Duncan J Topliss

The fundamental defect in NIDDM has not been established. Insulin resistance, an impairment of B-cell function, and overproduction of glucose by the liver have all been implicated. Genetic analysis of the strongly inherited form of NIDDM maturity-onset diabetes of the young has recently identified glucokinase deficiency as a cause,' with a variety of mutations that impair enzyme function resulting in glucose-blindness of the pancreatic B cell, and hepatic insulin resistance.

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.

Hyperthyroidism and atrial fibrillation (AF) are both common in the Australian community, and often encountered in general practice. 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. 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.

1Department of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 2Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland 3Clinical Trials Unit, University of Bern, Bern, Switzerland 4Adare Pharmaceuticals, Lawrenceville, NJ, USA 5Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland 6Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Email: i-hirano@northwestern.edu

Summary 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 ...

The most common cause of hyperthyroidism in Australia is Graves disease, caused by a defect in immunoregulation in genetically predisposed individuals, leading to production of thyroid-stimulating antibodies. Each of the three modalities of therapy for Graves disease--thionamide drugs, subtotal or total thyroidectomy, and radioactive iodine ablation--can render the patient euthyroid, but all have potential adverse effects and may not eliminate recurrences. Hypothyroidism occurs in about 5% of the adult population; most present with "subclinical" hypothyroidism (mild thyroid failure), characterised by raised levels of serum thyroid stimulating hormone (TSH) but normal free thyroxine (T(4)). The most common cause of hypothyroidism in Australia is autoimmune chronic lymphocytic thyroiditis, characterised by raised circulating levels of thyroid peroxidase antibody. Symptoms and signs of hypothyroidism are often mild or subtle and, when there is clinical suspicion, thyroid func...

SummaryA 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 ace...

OBJECTIVE: To examine patterns of use and clinical outcomes of total parenteral nutrition (TPN). DESIGN: A prospective six-month audit (December 1992-June 1993). PATIENTS AND SETTING: All inpatients administered TPN at a metropolitan teaching hospital during ...

5518 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In a phase II study of lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib at a starting dose of 24 mg oral once daily in 28-day cycles. Serum was collected at baseline (BL), on day 8 and on day 36 and concentrations of 47 CAFs were measured using multiplex bead arrays and enzyme-linked immunosorbent assay (ELISA). 33 genes (443 mutations) were examined in archival tumor tissues (n=25). Association of baseline CAF, changes in CAF levels upon treatment and gene mutation status with treatment outcomes was investigated. Results: Combination of low baseline VEGF and ANG-2 (p=0.02 and HR=0.386) correlated with longer PFS. Both baseline and changes in CAF levels demonstrated an association with gene mutation status. High baseline levels of VEGF were observed in pts with wild type R...

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. Multi-targeted 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 utilised 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 financi...

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. We 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 more accurately assess risks associated with alternative surgical approaches. A retrospective chart review of sMTC patients from 11 institutions over 29 years (1983 to 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. Patients from 4 continents and 7 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%) of patients, while multifocal disease was noted in 50/312 (16.0%) of 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%) of cases. When disease was multifocal in the ipsilateral lobe or isthmus, then bilateral disease was present in 8/37 (21.6%) of cases (p<0.001 by Fisher's Exact Test). No geographic differences in focality were identified. 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 fully address 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.

To facilitate studies of thyroid hormone (T3) binding to cytoplasmic proteins, we prepared monkey (M. fascicularis) liver cytosol (100,000g supernatant) and examined T3 binding using hydroxyapatite (HAP) separation. HAP adsorbs cytoplasmic and nuclear binding sites but not serum T4 binding proteins. Cytosol was incubated with [125I]T3 for 30 min at 4 degrees C and separated by adding an equal volume of HAP (15 g/100 mL). After a further incubation of 10 min, the HAP pellet was washed three times in buffer containing Triton X-100, 0.5%. With this method, a single class of T3 binding site was observed with Kd 15.8 +/- 1.2 nM, concentration 0.62 +/- 0.17 pmol/mg protein (n = 3, mean +/- SD). We used this assay to assess potential drug inhibitors of cytoplasmic binding and to evaluate the proposal that glutathione-S-transferases (GST) and cytoplasmic T3 binding proteins are identical. Displacement of [125I]T3 by unlabeled iodothyronines relative to T3 (100) was T4 58, Triac 7, rT3 7, Tetrac less than or equal to 1. This hierarchy indicates that this binding site is distinct from nuclear or serum binding sites. T3 binding was displaceable by nonsteroidal anti-inflammatory drugs (NSAID) and nonbile acid cholephils (NBAC). Half-inhibitory concentrations (microM, mean +/- SD, n greater than or equal to 3) were diclofenac 4.9 +/- 1.3, mefenamic acid 13.6 +/- 0.6, bromosulphthalein 45 +/- 3, iopanoic acid approximately 200. Amiodarone and furosemide were inactive up to 100 microM. No displacement was observed with cortisol or the bile acid taurocholate, up to 100 microM. Dithiothreitol, 5 mM, did not change binding affinity or capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality. Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports. The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p…

The aim of this cross-sectional study was to determine the prevalence and identify determinants of reduced bone mineral density (BMD) in adults with cystic fibrosis (CF). Adults (88) with CF (mean¡SD age 29.9¡7.7 yrs; forced expiratory volume in one second (FEV1) 58.2¡21.5% of the predicted value) were studied. BMD at the lumbar spine (LS) and femoral neck (FN) and body

Summary The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur following traumatic brain injury (TBI), but is usually transient. There are very few case reports describing chronic SIADH and all resolved within 12 months, except for one case complicated by meningo-encephalitis. Persistent symptomatic hyponatremia due to chronic SIADH was present for 4 years following a TBI in a previously well 32-year-old man. Hyponatremia consistent with SIADH initially occurred in the immediate period following a high-speed motorbike accident in 2010. There were associated complications of post-traumatic amnesia and mild cognitive deficits. Normalization of serum sodium was achieved initially with fluid restriction. However, this was not sustained and he subsequently required a permanent 1.2 l restriction to maintain near normal sodium levels. Multiple episodes of acute symptomatic hyponatremia requiring hospitalization occurred over the following years when he repeatedly st...

