Functional outcomes and complications in refractory dysthyroid optic neuropathy management: Experience with 3 different surgical protocols.

INTRODUCTION: Dysthyroid optic neuropathy (DON) is the most severe complication of Graves' orbitopathy (GO) and its management may require decompression surgery. Clear recommendations do not exist about which surgery should be performed and how extended the decompression should be. In this paper we present our experience regarding the management of DON via 3 different surgical protocols: a modified extended orbital apex decompression, a 2 walls decompression (inferior and lateral) and a 3 walls decompression (inferior, lateral and medial) and evaluate the functional outcomes. METHODS: Retrospective evaluation of subjects affected by DON not responding to medical therapy has been performed. All patients were submitted to pre- and post-operative ophthalmologic evaluations and orbital and sinuses CT scan in order to evaluate functional and surgical outcomes. RESULTS: 27 patients were enrolled in the study. Surgical procedures were performed on 42 orbits. A statistically significant post-operative improvement was recorded in visual acuity, proptosis, color vision and fundus oculi evaluation for all groups. No patient developed major or minor complications after surgery. CONCLUSIONS: Extended endonasal approach and 3 walls decompression have been proved effective in the management of DON. The choice between them is done according to degree of proptosis, general status and eye-surface damages.

Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial.

BACKGROUND: A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. METHODS: We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. FINDINGS: Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. INTERPRETATION: Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. FUNDING: Associazione Allievi Endocrinologia Pisana.

Retinal, choroidal and optic disc analysis in patients with Graves' disease with or without orbitopathy.

PURPOSE: To compare optic disc, retinal and choroidal measurements in patients with Graves' disease with or without orbitopathy, and healthy controls. METHODS: Optical coherence tomography and Heidelberg retinal tomography were performed in 40 patients with Graves' orbitopathy (GO), 40 subjects with Graves's disease (GD) with no sign of orbitopathy and 40 healthy controls. Degree of exophthalmos, ocular alignment, clinical activity score (CAS), choroidal thickness, retinal thickness, ganglion cell layer (GCL) thickness, disc area, cup area, rim area, cup/disc area ratio, linear cup/disc ratio and mean peripapillary retinal nerve fibre layer thickness were analysed. RESULTS: GO patients and healthy controls significantly differ regarding mean central retinal thickness (275 ± 19 µm and 285 ± 20 µm, P = 0.017); mean central GCL thickness (14.87 ± 3.0 µm and 17.92 ± 5.02 µm, P = 0.001); mean disc area (2.00 ± 0.44 mm2 and 1.72 ± 0.37 mm2, P = 0.003); mean cup area (0.53 ± 0.52 mm2 and 0.31 ± 0.20 mm2, P = 0.003); cup/disc area ratio (0.22 ± 0.10 and 0.17 ± 0.08, P = 0.010); and linear cup/disc ratio (0.47 ± 0.15 and 0.40 ± 0.13, respectively, P = 0.011). No difference was found between patients without orbitopathy and healthy controls. No significant difference was found regarding the choroidal thickness between the three groups. There was no statistically significant relationship between retinal thickness, ganglion cell layer thickness, mean disc area, mean cup area, cup/disc area ratio, linear cup/disc ratio, CAS, exophthalmometric value and ocular alignment. CONCLUSION: GO patients showed significant changes in foveal and GCL thickness, and optic nerve head morphology suggesting a possible influence of the orbital inflammatory process.

Occurrence of Graves' Orbitopathy and Graves' Hyperthyroidism after a Trauma to the Eye.

BACKGROUND: Graves' orbitopathy (GO) is believed to be the consequence of autoimmunity against antigens that are present both in the thyroid and orbital tissues. Massive release of thyroid antigens causes the appearance or deterioration of GO in patients with Graves' hyperthyroidism (GH), as it occurs following radioiodine treatment. In theory, a similar release of autoantigens may occur at the eye level, for example due to an orbital trauma or surgical manipulation. To our knowledge, this is the first report of a case of de novo appearance of GO and then GH after an eye trauma, possibly reflecting spreading of autoantigens and activation of the immune system against shared orbital and thyroid antigens. CASE REPORT: An otherwise healthy, 57-year-old man presented 6 months after the appearance of a monolateral right orbitopathy, which occurred 40 days after a trauma in the ipsilateral eye. His thyroid function was normal, with positive serum anti-TSH receptor autoantibodies. The thyroid was normal on ultrasound. A month later he developed hyperthyroidism and orbitopathy in the left eye. DISCUSSION: The development of GO after an eye trauma may reflect tissue damage with release of autoantigens and consequent autoimmunity in a predisposed individual (our patient had a familial history of autoimmune thyroid disease). The subsequent development of hyperthyroidism is in keeping with the hypothesis that GH and GO are due to autoimmunity against antigens present both in the thyroid and in orbital tissues.

