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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2135
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2440-2444
Copyright © 2005 by The Endocrine Society

CLINICAL CASE SEMINAR

Recombinant Thyrotropin-Induced Orbital Uptake of [111In-Diethylenetriamine-Pentacetic Acid-D-Phe1]Octreotide in a Patient with Inactive Graves’ Ophthalmopathy

Silvia Savastano, Rosario Pivonello, Wanda Acampa, Marco Salvatore, Gaetano Lombardi, Annamaria Colao and Gianfranco Fenzi

Departments of Molecular and Clinical Endocrinology and Oncology (S.S., R.P., G.L., A.C., G.F.) and Biomorphological and Functional Sciences (W.A., M.S.), Nuclear Medicine Centre of the National Council of Research, "Federico II" University of Naples, 5 Naples, Italy

Address all correspondence and requests for reprints to: Silvia Savastano, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Via Sergio Pansini, 5 Naples, Italy. E-mail: sisavast{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results and Discussion
 References
 
Here we describe the case of a 60-yr-old nonsmoking woman with a history of Graves’ disease associated with papillary thyroid carcinoma. After tumor removal, during the diagnostic follow-up for thyroid cancer, there was evidence of severe Graves’ ophthalmopathy (GO) successfully treated with iv glucocorticoids. After this treatment, GO entered inactive status. The patient was then reevaluated for thyroid cancer with human recombinant TSH (rTSH). Orbital [111In-diethylenetriamine-pentacetic acid (DTPA)-D-phe1]octreotide scan was also performed, and results were negative. Shortly after rTSH administration, a moderate and transient pain behind the eye globes at rest and during eye movement was reported, with an increase in the activity score but without further GO progression. Twenty-four hours after rTSH administration, the patient was submitted to a second [111In-DTPA-D-phe1]octreotide scan, revealing significant orbital uptake, likely related to rapid accumulation of activated lymphocytes with inflammatory cytokines or fibroblasts expressing somatostatin receptors in the orbital tissue or interstitial edema due to the inflammation process. At last follow-up performed after 1 yr, there was no evidence of active thyroid cancer or changes in GO severity and/or activity, and orbital [111In-DTPA-D-phe1]octreotide uptake was negative. This case further supports the involvement of TSH receptor in the pathogenesis of GO. It also confirms the usefulness of orbital [111In-DTPA-D-phe1]octreotide scan to evaluate GO activity.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results and Discussion
 References
 
GRAVES’ OPHTHALMOPATHY (GO), one of the most frequent complications of Graves’ disease (GD), is an etiologically poorly characterized disorder involving the soft tissue and the extraocular muscles of the orbit (1, 2, 3). GO is characterized by eye proptosis, caused by an enlargement of the extraocular muscles and augmentation of retrobulbar fat and orbital soft tissue inflammation (1, 3). The orbital infiltration primarily sustained by activate lymphocytes, local release of cytokines, and interaction of lymphocytes with retrobulbar fibroblasts suggests an organ-specific autoimmune disease with the orbital fibroblasts as key target cells of the autoimmune attack (3). Both experimental and clinical studies suggest that the TSH receptor (TSH-R) may be one of the possible antigens stimulating the autoantibodies implicated in the proliferative changes of retroorbital tissue (4, 5, 6). Because orbital fibroblasts have been reported to express the TSH-R (5, 6), the hypothesis of orbital fibroblast TSH-R as target of the autoimmune reaction in GO seems to be strongly supported.

Clinically, in the early stages, GO is characterized by the retrobulbar infiltration by lymphocytes and interstitial edema, whereas in later stages fatty infiltration and fibrosis occur (1, 2, 3, 4, 5, 6). The clinical examination often fails in defining the disease stage and particularly the presence or absence of fibrosis. Defining the disease stage is, however, crucial to address the correct treatment (1, 2, 3, 4, 5, 6). Indeed, treatment of GO varies from immunosuppressive to surgical therapy, the former being more useful in the early stages and the latter in the later stages of the disease (7). However, none of these treatments is fully satisfactory, reflecting the current lack of knowledge as to the best practice (7).

