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Insights Into the Pathogenesis of Thyroid-Associated Orbitopathy
Evolving Rationale for Therapy
Michael Kazim, MD;
Robert A. Goldberg, MD;
Terry J. Smith, MD
Arch Ophthalmol. 2002;120:380-386.
INTRODUCTION
Attempts to understand the pathogenesis of thyroid-associated orbitopathy
(TAO) have failed, in part because of confounding features associated with
its variable clinical presentation. In the absence of a more complete insight
into disease mechanisms, no specific and effective therapy can be developed.
It is our view that much of the information necessary to unravel the complexities
of TAO and therefore formulate rational therapy has already been gathered.
CLINICAL FEATURES OF TAO
Thyroid-associated orbitopathy varies widely in its pattern of presentation.
Generalizations about this disease are not particularly useful when treatment
plans are developed for an individual patient, but the following description
will serve as a point of reference for the subsequent discussion. Thyroid-associated
orbitopathy is identified in approximately 20% of those seen with Graves disease
on initial examination. A far larger group manifests subclinical, self-limited
forms of TAO. The prevalence of these milder forms of the disease is estimated
to be as high as 80%.1-4
It commonly affects women in the fifth decade of life and is usually diagnosed
soon after the glandular aspects of Graves disease appear.2, 5-7
Components of the orbital process include symmetric soft tissue swelling,
proptosis, lid retraction (with characteristic temporal flare), and strabismus,
due in large part to fibrosis of the extraocular muscles (Figure 1 and Figure 2).
The self-limited disease requires only supportive measures except in cases
where severe corneal exposure keratitis or compressive optic neuropathy threatens
vision and requires immediate medical attention. The active phase of TAO typically
lasts 1 year, after which most patients improve.1, 7
Residual stigmas of the disease often persist after the active phase resolves,
but few patients require surgical rehabilitation.3
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Figure 1. Magnetic resonance image of a
patient with Graves disease and congestive orbitopathy. The image demonstrates
enlargement of the superior ophthalmic vein (arrows), presumably secondary
to apical compression.
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Figure 2. Magnetic resonance image of a
patient with Graves disease showing enlargement of the intraconal fat compartment,
proptosis, and straightening of the optic nerve.
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SOME UNANSWERED QUESTIONS
It is a widely held view that TAO is an autoimmune disease and is not
believed to result directly from the metabolic perturbations caused by thyroid
hormone overproduction.1-3,8-16
If this assertion were correct, then a frequent absence of improvement after
successful treatment of the dysthyroid state would be expected. The apparent
dissociation between glandular and orbital disease would also explain why
patients with euthyroid Graves disease or Hashimoto thyroiditis can manifest
TAO.1, 3 However, evidence supporting
an autoimmune cause for TAO is largely circumstantial and includes the frequent
coincidence of other autoimmune processes such as systemic lupus erythematosus,
rheumatoid arthritis, and vitiligo in patients with Graves disease.3, 17 Women are considerably more likely
to develop Graves disease, and they are up to 8 times more likely to exhibit
severe orbital involvement. Yet, among patients with TAO, men are more likely
to develop optic neuropathy.1, 3, 11-13,16
Whether the levels of antibodies associated with thyroid enlargement and overactivity,
termed thyroid-stimulating immunoglobulins, correlate
well with the development, severity, or activity of orbital disease has remained
controversial.18-22
Despite substantial efforts, an autoantigen, restricted in its expression
to the orbit and thyroid gland, has not been identified.23-24 An antigen found exclusively in the
areas affected by Graves disease could link these tissues and thus might provide
an explanation for the anatomic site restriction of connective tissue manifestations
in Graves disease. Moreover, immunoglobulin complexes have not been found
in affected orbital tissue.
