Robert Murray

The effects of pituitary and thyroid disorders on haemostasis: potential clinical implications

Disturbances of coagulation and fibrinolysis are usually multifactorial and growing evidence suggests that endocrinopathies modulate the haemostatic balance. The thrombotic alterations in endocrine disorders range from mild laboratory clotting abnormalities with little clinical significance to serious thrombotic and bleeding disorders directly related to hormonal disturbances. This literature review focuses on presenting the current data on the effects of thyroid and pituitary disorders on various parameters of the haemostatic system. With the exception of overt hypothyroidism which appears to cause a bleeding tendency, the rest of the endocrinopathies discussed in this review (subclinical hypothyroidism, hyperthyroidism, endogenous hypercortisolaemia, growth hormone deficiency, acromegaly, prolactinoma/hyperprolactinaemia and hypogonadotrophic hypogonadism) are associated with a hypercoagulable and hypofibrinolytic state, increasing the overall cardiovascular risk and thromboembolic potential in these patients. In most studies, the haemostatic abnormalities seen in endocrine disorders are usually reversible with successful treatment of the underlying condition and biochemical disease remission. High‐quality studies on larger patient cohorts are needed to produce robust evidence on the effects of endocrine disorders and their therapeutic interventions on coagulation and fibrinolysis, as well as on the long‐term mortality and morbidity outcomes in association with endocrine‐related haemostatic imbalance. Given the rarity of some of the endocrine disorders, multicentre studies are required to achieve this target.

Late-onset X-linked adrenal hypoplasia (DAX-1, NR0B1): two new adult-onset cases from a single center

PurposeDAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo–pituitary–gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood.MethodsWe describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital.ResultsCase 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775Tu2009>u2009C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836Cu2009>u2009T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members.ConclusionsWe describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear.

Management of glucocorticoids following adrenalectomy for ACTH-independent Cushing's syndrome

Although potentially curative, unilateral adrenalectomy for ACTH-independent cortisol excess frequently results in transient, or occasionally permanent, post-operative adrenal insufficiency (AI), resulting from suppression of the hypothalamo-pituitary axis as well as atrophy of the contralateral adrenal gland. Adrenal crises and intercurrent infections are a significant contributor to morbidity and mortality in patients with AI, irrespective of aetiology1-3 . This remains true, even in populations who are on replacement glucocorticoids and educated as to increasing their steroid dosage with intercurrent illness and stresses4 . This article is protected by copyright. All rights reserved.

Potential mechanism for increased risk of premature vascular disease in long-term survivors of primary brain tumours with established hormone deficits

Abstract Background Long-term survivors of childhood-onset brain tumours have increased mortality rates, even after excluding deaths related to recurrence or regression of the original tumour. In particular, there is an increased risk of premature vascular disease by mechanisms that remain unclear. We tested our hypothesis that a thrombotic fibrin network profile is one mechanism for the increased vascular risk in this population. Methods We undertook a cross-sectional study in 33 patients (19 men, mean age 31·5 years [SD 14·2]) with previous history of primary brain tumours of either childhood or adulthood onset and 33 age-matched and sex-matched healthy controls. We performed clot structure analysis using a validated turbidimetric assay and also assessed plasma concentrations of thrombotic and inflammatory vascular markers including fibrinogen, C-reactive protein (CRP), and complement C3. The mean time from brain tumour diagnosis to the time of the study was 8·9 years (SD 6·2). Findings All patients had cranial radiotherapy, whereas 25 (76%) and 13 (39%) had additional surgery and chemotherapy, respectively. 31 patients (94%) had growth hormone deficiency, five (15%) had deficiences in luteinising hormone and follicle-stimulating hormone, four (12%) in adrenocorticotropic hormone, and two (6%) in thyroid-stimulating hormone. Patients had raised clot maximum absorbance (a measure of clot density) compared with controls (mean 0·412 arbritary units [SD 0·10] vs 0·277 [0·09], p vs 2720 [636], p vs 906 [704], p vs 0·78 [1·08], p=0·006) with similar findings for C3 (0·75 mg/mL [0·13] vs 0·67 [0·13], p=0·027). Interpretation We demonstrate, for the first time to our knowledge, that survivors of brain tumours with hypopituitarism display a thrombotic fibrin network profile, providing one mechanism for the increased vascular risk in this population. These changes are not related to altered fibrinogen concentrations suggesting that other plasma proteins or qualitative changes in the proteins might contribute to the observed differences. Further longitudinal studies are required to clarify whether optimisation of the hormonal profile results in amelioration of the thrombotic environment in this population. Funding Pfizer (investigator-initiated research grant).

A rare germline Leu63Pro missense mutation in CDC73 resulting in familial primary hyperparathyroidism with variable phenotype

Primary hyperparathyroidism (PHPT) is a common endocrine disorder. However, a familial hyperparathyroid syndrome is diagnosed in less than five percent of cases. We present two related cases of CDC73-related familial hyperparathyroidism due to a rarely described germline Leu63Pro missense mutation in CDC73 exon 2. CDC73-related familial hyperparathyroidism encompasses a spectrum of parathyroid disorders including the following phenotypes: • hyperparathyroidism-jaw tumour syndrome (HPT-JT) • Parathyroid carcinoma • Familial isolated hyperparathyroidism (FIHP)

THE PLACE OF OCCUPATIONAL MEDICINE IN COMMUNITY HEALTH

Abstract The Ministry of Health green-paper on the administration of the National Health Service, and several other reports which have been published in the past few years, provide an opportunity for discussion on the future of occupational health services in Britain. Earlier discussion has been bedevilled by a confusion between occupational medicine and occupational health services , and by differing concepts of the scope of both. The first should be defined as the study of health at work, the second as the application of knowledge gained. Responsibility for occupational health services should be transferred to the Ministry of Health, and they should be viewed in the whole context of community medicine; a publicly provided occupational health service should be provided under the proposed area health boards; and the work-load of general practitioner and hospital casualty departments could be lightened by an extension of the sort of work which such a service might be allowed to undertake.