AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ASSOCIAZIONE MEDICI ENDOCRINOLOGI MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND MANAGEMENT OF THYROID NODULES--2016 UPDATE.

Thyroid nodules are detected in up to 50 to 60% of healthy subjects. Most nodules do not cause clinically significant symptoms, and as a result, the main challenge in their management is to rule out malignancy, with ultrasonography (US) and fine-needle aspiration (FNA) biopsy serving as diagnostic cornerstones. The key issues discussed in these guidelines are as follows: (1) US-based categorization of the malignancy risk and indications for US-guided FNA (henceforth, FNA), (2) cytologic classification of FNA samples, (3) the roles of immunocytochemistry and molecular testing applied to thyroid FNA, (4) therapeutic options, and (5) follow-up strategy. Thyroid nodule management during pregnancy and in children are also addressed. On the basis of US features, thyroid nodules may be categorized into 3 groups: low-, intermediate-and high-malignancy risk. FNA should be considered for nodules ≤10 mm diameter only when suspicious US signs are present, while nodules ≤5 mm should be monitored rather than biopsied. A classification scheme of 5 categories (nondiagnostic, benign, indeterminate, suspicious for malignancy, or malignant) is recommended for the cytologic report. Indeterminate lesions are further subdivided into 2 subclasses to more accurately stratify the risk of malignancy. At present, no single cytochemical or genetic marker can definitely rule out malignancy in indeterminate nodules. Nevertheless, these tools should be considered together with clinical data, US signs, elastographic pattern, or results of other imaging techniques to improve the management of these lesions. Most thyroid nodules do not require any treatment, and levothyroxine (LT4) suppressive therapy is not recommended. Percutaneous ethanol injection (PEI) should be the first-line treatment option for relapsing, benign cystic lesions, while US-guided thermal ablation treatments may be considered for solid or mixed symptomatic benign thyroid nodules. Surgery remains the treatment of choice for malignant or suspicious nodules. The present document updates previous guidelines released in 2006 and 2010 by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE) and Associazione Medici Endocrinologi (AME).

LONG-TERM NONOPERATIVE RATE OF THYROID NODULES WITH BENIGN RESULTS ON THE AFIRMA GENE EXPRESSION CLASSIFIER.

OBJECTIVE: The primary objective was to assess the operative rate in patients with a benign result from the Afirma gene expression classifier (GEC) during long-term follow-up at nonacademic medical facilities. The secondary endpoint of this study was the treating physician's opinion regarding the safety of GEC use compared to the hypothetical situation of providing thyroid nodule management without the GEC. METHODS: This was a retrospective study of nonacademic medical practices utilizing the GEC. Those clinicians utilizing the GEC testing who had three or more 'benign' results during the data collection period (September 2010 through June 2014) were invited to participate. Operative status and patient demographics were documented for patients with GEC testing at least 36 months (± 3 months) prior to the date of data collection. A survey also was administered to the treating physicians to assess their perceived safety of using the GEC in patient care. RESULTS: During 36 months (± 3 months) of follow-up, 17 of 98 patients (17.3%) with a 'benign' GEC result underwent surgery. Within the first 2 years after a 'benign' GEC, 88% of surgeries were performed. Regarding safety of the GEC, the treating physicians reported that patient safety was improved by using the GEC compared to not using the GEC in 78 of 91 cases (86%). CONCLUSION: It appears that a 'benign' result on the GEC is associated with a reduction in the rate of thyroid surgeries compared to published data when patients are followed for 36 months after testing. A nonoperative approach to follow-up was felt to be a safe alternative to diagnostic surgery by the majority of responsible physicians in the study. ABBREVIATIONS: AUS = atypia of undetermined significance FLUS = follicular lesion of undetermined significance FN = follicular neoplasm FNA = fine-needle aspiration GEC = gene expression classifier.

A Computer-Interpretable Version of the AACE, AME, ETA Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules.

OBJECTIVE: Clinical practice guidelines (CPGs) could have a more consistent and meaningful impact on clinician behavior if they were delivered as electronic algorithms that provide patient-specific advice during patient-physician encounters. We developed a computer-interpretable algorithm for U.S. and European users for the purpose of diagnosis and management of thyroid nodules that is based on the "AACE, AME, ETA Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules," a narrative, evidence-based CPG. METHODS: We initially employed the guideline-modeling language GuideLine Interchange Format, version 3, known as GLIF3, which emphasizes the organization of a care algorithm into a flowchart. The flowchart specified the sequence of tasks required to evaluate a patient with a thyroid nodule. PROforma, a second guideline-modeling language, was then employed to work with data that are not necessarily obtained in a rigid flowchart sequence. Tallis-a user-friendly web-based "enactment tool"- was then used as the "execution engine" (computer program). This tool records and displays tasks that are done and prompts users to perform the next indicated steps. The development process was iteratively performed by clinical experts and knowledge engineers. RESULTS: We developed an interactive web-based electronic algorithm that is based on a narrative CPG. This algorithm can be used in a variety of regions, countries, and resource-specific settings. CONCLUSION: Electronic guidelines provide patient-specific decision support that could standardize care and potentially improve the quality of care. The "demonstrator" electronic thyroid nodule guideline that we describe in this report is available at http://demos.deontics.com/trace-review-app (username: reviewer; password: tnodule1). The demonstrator must be more extensively "trialed" before it is recommended for routine use.

