J Endocrinol Invest DOI 10.1007/s40618-014-0090-9
ORIGINAL ARTICLE
Transition from pediatric to adult care. Eight years after the transition from pediatric to adult diabetes care: metabolic control, complications and associated diseases Alessandra Rollo • S. Salardi • A. Ciavarella G. Forlani • M. Scipione • G. Maltoni • C. Balsamo • A. L. Martini • S. Zucchini
•
Received: 9 December 2013 / Accepted: 30 April 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Background Transition from pediatric to adult care is a critical process in the life of patients with diabetes. Aim Primary aim of the study was to compare the metabolic control between pediatric care and adult care at least 5 years in a group of patients with type 1 diabetes mellitus (T1DM). Secondary aim was to evaluate the presence of complications, associated diseases and psychological-psychiatric disorders. Subjects and methods We obtained data from 73 % (69/ 94) patients (current mean age 34 years) transferred to local adult centers between 1985 and 2005 at a mean age of 23.8 years. Data were collected for HbA1c, diabetic complications and associated diseases. Results Mean HbA1c did not change during the pediatric, transition and adult period [8.4 ± 1.8 % (68 ± 18 mmol/ mol), 8.3 ± 1.4 % (67 ± 15 mmol/mol) and 8.4 ± 1.3 % (68 ± 14 mmol/mol), respectively]. 13 patients dropped out, after 2–12 years since transition, and their HbA1c A. Rollo (&) M. Scipione G. Maltoni C. Balsamo A. L. Martini S. Zucchini Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 11, 40100 Bologna, Italy e-mail: [email protected] S. Salardi Alma Mater Studiorum University of Bologna, 40100 Bologna, Italy A. Ciavarella Department of Internal Medicine and Diabetes Clinic, S. Orsola-Malpighi Hospital, University of Bologna, 40100 Bologna, Italy G. Forlani Unit of Metabolic Disease and Clinical Dietetics, University of Bologna, 40100 Bologna, Italy
mean value at transition was 10.4 %. After a mean of 25.9 years of disease, 35/69 patients (50.7 %) showed retinopathy, and 12/69 patients (17.3 %) nephropathy. Thyroid diseases were the most frequent associated diseases (18.3 %), followed by depression (11.2 %) and benign neoplasms (9.8 %). Drug or alcohol addictions were present in four cases (5.6 %). Conclusions After a mean follow-up of 8 years metabolic control after transition did not change significantly in patients constantly attending to adult care centre. Patients with diabetes onset between 20 and 40 years ago were free from complications in 50 % of cases when considering retinopathy and in more than 80 % considering nephropathy. Thyroid problems were the most common associated diseases. Poor metabolic control at transition is associated with higher risk of drop-out and psychosocial morbidity. Keywords Type-1 diabetes Transition Metabolic control Microvascular complications Psychological-psychiatric disorders
Introduction All patients with childhood-onset chronic diseases have to face the transition from pediatric to adult care. The transition care for adolescents and youths with type 1 diabetes (T1DM) is a critical period since, if not well driven, may end up with a negative experience and lead to a care dropout and to an increased risk of long term complications. The transition process occurs during both physiological (end of pubertal age, modification of insulin sensitivity) and psychosocial (self independence needs, feel invulnerable, entering the world of work) phase [1]. The patients and their family are often scared of the differences between
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the pediatric care approaches and the adult ones and may feel a sense of abandonment [2]. Although several manuscripts have been published on this topic, data on long-term post-transition outcomes are limited [3, 4] and therefore, the outcome of these young adults of metabolic control, diabetes complications, comorbidity are often unknown. Furthermore, pediatricians are usually not familiar with the entity of the psychosocial troubles and the psychiatric diseases of young adult patients with chronic illnesses starting in childhood [5]. Nevertheless, many authors focused on the different methods and modalities of the transfer and the short-term consequences [6, 7]. Primary aim of this cohort study was to explore in an unselected group of patients how glycemic control during diabetic care in our single pediatric clinic was related to glycemic control as young adults after a mean of 8 years since the transition to two different adult clinics. The modalities of transition were not standardized, but rather based on patient’s maturity and depending on the two centers availability to perform a structured process in the various years. Secondary aim was to evaluate the presence of complications, associated diseases and psychologicalpsychiatric disorders at the end of follow-up.
