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Update in Endocrine Autoimmunity
Mark S. Anderson
Diabetes Center, Department of Medicine, University of California-San Francisco, San Francisco, California 94143-0540
Context: The endocrine system is a common target in pathogenic autoimmune responses, and
there has been recent progress in our understanding, diagnosis, and treatment of autoimmune
endocrine diseases.
Synthesis: Rapid progress has recently been made in our understanding of the genetic factors
involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that
include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and
confirmed many new genes outside of the established role of the human leukocyte antigen locus
with these diseases, and indicate an essential role of immune response pathways in these diseases.
Progress has also been made in identifying new autoantigens and the development of new animal
models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy
is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for
potentially treating and reversing the underlying autoimmune process.
Conclusion: Although autoimmune endocrine disorders are complex in etiology, these recent
advances should help contribute to improved outcomes for patients with, or at risk for, these
disorders. (J Clin Endocrinol Metab 93: 3663–3670, 2008)
A
utoimmune diseases represent a significant health burden in
the developed world afflicting 5–10% of the population
(1), and a sizable percentage of these diseases involve an untoward immune response against an endocrine organ. Virtually
any endocrine organ can be targeted by the immune system as
part of an autoimmune response, and frequently responses to
multiple organs can occur in the same patient as part of a
polyglandular autoimmune syndrome. More common endocrine autoimmune syndromes include Hashimoto’s thyroiditis,
Graves’ disease, and type 1 diabetes, whereas more rare syndromes include Addison’s disease, oophoritis, lymphocytic hypophysitis, and hypoparathyroidism. For years, the etiology and
pathogenesis of these disorders have remained obscure, but the
diseases are generally thought to involve a cellular and humoral
immune response that pathologically targets the affected organ(s). This is evidenced by a wide number of observations, including the presence of autoantibodies in affected patients, improvement of some diseases by immunosuppressive drugs, and
the demonstration of lymphocytic infiltrates in the targeted or-
gans. Over the last few years, rapid progress in our understanding of these diseases has come through a number of efforts, particularly in genetics. In this review, I will highlight some of the
recent advances in our understanding, diagnosis, and treatment
of endocrine autoimmune diseases.
0021-972X/08/$15.00/0
Abbreviations: Aire, Autoimmune regulator; APS1, autoimmune polyglandular syndrome
type 1; GWA, genome-wide association; HLA, human leukocyte antigen; IPEX, immune
dysregulation, polyendocrinopathy, enteropathy, X-linked; MHC, major histocompatibility
complex; mTEC, medullary epithelial cell; NALP5, NACHT leucine-rich-repeat protein 5;
Treg, regulatory T cell.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2008-1251 Received June 9, 2008. Accepted July 31, 2008.
Genetics
There is good evidence that most autoimmune endocrine diseases
have a genetic component to their etiology. Some of the best
evidence comes from familial inheritance studies on type 1 diabetes and thyroiditis (2, 3). In the case of type 1 diabetes, the
lifetime concordance rate for disease in monogenic twins is
around 50% and for siblings is around 3– 4%. This shows significant risk when compared with the general population risk of
around 0.3%. These data also show that there is a significant
genetic contribution to disease risk and that other factors (i.e.
environmental) are also involved in disease pathogenesis. For
several decades, the major genetic association of autoimmune
J Clin Endocrinol Metab, October 2008, 93(10):3663–3670
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Anderson
Update in Endocrine Autoimmunity
endocrine diseases with polymorphisms in the human leukocyte
antigen (HLA) region has been recognized. The HLA is a genetic
region on chromosome 6 that encodes a large number of immune
response genes, and in most cases disease risk maps to polymorphisms in the major histocompatibility complex (MHC) class II
genes DR and DQ. The MHC class II gene products along with
antigenic peptides are part of the ligand complex for CD4⫹
T-cell receptors, and the association likely highlights the importance of T cells in these diseases (4). Interestingly, it remains to
be determined how these risk polymorphisms lead to increased
susceptibility to autoimmunity. Some investigators have proposed promiscuous peptide binding by MHC risk alleles as a
potential mechanism, but more definitive data are needed (5). It
is also important to note that in most cases, subjects harboring
a MHC risk allele are more likely not to develop autoimmunity
except in rare isolated incidents (6), thus, these risk alleles should
be thought of as being necessary but not sufficient for the development of disease. Recently, significant progress has been made
in expanding our understanding of genetic disease risk beyond
the MHC, particularly with informative monogenic forms of
J Clin Endocrinol Metab, October 2008, 93(10):3663–3670
endocrine autoimmunity and in highly powered genetic studies
that include genome-wide association (GWA) efforts.
