Predicting dysglycaemia in patients under investigation for acute coronary syndrome.

AIMS: To examine methods for the identification of previously undetected dysglycaemia [diabetes and impaired glucose tolerance (IGT)] in patients investigated for possible acute coronary syndrome. Specifically, we wished to examine whether the recently advocated use of glycosylated haemoglobin (HbA1c) would enhance detection rates for diabetes in these patients. METHODS: Patients (n = 200) investigated for possible acute coronary syndrome and not previously known to have diabetes were recruited and anthropometric data collected. Random plasma glucose concentrations followed by oral glucose tolerance tests, HbA1c, fasting lipids, high sensitivity C-reactive protein and homeostatic modular assessment-insulin resistance were obtained during admission. Following discharge, the fasting plasma glucose (FPG) was repeated to determine the importance of sequential fasting levels. The accuracy of individual tests, combinations and sequential testing was assessed using receiver operating characteristic curves. A predictive index (PI) was generated using stepwise logistic regression models. RESULTS: The prevalence of diabetes and IGT were 21 and 32%, respectively. FPG >6.0 mmol/l and HbA1c ≥ 6.0% had specificities of 94.9% and 93.6% but sensitivities of only 31.7 and 39.0%, respectively. Combination and sequential testing provided little additional benefit. Use of a PI comprising FPG, HbA1c and age provided the best overall performance (75.6% sensitivity, 77.1% specificity, negative predictive value 92.4%). CONCLUSION: Our data confirm the high prevalence of dysglycaemia in this cohort. The commonly advocated screening tools have significant limitations if used in isolation, combination or sequentially. Our approach using a PI offers improved performance partly as it uses continuous data rather than arbitrary cut-off values.

Gestational diabetes screening and glycaemic management; national survey on behalf of the Association of British Clinical Diabetologists.

BACKGROUND: There is no UK consensus for screening methodology, diagnosis and management of gestational diabetes mellitus (GDM). AIM: To evaluate routine practice for GDM management across the UK. METHODS: Questionnaires were sent to all members of the Association of British Clinical Diabetologists. They were asked to describe how patients were screened for GDM, the diagnostic criteria and subsequent management and clinical targets. Centres that did not respond were followed up by personal communication. Variability trends within regions were assessed. RESULTS: The response rate averaged 46% nationally (35-67%). Most (85%) units hold a joint clinic, regardless of the size. Most (82%) centres routinely screen for GDM; half universally and half screening high risk pregnancies only. Screening tests, cut-off values, timings and subsequent action vary widely. The first screening test to be used varies, with 40% using glycosuria, followed by random plasma glucose (RPG)(28%), high risk features (11%) then FPG in 6%. Cut-off values for both random and plasma glucose as screening methods also vary. The 75 g oral glucose tolerance test (OGTT) is the most likely confirmatory test to be used if initial screening is positive; however, clinicians rely on different cut-off values and timing. Most (95%) centres routinely assess foetal growth. Postpartum screening is undertaken by 90%, using a 75 g OGTT (93%). Most (90%) centres counsel patients about their high risk for further GDM and type 2 diabetes mellitus. Variability trends in any of the responses could not be detected between different regions in the UK. CONCLUSION: Standards for GDM screening and management vary significantly across the UK. Although most centres utilize the 75 g OGTT to confirm the diagnosis, there is no consistency in its interpretation. This survey confirms the urgent need for consensus guideline development.

Pneumococcal necrotizing fasciitis in a patient with Type 2 diabetes.

Necrotizing fasciitis (NF) is a rare and often fatal soft-tissue infection involving the superficial fascial layers of the extremities, abdomen or perineum. Progression to septic shock can occur very rapidly with its associated high morbidity and mortality. NF is usually caused by beta haemolytic streptococci; less often a poly-microbial isolate is the cause. It typically occurs in patients with some degree of immune dysfunction. We present a case of severe pneumococcal necrotizing fasciitis in an obese patient with Type 2 diabetes. There was no history of trauma or evidence of diabetes-related complications. The initial presentation was with features of septic arthritis of the left knee, which subsequently progressed to NF. Differentiation from cellulitis is often difficult in the early stages. Invasive pneumococcal infections are extremely rare, with only a few reported in the literature. Moreover, our case highlights the need to consider other differential diagnoses (and to look out for complications) in patients with diabetes, especially if there is little clinical response to the initial treatment.

The TSH response to domperidone reflects the biological activity of prolactin in macroprolactinaemia and hyperprolactinaemia.

