LEARNING OBJECTIVES
After completing Module 3, the learner should be able to:
1. Describe patient historical elements that indicate higher risk for T1D.
2. Estimate the percentage of general population children and adolescents are positive for one or more islet autoantibodies
at some point during their lives.
3. Describe the peak and distribution of the incidence of islet autoantibody seroconversion (1 or more confirmed islet
autoantibodies) across the lifespan.
4. Explain why differentiating T1D from T2D in newly-diagnosed diabetes is important.
Epidemiology of Type 1 Diabetes and Target Populations for Screening
03 |
Module Authors: Marian Rewers, Brigitte Frohnert
INCIDENCE of Stage 3 (clinical, symptomatic) type 1 diabetes (T1D)
While type 1 diabetes has been historically considered a childhood-onset disease, there is a substantial —but often misdiagnosed—onset of T1D during adulthood. Globally, there is a peak in incidence at age 10 to 14 years, but there is a second rise in older age.(1)
• An estimated 62% of new Stage 3 T1D occurs at age 20 and older.(1)
• Up to 40% of those with adult onset T1D are misdiagnosed as T2D.(2)
What is known about the INCIDENCE and PREVALENCE
of islet autoimmunity in the general population in the U.S.?
INCIDENCE of Islet Autoimmunity:
While onset of symptomatic, Stage 3 T1D occurs across the lifespan, the initial events that trigger initiation of islet autoimmunity often occur in earliest childhood(3-5):
• First appearance of islet autoantibodies (IAb) can be detected very early in life,
beginning at 6-9 months.
• Incidence of IAb peaks at 9-12 months of age.
• Over the next 2 years, incidence of newly-developed IAb rapidly decreases by age 4.
• This is followed by a steady, lower rate of incidence of IAb until puberty (Figure 1).
• New cases of islet autoimmunity become rare after age 15.
FIGURE 1 The incidence of persistent confirmed islet autoantibodies (IAA, GADA or IA-2A) in genetically at-risk children participating in TEDDY (4.5)
It appears that in adults diagnosed with T1D, the autoimmune process began when they were children or adolescents. However, this evidence came from cohort studies following children at increased genetic risk for T1D (relatives or children expressing high-risk HLA genotypes). Little is known about the incidence of islet autoantibodies in general population children and adults, especially those from non-White ethnic groups.​
PREVALENCE of Islet Autoimmunity:
Extrapolation of results from prospective high-risk cohort studies suggests:
• Up to 2% of general population children and adolescents may be IAb positive for some time
in their life (Figure 2, gray line)
• Only ~0.5% progress to clinical T1D by age 18 (Figure 2, red line).(6,7)
The pool of autoantibody positive children detectable by screening (Figure 2, black dotted line) increases until age 14 and subsequently declines as some children progress to diabetes and new seroconversions wane. In addition, about 20% of people persistently positive for single islet autoantibodies become negative. In most cases, such a ‘remission’ lowers the risk of progression to Stage 3 diabetes.(8) However, the vast majority of those initially confirmed positive for multiple autoantibodies, progress to clinical diabetes, even if their autoantibodies decline in numbers or disappear.(8,9)
FIGURE 2 Estimated prevalence of confirmed persistent islet autoantibodies (IAb) in the general population.
Adapted from (23)
The prevalence rates of IAb documented by ASK confirm the estimated size of the at-risk pool of children and adolescents positive for IAb. In the Colorado multiethnic population, between 0.8% and 1.2% of youth screened were positive for at least one of four islet autoantibodies (IAA, GADA, IA-2A or ZnT8A). The proportion of those positive for multiple autoantibodies (Figure 2, orange area) decreases with age while that of single persistent autoantibody confirmed by a highly-specific assay increases (Figure 2, yellow area). After age 10, most of screening-detected high-risk persons are positive for a single islet autoantibody. They are more likely non-White, have no family history of T1D, and progress slower to Stage 3 T1D than those positive before 10 years of age. It appears that autoimmune damage to pancreatic islets occurs initially before age 15 in the vast majority of cases, although progression to Stage 3 T1D in adulthood may take decades.
Who should be screened for islet autoantibodies (IAb)?