Monogenic diseases
Autoimmune polyglandular syndrome type 1 (APS1) is a rare
monogenic autosomal recessive disorder characterized by a panoply of autoimmune syndromes in the same patient, many of
which are directed against endocrine organs. Prominent clinical
features are hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis (7). More variable endocrine features also
include Hashimoto’s thyroiditis, oophoritis, type 1 diabetes, and
lymphocytic hypophysitis. Through a positional cloning effort,
the defective gene was identified in 1997 by two independent
groups and termed autoimmune regulator (Aire) (8, 9). Since its
identification, much has been learned about the function of Aire
in promoting immune tolerance and has been accelerated by the
generation of a mouse model by knocking out the murine orthologue of the gene (10, 11). Aire appears to function as a
transcription factor and is mainly expressed in a specialized subset of cells in the thymus called medullary epithelial cells
(mTECs). Within mTECs, Aire helps promote the transcription of many self-antigen
A
genes, including the insulin gene (a known
endocrine autoantigen) (11). A consequence
of this self-antigen expression within the
“Organ
Specific”
Antigen-MHC
thymus is that it promotes the negative secomplexes for T
Transcription
cell presentation
lection (or deletion) of autoreactive thymoAIRE
cytes that naturally develop in the thymus
“Organ
Specific”
(12–14). Thus, in the absence of Aire, there
Antigens
is a failure to delete autoreactive T cells
within the thymus, which then leads to a
predisposition to widespread multi-organ
autoimmunity (Fig. 1). Mouse studies have
confirmed that the thymic defect is sufficient
to induce the autoimmune syndrome assoB
Aire-positive Thymus
Aire-negative Thymus
ciated with disease (11), and recent studies
in humans have suggested that the longknown association of thymomas with the
Cortex
autoimmune syndrome myasthenia gravis
may be attributable to the loss of AIRE expression in this thymic tumor (15). In addition, there is a developing picture that
similar mechanisms are in play for more
Medulla
common endocrine autoimmune syndromes, like type 1 diabetes, in which a polymorphism in the insulin gene has been demonstrated to control thymic expression
levels and correlates with disease risk (i.e.
Self organ-specific T
Self Organ-Specific T
high thymic expression alleles have lower
cells deleted
cells escape
disease risk) (16 –18). Recent associations
with variation in the thyroglobulin gene and
thyroiditis (3, 19) could involve a similar
Self organ autoimmunity
Self organ tolerance
mechanism, but this has yet to be tested. An
FIG. 1. Model of the function of Aire in the thymus. A, Aire appears to help mediate the transcription of
autosomal dominant allele of AIRE has also
many self-antigens in mTECs in the thymus. B, Impact of Aire on T-cell selection. These self-antigens are
then presented in the thymus to developing thymocytes (blue-colored cells) in the medulla, and this results
been recently associated with Hashimoto’s
in the deletion of self-antigen specific thymocytes in this compartment. In the absence of Aire, the selfthyroiditis (20), and recently the susceptiantigens fail to be generated by these mTECs, and self-antigen specific T cells mature and escape the
bility has been shown to be due to a quanthymus and migrate into the periphery and promote autoimmune responses.
J Clin Endocrinol Metab, October 2008, 93(10):3663–3670
titative effect on self-antigen expression within the thymus (21).
Together, these recent advances on Aire have helped establish a
critical relationship between thymic expression of self-antigens
and the prevention of autoimmune endocrine syndromes.
Another monogenic autoimmune syndrome that has brought
new mechanistic insights to immune tolerance is immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX).