OBJECTIVE: To test the hypothesis that patients with hyperprolactinaemia due to biologically inactive macroprolactin will not show the characteristically increased dopaminergic inhibition of TSH release seen in patients with microprolactinomas secreting biologically active monomeric PRL. DESIGN: Comparison of the TSH and PRL responses to dopamine antagonism with domperidone (10 mg i.v.) in patients with hyperprolactinaemia due to macroprolactinaemia or microprolactinomas. PATIENTS: Twenty-two patients referred for the investigation of their hyperprolactinaemia were studied: 11 patients with macroprolactinaemia and 11 patients with hyperprolactinaemia due to microprolactinoma. MEASUREMENTS: TSH and PRL levels were measured at baseline and 30 min following domperidone in both groups. RESULTS: Patients with macroprolactinaemia showed normal TSH and PRL responses to dopamine antagonism whereas patients with microprolactinomas showed exaggerated TSH responses and reduced PRL responses. Although there was considerable overlap between the PRL responses in the two groups, there was very clear separation between the PRL/TSH response ratios (normal > 1.0) of 4.0 +/- 1.8 for the macroprolactinaemia group and 0.4 +/- 0.2 for the microprolactinoma group (P < 0.0001). CONCLUSIONS: These data support the hypothesis that elevated circulating levels of macroprolactin, as opposed to biologically active monomeric PRL, do not exert increased positive feedback on the hypothalamic dopaminergic inhibition of TSH release.

Screening for gestational diabetes; past, present and future.

Gestational diabetes is carbohydrate intolerance, with onset or first recognition of hyperglycaemia during pregnancy. Several studies have suggested that gestational hyperglycaemia is associated with adverse maternal and fetal outcomes, promoting the case for screening. Conversely, others argue that screening for gestational diabetes may colour the clinical judgement, influencing further management, e.g. more 'unjustified' caesarean sections. Additionally, the lack of definitive data either on a clear-cut glycaemic threshold for the development of adverse outcomes or on the impact of intervention is emphasized by opponents of screening. This review attempts to evaluate the available data on screening for gestational diabetes. Oral glucose tolerance test is promoted on the basis that the diabetogenic stress of pregnancy is encountered during late gestation and is best recognized in the fed state. There are different tests, including the 1 h/50-g, 2 h/75-g and 3 h/100-g tests, with practical limitations, including the time and cost involved and the unpleasant supra-physiological glucose load that is unrelated to body weight, and issues of reproducibility and sensitivity/specificity profiles. Despite its convenience, the poor sensitivity of random glucose has precluded its routine use for screening. Fasting glucose appears to be promising but further testing is required to ensure satisfactory sensitivity/specificity in different populations. Despite its limitations, the oral glucose tolerance test has become established as the 'most acceptable' diagnostic test for gestational diabetes. More convenient methods, e.g. fasting or random or post-load glucose, have to be validated therefore against the oral glucose tolerance test to gain acceptance for routine screening.

Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission.

OBJECTIVE: Transsphenoidal selective adenomectomy (TSA) is widely accepted as the treatment of choice for Cushing's disease but not all patients are cured by this procedure. The success of surgery depends on the skill and experience of the surgeon but the criteria used to define remission are highly variable. We have analysed the outcome following surgery in our centre using the stringent requirement of a postoperative serum cortisol of < 50 nmol/l as our definition of remission and assessed whether changes in surgical policy, including a greater emphasis on selective procedures and the move in recent years to a single surgeon undertaking all pituitary surgery, have improved complication and remission rates. PATIENTS AND METHODS: The case notes, histology and pituitary imaging of 54 consecutive patients (42 females, mean age 41 years) with pituitary-dependent Cushing's syndrome who had undergone transsphenoidal surgery between January 1980 and November 2000 were reviewed. Follow-up was for a median of 6 years (range 6 months to 21 years). RESULTS: One patient died within 1 week of surgery (1.9%) and major morbidity occurred in eight patients (15%). Clinical and biochemical remission was achieved in 41 patients (77%) with only two recurrences (5%) to date. Success was related to tumour size with 37 (86%) of 43 intrasellar lesions successfully resected compared with only four (40%) of 10 extrasellar adenomas. Twenty-four (59%) of those in remission developed partial or complete hypopituitarism compared with four (33%) of those not in remission. The extent of surgical exploration predicted the development of hypopituitarism (88% total hypophysectomy, 33% hemihypophysectomy, 14% selective adenomectomy) but not remission (75% total hypophysectomy, 87% hemihypophysectomy, 71% selective adenomectomy). Among complications, an excess of venous thromboembolic disease was noted, with three patients (6%) developing deep venous thrombosis or pulmonary embolism postoperatively. Comparison of the data for individual surgeons revealed an improvement in outcome over time, with 100% remission of microadenomas, 29% hypopituitarism and 12% complications following the move to a single surgeon undertaking all pituitary surgery. CONCLUSION: Transsphenoidal surgery is a safe and effective treatment for Cushing's disease and our results compare favourably with those from published series, the majority of which comprise relatively small numbers. The presence of an intrasellar lesion and postoperative serum cortisol < 50 nmol/l are good predictors of remission in the long term but historically in our centre this can only be achieved in a significant number of patients at the expense of some degree of hypopituitarism. However, the surgical outcome for Cushing's disease, including a reduced frequency of hypopituitarism, can be improved if patients are operated on by a single pituitary surgeon, using selective adenomectomy as the preferred surgical approach wherever possible.

Pituitary apoplexy following metastasis of bronchogenic adenocarcinoma to a prolactinoma.