A 50-year-old woman with no history of thrombosis or recurrent abortions developed pulmonary thromboembolism and bilateral hemorrhagic adrenal infarction with adrenal failure after hysterectomy for uterine fibroids. Anticardiolipin antibodies (aCL) were detected in high titer and have persisted. She remains well, without further thromboses, taking steroid replacement and warfarin anticoagulation. The initial presentation of aCL related disease can be as thrombotic postoperative complications in middle-age.

In order to establish the significance of subnormal, detectable TSH values in the range 0.05-0.3 mU/L by sensitive immunoradiometric assay, we assessed 3150 consecutive tests of thyroid function in which TSH was measured on 1400. Sixty TSH values (4.3%) fell in this range and in 80% of these the result was confirmed on repeat assay. Conditions associated with subnormal detectable TSH values were treated hyperthyroidism (21), nonthyroidal illness (17), euthyroid multinodular goitre (10), T4 therapy for primary hypothyroidism (7), and pituitary disease (5). At follow-up 2-15 months later, a second sample showed that TSH remained in this range in only 9 of 41 patients (22%). These findings show a frequency of TSH values intermediate between normality and the suppressed values of hyperthyroidism sufficient to compromise the value of sensitive TSH measurement as the single initial test of thyroid function. While TSH values in the subnormal detectable range rule out hyperthyroidism, such results may merit follow-up in goitrous patients, in whom such a finding can precede overt hyperthyroidism.

To examine the usefulness of a single measurement of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE) in routine clinical practice. All 127 patients with SLE currently followed by our rheumatology unit had an aCL measurement on routine clinic review. Their charts were then reviewed for specific disease manifestations. Basic statistical correlations of the aCL result and the specific disease manifestations were performed, and the clinical utility of the aCL test assessed using Bayesian analysis. aCL was positive (> 2 SD) in 24% and was associated with recurrent fetal loss, thrombosis, cerebrovascular disease, livedo reticularis and digital infarcts. Bayesian analysis showed that a single positive aCL test increased the relative and absolute risk of all the above complications. The criterion of aCL positivity as > 15 units (2 SD) was associated with the highest relative risk. A single positive aCL test in routine management of SLE is a useful predictor of important clinical events.

The most common cause of hyperthyroidism in Australia is Graves disease, caused by a defect in immunoregulation in genetically predisposed individuals, leading to production of thyroid-stimulating antibodies. Each of the three modalities of therapy for Graves disease--thionamide drugs, subtotal or total thyroidectomy, and radioactive iodine ablation--can render the patient euthyroid, but all have potential adverse effects and may not eliminate recurrences. Hypothyroidism occurs in about 5% of the adult population; most present with "subclinical" hypothyroidism (mild thyroid failure), characterised by raised levels of serum thyroid stimulating hormone (TSH) but normal free thyroxine (T(4)). The most common cause of hypothyroidism in Australia is autoimmune chronic lymphocytic thyroiditis, characterised by raised circulating levels of thyroid peroxidase antibody. Symptoms and signs of hypothyroidism are often mild or subtle and, when there is clinical suspicion, thyroid func...

Radioactive iodine (RAI)-induced changes in the levels of antibodies to the thyroid-stimulating hormone (TSH) receptor (TRAb) in patients undergoing treatment for autoimmune thyroid disease have been well documented. Previous studies have reported effects on the overall level of the antibodies present, TSH-binding inhibitory immunoglobulins (TBII), without detailed studies of specific effects on the levels of thyroid-stimulating (TSAb) or thyroid-blocking antibodies (TBAb). More detailed studies have been reported only in individual cases. In this study, the values of TSAb, TBAb, and TBII were measured longitudinally in 33 patients (27 females and 6 males) who received RAI. The bioassays for TSAb and TBAb were performed in JPO9 cells. Following RAI, there were significant and immediate effects on the values of TBII in 70% of patients. TBII levels fell in 7 patients (20%) (Group 1), rose in 16 patients (48%) (Group 2) or remained unchanged but elevated in 10 patients (32%) (Group 3)....

The epidemic of chronic upper limb pain is the most important and controversial issue in industrial rheumatology in Australia today. Two hundred and twenty-nine consecutive patients referred with chronic upper limb pain which had been labelled "repetitive strain injury" or "overuse syndrome" were assessed according to a protocol designed to give insight into the questions: Is the pain genuine or falsely reported, i.e., malingering? If genuine is it due to a physical injury, a pain syndrome, or a mixture of both? Twenty-nine patients fulfilled criteria for specific rheumatological diagnoses (fibrositis 15, rotator cuff syndrome 3, rheumatoid arthritis 3, cervical referred pain 3, lateral epicondylitis 2, de Quervain's tenosynovitis 1, carpal tunnel syndrome 1, and psoriatic monoarthritis 1). In the remaining 200 (mean age 37 years, range 19-58, 91.5% female) many different pain patterns and nonspecific associated symptoms were recorded. Eighty-nine percent had...