An intriguing feature of TAO is the age-related variation in disease
expression. Patients younger than 40 years are more likely to exhibit orbital
fat expansion and proptosis in the absence of infiltration of the extraocular
muscles and eyelid retractors. It is our impression that the clinical behavior
of orbital inflammation in even younger patients is particularly sensitive
to changes in serum thyroxine and thyrotropin levels.25
In contrast, older patients are considerably more likely to develop multiple
fusiform enlargement of the extraocular muscles.25-29
We cannot explain the predilection of the disease for the inferior and medial
recti. Patients older than 70 years are more likely to develop severe extraocular
muscle involvement resulting in diplopia and compressive optic neuropathy.
This often occurs in the absence of proptosis or cutaneous inflammation.
The temporal relationship between the thyroid and orbital diseases is
variable. Whereas in 80% of patients the onset of the glandular and orbital
diseases occurs within 18 months of each other, the clinical appearance of
the two can be separated by as much as 20 years in some cases.5-7
Unlike other autoimmune diseases that are typically chronic with unpredictable
episodes of acute relapse, most patients with TAO undergo spontaneous remission
within 18 months of disease onset. This resolution does not appear to vary
according to the type of therapy used.
Only 5% of patients will develop recurrent orbital inflammatory disease.
The pattern and clinical features of recurrent, acute disease may differ from
those of the initial episode. In contrast to the first presentation, we have
found that recurrent orbital disease is more often associated with the onset
of dysthyroidemia. In many cases, these subsequent exacerbations resolve rapidly
after normalization of thyroid function.
Most cases of TAO are initially seen with symmetric-appearing orbital
involvement. However, a few patients exhibit marked asymmetry of the orbital
disease.1-3,6
Still fewer have unilateral disease that resolves before acute disease affects
the second orbit, sometimes more than 1 year later.
How and whether orbital radiotherapy alters the natural course of TAO,
especially the acute phase of the disease, remain unclear. The elimination
of activated orbital lymphocytes inadequately explains the phenomena. If radiotherapy
merely destroyed resident lymphocytes, new populations of these cells would
most likely repopulate the orbit and reinitiate the inflammatory response.30
We do not understand how smoking promotes and prolongs acute-phase TAO.31-33 This effect has been
demonstrated almost exclusively in women. Why men appear to be spared the
disease-promoting effect of cigarette smoke is uncertain. It would be enlightening
to determine the impact of continued smoke exposure on the persistence of
orbitopathy and whether the course of the disease is altered after its cessation.
RECENT INSIGHTS INTO THE PATHOGENESIS OF TAO
An appreciation of the embryologic derivation of orbital fibroblasts
is essential to understanding the pathogenesis of TAO. Unlike most other regions
of the body, connective tissue investing the orbit contains fibroblasts derived
from the neural crest. Although the significance of this embryologic derivation
is not fully understood, cells from the neural crest possess a particularly
high degree of phenotypic plasticity.34 In
addition to the orbital fibroblast, other periorbital cell types, including
osteoblasts and parasympathetic and postganglionic sympathetic neurons, also
derive from neural ectoderm.35 We hypothesize
that orbital fibroblasts exhibit a set of unique phenotypic attributes rendering
them particularly susceptible to the actions of proinflammatory cytokines
and other disease mediators, and that their embryologic derivation may underlie,
at least in part, their inflammatory phenotype.
The statement, "Few tissues are less interesting than adipose," attributed
to Jakobiec,36 reflects the pervasive attitude
toward orbital fat. Inspection of this tissue shows a complex array of fibrovascular
septae, highly permeable blood vessels, and smooth muscle cells. This network,
elegantly described by Koornneef,37 may represent
the end-organ target of TAO. Structures analogous to the fibrous septae in
fat may exist in extraocular muscles in the form of the endomysium, perimysium,
and epimysium.38 These sites are involved with
intense scar formation in acute TAO, resulting in restrictive strabismus.
Muscle fibers are relatively spared in TAO, suggesting that connective tissue
and not extraocular muscle fiber represents the primary disease target.
