How to manage Graves' disease in women of childbearing potential.

The management of Graves' disease (GD) in women of childbearing potential has multiple specific complexities. Many factors are involved, which differ at the various stages from preconception, conception, first trimester, later pregnancy, postpartum and lactation, with both maternal and foetal considerations. The incidence and significance of the risks incurred from antithyroid drugs (ATDs) in pregnancy have been re-evaluated recently and must be balanced against the risks of uncontrolled hyperthyroidism during childbearing years. Contraception is advised until hyperthyroidism is controlled. ATD cessation should be considered in those who are well controlled on low dose therapy before conception and in early pregnancy. Advice on iodine supplementation does not generally differ in those with GD. Radioiodine (RAI) is contraindicated from 6 months preconception until completion of breastfeeding. In all women who have a history of GD, monitoring of TSH receptor antibodies (TRAb) is strongly recommended during pregnancy, and if elevated, foetal monitoring and assessment of thyroid function in the neonate are required. Of note, RAI increases TRAb for up to a year, making this treatment option even less attractive in this patient group. A small amount of ATD is transferred into breast milk but low doses are safe during lactation. Routine periodic thyroid function testing is recommended in remission to detect postpartum GD recurrence. We present our approach to the Clinical Question 'How to manage GD in women of childbearing potential?'

Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit.

BACKGROUND: Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib. SUMMARY: Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment. CONCLUSIONS: Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

Medical and surgical treatment of thyroid eye disease.

Thyroid eye disease is an autoimmune inflammatory disease strongly associated with thyroid disease, principally Graves disease. It can range from mild disease requiring observation or symptomatic treatments only, through to sight-threatening disease requiring major drug therapy and orbital surgery. Severity is graded by the NOSPECS system and activity by the clinical activity score (CAS) to assist in treatment selection. Non-surgical management can extend from observation alone to minor therapy such as oral selenium, then glucocorticoid therapy, cyclosporin, mycophenolate, rituximab, immunoglobulin, teprotumumab, and orbital radiotherapy. High-dose intravenous methylprednisolone therapy is used in active vision-threatening disease with early use of tarsorrhaphy and orbital decompression. Inactive but moderate to severe disease may be treated by orbital decompression, strabismus and eyelid surgery. Systematic assessment and management by both an endocrinologist and ophthalmologist to achieve and maintain euthyroidism and select and sequence treatments according to activity and severity of thyroid eye disease gives the best results for quality of life and vision.

The Utility of Prophylactic Zoledronic Acid in Patients Undergoing Lung Transplantation.

Osteoporosis is prevalent among lung transplant candidates and is exacerbated post-transplant by immunosuppressive therapy. Low bone mineral density (BMD) is a well-recognized surrogate for fragility fracture risk, which is associated with significant morbidity and mortality. Intravenous zoledronic acid (ZA) effectively reduces BMD loss and prevents fractures in postmenopausal osteoporosis. Many groups, ours included, prophylactically treat lung transplant recipients (LTR) with bisphosphonates, but no documented consensus currently exists. Our protocol comprises ZA every 6-months from transplant wait-listing, with interval reassessment to guide ongoing treatment. We evaluate the impact of a dose of ZA within 6 months of transplantation on BMD and fracture occurrence. A retrospective analysis was performed on all adult LTR from April 2012 to October 2014, of which 60 met our inclusion criteria. LTR who received ZA within 6 months of transplantation (n = 37) were compared to those who did not (n = 23), and followed up for a minimum of three years. Outcome measures were BMD change at the lumbar spine and femur (primary), and fracture occurrence (secondary). LTR treated with ZA within 6 months of transplantation experienced a median BMD change of +8.11% at the lumbar spine and +1.39% at the femur, compared to -1.20% and -3.92%, respectively, in LTR who did not receive a ZA dose within 6 months of transplantation (p = 0.002 & p = 0.008 respectively). Our findings indicate that prophylactic ZA within 6 months of transplantation prevents BMD loss in LTR.

Hypothyroidism associated with therapy for multi-drug-resistant tuberculosis in Australia.

