Download Thyroid Ophthalmopathy

GRAVES’ DISEASE and THYROID ASSOCIATED OPHTHALMOPATHY
ICD – 9 : 376-21
Nicky R. Holdeman, O.D., M.D.
THE DISEASE
PATHOPHYSIOLOGY:
Thyroid associated ophthalmopathy (TAO) is a common autoimmune process that
affects the soft tissue and fat of the orbit. TAO most commonly occurs in Graves'
disease – both of which have autoantibodies directed against orbital antigens and
thyroid thyrotropin receptors, respectively.
The mechanism by which thyroid-stimulating antibodies bind to and activate
thyrotropin receptors is not well known; however, it has been found that the majority of
patients (≈50%) with autoimmune thyroid disease will eventually develop some form of
thyroid eye disease (TED), also called thyroid-associated ophthalmopathy.
ETIOLOGY: (see table 1)
Graves’ disease is the leading cause of hyperthyroidism, resulting from production of
thyroid stimulating hormone (TSH) receptor antibodies. These antibodies mimic the
action of TSH, thus stimulating thyroid gland growth, with subsequent thyroid
hormone synthesis and release. Thyroid ophthalmopathy is an extra-thyroidal
manifestation of Graves’ disease.
The major abnormality in thyroid ophthalmopathy appears to be inflammation and
enlargement of the orbital tissues, particularly orbital fibroblasts, rather than myocytes,
which lack significant TSH receptors. Exophthalmos and optic nerve compression are
caused by deposition of mucinous edema, proliferation of fibroblasts, and accumulation
of lymphocytes & glycosaminoglycans within the muscles, resulting in an increase of
orbital connective tissue, fluids, and fat. These structural changes ultimately interfere
with muscle function and increase orbital pressure. Orbital venous obstruction and
capillary collapse, due to inflammation and cigarette smoking, contribute significantly
to the clinical manifestations of TAO, by affecting oxygen delivery to the orbit.
THE PATIENT
CLINICAL SYMPTOMS:
The clinical presentation of the thyrotoxic patient may be extremely variable. The
actual features relate to the age of onset, the duration of the condition, and the degree of
hormone excess. The general symptoms of systemic thyrotoxicosis (hyperthyroidism)
are sweating, increased appetite, weight loss, nervousness, hyperdefication, heat
intolerance, restlessness, irritability, insomnia, exertional dyspnea, fatigue, skeletal
muscle weakness, tremor, palpitations, decreased menstrual flow in women, pruritus,
and warm, moist skin. With increasing age, weight loss and anorexia become more
common, whereas irritability and heat intolerance are less common.
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The onset of ocular manifestations may be acute or quite gradual. The symptoms of
TED are usually mild, consisting of eyelid retraction or “stare”, ocular irritation, dry
eyes, redness, tearing, retrobulbar pressure, eyelid swelling, and photophobia.
However, a clinically significant number of patients experience severe consequences
such as persistent diplopia, exposure keratopathy, or optic neuropathy.
TOA most commonly occurs concurrently in the setting of systemic thyroid disease.
Approximately 26% of patients with newly diagnosed Grave’s disease have evidence of
thyroid eye disease at baseline – 20% have mild TED and 6% have moderate to severe
disease. It is important to remember however, that ophthalmic symptoms and signs
can occur prior to the systemic manifestations of thyroid disease in about 20% of
patients.
CLINICAL SIGNS:
Signs of thyrotoxicosis may include a diffusely enlarged thyroid (often with overlying
bruit), warm, moist skin, thinning and loss of hair, tachycardia or atrial fibrillation,
muscle wasting, tremors, hyperreflexia, palmar erythema, onycholysis, and rarely high
output heart failure.
The characteristic findings in TED include upper eyelid retraction (the most common
feature, seen in ≈ 90% of patients), lid lag, conjunctival injection and chemosis, superior
limbic keratoconjunctivitis, periorbital edema, proptosis (either unilateral or bilateral),
restrictive dysmotility, elevation of intraocular pressure, resistance to retropulsion of
the globe, exposure keratopathy, pupillary defects, acquired color vision deficits,
and/or visual acuity loss, usually due to compressive optic neuropathy (see Table 2).
Graves’ ophthalmopathy usually involves both orbits, although an asymmetry may be
present. A small number of patients (5 – 11%) show no progression to bilateral disease
and have only unilateral involvement.
