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.

Demographics and outcomes of inpatients with diabetic foot ulcers treated conservatively and surgically in a metropolitan hospital network.

AIMS: To describe the demographics of patients with diabetic foot ulcers (DFU) and their impact on inpatient management. Secondary outcomes identified relationships of treatment modality with mortality, length of hospital admission, readmissions and post-admission care. METHODS: Retrospective cohort study including patients with DFU admitted to a hospital network in Melbourne, Australia from 2016 to 2018. Medical records were manually reviewed for acute admission with DFU as a major presenting diagnosis; incidental ulcers and traumatic amputations were excluded. Amputations distal and proximal to the ankle were labelled 'minor' and 'major' respectively. Patients were followed until October 31, 2019. RESULTS: Of 338 patients, 21 and 148 had major and minor amputations, and 169 were managed conservatively. 94% had ≥1 microvascular and/or macrovascular complication. Conservative management (7 days) was associated with a shorter length of stay (major 18, minor 10 days, p < 0.001). Readmission rates were not significantly different. Mortality was greatest (38%) and survival time shortest (999 days) after major amputation than after either other treatment. Other factors associated with mortality were age and a history of coronary artery disease. CONCLUSIONS: Early identification and multi-disciplinary management of DFU is essential to reduce the significant morbidity and mortality associated with amputation in these complex patients.

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.

Successful medical management of insulinoma with diazoxide for 27 years.

SUMMARY: Despite improvements in localisation techniques and surgical advances, some patients with insulinoma will not be cured by surgery or may not be suitable for surgery. Medical management with diazoxide is an option for such cases. This case report details 27 years of successful management of insulinoma using diazoxide. It has been effective and safe, with only minor adverse effects. LEARNING POINTS: Long term diazoxide use can be a safe, effective option for insulinoma when it cannot be localised or removed surgically. Common adverse effects include peripheral oedema, hyperuricaemia, and hirsutism. 68Ga-NOTA-exendin-4 PET/CT scan should be considered for insulinoma localisation when other modalities have been unhelpful.

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.

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.

Insulinoma presenting with post-prandial hypoglycaemia following fundoplication.

Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an uncommon and challenging case of insulinoma soon after upper gastrointestinal surgery. A 63-year-old man presented with 6 months of post-prandial hypoglycaemia beginning after a laparoscopic revision of Toupet fundoplication. Hyperinsulinaemic hypoglycaemia was confirmed during a spontaneous episode and in a mixed-meal test. Localisation studies including magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and gallium dotatate positron emission tomography (68Ga Dotatate PET) were consistent with a small insulinoma in the mid-body of the pancreas. The lesion was excised and histopathology was confirmed a localised well-differentiated neuroendocrine pancreatic neoplasm. There have been no significant episodes of hypoglycaemia since. This case highlights several key points. Insulinoma should be sought in proven post-prandial hyperinsulinaemic hypoglycaemia - even in the absence of fasting hypoglycaemia. The use of nuclear imaging targeting somatostatin and GLP1 receptors has improved accuracy of localisation. Despite these advances, accurate surgical resection can remain challenging. LEARNING POINTS: Hypoglycaemia is defined by Whipple's triad and can be provoked by fasting or mixed-meal tests.Although uncommon, insulinomas can present with post-prandial hypoglycaemia.In hypoglycaemia following gastrointestinal surgery (i.e. bariatric surgery or less commonly Nissen fundoplication) dumping syndrome or non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) should be considered.Improved imaging techniques including MRI, endoscopic ultrasound and functional nuclear medicine scans aid localisation of insulinomas.Despite advances in imaging and surgical techniques, accurate resection of insulinomas remains challenging.

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.

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.

The management of metastatic radioiodine-refractory differentiated thyroid cancer requires an integrated approach including both directed and systemic therapies.

