Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Management of thyroid cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides recommendations on the management of thyroid cancer in adults and is based on the 2014 British Thyroid Association guidelines. Recommendations • Ultrasound scanning (USS) of the nodule or goitre is a crucial investigation in guiding the need for fine needle aspiration cytology (FNAC). (R) • FNAC should be considered for all nodules with suspicious ultrasound features (U3-U5). If a nodule is smaller than 10 mm in diameter, USS guided FNAC is not recommended unless clinically suspicious lymph nodes on USS are also present. (R) • Cytological analysis and categorisation should be reported according to the current British Thyroid Association Guidance. (R) • Ultrasound scanning assessment of cervical nodes should be done in FNAC-proven cancer. (R) • Magnetic resonance imaging (MRI) or computed tomography (CT) should be done in suspected cases of retrosternal extension, fixed tumours (local invasion with or without vocal cord paralysis) or when haemoptysis is reported. When CT with contrast is used pre-operatively, there should be a two-month delay between the use of iodinated contrast media and subsequent radioactive iodine (I131) therapy. (R) • Fluoro-deoxy-glucose positron emission tomography imaging is not recommended for routine evaluation. (G) • In patients with thyroid cancer, assessment of extrathyroidal extension and lymph node disease in the central and lateral neck compartments should be undertaken pre-operatively by USS and cross-sectional imaging (CT or MRI) if indicated. (R) • For patients with Thy 3f or Thy 4 FNAC a diagnostic hemithyroidectomy is recommended. (R) • Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter or tumours of any size in association with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), familial disease and those with clinically or radiologically involved nodes and/or distant metastases. (R) • Subtotal thyroidectomy should not be used in the management of thyroid cancer. (G) • Central compartment neck dissection is not routinely recommended for patients with papillary thyroid cancer without clinical or radiological evidence of lymph node involvement, provided they meet all of the following criteria: classical type papillary thyroid cancer, patient less than 45 years old, unifocal tumour, less than 4 cm, no extrathyroidal extension on ultrasound. (R) • Patients with metastases in the lateral compartment should undergo therapeutic lateral and central compartment neck dissection. (R) • Patients with follicular cancer with greater than 4 cm tumours should be treated with total thyroidectomy. (R) • I131 ablation should be carried out only in centres with appropriate facilities. (R) • Serum thyroglobulin (Tg) should be checked in all post-operative patients with differentiated thyroid cancer (DTC), but not sooner than six weeks after surgery. (R) • Patients who have undergone total or near total thyroidectomy should be started on levothyroxine 2 µg per kg or liothyronine 20 mcg tds after surgery. (R) • The majority of patients with a tumour more than 1 cm in diameter, who have undergone total or near-total thyroidectomy, should have I131 ablation. (R) • A post-ablation scan should be performed 3-10 days after I131 ablation. (R) • Post-therapy dynamic risk stratification at 9-12 months is used to guide further management. (G) • Potentially resectable recurrent or persistent disease should be managed with surgery whenever possible. (R) • Distant metastases and sites not amenable to surgery which are iodine avid should be treated with I131 therapy. (R) • Long-term follow-up for patients with differentiated thyroid cancer (DTC) is recommended. (G) • Follow-up should be based on clinical examination, serum Tg and thyroid-stimulating hormone assessments. (R) • Patients with suspected medullary thyroid cancer (MTC) should be investigated with calcitonin and carcino-embryonic antigen levels (CEA), 24 hour catecholamine and nor metanephrine urine estimation (or plasma free nor metanephrine estimation), serum calcium and parathyroid hormone. (R) • Relevant imaging studies are advisable to guide the extent of surgery. (R) • RET (Proto-oncogene tyrosine-protein kinase receptor) proto-oncogene analysis should be performed after surgery. (R) • All patients with known or suspected MTC should have serum calcitonin and biochemical screening for phaeochromocytoma pre-operatively. (R) • All patients with proven MTC greater than 5 mm should undergo total thyroidectomy and central compartment neck dissection. (R) • Patients with MTC with lateral nodal involvement should undergo selective neck dissection (IIa-Vb). (R) • Patients with MTC with central node metastases should undergo ipsilateral prophylactic lateral node dissection. (R) • Prophylactic thyroidectomy should be offered to RET-positive family members. (R) • All patients with proven MTC should have genetic screening. (R) • Radiotherapy may be useful in controlling local symptoms in patients with inoperable disease. (R) • Chemotherapy with tyrosine kinase inhibitors may help in controlling local symptoms. (R) • For individuals with anaplastic thyroid carcinoma, initial assessment should focus on identifying the small proportion of patients with localised disease and good performance status, which may benefit from surgical resection and other adjuvant therapies. (G) • The surgical intent should be gross tumour resection and not merely an attempt at debulking. (G).

The role of colonoscopic screening in acromegaly revisited: review of current literature and practice guidelines.

