Page 993 - Clinical Immunology_ Principles and Practice ( PDFDrive )

958 Part seven Organ-Specific Inflammatory Disease

Second, the “obesity epidemic” has impacted on the T1D and the population distribution of specific-risk HLA genes, which
T2D stereotypes. “Hybrid” types with β-cell autoimmunity and account for up to 50% of the lifetime risk for T1DA. However,
insulin resistance (“double diabetes”) are becoming increasingly the incidence of T1DA is rising in many countries on a back-
common, characterized by weaker immune and genetic markers ground of lower-risk HLA alleles. In Western societies, the
(lower avidity autoantibodies predominantly to GAD and lower incidence in childhood has more than doubled since the 1980s
risk human leukocyte antigen [HLA] alleles). Low-grade innate and has been rising at ≈3% annually, particularly among younger
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immune inflammation, associated with insulin resistance in children. The same trend is also occurring in other countries,
obesity, could promote and uncover latent β-cell autoimmunity such as Kuwait and Saudi Arabia, and some parts of India and
in individuals with lower-risk genes for T1DA. China, where Western lifestyles have been adopted but where
T1DB excludes known specific causes of β-cell dysfunction, the prevalence of high-risk HLA genotypes for T1DA is much
such as monogenic diabetes. It encompasses forms of ketosis- lower. Just as in T2D, environmental factors may increase the
prone diabetes initially described in West Africans and African penetrance of risk genes for T1DA. In the case of HLA genes in
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Americans and subsequently in other ethnic groups, but rarely Caucasians, the increasing incidence of T1DA is accounted for
seen in Caucasians. Obesity and relatively well-preserved residual by children with intermediate-risk (DR 4,4 or DR 3,3) or low-risk
β-cell function were features of the African cases. T1DB also (DR 4,X or DR 3,X) phenotypes, not the highest-risk HLA
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includes fulminant diabetes initially described in Japan, where phenotypes (DR 3,4; DQ 2,8). These lower-risk phenotypes
it may account for 15–20% of new-onset T1D, and subsequently are also the ones seen in non-Caucasians and adults with T1DA.
elsewhere in Asia. 9,10 Fulminant diabetes is associated with The greatest number of children with diabetes will soon be found
widespread mononuclear cell infiltration of both the exocrine in the most populous regions of the world, that is, India and
and endocrine pancreas, and elevated concentrations of serum China. The impact of the modern Western environment on T1DA
pancreatic amylase, elastase, and lipase, in individuals with HLA is discussed further below.
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susceptibility genes for T1D. Case reports have associated it T1DA affects both sexes equally in childhood, with a slight
with acute viral infection and drug hypersensitivity reactions, excess of males in early adult life. Of newly diagnosed cases, no
but its etiology remains unclear. In Caucasians, T1DB includes more than 10–15% have a family history of T1DA. However,
T1D, in which islet autoantibodies are undetectable, but the studies of affected families have provided major insights into
latter may reflect assay insensitivity on a particular occasion. A the genetics and natural history of T1DA. In relatives with T1DA,
classification of diabetes that hinges on the presence or absence the rate of progression to clinical diabetes is positively associated
of islet autoantibodies is clearly not ideal. β cell–specific T cells, with the number and titer of islet autoantibodies, 2,3,5 the number
not islet autoantibodies, are the effectors of β-cell damage, and of HLA class 2 risk alleles (DR3, DR4) and specific HLA class I
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reciprocal relationships between autoantibodies and autoreactive alleles (A24), and the degree of insulin resistance and is
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T cells to islet antigens have been reported. In addition, the negatively correlated with age. The specificity of autoantibodies
more recent discovery of autoantibodies to ZT8 suggests the is also important. IAAs are more often the first sign of islet
possibility that autoantibodies to islet antigens remain to be autoimmunity in children who are followed up from birth and,
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discovered and might be markers of particular subtypes of T1D. of all the autoantibodies, has the highest predictive value. In
For example, in fulminant diabetes, the clinical picture suggests Europe, North America, and Australia, birth cohort studies of
that if autoimmunity is involved, it targets the exocrine pancreas. children who have a relative with T1DA have shown that the
Furthermore, in contrast to T1DA, in which there is an extended development of diabetes by the age of 18 years is almost always
preclinical history of islet autoimmunity, autoantibodies may associated with the appearance of islet autoantibodies in the
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not be present at the time when fulminant diabetes presents first few years of life. Of children with ≥2 islet autoantibodies
acutely. before the age of 3 years, 57% (95% confidence interval [CI]
51.7–62.3%) and 74.8% (95% CI 69.7–79.9%) progressed to
CLInICaL PearLs diabetes by 6 and 10 years of age, respectively. With a single islet
autoantibody, 14.5% progressed to diabetes by 10 years of age.
• The type 1 diabetes (T1D) stereotype of the thin juvenile now overlaps Men with early-onset T1DA are more likely to transmit diabetes
with the type 2 diabetes (T2D) stereotype of the obese, insulin-resistant to their offspring compared with women (Fig. 71.2), but it is
adult. not clear whether this results from genomic imprinting of a gene
• In Caucasian children, the diagnosis of T1D can be made on the basis expressed only from a paternally inherited allele or other possible
of classic clinical features. reasons. The risk is also greater in later-born offspring. The peak
• The presence of islet autoantibodies confirms the diagnosis of type
1A diabetes (T1DA). age of incidence in children is at the cusp of puberty, a time
• Islet autoantibodies are present in more than 90% of Caucasian children when the body’s requirement for insulin increases along with
but in only about 50% of Hispanic or African American children, some an increase in insulin resistance. Like the seasonal autumn–winter
of whom have T2D. peak in diagnosis that is attributed to viral infections, this is
• Islet autoantibodies can be detected in the first 3 years of life in the likely to be “the straw that breaks the camel’s back” on a back-
majority of Caucasian children who go on to develop T1DA. ground of longer-standing autoimmune β-cell dysfunction.
• The risk for T1DA increases with the number and titer of islet
autoantibodies.
PATHOGENESIS: NATURE AND NURTURE

EPIDEMIOLOGY AND NATURAL HISTORY OF T1DA The model for the staged natural history of T1DA, arising from
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the seminal studies of Eisenbarth, is illustrated in Fig. 71.3.
The incidence of T1DA varies widely across the globe, being Although the pattern and rate of β-cell loss is depicted as linear,
highest among Caucasians of northwestern Europe and countries it is more likely to be episodic, reflecting direct (e.g., virus,
to which they have emigrated (Fig. 71.1). This, in part, reflects chemical toxin) or indirect (e.g., diet, pollutants, microbiome)