Graves’ ophthalmopathy typically goes through three phases – progression,
stabilization, and perhaps improvement. In fact, spontaneous improvement of mild
ophthalmopathy is seen in approximately 60% of patients. However, unpredictable and
sudden worsening of ophthalmopathy can occur at any time, independent of
antithyroid therapy.
NOTE: Thyroid patients frequently develop eye findings that mimic dry eye,
conjunctivitis, cellulitis, allergic reactions, episcleritis, myositis, EOM nerve paresis
(esotropia from MR restriction and hypotropia from IR restriction are the most common
preoperative deviations), orbital tumors, AV malformations, and Parinaud’s syndrome.
Due to the vagueness of many signs, the early stages of thyroid orbitopathy can easily
be missed.
Clinicians must maintain a high index of suspicion for the varied
ophthalmic signs that may indicate thyroid disease.
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DEMOGRAPHICS:
The American Thyroid Association predicts that 12% of the U.S. population will
develop thyroid dysfunction in their lifetime. Depending on the diagnostic criteria, up
to 50% of patients with thyroid dysfunction will develop TED.
Graves’ disease is the most prevalent autoimmune disorder in the United States,
affecting 2.2% of the population.
The prevalence of Graves’ disease is similar among whites and Asians - it is lower
among blacks. The onset of disease is usually between the ages of 30 and 60.
Graves' disease may occur in men or women at any age; however, it is much more
common in women than in men (8:1), in part the result of the modulation of the
autoimmune response by estrogen.
TED affects women six times more frequently than men.
The clinical course of dysthyroid ophthalmopathy is likely to be more severe in men,
older patients (≥ 50 yrs of age), and those with a family history of thyroid disease.
Among patients with hyperthyroidism, 60-80% has Graves' disease. There appears to
be an increased risk of Graves' disease during pregnancy, but conversely, there is often
a spontaneous remission of hyperthyroidism in the last trimester, in which case therapy
can often times be stopped.
Graves' disease may be associated with other diseases that have autoantibody
production such as lupus, multiple sclerosis, pernicious anemia, scleroderma, vitiligo,
myasthenia gravis, inflammatory bowel disease, type 1 diabetes mellitus, rheumatoid
arthritis, and / or alopecia areata.
While myasthenia gravis is estimated to occur in less than 1% of patients with thyroid
dysfunction, the development of an exotropia, which is rare in a patient with TED,
should alert the clinician as to the possible development of myasthenia gravis.
Clinical activity scales exist to help classify the disease severity (i.e. European Group on
Graves Orbitopathy – EUGOGO). Using the clinical activity and severity scales, the
disease process can be stratified into mild, moderate, severe, and sight threatening. The
severity of eye disease does not always correlate with the degree of thyrotoxicosis,
although ophthalmopathy tends to be more severe in cigarette smokers and in patients
in whom hyperthyroidism is poorly controlled.
SIGNIFICANT HISTORY:
Since most patients with Graves’ disease are hyperthyroid, the systemic history and
ROS should emphasize questions related to unexplained weight loss, nervousness,
diarrhea, exertional dyspnea, increased perspiration, heat intolerance, irregular
menstrual cycles, sleep disturbances, and hair loss.
Graves' disease has a familial tendency; however, genes make only a moderate
contribution to susceptibility of Graves' disease. Approximately 20% of those affected
have a family history of thyroid disease.
3
Risk factors for worsening of Graves’ ophthalmopathy may include therapeutic
irradiation of the neck, diabetes, and smoking. Reactivation, severity, and treatment
failures are increased in patients who smoke. Adjusting for age and prior orbital
decompression, active smokers also have 2-fold risk of requiring strabismus surgery
compared to nonsmokers and ex-smokers.
There is a higher incidenceof TED in patients with hyperthyroidism (90%); however,
eye findings may occur in a euthyroid (5%) or even a hypothyroid (1%-5%) patient.
NOTE:  of orbitopathy patients will remain euthyroid, with no detectable form
of thyroid dysfunction - this may complicate confirmation of the clinical diagnosis.
Euthyroid and hypothyroid patients with Graves’ ophthalmopathy typically have less
severe and more asymmetric orbital involvement than patients who are hyperthyroid at
presentation.