BACKGROUND: Reports from resource-poor countries have associated thionamide- and para-aminosalicylate sodium (PAS)-based treatment of multi-drug-resistant tuberculosis (MDR-TB) with the development of hypothyroidism. AIM: To identify predictors and assess the cumulative proportions of hypothyroidism in patients treated for MDR-TB with these agents in Australia. METHODS: Retrospective multicentre study of MDR-TB patients from five academic centres covering tuberculosis (TB) services in Victoria, Australia. Patients were identified using each centre's pharmacy department and cross checked with the Victorian Tuberculosis Program. Hypothyroidism was categorised as subclinical if the thyroid-stimulating hormone was elevated and as overt if free thyroxine (fT4) was additionally reduced on two separate occasions. Our main outcome measured was the cumulative proportion of hypothyroidism (at 5 years from treatment initiation). RESULTS: Of the 29 cases available for analysis, the cumulative proportion of hypothyroidism at 5 years was 37% (95% confidence interval (CI): 0-57.8%). Eight of the nine affected cases developed hypothyroidism within the first 12 months of treatment. Hypothyroidism was marginally (P = 0.06) associated with higher prothionamide/PAS dosing and was reversible with cessation of the anti-tuberculosis medication. CONCLUSIONS: Prothionamide/PAS treatment-associated hypothyroidism is common in MDR-TB patients in Australia, emphasising the importance of regular thyroid function monitoring during this treatment. Thyroid hormone replacement, if initiated, may not need to be continued after MDR-TB treatment is completed.

Subclinical hypothyroidism during pregnancy: the Melbourne public hospitals consensus.

BACKGROUND: Interest in potential adverse outcomes associated with maternal subclinical hypothyroidism (normal free T4, elevated thyroid-stimulating hormone (TSH)) has increased significantly over recent years. In turn, the frequency of maternal thyroid function testing has risen, despite universal thyroid function screening not being recommended, leading to a marked increase in referrals to obstetric endocrinology clinics. In 2017 the American Thyroid Association revised their diagnostic and management guidelines. Although welcome, these new guidelines contain recommendations that may cause confusion in clinical practice. AIM: To ensure uniform practice in the diagnosis and management of subclinical hypothyroidism in pregnancy across all Melbourne public hospitals. METHODS: Endocrinology and obstetric representatives from all Melbourne public hospital networks reviewed the 2017 American Thyroid Association guidelines and other relevant literature to develop a consensus for diagnosing and treating subclinical hypothyroidism during pregnancy in Melbourne. The consensus guidelines were then referred to the Endocrine Society of Australia for comment and endorsement. RESULTS: Consensus was achieved and the guidelines were endorsed by the Council of the Endocrine Society of Australia. Trimester and assay-specific TSH reference intervals derived from healthy local populations should be used, where available. When unavailable, a TSH cut-off of 4 mU/L (replacing the previously recommended 2.5 mU/L) should be used to initiate treatment, irrespective of thyroid auto-antibody status. The recommended starting dose of levothyroxine is 50 µg daily, with a therapeutic TSH target of 0.1-2.5 mU/L. Levothyroxine should generally be ceased after delivery, with some exceptions. Hospitals will ensure smooth transfer of care back to the woman's general practitioner with clear documentation of pregnancy thyroid management and a recommended plan for follow-up. CONCLUSION: Fewer women will be classified as having subclinical hypothyroidism during pregnancy, which is likely to lead to reductions in emotional stress, hospital visits, repeated blood tests and financial costs. Uniform clinical practice will occur across Melbourne.

Clinical guidance for radioiodine refractory differentiated thyroid cancer.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.

Diagnosis and management of hyponatraemia in the older patient.