This is an X-linked disorder that is characterized by a severe
autoimmunity syndrome in which most affected subjects usually
die before the age of 2 yr if they do not receive bone marrow
transplantation. Common autoimmune endocrine syndromes in
these patients include type 1 diabetes and thyroiditis (22). The
defective gene in this disorder has been mapped to the transcription factor FoxP3, and recent studies have established that FoxP3
plays a critical role in the function of a special T-cell subset called
regulatory T cells (Tregs) (23–25). Tregs are CD4⫹CD25⫹ T
cells that have the remarkable capability to suppress effector
T-cell responses, including those directed at self (Fig. 2) (26).
These cells develop within the thymus and are thought to have a
preferential specificity for self-antigens, perhaps at least in part
due to Aire-dependent mechanisms (27). Preferential depletion
(28) or loss of function of these cells (through knocking out
Treg
CD4+
FoxP3+
Teff
CD4+
FoxP3-
unclear
suppression
mechanisms
Self-tolerance
Treg
CD4+
FoxP3+
Teff
CD4+
FoxP3-
IPEX
FIG. 2. Model of Treg function. Tregs expressing the FoxP3 gene play a key role
in dampening responses by effector T cells (Teff), including autoreactive T cells
specific for organ-specific antigens. This suppression is essential because the loss
of Treg function has been demonstrated to lead to catastrophic autoimmunity
like that in patients with the IPEX syndrome. The suppression by these cells in
vivo also appears to be antigen specific and raises the possibility that these cells
could be harnessed to induce antigen-specific immune tolerance in the future.
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FoxP3) has been demonstrated in animal models to lead to catastrophic autoimmunity similar to that in IPEX patients. FoxP3
likely plays a number of critical functions in allowing the suppressor activity of these cells to be promoted, but the exact details
of the suppression mechanism remain unclear, especially in vivo
(29). Interestingly, Tregs have been used as a tool to suppress and
reverse type 1 diabetes in animal models (30, 31), and this has
important future clinical implications. This is because the suppression mechanism in vivo appears to be dependent on the antigenic specificity of the Treg population that is used. Thus, it
may someday be possible to induce antigen or organ-specific
tolerance by treatment with clonal populations of Tregs as a
method to cure or reverse a given autoimmune disease without
conferring the risk of global immunosuppression.
GWA studies
Rapid advances in human genetics have afforded the opportunity to identify new risk alleles associated with common diseases, like type 1 diabetes and thyroiditis, that have previously
been elusive. This has been due to a number of factors, including
the completion of the human genome sequence, the development
of a catalog of common genetic variation (i.e. the haplotype
map), affordable technologies for high-density/high-throughput
genotyping, and adequately powered sample sizes of cases and
controls (32, 33). In this regard, the most progress has been made
with studies on type 1 diabetes and thyroiditis, in which adequately powered sample collections have been amassed to detect
common variants using GWA and confirm previously established associations. Studies with type 1 diabetes samples have
established a large number of genes associated with risk outside
of the HLA region. Before the advent of GWA, the insulin (17,
34), PTPN22 (35), CTLA4 (36), and interleukin-2 receptor
␣-chain (also known as CD25) (37) genes were established to be
associated with disease, and have also been confirmed with
GWA. With the advent of large GWA studies on type 1 diabetes,
MDA5 (38), KIAA0350 (a C-type lectin of unknown function)
(39 – 41), and several loci harboring other genes have been associated with disease (41). Although Hashimoto’s thyroiditis
and Graves’ disease are distinct in their clinical presentations,
they likely share many commonalities in their pathogenesis.