ANCILLARY TESTS (see Table 3)
Patients with TED may be euthyroid at presentation, but 25% will develop laboratoryevidenced thyroid dysfunction within 1 year and 50% will do so within 5 years.
Many drugs can affect the outcome of thyroid function tests. It is imperative to know
all the medications the patient is taking to avoid misinterpretation of the test results.
Thyroid function tests (TFT’s) - The typical thyroid panel often includes a T3 resin
uptake (T3RU), total serum thyroxin (T4), and a free thyroxin index (FT4I or T7). Serum
free T4 and total or free T3 should also be obtained, as 5-10% of hyperthyroid patients
will only manifest an elevated serum T3, a condition called "T3 toxicosis". Serum
triiodothyronine (T3) is particularly indicated if the thyrotropin (TSH) level is low but
the thyroxin level is normal (see below).
Sensitive serum thyroid stimulating hormone assays (TSH) - While rare exceptions
exist, the presence of a normal serum thyrotropin (TSH) concentration nearly always
excludes a diagnosis of hyperthyroidism. The highly sensitive TSH assays are
considered by most to be the single best screening test for thyroid disease and the most
important test used to regulate thyroid hormone dosing. However, thyroid hormone
concentrations and clinical presentation should be used to determine severity of
disease. One approach to the laboratory investigation of suspected hyperthyroidism is
as follows:
Order a serum thyrotropin (immunometric s-TSH) assay:
• If normal (0.3mIU/L to 3.0mIU/L), hyperthyroidism is excluded (except in rare
cases of a TSH secreting pituitary tumor or a pituitary resistance to thyroid
hormone.)
• If low, order a free T4 (thyroxin) level:
If T4 is high, hyperthyroidism confirmed
If T4 is normal, order a free T3 (triiodothyronine)
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• If the free T3 level is high, T3 toxicosis is confirmed
• If the free T3 level is normal, the patient may have subclinical
hyperthyroidism, evolving Graves' disease, toxic nodular goiter, etc. Tests
should be repeated in 2-3 months.
NOTE: There is some controversy as to what value should be assigned as the upper
limits of normal (ULN) for TSH. Regardless of the designated ULN, whether
patients, especially elderly individuals, with slightly elevated TSH levels benefit
from thyroid supplementation remains unclear. Since use of levothyroxine has
been associated with elevated fracture risk in elders, patients receiving
levothyroxine should be monitored to avoid suppressed TSH levels.
Thyroid scans (123I) - Useful for studying thyroid nodules. Functioning ("hot") nodules
are rarely malignant while nonfunctioning (cold) nodules could indicate malignancy.
Thyroid-stimulating hormone receptor autoantibodies (TSH-R Ab) – The presence of
TSH receptor antibodies can often be used to distinguish Graves' disease from other
forms of hyperthyroidism. TSH-R Ab’s are typically present in patients with Graves'
disease (>80%) but are not usually required for diagnosis, especially when eye disease
occurs in patients with known hyperthyroidism. Although TSH-R Ab’s cause Graves'
hyperthyroidism, the serum antibody concentrations are often very low and are even
undetectable in a few patients. In these particular cases, antibody production may be
confined to lymphocytes within the thyroid and the serum may be quite low. However,
in other patients, thyroid stimulating immunoglobulin levels correlate well with both
activity and severity of TED.
Thyroperoxidase autoantibody (TPO-ab) – Measurement of TPO-ab is a sensitive test
for the diagnosis of autoimmune thryroiditis. TPO-Ab’s are detectable in about 90% of
patients with Hashimoto thryroiditis and are present in about 75% of cases of Graves’
disease.
NOTE: If myasthenia gravis is suspected, the appropriate panel of tests includes:
acetylcholine receptor antibodies (i.e. serum ACHR binding Ab, serum ACHR blocking
Ab, ACHR modulating Ab) and striational antibodies. Clustered AChR-Ab may soon be
available, which could possibly improve the ability to diagnose ocular MG earlier.
Imaging – Non-contrast CT scanning (axial and coronal views to the orbital apex) is
used to visualize the orbits, the EOM's, the paranasal sinuses, and to exclude
retrobulbar tumors, orbital pseudotumors, or arteriovenous malformations as a cause of
exophthalmos, particularly with unilateral involvement. Typically enlargement of the
EOM’s involves the belly of the muscle while sparing the muscle tendon; this is in
contrast to orbital pseudotumor, in which the tendinous insertion tends to be thickened.
