Pediatr Transplantation 2015: 19: 452–459
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12523
Review Article
New-onset diabetes mellitus after pediatric liver transplantation Regelmann MO, Goldis M, Arnon R. (2015) New-onset diabetes mellitus after pediatric liver transplantation. Pediatr Transplant, 19: 452–459. DOI: 10.1111/petr.12523. Abstract: In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.
In the last several decades, mortality after pediatric LT has greatly improved, with a reported five-yr survival rate ranging from 69.5 to 86.2%, depending on the underlying indication for the LT (1–4). As the survival of children with ESLD has greatly improved, there has been an emergence of the long-term morbidities associated with both the underlying conditions causing the liver failure and the complications of the immunosuppressant medications used to maintain graft survival. The focus of this review is on NODAT in the pediatric population. Improvement in hyperglycemia has been associated with
Abbreviations: ADA, American Diabetes Association; CF, cystic fibrosis; DM, diabetes mellitus; ESLD, end-stage liver disease; FDA, Federal Drug Administration; GAD, glutamate decarboxylase; GC, glucocorticoids; ICU, intensive care unit; LT, liver transplantation; MMF, mycophenolate mofetil; NODAT, new-onset diabetes mellitus after liver transplant; OGTT, oral glucose tolerance test; PSC, primary sclerosis cholangitis; ZnT8, zinc transporter 8.
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Molly O. Regelmann1, Marina Goldis1 and Ronen Arnon2 1
Division of Pediatric Endocrinology & Diabetes, Hall Family Center for Diabetes, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 2Division of Pediatric Hepatology, Recanati/Miller Transplant Institute, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA Key words: new-onset diabetes after transplant – liver transplant – pediatric – insulin Molly O. Regelmann, MD, Division of Pediatric Endocrinology & Diabetes, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1616, New York, NY 10029, USA Tel.: +1 212 241 6936 Fax: +1 212 426 2132 E-mail: [email protected] Accepted for publication 15 April 2015
reduced risks of graft rejection and infection, as well as potential long-term complications of DM (5, 6). NODAT can become a chronic condition, and DM alone can be associated with damage to the eyes, kidneys, cardiovascular system, and nervous system (7), which makes identifying those at risk, properly diagnosing NODAT, and prescribing appropriate treatment critically important for long-term health outcomes. Epidemiology and risk factors for NODAT
Most studies report an incidence of NODAT close to 10% with a range of 8.0–14.1% for all indications for pediatric LT. There is a lack of uniform definition for NODAT in the literature, which is likely the reason for some of the variability (8–11). NODAT is not defined, and its presence, as well as treatment with insulin, is answered simply as “yes” or “no” on the United Network for Organ Sharing Transplant Recipient Follow-up form (12). The majority of patients with NODAT seem to be diagnosed in
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the first month after LT, and many seem to have transient DM. The incidence has been reported to increase with time from LT (8, 10), and Kuo et al. (9) reported a cumulative incidence of NODAT of 5.9%, 8.3%, and 11.2% at one, three, and five yr. Risk factors for developing NODAT have been difficult to tease out, in part, due to a lack of uniformity of diagnosis and data collection, as well as the heterogeneity of the pediatric LT patient population. The four studies that have attempted to identify risk factors for NODAT in pediatric LT are summarized in Table 1 (8–11). Older age at time of LT has been associated with a higher risk for NODAT, with an increase in risk noted at five yr of age and the highest rates noted in those 13 yr or older (9, 10). The higher risk in those 13 yr or older may be associated with pubertal status, as rates of insulin resistance and type 2 DM are known to increase with puberty (13). To date, there are no reports that evaluate risk for NODAT with pubertal status. And while having a living, vs. a deceased, donor transplant has been reported to reduce risk in the first year for NODAT in adult LT, this has not been reported in pediatric LT (9, 10, 14). The underlying etiologies for LT play a significant role in the risk for developing NODAT, with rates reported at 57.4% in those with CF and 22.3% in those with PSC three yr post-LT (9). Acute hepatic necrosis, cirrhosis, and HCV
infection have also been reported to be associated with a higher risk for NODAT (9). Having an LT for biliary atresia seems to be associated with a lower risk for developing NODAT with rates reported between 3.6 for NODAT and 8.9% for NODAT and glucose intolerance, but these reports may be confounded by the fact that older age seems to be a risk factor and most children undergoing LT for biliary atresia are younger than five yr (9, 10). Hispanic and African American/black ethnic backgrounds have also been reported to be associated with higher rates of developing NODAT. Much like age, this finding is likely related to associations with higher rates of insulin resistance and type 2 DM noted in these ethnic groups (15, 16). No studies have reported specifically on rates of NODAT in the pediatric population of Asian/Pacific Islander and American Indian/Alaska Native background, populations also known to have higher rates of type 2 DM (15). Unlike type 2 DM, however, risk for NODAT in the pediatric population does not have a strong association with BMI. In fact, the two largest cohort studies found no association with BMI and risk of NODAT, and the case–control study reported by Greig et al. suggested that a lower BMI was a risk factor for NODAT (8–10). One may conclude that the lack of association with BMI could be confounded by the underlying diagnosis, as patient with CF and chronic
Table 1. Summary of pediatric studies evaluating risk factors for NODAT Greig et al. (8)
Kuo et al. (9)
Hathout et al. (10)
Romero et al. (11)
Type of study Number of patients Prevalence
Age and sex-matched control 300 (24 with NODAT, then matched) 8.0% (persistent NODAT) 2.7% (transient hyperglycemia)
Cohort 1161 10.1% (during mean follow-up period) 11.2% (by 3 yr)
Cohort 1611 13.3% (glucose intolerance/NODAT); 10.3% in the 1st month
Mean follow-up
Factors assessed at 1-yr visit (NODAT diagnosed 0.03–74.0 mo, mean 14.0 19.6 mo) Rejection in 1st year Methylprednisolone bolus (both having had one and number of boluses) Tacrolimus level Use of 3 immunosuppressants Lower BMI
770 days
Study looked only at those diagnosed in the 1st month Age >5 yr Black and Hispanic race Reason for LT, other than biliary atresia Hospitalized in ICU Steroid use Tacrolimus (vs. cyclosporine) CMV positive
Cohort 81 14.1% (eliminating 3 with pretransplant DM; 17.2% all post-transplant DM) Not clear
Risk factors associated with increased risk
Not factors
Underlying cause of ESLD Race
Age >/=13 yr African American race Bilirubin >/3 mg/dL Cause of ESLD: CF Acute hepatic necrosis Cirrhosis Primary sclerosing cholangitis HCV infection Acute rejection in 1st year Sex BMI Donor—age, sex, type (living vs. deceased), diabetic Initial immunosuppressant Maintenance steroids at one yr
BMI Donor—age, type (living vs. deceased), CMV status
Older age (12.3 4.6 yr vs. 5.3 5.6 yr) Tacrolimus (vs. cyclosporine)
Sex Race
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liver disease may have lower BMIs at baseline. In fact, Perito et al. reported that once controlling for age, primary diagnosis, and ethnicity, the odds of developing NODAT did not differ by BMI for 2305 pediatric patients documented as not having DM prior to LT. Being overweight or obese following LT certainly may be associated with comorbidities, and further studies are needed to assess for the potential impact on cardiovascular disease and hyperlipidemia, as well as long-term risk for NODAT (17). The immunosuppressant medications have also been associated with varying rates of NODAT. While Kuo et al. did not report a noted association with initial immunosuppressant regimen, and the use of tacrolimus, versus cyclosporine, has been reported to be associated with an increased risk for NODAT by multiple studies (9–11). The use of steroids at the time of the transplant has also been associated with higher risk for NODAT (9–11). And, the use of three immunosuppressant medications, as well as rejection in the first year (presumably treated with more and higher doses of immunosuppressive medications), has been noted to be associated with a higher risk for NODAT (8, 9). Pathogenesis of NODAT
The pathogenesis of NODAT is likely a combination of insulin resistance and insulin insufficiency in the vast majority of patients. Medications have primarily been identified as the inciting agents for the carbohydrate metabolism dysfunction and are discussed more extensively below. However, in patient populations at risk for type 2 DM, it is likely that other genetic factors play a role. And in patients with particular conditions, such as CF, impairment of b-cell function is greatly influenced by the underlying disease. Although no cases are reported in the pediatric LT literature, pediatric patients with NODAT are not protected from an autoimmune destruction of b-cells. Type 1 DM has been described in patients with autoimmune hepatitis and PSC. Therefore, type 1 DM should be considered in any child with NODAT, particularly those with a history of autoimmunity (18, 19). Tacrolimus
When first introduced, tacrolimus, a calcineurin inhibitor, was primarily used to prevent and treat transplant rejection following other immunosuppressive failures. Initial reports suggested a relatively low incidence of NODAT in pediatric LT patients treated with tacrolimus (20). In the last decade, as tacrolimus has become more common 454
