Nephrogenic diabetes insipidus partially responsive to oral desmopressin in a subject with lithium-induced multiple endocrinopathy.

Lithium (Li) may cause multiple endocrinopathies, including hypercalcaemia, thyroid dysfunction and nephrogenic diabetes insipidus (NDI), but rarely in the same patient. The management of NDI remains a challenge. We report on a patient on long-term Li who had simultaneous NDI (paired serum and urine samples had abnormal osmolalities, typical of NDI, and treatment with parenteral desmopressin failed to affect urinary volume and serum osmolality), 'destructive' thyroiditis (hyperthyroidism, absent radioiodine uptake and absent thyrotrophin receptor antibodies) and primary hyperparathyroidism (compatible biochemistry, urine calcium excluding 'set point' anomalies and hypocalciuric hypercalcaemia, and normal parathyroid imaging). The thyroiditis resolved spontaneously and hypercalcaemia responded to reduction of Li dose. The NDI was unresponsive to amiloride, thiazides and ibuprofen in combination. However, urine output was reduced by 50% when a high dose of oral desmopressin was given. We conclude that Li-induced multiple endocrinopathy remains rare and, although NDI is difficult to manage, high dose oral desmopressin should be tried when other medications fail.

Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema.

CONTEXT: Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies. PATIENT: An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. MEASUREMENTS AND RESULTS: Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. CONCLUSIONS: The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function.

Targeted thyroid testing in acute illness: achieving success through audit.

Thyroid tests are done in acutely ill patients who often have confusing transient thyroid abnormalities, despite a lack of clarity about intervention and cost benefit. A retrospective analysis of patients admitted to the Medical Assessment Unit (MAU) was undertaken in 2004 to assess the frequency and utility, pattern of abnormalities and cost of thyroid testing. Guidelines were issued and the audit was repeated in 2008. 53.8% of 1593 subjects were offered thyroid tests in 2004 with a significant reduction to 21.7% of 1176 in 2008 (p<0.001). Free T4 or TSH was outside the reference range in 11.2% (2004) and 7.5% (2008) (p=0.10) and low TSH (52.7% in 2004 and 64.3% in 2008) was commonly combined with normal free T4. Appropriate indications for testing were documented in 43.9 vs 73.7% of patients with abnormal thyroid results (p=0.004) and in 14.3 vs 16% (2004 vs 2008) of a random sample of subjects with normal thyroid results, respectively (p=0.77). Documentation of intervention (25.5. vs 92.9%; p=0.001) and follow-up (45.5 vs 85.7%; p=0.001) had also improved significantly in 2008. We have demonstrated a significant reduction in thyroid testing in acutely ill patients after audit and the issue of guidelines. We currently recommend thyroid tests only in those with previous thyroid disease, the presence of clinical features and risk factors for thyroid disease, the use of relevant drugs, and unexplained tachydysrhythmias. The difficulties in interpreting results, the lack of clarity about intervention and follow up and possible cost savings would argue against an unrestricted policy.

Managing thymic enlargement in Graves' disease.

Thymic enlargement (TE) in Graves' disease (GD) is often diagnosed incidentally when chest imaging is done for unrelated reasons. This is becoming more common as the frequency of chest imaging increases. There are currently no clear guidelines for managing TE in GD. Subject 1 is a 36-year-old female who presented with weight loss, increased thirst and passage of urine and postural symptoms. Investigations confirmed GD, non-PTH-dependent hypercalcaemia and Addison's disease (AD). CT scans to exclude underlying malignancy showed TE but normal viscera. A diagnosis of hypercalcaemia due to GD and AD was made. Subject 2, a 52-year-old female, was investigated for recurrent chest infections, haemoptysis and weight loss. CT thorax to exclude chest malignancy, showed TE. Planned thoracotomy was postponed when investigations confirmed GD. Subject 3 is a 47-year-old female who presented with breathlessness, chest pain and shakiness. Investigations confirmed T3 toxicosis due to GD. A CT pulmonary angiogram to exclude pulmonary embolism showed TE. The CT appearances in all three subjects were consistent with benign TE. These subjects were given appropriate endocrine treatment only (without biopsy or thymectomy) as CT appearances showed the following appearances of benign TE - arrowhead shape, straight regular margins, absence of calcification and cyst formation and radiodensity equal to surrounding muscle. Furthermore, interval scans confirmed thymic regression of over 60% in 6 months after endocrine control. In subjects with CT appearances consistent with benign TE, a conservative policy with interval CT scans at 6 months after endocrine control will prevent inappropriate surgical intervention. Learning points: Chest imaging is common in modern clinical practice and incidental anterior mediastinal abnormalities are therefore diagnosed frequently. Thymic enlargement (TE) associated with Graves' disease (GD) is occasionally seen in view of the above. There is no validated strategy to manage TE in GD at present. However, CT (or MRI) scan features of the thymus may help characterise benign TE, and such subjects do not require thymic biopsy or surgery at presentation. In them, an expectant 'wait and see' policy is recommended with GD treatment only, as the thymus will show significant regression 6 months after endocrine control.

The role of thyrotrophin receptor antibody assays in graves' disease.

Thyrotrophin receptor antibodies (TRAb) exist as stimulating or blocking antibodies in the serum (neutral TRAb have been identified recently). The clinical features of GD occur when stimulating TRAb predominate. But the relationship of TRAb to clinical phenotype and outcome is not clear when current assay methods are used. Therefore no consensus exists about its utility in diagnosing and predicting outcome in GD. The most commonly used TRAb assays, measure thyroid binding inhibiting immunoglobulins (TBII or "receptor assays") and don't differentiate between stimulating and blocking antibodies. However, the more expensive, technically demanding and less freely available "biological assays" differentiate between them by their ability to stimulate cyclic AMP or failure to do so. Failure to differentiate between TRAb types and its heterogeneous molecular and functional properties has limited TBII use to GD diagnosis and differentiating from other forms of thyrotoxicosis. The current 2nd-3rd generation receptor assays are highly sensitive and specific when used for this purpose. TRAb assays should also be done in appropriate pregnant women. Current data do not support its use in outcome prediction as there is a significant variability of assay methodology, population characteristics and study design in published data, resulting in a lack of consensus.

Glucose intolerance and diabetes mellitus in endocrine disorders - two case reports and a review.

Impaired glucose tolerance and diabetes mellitus are a manifestation of several well recognised endocrine disorders. Hyperglycaemia subsides upon removal of the underlying cause in these conditions - usually a hormone secreting tumour. We describe two subjects who were cured of their poorly controlled diabetes mellitus following surgical removal of a phaeochromocytoma and a cortisol secreting adrenal adenoma and review the mechanisms underlying glucose intolerance in endocrine disorders. The reported incidence of diabetes is variable in these conditions and may range between 2-95%. The severity is also variable as some affected individuals have only minor glucose intolerance while others have frank symptomatic diabetes mellitus which forms a major manifestation of their illness. The mechanisms causing hyperglycaemia are (a) insulin resistance, (b) increased hepatic glucose production and output, (c) decreased insulin production and release and (d) increased intestinal glucose absorption. Multiple intermediate mechanisms which include electrolyte perturbations and hormone receptor and post receptor mediated effects are responsible for these abnormalities. An understanding of these mechanisms and diagnostic strategies is important as these may be used to advantage in managing these patients. We describe some of these in greater detail below.