In TED, the inferior rectus is the most commonly involved muscle, followed by the
medial rectus, superior rectus, and the lateral rectus.
Compared to CT, MRI does not offer significant advantages, except for the evaluation of
the optic nerve and in differentiating between EOM’s that are actually inflamed versus
those that are fibrosed.
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In addition to CT scanning, digital infrared thermal imaging is sometimes used to
detect local temperatures of the orbit which are elevated in active TED and decrease in
response to therapy.
Ultrasonography may be helpful in assessing anterior and midorbital disease.
TED remains a clinical diagnosis and a careful eye examination should be performed on
each patient. Depending on the stage of disease, (see Table 1) any or all of the following
procedures may be indicated: visual acuities, lid assessment, pupillary assessment
(RAPD), motility testing (including forced ductions), exophthalmometry, color vision
perception, threshold perimetry, biomicroscopy, intraocular pressures (primary gaze
and upgaze), ophthalmoscopy, MRI or CT scans of the orbit, and/or visual evoked
potentials. External and fundus photography is a useful method of recording clinical
status.
NOTE: Up to 50% of patients with optic nerve compression may have no optic disc
pathology. These patients may also present with normal acuity and / or visual fields.
THE TREATMENT
The patient should be referred to an endocrinologist for management of the underlying
thyroid disorder. Treatment may also include consultation with an orbital surgeon and
nuclear medicine specialist. The patient with Graves’ disease should be advised that
the ophthalmopathy might progress even if euthyroidism is achieved and that smoking
increases the risk of Graves’ ophthalmopathy, increases the frequency of strabismus
surgery, and is associated with poorer outcomes of treatment. Patients who smoke
should be given strong support to stop smoking.
The choice of therapy for systemic thyrotoxicosis is dictated by the etiology of the
disorder, the patient's age, the size of the gland, the severity of disease, and the desires
of the patient. The ideal treatment for Graves’ disease and for TED, which would
correct the autoimmune responses in the thyroid and the orbits, is not available.
Currently, there are 3 principal treatments for systemic Grave’s disease—1) antithyroid
drugs (methimazole and propylthiouracil), 2) radioiodine (131I), and 3) total or subtotal
thyroidectomy--all of which are effective in normalizing serum thyroid hormone
concentrations. Unfortunately, no single treatment is guaranteed to result in permanent
euthyroidism and each have certain advantages and adverse effects. 131I, when
compared to other forms of antithyroid therapy, is more likely to cause or exacerbate
thyroid ophthalmopathy (particularly in cigarette smokers) unless low to moderate
doses of oral prednisone is given for several weeks following radioiodine ablation.
The management of Grave’s orbitopathy involves treating active disease to prevent, or
at least ameliorate, later sequelae. Treatment for moderate to severe disease may
include oral steroids, intravenous steroids, periorbital steroid injections, rituximab IV,
or orbital radiation. Medical treatments are effective only during the active phase and
not the cicatricial phase, which can be difficult to determine.
Dysthyroid patients with eye signs should be evaluated and treated for the major
complications of thyroid orbitopathy. These conditions include:
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-
-
-
Exposure keratopathy - the cornea should be protected utilizing sunglasses,
artificial tears, punctal plugs, ointments, or taping of the lids. If dermatitis
develops from repeated tape use, patients may use a circle of plastic wrap
secured by a ring of petroleum jelly to fashion a moisture chamber. In patients
with severe proptosis, lateral tarsorrhaphy or botulinum injections may be
necessary to prevent corneal damage.
Diplopia - small-angle tropias due to EOM entrapment can sometimes be
managed with prism. Patients with large angle deviations may benefit by
recession of the restricted muscles. Strabismic surgery should typically be
considered only after the patient is euthyroid and the eye signs have been stable
for at least 6 months, unless the patient has a disabling head posture or disabling
diplopia.
Since muscle surgery can potentially result in further lid retraction due to
connective tissue attachments between the vertical muscles and the lid
musculature, lid surgery is best performed after strabismus surgery.
Optic neuropathy - signs of optic nerve compression indicate a need for immediate
treatment with high dose IV steroids (methylprednisolone 1g/day for three
days) followed by oral steroids (prednisone 60-100 mg p.o. qD for 2 weeks),
orbital radiotherapy (RT), or graded surgical decompression of the orbit.