DIFFERENCES BETWEEN ORBITAL FIBROBLASTS AND THOSE IN OTHER ANATOMIC
REGIONS
The behavior of orbital fibroblasts in vitro has been examined in detail.39 They express characteristic profiles of surface receptors,
gangliosides, and inflammatory genes.40-43
A number of phenotypic attributes exhibited by orbital fibroblasts suggest
that they may play an active role in tissue remodeling and modulation of local
inflammatory responses. Unlike some fibroblasts, those from the orbit display
cell-surface CD40, a receptor initially found on B lymphocytes and important
to the activation of those cells. The receptor CD40 is activated by CD154,
also known as CD40 ligand, which is displayed on the surface of T lymphocytes.
When CD40 on orbital fibroblasts is engaged by CD154, several inflammatory
fibroblast genes are activated. Interleukin 6 and interleukin 8 expression
is dramatically up-regulated, which, in turn, can result in enhanced chemotaxis
of bone marrow–derived inflammatory cells to the orbit.44
Prostaglandin endoperoxide H synthase 2, the inflammatory cyclooxygenase,
is induced by CD40 ligation on orbital fibroblasts.45
This induction results in substantial increases in the production of prostaglandin
E2. Synthesis of hyaluronan, an important glycosaminoglycan polymer
thought to accumulate in the orbital connective tissue in TAO, is also increased
by CD40 ligation.45 Many of the consequences
of CD40 ligation in human fibroblasts are mediated through the activation
of nuclear factor  B and can be attenuated with physiologic concentrations
of glucocorticoids.45 This finding is entirely
consistent with the therapeutic benefit associated with these corticosteroids
in acute TAO.1 The actions of other proinflammatory
cytokines, such as interleukin 1, and the T-lymphocyte–derived molecule
leukoregulin, also result in exaggerated orbital fibroblast gene inductions
that may have important roles in the orbital inflammatory response.46-49 For
instance, uridine diphosphate glucose dehydrogenase and members of the hyaluronan
synthase gene family are induced substantially in orbital fibroblasts treated
with proinflammatory cytokines.48, 50
We believe that these inductions underlie the exaggerated increases in hyaluronan
synthesis observed in cytokine-activated cultures.49
The increases in orbital fibroblast synthesis of hyaluronan, in turn, result
in the accumulation of the glycosaminoglycan that occurs in TAO.51
Many of these cellular responses differ quantitatively or qualitatively
in orbital and nonorbital fibroblasts. We postulate that the peculiar phenotype
of orbital fibroblasts renders the human orbit susceptible to inflammation,
such as that occurring in TAO. Moreover, fibroblasts from other anatomic regions
of the body that are affected by autoimmune diseases, such as rheumatoid arthritis,
exhibit several cellular characteristics that are not unlike those of their
orbital counterparts.52 A number of interesting
parallels have been shown to exist between TAO orbital fibroblasts and synovial
fibroblasts from patients with arthritis.
A subpopulation of orbital fibroblasts appears capable of undergoing
adipocyte differentiation in vitro.53 It is
as yet unclear whether the fat compartment of the orbit expands on the basis
of an increased number and/or size of adipocytes or whether hyaluronan infiltration
accounts entirely for the increases in fatty connective tissue volume. Another
open question relates to whether orbital fibroblasts present the immune system
with altered antigenic targets after differentiation into adipocytes. Does
the density of thyrotropin receptors displayed by the preadipocyte change
after differentiation? Are there differences in the expression or the coupling
of CD40 to its downstream signaling pathways and gene targets in the mature
adipocyte?
Our ignorance concerning the pathogenesis of TAO includes the obscure
mechanism by which immunocompetent cells are trafficked to the orbit. Are
the same factors involved in the initiation of the orbital and thyroidal components
of Graves disease? Much of our inability to define the very early pathogenic
events in TAO results from limited access to relevant tissue during the acute
disease phase. As a result, we have not identified the earliest cells that
infiltrate the soft tissues of the orbit. We have relied largely on histologic
examination of the stable phase occurring late in the process, when reactive
events rather than those involved in the initiation of the disease are likely
to predominate.