SUMMARY: A 58-year-old man with metastatic radioiodine-refractory differentiated thyroid cancer (DTC) presented with left thigh and right flank numbness. He had known progressive and widespread bony metastases, for which he received palliative radiotherapy, and multiple bilateral asymptomatic pulmonary metastases. CT scan and MRI of the spine revealed metastases at right T10-L1 vertebrae with extension into the central canal and epidural disease at T10 and T11 causing cord displacement and canal stenosis but retention of spinal cord signal. Spinal surgery was followed by palliative radiotherapy resulting in symptom resolution. Two months later, sorafenib received approval for use in Australia and was commenced and up-titrated with symptomatic management of mild adverse effects. Follow-up CT scan three months after commencement of sorafenib revealed regression of pulmonary metastases but no evident change in most bone metastases except for an advancing lesion eroding into the right acetabulum. The patient underwent a right total hip replacement, intra-lesional curettage and cementing. After six months of sorafenib therapy, CT scanning showed enlarging liver lesions with marked elevation of serum thyroglobulin. Lenvatinib was commenced and sorafenib was ceased. He now has stable disease with a falling thyroglobulin more than 5 years after metastatic radioiodine-refractory DTC was diagnosed. In DTC, 5% of distant metastases become radioiodine-refractory, resulting in a median overall survival of 2.5-3.5 years. Tyrosine kinase inhibitor (TKI) therapy has recently been demonstrated to increase progression-free survival in these patients but poses some unique management issues and is best used as part of an integrated approach with directed therapy. LEARNING POINTS: Directed therapies may have greater potential to control localised disease and related symptoms when compared to systemic therapies.Consider TKI therapy in progressive disease where benefits outweigh risks.Active surveillance and timely intervention are required for TKI-related adverse effects.There is a need for further research on the clinical application of TKI therapy in advanced DTC, including comparative efficacy, sequencing and identifying responders.

Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases.

Aspects of autoimmune thyroid disease updated in this review include: immunoglobulin G4 (IgG4)-related thyroid disease (Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, IgG4-related Hashimoto's thyroiditis, and Graves' disease with elevated IgG4 levels); recent epidemiological studies from China and Denmark indicating that excess iodine increases the incidence of Hashimoto's thyroiditis and hypothyroidism; immunomodulatory agents (ipilimumab, pembrolizumab, nivolumab) activate immune response by inhibiting T-cell surface receptors which down-regulate immune response, i.e., cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways; alemtuzumab is a humanised monoclonal antibody to CD52 which causes immune depletion and thyroid autoimmune disease especially Graves' hyperthyroidism; small molecule ligand (SML) agonists which activate receptors, SML neutral antagonists, which inhibit receptor activation by agonists, and SML inverse agonists which inhibit receptor activation by agonists and inhibit constitutive agonist independent signaling have been identified. SML antagonism of thyroid-stimulating hormone-receptor stimulatory antibody could treat Graves' hyperthyroidism and Graves' ophthalmopathy; and thyroxine treatment of subclinical hypothyroidism can produce iatrogenic subclinical hyperthyroidism with the risk of atrial fibrillation and osteoporosis. The increased risk of harm from subclinical hyperthyroidism may be stronger than the potential benefit from treatment of subclinical hypothyroidism.

Multifocality in Sporadic Medullary Thyroid Carcinoma: An International Multicenter Study.

BACKGROUND: Current surgical standard of care in sporadic medullary thyroid carcinoma (sMTC) consists of a minimum of total thyroidectomy with central neck dissection. Some have suggested thyroid lobectomy with isthmusectomy and central neck dissection for patients with sMTC, given their lower frequency of bilateral disease, although this topic has not been thoroughly studied. This study assessed the prevalence of multifocality in sMTC via a large international multi-institutional retrospective review to quantify this prevalence, including the impact of geography, to assess more accurately the risks associated with alternative surgical approaches. METHODS: A retrospective chart review of sMTC patients from 11 institutions over 29 years (1983-2011) was undertaken. Data regarding focality, extent of disease, RET germline analysis plus family and clinical history for multiple endocrine neoplasia type 2 (MEN2), and demographic data were collected and analyzed. RESULTS: Patients from four continents and seven countries were included in the sample. Data for 313 patients with documented sMTC were collected. Of these, 81.2% were confirmed with negative RET germline testing, while the remaining 18.8% demonstrated a negative family history and no manifestations of MEN2 syndromes other than MTC. Bilateral disease was identified in 17/306 (5.6%) patients, while multifocal disease was noted in 50/312 (16.0%) sMTC patients. When only accounting for germline negative patients, these rates were not significantly different (5.6% and 17%, respectively). Among them, when disease was unifocal in the ipsilateral lobe and isthmus, bilateral disease was present in 6/212 (2.8%) cases. When disease was multifocal in the ipsilateral lobe or isthmus, then bilateral disease was present in 8/37 (21.6%) cases (p < 0.001). No geographic differences in focality were identified. CONCLUSIONS: The 5.6% prevalence of bilateral foci in sMTC suggests that total thyroidectomy should remain the standard of care for initial surgery, as less complete thyroid surgery may fail to address fully the primary site of disease. Whether ipsilateral tumor focality should be an independent factor determining the need for completion thyroidectomy when sMTC is diagnosed after hemithyroidectomy remains to be determined.