Decompression can entail removing bony walls of the orbit, allowing prolapse of
the orbital contents, or be accomplished by removing orbital fat, thereby
decreasing the amount of tissue in the orbit.
The method of orbital
decompression is often based on whether the patient has a type II (myogenic) or
type I (lipogenic) variant of orbital disease.
While all three forms of therapy for optic neuropathy have been used
successfully, some have questioned external beam orbital radiation, as it
appeared to offer little in the way of long-term benefits. Others have found that
treatment with corticosteroids and orbital RT reduced the risk of compressive
optic neuropathy compared to corticosteroids alone in patients with active TED.
While the controversy regarding RT continues, RT should be considered for
patients with active, compressive optic neuropathy, but not for patients with
mild to moderate ophthalmopathy. In addition, there appears to be an increased
risk to diabetics with concurrent hypertension to develop retinopathy after
orbital radiotherapy.
NOTE: When optic neuropathy develops in thyroid disease, it may occur on the side
of the less proptotic, more crowded orbit, as truly unilateral involvement occurs in a
minority of cases. Compressive optic neuropathy can be more devastating in this
setting due to the tightness and small volume of the orbits.
Several other forms of therapy have proven useful:
- Cessation of smoking (always a critical component of treatment)
- Moisture chambers or swimmers goggles to protect exposed corneas
- Elevation of the head to help reduce eyelid and orbital edema
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-
-
-
Botulinum toxin injections for dysthyroid upper lid retraction and for selected
cases of strabismus
Other immunosuppressive and immunomodulatory agents (i.e.) cyclosporine,
azathioprine, methotrexate, rapamycin, rituximab, or infliximab may be effective
in steroid resistant TED and a single 500 mg dose of rituximab may result in a
much lower incidence of relapse when compared to IV methylprednisolone.
However, these agents are typically reserved for patients with severe
orbitopathy and are most often administered by a rheumatologist.
Peribulbar triamcinolone injections for TED appear equally effective as high dose
oral prednisolone with less adverse reactions.
Compared with placebo, patients with TED treated with selenium (100
micrograms twice daily) reported much better quality of life and better
ophthalmic endpoints by examination. A six-month course of selenium
supplementation appears to be a safe, low cost, and effective intervention for
patients with mild disease.
Tarsorrhaphy can be performed if needed
NOTE: A minimally invasive, non-ablative means of reducing the volume of orbital fat
in patients with symptomatic TED has received orphan drug approval from the FDA.
LIPO-102 is an injectable aqueous combination of salmeterol xinafoate and fluticasone
propionate. Injection of LIPO-102 is intended to shrink the fat in the orbit, thus
reducing exophthalmos in patients with TED. Proptosis has been historically managed
by surgical decompression of the orbit.
For additional information:
American Association of Clinical Endocrinologists: www.aace.com
Graves’ Disease Foundation: www.ngdf.org
The Hormone Foundation: www.hormone.org
American Thyroid Association: www.thyroid.org
Thyroid Foundation of America: www.allthyroid.org
American Autoimmune Related Diseases Association: www.aarda.org
Effective Health Care Program: www.effectivehealthcare.ahrq.gov
www.thyroidawareness.com
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Table 1
Common Causes of Hyperthyroidism
Autoimmune thyroid disease
Grave’ disease
Autonomous thyroid tissues
Toxic adenoma
Toxic multinodular goiter
Subacute thyroiditis
Granulomatous thyroiditis
Postpartum thyroiditis
Exogenous thyroid hormone intake
Excessive replacement dose
Factitious hyperthyroidism
Iodine-induced hyperthyroidism
Other rare causes
Strumi ovarii
TSH-mediated (TSH-secreting pituitary adenoma)
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Table 2
"NO SPECS" Classification of Graves' Orbitopathy
CLASS
CHARACTERISTICS
0
No physical signs or symptoms
1
Only signs (i.e.) lid retraction, stare
2
Soft tissue signs and symptoms (i.e.) conjunctival injection, conjunctival
and lid edema, lacrimation
3
Proptosis (upper limits of normal is approximately 22 mm in Caucasians
and 24 mm in African-Americans. There should be no more than a 2 mm
difference between the two eyes.)