Most large genetic studies on autoimmune thyroid disease have
used large Graves’ collections, and there has been difficulty in
detecting loci when Graves’ and Hashimoto’s patients are pooled
together (42). In fact, a very recent study on Hashimoto’s thyroiditis patients has demonstrated different HLA class II associations when compared with Graves’ (43). To date, established
genes outside of HLA for Graves’ include the TSH receptor (44,
45), PTPN22 (46, 47), CTLA4 (36), and FCRL3 (a Fc receptor
family member) (45). Beyond these recent findings, it should be
noted that there is an extensive body of literature examining
candidate gene associations with thyroiditis, type 1 diabetes, and
Addison’s disease. These reported associations may hold true
associations but have yet to be replicated in these large collection
studies for thyroiditis and type 1 diabetes. This may be due to
many factors, but caution is warranted given the likely bias for
reporting false-positive results in such studies, especially those
that may be underpowered or may have unrecognized popula-
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TABLE 1. Autoimmune endocrine disease susceptibility genes identified or confirmed in recent high-powered genetic studies (see
text for references)
Gene
Associated autoimmune endocrine disease
Putative role of gene variant
HLA-DR,DQ (MHC class II)
HLA-B (MHC class I)
HLA-C (MHC class I)
Insulin
TSH receptor
CTLA4
PTPN22
CD25
MDA5
FCRL3
KIAA0350
T1D,GD,HT
T1D
GD
T1D
GD
T1D,GD,HT
T1D,GD,HT
T1D
T1D
GD
T1D
Antigen presentation to CD4⫹ T cells
Antigen presentation to CD8⫹ T cells
Antigen presentation to CD8⫹ T cells
Thymic expression to promote negative selection
? Antigen recognition, ? thymic expression
Inhibitory T-cell signaling
? T-cell signaling
? Treg activity and function
Innate immune response signaling
Unknown
Unknown
AD, Addison’s disease; GD, Graves’ disase; HT, Hashimoto’s thyroiditis; T1D, type 1 diabetes; ?, possible but not clearly established.
tion stratification (48). The NALP1 gene, a likely regulator in the
innate immune system, was also recently shown to have an association with multiple autoimmune diseases in families with
vitiligo (49). In this study, families with two or more members
with vitiligo and at least one with an autoimmune condition that
included but was not limited to type 1 diabetes, Addison’s disease, and thyroiditis were collected, and convincing linkage was
demonstrated to this gene.
In terms of the non-HLA genes outlined previously, the risk
conferred by them, with few exceptions, is relatively small, with
most having an odds ratio less than 1.5. In addition, the biological mechanisms by which these common alleles confer genetic
risk still remain to be completely elucidated (Table 1). Despite
this, when these findings are put into the context of what we
know about autoimmunity and immune tolerance mechanisms,
a picture is starting to emerge. First, there appears to be at least
a set of genes that generally increase autoimmune disease risk,
like PTPN22, CTLA4, NALP1, and FCRL3, which have established risk for many autoimmune diseases. For example,
PTPN22 has been established as a risk gene for rheumatoid arthritis, systemic lupus erythematosus, juvenile rheumatoid arthritis, and myasthenia gravis, in addition to its established association with thyroiditis and type 1 diabetes. Second, some
disease risk genes fit into context with established pathways related to immune tolerance. For example, CTLA4 (which is highly
expressed in T cells) is known to play a critical role in dampening
and suppressing T-cell responses in biological studies (50), and
its association with multiple autoimmune diseases makes good
sense. PTPN22 encodes a signaling phosphatase expressed in T
cells that likely controls T-cell signaling, and the risk variant
encodes an amino acid change that likely confers biological activity in T-cell activation pathways. Third, there are associations
with emerging immune tolerance pathways. For instance, the
association with CD25 may have a relationship with the function
and activity of CD4⫹CD25⫹Tregs. The association of innate
immune response genes like MDA5 and NALP1 may help explain the bridge between environmental triggers and activation
of autoimmune responses. The association of the TSH receptor
with Graves’ may also have a relationship with thymic expression of self-antigens, but making these links will need more study.
Finally, there are some associations that are not completely clear,
like KIAA0350, which may help identify unexpected pathways
associated with disease.
Another general emerging set of findings with large case control collections has been a more thorough analysis of the HLA
region with high-density marker genotyping. The HLA poses a
particular challenge to geneticists because it is such a polymorphic and gene-rich region. This makes identifying true risk associations more difficult because the identified risk may be in
linkage disequilibrium with the true risk variant. In type 1 diabetes, recent new data have emerged that have extended our
growing knowledge of MHC class II alleles associated with disease risk and protection (51), and also in identifying additional
disease risk (albeit lower) associated with MHC class I alleles
(52). Additional studies have identified MHC haplotypes that
provide extreme risk for the development of type 1 diabetes (6),
which likely contain several synergistic loci. Likewise, a recent
study on Graves’ patients has demonstrated disease risk attributable to MHC class I (53). Together, these findings reveal the
rich complexity of the HLA region, and clearly a more detailed
study of the region will be needed to unravel completely the risk
associated with this locus.