High Serum Cholesterol Is a Novel Risk Factor for Graves' Orbitopathy: Results of a Cross-Sectional Study.

BACKGROUND: Limited data suggest that treatment with statins is associated with a reduced risk of Graves' orbitopathy (GO) in patients with Graves' disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the relation between severity or activity (the clinical activity score [CAS]) of GO and LDL-cholesterol. METHODS: A cross-sectional investigation was conducted in consecutive patients with GD who came under the authors' observation to undergo radioiodine treatment, a stratification aimed at forming two distinct groups of patients under the same conditions. A total of 250 patients were enrolled, 133 with and 117 without GO. Ophthalmological assessments and serum lipids measurements were performed. RESULTS: In multivariate analyses with correction for the duration of hyperthyroidism, a variable that differed between patients with respect to the presence or absence of GO, a correlation between the presence of GO and both total (p = 0.01) and LDL-cholesterol (p = 0.02) was observed. In patients with hyperthyroidism lasting <44 months, total and LDL-cholesterol were higher (p = 0.01 and p = 0.008, respectively) among GO patients. In this subgroup, based on the presence/absence of GO, cutoff values were established for total (191 mg/dL) and LDL-cholesterol (118.4 mg/dL), above which an increased risk of GO was observed (total cholesterol relative risk: 1.47; p = 0.03; LDL-cholesterol relative risk: 1.28; p = 0.03). GO severity and CAS did not correlate with serum lipids. However, CAS was found to be higher (p = 0.02) in patients with high total cholesterol. When the analysis was restricted to untreated GO patients, a correlation was found between CAS and both total (p = 0.04) and LDL-cholesterol (p = 0.03), after adjustment for GO duration. CONCLUSIONS: In patients with a short duration of hyperthyroidism, total and LDL-cholesterol correlate with the presence of GO, suggesting a role of cholesterol in the development of GO. Depending on GO duration, total and LDL-cholesterol correlate with GO activity, suggesting a role of cholesterol in the clinical expression of GO.

Does Graves' Orbitopathy Ever Disappear? Answers to an Old Question.

OBJECTIVES: There is a general belief that Graves' orbitopathy (GO) is a "chronic" disease, namely that patients' eyes do not return to how they were before GO appeared. Here, we investigate this issue from both the patient's and the physician's point of view. STUDY DESIGN: We studied the disappearance of GO, regardless of treatment, in all consecutive patients with a GO history of at least 10 years who came for a follow-up visit over a period of 5 years. Patients underwent an ophthalmological examination and were asked to answer a questionnaire on self-perception related to GO. RESULTS: We studied 99 consecutive patients with a GO duration ≥10 years. Between the first and the last observation, patients received several types of treatment for their thyroid disease and/or for GO. At the end of follow-up, GO was considered disappeared based on objective criteria in 8 patients (∼8%) and based on subjective criteria in 24 patients (∼24%). When we considered both subjective and objective criteria, only 2 patients (∼2%) had all criteria fulfilled and could be considered as GO-free. CONCLUSIONS: GO is a chronic disease in the vast majority of patients. Even after a very long time since its onset, complete disappearance is rare, although a minority of patients believe they do not have GO anymore and an even lower proportion do not have relevant GO signs. Our findings have obvious implications in patient management and counseling.

VARIABLES AFFECTING THE LONG-TERM OUTCOME OF GRAVES ORBITOPATHY FOLLOWING HIGH-DOSE INTRAVENOUS GLUCOCORTICOID PULSE THERAPY IN PATIENTS NOT TREATED WITH ORBITAL RADIOTHERAPY.

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. METHODS: We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. RESULTS: GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. CONCLUSION: Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ABBREVIATIONS: ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies.

Dissecting the Genetic Susceptibility to Graves' Disease in a Cohort of Patients of Italian Origin.