INTRODUCTION: Acromegaly is a chronic, debilitating and disfiguring condition with a significantly increased morbidity and mortality due to cardiovascular, as well as respiratory complications. Patients with acromegaly are usually diagnosed at the age of 40, however, the duration of symptoms can vary from 5 to 10 years before the formal diagnosis is confirmed. Recent advances in the field of acromegaly have improved survival significantly. A strong association between acromegaly and premalignant colonic lesions and colon cancer has been highlighted. Furthermore, patients with acromegaly have a greater lifetime risk of malignant transformation and a far worse overall prognosis from colorectal cancer, which is now considered a major disease related complication. MATERIALS AND METHODS: A comprehensive search strategy was applied for the Medline/PubMed electronic database from its inception until April 2014. We considered all human research articles published in English, not classified as case report, editorial, comment, letter, or news. CONCLUSION: Specific recommendations for large bowel endoscopic screening in patients with acromegaly have been proposed. In this comprehensive review we discuss the current state of knowledge and evidence on colonoscopic screening in patients with acromegaly illustrated by a case of aggressive colorectal cancer presenting late in a young woman with difficult to control acromegaly.

Pilot of BRAF mutation analysis in indeterminate, suspicious and malignant thyroid FNA cytology.

BACKGROUND: BRAF V600E mutation has been reported to show a high specificity for papillary thyroid carcinoma (PTC). Using this marker to upgrade 'indeterminate' or 'suspicious' thyroid fine needle aspiration (FNA) cytology to 'malignant' could potentially allow one-stage therapeutic total thyroidectomy. METHODS: For a 14-month period, FNA cytology specimens in the Thy3-5 categories, which are the UK equivalents of indeterminate (Thy3a, atypical; Thy3f, follicular), suspicious for malignancy (Thy4) and malignant (Thy5) in the Bethesda System, underwent BRAF mutation testing by melt curve analysis. The results were correlated with histology. RESULTS: We tested 123 cytology specimens of which 12 (9.8%) failed. The BRAF mutation rate in the remainder was 16.2% (18/111), with 93 showing the wild-type. Seventeen mutations were V600E and one was non-V600E. The rate of mutation increased significantly (P < 0.0001 if Thy3a and Thy3f were combined) with the cytology category: 1/42 Thy3a (2.4%), 1/36 Thy3f (2.8%), 4/15 Thy4 (26.7%), 12/18 Thy5 (66.7%). All BRAF mutations correlated with PTC on histology, except for one recurrent PTC without histology. One mutation-positive case with Thy3a cytology showed the target lesion to be a 10-mm follicular adenoma on histology with an immediately adjacent 4-mm micro-PTC, in a patient who did not require total thyroidectomy. CONCLUSION: BRAF mutational analysis by melt curve analysis is feasible in routine thyroid cytology, and in our series had a 100% specificity for PTC in subsequent histology. The application of BRAF analysis could be useful for indeterminate cytology, but we suggest that it would be most appropriate and cost-effective for Thy4/suspicious cases, for which it could enable one-stage therapeutic surgery in the context of multidisciplinary discussion. In contrast, the sensitivity is low and there is no role for avoiding diagnostic thyroid surgery if wild-type BRAF is found.

Is Recombinant Human TSH a Trigger for Graves' Orbitopathy?

The pathogenesis of Graves' orbitopathy (GO) remains unknown. The hypothesis of a causal relationship between autoimmunity against the TSH receptor (TSHR) and GO is supported by clinical studies. Radioiodine treatment is associated with worsening or new onset of GO, possibly via antigen shedding or by inducing hypothyroidism. The coexistence of thyroid cancer with Graves' disease (GD) and GO is rare. Here we report 3 cases of reactivation of GO in patients who underwent treatment with recombinant human TSH (rhTSH) and radioiodine ablation. In each case, a thyroidectomy was performed to treat the GD, and an incidental thyroid cancer was discovered. In all 3 cases, reactivation of GO was observed 3-6 weeks after administration of rhTSH, despite maintaining euthyroidism, which was unaccompanied by a rise in serum TSHR antibodies after radioiodine and despite steroids in 1 of the 3 patients. These observations suggest that binding of either TSH or TSHR antibodies to the TSHR, independently of thyroid status, may be causally related to deterioration of GO. Clinicians should be aware of a possible association between rhTSH administration and reactivation of GO, which should be taken into account before prescribing rhTSH in patients with GO. Prophylactic steroids may need to be considered for patients at high risk of exacerbation of GO.

2009 American Thyroid Association guidelines on thyroid nodules.

The American Thyroid Association guidelines on thyroid nodules and differentiated thyroid cancer, published in 2009, provide valuable recommendations based on current evidence. Inevitably, controversies and uncertainties will continue to challenge clinicians and patients. On topics where evidence is not clear-cut, judgement may be coloured by pre-existing practises and the structure of the health service in each country, so one has to be aware of the pitfalls of transferring recommendations to one's own practise.

Metachronous testicular teratoma, testicular seminoma and papillary thyroid carcinoma occurring in a single individual: a report of two unrelated cases.

We describe two unrelated men who both developed teratomas in one testis followed by seminomas in the contralateral testis followed by papillary thyroid carcinomas. Neither man had a family history of cancers. Although random occurrence is possible, genetic predisposition and/or environmental influence would seem a likely explanation for this previously unreported combination of tumours.

SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis.