in immunosuppressive protocols following LT, reports suggest that tacrolimus is associated with an increased risk for NODAT, particularly when blood levels are higher (8–10). The mechanism by which tacrolimus induces hyperglycemia is likely a combination of decreased insulin secretion, b-cell necrosis, and increased insulin resistance, which have been demonstrated in rats (21, 22). In human subjects with LT, patients, without known autoimmunity, treated with tacrolimus have been described to present in diabetic ketoacidosis, suggesting an insulin deficiency related to tacrolimus (8, 23, 24). Measurable c-peptide levels and high insulin dose requirements have also been described in patients treated with tacrolimus for LT, consistent with insulin resistance (25). The DM associated with tacrolimus has been reported to be reversible with tapering of tacrolimus dose or selecting an alternative immunosuppressive regimen (26, 27). Cyclosporine A
Cyclosporine A, a calcineurin inhibitor, has been used successfully in LT since the 1980s. Rodent studies have shown impaired glucose tolerance and insulin resistance, as well as an increase in gluconeogenesis in rats treated with cyclosporine A (28). Cyclosporine A has also been demonstrated to impair insulin secretion in in vitro and in vivo studies (29, 30). While cyclosporine A, by itself, has been shown to be diabetogenic, it is thought to be associated with a reduced risk for NODAT, when compared to tacrolimus, as noted above (10, 11). A series reported by Emre et al. (27) reported that 15 of 17 adult patients with NODAT, treated initially with tacrolimus and converted to cyclosporine A for uncontrolled NODAT, had resolution of DM. A pediatric case series reported that seven of 18 patients with NODAT were converted from tacrolimus to cyclosporine, with steroid taper and addition of MMF, and had resolution of NODAT at 1– 19 months after diagnosis; the other patients in the series had steroid tapers alone, or with the addition of MMF, with resolution of NODAT at 0.5–2 months (26). Not all studies have reported positive results, and in another series of adult patients, there was no significant difference in glucose intolerance or frank NODAT when comparing cyclosporine A and tacrolimus immunosuppressive regimens (31). Glucocorticoids
Since the first successful LT, GC have been a standard part of immunosuppressive protocols in
Diabetes post-pediatric liver transplant
LT and are still routinely used in many protocols today. GC are well documented to be associated with increased risk of DM, as well as other complications, including but not limited to obesity, hypertension, and hyperlipidemia (32). The mechanism by which GC induce NODAT is likely related to both reduced insulin sensitivity and b-cell dysfunction (33). In humans, insulin resistance has been documented to increase with escalating doses of GC; however, the way in which GC induces skeletal muscle resistance is not well understood (34). In vitro, as well as human in vivo, studies have demonstrated that GC impair insulin secretion; b-cell function is affected by reducing glucose-adjusted insulin secretion (34, 35). GC are also known to increase hepatic glucose production (35). Sirolimus
Sirolimus, a mammalian target of rapamycin inhibitor, is used as an immunosuppressive medication and has the advantage of being less nephrotoxic when compared to calcineurin inhibitors but may not have as favorable outcomes in terms of graft survival (36, 37). Sirolimus has been noted to be associated with the development of NODAT, but the exact mechanisms of immunosuppressant-induced hyperglycemia are still being delineated. Rat studies have demonstrated insulin resistance in those treated with sirolimus (38). Sirolimus has also been found to be associated with reduced b-cell size, mass, and proliferation (39). Higher incidences of new-onset DM and insulin resistance have been reported in renal transplant patients treated with sirolimus, when compared to other regimens, including those with calcineurin inhibitors (40, 41). Interestingly, in patients with LT, sirolimus has been reported to have a lower incidence of NODAT (42). Conversion from calcineurin inhibitor to sirolimus has also been reported to improve insulin requirements in three patients with NODAT (43). Mycophenolate mofetil and azathioprine
MMF and azathioprine are purine analogs used, primarily as adjuvants, for immunosuppression
in prophylaxis for LT rejection. MMF has not been reported to increase risk for NODAT and also has the advantage that it does not have significant nephrogenic or cardiovascular toxicities (44, 45). MMF monotherapy is not common in pediatric LT, but in one adult study, MMF monotherapy seemed to have positive effects on DM, and patients treated with MMF, rather than a calcineurin inhibitor, were less likely to have progression of DM (46). There are also no reports of NODAT specifically associated with azathioprine (47). Screening and diagnosis new-onset DM after liver transplant
There are no data reporting presenting symptoms for NODAT. As most patients with NODAT still produce some insulin at diagnosis, it is rare for patients to present in diabetic ketoacidosis, although it has been reported in the pediatric literature (23, 24, 26). The percentage of patients at NODAT diagnosis with frank polyuria and polydipsia, versus asymptomatic hyperglycemia, is unknown. Given the natural history of DM, it is likely that the majority of patients with NODAT are asymptomatic for a period of time prior to developing obvious symptoms of NODAT. Because of the increased risk for morbidity and mortality associated with NODAT, identifying and screening those at risk for NODAT is critically important. For the purposes of uniformity, to aid in the clinical and research setting, we agree with First et al. (48) that uniform definitions for DM, as established by the ADA, should be used for LT patients. The ADA criteria for the diagnosis of DM are an 8-h fasting plasma glucose of ≥126 mg/dL (7.0 mmol/L), two-h plasma glucose of ≥200 mg/dL (11.1 mmol/L) during OGTT (using 1.75 g/kg, to maximum dose of 75 g of anhydrous glucose dissolved in water), or in a patient with symptoms of polyuria and polydipsia, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). Table 2 summarizes diagnostic criteria, as well as criteria for “prediabetes,” which can be defined as either impairment of glucose tolerance (post-prandial glucose 140–199 mg/dL) or impaired fasting glucose (100–125 mg/dL). Hemoglobin A1c, which takes
Table 2. Criteria for “prediabetes” and DM (modified from ADA) (7)
Hemoglobin A1c 8-h fasting plasma glucose 2-h plasma glucose—OGTT 75 g Random plasma glucose + symptoms of diabetes
Prediabetes
DM
5.0–6.4% 100–125 mg/dL (5.6–6.9 mmol/L) 140–199 mg/dL (7.8–11.0 mmol/L)
>/=6.5% >/=126 mg/dL (7.0 mmol/L) >/=200 mg/dL (11.1 mmol/L) >/=200 mg/dL (11.1 mmol/L)
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an average blood glucose over 2–3 months, has recently been added as a diagnostic test, with a hemoglobin A1c of 6.5% or greater on a standardized assay being diagnostic of DM (7). Hemoglobin A1c should be used with caution as the sole screening tool, as it may miss or overdiagnose cases of DM. Hemoglobin A1c can be lower in those with chronic liver disease, administered erythropoietin, taking aspirin, and with hypertriglyceridemia. An increased hemoglobin A1c can be seen in iron deficiency, B12 deficiency, decreased erythropoiesis, chronic renal disease, after splenectomy, with chronic opiate use, after large doses of aspirin, with alcoholism, and with hyperbilirubinemia. Hemoglobinopathies can also have variable effects on the hemoglobin A1c (49). In the immediate post-LT period, when patients are typically on their highest doses of immunosuppressive medications, NODAT is more common. Likewise, NODAT is more frequently noted during episodes of acute rejection, when immunosuppressive medications, particularly GC, are given in higher doses (8, 10). The American Association for the Study of Liver Diseases and the American Society of Transplantation recommend screening LT recipients older than five yr annually with fasting glucose in the early post-LT period and during long-term follow-up (50). While this is a reasonable starting point, we propose that screening should also be performed during times of higher risk for hyperglycemia, such as immediately post-LT, during treatment for acute rejection, chronic rejection, and with de novo autoimmune hepatitis, which also typically is treated with high doses of GC and/or calcineurin inhibitors (2, 50, 51). The guidelines are also likely to miss glucose intolerance and early DM in those with b-cell dysfunction. Screening guidelines for patients with CF, for example, recommend yearly OGTT, because the first abnormality of carbohydrate metabolism is typically a delayed or blunted peak insulin secretion, and later in the course of disease, abnormally elevated fasting glucose is noted (52). Hogler et al. (53) suggested that those identified as being “high risk” following LT should have yearly screening oral glucose tolerance (OGTT). “High risk” was defined as children >5 yr of age, CF, PSC, acute hepatic necrosis. We propose that urinary frequency and fluid intake be assessed as part of the review of systems at all medical follow-up visits for patients with LT. Any patients with reported symptoms of polyuria or polydipsia should have screening tests. We also agree with the Hogler et al. recommendation to perform yearly screening OGTT 456
and propose that children with risk factors for type 2 DM, including those with a family history of type 2 DM and of a high-risk ethnicity (African American, Hispanic, American Indian/ Alaska Native, and Asian/Pacific Islander), should be included in the “high-risk” group (15, 16, 53). We also suggest that any patient noted to have resolved transient DM also be screened with yearly OGTT, as they theoretically are at higher risk for recurrence. Once the diagnosis of DM has been established, we also recommend considering screening for type 1 DM, particularly in those at higher risk for autoimmunity (for example, those previously diagnosed with PSC or autoimmune hepatitis), with diabetes-related antibody testing [islet antigen-2 (IA-2), GAD, ZnT8, and insulin antibodies)]. Distinguishing the diagnosis of type 1 DM vs. NODAT is important, because patients with type 1 DM must be managed with insulin. Treatment and management