Graves' disease (GD) is an autoimmune oligogenic disorder with a strong hereditary component. Several GD susceptibility genes have been identified and confirmed during the last two decades. However, there are very few studies that evaluated susceptibility genes for GD in specific geographic subsets. Previously, we mapped a new locus on chromosome 3q that was unique to GD families of Italian origin. In the present study, we used association analysis of single-nucleotide polymorphism (SNPs) at the 3q locus in a cohort of GD patients of Italian origin in order to prioritize the best candidates among the known genes in this locus to choose the one(s) best supported by the association. DNA samples were genotyped using the Illumina GoldenGate genotyping assay analyzing 690 SNP in the linked 3q locus covering all 124 linkage disequilibrium blocks in this locus. Candidate non-HLA (human-leukocyte-antigen) genes previously reported to be associated with GD and/or other autoimmune disorders were analyzed separately. Three SNPs in the 3q locus showed a nominal association (p < 0.05): rs13097181, rs763313, and rs6792646. Albeit these could not be further validated by multiple comparison correction, we were prioritizing candidate genes at a locus already known to harbor a GD-related gene, not hypothesis testing. Moreover, we found significant associations with the thyroid-stimulating hormone receptor (TSHR) gene, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, and the thyroglobulin (TG) gene. In conclusion, we identified three SNPs on chromosome 3q that may map a new GD susceptibility gene in this region which is unique to the Italian population. Furthermore, we confirmed that the TSHR, the CTLA-4, and the TG genes are associated with GD in Italians. Our findings highlight the influence of ethnicity and geographic variations on the genetic susceptibility to GD.

Age and Dose Are Major Risk Factors for Liver Damage Associated with Intravenous Glucocorticoid Pulse Therapy for Graves' Orbitopathy.

BACKGROUND: High-dose intravenous glucocorticoid (ivGC) pulse therapy, which is commonly used for Graves' orbitopathy (GO), has been associated with acute liver damage (ALD), resulting in a fatal outcome in a few cases. No certain risk factors for ALD have been established. Consequently, a large retrospective cohort study was performed. METHODS: The relationship between ALD and several potential risk factors was assessed in 1076 consecutive patients with GO given ivGC. ALD was defined as an increase of alanine aminotransferase ≥300 IU/L. RESULTS: Fourteen cases of ALD were recorded, resulting in a morbidity of 1.3%. Thirteen patients recovered and one died, resulting in a mortality of 0.09%. There was a significant, positive correlation of ALD with age and methylprednisolone acetate (MPA) cumulative dose, and ALD was more common (relative risk [RR]=2.8; p=0.05) in patients aged ≥53 years (9/420; 2.14%) than in those aged <53 years (5/656; 0.76%). In patients aged ≥53 years, there was a significant positive correlation of ALD with MPA cumulative dose, and with MPA dose per infusion. Thus, the frequency of ALD in this age group was greater (RR=3.48; p=0.04) in patients with a MPA dose per infusion ≥0.7 g (5/111, 4.5% vs. 4/308, 1.29%). Regardless of age, no cases of ALD were observed for MPA doses per infusion <0.57 g. CONCLUSIONS: Age and MPA dose are significant risk factors for ALD, with the following practical implications. First, the total MPA cumulative dose should not exceed 8.5 g (the average dose in patients without ALD). Second, in patients aged ≥53 years, selection and observation should be quite strict. However, being aged ≥53 years should not be seen as an absolute contraindication to ivGC, especially in patients with severe GO, considering that the risk of ALD, although statistically significant, was relatively low. Third, the MPA dose should not exceed 0.57 g per infusion, a measure to be applied regardless of age.

Intravenous glucocorticoid therapy for Graves' ophthalmopathy and acute liver damage: an epidemiological study.