Patients and methods Ninety-four patients resident in our district with onset of T1DM between 1972 and 1992 in our Pediatric Department, were transferred to adult care between 1985 and 2005. 69 of these patients (73 % of the initial number) were tracked between January and September of 2010 in the two main adult diabetes centers of our city. Among the others 25 patients, two had died (one in a car accident and one of heart attack), 13 had moved abroad and 10 were not traced. The characteristics of the patients are summarized in Table 1. Data on metabolic control, complications and\or comorbidities (autoimmune and not autoimmune diseases) were collected for each patient from the medical records of the pediatric clinic and the diabetology adult centre. We Table 1 Clinical characteristics of the patients diagnosed between 1972 and 1992 and transferred to adult care between 1985 and 2005 Patients (M/F)
n = 69 (32/37)
Present age (years)
34.1 ± 4.6 (25–43)
Age at diabetes onset (years)
8.4 ± 3.8 (1.6–15)
Age at transition (years)
23.8 ± 3.9 (17–32)
Disease duration at last examination (years)
25.9 ± 5.1 (15–36)
Duration of pediatric care (years)
15.9 ± 5.8 (2–27)
Duration of adult care (years)
8.4 ± 3.1 (5–25)
Data are expressed as mean ± standard deviation (range)
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did a telephonic structured interview and received a formal approval allowing their doctor to release medical data, collecting further information on transition satisfaction. The parameters were evaluated during follow-up in the pediatric and adult centre. HbA1c levels were assessed at diagnosis and every 3–6 months and mean values were calculated both during the whole follow-up (lifetime HbA1c) and in the pediatric and adult period separately. Furthermore, for each patient HbA1c mean value at the transition (last year in the pediatric centre) was calculated. We also recorded HbA1c level after the transition as improved or worsened depending on its increase or decrease by a 0.5 % minimum. The assay of the celiac disease related antibodies, thyroid autoantibodies, lipid profile, urinary albumin excretion and retinal examination (fundus oculi) were yearly performed. The transition occurred through close collaboration between pediatric and adult diabetes centers. The age at transition was not predefined, but timed on an individual basis, targeting youth in 16–32 years of age. There were two different methods used for the transition, happening congruently, and were consistent with the availability of the caregivers in the different years. The non-structured method was performed in 40 patients. Pediatrician, at any time during the year, simply sent the patient to the adult diabetologist with a written medical history. The structured transition process was performed about once a year and involved 29 patients. Eligible patients (about 10–15) were identified 6–12 months before transition. During this period, the medical examinations were performed by the adult diabetologist team and the pediatrician at the same time. At the end of the period the patients chose which doctor would be their next caregiver and official transition occurred. A medical specific chart was provided. Before 1983 metabolic control was evaluated by measuring the total glycosylated hemoglobin (HbA1) using the Bio-rad column method, since 1983 through 1991 it was performed by measuring both HbA1 and HbA1c using high-performance liquid chromatography (HPLC, Auto A1C TM Analyser HA 8110, Kyoto Daiichi, Kagaku, Japan) and then from 1991 onwards by measuring the only HbA1c using HPLC. To unify all HbA1c values, we used the method published in our previous work [8], i.e., converting HbA1 values prior to 1983 to HbA1c values and subtracting 2.18 from each value, this being the mean difference (2.18 ± 0.40) between HbA1 and HbA1c measured with HPLC in 180 diabetic children. Microalbuminuria was defined in pediatric center as the value of urinary albumin excretion (UAE) in 24 h between 30 and 300 mg/die, and in adult Centre as the urinary albumin concentration (UAC) in the first morning urine sample [20 mg/L. Macroalbuminuria was defined as the UAE
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[300 mg/die. UAE was valued by nephelometric method (Behring Nephelometer Analyzer II). Retinal evaluation was performed by direct ophthalmoscopy or colour photography. Fundus oculi examination was performed by various oculists from the same ophthalmic centre. The retinal changes were graded according to a 5° severity scale based upon the American Academy of Ophthalmology simplified classification [9], from no diabetic retinopathy (DR) (grade 1), to mild non proliferative DR (grade 2), moderate non proliferative DR (grade 3), severe non proliferative DR (grade 4), and proliferative DR (grade 5). The duration of the disease at the first appearance of any form of retinopathy was recorded as a time free of DR. This study was performed in accordance with the Declaration of Helsinki as revised in the year 2000 and was approved in the participating centres by an institutional review board. Statistical analysis The data analysis was performed by the statistical software SPSS 14.0 (Statistical Package for Social Science, Chicago, III). Data distribution was analyzed with the calculation of the asymmetric and kurtosis coefficients and with the Kolmogorov-Smirnoff test. Data with normal distribution were analyzed with the Student t test and the Pearson correlation coefficient; other data with nongaussian distribution were studied with the Mann–Whitney non parametric test and with the Wilcoxon test. The Chisquared test was used for the frequency comparison. We reported only the significant data having a p \ 0.05.
Results HbA1c HbA1c lifetime mean values ranged from 6.2 % (44 mmol/ mol) to 11.9 % (107 mmol/mol) with a mean of 8.4 ± 1.1 % (68 ± 12 mmol/mol), similar for both male and female subjects. During the whole pediatric follow-up values were 8.4 ± 1.8 % (68 ± 18 mmol/mol), in the year of transition 8.3 ± 1.4 % (67 ± 15 mmol/mol) and during adult center follow up 8.4 ± 1.3 % (68 ± 14 mmol/mol). There was no statistical difference between the HbA1c mean the transition (Wilcoxon test). 13 patients (19 %) dropped out after a mean of 7 years from transition (2–12 years). HbA1c mean values at transition time of dropped out patients was 10.4 ± 1.2 % (90 ± 13 mmol/ mol). This value was significantly higher (p \ 0.0001) than the HbA1c values reported in the group of patients attending the adult care structures.
During the adult care period (mean length 8.4 years) 52 % (36 out of 69) of the patients showed a worsening of metabolic control compared to the pediatric data, 39 % (27 out of 69) a better metabolic control, and six out of 69 (9 %) stable HbA1c values. The percentage of patients with the worsening of HbA1c values was almost the same for both modalities of transition, but it was lower among patients older at the transition (r = -0.287, p \ 0.025, Wilcoxon test). During the telephone interview, the patients gave an opinion on their satisfaction about the transition: 65 % of these patients declared of being satisfied, whereas 35 % complained about it. The most frequent reason for dissatisfaction was the repeated change of their adult health care provider. Complications In the last retinal examination, after a mean of 25.9 years of the disease, 34 out of the 69 patients (49.3 %) did not present diabetic retinopathy (RD), while 35 patients (50.7 %) showed any DR: 20 cases (29 %) mild non-proliferative DR, six cases (9 %) severe non-proliferative laser treated DR, seven cases (10 %) proliferative DR, and two patients (3 %) with diabetes onset in the 70s, were blind. The comparisons between the characteristics of the two groups (with and without complications) are summarized in Table 2. Subdividing the patients according to retinopathy grading, HbA1c values progressively increased, from 7.9 % (63 mmol/mol) to 10.6 % (92 mmol/mol) (p \ 0.001, Mann–Whitney non parametric test). Among dropped-out patients, the percentage of retinopathy was 49 %. This percentage was similar to the percentage of retinopathy among the attending group, however the duration of follow-up for dropped-out patients was shorter than follow-up of the attending group. In the group with a more recent diagnosis (years 1983–1992, n = 36), the percentage of patients affected by any retinopathy (42.8 %) was lower, although not significantly, than the one in the group (58.1 %) with a diagnosis between 1972 and 1982 (n = 33). Diabetes duration was similar in the two groups (16.3 ± 2.6 and 15.6 ± 6.4 years, respectively). Among the nine patients with proliferative retinopathy, six had the diagnosis of T1DM in the first decade and three in the second. The prevalence of nephropathy was 17.3 % (12 out of 69): eight patients (11.5 %) had microalbuminuria, one had macroalbuminuria (1.4 %), and three (4.3 %) had overt nephropathy. One of these, with onset of T1DM in 1972, had been under in dialysis treatment for 3 years and was waiting for a renal transplant. Retinopathy was present in all but two patients (presenting microalbuminuria) with nephropathy. Of the four patients affected by severe nephropathy, two had onset of T1DM in the decade 1972–1982, and two in the decade 1982–1992.