Recent interest in the thyrotropin receptor as the critical autoantigen
in TAO derives largely from the contention that it is expressed exclusively
on thyroid epithelial cells and in tissues manifesting Graves disease, including
orbital connective tissue and pretibial skin. Indeed, reports have appeared
demonstrating the thyrotropin receptor messenger RNA (mRNA) in orbital tissues
from patients with TAO and from individuals without the disease.54
Early studies relied on nonquantitative polymerase chain reaction but have
been substantiated subsequently by reports using in situ hybridization. They
have clearly demonstrated target transcripts in orbital tissues.55
Several studies have shown that orbital fibroblasts can also express both
thyrotropin receptor mRNA and protein.56-58
One recent study failed to detect thyrotropin receptor mRNA in abdominal adipose–connective
tissue by means of an RNase protection assay.57
However, another study indicated that thyrotropin receptor mRNA is expressed
in fat deposits distant from the orbit59 and
by fibroblasts and preadipocytes-adipocytes derived from several tissues including
those not ordinarily manifesting Graves disease.60
These receptors appear to be functional by virtue of their competence to activate
the p70S6k pathway, a newly identified downstream target of the
thyrotropin receptor expressed by the thyrocyte. Thus, the concept that the
thyrotropin receptor represents an anatomically restricted antigen and that
this limited expression underlies the localization of disease manifestations
is probably incorrect. This is not to say that the thyrotropin receptor does
not play an important role in the pathogenesis of TAO. We believe a more likely
disease model involves the thyrotropin receptor functioning as a conduit for
the exchange of molecular information between the immune system and connective
tissue, such as that investing the orbit.
Our current overview of orbital fibroblast involvement in the pathogenesis
of TAO is summarized in Figure 3.
From that schematic diagram, it becomes clear how multiple interactions are
possible between immunocompetent cells and fibroblasts. However, there is
certainly no reason to believe that fibroblasts, once activated, would not
modify the behavior of the immune cells trafficked to the orbit. Thus, the
model should be seen as a dynamic interplay between cells that leads to a
variety of tissue changes and could culminate in terminal events such as fibrosis.
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Figure 3. Schematic diagram of our current
model of the proposed immune cascade in thyroid-associated orbitopathy. The
orbital fibroblast is involved in a dynamic interplay with immunocompetent
cells such as T and B lymphocytes and mast cells. CD40 and its ligand CD154
are prominent features of this interaction. IL indicates interleukin; MAPK,
mitogen-activated protein kinase; NF-B, nuclear factor B; IL-1ra,
interleukin 1 receptor antagonist; mRNA, messenger RNA; PGE2, prostaglandin
E2; PGHS, prostaglandin endoperoxide H synthase; HAS, hyaluronan
synthase; UDP-GD, uridine diphosphate glucose dehydrogenase; TSHr, thyrotropin
receptor; TSI, thyroid-stimulating immunoglobulin; and HA, hyaluronan.
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CLINICAL AND THERAPEUTIC CONSEQUENCES OF THE ORBITAL FIBROBLAST PHENOTYPE
It appears likely to us that the orbital fibroblast possesses a central
role in the pathogenesis of TAO. How does this new insight help clarify the
questions remaining?
The expansion of the orbital fat compartment in TAO could result from
the differentiation of orbital fibroblasts with adipogenic potential after
exposure to an altered cytokine milieu occurring in the disease. Loss of this
adipogenic potential with aging could account for the more pronounced expansion
of fat found in younger patients as compared with older adults with TAO. In
older individuals, nonadipogenic fibroblasts might predominate and thus preferentially
exhibit biosynthetic activities that lead to fibrosis. Of interest is the
small subset of patients who demonstrate evidence on computed tomography and
magnetic resonance imaging of fatty density within the substance of extraocular
muscles (Figure 4). This process
could represent adipocyte expansion in the endomysium and perimysium.61
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Figure 4. Magnetic resonance image of a
patient with Graves disease demonstrating fat-density infiltrates within the
extraocular muscles.