Mutations in SDHB are one of the causes of hereditary paraganglioma syndrome. Germline mutations in SDHB predispose to the development of head and neck paragangliomas and phaeochromocytomas. Renal tumours are also increasingly being reported as component tumours in hereditary paragangliomatosis associated with mutations in SDHB. We present the first reported case of a family in whom an individual shown to carry a mutation in SDHB developed a renal oncocytoma. We review other reports of renal tumours associated with SDHB-associated hereditary paragangliomatosis and suggest that various histological subtypes of renal tumours are part of this condition. This observation indicates that SDHB-associated hereditary paragangliomatosis is unlike most tumour predisposition syndromes associated with the development of renal tumours which are usually associated with specific histological sub-types. The increasing recognition of the involvement of renal tumours in SDHB mutation carriers suggests that renal screening is likely to be valuable for these patients. SDHB mutations should also be considered in the context of genetic testing when renal tumours, regardless of histopathology, present in families with other tumours consistent hereditary paraganglioma syndrome.

Phaeochromocytomas presenting as acute crises after beta blockade therapy.

OBJECTIVE: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period. RESULTS: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully. CONCLUSION: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

The impact of clinical guidelines on surgical management in patients with thyroid cancer.

AIMS: Thyroid cancer is an uncommon but highly curable disease if treated optimally. The aim of this study was to determine whether clinical guidelines introduced locally at the beginning of 1999 were associated with better surgical outcome, using radioiodine uptake as a surrogate measure of completeness of thyroidectomy. MATERIALS AND METHODS: We reviewed the medical records of all patients with thyroid cancer referred to a cancer centre (n=176) 3 years before and 3 years after the introduction of guidelines. The uptake of radioiodine in the thyroid bed after thyroidectomy and before radioiodine ablation was used to assess the completeness of primary surgical treatment. RESULTS: The number of new cases referred to our centre increased from 80 in the 1996-1998 period to 94 during 1999-2001. This was largely because of an excess of papillary thyroid cancers. Documentation in the medical records of the pathological primary tumour size improved from 47.5% to 80.8% following the introduction of guidelines. A significant reduction in radioiodine uptake in the thyroid bed was observed following the introduction of guidelines (5.03% +/- 6.82 (SD) vs 2.75% +/- 5.10 (SD); P=0.005). Linear regression analysis of clinical variables indicated that the year of surgery was the only significant factor influencing radioiodine uptake in the thyroid bed (P=0.014). Twelve hospitals within the Northern Cancer Network carried out thyroid surgery for thyroid cancer in the pre-guideline era compared with seven hospitals in the post-guideline era. Surgeons who were members of the regional multidisciplinary thyroid cancer team operated on 35% of cases in the 1996-1998 period and 56.4% in the 1999-2001 period (P<0.01). CONCLUSIONS: The introduction of clinical guidelines in 1999 was associated with a reduction in the size of thyroid remnant after primary surgical treatment. This was accompanied by fewer hospitals undertaking thyroid surgery and more patients being operated on by surgeons who were members of the thyroid cancer multidisciplinary team.

Thyroid disease and male reproductive function.

Despite the high prevalence of thyroid diseases in the general population, male reproductive function in patients with thyroid disease has been the subject of only a few studies. Hyperthyroidism appears to cause sperm abnormalities (mainly reduction in motility), which reverse after restoration of euthyroidism. Radioiodine therapy for hyperthyroidism or thyroid cancer may cause transient reductions in sperm count and motility, but there appears to be little risk of permanent effects provided that the cumulative dose is less than 14 MBq. The effects of hypothyroidism on male reproduction appear to be more subtle than those of hyperthyroidism and reversible. Severe, prolonged hypothyroidism in childhood may be associated with permanent abnormalities in gonadal function.

CTLA4 gene and Graves' disease: association of Graves' disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism.

OBJECTIVE: Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(-318)C/T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(-318)C/T, exon 1 CTLA4(49)A/G and intron 1 CTLA4(1822)C/T in our GD cohort from the UK. PATIENTS AND METHODS: We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid-associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(-318)C/T, CTLA4(49)A/G and CTLA4(1822)C/T polymorphisms were genotyped by using the restriction enzymes MseI, Bst71I and HaeIII, respectively. RESULTS: We found no association between GD and alleles of CTLA4(-318)C/T. GD was found to be associated with the G allele of CTLA4(49)A/G[P = 5.9 x 10(-6), odds ratio (OR) 1.65] and the T allele of CTLA4(1822)C/T (P = 7.7 x 10(-6), OR 1.64). The frequencies of these alleles were significantly higher in GD probands with significant TAO than in those without TAO (G allele: P = 0.001, OR 1.68; T allele: P = 0.001, OR 1.70). CONCLUSIONS: The promoter CTLA4(-318)C/T polymorphism is not in linkage disequilibrium with the pathogenic polymorphism(s) at the CTLA4 locus. The alleles of both the exon 1 CTLA4(49)A/G and the intron 1 CTLA4(1822)C/T polymorphisms are associated with GD, which is stronger in patients with TAO.

Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population.

Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P = 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (lambda(s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population.