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J Endocrinol Invest Table 2 Comparison between patients with and without diabetic complications Group 1 (without DR) (n = 34) Age at onset (years) Age at transition (years)
Group 2 (with DR) (n = 35)
p*
Group 1 (without nephropathy) (n = 57)
Group 2 (with nephropathy) (n = 12)
p*
8.7 ± 4
8.4 ± 3.9
NS
7.6 ± 5
8.0 ± 4.6
NS
24.7 ± 0.7
22.8 ± 4.5
NS
24.1 ± 4.2
22.5 ± 5.6
NS
Lifetime HbA1c (%) (mmol/mol)
7.9 ± 0.8 (63 ± 9)
8.8 ± 1.1 (73 ± 12)
0.004
8.1 ± 0.9 (65 ± 10)
9.3 ± 1.2 (78 ± 13)
0.001
HbA1c during pediatric care (%) (mmol/mol)
8.2 ± 1.2 (66 ± 13)
9.1 ± 1.7 (76 ± 19)
0.008
8.3 ± 1.3 (67 ± 14)
9.8 ± 1.7 (84 ± 19)
0.006
HbA1c during adult care (%) (mmol/mol)
7.9 ± 1.2 (63 ± 13)
8.8 ± 1.5 (73 ± 17)
0.008
8.4 ± 1.6 (68 ± 18)
9.8 ± 2.4 (84 ± 27)
0.006
Duration disease free from complications (years)
24.2 ± 4.1
16.9 ± 5.3
0.0001
25.9 ± 4.8
\0.0001
19.9 ± 5.7
Data are expressed as mean ± standard deviation (range) * Mann–Whitney non parametric test
Microalbuminuria was present in 19 % among dropped out patients at their last examination. This percentage was similar to the percentage of nephropathy among the attending group. Patients with any kind of retinal or renal complication showed HbA1c mean lifetime values in both pediatric and adult follow-up periods, higher than patients without complications, despite a significantly lower mean duration of disease free from complications (Table 2).
Table 3 Associated diseases and/or co-morbidities in patients with onset either before or after the transition period
Associated diseases One or more physical or mental illnesses were found in 30 out of 69 patients (43 %), for a total of 71 diseases. Table 3 shows how some of the diseases, as celiac disease, were already present during the pediatric follow-up and the prevalence remained stable, others, as thyroid diseases, increased the percentage during adulthood, and finally others, as benign neoplasm appeared de novo during adult care. Thyroid diseases were the most frequent associated comorbidities (18.3 % of all illnesses and 18.8 % of patients): 12 patients had chronic autoimmune thyroiditis, six of which under replacement therapy with L-thyroxine. One patient underwent thyroidectomy because of Graves’ disease. Besides thyropathies, the most common illnesses (in 12 patients: 16.8 % of all diseases and 17.4 % of patients) were related to severe psychological problems: depression or panic attacks in eight cases, binge eating in four cases (three females and one male). By adding these disorders with addiction to drugs or alcohol (four cases), 16/69 (23 %) of patients were suffering from severe psychological problems as emerging adults. Mean HbA1c at transition of patients experiencing psychological problems was 9.0 ± 1.9 % (75 ± 21 mmol/mol), mean HBA1c
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Associated diseases/comorbidities
N affected patients Before transition
After transition
Total
Percentage of diseases (%)
Thyroid diseases Depression
9 4
4 4
13 8
18.3 11.2
Benign tumors (breast, hepatic adenoma, lipoma)
0
7
7
9.8
Hypertension
1
5
6
8.4
Ovarian cysts
3
1
4
5.6
Eating disorder
2
2
4
5.6
Gastro esophageal reflux disease (GERD)
1
3
4
5.6
Celiac disease
3
0
3
4.2
Dyslipidemia
3
0
3
4.2
Drug abuse
1
2
3
4.2
Kidney stones
1
1
2
2.8
Deficit of IgA
2
0
2
2.8
Hepatitis C
0
2
2
2.8
Tunnel carpal syndrome
0
2
2
2.8
Hepatosteatosis
0
2
2
2.8
Hyperhomocysteinemia
1
1
2
2.8
Cardiopathy
0
2
2
2.8
Alcohol abuse
0
1
1
1.4
Ischemic heart disease
0
1
1
1.4
31
40
71
100.0
Total disease
during adult follow up was 9.7 ± 1.7 % (83 ± 19 mmol/ mol). The latter value was significantly higher than the mean of HbA1c values in patients without any kind of
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psychological troubles (p \ 0.001). Associated diseases are listed in Table 3. Hepatosteatosis (two cases) and hepatitis C (two cases) were probable consequences of drug abuse.