DM management and treatment is very much individualized and dependent on age, other medical conditions, immunosuppressant medications, and psychosocial circumstances. Management should ideally be a team approach with pediatric endocrinologists working with the transplant physicians, intensive care physicians, nutritionists, and psychosocial support services, to optimize blood glucose control. The goal for any child with DM is to normalize blood glucose to as close to normal without frequent episodes of hypoglycemia. This can be particularly daunting in children with LT, as many already have multiple other medications and health concerns. Adjustments to the immunosuppressive medications are typically managed by the transplant physicians, and the clinicians managing the diabetes should understand the potential effects of the various immunosuppressive medications on DM control, as outlined above. All patients with LT should be counseled regarding a healthy lifestyle, including a balanced diet and routine exercise. Those with NODAT should have more extensive nutrition counseling, including limitations on concentrated sweets (54). In critically ill patients with NODAT, an intravenous insulin drip is considered standard of care. Goldberg, in a review of management of post-transplant DM, proposed that tight glycemic control, with a goal of 80–110 mg/dL, should be used (55). However, others have reported that tight glycemic control (Macrae et al.: 72–126 mg/dL versus less than 216 mg/dL; and Agus et al.: 80–110 mg/dL versus standard care with
Diabetes post-pediatric liver transplant
blood glucose range at the discretion of the attending physician) in the pediatric ICU is associated with greater risk for hypoglycemia and does not lead to significantly improved infection rates or mortality among other major clinical outcomes (56, 57). A large adult ICU study also showed higher mortality among adults with tight (81–108 mg/dL) glucose control, rather than broader blood glucose goals of 180 mg/dL or less (58). Based on available literature and safety concerns, particularly in young children who are more vulnerable to the cognitive effects of hypoglycemia, we propose that a broader blood glucose range of 80–180 mg/dL be used when implementing an intravenous insulin drip. NODAT management in the pediatric outpatient and non-critical hospital setting typically is a combination of lifestyle modifications and subcutaneous insulin. The FDA has approved various insulin analogs and metformin, for use in pediatric patients, and metformin is only FDAapproved in children 10 yr and older with type 2 DM. Metformin is considered a first-line agent in children with type 2 DM; however, in a large prospective randomized-controlled trial, roughly 50% of pediatric patients with type 2 DM failed treatment with metformin alone, or metformin and intensive lifestyle management, within two yr (59, 60). In children with NODAT, there is an additional concern regarding the potential risk for lactic acidosis in those with renal dysfunction, and caution should be used with liver dysfunction, as metformin is metabolized by the liver. Both of these concerns have further limited the use of metformin in the LT population (54). Depending on the degree of hyperglycemia and its association with immunosuppressive medications, various insulin regimens may be utilized, including but not limited to basal insulin alone, basal–bolus insulin, and NPH insulin (55). Any patient treated with insulin is at risk for hypoglycemia and must be trained to monitor finger-stick blood glucose and appropriately
Table 3. Pharmokinetics of commonly used insulin analogs
Long-acting Intermediate-acting Short-acting Rapid-acting
Insulin
Onset
Peak
Duration
Glargine Detemir NPH Regular Aspart Lispro Glulisine
1h 1–2 h 2–4 h 30–60 min 15 min
None None 4–10 h 2–3 h 30–90 min
20–24 h 6–23 h* 12–18 h 8–10 h 3–5 h
Modified from Bolli (61) and Tridgell et al. (62). *Duration of action may vary with dose.
treat hypoglycemia. Table 3 summarizes the various insulin analogs, peak onset of action, and duration of action (61, 62). Renal dysfunction is associated with prolonged half-life of insulin, and lower doses of insulin may be required to avoid hypoglycemia (54). An experienced diabetologist should be consulted regarding subcutaneous insulin management in pediatric patients with NODAT. While some have proposed the use of sulfonylureas and thiazides for treatment of NODAT, the safety and efficacy have not been established in the pediatric DM population (55, 63). Likewise, DDP-4 inhibitors and GLP-1 agonists have not been extensively studied in the pediatric population. Pediatric patients with NODAT should also be screened and monitored for potential complications associated with NODAT. Yearly screening for hypertension and dyslipidemia is recommended for all pediatric LT patients and especially for those with NODAT (50, 55). Dilated retinal examinations and microalbuminuria screening are recommended at or shortly after diagnosis for type 2 DM patients and then annually (64). As there are overlapping risk factors for type 2 DM and NODAT, we propose yearly screening for nephropathy, with a urine microalbumin-to-creatinine ratio, and retinopathy, with a dilated retinal exam, should also be considered for those with NODAT. Conclusion
NODAT is a relatively common complication, with an incidence of roughly 10% for pediatric patients. Fortunately, the majority of patients with NODAT seem to have resolution of the DM with adjustments to immunosuppressive medications, but the long-term risk for recurrence is unknown at this time. Future studies will be aided by uniform definitions for DM and prospective assessments. We propose that future studies be designed to control for the heterogeneity of the pediatric LT population and subclassify patients based on age, pubertal status, underlying etiology of liver disease, ethnicity, family history of DM, immunosuppressive medications, and number of rejection episodes. Pediatric patients at high risk for NODAT should have close monitoring and, when diagnosed, appropriate treatment under the care of a comprehensive medical team. Authors’ contributions Molly O. Regelmann, MD: Principal author. Marina Goldis, MD: Contributed to the literature search, contributed to the initial draft of the pathogenesis section, and gave final
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Regelmann et al. approval of the article. Ronen Arnon, MD: Developed the concept for the review article, contributed to the literature search, critically revised the article, and gave final approval of the article.
References 1. ARNON R, ANNUNZIATO R, MILOH T, et al. Orthotopic liver transplantation for children with Alagille syndrome. Clin Transplant 2012: 26: E94–E100. 2. MILOH T, KERKAR N, PARKAR S, et al. Improved outcomes in pediatric liver transplantation for acute liver failure. Pediatr Transplant 2010: 14: 863–869. 3. MOHAMED EL MOGHAZY W, OGURA Y, MUTSUKO M, et al. Pediatric living-donor liver transplantation for acute liver failure: Analysis of 57 cases. Transpl Int 2010: 23: 823–830. 4. FARMER DG, VENICK RS, MCDIARMID SV, et al. Fulminant hepatic failure in children: Superior and durable outcomes with liver transplantation over 25 years at a single center. Ann Surg 2009: 250: 484–493. 5. WALLIA A, PARIKH ND, MOLITCH ME, et al. Post-transplant hyperglycemia is associated with increased risk of liver allograft rejection. Transplantation 2010: 89: 222–226. 6. WALLIA A, PARIKH ND, O’SHEA-MAHLER E, et al. Glycemic control by a glucose management service and infection rates after liver transplant. Endocr Pract 2011: 17: 546–551. 7. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014: 37: S81–S90. 8. GREIG F, RAPAPORT R, KLEIN G. Characteristics of diabetes after pediatric liver transplant. Pediatr Transplant 2013: 17: 27–33. 9. KUO HT, LAU C, SAMPAIO MS, et al. Pretransplant risk factors for new-onset diabetes mellitus after transplant in pediatric liver transplant recipients. Liver Transpl 2010: 16: 1249–1256. 10. HATHOUT E, ALONSO E, ANAND R, et al. Post-transplant diabetes mellitus in pediatric liver transplantation. Pediatr Transplant 2009: 13: 599–605. 11. ROMERO R, MELDE K, PILLEN T, et al. Persistent hyperglycemia in pediatric liver transplant recipients. Transplant Proc 2001: 33: 3617–3618. 12. UNOS Pediatric Liver Transplant Recipient Follow-up Worksheet. Available at: https://www.unos.org/docs/Liver-Pediatric_Transplant_Recipient_Follow-Up.pdf (accessed October 18, 2014). 13. CREE-GREEN M, TRIOLO TM, NADEAU KJ. Etiology of insulin resistance in youth with type 2 diabetes. Curr Diab Rep 2013: 13: 81–88. 14. YADAV AD, CHANG YH, AGEL BA, et al. New onset diabetes mellitus in living donor versus deceased donor liver transplant recipients: Analysis of the UNOS/OPTN database. Transplant 2013: 20: 634–638. 15. MAYER-DAVIS EJ, BELL RA, DABELEA D, et al. SEARCH for Diabetes in Youth Study Group. The many faces of diabetes in American youth: Type 1 and type 2 diabetes in five race and ethnic populations: The SEARCH for Diabetes in Youth Study. Diabetes Care 2009: 32: S99–S101. 16. AMED S, DEAN H, SELLERS EAC, et al. Risk factors for medication-induced diabetes and type 2 diabetes. J Pediatr 2011: 159: 291–296. 17. PERITO ER, GLIDDEN D, ROBERTS JP, et al. Overweight and obesity in pediatric liver transplant recipients: Prevalence and predictors before and after transplant, United Network for Organ Sharing Data, 1987–2010. Pediatr Transplant 2012: 16: 41–49. 18. HOVINGA IC, STAM ED, MEARIN ML, MUL D. A girl with type 1 diabetes and a yellowish appearance. BMJ Case Rep 2010: 26: 1–4.