Hyponatraemia (serum sodium concentration below 135 mmol/L) is the most common electrolyte disturbance and occurs commonly in older people. The causes can be complex to diagnose and treat and many published guidelines do not focus on the issues in an older patient group. Here, we are principally concerned with diagnosis and management of euvolaemic and hypervolaemic hyponatraemia in hospitalised patients over 70 years old. We also aim to increase awareness of hyponatraemia in residential aged care facilities and the community. Hyponatraemia can have many causes; in older people, chronic hyponatraemia can often be the result of medications used to treat chronic disease, particularly thiazide or thiazide-like drugs (such as indapamide) or drugs acting on the central nervous system. Where a reversible trigger (such as drug-induced hyponatraemia) can be identified, hyponatraemia may be treated relatively simply. Chronic hyponatraemia due to an irreversible cause will require ongoing treatment. Fluid restriction can be an effective therapy in dilutional hyponatraemia, although poor compliance and the burdensome nature of the restrictions are important considerations. Tolvaptan is an oral vasopressin receptor antagonist that can increase serum sodium concentrations by increasing electrolyte-free water excretion. Tolvaptan use is supported by clinical trial evidence in patients with hypervolaemic or euvolaemic hyponatraemia below 125 mmol/L. Clinical trial evidence also supports its use after a trial of fluid restriction in patients with symptomatic hyponatraemia above 125 mmol/L. The use of tolvaptan is affected by regulatory restriction of chronic therapy due to safety concern and the non-subsidised cost of treatment.

Evaluation of NovoRapid infusion as a treatment option in the management of diabetic ketoacidosis.

This study evaluates the clinical efficacy and safety of NovoRapid (insulin aspart) compared to Actrapid™ (human neutral insulin) for diabetic ketoacidosis (DKA). In this retrospective study involving 40 patients, no statistically significant differences were observed between biochemical variables, infusion duration or complications in patients treated with insulin aspart or human neutral insulin. These results support the use of insulin aspart as an effective and safe alternative to human neutral insulin in DKA.

Use of anticoagulation in thyroid disease.

BACKGROUND: Hyperthyroidism and atrial fibrillation (AF) are both common in the Australian community, and often encountered in general practice. OBJECTIVE: This article discusses the risk of AF and thromboembolism in hyperthyroidism, the role of antithrombotic therapy in this setting, and appropriateness and safety of various antithrombotic agents in thyroid disease. DISCUSSION: Prevention of thromboembolism is an important consideration in the care of patients with AF and hyperthyroidism. However, the evaluation of thromboembolic risk and management in this setting is challenging. Thyroid disease results in a pro-coagulant state via disruption of coagulation pathways and alters the pharmacodynamics of anticoagulants. Currently, guidelines regarding anticoagulation in AF do not incorporate hyperthyroidism as an additional risk factor. Until further evidence becomes available, we recommend warfarin as the oral anticoagulant of choice in thyroid disease because of ease of monitoring and reversibility.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.

BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.

The prevalence of thyroglossal tract thyroid tissue on SPECT/CT following (131) I ablation therapy after total thyroidectomy for thyroid cancer.

OBJECTIVE: To determine the prevalence of thyroglossal tract thyroid tissue on SPECT/CT and to assess the contribution of this tissue to total neck radioactive iodine (RAI) activity in patients given (131) I ablation therapy after total thyroidectomy for thyroid cancer. PATIENTS AND METHODS: Eighty-three consecutive patients with thyroid cancer treated with total thyroidectomy underwent whole-body planar and SPECT/CT imaging of the neck following initial RAI ablation. On SPECT/CT, thyroglossal tract thyroid tissue was defined as RAI in the anterior neck, superior to the thyroid bed in close proximity to the midline without evidence of localization to lymph nodes. Quantification was performed using region of interest analysis on planar imaging following localization on SPECT/CT. SPECT/CT, and planar images were classified by two reviewers as positive, negative or equivocal with interobserver agreement quantified using a Kappa score. Disagreement was resolved using a third reviewer. RESULTS: Thyroglossal tract thyroid tissue was present in 39/83 (47%; 95%CI: 36-58%) patients on SPECT/CT. In these 39 patients, this tissue contributed to a significant amount of total neck activity (median = 50%; IQR 19-74%). Interobserver agreement for the presence of thyroglossal tract thyroid tissue was substantial on SPECT/CT (Kappa = 0.73) and fair on planar imaging (Kappa = 0.31). CONCLUSION: Thyroglossal tract thyroid tissue was present in one half of our study population and contributed to a significant amount of total neck RAI activity. Given the high prevalence of this tissue, our results suggest that total neck RAI activity on planar imaging may not be suitable to assess the completeness of thyroid bed surgery.

Phase 1 study of the iodine absorption, safety, and tolerability of a 0.5% povidone-iodine nasal spray (Nasodine).