Discussion The present study shows that after a mean period of 8 years since the transition to the adult centre, HbA1c levels did not significantly change, and the results seem to identify a tracking effect of HbA1c from late adolescence to adulthood. This would indicate that the transition method is not probably so important, but rather than the pediatric care is fundamental since it provides the decisive groundwork for disease control in young adults. The results by Garvey et al. and by Busse et al. [4, 10], are consistent with ours, while other studies report different and discrepant findings. In fact, Neu et al. [11] and Sparud-Lundin et al. [12], described a mild improvement in HbA1c values after the transition. In contrast, according to other studies [2, 13], the clinical conditions worsened after the transition and, in more than 1,500 patients observed in the following 2 years [2], the number of DM-related hospitalizations increased. Such different results could be explained both by different observation length period and by high drop-out rate (about one-fifth in our study; similar percentages were reported in several other studies). Therefore, as already suggested by other authors [11], the lack of metabolic information about the dropout patients may be considered a selection bias, as their metabolic control could actually be worse than that of those who did not dropped out. The evidence, also confirmed by our study, that at the time of transition HbA1c values of dropout patients were higher than the values of attending patients, seems to validate this hypothesis. According to our data, an older age at transition was linked to a lower percentage of worsening of metabolic control. Despite the possible bias that more compliant patients remaining longer in our pediatric centre, the recent studies in agreement with our results should be taken it into account [4, 14]. Mean age at transition was higher in our centre than in other countries, such as in Germany (17.8 years) [10] where for national legislation of the health care system the transfer occurs at the age of 18 years. In a worldwide ISPAD survey led in 36 countries, it is shown that 1/3 of the pediatric centres examine adult patients older than 25 years [15]. Regarding complications, our investigation confirmed many already known concepts, described in other studies examining more rigorously this topic, particularly the main role of HbA1c in the development of diabetic retinopathy and nephropathy [16, 17]. Despite its limited size, our
population seems representative for this age group. Although not significant, our data showed a downward trend, in the incidence of retinopathy (above all the most severe types) among the patients with T1DM onset in the decade 1983–1992 compared to those with onset in the previous decade. A recent study by Downie et al. [18] led in over 1,600 patients demonstrated the continued reduction in the prevalence of retinopathy in diabetic adolescents in the past 20 years. In our sample, such as in other studies [16, 19] the prevalence of any DR was higher than that of nephropathy. While 50.7 % of patients were affected by any type of retinopathy and 21.7 % by severe retinopathy, only 17.4 % was affected by any renal complications: 4.3 % was affected by overt nephropathy and 1.4 % by renal failure. Regarding the autoimmune diseases associated to T1DM our results confirm the data of the literature [20, 21], showing higher prevalence of thyroid disease (almost 18 % of all patients). Notably, despite thyroid screening was performed once a year in pediatric care, many thyroid diseases started in adult age and therefore whole prevalence was higher than the one found in pediatric age. As a consequence it seems advisable to screen for thyroid disease also in adulthood. An opposite trend was found for celiac disease. Markers of this disease were screened regularly since T1DM onset and the prevalence of disease was unchanged in adult age. This is probably due to the fact that the diagnosis after the pediatric age is rare and confirms that the onset of celiac disease is temporally related to the diagnosis of T1DM [22]. It seems, therefore, that if the screening for celiac disease was performed regularly during pediatric care, it is not advisable to continue it in the asymptomatic adult patients. Hypertension was found in six cases, with a prevalence of 8.4 %; one of whom was already present in childhood. Published data on hypertension are numerous and sometimes conflicting. In a French study the prevalence was 2 % in female and 7 % in male [23], while it was 17 % in an Italian multicentre study [24]. A multicentre study of Dost et al. [25] showed that the prevalence of hypertension was 1.5–3 times higher in T1DM patients compared to healthy controls. On the other hand, it is known that the age-related changes of blood pressure pattern starts in T1DM about 15–20 years before than in healthy subjects [26]. Surprisingly enough, we found in young adults (\43 years) a high rate of comorbid disorders, not strictly related to hyperglycemia. The explanation could be the more intense clinical-laboratory checks carried out in diabetic patients than in non-diabetic population, or rather to a real increase of the same comorbidities. The question also concerns the benign neoplasms, whose high frequency in early adulthood might suggest a link with the high doses of insulin administered [27]. The focus is, however, especially on high frequency, second only to thyroid disease, of
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severe psychological disorders and psychosocial problems, such as addiction to alcohol or drugs. High prevalence of psychiatric morbidity has already been reported [5, 28] above all during vulnerable periods after high school years. This morbidity, more frequent in females, was strongly associated with poor glycemic control and the development of microvascular complications. Among these mental health problems, the eating disorders were frequent and reported in about 25–30 % of young women with T1DM [29, 30]. This higher prevalence of eating disorders can be explained by considering only the cases clinically manifest, i.e., meeting the criteria for nervous anorexia or bulimia, and not all cases with disordered eating features. As for other illnesses, such as urolithiasis, gastro esophageal reflux disease (GERD) or carpal tunnel there are some reports in the literature that would confirm their links with diabetes [31–34]. Main strength of our work is the extended post transfer period of observation that allowed us to have an extensive knowledge about long-term outcome of our patients. On the other hand, we are aware of the limitations of our study that was retrospective, included a limited number of subjects and was influence by several drop-out patients. In conclusion, metabolic control after the transition to the adult centre did not change significantly in our patients constantly attending to adult care centre during a mean period of 8 years of follow-up. However, it should be considered the presence of drop-out patients with poor metabolic control. Although the number of cases is limited and cohort studied is not contemporary one, the fact that 25 % of our children with diabetes, will suffer in young adulthood with severe psychological disorders, led us to focus the attention from early ages, not only to the best metabolic control, but also to the mental illness. Our data suggest to put extra attention on patients with poor metabolic control at transition: they are at higher risk of drop-out and future psychological morbidity. Conflict of interest
The authors declare no conflict of interest.
