Rebecca S. Bahn

Approach to the patient with nontoxic multinodular goiter.

Thyroid nodules are very common, and although the majority are benign, approximately 5% may harbor malignancy. The evaluation of the patient with solitary thyroid nodule is generally straightforward and will typically include measurement of serum TSH to assess thyroid function and fine-needle aspiration biopsy of the nodule, with or without ultrasound (US) guidance. The approach to the patient with nontoxic multinodular goiter represents a more difficult problem for the clinician. All patients should have serum TSH measured to assess functional thyroid status and US examination to evaluate the number, size, and sonographic features of the nodules and assist in the selection of nodules that may need fine-needle aspiration biopsy. Patients with nodules yielding malignant cytology should be referred for surgery. Given the lack of reliable markers to predict biological behavior of nodules with suspicious (indeterminate) cytology, patients with such nodules are generally advised to have surgery, unless autonomous function of these nodules can be confirmed by scintigraphy. Most of these patients, however, will ultimately prove to have benign follicular tumors. Many patients with benign but large goiters may experience clinical symptoms of pressure, such as dysphagia, choking sensation, or airway obstruction. Such patients will often require surgery for alleviation of symptoms. In the absence of malignancy, asymptomatic patients may be observed. Radioactive iodine, commonly used in many parts of Europe, is safe and effective and may be a reasonable option for many patients. Periodic follow-up with neck palpation and US exam is recommended for all patients.

Predictors of Malignancy in Patients with Cytologically Suspicious Thyroid Nodules

BACKGROUND Fine needle aspiration (FNA), although very reliable for cytologically benign and malignant thyroid nodules, has much lower predictive value in the case of suspicious or indeterminate nodules. We aimed to identify clinical predictors of malignancy in the subset of patients with suspicious FNA cytology. METHODS We reviewed the electronic medical records of 462 patients who had FNA of thyroid nodules at our institution with a suspicious cytological diagnosis, and underwent surgery at Mayo Clinic between January 2004 and September 2008. Demographic data including age, gender, history of exposure to radiation and use of thyroid hormone was collected. The presence of single versus multiple nodules by ultrasonography, nodule size, and serum thyroid-stimulating harmone (TSH) level before thyroid surgery were recorded. Analysis of the latter was limited to patients not taking thyroid hormone or antithyroid drugs at the time of FNA. RESULTS Of the 462 patients, 327 had lesions suspicious for follicular neoplasm (S-FN) or Hürthle cell neoplasm (S-HCN), 125 had cytology suspicious for papillary carcinoma (S-PC) and 10 had a variety of other suspicious lesions (medullary cancer, lymphoma and atypical). Malignancy rate for suspicious neoplastic lesions (FN+HCN) was ∼15%, whereas malignancy rate for lesions S-PC was 77%. Neither age, serum TSH level, or history of radiation exposure were associated with increased malignancy risk. The presence of multiple nodules (41.1% vs. 26.4%, p=0.0014) or smaller nodule size (2.6±1.8 cm vs. 2.9±1.6 cm, p=0.008) was associated with higher malignancy risk. In patients with cytology suspicious for neoplasm (FN, HCN) malignancy risk was higher in those receiving thyroid hormone therapy than in nonthyroid hormone users (37.7% vs. 16.5%, p=0.0004; odds ratio: 3.1), although serum TSH values did not differ significantly between thyroid hormone users and nonusers. CONCLUSION In patients with cytologically suspicious thyroid nodules, the presence of multiple nodules or smaller nodule size was associated with increased risk of malignancy. In addition, our study demonstrates for the first time, an increased risk of malignancy in patients with nodules suspicious for neoplasm who are taking thyroid hormone therapy. The reason for this association is unknown.

A Small Molecule Antagonist Inhibits Thyrotropin Receptor Antibody-Induced Orbital Fibroblast Functions Involved in the Pathogenesis of Graves Ophthalmopathy

CONTEXT Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. OBJECTIVE The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). DESIGN Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. MAIN OUTCOME MEASURES cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed. RESULTS Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production. CONCLUSIONS Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.

TSH receptor expression in orbital tissue and its role in the pathogenesis of Graves’ ophthalmopathy

The TSH receptor (TSHr) is the autoantigen responsible for the hyperthyroidism of Graves’ disease. Recent studies suggest that this receptor may also be an autoimmune target in Graves’ ophthalmopathy (GO) and pretibial dermopathy (PTD). Its involvement in the pathogenesis of these conditions would help to explain the close clinical associations between hyperthyroidism, GO and PTD. TSHr has been shown to be present in normal orbital and dermal tissues and evidence supports the conviction that expression may be increased in tissues involved in GO and PTD. In the setting of Graves’ disease, the expression of this antigen in connective tissues throughout the body may lead to systemic, subclinical connective tissue inflammation. Given this background, local or environmental factors such as circulating or local cytokines, gravitational dependency, anatomic constraint of the bony orbit, or trauma, may augment clinical disease involvement within the orbit and pretibial skin. Alternately, locally enhanced expression of this protein at the sites of clinical disease may not be directly involved in pathogenesis, but could be secondary to the ongoing process, and nonetheless important in disease progression.