The best approach for screening for early-stage T1D is a topic of active research and discussion. Two strategies currently used in clinical care and research include:
1. IAb screening in high-risk individuals
2. Population-wide IAb screening
1. HIGH-RISK INDIVIDUALS
Family History of T1D
Children and adults who have a relative with T1D (first-, second- or third-degree) are at significantly higher risk than the general population and standard practice should include routine screening for islet autoantibodies (IAA, GADA, IA-2A and ZnT8A).(10,11)
(Adapted from 23)
Elevated Genetic Risk
American Diabetes Association (ADA) standards of care recommend screening for early-stage T1D in not only those with family history of T1D, but also those with “otherwise known elevated genetic risk.”(10) One strategy to identify individuals at increased genetic risk is the assessment of personal and family history of autoimmune disease. A population-based cohort of 22 million individuals in in the UK showed significant co-occurrence of T1D with celiac, Addison’s disease, autoimmune thyroid disease, polymyalgia rheumatica, myasthenia gravis, rheumatoid arthritis, multiple sclerosis, vitiligo, pernicious anemia and systemic lupus erythematosus (12) (Figure 3). An association with primary bilary cholangitis was not significant in this analysis; however, analysis of several large European genetic datasets, supported an association between genetic risk for T1D and autoimmune liver disease (autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis).(13)
​
Beyond personal history of autoimmune disease, a family history of several autoimmune diseases are associated with increased rates of T1D. About one third of children under age 15 years diagnosed with T1D have a first-degree relative with an autoimmune disease.(14) In over 58,000 family trios from Finland, aside from a parental history of T1D, the highest odds ratio for developing T1D, are in children whose parents have autommune thyroid disease (Hashimoto’s and Graves’), celiac disease, rheumatoid arthritis, pernicious anemia, sarcoidosis, mixed connective tissue disease and Sjogren syndrome.(15)
Another high-risk population are individuals with trisomy 21 (Down syndrome) who have a 4-fold higher prevalence of T1D compared to the general population.(15) One report found multiple islet autoantibodies in 5.7% of children with Down syndrome, a significantly higher prevalence than the general population.(16)
In summary, screening for islet autoimmunity in individuals with a known elevated genetic risk, such as those with a personal or family history of autoimmunity as well as in persons with Down syndrome should be considered an accepted element of clinical decision-making.
FIGURE 3 Associations between T1D and other autoimmune diseases in the individual (A) and in family members (B).
100
(A) Incidence rate ratio for T1D in individuals with 17 other autoimmune diseases is shown with 95% confidence intervals. (Adapted from 12)
(B) Odds ratio for T1D in the offspring of individuals with various autoimmune disease are shown with 95% confidence intervals. Those with significance after correction for multiple comparison’s are shown in the green-shaded upper portion of the figure. (Adapted from 15)
Dysglycemia:
Children or adults with early-stage T1D have been shown to have temporal variability in glycemic profiles. Those with otherwise normal findings may develop elevated glucose levels in response to the illness or when treated with steroids. Thus, children and adults who experience dysglycemia should have IAb tested to rule out Stage 2 T1D. It is recommended that all patients with newly-diagnosed diabetes be screened for IAb regardless of age or BMI. Misdiagnosis of T1D as T2D can lead to serious and preventable medical error. Of note, overweight youth develop T1D as often as lean youth. Many adults with T1D are initially misdiagnosed as having T2D, even when presenting in DKA, and mismanaged until evident treatment failure.(17)
2. POPULATION-WIDE SCREENING
Screening General Population CHILDREN for Pre-Symptomatic T1D
Extrapolating ASK results, islet autoimmunity is present in an estimated 700,000 (1%) of children living in the US. Half of these children (0.5%) have multiple islet autoantibodies (mIAb) (Stage 1 or Stage 2 pre-symptomatic T1D) and an estimated 70% of those will progress to Stage 3 (symptomatic insulin-dependent diabetes) in the next 10 years.(9) An additional 0.5% have a single islet autoantibody confirmed by a highly specific method and up to 50% of those will progress to Stage 3 in the next 10 years.
Fewer than 50,000 out of 73 million children in the US have ever been screened for IAb. At present, we recommend screening for all four IAb in all children older than 1 year, if they have not been previously screened. Youth older than 10 do benefit from screening;(18) a negative screening at that age does not need to be repeated in the absence of symptoms of dysglycemia.
Optimally, the screening could begin at 1-3 years of age and, if negative, should be repeated at 4-6 and 9-11 years.(18,19) If implemented consistently in a primary care setting, it could detect islet autoimmunity in nearly 90% of children destined to develop clinical T1D by age 15. The median time interval between the initial positive screening and diagnosis of Stage 3 T1D would be 4.0 years [IQR 2.0-7.0] allowing sufficient time for interventions, e.g., with teplizumab and anticipatory education in diabetes management.
In 2023:
ITALY became the first country to mandate a nationwide screening program for T1D and celiac disease in children ages
1-17. At present, four regions are piloting screening with a planned nationwide rollout in 2025.(20)
Screening General Population ADULTS for Pre-Symptomatic T1D
Data for adults are sparse and biased by overrepresentation of relatives of people with T1D. Preliminary data from ASK suggest that IAb are as frequent in adults as in children, but in most cases only a single autoantibody is detected.(21) GADA is the most frequent autoantibody observed in adults, but other autoantibodies are also important. While an estimated 35,000 adults in the US develop T1D, annually, routine screening of the adult population for islet autoantibodies is currently not recommended outside of aforementioned high-risk groups.
​
Differences in Progression to Stage 3 T1D by AGE
TrialNet has demonstrated that the rate of progression from multiple islet autoantibodies (Stage 1) to Stage 3 T1D decreases rapidly with age (Figure 4) which may have important implications for both the cadence of screening as well as the intensity of follow-up to monitor progression and diagnose the Stage 3 disease in a timely manner. These prevalence estimates and the rates of progression to diabetes must be confirmed in a large sample from the general population.
FIGURE 4
Impact of age on risk for disease progression in multiple IAb positive relatives participating in TrialNet Pathway to Prevention Study
(Modified from reference 22)
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