OBJECTIVE: Intravenous glucocorticoid (i.v.GC) pulse therapy for Graves' ophthalmopathy (GO) can be associated with acute liver damage (ALD), which was roughly estimated to occur in ∼1% of patients, with an overall mortality of 0.4%. The aim of this study was to evaluate the frequency of ALD after the introduction of a series of exclusion criteria and preventive measures. DESIGN: Retrospective evaluation of all consecutive patients candidate to i.v.GC over a period of 5 years. METHODS: The study includes 376 GO patients candidate to i.v.GC. Several liver tests were performed before, during, and after i.v.GC. To prevent ALD morbidity and mortality, the following measures were applied: i) exclusion of patients with active viral hepatitis and/or severe liver steatosis; ii) reduction in the GC dose, frequency, and number of pulses; and iii) administration of oral GC after i.v.GC, and also during i.v.GC in patients positive for nonorgan-specific autoantibodies (to prevent autoimmune hepatitis due to immune rebound). ALD was defined as an increase in alanine aminotransferase ≥ 300 U/l. RESULTS: A total of 353 patients were given i.v.GC and 23 were excluded for various conditions. ALD was detected in 4/376 patients candidate to i.v.GC, resulting in a morbidity of 1.06%. One patient recovered spontaneously and three after additional treatment with oral GC, given to re-establish immune suppression in the suspect of an autoimmune hepatitis. CONCLUSIONS: ALD related to i.v.GC is a relatively rare adverse event. Provided an accurate selection of patients and a series of preventive measures are applied, i.v.GC is a safe treatment for the liver.

Role of the underlying thyroid disease on the phenotype of Graves' orbitopathy in a tertiary referral center.

BACKGROUND: Clinically overt Graves' orbitopathy (GO) is associated with Graves' disease (GD) in approximately 95% of cases, whereas the remaining 5% is observed in patients with hypothyroid autoimmune thyroiditis (AT) or without overt thyroid dysfunction (euthyroid GO). However, it is not known whether there is a difference in terms of GO phenotype between patients with GD and those with hypothyroid AT or without thyroid dysfunction, and hence this is investigated here. METHODS: The study design was to evaluate retrospectively all consecutive patients with a recent manifestation of GO, seen at their first visit to a tertiary referral center over a period of 10 years. In total, 358 GO patients were studied, and all of them underwent GO assessment. RESULTS: Of the 358 patients studied, 341 had hyperthyroid GD, 10 had AT with hypothyroidism, and seven had euthyroid GO. Age, sex, and smoking habits were similar in the three groups, as was the time since GO was first noticed (GO duration). The vast majority of patients had moderate to severe, active GO, as expected in a tertiary referral center. Exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity did not differ between patients with GD and those with AT or euthyroid GO, suggesting that the GO phenotype was similar. Accordingly, the NOSPECS score did not differ between the three groups. CONCLUSIONS: The phenotype of GO is similar regardless of the underlying thyroid disease. Because this study was performed in a tertiary referral center, this conclusion can be restricted only to patients who develop moderate to severe GO.

Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited.

BACKGROUND: According to Rundle's curve, Graves' ophthalmopathy (GO) worsens during an initial phase up to a peak of maximum severity, then improves and reaches a static plateau, with the activity curve preceding the severity curve by a few months. To our knowledge, no studies have tried to replicate Rundle's curve, and very few have investigated the natural history of GO. Here, we studied GO natural history retrospectively and tried to identify factors that may affect it. METHODS: A total of 65 patients with untreated GO underwent an eye assessment after a median of seven months after the appearance of GO and then after a median of 40 months. The primary endpoints were the variation of the single GO features and of the NOSPECS score, as well as the overall outcome of GO. The secondary endpoint was the influence of several variables (age, sex, smoking, GO and thyroid disease duration, thyroid treatment, thyroid status, thyroid volume, anti-TSH receptor autoantibodies) on the outcome of GO. RESULTS: The majority of patients had mild, minimally active GO, and only five had a Clinical Activity Score (CAS) >3. There was a significant reduction of CAS (p<0.0001) and NOSPECS (p=0.01) between the first and last observation, with a timing pattern resembling Rundle's curve. This difference was confirmed even when patients with a CAS >3 at first observation were excluded. At the last observation, 50.8% of patients had improved, 33.8% had remained stable, and 15.4% had worsened moderately or substantially. The overall outcome of GO was not affected by any of the variables under examination. CONCLUSIONS: In confirmation of Rundle's observations, untreated GO improves spontaneously with time in the majority of patients, with an activity peak between 13 and 24 months, which may have implications in determining the proper timing of GO treatments.