4
Extraocular muscle involvement (i.e.) restrictions, adhesions
Compression of the globe by thickened EOM’s may increase the IOP in
upgaze *
5
Corneal involvement (i.e.) stippling, ulceration, scarring
6
Sight loss (i.e.) compressive optic neuropathy, field loss, reduced acuity
Van Dyk JHL: Orbital Graves' disease:
classification. Ophth 88: 479-483, 1981.
A modification of the "NO SPECS"
NOTE: While the NOSPEC mnemonic is often helpful in directing the eye examination,
it is not useful in predicting the course of disease or in guiding treatment.
* Traditionally, an increase in IOP in upgaze has been considered useful sign in
TED. However, there is significant overlap between normal volunteers and
patients with TED and a rise in IOP does not discriminate well between these
groups – partly due to applanation on the thicker, peripheral cornea.
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TABLE 3
Tests Employed in the Evaluation
of Patients with Thyroid Abnormalities
Test
Purpose
Methodology
Comments
Detects >90% of cases of hyperthyroidism
Total serum T4
(Thyroxin)
T4 level
Enzyme linked
immunosorbant
assay (ELISA)
Radioimmunoassay
(RIA)
Resin T3 uptake
(RT3U)
Free
T4
thyroxine)
(free
Serum T3
(Triiodothyronine)
Affected by alterations in the thyroxine-binding
globulin (TBG) level and can be misleadingly
high or low
Free T4 (FT4) makes up only a fraction of T4 level
(0.04%)
Assessment of free
T4
Binding of labeled T3
to resin versus patient’s
serum
Clarifies whether alterations in T4 are the result
of thyroid pathology or alterations in T4-binding
proteins
Assessment
unbound T4
Equilibrium dialysis
Directly measures FT4
T3 level
Radioimmunoassay
Independent of TBG levels
Used for detecting hyperthyroidism, especially
T3 toxocosis in which T3 is elevated but T4 is
within normal limits
Not to be confused with RT3U
Radioactive iodine
uptake (RAIU)
Extent of thyroid
function
Measurement
of
percentage
uptake of
iodine tracer dose after
given time
Normal range must be determined for each
population district
Difficult to distinguish low values from lownormal values when dietary iodine is high
Hyperthyroidism does not always cause high
iodine uptake
Immunoradiometric assay
(IRMA)
Most sensitive test for primary hypothyroidism
(i.e., TSH level is high before other tests show
low T4)
Thyroid-stimulating
hormone (TSH)
(also
called
thyrotropin)
Serum TSH level:
an
index
of
thyroid status
Thyroid scan
Functional status
of nodular goiter
Radionuclide scanning
Often not needed in other types of thyroid
pathology
Ultrasonography
Status of
nodules
Ultrasound scanning
Reliably discriminates between cystic and solid
nodules in 90% of cases
Serum
thyroid
antimicrosomal
antibodies
Distinguish
between nodular
goiter
and
thyroiditis
single
Chemiluminescent assay
(ICMA)
Tanned red blood cell
agglutination test
Complement fixation test
Standard assay not reliable at low TSH levels;
sensitive immunoradiometric and chemiluminescent assays improve detection of low levels
High titers suggest Hashimoto’s thyroiditis.
Antibodies to thyroid microsomes are present in
70-90% of patients with chronic thyroiditis
Antimicrobial antibodies
Free
thyroxine
index (FT4I)
Indirect
correlation of free
T4
Calculation from results
of T3 resin uptake and
total T4
(Serum T4 x RT3U)
Good screening test since it is not affected by
alterations in thyroxin-binding protein sites
An index which generally correlates with free T 4
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Hyperthyroidism
Hypothyroidism
Euthyroid with
Increased TBG*
Euthyroid with
Decreased TBG*
TOTAL T4
Increased
Decreased
Increased
Decreased
T3RU
Increased
Decreased
Decreased
Increased
FT4I
Increased
Decreased
Normal
Normal
TSH
Decreased
Increased
Normal
Normal
*
Thyroxin Binding Globulins (TBG's)
TBG's may be increased in pregnancy, acute hepatitis, oral contraceptives, heroin abuse, or clofibrate use.
TBG's may be decreased in cirrhosis, nephrotic syndrome, androgens, and glucocorticoids.
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