Overview of molecular biomarkers for enhancing the management of cytologically indeterminate thyroid nodules and thyroid cancer.

OBJECTIVE: To provide information on molecular biomarkers that can help assess cytologically indeterminate thyroid nodules. METHODS: Published studies on immunohistologic, somatic mutation, gene expression classifier, microRNA, and thyrotropin receptor messenger RNA biomarkers are reviewed, and commercially available molecular test panels are described. RESULTS: Thyroid nodules are common, and clinical guidelines delineate an algorithmic approach including serum thyroid-stimulating hormone measurement, diagnostic ultrasound examination, and, when appropriate, fine-needle aspiration (FNA) biopsy for determination of a benign versus malignant status. In clinical practice, approximately 20% of FNA-derived cytology reports are classified as "indeterminate" or follicular nodules that do not fulfill either benign or malignant criteria. In this setting, the actual risk for malignancy of a cytologically indeterminate nodule ranges from approximately 15% to 34%. Research describing molecular biomarkers from thyroid cancer tissue has been applied to FNA-derived thyroid nodule material. There is also a serum molecular marker that has been reported with goals similar to those for the FNA-derived molecular markers: to enhance the preoperative diagnosis of thyroid cancer and reduce the large number of patients who have a diagnostic surgical procedure for benign thyroid nodules. CONCLUSION: Progress toward the foregoing goals has been made and continues to evolve with the recent appearance of molecular biomarker tests that can be selectively applied for further assessment of cytologically indeterminate thyroid nodules.

The impact of benign gene expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with indeterminate fine-needle aspiration cytopathology.

BACKGROUND: Seventy-five percent of thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology are found to be benign postoperatively. A novel genomic test, the Afirma gene expression classifier (AGEC), has been available for clinical use in the United States, since late 2010. In 2010, two modest-sized validation studies showed that the AGEC could identify a benign gene expression signature in indeterminate cytology thyroid FNA samples with a negative predictive value >95%. The objective of this study was to evaluate how the AGEC impacted the joint decision of the endocrinologist and patient to operate when FNA cytology was indeterminate, but the AGEC reading of the nodule was benign. METHODS: In this cross-sectional cohort study, data were contributed retrospectively by 51 endocrinologists at 21 practice sites that had previously obtained ≥3 benign AGEC readings in ≥1 cm nodules with indeterminate FNA cytology readings. Information regarding demographic data, nodule size and location, decision to operate, surgery type (hemithyroidectomy [HT] or total thyroidectomy [TT]), and reason for recommending surgery was retrospectively collected. RESULTS: Compared to a 74% previous historical rate of surgery for cytologically indeterminate nodules, the operative rate fell to 7.6% during the period that AGEC were obtained in the clinical practices, a highly significant reduction in the decision to operate (p<0.001). The rate of surgery on cytologically indeterminate nodules that were benign by the AGEC reading did not differ from the historically reported rate of operation on cytologically benign nodules (p=0.41). The four primary reasons reported by the physicians for operating on nodules with a benign AGEC reading, in descending order: large nodule size (46.4%), symptomatic nodules (25.0%), rapidly growing nodules (10.7%), or a second suspicious or malignant nodule in the same patient (10.7%). These reasons are concordant with those typically given for operation on cytologically benign nodules. CONCLUSIONS: In a substantial group of medical practices, obtaining an AGEC test in patients with cytologically indeterminate nodules was associated with a striking reduction in the rate of diagnostic thyroidectomy. Approximately, one surgery was avoided for every two AGEC tests run on thyroid FNAs with indeterminate cytology.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied.These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Identifying prediabetes using fasting insulin levels.