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ORIGINAL ARTICLE
Transition from pediatric to adult care. Eight years after the transition from pediatric to adult diabetes care: metabolic control, complications and associated diseases Alessandra Rollo • S. Salardi • A. Ciavarella G. Forlani • M. Scipione • G. Maltoni • C. Balsamo • A. L. Martini • S. Zucchini
•
Received: 9 December 2013 / Accepted: 30 April 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Background Transition from pediatric to adult care is a critical process in the life of patients with diabetes. Aim Primary aim of the study was to compare the metabolic control between pediatric care and adult care at least 5 years in a group of patients with type 1 diabetes mellitus (T1DM). Secondary aim was to evaluate the presence of complications, associated diseases and psychological-psychiatric disorders. Subjects and methods We obtained data from 73 % (69/ 94) patients (current mean age 34 years) transferred to local adult centers between 1985 and 2005 at a mean age of 23.8 years. Data were collected for HbA1c, diabetic complications and associated diseases. Results Mean HbA1c did not change during the pediatric, transition and adult period [8.4 ± 1.8 % (68 ± 18 mmol/ mol), 8.3 ± 1.4 % (67 ± 15 mmol/mol) and 8.4 ± 1.3 % (68 ± 14 mmol/mol), respectively]. 13 patients dropped out, after 2–12 years since transition, and their HbA1c A. Rollo (&) M. Scipione G. Maltoni C. Balsamo A. L. Martini S. Zucchini Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 11, 40100 Bologna, Italy e-mail: [email protected] S. Salardi Alma Mater Studiorum University of Bologna, 40100 Bologna, Italy A. Ciavarella Department of Internal Medicine and Diabetes Clinic, S. Orsola-Malpighi Hospital, University of Bologna, 40100 Bologna, Italy G. Forlani Unit of Metabolic Disease and Clinical Dietetics, University of Bologna, 40100 Bologna, Italy
mean value at transition was 10.4 %. After a mean of 25.9 years of disease, 35/69 patients (50.7 %) showed retinopathy, and 12/69 patients (17.3 %) nephropathy. Thyroid diseases were the most frequent associated diseases (18.3 %), followed by depression (11.2 %) and benign neoplasms (9.8 %). Drug or alcohol addictions were present in four cases (5.6 %). Conclusions After a mean follow-up of 8 years metabolic control after transition did not change significantly in patients constantly attending to adult care centre. Patients with diabetes onset between 20 and 40 years ago were free from complications in 50 % of cases when considering retinopathy and in more than 80 % considering nephropathy. Thyroid problems were the most common associated diseases. Poor metabolic control at transition is associated with higher risk of drop-out and psychosocial morbidity. Keywords Type-1 diabetes Transition Metabolic control Microvascular complications Psychological-psychiatric disorders
Introduction All patients with childhood-onset chronic diseases have to face the transition from pediatric to adult care. The transition care for adolescents and youths with type 1 diabetes (T1DM) is a critical period since, if not well driven, may end up with a negative experience and lead to a care dropout and to an increased risk of long term complications. The transition process occurs during both physiological (end of pubertal age, modification of insulin sensitivity) and psychosocial (self independence needs, feel invulnerable, entering the world of work) phase [1]. The patients and their family are often scared of the differences between
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the pediatric care approaches and the adult ones and may feel a sense of abandonment [2]. Although several manuscripts have been published on this topic, data on long-term post-transition outcomes are limited [3, 4] and therefore, the outcome of these young adults of metabolic control, diabetes complications, comorbidity are often unknown. Furthermore, pediatricians are usually not familiar with the entity of the psychosocial troubles and the psychiatric diseases of young adult patients with chronic illnesses starting in childhood [5]. Nevertheless, many authors focused on the different methods and modalities of the transfer and the short-term consequences [6, 7]. Primary aim of this cohort study was to explore in an unselected group of patients how glycemic control during diabetic care in our single pediatric clinic was related to glycemic control as young adults after a mean of 8 years since the transition to two different adult clinics. The modalities of transition were not standardized, but rather based on patient’s maturity and depending on the two centers availability to perform a structured process in the various years. Secondary aim was to evaluate the presence of complications, associated diseases and psychologicalpsychiatric disorders at the end of follow-up.