Somatostatin (SS) receptors (sst) have been demonstrated to be expressed in cells of neuroendocrine origin but also in cells not originated from neuroendocrine precursors, such as lymphocytes (8, 9, 10). The scintigraphy with [111In-diethylenetriamine-pentacetic acid (DTPA)-D-phe1]octreotide, a radionuclide-coupled SS analog, is commonly used to visualize sst-expressing cells (11, 12). sst Scintigraphy (SRS) was shown to be able to reveal the presence of activated lymphocytes in inflammatory foci of several autoimmune diseases (13). In patients with active GO, SRS showed markedly increased orbital uptake of [111In-DTPA-D-phe1]octreotide, compared with healthy subjects and patients with stable disease (14, 15, 16, 17). Orbital uptake to SRS correctly predicted the response to SS analog treatment in a few studies (16, 17). Moreover, we demonstrated that SRS also predicted the clinical response to the immunosuppressive therapy (18).

The coexistence of GD and thyroid cancer is a relatively rare event (19, 20). The concomitant presence of GD is considered a negative prognostic factor in the natural course of thyroid cancer.

In a patient with inactive GO, we report on the appearance of orbital uptake to [111In-DTPA-D-phe1]octreotide after the use of human recombinant TSH (rTSH) administration. This was performed before the radioiodine total body scintigraphy, routinely performed during the follow-up of the patient because of a concomitant papillary thyroid carcinoma (PTC).


   Patient and Methods
Top
 Abstract
 Introduction
 Patient and Methods
Results and Discussion
 References
 
Case history

A 60-yr-old nonsmoking woman presented at our department in 1993 because a 1.5-cm size PTC was incidentally discovered after a subtotal thyroidectomy performed for recurrence of GD. The patient received a first course of 131I therapy (3700 MBq). Postablation whole-body scan (WBS) showed moderate uptake at the thyroid bed level. After this treatment, thyroglobulin levels were undetectable. At the first-year follow-up, no uptake was evidenced by a diagnostic WBS after L-thyroxine withdrawal, thyroglobulin levels remained undetectable, and thyroid autoantibodies were moderately elevated (thyroperoxidase antibodies, 98 IU/ml; thyroglobulin antibodies, 150 IU/ml; normal range < 40). At this time, any history of ocular discomfort after L-thyroxine withdrawal was never referred. At the 3-yr follow-up, WBS revealed local signs of recurrence, and the patient received a second course of 131I therapy (3700 MBq). Shortly after 131I administration, the patient developed severe bilateral GO.

The diagnosis of GO was based on ophthalmologic investigations, in combination with enlargement of extraocular muscles and retrobulbar edema on a coronal computed tomography (CT) scan of the orbits. GO severity and activity were assessed according to the classification of no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction (NOSPECS) and clinical activity score (CAS), respectively (4, 21, 22) (Table 1Go). Circulating TSH-R antibody levels were also present (20 U/liter). Orbital [111In-DTPA-D-phe1]octreotide scan was positive. Intravenous glucocorticoid pulse therapy was therefore quickly performed. After this treatment, GO entered inactive status, and either TSH-R antibodies or thyroperoxidase and thyroglobulin antibodies levels became undetectable. GO remained unchanged, and no tumor relapse occurred in the subsequent 5 yr. At the 7-yr follow-up, the patient was reevaluated for thyroid cancer with human rTSH. To avoid any possible acute effect of rTSH in the presence of active GO, a second orbital [111In-DTPA-D-phe1]octreotide scan was also performed before rTSH administration and shown to be negative (Fig. 1Go). Shortly after rTSH administration, a moderate pain behind the eye globes was reported, both at rest and during eye movements. Twenty-four hours after rTSH administration, the patient underwent a new [111In-DTPA-D-phe1]octreotide scan, revealing a mild orbital uptake (Fig. 1Go). A coronal orbital CT scan showed a moderate increase of globe volume, likely due to intraorbital swelling. Thyroperoxidase and thyroglobulin as well as TSH-R antibodies levels remained undetectable. Painful feeling was reported for no more than 4 wk, with a moderate increase in the activity score but without any further signs or symptoms of GO progression. The NOSPECS and CAS in the patient at the different follow-up controls is shown in Table 2Go. At present, 1 yr after last follow-up, the patient has no evidence of active thyroid cancer or changes in GO severity and/or activity, and orbital [111In-DTPA-D-phe1]octreotide uptake is again negative.