A 42-year-old house wife presented with worsening headaches over 6 months in the absence of visual symptoms or symptoms suggestive of focal neurology. She was a life-long smoker. Systems review was unremarkable apart from secondary amenorrhoea and galactorrhoea of 6 months duration. Her serum prolactin was found to be 620 mU/l (60-400), FT4 12.6 nmol/l (9.8-23.1), TSH 1.38 mU/l (0.35-5.5), oestradiol < 73 pmol/l, LH and FSH of 4.4 and 12.6 mIU/l, respectively. She was on bromocriptine. A presumptive diagnosis of pneumonia, based on pyrexia and CXR findings, was made and she was started on IV antibiotics. Two days later she developed meningism and deterioration of conscious level. (Lumbar puncture results: no organisms, 312 neutrophils and 164 lymphocytes). CT scan revealed a 2.5-cm pituitary adenoma, with suprasellar extension. A repeat hormonal profile revealed FSH 1.4, LH < 0.3 mU/l, oestradiol < 73 pmol/l, prolactin 488 mU/l (60-400), and low random cortisol at 29 nmol/l. T1-weighted MRI revealed a large pituitary mass with evidence of haemorrhage. The patient subsequently underwent a transsphenoidal exploration with resection of the pituitary lesion. Whilst awaiting the histopathology results, CT of chest revealed a 1. 5-cm diameter rounded well defined density in the right lower lobe associated with hilar, pre- and right para-tracheal lymphadenopathy. The histopathology of the pituitary lesion, obtained piecemeal, revealed fragments of fibrous tissue infiltrated by sheets of acidophilic prolactin-positive cells, in keeping with a prolactinoma. In addition, other fragments with blood clot included highly atypical epithelial cells with mitotic figures. These were negative for prolactin but showed HMFG-and CEA-positivity, excluding them from a pituitary lineage. Transbronchial biopsy revealed moderately differentiated adenocarcinoma, with evidence of lymphatic spread. The overall conclusion was of bronchogenic adenocarcinoma, metastasizing to a prolactinoma and complicated by apoplexy.

Effect of replacement doses of thyroxine on bone mineral density.

INTRODUCTION: Hyperthyroidism is associated with a reduction in bone mineral density (BMD). Suppressive doses of thyroxine (T4), inducing subclinical hyperthyroidism, have been reported by some investigators to reduce BMD. Little work has been done on replacement doses of T4. AIM: The aim was to investigate the effect of replacement doses of T4 on BMD. STUDY DESIGN: Cross-sectional study of hypothyroid patients on long-term T4 replacement doses, comparing those who had primary hypothyroidism with those who were previously hyperthyroid. PATIENTS: Fifty women on replacement doses of T4 for more than 5 years were recruited. Twenty-five were treated for primary (group 1) and 25 for radioiodine-induced hypothyroidism (group 2). They were well matched for age, menstrual status, smoking history, body mass index (BMI), dose and duration of T4 replacement as well as thyroid status. MEASUREMENTS: BMD was assessed by dual energy X-ray absorptiometry. Free T4 (FT4), FT3 as well as ultrasensitive TSH assays were used to assess thyroid status. RESULTS: The two groups showed no difference in BMD (g/cm2) of the lumbar spine (1.008 vs. 0.957, P = 0.25), femoral neck (0.745 vs. 0.735, P = 0.79) and total hip (0.878 vs. 0.837, P = 0.24). When the two groups were pooled, there was no significant difference between the patients and a reference population with femoral neck and total hip BMD expressed as a standard deviation (Z) score. However, the lumbar spine mean Z score was significantly greater than zero. For each site, there was a negative correlation of BMD with age in at least one group but, in general, BMI, FT4, FT3 and duration of T4 replacement did not correlate with BMD. T4 dose, however, had a consistent positive correlation with BMD in the spine, femoral neck and the hip (P = 0.01, 0.04 and 0.02, respectively) in group 2 but not group 1. CONCLUSION: In this study, there is no evidence for a difference in bone mineral density in patients receiving replacement doses of thyroxine irrespective of the aetiology of their hypothyroidism. The reduced bone mineral density associated with hyperthyroidism appears to be restored, maintained and in some cases possibly improved while on long-term thyroxine replacement post-radioiodine.

Regulatory peptides and other neuroendocrine markers in medullary carcinoma of the thyroid.

Medullary thyroid carcinoma (MTC) is an APUDoma (APUD refers to amine precursor uptake and decarboxylation) arising from the parafollicular cells. Diarrhoea has been reported in some 30% of patients, variously attributed to excess production of calcitonin (CT), serotonin (5-HT), vasoactive intestinal peptide (VIP) or other factors. The regulatory factors in MTC were examined employing immunocytochemistry and RIA to tumours and their extracts. The patients were followed up for more than 15 years. CT and calcitonin gene-related peptide were universally expressed in all the tumours. The neuroendocrine markers chromogranin A (and its fragments pancreastatin and WE-14), neurone-specific enolase, protein gene product 9.5 and carcino-embryonic antigen were found in the majority of MTCs and might be useful as immunocytochemical markers. 5-HT, substance P, neurokinin A, glucagon and VIP could not be detected, excluding them as candidates in the diarrhoea of MTC.