Patients and methods Ninety-four patients resident in our district with onset of T1DM between 1972 and 1992 in our Pediatric Department, were transferred to adult care between 1985 and 2005. 69 of these patients (73 % of the initial number) were tracked between January and September of 2010 in the two main adult diabetes centers of our city. Among the others 25 patients, two had died (one in a car accident and one of heart attack), 13 had moved abroad and 10 were not traced. The characteristics of the patients are summarized in Table 1. Data on metabolic control, complications and\or comorbidities (autoimmune and not autoimmune diseases) were collected for each patient from the medical records of the pediatric clinic and the diabetology adult centre. We Table 1 Clinical characteristics of the patients diagnosed between 1972 and 1992 and transferred to adult care between 1985 and 2005 Patients (M/F)
n = 69 (32/37)
Present age (years)
34.1 ± 4.6 (25–43)
Age at diabetes onset (years)
8.4 ± 3.8 (1.6–15)
Age at transition (years)
23.8 ± 3.9 (17–32)
Disease duration at last examination (years)
25.9 ± 5.1 (15–36)
Duration of pediatric care (years)
15.9 ± 5.8 (2–27)
Duration of adult care (years)
8.4 ± 3.1 (5–25)
Data are expressed as mean ± standard deviation (range)
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did a telephonic structured interview and received a formal approval allowing their doctor to release medical data, collecting further information on transition satisfaction. The parameters were evaluated during follow-up in the pediatric and adult centre. HbA1c levels were assessed at diagnosis and every 3–6 months and mean values were calculated both during the whole follow-up (lifetime HbA1c) and in the pediatric and adult period separately. Furthermore, for each patient HbA1c mean value at the transition (last year in the pediatric centre) was calculated. We also recorded HbA1c level after the transition as improved or worsened depending on its increase or decrease by a 0.5 % minimum. The assay of the celiac disease related antibodies, thyroid autoantibodies, lipid profile, urinary albumin excretion and retinal examination (fundus oculi) were yearly performed. The transition occurred through close collaboration between pediatric and adult diabetes centers. The age at transition was not predefined, but timed on an individual basis, targeting youth in 16–32 years of age. There were two different methods used for the transition, happening congruently, and were consistent with the availability of the caregivers in the different years. The non-structured method was performed in 40 patients. Pediatrician, at any time during the year, simply sent the patient to the adult diabetologist with a written medical history. The structured transition process was performed about once a year and involved 29 patients. Eligible patients (about 10–15) were identified 6–12 months before transition. During this period, the medical examinations were performed by the adult diabetologist team and the pediatrician at the same time. At the end of the period the patients chose which doctor would be their next caregiver and official transition occurred. A medical specific chart was provided. Before 1983 metabolic control was evaluated by measuring the total glycosylated hemoglobin (HbA1) using the Bio-rad column method, since 1983 through 1991 it was performed by measuring both HbA1 and HbA1c using high-performance liquid chromatography (HPLC, Auto A1C TM Analyser HA 8110, Kyoto Daiichi, Kagaku, Japan) and then from 1991 onwards by measuring the only HbA1c using HPLC. To unify all HbA1c values, we used the method published in our previous work [8], i.e., converting HbA1 values prior to 1983 to HbA1c values and subtracting 2.18 from each value, this being the mean difference (2.18 ± 0.40) between HbA1 and HbA1c measured with HPLC in 180 diabetic children. Microalbuminuria was defined in pediatric center as the value of urinary albumin excretion (UAE) in 24 h between 30 and 300 mg/die, and in adult Centre as the urinary albumin concentration (UAC) in the first morning urine sample [20 mg/L. Macroalbuminuria was defined as the UAE
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[300 mg/die. UAE was valued by nephelometric method (Behring Nephelometer Analyzer II). Retinal evaluation was performed by direct ophthalmoscopy or colour photography. Fundus oculi examination was performed by various oculists from the same ophthalmic centre. The retinal changes were graded according to a 5° severity scale based upon the American Academy of Ophthalmology simplified classification [9], from no diabetic retinopathy (DR) (grade 1), to mild non proliferative DR (grade 2), moderate non proliferative DR (grade 3), severe non proliferative DR (grade 4), and proliferative DR (grade 5). The duration of the disease at the first appearance of any form of retinopathy was recorded as a time free of DR. This study was performed in accordance with the Declaration of Helsinki as revised in the year 2000 and was approved in the participating centres by an institutional review board. Statistical analysis The data analysis was performed by the statistical software SPSS 14.0 (Statistical Package for Social Science, Chicago, III). Data distribution was analyzed with the calculation of the asymmetric and kurtosis coefficients and with the Kolmogorov-Smirnoff test. Data with normal distribution were analyzed with the Student t test and the Pearson correlation coefficient; other data with nongaussian distribution were studied with the Mann–Whitney non parametric test and with the Wilcoxon test. The Chisquared test was used for the frequency comparison. We reported only the significant data having a p \ 0.05.
Results HbA1c HbA1c lifetime mean values ranged from 6.2 % (44 mmol/ mol) to 11.9 % (107 mmol/mol) with a mean of 8.4 ± 1.1 % (68 ± 12 mmol/mol), similar for both male and female subjects. During the whole pediatric follow-up values were 8.4 ± 1.8 % (68 ± 18 mmol/mol), in the year of transition 8.3 ± 1.4 % (67 ± 15 mmol/mol) and during adult center follow up 8.4 ± 1.3 % (68 ± 14 mmol/mol). There was no statistical difference between the HbA1c mean the transition (Wilcoxon test). 13 patients (19 %) dropped out after a mean of 7 years from transition (2–12 years). HbA1c mean values at transition time of dropped out patients was 10.4 ± 1.2 % (90 ± 13 mmol/ mol). This value was significantly higher (p \ 0.0001) than the HbA1c values reported in the group of patients attending the adult care structures.
During the adult care period (mean length 8.4 years) 52 % (36 out of 69) of the patients showed a worsening of metabolic control compared to the pediatric data, 39 % (27 out of 69) a better metabolic control, and six out of 69 (9 %) stable HbA1c values. The percentage of patients with the worsening of HbA1c values was almost the same for both modalities of transition, but it was lower among patients older at the transition (r = -0.287, p \ 0.025, Wilcoxon test). During the telephone interview, the patients gave an opinion on their satisfaction about the transition: 65 % of these patients declared of being satisfied, whereas 35 % complained about it. The most frequent reason for dissatisfaction was the repeated change of their adult health care provider. Complications In the last retinal examination, after a mean of 25.9 years of the disease, 34 out of the 69 patients (49.3 %) did not present diabetic retinopathy (RD), while 35 patients (50.7 %) showed any DR: 20 cases (29 %) mild non-proliferative DR, six cases (9 %) severe non-proliferative laser treated DR, seven cases (10 %) proliferative DR, and two patients (3 %) with diabetes onset in the 70s, were blind. The comparisons between the characteristics of the two groups (with and without complications) are summarized in Table 2. Subdividing the patients according to retinopathy grading, HbA1c values progressively increased, from 7.9 % (63 mmol/mol) to 10.6 % (92 mmol/mol) (p \ 0.001, Mann–Whitney non parametric test). Among dropped-out patients, the percentage of retinopathy was 49 %. This percentage was similar to the percentage of retinopathy among the attending group, however the duration of follow-up for dropped-out patients was shorter than follow-up of the attending group. In the group with a more recent diagnosis (years 1983–1992, n = 36), the percentage of patients affected by any retinopathy (42.8 %) was lower, although not significantly, than the one in the group (58.1 %) with a diagnosis between 1972 and 1982 (n = 33). Diabetes duration was similar in the two groups (16.3 ± 2.6 and 15.6 ± 6.4 years, respectively). Among the nine patients with proliferative retinopathy, six had the diagnosis of T1DM in the first decade and three in the second. The prevalence of nephropathy was 17.3 % (12 out of 69): eight patients (11.5 %) had microalbuminuria, one had macroalbuminuria (1.4 %), and three (4.3 %) had overt nephropathy. One of these, with onset of T1DM in 1972, had been under in dialysis treatment for 3 years and was waiting for a renal transplant. Retinopathy was present in all but two patients (presenting microalbuminuria) with nephropathy. Of the four patients affected by severe nephropathy, two had onset of T1DM in the decade 1972–1982, and two in the decade 1982–1992.
