and it has negative effect on graft function, posttransplant infections, and patient survival.¹ The incidence of NODAT is not yet clear, but it is estimated to be approximately 18.2% in patients on a tacrolimus-based immunosuppressive regimen compared with patients on a cyclosporine-based regimen (7.7%).² Several factors have been suggested as risk factors for developing NODAT including sex, ethnicity, impaired fasting glucose (IFG) before transplant, hepatitis C virus infection as an underlying liver disease, a family history of diabetes, or being elderly and obese.³ An immunosuppressive regimen including steroids and calcineurin inhibitors also are suspected as having an effect.⁴ Recently, it has been shown that not only frank diabetes but also new-onset of IFG during the posttransplant period is associated with an increased risk of cardiovascular events after transplant.5 Therefore, it is clinically relevant to monitor IFG in patients after a transplant. This study sought to evaluate the incidence and risk factors of NODAT and IFG after a liver transplant.

Materials and Methods

All adult patients (aged ≥ 18 years) who were transplanted because of chronic liver disease at the Shiraz Liver Transplant Center in Shiraz, Iran, between June 2002, through September 2010, with at least 6 months’ follow-up were included. Information about sex, age, time of transplant, immunosuppressive regimen, weight, height, blood sugar during the pretransplant and posttransplant periods, underlying disease leading to end-stage liver disease, and the source of allografts were taken from the old charts, and when necessary, by contacting patients. Patient follow-up was at least 6 months.

Diabetes mellitus and IFG were defined, based on American Diabetes Association guidelines for diagnosis of diabetes and IFG. According to this guideline, patients with a fasting plasma glucose ≥ 6.99 mmol/L (≥ 126 mg/dL) or a random plasma glucose ≥ 11.1 mmol/L ( ≥ 200 mg/dL) with classic symptoms of hyperglycemia, were considered diabetic, and IFG was defined as fasting plasma glucose between 5.5 and 6.93 mmol/L (100 and 125 mg/dL).⁶

Exclusion criteria were patients with an unknown blood glucose status before transplant, a history of acute graft rejection during the 3 months before the transplant, if they had received corticosteroid pulse therapy, if they were recipients of multiple organ transplants, if they had the presence of a serious intercurrent disease or human immunodeficiency virus infection, or if they had participated in a phase II or III clinical trial since the transplant. Patients with NODAT were compared to those liver transplant patients without progression of diabetes mellitus after transplant as control group. Controls were randomly selected among transplant patients during the same time. We searched the transplant list during a 3-month interval onward from the time of the liver transplant for each patient with NODAT. The first transplanted adult patient without NODAT was considered as a control.

Statistical analyses
All data are expressed as means ± standard deviation (SD). Parameter comparisons were performed with a t test, and a correlation analysis was performed using a chi-square test and a Pearson product moment correlation analysis. Values for P < .05 were considered statistically significant. Multivariate logistic regression analysis was performed to identify independent risk factors. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA).

Ethics and consent
This study was approved by the Ethics Committee of the Shiraz University of Medical Science. The study protocol conformed with the ethical guidelines of the 1975 Helsinki Declaration. Written, informed consent was obtained from patients, when appropriate.

Among 457 patients, a total of 86 patients (18.81%) were found to have diabetes after a liver transplant. Forty-six of these patients (10.06%) had diabetes mellitus before the transplant. Forty patients (8.75%; 27 men, 13 women) developed NODAT after the liver transplant. Thirty-four patients with NODAT (85%) developed diabetes mellitus in the first month after the liver transplant, and only 6 patients (15%) developed diabetes after the first month (P < .001). Among those with NODAT, 17 patients (42.5%) had IFG before the transplant.

Patients with NODAT were compared to the 43 liver transplant patients (25 men, 18 women) without development of diabetes after transplant as controls. Baseline characteristics of patients with NODAT and controls were outlined in Table 1.

The mean age of patients with NODAT was 43.31 ± 9.40 years, while it was 31.21 ± 9.96 years in nondiabetic patients (P = .001). Mean weight of diabetic patients before transplant was 68.40 ± 13.99 kg versus 63.65 ± 8.75 kg in nondiabetic patients (P = .17). Mean fasting plasma glucose before liver transplant was significantly higher in diabetic patients compared with nondiabetic patients (P = .002; 5.20 ± 0.93 mmol/L vs 4.44 ± 0.56 mmol/L) (93.86 ± 16.80 mg/dL vs 80 ± 10.14 mg/dL). In patients with NOADT, 31 patients (77.5%) received a tacrolimus-based immunosuppressive regimen and 9 patients (22.5%) received a cyclosporine-based regimen (P = .02). Patients who developed NODAT received higher doses of tacrolimus as an immunosuppressive medication than did nondiabetic patients (P = .001) (Table 2). Multivariate logistic regression analysis of risk factors showed that only age and mean tacrolimus dosage correlated with development of NODAT after a liver transplant (Table 3). Patients with NODAT and controls were categorized to (1) those receiving > 2 mg daily tacrolimus, and (2) those with ≤ 2 mg daily tacrolimus. In patients with NODAT, 29 individuals (72.5%) received > 2 mg daily tacrolimus compared with 6 individuals without NODAT (13.95%; OR: 16.25; 95% confidence interval: 5.37-49.19; P = .001) (Table 2).