KEY POINTS: PVP-I is a widely used antiseptic but only recently proposed for intranasal use. The extent of iodine absorption from available PVP-I nasal products is unknown. Iodine absorption from use of Nasodine (0.5% PVP-I nasal spray) is not clinically significant.

Incidence and implications of negative serum thyroglobulin but positive I-131 whole-body scans in patients with well-differentiated thyroid cancer prepared with rhTSH or thyroid hormone withdrawal.

AIMS: To evaluate the incidence and clinical implications of a positive whole-body I-131 scan but negative stimulated serum Tg/TgAb level following an ablative or diagnostic I-131 dose in patients with well-differentiated thyroid cancer and whether there is a difference in incidence if prepared with thyroid hormone withdrawal compared with rhTSH stimulation. METHODS: I-131 scan findings, serum Tg/TgAb levels, TNM stage and method of thyroid tissue stimulation in 193 consecutive patients (138F, 55M) with well-differentiated thyroid cancer undergoing postoperative ablative I-131 therapy and 121 consecutive (94F, 27M) patients undergoing diagnostic I-131 surveillance scans were retrospectively reviewed. Comparisons of proportions were performed using Chi-square tests. Clinical, biochemical and I-131 scan follow-up data were obtained for each patient cohort. RESULTS: 39/193 (20·2%) postablative I-131 and 10/121 (8·3%) diagnostic I-131 patients had negative stimulated serum Tg/TgAb levels but positive I-131 scans for residual thyroid tissue. Nine (4·7%) of the postablative patients had I-131 uptake in the lateral neck suspicious for loco-regional metastatic disease. In the postablative I-131 group, 38/169 (22·5%) prepared with rhTSH compared to 1/24 (4·2%) prepared with thyroid hormone withdrawal were Tg/TgAb negative but I-131 scan positive (P = 0·04). Follow-up of 21/39 postablative I-131 patients with negative Tg/TgAb but positive I-131 scans confirmed a significant proportion of patients (4/21) (19·1%), remained Tg/TgAb negative/I-131 scan positive, some of whom had higher-risk disease at original diagnosis (2/4) (50%). CONCLUSIONS: Our study confirms that in the setting of I-131 ablation therapy or diagnostic I-131 scanning, a significant proportion of patients (20·2% and 8·3%, respectively) have residual benign or malignant thyroid tissue on whole-body scanning despite a negative stimulated serum Tg level. Whether such patients who would otherwise be missed as having residual thyroid tissue on serum Tg testing alone have a worse clinical outcome remains uncertain. Our findings do however suggest performing both stimulated serum Tg/TgAb levels and I-131 scans for the follow-up of patients with higher-risk thyroid cancer may be important. There may also be a slightly higher incidence of this phenomenon in patients prepared with rhTSH rather than by thyroxine withdrawal.

A prospective evaluation of the role of transient elastography for the detection of hepatic fibrosis in type 2 diabetes without overt liver disease.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and subsequently hepatic fibrosis. Transient elastography (TE) is a rapid, reproducible non-invasive test that may be appropriate as a screening tool for the presence of hepatic fibrosis. AIM: Assess the utility of TE as a screening tool for the presence of hepatic fibrosis in a T2DM population with no known liver disease. METHODS: T2DM patients without known liver disease were included. Patients were assessed with TE in addition to biochemical parameters. RESULTS: A successful TE evaluation could be obtained in 74 of 81 (91%) included subjects. Of these, 26 (35%) had a liver stiffness measurement (LSM) ≥ 7.65 kPa. Sixteen of these subjects had confirmatory liver biopsies with significant (≥ F2 fibrosis) present in 12 (75%) and cirrhosis diagnosed in 2 subjects. 15/16 (94%) had histological steatohepatitis. Compared with those with a lower LSM, subjects with an LSM ≥ 7.65 kPa had higher ALT levels (38.0 ± 21.7 vs 26.1 ± 11.1 U/L, p = 0.021) and increased prevalence of hepatic steatosis by ultrasound (85% vs 63%, p = 0.005). CONCLUSION: Significant hepatic fibrosis in the T2DM population is frequently under-recognized. TE may be a feasible tool for the screening of T2DM patients for the presence of hepatic fibrosis.

A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls.

OBJECTIVE: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. METHODS: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients' medical records. RESULTS: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10-33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown. CONCLUSION: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.