OBJECTIVE: To determine whether patients with prediabetes can be accurately and easily identified in clinical settings using a predictive clinical and laboratory model. METHODS: This retrospective study examined demographic and laboratory data from patients who had undergone 2-hour glucose testing for suspected prediabetes or diabetes between 2000 and 2004. Patients who met the diagnostic criteria for diabetes mellitus were excluded. Prediabetes was defined as a fasting glucose concentration > or = 100 mg/dL and < or = 125 mg/dL or a 2-hour postprandial glucose concentration > or = 140 mg/dL and < 200 mg/dL. Multivariate logistic regression was conducted to identify calculated or measured clinical and laboratory attributes that predict the presence of prediabetes, including fasting insulin quartiles, homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index. RESULTS: Of 965 patients, 287 (29.7%) had prediabetes. The study population primarily consisted of white, obese, female patients. A multivariate model revealed that compared with the referent lowest quartile of fasting insulin (mu = 4.9 [+/-SD] +/-1.2 microIU/mL), subsequent insulin quartiles increased the likelihood of identifying prediabetes (quartile 2: mu = 8.0 +/-0.8 microIU/mL, odds ratio [OR] = 2.076, confidence interval [CI] = 1.241-3.273; quartile 3: mu = 12.2 +/-1.7 microIU/mL, OR = 3.151, CI = 1.981-5.015; quartile 4: mu = 25.9 +/-12.4 microIU/mL, OR = 5.035, CI = 3.122-8.122). Older age and increased diastolic blood pressure also contributed modestly to this model. Further analysis using the area under the curve revealed that at a fasting insulin level > 9.0 microIU/mL, prediabetes would be correctly identified in 80% of affected patients. A second model revealed that increased HOMA-IR index (OR = 1.303, CI = 1.205-1.410) and older age (OR = 1.037, CI = 1.024-1.05) predicted prediabetes. CONCLUSIONS: The most robust model, which used fasting insulin levels, may provide the most utility as a clinical tool because the highest quartiles suggest significantly greater likelihood of identifying prediabetes.

American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules.

Thyroid nodules are common and are frequently benign. Current data suggest that the prevalence of palpable thyroid nodules is 3% to 7% in North America; the prevalence is as high as 50% based on ultrasonography (US) or autopsy data. The introduction of sensitive thyrotropin (thyroid-stimulating hormone or TSH) assays, the widespread application of fine-needle aspiration (FNA) biopsy, and the availability of high-resolution US have substantially improved the management of thyroid nodules. This document was prepared as a collaborative effort between the American Association of Clinical Endocrinologists (AACE) and the Associazione Medici Endocrinologi (AME). Most Task Force members are members of AACE. We have used the AACE protocol for clinical practice guidelines, with rating of available evidence, linking the guidelines to the strength of recommendations. Key observations include the following. Although most patients with thyroid nodules are asymptomatic, occasionally patients complain of dysphagia, dysphonia, pressure, pain, or symptoms of hyperthyroidism or hypothyroidism. Absence of symptoms does not rule out a malignant lesion; thus, it is important to review risk factors for malignant disease. Thyroid US should not be performed as a screening test. All patients with a palpable thyroid nodule, however, should undergo US examination. US-guided FNA (US-FNA) is recommended for nodules > or = 10 mm; US-FNA is suggested for nodules < 10 mm only if clinical information or US features are suspicious. Thyroid FNA is reliable and safe, and smears should be interpreted by an experienced pathologist. Patients with benign thyroid nodules should undergo follow-up, and malignant or suspicious nodules should be treated surgically. A radioisotope scan of the thyroid is useful if the TSH level is low or suppressed. Measurement of serum TSH is the best initial laboratory test of thyroid function and should be followed by measurement of free thyroxine if the TSH value is low and of thyroid peroxidase antibody if the TSH value is high. Percutaneous ethanol injection is useful in the treatment of cystic thyroid lesions; large,symptomatic goiters may be treated surgically or with radioiodine. Routine measurement of serum calcitonin is not recommended. Suggestions for thyroid nodule management during pregnancy are presented. We believe that these guidelines will be useful to clinical endocrinologists, endocrine surgeons, pediatricians, and internists whose practices include management of patients with thyroid disorders. These guidelines are thorough and practical, and they offer reasoned and balanced recommendations based on the best available evidence.

Significance of radioiodine uptake at 72 hours versus 24 hours after pretreatment with recombinant human thyrotropin for enhancement of radioiodine therapy in patients with symptomatic nontoxic or toxic multinodular goiter.

