Metabolic Syndrome Post-Liver Transplant: Can We Predict?

Abstract

Long-term complications related to liver transplant (LT) are well known and include risks of chronic immunosuppression and cardiovascular disease. Metabolic risk factors such as new onset diabetes after transplant (NODAT) and metabolic syndrome (MS) have emerged as strong predictors of cardiovascular complications and graft function post-transplant. It is estimated that about 30% of patients post-orthotopic liver transplant may go on to develop new onset diabetes.¹ This may lead to poorer long-term outcomes in both graft function and survival. Morbitzer et al. retrospectively examined patients with hepatitis C virus (HCV) post-LT and found that patients who either had diabetes before transplant or NODAT had higher mortality rates and higher stages of fibrosis post-transplant than patients who never developed diabetes during the 11-year follow-up period.²

Although these results suggest a relationship between glycemic control and long-term outcomes, the results are difficult to generalize since HCV may play a role in insulin resistance through multiple pathways, directly or indirectly. These include the direct downregulation of Glut2 by the HCV core protein,³ modulation of forkhead transcription factors with insulin-induced metabolic gene expression,⁴ and proinflammatory cytokine release and downstream pathways that may ultimately lead to poor insulin sensitivity.^2
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Similarly, the development of MS in the post-transplant period is very common and may portend increased cardiovascular risk.⁵ Fussner et al. examined post-LT patients and found that the highest rate of MS occurred in the first year after transplant independent of the type of immunosuppression used.⁶ Moreover, cardiovascular events also steadily increased during the follow-up period with one of the highest risk being impaired glucose tolerance and diabetes (HR 1.56, CI 1.03–2.37, P = 0.035). An earlier study by Laryea et al. found an incidence of MS occurring in 58% of their post-transplant cohort, which is far higher than the average, nontransplant population.⁷ Moreover, there was a significant increase in cardiovascular events in patients with MS compared with those without. Since MS includes potential modifiable risk factors including body mass index (BMI), fasting glucose, blood pressure, triglyceride, and high-density lipoprotein levels, it is imperative that early signs of MS need to be intervened upon to mitigate long-term cardiovascular risk.

In this issue of Metabolic Syndrome and Related Disorders, Kahn et al.⁸ from the Mayo Clinic Scottsdale present a prospective study examining the use of early hyperglycemia screening tools and metabolic markers to detect new onset diabetes mellitus (DM) and MS in post-LT patients. A new diagnosis of diabetes was defined as patients who had no personal history of DM before transplant, no current or past use of antihyperglycemic medications, and normal fasting plasma glucose and hemoglobin A1c before transplant who then develop either an elevated fasting plasma glucose or >126 mg/dL or 2 hr oral glucose tolerance test (OGTT) >200 mg/dL. Patients with post-transplant MS were defined as having at least three criteria according to the National Cholesterol Education Program-Adult Treatment Plan III guidelines. The primary outcomes included the diagnosis of new onset DM and MS post-transplant. Patients were initially screened with fasting plasma glucose, 2-hr OGTT fasting lipid panel, hemoglobin A1c, and plasma adiponectin. These parameters were collected again at 4 and 12 months post-transplant. All patients received a standard immunosuppression protocol after transplant. Of the 49 LT candidates included in the study, about 25% were excluded due to elevated 2-hr OGTT during the pretransplant screening process. Of the remaining 37 patients, 15 did not return for subsequent testing, which left only 22 patients in the prospective cohort. A small percentage developed new onset DM after transplant, whereas the total number of patients with MS increased from 4.5%, 19%, and 31.3% at baseline, 4, and 12 months post-transplant, respectively. Despite the low number of patients with new diagnosis of diabetes, impaired glucose tolerance was detected in a much higher proportion of patients using a 2-hr OGTT despite normal fasting plasma glucose levels.

The strength of this study lies in its prospective design and it is the first study to prospectively examine the use of early diabetic screening tools in patients who are newly post-transplant. Although the number of patients who developed DM was small, it does highlight a higher rate of impaired glucose tolerance after transplant, which may serve as marker for those patients at highest risk of subsequently developing diabetes post-transplant. Unfortunately based on the small sample size, it is difficult to draw definitive conclusions. However, this study serves as an impetus for future prospective studies. Future studies should aim to have larger sample sizes across multiple centers, control for etiology of liver disease, and donor specimen (deceased versus living donor), as either of these may potentially confound results. The authors point out that the use of OGTT is often limited by the time and expense of performing this test, but their results show that early use of this tool may help to detect early stages of diabetes. Future projects may also aim to compare the use of this tool with more conventional measures such as hemoglobin A1c.

In summary, new onset diabetes and MS with progression to cardiovascular disease are high among post-LT patients. There are many factors that play a role in this development, which include baseline glycemic control before transplant, donor, etiology of chronic liver disease, race, gender, and immunosuppression (steroids and/or calcineurin inhibitors). Obviously some of these risk factors cannot be modified, but designing better ways to screen for modifiable risk factors in this high-risk population is imperative to reduce long-term cardiovascular disease and mortality rates.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

References

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