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The supraorbital fat pads enlarge in advanced TAO.62
This, we believe, is a consequence of both enhanced adipocyte differentiation
and proinflammatory cytokine-driven hyaluronan accumulation. We suspect that
a similar process is occurring in the premalar fat pads, accounting perhaps
for the subtle changes in facial morphologic characteristics that have been
attributed to effects of long-term corticosteroid use.
Preliminary studies conducted in culture have demonstrated that the
synthesis of glycosaminoglycans and collagen is enhanced when fibroblasts
are subjected to low oxygen tension. Moreover, dermal fibroblasts subjected
to similar atmospheric conditions expressed high levels of transforming growth
factor ß and collagen mRNA and exhibited increased rates of proliferation.63 Thus, conditions that lower oxygen levels in orbital
tissue could influence the inflammatory responses occurring there. Orbital
ischemia might result from obstruction of venous and, perhaps, lymphatic outflow.
Outflow through the superior and inferior ophthalmic veins may become obstructed
as a consequence of diffuse expansion of the extraocular muscles or connective
tissue.64-65 Alternatively, it
may be caused by obstruction of the superior ophthalmic vein.66-68
The inferior ophthalmic vein may be compressed within the infraorbital canal
by Mueller orbital muscle.69 Feldon and colleagues67 demonstrated that the ligation of the superior ophthalmic
vein in the cat results in an orbital syndrome resembling TAO. If the cycle
of ischemia-induced inflammation were interrupted, improvement might occur.
This mechanism has been proposed as underlying the rapid improvement in inflammation
and edema seen after orbital decompression. We would argue that the benefit
associated with those surgical maneuvers might result directly from the decompression
of the orbital circulation. Were it not for greater attendant risk, surgery
might be routinely indicated in cases of acutely congested orbits.
Multiple factors could contribute to decreased oxygen tension in orbital
tissues and therefore might affect the course and severity of TAO. The association
between smoking and the increased incidence of TAO in women with Graves disease
may be related to a decrease in orbital tissue oxygen tension. Although no
direct and reliable evidence currently supports this concept, it is our impression
that smoking in both men and women causes more persistent and severe TAO.
The mechanism by which orbital radiotherapy resolves acute-phase TAO
is not understood.30, 70-71
External beam photon radiation in the range of 2000 rad (20 Gy) sterilizes
the orbital field of resident lymphocytes. If the entire effect of radiotherapy
were explained by its lymphocidal actions, a population of newly trafficked
T cells could repopulate the orbit and inflammation would recur rapidly. What
if the lymphocytes in the orbit were somehow independently driving the disease?
Would their demise reset the process? It is unclear whether there is, in addition,
a long-lasting effect of radiotherapy on local orbital immunity. Cultured
fibroblasts, when exposed to radiation, express cell-surface antigens differently.72 In theory, radiotherapy might alter the inflammatory
phenotype of the orbital fibroblast to more closely resemble that of the extraorbital
fibroblast. Alternatively, radiotherapy may destroy or inactivate local antigen-presenting
cells such as tissue macrophages and dendritic and mast cells.
The inflammatory events occurring in TAO are complex and incompletely
understood. Currently, no pharmacologic agents are available to specifically
reverse either the systemic or orbital manifestations of Graves disease. Glucocorticoids
are powerful modulators of immune function that appear to act at several levels
of the inflammatory cascade. While they attenuate many of the signs and symptoms
of disease, they are associated with adverse effects. Less toxic and more
specific agents are clearly needed. Nonsteroidal anti-inflammatory agents
act by inhibiting cyclooxygenases. Inhibitors of the inflammatory cyclooxygenase
2 have been introduced to the marketplace recently and are purported to be
less toxic than traditional inhibitors. Although less effective than glucocorticoids,
their lower toxicity makes them potentially valuable therapy for the mild,
acute-phase disease. Clearly, well-controlled studies examining their efficacy
in TAO are warranted.
TREATMENT RECOMMENDATIONS
On the basis of our current understanding of TAO and its pathogenesis,
the following therapeutic recommendations can be made. Early identification
of the glandular and orbital manifestations of Graves disease is invaluable.