OBJECTIVE: To report the effects of pretreatment with recombinant human thyrotropin (rhTSH) on radioiodine uptake (RAIU) and subsequent radioiodine therapy in 30 patients with symptomatic nontoxic or toxic multinodular goiter. METHODS: Patients received a single injection of rhTSH (0.1 mg in 21 and 0.3 mg in 9 patients). Thyroid function tests were performed before and 72 hours after rhTSH administration. Both 4-hour and 24-hour RAIU studies were done after rhTSH administration and repeated at 48 to 52 hours and at 72 hours, respectively. Then all patients were treated with 30 mCi of 131 I. RESULTS: All study patients experienced symptomatic relief by 1 to 2 months. In addition to the previously reported twofold increase over the baseline RAIU at 24 hours, we found that a second 24-hour RAIU showed a further twofold increase (quadrupling of the RAIU over baseline) at 72 hours after administration of 0.1 mg of rhTSH (from 22% to 43%; P<0.001) and 0.3 mg of rhTSH (from 16% to 37%; P = 0.002), with no significant difference between doses on the RAIU at 24 hours or at 72 hours. Additionally, the RAIU value at 4 hours and 52 hours after administration of 0.1 mg and 0.3 mg of rhTSH revealed a fourfold increase for each dose--from 7% to 28% (P<0.001) and from 5% to 21% (P = 0.002), respectively. CONCLUSION: In patients with symptomatic toxic or nontoxic multinodular goiter, 0.1 mg and 0.3 mg of rhTSH were equally efficacious at inducing a quadrupling of the low or low-normal baseline RAIU values at 72 hours after injection. Subsequent radioiodine therapy alleviated compressive and thyrotoxic symptoms in all 30 treated patients. Future studies should help determine doses of rhTSH and radioiodine therapy that are optimal in iodine-sufficient and insufficient regions of the world.

Utility of recombinant human thyrotropin for augmentation of radioiodine uptake and treatment of nontoxic and toxic multinodular goiters.

OBJECTIVE: To report our results in treating 16 patients with low radioiodine uptake (RAIU) multinodular goiter who had obstructive symptoms or suppressed thyroid-stimulating hormone (TSH or thyrotropin), indicating mild hyperthyroidism. METHODS: Six patients were treated with 0.3 mg of recombinant human thyrotropin (rhTSH) followed by 30 mCi of (131)I 72 hours later. Ten patients were treated with 0.9 mg of rhTSH followed by 30 mCi of (131)I 24 hours later. RESULTS: Of the 16 treated patients, all 10 with compressive symptoms and both patients with weight loss had remission or improvement, as did 1 of 2 patients with atrial fibrillation. All patients with suppressed TSH had a return to normal levels or became hypothyroid. During the next 3 to 7 months, estimated gland size reduction was 30 to 40%. Three of the 6 patients who received 0.3 mg of rhTSH and 6 of the 10 patients who received 0.9 mg of rhTSH, in conjunction with (131)I therapy, ultimately had TSH levels indicative of hypothyroidism. Mild radiation thyroiditis developed in only one patient, and no other side effects occurred. CONCLUSION: The 0.3-mg dose of rhTSH seemed to be as efficacious as the 0.9-mg dose. The greater than fourfold increase in RAIU at 72 hours after administration of rhTSH in our study is more than twofold higher than the 24-hour RAIU results previously reported in normal subjects and in patients with multinodular goiter. These findings have implications for future expanded studies and alternative dosing regimens in treating patients with both multinodular goiter and subclinical hyperthyroidism.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE EVALUATION AND TREATMENT OF HYPERTHYROIDISM AND HYPOTHYROIDISM.

These clinical practice guidelines summarize the recommendations of the American Association of Clinical Endocrinologists for the diagnostic evaluation of hyperthyroidism and hypothyroidism and for treatment strategies in patients with these disorders. The sensitive thyroid-stimulating hormone (TSH or thyrotropin) assay has become the single best screening test for hyperthyroidism and hypothyroidism, and in most outpatient clinical situations, the serum TSH is the most sensitive test for detecting mild thyroid hormone excess or deficiency. Therapeutic options for patients with Graves' disease include thyroidectomy (rarely used now in the United States), antithyroid drugs (frequently associated with relapses), and radioactive iodine (currently the treatment of choice). In clinical hypothyroidism, the standard treatment is levothyroxine replacement, which must be tailored to the individual patient. Awareness of subclinical thyroid disease, which often remains undiagnosed, is emphasized, as is a system of care that incorporates regular follow-up surveillance by one physician as well as education and involvement of the patient.

American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism.

These clinical practice guidelines summarize the recommendations of the American Association of Clinical Endocrinologists for the diagnostic evaluation of hyperthyroidism and hypothyroidism and for treatment strategies in patients with these disorders. The sensitive thyroid-stimulating hormone (TSH or thyrotropin) assay has become the single best screening test for hyperthyroidism and hypothyroidism, and in most outpatient clinical situations, the serum TSH is the most sensitive test for detecting mild thyroid hormone excess or deficiency. Therapeutic options for patients with Graves' disease include thyroidectomy (rarely used now in the United States), antithyroid drugs (frequently associated with relapses), and radioactive iodine (currently the treatment of choice). In clinical hypothyroidism, the standard treatment is levothyroxine replacement, which must be tailored to the individual patient. Awareness of subclinical thyroid disease, which often remains undiagnosed, is emphasized, as is a system of care that incorporates regular follow-up surveillance by one physician as well as education and involvement of the patient.