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19. SAARINEN S, OLERUP O, BROOME U. Increased frequency of autoimmune disease in patients with sclerosing cholangitis. Am J Gastroenterol 2000: 95: 3195–3199. 20. CARROLL PB, RILO H, REYES J, et al. FK 506-associated diabetes mellitus in the pediatric transplant population is a rare complication. Transplant Proc 1991: 23: 3171–3172. 21. NIU YJ, SHEN ZY, XU C, et al. Establishment of tacrolimusinduced diabetes in rat model and assessment of clinical treatments for post-transplant diabetes mellitus in liver transplant recipients. Clin Lab 2013: 59: 869–874. 22. LARSEN JL, BENNETT RG, BURKMAN T, et al. Tacrolimus and sirolimus cause insulin resistance in normal Sprague Dawley rats. Transplantation 2006: 82: 466–470. 23. KESHAVARZ R, MOUSAVI MA, HASSANI C. Diabetic ketoacidosis in a child on FK506 immunosuppression after a liver transplant. Pediatr Emerg Care 2002: 18: 22–24. 24. DEHGHANI SM, NIKEGHBALIAN S, ESHRAGHIAN A, et al. Newonset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation. Pediatr Transplant 2009: 13: 536–539. 25. DI COSMO N, VAIRO P, DEBRAY D, et al. Normal b-cell function in post-liver transplantation diabetes treated with tacrolimus. Diabetes Care 2004: 27: 1837–1838. 26. CHO JM, OH SH, KIM KM, et al. Prevalence and treatment of new-onset diabetes mellitus after liver transplantation in Korean children: A single-center study. Transplant Proc 2014: 46: 873–875. 27. EMRE S, GENYK Y, SCHLUGER LK, et al. Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients. Transpl Int 2000: 13: 73–78. 28. LOPES PC, FUHRMANN A, CARVALHO F, et al. Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment. Biochem Pharmacol 2014: 91: 61–73. 29. SJOHOLM A. Inhibitory effects of cyclosporine A on rat insulinoma cell proliferation, polyamine content and insulin secretion. Mol Cell Endocrinol 1994: 99: 21–24. 30. BORLAK J, NIEHOF M. HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced post-transplantation diabetes mellitus. PLoS One 2009: 4: e4662. 31. STEINMULLER TM, GRAF KJ, SCHLEICHER J. The effect of FK506 versus cyclosporine on glucose and lipid metabolism—a randomized trial. Transplantation 1994: 58: 669–674. 32. RAMIREZ CB, DORIA C, FRANK AM. Completely steroid-free immunosuppression in liver transplantation: A randomized study. Clin Transplant 2013: 27: 463–471. 33. VAN RAALTE DH, DIAMANT M. Steroid diabetes: From mechanism to treatment? Neth J Med 2014: 72: 62–72. 34. MATSUMOTO K, YAMASAKI H, AKAZAWA S. High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic b-cells in normal men. J Clin Endocrinol Metab 1996: 81: 2621–2626. 35. DELAUNAY F, KHAN A, CINTRA A, et al. Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest 1997: 100: 2094–2098. 36. SINDHI R, SEWARD J, MAZARIEGOS G, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant 2005: 9: 391–397. 37. ASRANI SK, WIESNER RH, TROTTER JF. De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: The 2000–2003 phase II prospective randomized trial. Am J Transplant 2014: 14: 356–366. 38. SHIVASWAMY V, BENNETT RG, CLURE CC. Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats. Transl Res 2014: 163: 221–231.
Diabetes post-pediatric liver transplant 39. BARLOW AD, NICHOLSON ML, HERBERT TP. Evidence for rapamycin toxicity in pancreatic b-cells and a review of the underlying molecular mechanisms. Diabetes 2013: 62: 2674–2682. 40. TEUTONICO A, SCHENA PF, DI PAOLO S. Glucose metabolism in renal transplant recipients: Effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005: 16: 3128–3135. 41. CIANCIO G, BURKE GW, GAYNOR JJ, et al. A randomized longterm trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate versus cyclosporine/sirolimus in renal transplantation: Three-year analysis. Transplantation 2006: 81: 845–852. 42. VIVARELLI M, DAZZI A, CUCCHETTI A, et al. Sirolimus in liver transplant recipients: A large single-center experience. Transplant Proc 2010: 42: 2579–2584. 43. JU WQ, GUO ZY, LIANG WH, et al. Sirolimus conversion in liver transplant recipients with calcineurin inhibitor-induced complications: Efficacy and safety. Exp Clin Transplant 2012: 10: 132–135. 44. KALTENBORN A, SCHREM H. Mycophenolate mofetil in liver transplantation: A review. Ann Transplant 2013: 18: 685–696. 45. PAGEAUX GP, ROSTAING L, CALMUS Y, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 2006: 12: 1755–1760. 46. SCHMEDING M, KIESSLING A, NEUHAUS R, et al. Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation 2011: 92: 923–999. 47. PROKAI A, FEKETE A, PASTI K. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012: 13: 81–91. 48. FIRST MR, DHADDA S, CROY R, et al. New-onset diabetes after transplantation (NODAT): An evaluation of definitions in clinical trials. Transplantation 2013: 96: 58–64. 49. GALLAGHER EJ, BLOOMGARDEN ZT, LE ROITH D. Review of hemoglobin A1c in the management of diabetes. J Diabetes 2009: 1: 9–17. 50. KELLY DA, BUCUVALAS JC, ALONSO EM, et al. Long-term medical management of the pediatric patient after liver transplantation: 2013 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013: 19: 798–825.
51. KERKAR N, HADZIC N, DAVIES ET, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998: 351: 409–413. 52. MORAN A, PILLAY K, BECKER DJ, ACERINI CL. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2014: 15(Suppl. 20): 65–76. 53. HOGLER W, BAUMANN U, KELLY D. Endocrine and bone metabolic complications in chronic liver disease and after liver transplantation in children. J Pediatr Gastroenterol Nutr 2012: 54: 313–321. 54. THERASSE A, WALLIA A, MOLITCH ME. Management of posttransplant diabetes. Curr Diab Rep 2013: 13: 121–129. 55. GOLDBERG PA. Comprehensive management of post-transplant diabetes mellitus: From intensive care to home care. Endocrinol Metab Clin North Am 2007: 36: 907–922. 56. MACRAE D, GRIEVE R, ALLEN E. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014: 370: 107–118. 57. AGUS MS, STEIL GM, WYPIJ D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012: 367: 1208–1219. 58. NICE-SUGAR Study Investigators, FINFER S, CHITTOCK DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009: 360: 1283– 1297. 59. COPELAND K, SILVERSTEIN J, MOORE KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013: 131: 364–382. 60. TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012: 366: 2247–2256. 61. BOLLI GB. Insulin treatment in type 1 diabetes. Endocr Pract 2006: 12: s105–s109. 62. TRIDGELL DM, TRIDGELL AH, HIRSCH IB. Inpatient management of adults and children with type 1 diabetes. Endocrinol Metab Clin North Am 2010: 39: 595–608. 63. NOBILI V, DEVILLE DE GOYET J. Pediatric post-transplant metabolic syndrome: New clouds on the horizon. Pediatr Transplantation 2013: 17: 216–223. 64. SPRINGER SC, SILVERSTEIN J, COPELAND K, et al. Management of type 2 diabetes mellitus in children and adolescents. Pediatrics 2013: 131: e648–e664.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12523
Review Article
New-onset diabetes mellitus after pediatric liver transplantation Regelmann MO, Goldis M, Arnon R. (2015) New-onset diabetes mellitus after pediatric liver transplantation. Pediatr Transplant, 19: 452–459. DOI: 10.1111/petr.12523. Abstract: In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.
