Maria Antonietta Altea

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures

Aim: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves’ orbitopathy (GO) receiving surgery for disfiguring proptosis. Method: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. Results: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. Conclusions: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves’ ophthalmopathy treated successfully with glucocorticoids themselves

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves’ ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Role of thyroglobulin in the pathogenesis of Graves’ ophthalmopathy: The hypothesis of Kriss revisited

One of the hypothesis to explain the pathogenesis of Graves’ ophthalmopathy (GO) was formulated by Joseph P. Kriss in the early 1970s. He postulated that the initiating event in the pathogenesis of GO is the deposition and accumulation of thyroglobulin (Tg) in orbital tissues, followed by an autoimmune reaction against Tg. In the last 30 yr several studies have addressed this hypothesis, through various, different experimental approaches, raising results that are both in favor and against the possibility that Tg plays a role in the pathogenesis of GO. The finding that intact Tg is present in orbital tissues of GO patients supports Kriss’ hypothesis, although the role of Tg as an autoantigen seems to be unlikely, as GO is not significantly associated with serum TgAb and mice immunized with Tg do not develop GO. Whether Tg is indeed involved in the pathogenesis of GO remains to be established. Our current view is that, provided that Tg plays a role, it is unlikely the only factor involved and Tg in orbital tissues may rather reinforce or worsen a damage initiated by other mechanisms.

Oxidative stress in graves' disease.

Increased reactive oxygen species (ROS) generation and the consequent oxidative damage are involved in the development of several diseases, including autoimmune diseases. Graves’ disease is an autoimmune disorder characterized by hyperthyroidism and, less frequently, orbitopathy. Hyperthyroidism is characterized by increased oxidative stress. Untreated hyperthyroidism is associated with an increase of several parameters of oxidative stress and in most studies (but not all) by an increase of antioxidant defense enzymes. Restoration of euthyroidism with antithyroid drug is associated with a reversal of the biochemical abnormalities associated with oxidative stress. Animal and human studies suggest that increased ROS may directly contribute to some clinical manifestation of the disease, including orbitopathy. Antioxidants administered alone improve some clinical signs and symptoms of hyperthyroidism and, when associated with antithyroid drugs, induce a more rapid control of clinical manifestations and a faster achievement of euthyroidism. A large randomized clinical trial has shown that antioxidant supplementation (selenium) may also be beneficial for mild Graves’ orbitopathy.

Quercetin decreases proliferation of orbital fibroblasts and their release of hyaluronic acid

Background: Inhibition of fibroblast (FB) proliferation and hyaluronic acid (HA) production may be a therapeutic approach to Graves’ ophthalmopathy (GO). The flavonoid quercetin has a wide range of activities, including reduction of FB growth. Aim: To investigate the effects of quercetin in orbital FB from GO patients and control subjects. Methods: Primary cultures of orbital FB were treated with quercetin or with its glycosides rutin and quercitrin. Cell proliferation, necrosis, apoptosis, HA production, and cell cycle were measured. Results: Beginning at a 30 µM concentration, quercetin, but not rutin and quercitrin, reduced cell proliferation, with no difference between GO and control FB. The effect of quercetin on proliferation was due to necrosis and cell cycle blockade, whereas apoptosis was unaffected. Quercetin reduced HA in the cell media, with no difference between GO and control FB. Conclusions: Quercetin reduces cell proliferation and HA release in orbital FB. Whether these initial findings have any potential for the use of quercetin in the clinical practice remains to be established.

Impaired thyroglobulin (Tg) secretion by FRTL-5 cells transfected with soluble receptor associated protein (RAP): evidence for a role of RAP in the Tg biosynthetic pathway.

Secretion of thyroglobulin (Tg) by thyrocytes requires several endoplasmic reticulum (ER)-resident molecular chaperones. The receptor-associated protein (RAP), a known molecular chaperone, binds to Tg in thyroid cells shortly after biosynthesis. Here we investigated whether RAP is involved in Tg secretion by FRTL-5 cells. For this purpose, we studied Tg secretion by FRTL-5 cells transfected with a soluble RAP chimera, as a mean for interfering with endogenous RAP. We used a RAP-human IgG Fc (RAP-Ig) chimeric cDNA, which was designed in order to exclude the ER retention sequence of RAP and to allow generation of a secreted form of RAP. FRTL-5 cells were transiently transfected with the RAP-Ig cDNA or, as control, with a CD8-Ig cDNA. Media were collected at 24, 48 and 72 h after transfection. Secretion of fusion proteins and of Tg in the media was measured by ELISA. As expected, under standard culture conditions, RAP was not secreted into the media by FRTL-5 cells, even though it could be detected by Western blotting in cell extracts. In transfection experiments, fusion proteins were present in the media of FRTL-5 cells transfected with either RAP-Ig or CD8-Ig, indicating that transfection was successful. Although Tg was found in the media of FRTL-5 cells transfected with either CD8-Ig or RAP-Ig, a lower amount was found in cells transfected with RAP-Ig. Therefore, we concluded that RAP is involved in Tg secretion by FRTL-5 cells suggesting that RAP may function as a Tg molecular chaperone.

Optic Neuropathy in 2 Thyroidectomized Patients with Moderate to Severe Graves Ophthalmopathy Following L-Thyroxine Withdrawal Prior to Radioiodine Treatment for Thyroid Carcinoma

ABSTRACT Objective: To report on 2 patients with moderate to severe Graves ophthalmopathy (GO) who developed dysthyroid optic neuropathy following levothyroxine (LT4) withdrawal in preparation for ...

Front & Back Matter

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Epatopatia e glucocorticoidi nella oftalmopatia basedowiana: un limite alla terapia?

RiassuntoI glucocorticoidi (GC) per via endovenosa (ev) rappresentano lo strumento terapeutico più diffuso ed efficace per l’oftalmopatia basedowiana (OB). Tuttavia, l’osservazione di alcuni casi di danno epatico acuto (DEA) durante o dopo terapia con GC ev ha sollevato importanti interrogativi sulla sicurezza di questo tipo di terapia e sull’opportunità di effettuarla indiscriminatamente in tutti i pazienti con OB in cui sarebbe indicata. Un importante aspetto da considerare è se l’osservazione di DEA durante o dopo terapia con GC ev sia un evento casuale, o da mettere effettivamente in relazione con la terapia. A tale proposito, non esistono studi epidemiologici che consentano di confrontare la frequenza del DEA tra pazienti trattati con GC ev e popolazione generale. In questo articolo abbiamo analizzato in maniera retrospettiva i casi di DEA riportati in letteratura e gli studi su casistica disponibili, allo scopo di valutarne la frequenza e individuarne i possibili predisponenti.