We report a high prevalence of metabolic syndrome (49%) and elevated triglycerides (58%) and elevated blood pressure (56%) among adult allogeneic HCT survivors compared with general population controls. Although not significantly more common than controls, a large proportion of HCT recipients also had elevated waist circumference (44%), elevated fasting glucose (41%) and reduced HDL-C (41%). For comparison purposes, the general age-adjusted adult US population prevalence of metabolic syndrome has been reported to be 27%; the prevalence of its individual components is 44% for abdominal obesity, 40% for low HDL-C, 39% for elevated blood pressure, 33% for hypertriglyceridemia and 31% for elevated fasting glucose.6
A high prevalence of metabolic syndrome among transplant recipients has also been recently reported by Annaloro et al
In their cross-sectional study that included 39 allogeneic HCT recipients who had survived for at least 5 years since transplantation and had discontinued all immunosuppressive therapy, 12 (31%) had metabolic syndrome. Hypertriglyceridemia was the most prevalent component of metabolic syndrome, and this was followed in frequency by abdominal obesity, hyperglycemia, high blood pressure and low HDL-C, respectively. Age, insulin resistance, hypogonadism and serum leptin levels were observed to be predictive of metabolic syndrome, whereas a history of GVHD was not.
Taskinen et al
studied impaired glucose tolerance and dyslipidemia among 23 pediatric allogeneic HCT recipients (median age 20 years at study enrollment) who had survived for 3–18 years after HCT and compared them to 13 leukemia survivors who did not receive a transplant and 23 healthy controls. HCT survivors had a significantly higher prevalence of hyperinsulinemia (52 vs 31 vs 0%), abnormal glucose metabolism (43 vs 8 vs 0%) and hypertriglyceridemia (39 vs 8 vs 4%). A similar increased prevalence of insulin resistance among 34 pediatric HCT survivors has also been described by Lorini et al
In an analysis from the Bone Marrow Transplant Survivor Study, a retrospective cohort study that compared self-reported late complications between transplant recipients who had survived for 2 years or more and sibling controls, allogeneic HCT recipients were observed to have a significantly higher risk of diabetes and hypertension compared with controls and recipients of autologous HCT.16
Furthermore, the risks of diabetes and hypertension remained high irrespective of whether patients had received immunosuppressive therapy within the 2 years before study enrollment. A history of chronic GVHD was not found to be associated with an increased risk of either of these two diseases.
As reported by others, we did not find an association between metabolic syndrome or its individual components and GVHD. Also, the use of corticosteroids or calcineurin inhibitors was not associated with the risk of developing metabolic syndrome, although our study was not specifically designed and powered for risk factor analysis. Glucocorticoids have direct effects on the heart and blood vessels, and chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, dyslipidemia and hypertension.22
A high risk of insulin resistance and metabolic syndrome has been reported after solid organ transplantation, especially among kidney allograft recipients.23-26
Immunosuppression with corticosteroids, calcineurin inhibitors and sirolimus is thought to have an important role in the pathogenesis of insulin resistance and dyslipidemia in this population.23
Although mixed results have been reported, early withdrawal of corticosteroids might not alter the risks of glucose intolerance, and new-onset diabetes tends to persist after the withdrawal of steroids.27–29
Further investigation is needed to identify the specific subgroups of HCT recipients at highest risk for developing this syndrome and to study the natural history of these metabolic risk factors after the withdrawal of immunosuppressive treatment. Additional studies should evaluate the prevalence of metabolic syndrome in autologous transplant populations, patients with hematologic malignancies treated with conventional chemotherapy and in solid organ transplant recipients. These populations would shed further light on the potential etiologies for increased rates of metabolic syndrome in the allogeneic HCT population as well as possibly unearth other vulnerable populations that could benefit from heightened attention to the risks of metabolic syndrome.
We also observed an association between C-reactive protein and metabolic syndrome, as has been reported in general population-based studies.30
Patients with chronic GVHD have also been reported to have high C-reactive protein and leptin levels.31,32
Future studies of metabolic syndrome among HCT recipients should include other biomarkers such as uric acid, plasminogen activator inhibitor-1, cytokines, adiponectin, leptin and non-esterified fatty acids.2
Metabolic syndrome has also been identified as an important risk factor for chronic kidney disease,33,34
and the elevated rates of increased creatinine and microalbuminuria among HCT recipients with the metabolic syndrome need further exploration.
We could not determine why a relatively large proportion of patients had previously undiagnosed or untreated cardiovascular risk factors. Chronic GVHD was very prevalent in our cohort and its active management may have taken priority over identification and treatment of risk factors for cardiovascular disease, which may not manifest till late after transplantation. Also, compared to transplant physicians, diabetes, hypertension and dyslipidemia may be managed more aggressively in HCT survivors who are followed by an internist or within a comprehensive survivorship clinic. More studies are needed to identify the barriers to early recognition and treatment of these risk factors among HCT recipients.
Our cohort was drawn from a sample of patients returning to their transplant center for long-term follow-up. Hence, our study population is enriched with patients with transplant-related problems such as chronic GVHD. On account of this limitation, we are not able to comment on the overall prevalence of metabolic syndrome among all HCT recipients. Nonetheless, several practical implications emerge from the high prevalence of metabolic syndrome observed in our cross-sectional study. First, late effect assessment should include routine screening for this disorder and its individual components, with the expectation that many patients will have abnormal findings. Referral to a comprehensive survivorship clinic or an internist or endocrinologist should be considered for patients in whom these abnormalities are detected. Second, HCT recipients should be offered appropriate prevention and treatment, as has been recommended for the general population to prevent overt cardiovascular disease, diabetes and loss of renal function.3,7
Physicians may be reluctant to initiate treatment because they believe that diabetes, hypertension and dyslipidemia are transient phenomena that will resolve with time and withdrawal of immunosuppression. Our data and the literature offer little support for this assumption. Finally, studies are needed to evaluate the safety and efficacy of various management options for transplant recipients and to determine whether long-term morbidity and mortality can be reduced by better recognition and treatment of metabolic syndrome. As we know that transplant survivors are at increased risk for late cardiovascular complications, it behoves physicians to try to mitigate known predisposing conditions as part of a comprehensive approach to survivorship care.