Diagnostics
Autoantibodies
Autoantibodies are a key tool in the diagnosis of patients with
autoimmune endocrine diseases and those at risk for these diseases. As outlined earlier, a major clinical phenotype of patients
with the APS1 disorder is the presence of hypoparathyroidism,
which is presumably autoimmune in origin, and a recent study
has identified a parathyroid autoantigen called NACHT leucinerich-repeat protein 5 (NALP5) (54). Interestingly, NALP5 is
highly expressed in both the parathyroid and ovary, and autoreactivity to NALP5 may explain both the hypoparathyroidism
and oophoritis associated with the APS1 disorder. However, it
still remains to be determined if NALP5 is expressed in the thymus under the control of AIRE. A similar set of studies searching
for pituitary autoantibodies has revealed tudor domain containing protein 6 as a pituitary autoantigen in APS1 subjects (55).
The autoantigen is quite prevalent in APS1 subjects, but its direct
J Clin Endocrinol Metab, October 2008, 93(10):3663–3670
correlation with pituitary autoimmunity in APS1 or in isolated
lymphocytic hypophysitis remains to be established. Another set
of recent studies has found that autoantibodies to type 1 interferons are generally predictive of the APS1 disorder (56 –58). The
clinical meaning of these autoantibodies currently remains unclear but may have some relationship to the candidiasis commonly observed in APS1 subjects. The specificity of this test for
APS1 also appears to be on par with gene sequencing of AIRE in
the initial studies, and raises the possibility that this assay may be
of utility in patients and those at risk for the disorder. Recently,
a new autoantigen has also been established for subjects with
type 1 diabetes (59). ZnT8 is an islet-specific zinc transporter for
which a large number of subjects with type 1 diabetes have reactive autoantibodies. The marker may prove particularly useful
in subjects who test negative for other established autoantibodies
to glutamate decarboxylase, insulin, and I-A2.
Animal Models
Animal models have proven to be invaluable in furthering our
understanding of autoimmunity, given the inherit complexity of
these diseases. Both the Aire knockout and FoxP3 knockout lines
of mice have been valuable in unraveling the function of Aire and
FoxP3 as outlined previously, but there have also been other
recent advances with other animal models. A broad concept
worth mentioning with animal models is segregating these models into those that have spontaneous development of autoimmune disease vs. those that are induced (i.e. immunizing with
organ extract or antigen in the context of a strong adjuvant).
Although induced models may be of some value, they are also
hampered in identifying precipitating factors for disease because
this is likely bypassed by the immunization process. Certainly,
one of the most widely used spontaneous models in autoimmune
endocrine disease research is the nonobese diabetic mouse strain
model of autoimmune diabetes, which shows defects in multiple
pathways of immune tolerance (60). This mouse strain has
proven to be valuable in dissecting out the role of various immune cell populations and immune pathways in their contribution to the autoimmune diabetes process. In addition, it should
also be noted that this strain has been shown to have an increased
susceptibility to spontaneous autoimmune thyroiditis when its
MHC locus is replaced in a congenic fashion (61) or when
crossed to a dominant point mutation in Aire (21). A spontaneous thyroiditis model was also recently described using a T-cell
receptor transgenic approach and emphasizes the importance
again of T cells in driving this autoimmune disease (62). Another
interesting development in animal models is the recent demonstration of genetic susceptibility loci in Portuguese water dogs for
Addison’s disease (63). This dog breed shows a relatively high
predisposition to acquired adrenal insufficiency with estimates
around 1.5% of these dogs being affected [compared with approximately 0.01% in the human population (64)]. With recent
advances in the genetic study of dogs and excellent pedigree
records for this breed, Chase et al. (63) were able to demonstrate
significant linkage for Addison’s disease to two loci in the dog
genome. One locus was in the region of the dog MHC, and the
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second was in a genetic region rich for immune response-related
genes, which includes CTLA4. Further work will be needed in
this system to unravel the exact genes and polymorphisms responsible for the Addison’s disease risk, but this unique animal
model may bring new mechanistic insights for this disorder.