Thyroid volume and severity of Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is thought to be related to one or more autoantigens present in the thyroid and in orbital tissues. Although this may not imply a quantitative relation between thyroid antigens and degree of GO, which in turn is a risk factor for a more pronounced GO, we postulated that the severity of GO may parallel the amount of thyroid tissue, namely, the size of the thyroid gland. This hypothesis is also based on the observation that patients with Graves' disease presenting with large goiters tend to have more severe hyperthyroidism. Thus, we evaluated retrospectively whether there is a correlation between the degree of GO at its first observation and, among other parameters, the thyroid volume. METHODS: Eighty-six consecutive patients with untreated GO lasting for no longer than 24 months underwent an endocrinological and an ophthalmological evaluation, the latter including: exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity. The overall degree of GO was ranked using the NOSPECS score as well as a modification of the NOSPECS score. The following parameters were considered for correlations: time since GO appearance, time since detection of hyperthyroidism, FT3, anti-thyrotropin receptor antibodies, thyroid volume, and cigarette-years. RESULTS: Thyroid volume, but not the other parameters, correlated significantly by simple regression with exophthalmometry (p=0.02) and CAS (p=0.02). The standard NOSPECS score correlated with FT3 (p=0.05), thyroid volume (p=0.02), and cigarette-years (p=0.03), by simple, but not by multiple regression analysis. The modified NOSPECS score correlated with thyroid volume (p=0.007) and cigarette-years (p=0.04) by simple regression, and with thyroid volume also by multiple regression analysis (p=0.05). CONCLUSIONS: Thyroid volume correlates with the severity of GO at its first observation, especially with exophthalmometry and CAS. The finding is in line with a possible pathogenetic role of antigens shared by the thyroid and orbital tissues. Nevertheless, other mechanisms may explain this observation, including an overall more reactive immune system in patients with a large goiter, resulting in more severe thyroid and eye disease, regardless of the nature of the autoantigen, or whether it is shared by the thyroid and the orbit.

Enalapril reduces proliferation and hyaluronic acid release in orbital fibroblasts.

BACKGROUND: Orbital fibroblast proliferation and hyaluronic acid (HA) release are responsible for some of the clinical features of Graves' ophthalmopathy (GO). Thus, inhibition of these processes may be a possible therapeutic approach to this syndrome. Enalapril, a widely used antihypertensive drug, was found to have some inhibitory actions on fibroblast proliferation in cheloid scars in vivo, based on which we investigated its effects in primary cultures of orbital fibroblasts from GO patients and control subjects. METHODS: Primary cultures of GO and control fibroblasts were treated with enalapril or with a control compound (lisinopril). Cell proliferation assays, lactate dehydrogenase release assays (as a measure of cell necrosis), apoptosis assays, and measurement of HA in the cell media were performed. RESULTS: Enalapril significantly reduced cell proliferation in both GO and control fibroblasts. Because enalapril did not affect cell necrosis and apoptosis, we concluded that its effects on proliferation reflected an inhibition of cell growth and/or a delay in cell cycle. Enalapril significantly reduced HA concentrations in the media from both GO and control fibroblasts. CONCLUSIONS: Enalapril has antiproliferative and HA suppressing actions in both GO and control fibroblasts. Clinical studies are needed to investigate whether enalapril has any effects in vivo in patients with GO.

Rehabilitative orbital decompression for Graves' orbitopathy: risk factors influencing the new onset of diplopia in primary gaze, outcome, and patients' satisfaction.

BACKGROUND: Patients with moderate to severe Graves' orbitopathy (GO) rather frequently require rehabilitative surgery after medical therapy. Diplopia is the most common side effect of orbital decompression (OD). The aim of this study was to evaluate the occurrence of postoperative diplopia in primary gaze after OD, and the influence of the surgical approach on this outcome. Moreover, we investigated the results in terms of proptosis reduction, and the long-term subjective satisfaction of patients treated with OD with regard to their appearance and ocular function. METHODS: A retrospective evaluation of 247 patients with GO treated with medial and lateral decompression (MLD) or lateral decompression (LD) OD between January 2002 and December 2009 was performed. RESULTS: The overall prevalence of postoperative diplopia in primary gaze was 55/247 (22.3%), with a statistically significant difference (p<0.001) between patients with (36/113, 31.2%) and those without (19/134, 14.2%) preoperative diplopia in secondary gaze. The surgical procedure influenced the outcome in patients without preoperative diplopia (17.8% after MLD and 0% after LD, p=0.02), but not in patients with preoperative diplopia in secondary gaze (33.3% after MLD and 26.1% after LD, p=0.5). Overall, proptosis reduction was 5.7±2.2 mm (1-11 mm), after MLD and 4.0±1.6 mm (1-8 mm) after LD (p<0.001). Fifty-one out of 55 patients with constant, postoperative diplopia in primary gaze after OD underwent squint surgery, which was successful in all but two. Four patients refused squint surgery. Patients were also interviewed for satisfaction in terms of recovery of their appearance and ocular function after a mean of 6 years from surgery (range 2-9 years): more than 85% of patients reported a good to excellent postoperative satisfaction for both items. CONCLUSIONS: Preoperative diplopia in secondary gaze is a risk factor for the development of diplopia in primary gaze after OD, independently of the surgical approach (MLD vs. LD). In absence of diplopia, MLD, but not LD, seems to be associated with its development in primary gaze. The reduction in proptosis after MLD is greater than that after LD. Most patients were satisfied with the results of both appearance and ocular function after OD.

Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: comparison of different assays and evaluation of causes of discrepancies.

CONTEXT: Thyroglobulin autoantibodies (TgAb) have been proposed as a surrogate marker of thyroglobulin in the follow-up of differentiated thyroid carcinoma. Commercially available TgAb assays are often discordant. We investigated the causes of discrepancy. DESIGN: TgAb were measured by three noncompetitive immunometric assays and three competitive RIA in 72 patients with papillary thyroid carcinoma and associated lymphocytic thyroiditis (PTC-T), 105 with papillary thyroid carcinoma and no lymphocytic thyroiditis (PTC), 160 with Hashimoto's thyroiditis, and in 150 normal subjects. The results of the six assays were correlated. TgAb epitope pattern, evaluated by inhibition of serum TgAb binding to thyroglobulin by TgAb-Fab regions A, B, C, and D, were compared in sera which were positive in all six assays (concordant sera) and positive in only one to five assays (discordant sera) were compared. TgAb International Reference Preparation (IRP) was measured in 2007 and 2009. RESULTS: The correlations of the six assays ranged from -0.01 to 0.93 and were higher in PTC-T and Hashimoto's thyroiditis than in PTC and normal subjects. Two uncorrelated components, one including the three immunometric assays, the other the three RIA, explained 40 and 37% of the total variance of the results of the six assays. The levels of inhibition were higher in concordant sera than in discordant sera by TgAb-Fab region B (27.0%, 21.2-34.0 vs. 6.0%, and 2.7-12.7%) and region C (30.5%, 21.3-37.7 vs. 4.0%, and 1.0-6.5%); thus, the epitope pattern was more homogeneous in concordant sera than in discordant sera. TgAb IRP ranged from 157 to 1088 (expected 1000) IU/ml in 2009; results in 2007 were similar in all but two assays. CONCLUSIONS: TgAb assays are highly discordant. Discrepancy is lower when comparing assays with similar methodology. Results of TgAb from PTC-T are more concordant than those from PTC because their epitope pattern is more restricted. The internal standardization of TgAb is generally, but not completely, satisfactory.

[Multicentre, prospective cohort study, to validate the Italian version of the Braden Q scale for the risk of the pressure sores in newborns and up to 8 years old children]. / Studio di coorte prospettico multicentrico per la validazione italiana della Braden Q per la valutazione del rischio di lesioni da decubito nei neonati e nei bambini fino ad 8 anni.

UNLABELLED: Multicenter prospective cohort study, to validate the Italian version of the Braden Q scale for the risk of pressure sores in newborns and up to 8 years old children. INTRODUCTION: Children admitted to Intensive care Units (ICU), oncology and neurology/neurosurgery wards are at risk of developing pressure sores. AIM: To validate the Italian version of the Braden Q scale for the assessment of the risk of developing pressure sores in children. METHODS: Children from 21 days to 8 years, admitted to intensive and sub intensive units were recruited. Premature babies, children admitted with a pressure sore and with a story of congenital cardiomiopathy were excluded. In this cohort, multicentre and with repeated measurements study, the first assessment was performed after 24 hours from hospital admission, using the Braden Q Scale (Suddaby's version). The pressure sores were assessed with the Skin assessment Tool and staged according to the National Pressure Ulcer Advisory Panel. RESULTS. On the 157 children 524 observation were conducted. The incidence of pressure sores was 17.2%. Only the analysis on specific subgroups of patients showed a good diagnostic accuracy: 71.4% on children 3-8 years; 85.6% in sub intensive wards. CONCLUSIONS: The Braden Q scale may be reliably used and shows a good diagnostic accuracy in children 3-8 years of age admitted to sub-intensive, neurology, oncology and heamatology wards.