In the last several decades, mortality after pediatric LT has greatly improved, with a reported five-yr survival rate ranging from 69.5 to 86.2%, depending on the underlying indication for the LT (1–4). As the survival of children with ESLD has greatly improved, there has been an emergence of the long-term morbidities associated with both the underlying conditions causing the liver failure and the complications of the immunosuppressant medications used to maintain graft survival. The focus of this review is on NODAT in the pediatric population. Improvement in hyperglycemia has been associated with
Abbreviations: ADA, American Diabetes Association; CF, cystic fibrosis; DM, diabetes mellitus; ESLD, end-stage liver disease; FDA, Federal Drug Administration; GAD, glutamate decarboxylase; GC, glucocorticoids; ICU, intensive care unit; LT, liver transplantation; MMF, mycophenolate mofetil; NODAT, new-onset diabetes mellitus after liver transplant; OGTT, oral glucose tolerance test; PSC, primary sclerosis cholangitis; ZnT8, zinc transporter 8.
452
Molly O. Regelmann1, Marina Goldis1 and Ronen Arnon2 1
Division of Pediatric Endocrinology & Diabetes, Hall Family Center for Diabetes, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 2Division of Pediatric Hepatology, Recanati/Miller Transplant Institute, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA Key words: new-onset diabetes after transplant – liver transplant – pediatric – insulin Molly O. Regelmann, MD, Division of Pediatric Endocrinology & Diabetes, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1616, New York, NY 10029, USA Tel.: +1 212 241 6936 Fax: +1 212 426 2132 E-mail: [email protected] Accepted for publication 15 April 2015
reduced risks of graft rejection and infection, as well as potential long-term complications of DM (5, 6). NODAT can become a chronic condition, and DM alone can be associated with damage to the eyes, kidneys, cardiovascular system, and nervous system (7), which makes identifying those at risk, properly diagnosing NODAT, and prescribing appropriate treatment critically important for long-term health outcomes. Epidemiology and risk factors for NODAT
Most studies report an incidence of NODAT close to 10% with a range of 8.0–14.1% for all indications for pediatric LT. There is a lack of uniform definition for NODAT in the literature, which is likely the reason for some of the variability (8–11). NODAT is not defined, and its presence, as well as treatment with insulin, is answered simply as “yes” or “no” on the United Network for Organ Sharing Transplant Recipient Follow-up form (12). The majority of patients with NODAT seem to be diagnosed in
Diabetes post-pediatric liver transplant
the first month after LT, and many seem to have transient DM. The incidence has been reported to increase with time from LT (8, 10), and Kuo et al. (9) reported a cumulative incidence of NODAT of 5.9%, 8.3%, and 11.2% at one, three, and five yr. Risk factors for developing NODAT have been difficult to tease out, in part, due to a lack of uniformity of diagnosis and data collection, as well as the heterogeneity of the pediatric LT patient population. The four studies that have attempted to identify risk factors for NODAT in pediatric LT are summarized in Table 1 (8–11). Older age at time of LT has been associated with a higher risk for NODAT, with an increase in risk noted at five yr of age and the highest rates noted in those 13 yr or older (9, 10). The higher risk in those 13 yr or older may be associated with pubertal status, as rates of insulin resistance and type 2 DM are known to increase with puberty (13). To date, there are no reports that evaluate risk for NODAT with pubertal status. And while having a living, vs. a deceased, donor transplant has been reported to reduce risk in the first year for NODAT in adult LT, this has not been reported in pediatric LT (9, 10, 14). The underlying etiologies for LT play a significant role in the risk for developing NODAT, with rates reported at 57.4% in those with CF and 22.3% in those with PSC three yr post-LT (9). Acute hepatic necrosis, cirrhosis, and HCV
infection have also been reported to be associated with a higher risk for NODAT (9). Having an LT for biliary atresia seems to be associated with a lower risk for developing NODAT with rates reported between 3.6 for NODAT and 8.9% for NODAT and glucose intolerance, but these reports may be confounded by the fact that older age seems to be a risk factor and most children undergoing LT for biliary atresia are younger than five yr (9, 10). Hispanic and African American/black ethnic backgrounds have also been reported to be associated with higher rates of developing NODAT. Much like age, this finding is likely related to associations with higher rates of insulin resistance and type 2 DM noted in these ethnic groups (15, 16). No studies have reported specifically on rates of NODAT in the pediatric population of Asian/Pacific Islander and American Indian/Alaska Native background, populations also known to have higher rates of type 2 DM (15). Unlike type 2 DM, however, risk for NODAT in the pediatric population does not have a strong association with BMI. In fact, the two largest cohort studies found no association with BMI and risk of NODAT, and the case–control study reported by Greig et al. suggested that a lower BMI was a risk factor for NODAT (8–10). One may conclude that the lack of association with BMI could be confounded by the underlying diagnosis, as patient with CF and chronic
Table 1. Summary of pediatric studies evaluating risk factors for NODAT Greig et al. (8)
Kuo et al. (9)
Hathout et al. (10)
Romero et al. (11)
Type of study Number of patients Prevalence
Age and sex-matched control 300 (24 with NODAT, then matched) 8.0% (persistent NODAT) 2.7% (transient hyperglycemia)
Cohort 1161 10.1% (during mean follow-up period) 11.2% (by 3 yr)
Cohort 1611 13.3% (glucose intolerance/NODAT); 10.3% in the 1st month
Mean follow-up
Factors assessed at 1-yr visit (NODAT diagnosed 0.03–74.0 mo, mean 14.0 19.6 mo) Rejection in 1st year Methylprednisolone bolus (both having had one and number of boluses) Tacrolimus level Use of 3 immunosuppressants Lower BMI
770 days
Study looked only at those diagnosed in the 1st month Age >5 yr Black and Hispanic race Reason for LT, other than biliary atresia Hospitalized in ICU Steroid use Tacrolimus (vs. cyclosporine) CMV positive
Cohort 81 14.1% (eliminating 3 with pretransplant DM; 17.2% all post-transplant DM) Not clear
Risk factors associated with increased risk
Not factors
Underlying cause of ESLD Race
Age >/=13 yr African American race Bilirubin >/3 mg/dL Cause of ESLD: CF Acute hepatic necrosis Cirrhosis Primary sclerosing cholangitis HCV infection Acute rejection in 1st year Sex BMI Donor—age, sex, type (living vs. deceased), diabetic Initial immunosuppressant Maintenance steroids at one yr
BMI Donor—age, type (living vs. deceased), CMV status
Older age (12.3 4.6 yr vs. 5.3 5.6 yr) Tacrolimus (vs. cyclosporine)
Sex Race
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liver disease may have lower BMIs at baseline. In fact, Perito et al. reported that once controlling for age, primary diagnosis, and ethnicity, the odds of developing NODAT did not differ by BMI for 2305 pediatric patients documented as not having DM prior to LT. Being overweight or obese following LT certainly may be associated with comorbidities, and further studies are needed to assess for the potential impact on cardiovascular disease and hyperlipidemia, as well as long-term risk for NODAT (17). The immunosuppressant medications have also been associated with varying rates of NODAT. While Kuo et al. did not report a noted association with initial immunosuppressant regimen, and the use of tacrolimus, versus cyclosporine, has been reported to be associated with an increased risk for NODAT by multiple studies (9–11). The use of steroids at the time of the transplant has also been associated with higher risk for NODAT (9–11). And, the use of three immunosuppressant medications, as well as rejection in the first year (presumably treated with more and higher doses of immunosuppressive medications), has been noted to be associated with a higher risk for NODAT (8, 9). Pathogenesis of NODAT
The pathogenesis of NODAT is likely a combination of insulin resistance and insulin insufficiency in the vast majority of patients. Medications have primarily been identified as the inciting agents for the carbohydrate metabolism dysfunction and are discussed more extensively below. However, in patient populations at risk for type 2 DM, it is likely that other genetic factors play a role. And in patients with particular conditions, such as CF, impairment of b-cell function is greatly influenced by the underlying disease. Although no cases are reported in the pediatric LT literature, pediatric patients with NODAT are not protected from an autoimmune destruction of b-cells. Type 1 DM has been described in patients with autoimmune hepatitis and PSC. Therefore, type 1 DM should be considered in any child with NODAT, particularly those with a history of autoimmunity (18, 19). Tacrolimus
When first introduced, tacrolimus, a calcineurin inhibitor, was primarily used to prevent and treat transplant rejection following other immunosuppressive failures. Initial reports suggested a relatively low incidence of NODAT in pediatric LT patients treated with tacrolimus (20). In the last decade, as tacrolimus has become more common 454