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J Endocrinol Invest Table 2 Comparison between patients with and without diabetic complications Group 1 (without DR) (n = 34) Age at onset (years) Age at transition (years)
Group 2 (with DR) (n = 35)
p*
Group 1 (without nephropathy) (n = 57)
Group 2 (with nephropathy) (n = 12)
p*
8.7 ± 4
8.4 ± 3.9
NS
7.6 ± 5
8.0 ± 4.6
NS
24.7 ± 0.7
22.8 ± 4.5
NS
24.1 ± 4.2
22.5 ± 5.6
NS
Lifetime HbA1c (%) (mmol/mol)
7.9 ± 0.8 (63 ± 9)
8.8 ± 1.1 (73 ± 12)
0.004
8.1 ± 0.9 (65 ± 10)
9.3 ± 1.2 (78 ± 13)
0.001
HbA1c during pediatric care (%) (mmol/mol)
8.2 ± 1.2 (66 ± 13)
9.1 ± 1.7 (76 ± 19)
0.008
8.3 ± 1.3 (67 ± 14)
9.8 ± 1.7 (84 ± 19)
0.006
HbA1c during adult care (%) (mmol/mol)
7.9 ± 1.2 (63 ± 13)
8.8 ± 1.5 (73 ± 17)
0.008
8.4 ± 1.6 (68 ± 18)
9.8 ± 2.4 (84 ± 27)
0.006
Duration disease free from complications (years)
24.2 ± 4.1
16.9 ± 5.3
0.0001
25.9 ± 4.8
\0.0001
19.9 ± 5.7
Data are expressed as mean ± standard deviation (range) * Mann–Whitney non parametric test
Microalbuminuria was present in 19 % among dropped out patients at their last examination. This percentage was similar to the percentage of nephropathy among the attending group. Patients with any kind of retinal or renal complication showed HbA1c mean lifetime values in both pediatric and adult follow-up periods, higher than patients without complications, despite a significantly lower mean duration of disease free from complications (Table 2).
Table 3 Associated diseases and/or co-morbidities in patients with onset either before or after the transition period
Associated diseases One or more physical or mental illnesses were found in 30 out of 69 patients (43 %), for a total of 71 diseases. Table 3 shows how some of the diseases, as celiac disease, were already present during the pediatric follow-up and the prevalence remained stable, others, as thyroid diseases, increased the percentage during adulthood, and finally others, as benign neoplasm appeared de novo during adult care. Thyroid diseases were the most frequent associated comorbidities (18.3 % of all illnesses and 18.8 % of patients): 12 patients had chronic autoimmune thyroiditis, six of which under replacement therapy with L-thyroxine. One patient underwent thyroidectomy because of Graves’ disease. Besides thyropathies, the most common illnesses (in 12 patients: 16.8 % of all diseases and 17.4 % of patients) were related to severe psychological problems: depression or panic attacks in eight cases, binge eating in four cases (three females and one male). By adding these disorders with addiction to drugs or alcohol (four cases), 16/69 (23 %) of patients were suffering from severe psychological problems as emerging adults. Mean HbA1c at transition of patients experiencing psychological problems was 9.0 ± 1.9 % (75 ± 21 mmol/mol), mean HBA1c
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Associated diseases/comorbidities
N affected patients Before transition
After transition
Total
Percentage of diseases (%)
Thyroid diseases Depression
9 4
4 4
13 8
18.3 11.2
Benign tumors (breast, hepatic adenoma, lipoma)
0
7
7
9.8
Hypertension
1
5
6
8.4
Ovarian cysts
3
1
4
5.6
Eating disorder
2
2
4
5.6
Gastro esophageal reflux disease (GERD)
1
3
4
5.6
Celiac disease
3
0
3
4.2
Dyslipidemia
3
0
3
4.2
Drug abuse
1
2
3
4.2
Kidney stones
1
1
2
2.8
Deficit of IgA
2
0
2
2.8
Hepatitis C
0
2
2
2.8
Tunnel carpal syndrome
0
2
2
2.8
Hepatosteatosis
0
2
2
2.8
Hyperhomocysteinemia
1
1
2
2.8
Cardiopathy
0
2
2
2.8
Alcohol abuse
0
1
1
1.4
Ischemic heart disease
0
1
1
1.4
31
40
71
100.0
Total disease
during adult follow up was 9.7 ± 1.7 % (83 ± 19 mmol/ mol). The latter value was significantly higher than the mean of HbA1c values in patients without any kind of
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psychological troubles (p \ 0.001). Associated diseases are listed in Table 3. Hepatosteatosis (two cases) and hepatitis C (two cases) were probable consequences of drug abuse.