Lymphocytic thyroiditis on histology correlates with serum thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: impact on detection of serum thyroglobulin.

CONTEXT: Serum thyroglobulin (Tg), the marker of residual tumor in papillary thyroid carcinoma, can be underestimated in patients with Tg autoantibodies (TgAb). TgAb are due to a coexistent lymphocytic thyroiditis (LT) or the papillary thyroid carcinoma per se. TgAb assays are highly discordant. DESIGN: We evaluated 141 patients with a clinical diagnosis of nodular thyroid disease, 32 of Hashimoto's thyroiditis, and four of Graves' disease, who underwent total thyroidectomy for an associated papillary thyroid carcinoma. Patients were classified as papillary thyroid carcinoma-lymphocytic thyroiditis (PTC-T) and papillary thyroid carcinoma (PTC) according to the presence or absence of LT on histology. Tg was measured before thyroid remnant ablation, when it is expectedly detectable, by an immunometric assay (IMA) and TgAb by three noncompetitive IMA and three competitive radioimmunoassays (RIA). The number of lymphocytes was compared with TgAb concentration. RESULTS: Seventy-two of 177 patients (40.7%) were classified as PTC-T and 105 (59.3%) as PTC. Although the tumor stage was similar in the two groups, Tg was undetectable in more PTC-T (37 of 72) than PTC (12 of 105) (P < 0.01), and Tg values were lower in the former (0; 0-4.7 ng/ml) (median; 25th to 75th percentiles) than in the latter group (9.7; 2.7-24.2) (P < 0.01). Accordingly, the percent of positive TgAb by the six assays resulted in higher PTC-T (29.2-50.0%) than PTC (1.9-6.7%) (P < 0.01). Among 49 patients with undetectable Tg, TgAb were more frequently positive by IMA (57.1-63.3%) than RIA (30.6-42.9%). The number of lymphocytes correlated with TgAb concentration in all six assays (0.34 < Rho < 0.46) (all P < 0.01). CONCLUSIONS: In papillary thyroid carcinoma, LT on histology must be carefully searched for because it is frequently associated with TgAb and therefore mistakenly low or undetectable Tg. TgAb can be missed by some assays. In absence of LT, TgAb are rare.

Outcome of Graves' orbitopathy after total thyroid ablation and glucocorticoid treatment: follow-up of a randomized clinical trial.

CONTEXT: In a previous study, we found that total thyroid ablation (thyroidectomy plus (131)I) is associated with a better outcome of Graves' orbitopathy (GO) compared with thyroidectomy alone, as observed shortly (9 months) after glucocorticoid (GC) treatment. OBJECTIVE: The objective of the study was to evaluate the outcome of GO in the same patients of the previous study over a longer period of time. DESIGN: This was a follow-up of a randomized study. SETTING: The study was conducted at a referral center. PATIENTS: Fifty-two of 60 original patients with mild to moderate GO participated in the study. INTERVENTIONS: Patients randomized into thyroidectomy (TX) or total thyroid ablation and treated with GC were reevaluated in 2010, namely 88.0 ± 17.7 months after GC, having undergone an ophthalmological follow-up in the intermediate period. MAIN OUTCOME MEASURES: The main outcome measures included the following: 1) GO outcome; 2) time to GO best possible outcome and to GO improvement; and 3) additional treatments. RESULTS: GO outcome at the end of the follow-up was similar in the two groups. However, the time required for the best possible outcome to be achieved was longer in the TX group (24 vs. 3 months, P = 0.0436), as was the time required for GO to improve (60 vs. 3 months, P = 0.0344). Additional treatments were given to a similar proportion of patients in each group (TX, 28%, total thyroid ablation, 25.9%), but they affected GO beneficially more often in the TX group (28 vs. 3.7%, P: 0.0412). CONCLUSIONS: Compared with thyroidectomy alone, total thyroid ablation allows the achievement of the best possible outcome and an improvement of GO within a shorter period of time.

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

BACKGROUND: Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE: In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.