Restoration of a euthyroid state is probably of considerable importance in
minimizing orbital inflammation. Profound and prolonged intervals of hypothyroidism
with associated elevations of serum thyrotropin levels should be avoided.
When recognized early, orbitopathy might be effectively treated with nonsteroidal
anti-inflammatory drugs. When the inflammation is advanced, and certainly
in the presence of compressive optic neuropathy, glucocorticoids administered
orally or by orbital injection are required to control the soft tissue features.
Patients with Graves disease should be strongly encouraged to discontinue
smoking, whether or not they have orbitopathy. Radiotherapy has a defined
therapeutic role in the treatment of TAO, and we strongly hold that it abbreviates
the acute phase of the orbitopathy. As a general rule, the acute phase will
usually resolve within 3 to 6 months after radiotherapy, as compared with
1 to 3 years in untreated cases. Radiotherapy is strongly recommended in patients
with compressive optic neuropathy. That intervention may reduce the effective
dose and duration of corticosteroid therapy. Moreover, surgical decompression
may be avoided. When required to relieve residual proptosis, decompression
after radiotherapy is simplified by the absence of acute inflammation. We
also recommend radiotherapy for the unusual case in which inflammation progresses
rapidly. It should be avoided in patients with underlying vasculitis, in those
with concomitant diabetic retinopathy, and when the orbital inflammation has
remitted spontaneously. When used properly, radiotherapy in acute TAO should
limit surgery in the acute phase of disease to the rare instance. We advocate
relegating most surgery to reversing the residual clinical consequences of
orbital fibrosis and fatty expansion, at a stage when the disease has stabilized.
CONCLUSION
Thyroid-related orbitopathy is characterized by clinical paradoxes that
continue to challenge the clinician and intrigue the scientist. The thyrotropin
receptor has attracted substantial attention in our search for a single molecule
that might explain the anatomic localization of Graves disease to specific
tissues. This receptor, which is expressed by fibroblasts throughout the body,
may serve as a conduit for molecular communication between connective tissues
and the immune system in TAO. Additional self-antigens, particularly those
displayed by fibroblasts, may well be involved in cell activation through
their recognition by disease-specific immunoglobulins. Thus, the overlooked
fibroblast may orchestrate a complex immune cascade that initiates, perpetuates,
and eventually attenuates the clinical disease. This proposed mechanism might
explain some of the clinical features of the disease, including adipose accumulation
in the orbit, within the muscles, and on the face. It may also underlie age-related
differences in disease presentation, the worsening disease in states of hypoxia,
and responses to radiotherapy. Many questions concerning TAO remain to be
addressed. New technology is allowing us to probe and dissect aspects of its
pathogenesis that likely result from genetic and acquired factors. Avenues
for further investigation include the characterization of the specific mediators
of the immune cascade, development of clinically useful tests to determine
disease activity, and identification of the earliest cells initiating inflammatory
responses in the orbit.
AUTHOR INFORMATION
Submitted for publication June 7, 2001; final revision received October
3, 2001; accepted October 26, 2001.
This work was supported in part by grants EY08976 and EY11708 from the
National Eye Institute, Bethesda, Md (Dr Smith), and a merit review award
from the Research Service of the Department of Veterans Affairs, Washington,
DC (Dr Smith).
We thank Consuelo Madrigal for her outstanding help in preparing the
manuscript.
Corresponding author and reprints: Terry J. Smith, MD, Division of
Molecular Medicine, Bldg C-2, Harbor-UCLA Medical Center, 1124 W Carson St,
Torrance, CA 90502 (e-mail: tjsmith{at}ucla.edu).
From the Department of Ophthalmology, College of Physicians and Surgeons,
Columbia University, New York, NY (Dr Kazim); Jules Stein Eye Institute, Los
Angeles, Calif (Drs Goldberg and Smith); Division of Molecular Medicine, Department
of Medicine, Harbor-UCLA Medical Center, Torrance, Calif (Dr Smith); and School
of Medicine, University of California, Los Angeles (Drs Goldberg and Smith).
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