Discussion The present study shows that after a mean period of 8 years since the transition to the adult centre, HbA1c levels did not significantly change, and the results seem to identify a tracking effect of HbA1c from late adolescence to adulthood. This would indicate that the transition method is not probably so important, but rather than the pediatric care is fundamental since it provides the decisive groundwork for disease control in young adults. The results by Garvey et al. and by Busse et al. [4, 10], are consistent with ours, while other studies report different and discrepant findings. In fact, Neu et al. [11] and Sparud-Lundin et al. [12], described a mild improvement in HbA1c values after the transition. In contrast, according to other studies [2, 13], the clinical conditions worsened after the transition and, in more than 1,500 patients observed in the following 2 years [2], the number of DM-related hospitalizations increased. Such different results could be explained both by different observation length period and by high drop-out rate (about one-fifth in our study; similar percentages were reported in several other studies). Therefore, as already suggested by other authors [11], the lack of metabolic information about the dropout patients may be considered a selection bias, as their metabolic control could actually be worse than that of those who did not dropped out. The evidence, also confirmed by our study, that at the time of transition HbA1c values of dropout patients were higher than the values of attending patients, seems to validate this hypothesis. According to our data, an older age at transition was linked to a lower percentage of worsening of metabolic control. Despite the possible bias that more compliant patients remaining longer in our pediatric centre, the recent studies in agreement with our results should be taken it into account [4, 14]. Mean age at transition was higher in our centre than in other countries, such as in Germany (17.8 years) [10] where for national legislation of the health care system the transfer occurs at the age of 18 years. In a worldwide ISPAD survey led in 36 countries, it is shown that 1/3 of the pediatric centres examine adult patients older than 25 years [15]. Regarding complications, our investigation confirmed many already known concepts, described in other studies examining more rigorously this topic, particularly the main role of HbA1c in the development of diabetic retinopathy and nephropathy [16, 17]. Despite its limited size, our
population seems representative for this age group. Although not significant, our data showed a downward trend, in the incidence of retinopathy (above all the most severe types) among the patients with T1DM onset in the decade 1983–1992 compared to those with onset in the previous decade. A recent study by Downie et al. [18] led in over 1,600 patients demonstrated the continued reduction in the prevalence of retinopathy in diabetic adolescents in the past 20 years. In our sample, such as in other studies [16, 19] the prevalence of any DR was higher than that of nephropathy. While 50.7 % of patients were affected by any type of retinopathy and 21.7 % by severe retinopathy, only 17.4 % was affected by any renal complications: 4.3 % was affected by overt nephropathy and 1.4 % by renal failure. Regarding the autoimmune diseases associated to T1DM our results confirm the data of the literature [20, 21], showing higher prevalence of thyroid disease (almost 18 % of all patients). Notably, despite thyroid screening was performed once a year in pediatric care, many thyroid diseases started in adult age and therefore whole prevalence was higher than the one found in pediatric age. As a consequence it seems advisable to screen for thyroid disease also in adulthood. An opposite trend was found for celiac disease. Markers of this disease were screened regularly since T1DM onset and the prevalence of disease was unchanged in adult age. This is probably due to the fact that the diagnosis after the pediatric age is rare and confirms that the onset of celiac disease is temporally related to the diagnosis of T1DM [22]. It seems, therefore, that if the screening for celiac disease was performed regularly during pediatric care, it is not advisable to continue it in the asymptomatic adult patients. Hypertension was found in six cases, with a prevalence of 8.4 %; one of whom was already present in childhood. Published data on hypertension are numerous and sometimes conflicting. In a French study the prevalence was 2 % in female and 7 % in male [23], while it was 17 % in an Italian multicentre study [24]. A multicentre study of Dost et al. [25] showed that the prevalence of hypertension was 1.5–3 times higher in T1DM patients compared to healthy controls. On the other hand, it is known that the age-related changes of blood pressure pattern starts in T1DM about 15–20 years before than in healthy subjects [26]. Surprisingly enough, we found in young adults (\43 years) a high rate of comorbid disorders, not strictly related to hyperglycemia. The explanation could be the more intense clinical-laboratory checks carried out in diabetic patients than in non-diabetic population, or rather to a real increase of the same comorbidities. The question also concerns the benign neoplasms, whose high frequency in early adulthood might suggest a link with the high doses of insulin administered [27]. The focus is, however, especially on high frequency, second only to thyroid disease, of
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severe psychological disorders and psychosocial problems, such as addiction to alcohol or drugs. High prevalence of psychiatric morbidity has already been reported [5, 28] above all during vulnerable periods after high school years. This morbidity, more frequent in females, was strongly associated with poor glycemic control and the development of microvascular complications. Among these mental health problems, the eating disorders were frequent and reported in about 25–30 % of young women with T1DM [29, 30]. This higher prevalence of eating disorders can be explained by considering only the cases clinically manifest, i.e., meeting the criteria for nervous anorexia or bulimia, and not all cases with disordered eating features. As for other illnesses, such as urolithiasis, gastro esophageal reflux disease (GERD) or carpal tunnel there are some reports in the literature that would confirm their links with diabetes [31–34]. Main strength of our work is the extended post transfer period of observation that allowed us to have an extensive knowledge about long-term outcome of our patients. On the other hand, we are aware of the limitations of our study that was retrospective, included a limited number of subjects and was influence by several drop-out patients. In conclusion, metabolic control after the transition to the adult centre did not change significantly in our patients constantly attending to adult care centre during a mean period of 8 years of follow-up. However, it should be considered the presence of drop-out patients with poor metabolic control. Although the number of cases is limited and cohort studied is not contemporary one, the fact that 25 % of our children with diabetes, will suffer in young adulthood with severe psychological disorders, led us to focus the attention from early ages, not only to the best metabolic control, but also to the mental illness. Our data suggest to put extra attention on patients with poor metabolic control at transition: they are at higher risk of drop-out and future psychological morbidity. Conflict of interest
The authors declare no conflict of interest.
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