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  		TABLE 1. Assessment of severity of GO

 


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  		FIG. 1. Orbital uptake after 111In-DTPA-D-phe1]octreotide. A, Before the use of human rTSH administration. B, Twenty-four hours after rTSH administration. Values of O/B ratio obtained before and after rTSH administration were 0 and 2.6, respectively.

 

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  		TABLE 2. NOSPECS classification and CAS in the patient at presentation and during the follow-up

 
111In-pentetreotide scintigraphy

111In-pentetreotide (specific activity range, 120–190 MBq) was purchased from Mallinnkrodt (Petten, The Netherlands). The labeling was performed as previously described by Bakker et al. (23). Quality controls were performed on labeled peptide before the injection. More than 95% of the radioactivity was peptide bound in injectable preparations. Planar and single-photon emission-CT (SPECT) images were obtained 24 h after the iv injection of the radioligand. The studies were performed by a single-head {gamma}-camera (Orbiter II, Siemens, Erlangen, Germany) equipped with a medium-energy collimator and connected to a computer system. Acquisition was performed in a step-and-shoot mode. For SPECT, 64 frames of 40 sec each were collected during the 360° rotation. Reconstruction was performed using a Hanning filter on backprojected images. No attenuation correction was applied. Irregular regions of interest were manually drawn on planar images as well as in SPECT reconstruction by the same observer (W.A.). The degree of 111In-pentetreotide uptake within each orbit (O) and brain (B) was studied by the region of interest method on planar images acquired after 24 h from injection and the ratio between O and B was calculated. On the basis of the calculation of O to B ratios, the images were classified using the following three-point score: 0, negative; 1, faint uptake (O to B ratio 0–2.5); and 2, defined (O to B ratio > 2.5). In this patient, values of O to B ratio obtained before and after rTSH administration were 0 and 2.6, respectively.

Assessment of disease severity

The patient was examined by the same clinician, and the clinical evaluation of GO was performed with a modified NOSPECS classification (21). The GO severity was based on no signs or symptoms (class 0); signs only (class 1: o, a, b, c, d); soft tissue involvement (class 2: o, a, b, c, d); proptosis (class 3: o, a, b, c, d); extraocular muscle involvement (class 4: o, a, b, c, d); corneal involvement (class 5: o, a, b, c); and sight visual activity reduction (class 6: o, a, b, c). Lid aperture (in millimeters) was measured at the midline in primary gaze; proptosis (in millimeters) was measured by Hertel exophthalmometer; eye muscle function was evaluated by Hess chart; the proptosis and thickness of eye muscles were also investigated by orbital CT scan; visual acuity was evaluated using the decimal system; and subclinical involvement (in the absence of a reduced visual acuity) was established on the basis of CT scan, visual field examination, visual-evoked potentials, and color test. According to Bartalena et al. (4), the severity of GO was graded into three categories, as indicated in Table 1Go. At each visit the patient provided a self-assessment evaluation sheet, describing ocular changes as improved, unchanged, or worsened, compared with previous status. Progression or improvement was defined by changes in at least two major criteria (variations in proptosis and lid width in ≥ 2 mm, changes in the degree of diplopia, changes in CAS 2 points or more, and changes on one tenth or more in visual activity) and one minor criterion (soft tissue changes, self-assessment evaluation) (24, 25).