In addition to patients with NODAT, 53 patients (11.59%) had IFG after the liver transplant. Among these cases, 36 patients (7.87%) developed IFG after the transplant, while 17 patients had IFG before the transplant. To identify risk factors for developing IFG after the liver transplant, these patients were compared with patients with NODAT and patients without developing diabetes after transplant. Fasting plasma glucose before transplant was 4.8285 ± 0.55 mmol/L (87 ± 10.07 mg/dL) in patients who developed IFG, and while it was 4.44 ± 0.56 (80 ± 10.14 mg/dL) in nondiabetic (P = .012) and 5.20 ± 0.93 mmol/L (93.86 ± 16.80 mg/dL) in patients developed NODAT (P = .05) (Figure 1). There was no statistically significant association between other risk factors and development of IFG after a liver transplant (Figure 1, 2, and 3).

Occurrence of diabetes mellitus after solid-organ transplant was first described in kidney transplant patients in 1964 and has been called “posttransplant diabetes mellitus” until recently.⁷ The term “NODAT” recently has replaced posttransplant diabetes mellitus to distinguish new cases of diabetes mellitus after transplant from cases with pretransplant diabetes. In previous studies, older recipient age, high BMI, recipient hepatitis C virus infection, cirrhosis, advanced donor age, tacrolimus use, and steroid use were independent risk factors for NODAT.⁸ But the influence of IFG before a transplant or before transplant plasma glucose status on developing NODAT has not been well elucidated. New-onset diabetes after transplant and IFG are not only components of the metabolic syndrome after a liver transplant, but they also are indicators of higher posttransplant mortality, especially caused by cardiovascular issues.^9,10 Therefore, monitoring patients for these complications during the posttransplant period is necessary. Understanding risk factors for developing these adverse outcomes will guide clinicians to intensify their monitoring plans in more susceptible groups.

Our study shows that older age of the patients at the time of the transplant and higher fasting plasma glucose levels before liver the transplant were major risk factors for NODAT. Higher dosages of tacrolimus as an immunosuppressive regimen were associated with developing diabetes after a liver transplant. However, no correlation between dosage of a steroid and developing NODAT were found.

In this study, the first month after the liver transplant was the most crucial time regarding occurrence of NODAT, because nearly 85% of patients developed diabetes mellitus during the first month after a liver transplant.

In another study of pretransplant glycemia, alcohol use and steroid dosage were independent risks for NODAT.¹¹ Cytomegalovirus infection, pretransplant, and early posttransplant hypomagnesemia also are reportedly associated with NODAT.^12,13 Among causes of liver cirrhosis, hepatitis C virus infection has been associated with developing diabetes after a transplant. A meta-analysis of retrospective studies also revealed a significant relation between hepatitis C virus infection and developing NODAT.¹⁴ In our study, HBV infection was associated with NODAT in univariate analysis, but it was not an independent risk factor on a multivariate analysis. It simply may be justified by the low numbers of hepatitis C virus patients who were transplanted in our center.

Tacrolimus-based versus cyclosporine-based immunosuppressive regimens have been reported as being related with a higher risk of NODAT.² This finding also was observed in our study. Furthermore, we showed that a higher dosage of tacrolimus is an independent risk factor for NODAT. Only 1 other study had the similar results and showed that reduced tacrolimus dosage was associated with reduced occurrence of renal dysfunction and diabetes.¹⁵ Previously, it has been shown that conversion from tacrolimus to cyclosporine will improve NODAT.¹⁶ Considering our results, it may not always be necessary to shift from tacrolimus to cyclosporine in patients with NODAT, and reducing the tacrolimus dosage may help during the initial management of these patients.

It has been suggested that NODAT may influence liver allograft and patient survival after transplant. John and Thuluvath showed that the incidence of acute rejection was higher in patients with NODAT and explained that as being attributable to higher dosages of steroid bolus injections.¹⁷ However, similar to our results, they could not find any association between occurrences of NODAT and mean steroid dosages. It should be noted that cumulative dosages of steroids instead of mean dosages of steroids may be a more reliable index for checking an association of NODAT with steroids. Furthermore, other pathophysiological basis for NODAT, including a genetic predisposition, should be considered.^18,19 Patient and graft survival were worse among patients with NODAT compared with nondiabetic patients. Patients also are at a greater risk of death and infection.²⁰

Other interesting aspects of NODAT are screening, diagnosing, and managing these patients. Diabetes in liver transplant recipients has serious adverse consequences and may require multiple therapies to achieve glycemic control.²¹ Furthermore, NODAT may present first with grave complications (eg, diabetic keto-acidosis).²² Therefore, intense and regular screening of higher risk patients is necessary to prevent grave complications.

In addition to patients with NODAT, 36 patients developed IFG after the liver transplant. Pretransplant fasting plasma glucose was the only predictor for developing IFG after the liver transplant. Comparing patients with IFG with patients with NODAT after liver transplant, neither age nor weight nor dosages of immunosuppressive agents were significantly different between these groups. These findings suggest that NODAT may have unknown components, such as genetic and environmental conditions, other than currently described risk factors.

Our study also has several limitations. It was conducted among a limited proportion of our liver transplant patients. With more than 1300 liver transplant patients, the Shiraz Transplant Center is the leading center in Iran, and we only included 457 liver transplant patients. However, it should be noted that our study population is larger than many previous studies. The retrospective nature of this study has its own limitations. In consideration of this, the follow-up of our patients was only 6 months. This may explain the relatively low incidence of NODAT (8.75%) in our study compared with previous studies. The other reason for this low incidence may be attributable to the lower numbers of hepatitis C virus patients, which are known to be associated with developing diabetes after a transplant. Despite its limitations, though, the study is important regarding risk assessment and selecting patients for regular screening programs for preventing and rapidly diagnosing NODAT.

Based on our results, older patients, and patients receiving higher tacrolimus dosages, are considered to be at a higher risk of developing NODAT and require intense follow-up. Finally, we emphasize conducting prospective cohorts for more investigation of the nature and risk factors of NODAT.

Volume: 12 Issue: 1 February 2014

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