in immunosuppressive protocols following LT, reports suggest that tacrolimus is associated with an increased risk for NODAT, particularly when blood levels are higher (8–10). The mechanism by which tacrolimus induces hyperglycemia is likely a combination of decreased insulin secretion, b-cell necrosis, and increased insulin resistance, which have been demonstrated in rats (21, 22). In human subjects with LT, patients, without known autoimmunity, treated with tacrolimus have been described to present in diabetic ketoacidosis, suggesting an insulin deficiency related to tacrolimus (8, 23, 24). Measurable c-peptide levels and high insulin dose requirements have also been described in patients treated with tacrolimus for LT, consistent with insulin resistance (25). The DM associated with tacrolimus has been reported to be reversible with tapering of tacrolimus dose or selecting an alternative immunosuppressive regimen (26, 27). Cyclosporine A
Cyclosporine A, a calcineurin inhibitor, has been used successfully in LT since the 1980s. Rodent studies have shown impaired glucose tolerance and insulin resistance, as well as an increase in gluconeogenesis in rats treated with cyclosporine A (28). Cyclosporine A has also been demonstrated to impair insulin secretion in in vitro and in vivo studies (29, 30). While cyclosporine A, by itself, has been shown to be diabetogenic, it is thought to be associated with a reduced risk for NODAT, when compared to tacrolimus, as noted above (10, 11). A series reported by Emre et al. (27) reported that 15 of 17 adult patients with NODAT, treated initially with tacrolimus and converted to cyclosporine A for uncontrolled NODAT, had resolution of DM. A pediatric case series reported that seven of 18 patients with NODAT were converted from tacrolimus to cyclosporine, with steroid taper and addition of MMF, and had resolution of NODAT at 1– 19 months after diagnosis; the other patients in the series had steroid tapers alone, or with the addition of MMF, with resolution of NODAT at 0.5–2 months (26). Not all studies have reported positive results, and in another series of adult patients, there was no significant difference in glucose intolerance or frank NODAT when comparing cyclosporine A and tacrolimus immunosuppressive regimens (31). Glucocorticoids
Since the first successful LT, GC have been a standard part of immunosuppressive protocols in
Diabetes post-pediatric liver transplant
LT and are still routinely used in many protocols today. GC are well documented to be associated with increased risk of DM, as well as other complications, including but not limited to obesity, hypertension, and hyperlipidemia (32). The mechanism by which GC induce NODAT is likely related to both reduced insulin sensitivity and b-cell dysfunction (33). In humans, insulin resistance has been documented to increase with escalating doses of GC; however, the way in which GC induces skeletal muscle resistance is not well understood (34). In vitro, as well as human in vivo, studies have demonstrated that GC impair insulin secretion; b-cell function is affected by reducing glucose-adjusted insulin secretion (34, 35). GC are also known to increase hepatic glucose production (35). Sirolimus
Sirolimus, a mammalian target of rapamycin inhibitor, is used as an immunosuppressive medication and has the advantage of being less nephrotoxic when compared to calcineurin inhibitors but may not have as favorable outcomes in terms of graft survival (36, 37). Sirolimus has been noted to be associated with the development of NODAT, but the exact mechanisms of immunosuppressant-induced hyperglycemia are still being delineated. Rat studies have demonstrated insulin resistance in those treated with sirolimus (38). Sirolimus has also been found to be associated with reduced b-cell size, mass, and proliferation (39). Higher incidences of new-onset DM and insulin resistance have been reported in renal transplant patients treated with sirolimus, when compared to other regimens, including those with calcineurin inhibitors (40, 41). Interestingly, in patients with LT, sirolimus has been reported to have a lower incidence of NODAT (42). Conversion from calcineurin inhibitor to sirolimus has also been reported to improve insulin requirements in three patients with NODAT (43). Mycophenolate mofetil and azathioprine
MMF and azathioprine are purine analogs used, primarily as adjuvants, for immunosuppression
in prophylaxis for LT rejection. MMF has not been reported to increase risk for NODAT and also has the advantage that it does not have significant nephrogenic or cardiovascular toxicities (44, 45). MMF monotherapy is not common in pediatric LT, but in one adult study, MMF monotherapy seemed to have positive effects on DM, and patients treated with MMF, rather than a calcineurin inhibitor, were less likely to have progression of DM (46). There are also no reports of NODAT specifically associated with azathioprine (47). Screening and diagnosis new-onset DM after liver transplant
There are no data reporting presenting symptoms for NODAT. As most patients with NODAT still produce some insulin at diagnosis, it is rare for patients to present in diabetic ketoacidosis, although it has been reported in the pediatric literature (23, 24, 26). The percentage of patients at NODAT diagnosis with frank polyuria and polydipsia, versus asymptomatic hyperglycemia, is unknown. Given the natural history of DM, it is likely that the majority of patients with NODAT are asymptomatic for a period of time prior to developing obvious symptoms of NODAT. Because of the increased risk for morbidity and mortality associated with NODAT, identifying and screening those at risk for NODAT is critically important. For the purposes of uniformity, to aid in the clinical and research setting, we agree with First et al. (48) that uniform definitions for DM, as established by the ADA, should be used for LT patients. The ADA criteria for the diagnosis of DM are an 8-h fasting plasma glucose of ≥126 mg/dL (7.0 mmol/L), two-h plasma glucose of ≥200 mg/dL (11.1 mmol/L) during OGTT (using 1.75 g/kg, to maximum dose of 75 g of anhydrous glucose dissolved in water), or in a patient with symptoms of polyuria and polydipsia, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). Table 2 summarizes diagnostic criteria, as well as criteria for “prediabetes,” which can be defined as either impairment of glucose tolerance (post-prandial glucose 140–199 mg/dL) or impaired fasting glucose (100–125 mg/dL). Hemoglobin A1c, which takes
Table 2. Criteria for “prediabetes” and DM (modified from ADA) (7)
Hemoglobin A1c 8-h fasting plasma glucose 2-h plasma glucose—OGTT 75 g Random plasma glucose + symptoms of diabetes
Prediabetes
DM
5.0–6.4% 100–125 mg/dL (5.6–6.9 mmol/L) 140–199 mg/dL (7.8–11.0 mmol/L)
>/=6.5% >/=126 mg/dL (7.0 mmol/L) >/=200 mg/dL (11.1 mmol/L) >/=200 mg/dL (11.1 mmol/L)
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an average blood glucose over 2–3 months, has recently been added as a diagnostic test, with a hemoglobin A1c of 6.5% or greater on a standardized assay being diagnostic of DM (7). Hemoglobin A1c should be used with caution as the sole screening tool, as it may miss or overdiagnose cases of DM. Hemoglobin A1c can be lower in those with chronic liver disease, administered erythropoietin, taking aspirin, and with hypertriglyceridemia. An increased hemoglobin A1c can be seen in iron deficiency, B12 deficiency, decreased erythropoiesis, chronic renal disease, after splenectomy, with chronic opiate use, after large doses of aspirin, with alcoholism, and with hyperbilirubinemia. Hemoglobinopathies can also have variable effects on the hemoglobin A1c (49). In the immediate post-LT period, when patients are typically on their highest doses of immunosuppressive medications, NODAT is more common. Likewise, NODAT is more frequently noted during episodes of acute rejection, when immunosuppressive medications, particularly GC, are given in higher doses (8, 10). The American Association for the Study of Liver Diseases and the American Society of Transplantation recommend screening LT recipients older than five yr annually with fasting glucose in the early post-LT period and during long-term follow-up (50). While this is a reasonable starting point, we propose that screening should also be performed during times of higher risk for hyperglycemia, such as immediately post-LT, during treatment for acute rejection, chronic rejection, and with de novo autoimmune hepatitis, which also typically is treated with high doses of GC and/or calcineurin inhibitors (2, 50, 51). The guidelines are also likely to miss glucose intolerance and early DM in those with b-cell dysfunction. Screening guidelines for patients with CF, for example, recommend yearly OGTT, because the first abnormality of carbohydrate metabolism is typically a delayed or blunted peak insulin secretion, and later in the course of disease, abnormally elevated fasting glucose is noted (52). Hogler et al. (53) suggested that those identified as being “high risk” following LT should have yearly screening oral glucose tolerance (OGTT). “High risk” was defined as children >5 yr of age, CF, PSC, acute hepatic necrosis. We propose that urinary frequency and fluid intake be assessed as part of the review of systems at all medical follow-up visits for patients with LT. Any patients with reported symptoms of polyuria or polydipsia should have screening tests. We also agree with the Hogler et al. recommendation to perform yearly screening OGTT 456
and propose that children with risk factors for type 2 DM, including those with a family history of type 2 DM and of a high-risk ethnicity (African American, Hispanic, American Indian/ Alaska Native, and Asian/Pacific Islander), should be included in the “high-risk” group (15, 16, 53). We also suggest that any patient noted to have resolved transient DM also be screened with yearly OGTT, as they theoretically are at higher risk for recurrence. Once the diagnosis of DM has been established, we also recommend considering screening for type 1 DM, particularly in those at higher risk for autoimmunity (for example, those previously diagnosed with PSC or autoimmune hepatitis), with diabetes-related antibody testing [islet antigen-2 (IA-2), GAD, ZnT8, and insulin antibodies)]. Distinguishing the diagnosis of type 1 DM vs. NODAT is important, because patients with type 1 DM must be managed with insulin. Treatment and management