Assessment of disease activity

The activity of GO was scored by a revised formulation of the method by Mourits et al. according to the classification of American Thyroid Association (22, 26) using the CAS, which takes into consideration seven manifestations of disease [spontaneous retrobulbar pain, pain on eye movement, eyelid erythema, eyelid edema or fullness, conjunctival injection, chemosis, and swelling of the caruncle. One point is given for any manifestation, and the score may range from 0 (no activity) to 7 (very high activity)]. CAS scores 3 or greater or 2 or less indicate active or inactive GO, respectively.

Treatment protocol

The patient was treated on a day hospital basis with methylprednisolone (Solumedrol; Upjohn, Milan, Italy) at a dose of 1 g diluted in 250–500 cc of saline solution (NaCl 0.9%), administered in slow infusion in 2 consecutive days a week for 6 wk. Before treatment, diabetes mellitus was excluded by a standard oral glucose tolerance test (75 g orally), and gastric lesions were excluded by Hemoccult analysis. General clinical conditions and blood glucose were carefully monitored throughout the treatment period. The treatment with rTSH was performed as follows: patients received two consecutive doses of rTSH (0.9 mg im) 24 h apart. Samples were collected before (d –3 and 0) and after (d 3 and 6) rTSH administration. Thyroglobulin, TSH, free T3, and free T4 were evaluated at each experimental time by commercially available kits. TSH-R antibody levels were measured with a second-generation TSH-binding inhibitory assay based on the porcine TSH-R (CIS Biointernational, Gif-sur-Yvette, France; values ≤ 10 UI/liter were regarded as positive).


   Results and Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results and Discussion
References
 
In this report, we described the case of a woman who, after a history of GD associated with PTC and a severe bilateral GO developed during the diagnostic follow-up for thyroid cancer and successfully treated with glucocorticoids, showed the appearance of a previously absent orbital uptake at SRS after human rTSH administration. The current report raises some interesting issues concerning the specific role of TSH-R in the pathogenesis of GO and the diagnostic usefulness of SRS.

To the best of our knowledge, no evidence of acute effects of exogenous rTSH administration in GO and orbital SRS is currently available in humans. Although an autoimmune basis for GO is widely accepted, the earliest events triggering GO are still incompletely understood. It is well established that a complex set of interactions between orbital fibroblasts and immune cells is able to activate the connective tissue, resulting in orbital remodeling (3, 27). The natural course of GO begins with active inflammation and ends in fibrosis, often associated with a gradual spontaneous improvement, known as Rundle’s curve (3, 28). This peculiar course reflects the typical course of an autoimmune disease. TSH-R is considered the leading candidate as a self-antigen that might connect the orbit with the thyroid. Several reports in both humans (29, 30) and animals (3, 31) demonstrated higher TSH-R expression in orbital than nonorbital fibroblasts. The TSH-R activation and the presence of very high TSH levels were also reported to enhance the likelihood of GO progression, strongly influencing the course of eye disease (4).

The use of SRS in GO is based on the observation that thyroid and orbital tissues express high levels of sst (4, 32, 33). These receptors seems to be mainly expressed in activated lymphocytes, although they were also demonstrated in orbital fibroblasts and muscular and endothelial cells (34, 35). Alternatively, the accumulation of [111In-DTPA-D-phe1]octreotide has been hypothesized to be due to an increasing blood pooling and by leakage to the interstitium due to inflammation (36). Beyond the pathophysiological mechanism of [111In-DTPA-D-phe1]octreotide uptake in GO, SRS seems to be able to assess the activity of GO and predict the outcome of immunosuppressive therapy or SS analogs, although with exceptions (14, 15, 16, 17, 18, 36, 37). This evidence is relevant because no clinical parameter is able to clearly establish the GO stage.