These recent findings also suggest that further work in nonrodent
models of autoimmune endocrine conditions may be genetically
tractable given the rapid advances in whole genome sequencing.
Environmental Effects
Recent epidemiological evidence has suggested that there is an
increasing incidence of many autoimmune conditions, including
type 1 diabetes (65, 66). A prevailing hypothesis for the increase
in these recent trends is the “hygiene hypothesis,” whereby the
relative decrease in childhood infections from improved living
conditions and increased immunizations may be a factor (67).
Along these lines, Kondrashova et al. (68) recently examined the
prevalence of thyroid autoimmunity in two geographically adjacent
regions in Russia and Finland that share similar genetic ancestry. In
this study an increased prevalence of antithyroid peroxidase and
antithyroglobulin antibodies was observed in Finnish children over
Russian children. The authors go on to suggest that the increased
rate in Finland could be due to socioeconomic factors that include
a lower rate of childhood infections.
Treatment
The mainstay of treatment for most autoimmune endocrine disorders is of course replacement therapy with the exception of
Graves’ disease. To date, the main area for which some progress
has been made in reversing or treating the underlying autoimmune process has been in type 1 diabetes, and this was recently
reviewed in this series (69). One developing area of immunotherapy outside of type 1 diabetes worth mentioning involves the
B-cell depleting agent rituximab (anti-CD20). This drug has been
demonstrated to have efficacy in the treatment of several autoimmune diseases (70) with a relatively good side effect profile,
and initial case reports suggested that it may have some efficacy
in the treatment of Graves’ disease (71, 72). Because a pathogenic
autoantibody is responsible for this disorder, this is a rational
treatment, however, it should be noted that plasma cells do not
express CD20, and depletion of mature anti-TSH receptor antibody producing cells may be intractable to this approach. Recently, two controlled pilot studies for the treatment of Graves’
with anti-CD20 showed less encouraging results but some efficacy in patients with low anti-TSH receptor antibody levels (73,
74). There has also been a case report of ulcerative colitis being
associated with the treatment of a Graves’ patient in a similar trial
(75) and brings into question the need for this therapy over established treatments. Despite this, rituximab may prove to be worthwhile in unique circumstances such as in the prevention of severe
ophthalmopathy in those patients receiving thyroid ablation.
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Conclusion
The endocrine system is commonly pathologically targeted
by the immune system and can often lead to clinical disease
through complete destruction of the organ. For years, our
main genetic understanding of these disorders has been that
the MHC genetic region encodes a significant degree of risk.
Recent, rapid advances in genetics have shed new light on
immune pathways and mechanisms that are involved in the
pathogenesis of these diseases. These pathways include those
revealed by monogenic autoimmune diseases, like APS1 and
IPEX, which reveal the importance of thymic selection and
Tregs in maintaining tolerance. In addition, rigorously powered genetic studies have reinforced the notion that T-cell
response genes are involved in disease pathogenesis and that
many autoimmune endocrine diseases share similar genetic
risk. In addition, to our advancing knowledge in genetics,
there have also been recent strides in identifying new diagnostic markers and new treatments for these diseases. Despite
these advances, much work remains to be done, including
addressing the fundamental question of why the endocrine
system is so commonly targeted by autoimmune responses.
Acknowledgments
I thank Jason DeVoss for help with the figures.
Address all correspondence and requests for reprints to: Mark
S. Anderson, M.D., Ph.D., University of California-San Francisco
Diabetes Center, Box 0540, 513 Parnassus Avenue, San Francisco,
California 94143-0540. E-mail: [email protected].
M.S.A. is supported by the National Institutes of Health, The Pew
Scholars, The Burroughs Wellcome Fund, the Juvenile Diabetes Research
Foundation, and the Sandler Foundation.
Disclosure Statement: The author has nothing to disclose.
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International Society for Clinical Densitometry 2009 Annual Meeting
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