DM management and treatment is very much individualized and dependent on age, other medical conditions, immunosuppressant medications, and psychosocial circumstances. Management should ideally be a team approach with pediatric endocrinologists working with the transplant physicians, intensive care physicians, nutritionists, and psychosocial support services, to optimize blood glucose control. The goal for any child with DM is to normalize blood glucose to as close to normal without frequent episodes of hypoglycemia. This can be particularly daunting in children with LT, as many already have multiple other medications and health concerns. Adjustments to the immunosuppressive medications are typically managed by the transplant physicians, and the clinicians managing the diabetes should understand the potential effects of the various immunosuppressive medications on DM control, as outlined above. All patients with LT should be counseled regarding a healthy lifestyle, including a balanced diet and routine exercise. Those with NODAT should have more extensive nutrition counseling, including limitations on concentrated sweets (54). In critically ill patients with NODAT, an intravenous insulin drip is considered standard of care. Goldberg, in a review of management of post-transplant DM, proposed that tight glycemic control, with a goal of 80–110 mg/dL, should be used (55). However, others have reported that tight glycemic control (Macrae et al.: 72–126 mg/dL versus less than 216 mg/dL; and Agus et al.: 80–110 mg/dL versus standard care with
Diabetes post-pediatric liver transplant
blood glucose range at the discretion of the attending physician) in the pediatric ICU is associated with greater risk for hypoglycemia and does not lead to significantly improved infection rates or mortality among other major clinical outcomes (56, 57). A large adult ICU study also showed higher mortality among adults with tight (81–108 mg/dL) glucose control, rather than broader blood glucose goals of 180 mg/dL or less (58). Based on available literature and safety concerns, particularly in young children who are more vulnerable to the cognitive effects of hypoglycemia, we propose that a broader blood glucose range of 80–180 mg/dL be used when implementing an intravenous insulin drip. NODAT management in the pediatric outpatient and non-critical hospital setting typically is a combination of lifestyle modifications and subcutaneous insulin. The FDA has approved various insulin analogs and metformin, for use in pediatric patients, and metformin is only FDAapproved in children 10 yr and older with type 2 DM. Metformin is considered a first-line agent in children with type 2 DM; however, in a large prospective randomized-controlled trial, roughly 50% of pediatric patients with type 2 DM failed treatment with metformin alone, or metformin and intensive lifestyle management, within two yr (59, 60). In children with NODAT, there is an additional concern regarding the potential risk for lactic acidosis in those with renal dysfunction, and caution should be used with liver dysfunction, as metformin is metabolized by the liver. Both of these concerns have further limited the use of metformin in the LT population (54). Depending on the degree of hyperglycemia and its association with immunosuppressive medications, various insulin regimens may be utilized, including but not limited to basal insulin alone, basal–bolus insulin, and NPH insulin (55). Any patient treated with insulin is at risk for hypoglycemia and must be trained to monitor finger-stick blood glucose and appropriately
Table 3. Pharmokinetics of commonly used insulin analogs
Long-acting Intermediate-acting Short-acting Rapid-acting
Insulin
Onset
Peak
Duration
Glargine Detemir NPH Regular Aspart Lispro Glulisine
1h 1–2 h 2–4 h 30–60 min 15 min
None None 4–10 h 2–3 h 30–90 min
20–24 h 6–23 h* 12–18 h 8–10 h 3–5 h
Modified from Bolli (61) and Tridgell et al. (62). *Duration of action may vary with dose.
treat hypoglycemia. Table 3 summarizes the various insulin analogs, peak onset of action, and duration of action (61, 62). Renal dysfunction is associated with prolonged half-life of insulin, and lower doses of insulin may be required to avoid hypoglycemia (54). An experienced diabetologist should be consulted regarding subcutaneous insulin management in pediatric patients with NODAT. While some have proposed the use of sulfonylureas and thiazides for treatment of NODAT, the safety and efficacy have not been established in the pediatric DM population (55, 63). Likewise, DDP-4 inhibitors and GLP-1 agonists have not been extensively studied in the pediatric population. Pediatric patients with NODAT should also be screened and monitored for potential complications associated with NODAT. Yearly screening for hypertension and dyslipidemia is recommended for all pediatric LT patients and especially for those with NODAT (50, 55). Dilated retinal examinations and microalbuminuria screening are recommended at or shortly after diagnosis for type 2 DM patients and then annually (64). As there are overlapping risk factors for type 2 DM and NODAT, we propose yearly screening for nephropathy, with a urine microalbumin-to-creatinine ratio, and retinopathy, with a dilated retinal exam, should also be considered for those with NODAT. Conclusion
NODAT is a relatively common complication, with an incidence of roughly 10% for pediatric patients. Fortunately, the majority of patients with NODAT seem to have resolution of the DM with adjustments to immunosuppressive medications, but the long-term risk for recurrence is unknown at this time. Future studies will be aided by uniform definitions for DM and prospective assessments. We propose that future studies be designed to control for the heterogeneity of the pediatric LT population and subclassify patients based on age, pubertal status, underlying etiology of liver disease, ethnicity, family history of DM, immunosuppressive medications, and number of rejection episodes. Pediatric patients at high risk for NODAT should have close monitoring and, when diagnosed, appropriate treatment under the care of a comprehensive medical team. Authors’ contributions Molly O. Regelmann, MD: Principal author. Marina Goldis, MD: Contributed to the literature search, contributed to the initial draft of the pathogenesis section, and gave final
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Regelmann et al. approval of the article. Ronen Arnon, MD: Developed the concept for the review article, contributed to the literature search, critically revised the article, and gave final approval of the article.
References 1. ARNON R, ANNUNZIATO R, MILOH T, et al. Orthotopic liver transplantation for children with Alagille syndrome. Clin Transplant 2012: 26: E94–E100. 2. MILOH T, KERKAR N, PARKAR S, et al. Improved outcomes in pediatric liver transplantation for acute liver failure. Pediatr Transplant 2010: 14: 863–869. 3. MOHAMED EL MOGHAZY W, OGURA Y, MUTSUKO M, et al. Pediatric living-donor liver transplantation for acute liver failure: Analysis of 57 cases. Transpl Int 2010: 23: 823–830. 4. FARMER DG, VENICK RS, MCDIARMID SV, et al. Fulminant hepatic failure in children: Superior and durable outcomes with liver transplantation over 25 years at a single center. Ann Surg 2009: 250: 484–493. 5. WALLIA A, PARIKH ND, MOLITCH ME, et al. Post-transplant hyperglycemia is associated with increased risk of liver allograft rejection. Transplantation 2010: 89: 222–226. 6. WALLIA A, PARIKH ND, O’SHEA-MAHLER E, et al. Glycemic control by a glucose management service and infection rates after liver transplant. Endocr Pract 2011: 17: 546–551. 7. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014: 37: S81–S90. 8. GREIG F, RAPAPORT R, KLEIN G. Characteristics of diabetes after pediatric liver transplant. Pediatr Transplant 2013: 17: 27–33. 9. KUO HT, LAU C, SAMPAIO MS, et al. Pretransplant risk factors for new-onset diabetes mellitus after transplant in pediatric liver transplant recipients. Liver Transpl 2010: 16: 1249–1256. 10. HATHOUT E, ALONSO E, ANAND R, et al. Post-transplant diabetes mellitus in pediatric liver transplantation. Pediatr Transplant 2009: 13: 599–605. 11. ROMERO R, MELDE K, PILLEN T, et al. Persistent hyperglycemia in pediatric liver transplant recipients. Transplant Proc 2001: 33: 3617–3618. 12. UNOS Pediatric Liver Transplant Recipient Follow-up Worksheet. Available at: https://www.unos.org/docs/Liver-Pediatric_Transplant_Recipient_Follow-Up.pdf (accessed October 18, 2014). 13. CREE-GREEN M, TRIOLO TM, NADEAU KJ. Etiology of insulin resistance in youth with type 2 diabetes. Curr Diab Rep 2013: 13: 81–88. 14. YADAV AD, CHANG YH, AGEL BA, et al. New onset diabetes mellitus in living donor versus deceased donor liver transplant recipients: Analysis of the UNOS/OPTN database. Transplant 2013: 20: 634–638. 15. MAYER-DAVIS EJ, BELL RA, DABELEA D, et al. SEARCH for Diabetes in Youth Study Group. The many faces of diabetes in American youth: Type 1 and type 2 diabetes in five race and ethnic populations: The SEARCH for Diabetes in Youth Study. Diabetes Care 2009: 32: S99–S101. 16. AMED S, DEAN H, SELLERS EAC, et al. Risk factors for medication-induced diabetes and type 2 diabetes. J Pediatr 2011: 159: 291–296. 17. PERITO ER, GLIDDEN D, ROBERTS JP, et al. Overweight and obesity in pediatric liver transplant recipients: Prevalence and predictors before and after transplant, United Network for Organ Sharing Data, 1987–2010. Pediatr Transplant 2012: 16: 41–49. 18. HOVINGA IC, STAM ED, MEARIN ML, MUL D. A girl with type 1 diabetes and a yellowish appearance. BMJ Case Rep 2010: 26: 1–4.