The clinical data of the patient of the current report suggested that long before the administration of rTSH, GO had entered the inactive phase after glucocorticoid treatment. Although the SRS is not able to rule out an active disease, the duration of eye disease, the lack of subsequent eye changes, and the absence of [111In-DTPA-D-phe1]octreotide uptake before rTSH were in line with the hypothesis of an inactive GO. The appearance of a moderate transient pain behind the eye globes reported by the patient immediately after the rTSH administration, with increase in CAS up to 4, is likely consistent with the hypothesis of an acute although moderate reexacerbation of GO. Orbital CT scan was also performed, confirming a moderate increase of the orbital volume. Although no final conclusion can be drawn, it is tempting to speculate that both eye symptoms and mild orbital [111In-DTPA-D-phe1]octreotide uptake 24 h apart the rTSH administration might suggest the rapid accumulation of activated lymphocytes with inflammatory cytokines and/or fibroblasts expressing sst. Alternatively, enhanced local hydrophily and interstitial edema due to activation of the orbital target cells bearing the TSH-R might have occurred. However, the absence of any further signs or symptoms of GO progression during the follow-up of the patient also suggested a rapid recovery of this supposed acute GO reexacerbation, and 1 yr later at last follow-up, orbital [111In-DTPA-D-phe1]octreotide uptake was negative, confirming the return of GO in an inactive state and the transience of the phenomenon.

The relationship between appearance of GO and the combined effects of hypothyroidism and radioiodine therapy because of PTC in our patient suggests a pivotal role for increase in endogenous TSH in GO pathogenesis. Nevertheless, due to the rarity of the association of GO with differentiated thyroid carcinoma, there are few data on the combined risk of GO worsening in patients who periodically experience hypothyroidism after L-thyroxine withdrawal and receive ablative doses of 131I during their long-term diagnostic and therapeutic follow-up (38). In this context, recent preliminary data suggest the safety of rTSH on the course of severe GO for the radiometabolic ablation on L-thyroxine of postthyroidectomy remnant (39).

However, to the best of our knowledge, there are no available data on both GO course and orbital SRS after TSH increase after rTSH administration in the follow-up of thyroid cancer. Because mean TSH levels were reported to be higher after rTSH than L-thyroxine withdrawal (40), different TSH levels could be taken as explanation for the transient activation of GO with the appearance of orbital [111In-DTPA-D-phe1]octreotide uptake after rTSH. It is also evident that serum TSH increase after rTSH administration is more rapid than after L-thyroxine withdrawal. It is, therefore, possible to hypothesize that only a rapid and remarkable increase in mean serum TSH levels, as that induced by rTSH administration, might induce orbital [111In-DTPA-D-phe1]octreotide uptake and so temporarily activate GO. Unfortunately, no data are available regarding orbital [111In-DTPA-D-phe1]octreotide uptake after TSH increase after repeated L-thyroxine withdrawals in our patient. However, after GO presentation, any acute eye disease changes had never been evidenced after repeated L-thyroxine withdrawal. Extensive evaluations of patients with GO, also including orbital [111In-DTPA-D-phe1]octreotide uptake before and after rTSH administration during diagnostic follow-up in differentiated thyroid carcinoma, are required to draw definitive conclusion of this issue.

In conclusion, the present case represents the first demonstration of an acute reactivation of GO as demonstrated by an appearance of orbital uptake at SRS after rTSH administration in a patient with inactive GO. This suggests that rTSH administration stimulates TSH-R in the orbit and so possibly triggering activity of GO, further supporting the TSH-R involvement in GO pathogenesis. Besides, this case confirms the clinical use of SRS to evaluate GO activity and discriminate patients who can respond to immunosuppressive treatment.


   Footnotes
 
The study was supported by Grant 2004062889-002 from the Ministry for Education, the University and the Research, Rome, Italy.

First Published Online February 1, 2005

Abbreviations: B, Brain; CAS, clinical activity score; CT, computed tomography; DTPA, 111In-diethylenetriamine-pentacetic acid; GD, Graves’ disease; GO, Graves’ ophthalmopathy; NOSPECS, no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction; O, orbit; PTC, papillary thyroid carcinoma; rTSH, recombinant TSH; SPECT, single-photon emission-computed tomography; SRS, sst scintigraphy; SS, somatostatin; sst, SS receptor(s); TSH-R, TSH receptor; WBS, whole-body scan.

Received October 29, 2004.

Accepted January 24, 2005.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results and Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals