Glycated haemoglobin and the risk of postoperative complications in people without diabetes: a prospective population-based study in UK Biobank.

The aim of our study was to clarify the association between glycated haemoglobin (HbA1c ) and postoperative outcomes in people without an existing diagnosis of diabetes. Half a million adults were recruited into the UK Biobank prospective cohort study between March 2006 and October 2010. We divided participants into three groups: no diagnosis of diabetes and HbA1c < 42 mmol.mol-1 ; no diagnosis of diabetes and elevated HbA1c (≥ 42 mmol.mol-1 with no upper limit); and prevalent diabetes (regardless of HbA1c concentration) at recruitment. We followed up participants by linkage with routinely collected hospital data to determine any surgical procedures undertaken after recruitment and the associated postoperative outcomes. Our main outcome measure was a composite primary outcome of 30-day major postoperative complications and 90-day all-cause mortality. We used logistic regression to estimate the odds of the primary outcome by group. We limited analyses to those who underwent surgery within one year of recruitment (n = 26,653). In a combined effects logistic regression model, participants not known to have diabetes with HbA1c ≥ 42 mmol.mol-1 had increased odds of the primary outcome (OR [95% CI] 1.43 [1.02-2.02]; p = 0.04), when compared with those without diabetes and HbA1c < 42 mmol.mol-1 . This effect was attenuated and no longer statistically significant in a direct effects model with adjustment for hyperglycaemia-related comorbidity (OR [95% CI] 1.37 [0.97-1.93]; p = 0.07). Elevated pre-operative HbA1c in people without diabetes may be associated with an increased risk of complications, but the association is likely confounded by end-organ comorbidity. In contrast to previous evidence, our findings suggest that to prevent adverse postoperative outcomes, optimisation of pre-existing morbidity should take precedence over reducing HbA1c in people without diabetes.

Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes.

BACKGROUND: Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown. METHODS: Data from patients who underwent endoscopic TSS for a NFPMA (2009-2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes. RESULTS: Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004). CONCLUSION: Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

A case of parathyroid carcinoma with severe hungry bone syndrome and review of literature.

We present a 45 year old female who was initially seen by Rheumatologist with long standing knee pain affecting her mobility. She was found to be severely hypercalcaemic and exhibited features suggestive of parathyroid carcinoma (palpable neck mass, extremely high parathyroid hormone, high alkaline phosphatase, concomitant presence of renal disease and skeletal involvement). Hence she was referred for parathyroidectomy. Postoperatively she developed profound hypocalcaemia with markedly raised serum alkaline phosphatase, requiring intensive intravenous calcium and oral vitamin D supplements, consistent with the development of hungry bone syndrome (HBS). HBS is a complication of parathyroid surgery where the correction of primary hyperparathyroidism is associated with rapid bone remineralisation, causing severe and prolonged hypocalcaemia. HBS is relatively rare but has to be considered in the differential diagnosis of postoperative hypocalcaemia particularly in severe cases. In the current report, we discuss pathogenesis, clinical course and management of HBS.

Utility of biochemical screening in the context of evaluating patients with a presumptive diagnosis of osteoporosis.

The ageing population is expected to increase the burden of osteoporosis on the health care system. Secondary causes of osteoporosis are found in a proportion of patients. There is much controversy regarding the best work-up for patients who have been diagnosed as having osteoporosis based on bone mineral density. It is difficult to decide where interventions should be targeted both from a patient's perspective and for cost effectiveness. We evaluated the utility of a standard panel (full blood count, plasma viscosity, plasma protein, electrophoresis, urine Bence Jones protein, thyroid function test, bone profile, fasting lipids and liver function test) of biochemical investigations in 327 consecutive patients (287 females, 40 males) referred to the new patient osteoporosis clinic from April 1999 to March 2000. Patients were characterised after measurement of spinal/femoral neck bone mineral density after a dual energy X-ray absorptiometry (DEXA) scan. There were 88 patients with osteoporosis, 91 with osteopenia, 130 had normal bone mineral density and 20 who did not have a bone scan. No case of multiple myeloma was found in this cohort of patients. There was no difference in the mean plasma viscosity of patients with and without osteoporosis (P=0.182). There was no significant difference in the abnormal urine calcium/creatinine (Ca/Cr ratio) in patients with osteoporosis and those without osteoporosis (P=0.316). There was no significant difference in the prevalence of hypothyroidism (P=0.213) or thyrotoxicosis (P=0.138) in patients with and without osteoporosis. There was no strong correlation between cholesterol concentrations and osteoporosis (r=0.069). We found no utility in performing a myeloma screen. A small proportion of patients had abnormalities of calcium homeostasis or thyroid disease. We recommend that a screening biochemical evaluation should be restricted to calcium/bone profile and thyroid function tests in patients with a presumptive diagnosis of osteoporosis.

High-dose oral colecalciferol loading in obesity: impact of body mass index and its utility prior to bariatric surgery to treat vitamin D deficiency.

Obesity is associated with lower vitamin D levels compared with normal weight subjects, and if levels are not replaced prior to bariatric surgery, this can increase fracture risk as bone density typically falls post-operatively. We analysed the effect of body mass index (BMI) on vitamin D levels in response to 300 000 IU of colecalciferol in patients with vitamin D deficiency (<30 nmol L-1 ). Patients were grouped according to their BMI as normal weight (20-24.9 kg m-2 ), overweight (25-29.9 kg m-2 ), obese class I (30-34.9 kg m-2 ) and obese class II and above (>35 kg m-2 ). The records were retrospectively analysed to investigate the effects of BMI on vitamin D (total 25-hydroxy vitamin D [25(OH)D]), serum Ca2+ and parathyroid hormone (PTH) levels at 6, 12, 26 and 52 weeks compared with baseline. Compared with normal weight subjects, overweight and obese patients achieved lower mean peak total 25(OH)D levels (6 weeks post-loading), which was most significant in the class II and above group (mean total 25(OH)D levels 96.5 ± 24.2 nmol L-1 and 72.42 ± 24.9 nmol L-1 , respectively; P = 0.003). By 26 weeks, total 25(OH)D levels fell in all groups; however, there was now a significant difference between the normal weight subjects and all other groups (mean total 25(OH)D levels 84.1 ± 23.7 nmol L-1 ; 58 ± 20 nmol L-1 , P = 0.0002; 62.65 ± 19.2 nmol L-1 , P = 0.005; 59.2 ± 21 nmol L-1 , P = 0.005, respectively). Far fewer patients in the overweight and obese groups maintained levels above the recommended level of 75 nmol L-1 52 weeks post-loading (93%; 20%, P = 0.0003; 23%, P = 0.01; and 14%, P = 0.001, respectively). Alternative regimes for the treatment of vitamin D deficiency are needed in overweight and obese patients, especially those in whom bariatric surgery is planned.

Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group.

Patients with acromegaly have a reduced life expectancy, with the accepted causes for premature death being vascular and respiratory disease. Increased mortality from malignant disease has also been reported. We, therefore, performed a multicenter retrospective cohort study of 1362 patients with acromegaly and investigated the relationships of mortality and cancer incidence with GH levels, duration of disease, and age at diagnosis. The overall cancer incidence rate [standardized incidence ratio, 0.76; 95% confidence interval (CI), 0.60-0.95] was lower than that in the general population of the United Kingdom, and there was no significant increase in site-specific cancer incidence rates. The overall cancer mortality rate was not increased, but the colon cancer mortality rate (standardized mortality ratio, 2.47; 95% CI, 1.31-4.22) was higher than expected. Mortality rates due to colon cancer, all malignant disease, cardiovascular disease and overall mortality were increased with higher posttreatment GH levels (P for trends, <0.02, <0.05, <0.02, and <0.0001). The overall mortality rate in patients with acromegaly with posttreatment GH levels less than 2.5 ng/mL (5 mU/L) was comparable to that in the general population of the United Kingdom (standardized mortality ratio, 1.10; 95% CI, 0.89-1.35). We conclude that high posttreatment GH levels are associated with an increased overall mortality rate and increased mortality rates due to colon cancer, cardiovascular disease, and all malignant disease. Posttreatment GH levels less than 2.5 ng/mL (5 mU/L) result in an overall mortality rate similar to that in the general population.

The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies.

In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10(6) cells (range 21-91) to 144 ng/10(6) cells (range 128-169) after 24 h (p < 0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p < 0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral sequential inferior petrosal sinus sampling with corticotrophin-releasing hormone stimulation in the diagnosis of Cushing's disease.

OBJECTIVE: The demonstration of a central to peripheral ACTH gradient in a hypercortisolaemic patient is diagnostic of Cushing's disease. We tried to determine whether single blood samples for ACTH obtained sequentially from each of the inferior petrosal sinuses following human corticotrophin-releasing hormone (hCRH) stimulation can reliably establish such a gradient. DESIGN: Prospective study. PATIENTS: Seventeen patients with clinical and biochemical features of Cushing's syndrome. METHODS: After the administration of hCRH, the patients underwent bilateral sequential inferior petrosal sinus sampling, with a single blood sample obtained from each of the inferior petrosal sinuses sequentially, along with a peripheral venous sample. The petrosal sinus catheter was withdrawn immediately after obtaining a blood sample. Patients did not require indwelling catheters in the petrosal sinuses, nor heparinisation. RESULTS: Bilateral sequential inferior petrosal sinus sampling correctly identified a pituitary source of ACTH, as shown by a central to peripheral ACTH ratio >2, in all patients in whom the procedure was successfully carried out. All patients underwent transsphenoidal pituitary surgery resulting in remission. CONCLUSIONS: The simplified method of inferior petrosal sinus sampling, using a single sequential sample from each of the inferior petrosal sinuses, following initial hCRH stimulation, is as accurate as the more complex test using multiple bilateral simultaneous inferior petrosal sinus samples. It avoids the use of indwelling cerebral venous catheters and is therefore unlikely to cause brain stem damage.

Thyroid dysfunction and fibrin network structure: a mechanism for increased thrombotic risk in hyperthyroid individuals.

CONTEXT: Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE: Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN: Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS: Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS: Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.

Isolated ACTH deficiency.

Isolated ACTH deficiency is a rare disorder. We report four cases of this disease which presented to the Department of Endocrinology at Leeds General Infirmary over a one-year period. The diagnostic clinical and biochemical features of each case are discussed and the pertinent literature is reviewed. The clinical investigations vary somewhat between cases as the four patients presented in markedly different ways. Well validated dynamic endocrine investigations were employed including glucagon stimulation test (GST) and the corticotrophin releasing hormone (CRH) test (using 100 micrograms of human CRH with samples for ACTH and cortisol). Two patients probably had CRH deficiency and two had ACTH deficiency. All the cases are instructive, illustrating different features of this heterogeneous condition. We conclude that the diagnosis of this condition may be difficult due to the varied clinical presentation. We suggest that it is commoner than previously thought and that the precision of diagnosis can be improved using the CRH test.

Is a low skinfold thickness an indicator of osteoporosis?

OBJECTIVE: The association between thin skin and osteoporosis has been known for some years. We wished to assess a simple measure of skinfold thickness (SFT) as a screening test for osteoporosis and to study the effect of chronological and menopausal age on SFT in a group of osteoporotic women and normal controls. DESIGN: A case control study of 225 consecutive women who attended an osteoporosis clinic. PATIENTS: We studied 225 women, 141 with osteoporosis (mean age 61.8 +/- 10.5 years) and 65 normal controls (mean age 59.9 +/- 8.8 years), with 19 exclusions. METHODS: Each patient had routine biochemistry, spinal X-rays and a dual-energy X-ray absorptiometry (DEXA) scan of lumbar spine and femoral neck. In addition they had skinfold thickness measured by a single observer using Holtain Tanner Whitehouse callipers over the 4th metacarpal of the right hand. RESULTS: Mean skinfold thickness was lower in the osteoporotic group, 1.6 +/- 0.4 mm compared to normals 1.8 +/- 0.3 mm (P < 0.0001). SFT did not decline significantly with chronological or menopausal age in the normals (correlation coefficients r = -0.06, r = -0.09) in contrast to the osteoporotic group (correlation coefficients r = -0.52, P < 0.001; r = -0.27, P < 0.0001). Subjects with a SFT of < or = 1.5 mm had a higher probability of osteoporosis (odds ratio 3.12, 95% confidence interval 1.58-6.14). Subjects with a SFT of > or = 2.1 mm had a lower probability of osteoporosis (odds ratio 0.305, 95% confidence interval 0.126-0.740). CONCLUSION: Our results demonstrate a lower mean SFT in osteoporotic compared with normal women, with a negative correlation between SFT and chronological and menopausal age in osteoporotics, but not in normal controls. A low skinfold thickness appears to be an indicator of developing osteoporosis and a high SFT may indicate a normal bone mass.

CD40-mediated signals inhibit the binding of TNF receptor-associated factor 2 to the CD40 cytoplasmic domain.

TNF receptor-associated factor 2 (TRAF2) is a signal-transducing protein associated with the CD40 cytoplasmic domain. It has been hypothesized that during signal transduction, TRAF2 must be released from CD40 in order for it to interact with downstream signaling molecules. We found that CD40 and TRAF2 were constitutively associated with each other in a human B cell line. Following stimulation with an anti-CD40 Ab, a decrease in the amount of CD40-associated TRAF2 was observed that could not be explained by a change in total level of either of the proteins. These results, as well as similar findings obtained with 293 cells overexpressing CD40 and TRAF2, suggested that CD40-mediated signals inhibited the CD40-TRAF2 interaction. We then conducted binding studies using CD40 cytoplasmic domain fusion proteins and TRAF2 derived from either control or CD40-stimulated cell lines. These in vitro studies also indicated that the binding of TRAF2 to the CD40 cytoplasmic domain was inhibited by CD40 stimulation. The results of these experiments, as well as differences between the in vitro and in vivo findings, indicated that multiple mechanisms were involved in the inhibition of the CD40-TRAF2 interaction by CD40 signals. Possible mechanisms of inhibition are discussed based on mapping of the TRAF2 binding site on the CD40 cytoplasmic domain.