458
19. SAARINEN S, OLERUP O, BROOME U. Increased frequency of autoimmune disease in patients with sclerosing cholangitis. Am J Gastroenterol 2000: 95: 3195–3199. 20. CARROLL PB, RILO H, REYES J, et al. FK 506-associated diabetes mellitus in the pediatric transplant population is a rare complication. Transplant Proc 1991: 23: 3171–3172. 21. NIU YJ, SHEN ZY, XU C, et al. Establishment of tacrolimusinduced diabetes in rat model and assessment of clinical treatments for post-transplant diabetes mellitus in liver transplant recipients. Clin Lab 2013: 59: 869–874. 22. LARSEN JL, BENNETT RG, BURKMAN T, et al. Tacrolimus and sirolimus cause insulin resistance in normal Sprague Dawley rats. Transplantation 2006: 82: 466–470. 23. KESHAVARZ R, MOUSAVI MA, HASSANI C. Diabetic ketoacidosis in a child on FK506 immunosuppression after a liver transplant. Pediatr Emerg Care 2002: 18: 22–24. 24. DEHGHANI SM, NIKEGHBALIAN S, ESHRAGHIAN A, et al. Newonset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation. Pediatr Transplant 2009: 13: 536–539. 25. DI COSMO N, VAIRO P, DEBRAY D, et al. Normal b-cell function in post-liver transplantation diabetes treated with tacrolimus. Diabetes Care 2004: 27: 1837–1838. 26. CHO JM, OH SH, KIM KM, et al. Prevalence and treatment of new-onset diabetes mellitus after liver transplantation in Korean children: A single-center study. Transplant Proc 2014: 46: 873–875. 27. EMRE S, GENYK Y, SCHLUGER LK, et al. Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients. Transpl Int 2000: 13: 73–78. 28. LOPES PC, FUHRMANN A, CARVALHO F, et al. Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment. Biochem Pharmacol 2014: 91: 61–73. 29. SJOHOLM A. Inhibitory effects of cyclosporine A on rat insulinoma cell proliferation, polyamine content and insulin secretion. Mol Cell Endocrinol 1994: 99: 21–24. 30. BORLAK J, NIEHOF M. HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced post-transplantation diabetes mellitus. PLoS One 2009: 4: e4662. 31. STEINMULLER TM, GRAF KJ, SCHLEICHER J. The effect of FK506 versus cyclosporine on glucose and lipid metabolism—a randomized trial. Transplantation 1994: 58: 669–674. 32. RAMIREZ CB, DORIA C, FRANK AM. Completely steroid-free immunosuppression in liver transplantation: A randomized study. Clin Transplant 2013: 27: 463–471. 33. VAN RAALTE DH, DIAMANT M. Steroid diabetes: From mechanism to treatment? Neth J Med 2014: 72: 62–72. 34. MATSUMOTO K, YAMASAKI H, AKAZAWA S. High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic b-cells in normal men. J Clin Endocrinol Metab 1996: 81: 2621–2626. 35. DELAUNAY F, KHAN A, CINTRA A, et al. Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest 1997: 100: 2094–2098. 36. SINDHI R, SEWARD J, MAZARIEGOS G, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant 2005: 9: 391–397. 37. ASRANI SK, WIESNER RH, TROTTER JF. De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: The 2000–2003 phase II prospective randomized trial. Am J Transplant 2014: 14: 356–366. 38. SHIVASWAMY V, BENNETT RG, CLURE CC. Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats. Transl Res 2014: 163: 221–231.
Diabetes post-pediatric liver transplant 39. BARLOW AD, NICHOLSON ML, HERBERT TP. Evidence for rapamycin toxicity in pancreatic b-cells and a review of the underlying molecular mechanisms. Diabetes 2013: 62: 2674–2682. 40. TEUTONICO A, SCHENA PF, DI PAOLO S. Glucose metabolism in renal transplant recipients: Effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005: 16: 3128–3135. 41. CIANCIO G, BURKE GW, GAYNOR JJ, et al. A randomized longterm trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate versus cyclosporine/sirolimus in renal transplantation: Three-year analysis. Transplantation 2006: 81: 845–852. 42. VIVARELLI M, DAZZI A, CUCCHETTI A, et al. Sirolimus in liver transplant recipients: A large single-center experience. Transplant Proc 2010: 42: 2579–2584. 43. JU WQ, GUO ZY, LIANG WH, et al. Sirolimus conversion in liver transplant recipients with calcineurin inhibitor-induced complications: Efficacy and safety. Exp Clin Transplant 2012: 10: 132–135. 44. KALTENBORN A, SCHREM H. Mycophenolate mofetil in liver transplantation: A review. Ann Transplant 2013: 18: 685–696. 45. PAGEAUX GP, ROSTAING L, CALMUS Y, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 2006: 12: 1755–1760. 46. SCHMEDING M, KIESSLING A, NEUHAUS R, et al. Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation 2011: 92: 923–999. 47. PROKAI A, FEKETE A, PASTI K. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012: 13: 81–91. 48. FIRST MR, DHADDA S, CROY R, et al. New-onset diabetes after transplantation (NODAT): An evaluation of definitions in clinical trials. Transplantation 2013: 96: 58–64. 49. GALLAGHER EJ, BLOOMGARDEN ZT, LE ROITH D. Review of hemoglobin A1c in the management of diabetes. J Diabetes 2009: 1: 9–17. 50. KELLY DA, BUCUVALAS JC, ALONSO EM, et al. Long-term medical management of the pediatric patient after liver transplantation: 2013 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013: 19: 798–825.
51. KERKAR N, HADZIC N, DAVIES ET, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998: 351: 409–413. 52. MORAN A, PILLAY K, BECKER DJ, ACERINI CL. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2014: 15(Suppl. 20): 65–76. 53. HOGLER W, BAUMANN U, KELLY D. Endocrine and bone metabolic complications in chronic liver disease and after liver transplantation in children. J Pediatr Gastroenterol Nutr 2012: 54: 313–321. 54. THERASSE A, WALLIA A, MOLITCH ME. Management of posttransplant diabetes. Curr Diab Rep 2013: 13: 121–129. 55. GOLDBERG PA. Comprehensive management of post-transplant diabetes mellitus: From intensive care to home care. Endocrinol Metab Clin North Am 2007: 36: 907–922. 56. MACRAE D, GRIEVE R, ALLEN E. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014: 370: 107–118. 57. AGUS MS, STEIL GM, WYPIJ D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012: 367: 1208–1219. 58. NICE-SUGAR Study Investigators, FINFER S, CHITTOCK DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009: 360: 1283– 1297. 59. COPELAND K, SILVERSTEIN J, MOORE KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013: 131: 364–382. 60. TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012: 366: 2247–2256. 61. BOLLI GB. Insulin treatment in type 1 diabetes. Endocr Pract 2006: 12: s105–s109. 62. TRIDGELL DM, TRIDGELL AH, HIRSCH IB. Inpatient management of adults and children with type 1 diabetes. Endocrinol Metab Clin North Am 2010: 39: 595–608. 63. NOBILI V, DEVILLE DE GOYET J. Pediatric post-transplant metabolic syndrome: New clouds on the horizon. Pediatr Transplantation 2013: 17: 216–223. 64. SPRINGER SC, SILVERSTEIN J, COPELAND K, et al. Management of type 2 diabetes mellitus in children and adolescents. Pediatrics 2013: 131: e648–e664.
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