The evaluation and treatment of graves ophthalmopathy.

Optimum care of the patient with Graves ophthalmopathy (GO) is achieved through teamwork between the endocrinologist and ophthalmologist, with input from ancillary specialists as needed. Clinical evaluation should include determination of both the severity and the activity of the disease. It is important to assess early in the evaluation the impact of the disease on the patients quality of life and their priorities and expectations regarding management. Once this information has been gathered, careful discussion between patient and physicians can define the management plan. This article reviews the pathophysiology, epidemiology, evaluation, and management of GO.

Relationships Between Thyroid Function and Lipid Status or Insulin Resistance in a Pediatric Population

BACKGROUND In adults without thyroid disease, increasing levels of thyroid-stimulating hormone (TSH) within the range of that considered normal have been shown to be associated with increases in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, and with decreases in high-density lipoprotein cholesterol. Serum TSH has also been found to be positively associated with fasting and postload insulin concentrations and negatively associated with insulin sensitivity in euthyroid adults. We hypothesized that such relationships also exist in euthyroid children and adolescents. METHODS This was a retrospective record review of pediatric outpatients (ages 2-18 years) having measurements of TSH or free thyroxine (T4) and a concurrent lipid panel, fasting glucose, or fasting insulin. Pearson correlation coefficient was used to estimate the correlation between TSH or free T4 and logarithmic transformed lipid, plasma glucose, or insulin levels. Lipid levels, fasting plasma glucose, insulin, and homeostasis model assessment (HOMA) were also compared between subjects with TSH levels in the high normal range (2.5-5 mIU/L) and those with TSH in the low normal range (0.3-2.4 mIU/L). RESULTS TSH levels were positively correlated with triglyceride levels (r = 0.10, p = 0.001). Conversely, free T4 levels were inversely correlated with triglyceride levels (r = -0.10, p = 0.011). TSH levels were also positively correlated with fasting insulin (r = 0.26, p = 0.002) and with HOMA (r = 0.27, p = 0.001). These associations remained significant after adjustment for age, gender, and body mass index z-score. Children who had TSH levels between 2.5 and 5.0 mIU/L had higher triglycerides (p = 0.003), insulin levels (p = 0.040), and HOMA (p = 0.021) than those having TSH values between 0.3 and 2.4 mIU/L. CONCLUSIONS In euthyroid children without a history of hypo- or hyperthyroidism, increasing levels of TSH and decreasing levels of free T4 are associated with higher triglyceride levels and elevated markers of insulin resistance. Whether these findings carry implications regarding optimal TSH levels in children at increased risk for cardiovascular disease awaits further study.

Speed mentoring: An innovative method to facilitate mentoring relationships

Background: Junior faculty members have difficulty in identifying mentors. Speed dating permits people to efficiently try out interpersonal relationships. Aim: Evaluate a “speed mentoring” event to help junior faculty answer questions and initiate mentoring relationships. Methods: This single-group pre–post study involved junior (mentee) and senior (mentor) faculty members at an academic medical center. During the event, each mentee spent 10 min talking with each mentor in rotation. Results: Seven mentees and six mentors participated. All participants felt that time was well spent (mentees, mean [SD] = 6.3 [0.8] on a seven-point Likert scale [7 = strongly agree]; mentors, 5.7 [1.4]). Topics discussed included mentoring relationships, getting started in research, and time management. Conclusions: Participants perceived benefits from this low-cost, brief intervention to facilitate mentoring relationships.

Body mass index and the development of amiodarone-induced thyrotoxicosis in adults with congenital heart disease—A cohort study

INTRODUCTION Amiodarone-induced thyrotoxicosis (AIT) is a recognized complication of amiodarone treatment with limited management options. Its predisposing factors are incompletely defined yet a higher prevalence was reported in adults with congenital heart disease (CHD). Therefore we sought to determine the incidence and risk factors for AIT in adults with CHD. METHODS At a tertiary care center we followed a historical cohort of amiodarone-treated CHD patients for the period 1987-2009. Follow-up concluded at AIT diagnosis or with last thyroid assessment on amiodarone. Cumulative incidence of AIT was calculated. AIT association with nutritional status was hypothesized a priori. RESULTS AIT developed in 23/169 patients or 13.6%. The AIT incidence peaked in the 3rd year at 7.7%. AIT patients had a lower body mass index (BMI) at AMIO initiation compared with the rest of the cohort (mean ± standard deviation: 21.9 ± 2.9 vs. 25.1 ± 5.0; p<0.001). Patients with BMI<21 were more likely to develop thyrotoxicosis (RR=6.1) compared to those with BMI>25 (p<0.001). Presence of goiter was strongly associated with AIT (RR 3.6, p=0.002). Affected patients had a trend for higher cyanotic heart disease prevalence (34.8% vs. 17.8%, p=0.059). On multivariate analysis body mass index and goiter remained independent predictors of outcome. CONCLUSIONS BMI<21 at initiation of amiodarone therapy and presence of goiter are strong predictors of AIT in this population. Its incidence is time dependent. These predictors can be used clinically in assessing overall impact of amiodarone therapy in congenital heart disease patients.

