The course of diabetes in children, adolescents and young adults: does the autoimmunity status matter?
The main strength of this study is the clinical and immunological characterization of a national cohort of all children and the majority of young adults up to 25 years of age with type 1 diabetes.
Epidemiological data on childhood diabetes (0–14 years) in Lithuania are registered since 1983 [18, 19]. According to national registry, average annual type 1 diabetes incidence increase is 4.75%, and that of prevalence – 6.5%; therefore, the population of young people with diabetes constantly increases [20]. Traditionally, the diagnosis of diabetes is based on clinical data only, the age at onset of hyperglycemia without obesity being the main diagnostic criteria.
The appearance of autoantibodies to one or several of the autoantigens -GAD65, IA-2, IAAs, ICA or ZnT8 signals an autoimmune pathogenesis of ?-cell destruction and indicates condition‘s severity, the presence of multiple autoantibodies having the highest positive predictive value for type 1 diabetes [6, 21, 22].
The presence of GAD65 in type 1 diabetes was shown to depend on age at diagnosis and gender: GAD65 positive female diabetic patients have higher GAD65 levels and a more severe loss of ?-cell function than male patients with the same age at diagnosis [23]. GAD65 is less frequent among boys developing diabetes before the age of 10 years, with diagnostic sensitivity over 80% in both males and females in older children, teenagers, and young adults [22]. In our cohort, highest frequency of positive GAD65 antibodies was in patients with disease onset between 14 and 19 years (66.4%).
We have found positive GAD65 antibodies in 52.7%, IA-2 in 57.8%, IAAs in 73.9%, and ICAs in 7% of cases; 36.5% of patients had both GAD65 and IA-2 antibodies. Pardini et al have reported positive GAD65 in 80.0%, IA-2 – in 62.9% and both GAD65 and IA-2 – in 82.9% of cases with recent-onset type 1 diabetes. The frequency of positive antibodies was lower in cases with long duration of type 1 diabetes [24],which is similar to our findings: all types of antibodies had tendency to be lower in subjects with longer duration of diabetes, and highest proportion of all negative antibodies was found in patients with longest duration of type 1 diabetes.
It has previously been reported that frequency of positive ICAs declines following diagnosis, and remains positive in less than 5–10% of type 1 diabetes patients after 10 years [25]. On the contrary, in our study frequency of positive ICAs was surprisingly low in the 0–4 years disease duration group (5.4%), and much higher in those with 15–19 years duration (11.1%). Several longitudinal studies indicate that type 1 diabetes patients remain GAD65 and/or IA-2 positive up to 80% after 12 years [26, 27].
Ketosis at the time of diagnosis is a typical feature of type 1 diabetes, and was present in 87.3% of cases in our study. It was less frequent among youth with family history of diabetes, which is probably due to alertness of family members to initial signs and symptoms of the disease. Also, ketosis was less frequent finding at diagnosis in patients with non-autoimmune diabetes, which might indicate a different cause and mechanism of hyperglycemia, at least in part of these patients group.
Most cases of type 1 diabetes occur sporadically in the absence of family history of diabetes [28]. The empiric risk of being affected if a first-degree relative has diabetes is 5% [29]. Although more than 85% of patients with type 1 diabetes lack a positive family history, a high familial clustering with a mean prevalence of 6% in siblings is usually found [30]. In our study, the frequency of first-degree relatives with either types of diabetes was 10.8% in the whole cohort, and was significantly higher in patients with negative autoantibodies (24.1% vs. 9.4%, p??0.001), possibly indicating different pathways of disease inheritance.
Nonproliferative retinopathy was found in 8.2% of our patients, and was observed in older patients with longer duration of diabetes. Although the facilities for the management of diabetes are constantly improving, the risk of retinopathy remains high. The Oulu cohort study reports extremely high prevalence of diabetic retinopathy and proliferative diabetic retinopathy (94% and 35%, respectively) in patients who have had diabetes since childhood after 18 years of follow up [31]. Interestingly, we found significantly higher frequency of all negative antibodies among patients with retinopathy in our cohort, indicating a similar or even higher risk for development of this complication in antibodies-negative forms of diabetes. We also found higher levels of IA-2 antibody and IAAs levels among patients without retinopathy, this could be related with higher residual ?-cell function, as reported by other authors, although they mainly analyzed inverse relationship between GAD65 antibody levels and severe retinopathy in young type 1 diabetic patients [32].
Neuropathy was present in 8.8% of cases in our study. Autoimmunity status was not different in patients with and without neuropathy. Similar frequency of neuropathy (8.2%) was found in type 1 diabetes patients in SEARCH pilot study [33], although low reproducibility of vibration perception threshold values in young age was previously reported [34].
Elevated AER was found in 94 (8.1%) cases of our young cohort, and was linked to older age at study entry, longer disease duration, higher HbA1c and higher daily insulin dose. Presence of pancreatic autoantibodies was again not related to elevation of AER, indicating comparable risk of diabetic nephropathy in both antibodies-positive and antibodies-negative diabetes, which seems to be more related to diabetes duration and control. A more intensive follow-up is needed in these cases, since the data from Finnish FinnDiane study showed that almost all of the excess mortality seen in type 1 diabetes was related to the development of micro- or macroalbuminuria [35]. Similar results were reported in The Pittsburgh Complications Study [36]. On the other hand, frequency of increased AER in our study was twice lower in the antibodies-negative group, and possibly did not reach statistical significance because of small number of patients with elevated AER in this group.
We must admit that the main weakness of our study was measurement of pancreatic antibodies in both newly diagnosed patients and in patients who were already on insulin treatment, which was partly responsible for high frequency of IAAs in our cohort. Therefore, a proportion of subjects with positive only IAAs might in fact have non-autoimmune form of diabetes, as one patient with neonatal diabetes positive for IAA. Moreover, even in presence of autoimmune markers, the likelihood of monogenic diabetes origin cannot be excluded, as demonstrated in some studies [37]. On the other hand, ZnT8 antibodies have not been determined in our cohort, implying that some subjects with negative antibodies might include individuals with undetected autoimmunity. Furthermore, reduction in levels and even disappearance of autoantibodies in the course of the disease is a well known phenomenon in diabetic patients, making the subject even more complex.
Another study limitation is that according to national type 1 diabetes register the study population covered 70% of young 18–25 years old adults, since at this age many young individuals are moving abroad or are busy in their work and therefore are not available for investigations. Nevertheless, we screened all pediatric and 70% of young adult population with type 1 diabetes in Lithuania, identifying their autoimmune status, metabolic control and diabetes complications. This extensive characterization of the cohort will allow us to proceed to genetic testing of subjects with antibodies-negative diabetes for eventual identification of monogenic forms, which might enable an optimization of treatment and further follow-up of such patients.