Nonidentical expressions of multiple endocrine neoplasia, type I, in identical twins

We studied 25-year-old HLA- and blood group-identical male twins who had multiple endocrine neoplasia, type I (MEN I). At the time of initial examination, one twin (case 1) had epigastric pain and diarrhea; he was cushingoid in appearance. Further evaluation revealed primary hyperparathyroidism, Zollinger-Ellison syndrome, Cushings disease, and hyperprolactinemia. Immunostaining of a resected pituitary specimen demonstrated both prolactin and, to a lesser extent, growth hormone reactivity. The nontumorous adenohypophysis showed corticotropic hyperplasia. In contrast, the other twin (case 2) was asymptomatic. He had only primary hyperparathyroidism and hyperprolactinemia. An invasive pituitary adenoma was resected and showed similar proportions of cells with immunoreactive prolactin and those with growth hormone; no nontumorous gland was available for study. Apparently, factors other than heredity may play a role in the expression of MEN I.

The EUGOGO consensus statement on the management of Graves' orbitopathy: Equally applicable to North American clinicians and patients

The European group on Graves’ orbitopathy (EUGOGO; www.eugogo.org) is a multidisciplinary consortium of clinicians committed to improving the management of patients with the ocular complications of Graves’ disease. The group developed a consensus statement on the management of Graves’ orbitopathy (GO) that was unveiled at the annual meeting of the European Thyroid Association in Leipzig, Germany, in September 2007, and simultaneously appears in this issue of Thyroid and in the European Journal of Endocrinology (1). EUGOGO is to be commended for their efforts that reflect a remarkable degree of international cooperation by academic endocrinologists and ophthalmologists. The authors refer to the document as a ‘‘consensus statement’’ by experts in the field, rather than a practice guideline. This seems appropriate, because while the EUGOGO group can be credited with having performed the majority of randomized controlled trials (RCTs) in this area, they are not of sufficient scope to support formal practice guidelines. Despite this, the document is timely and should prove useful to clinicians who manage GO patients. The authors rightly anticipate that the document will ‘‘provide a focus for audit and research’’ and aid in the identification of topics for future RCTs. The consensus statement is scholarly and concise, and the recommendations are generally applicable to North American, as well as European, clinicians and patients. The graded recommendations are appended in the document, and the evidence supporting each is discussed in detail in the body of the text. The application of the recommendations requires that clinicians must first segregate their GO patients into ‘‘mild,’’ ‘‘moderate to severe,’’ or ‘‘sight-threatening’’ categories, and determine whether or not the disease is active. Sufficient details are provided within the text regarding the assessment of disease severity and activity to allow classification into these broad categories. EUGOGO does not advocate using any detailed grading or scoring system other than the relatively simple ‘‘clinical activity score’’ and specific ocular measurements to assess the severity of the disease. While this approach may not ideally capture all features of the disease, it has been validated by the group in numerous clinical studies and should serve as the gold standard against which other GO classification systems are measured. The document will serve as an especially useful tool for clinicians who already have some expertise in managing GO patients. Others not so experienced but encounter GO patients in their practice are advised to ‘‘refer patients with GO, except for the mildest cases, to combined thyroid–eye clinics for further assessment and management.’’ Which referrals should be made urgently and which are nonurgent is carefully outlined in the text. The problematic aspect of this recommendation for clinicians in North America, however, is that regional GO consultants are frequently ophthalmologists who do not work in combined thyroid–eye clinics. One of the many positive results stemming from the inception of EUGOGO has been the mandatory establishment of a combined thyroid–eye clinic within each of the European medical center wishing to participate in the consortium. Only through this type of cooperation can GO patients benefit from the full range of expertise needed to understand and manage all aspects of this perplexing disease. While the vast majority of the recommendations seem to me to be quite reasonable and based to the extent possible on pertinent literature, I do take issue with the statement that ‘‘the treatment of choice for moderate to severe and active GO is pulses of intravenous glucocorticoids (GCs).’’ While severe GO may warrant this approach, I remain reluctant to recommend iv GCs to patients with only moderate disease (i.e., those having only a single feature that would place them in the ‘‘moderate to severe’’ category, or a few features measuring just above mild). My concern stems both from reports of fatal acute liver failure in four GO patients during or following completion of iv GC treatment (2,3), and from the natural history of the disease showing improvement in the majority of (albeit unselected) patients within a years’ time. Fortunately, the frequency of hepatotoxicity appears to be very low; 7 of approximately 800 GO patients treated in Italy with iv GCs suffered severe liver damage, of whom 3 died (3). Because no case of liver failure has been reported in GO patients receiving< 8 g methylprednisolone, the consensus statement indicates that the cumulative dose in one course should be less than this amount and specifies that iv GCs should only be administered in centers experienced in this therapy. Despite this, the risk–benefit ratio for iv GCs in patients with active disease of only moderate severity who might do equally well with oral steroids or even careful THYROID Volume 18, Number 3, 2008 a Mary Ann Liebert, Inc. DOI: 10.1089=thy.2008.0034