Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

BACKGROUND/OBJECTIVES: Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. SUBJECTS/METHODS: In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. RESULTS: Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). CONCLUSIONS: Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Presentation, management and outcomes in acute pituitary apoplexy: a large single-centre experience from the United Kingdom.

OBJECTIVE: To study the presentation, management and outcomes and to apply retrospectively the Pituitary Apoplexy Score (PAS) (United Kingdom (UK) guidelines for management of apoplexy) to a large, single-centre series of patients with acute pituitary apoplexy. DESIGN: Retrospective analysis of casenotes at a single neurosurgical centre in Liverpool, UK. RESULTS: Fifty-five patients [mean age, 52·4 years; median duration of follow-up, 7 years] were identified; 45 of 55 (81%) had nonfunctioning adenomas, four acromegaly and six prolactinomas. Commonest presenting features were acute headache (87%), diplopia (47·2%) and visual field (VF) defects (36%). The most frequent ocular palsy involved the 3rd nerve (81%), followed by 6th nerve (34·6%) and multiple palsies (19%). Twenty-three patients were treated conservatively, and the rest had surgery either within 7 days of presentation or delayed elective surgery. Indications for surgery were deteriorating visual acuity and persistent field defects. Patients presenting with VF defects (n = 20) were more likely to undergo surgery (75%) than to be managed expectantly (25%). There was no difference in the rates of complete/near-complete resolution of VF deficits and cranial nerve palsies between those treated conservatively and those who underwent surgery. Endocrine outcomes were also similar. We were able to calculate the PAS for 46 patients: for the group treated with early surgery mean, PAS was 3·8 and for those managed conservatively or with delayed surgery was 1·8. CONCLUSIONS: Patients without VF deficits or whose visual deficits are stable or improving can be managed expectantly without negative impact on outcomes. Clinical severity based on a PAS ≥ 4 appeared to influence management towards emergency surgical intervention.

A clone of elusive parents: gonadotroph adenoma-female type.

A 69-year-old woman presented with visual disturbance. Perimetry testing revealed a bitemporal hemianopia. Brain MRI demonstrated a 2.2-cm gadolinium-enhancing pituitary mass. Previously she had been treated for hypothyroidism, hypertension, and dyslipidemia. She had hyperprolactinemia. Endoscopic transsphenoidal debulking improved her visual field defects. Histology showed a chromophobic adenoma. Electron microscopy showed elongated, polar cells with long, slender processes. The small uniform secretory granules were peripherally disposed, collecting heavily within cell processes. Based on electron microscopical characteristics the tumor is consistent with an ACTH-negative female gonadotroph adenoma. The parent cell of this rare variant of a pituitary adenoma is yet unknown.

Hypopituitarism--a late consequence of aneurysmal subarachnoid haemorrhage?

Over the last decade subarachnoid haemorrhage (SAH) has increasingly been recognised as a cause of hypopituitarism. We report on the case of a patient with evidence of growth hormone deficiency manifesting after a period of time, with a favourable response to growth hormone replacement. This is followed by a review of the current literature.

The outcome of brittle type 1 diabetes--a 20 year study.

AIMS: To determine the long-term (20 years from presentation) outcome of brittle type 1 diabetes characterized by recurrent episodes of ketoacidosis (DKA). METHODS: The cohort studied was a group of brittle diabetic patients from various parts of UK originally identified between 1979 and 1985. Patients were traced, where possible, via their diabetic clinics and/or general practitioners. Data on survival or otherwise were obtained from hospital case notes and information from diabetes care team members. For survivors, clinical and demographic information obtained included complication status and whether they still had brittle characteristics. They were also compared with a matched case-control group of type 1 patients with no history of brittle behaviour. RESULTS: The original cohort comprised 33 patients- all female and mean ± SD, aged 18 ± 5 years and diabetes duration 8 ± 4 years. Thirteen were not traceable and 10 of the remaining 20 (50%) had died during the mean 22 years of follow-up. Deaths occurred evenly throughout the period, and causes were chronic renal failure (3), DKA (3), hypoglycaemia (2), subarachnoid haemorrhage (1) and uncertain (1). Age at death ranged from 27 to 45 years. Of the 10 survivors, none remained brittle, but they had a substantial burden of complications. Compared with the non-brittle control group, there was a significant excess of nephropathy and autonomic neuropathy. CONCLUSION: We conclude that brittle diabetes characterized by recurrent DKA has high long-term outcome mortality. These deaths were premature and almost all diabetes related. Those who survived had resolution of brittleness, but suffered a significant complication burden.

Nurse-led cardiovascular risk factor intervention leads to improvements in cardiovascular risk targets and glycaemic control in people with Type 1 diabetes when compared with routine diabetes clinic attendance.

AIM: To compare the effects of a dedicated cardiovascular risk factor clinic run by a nurse consultant with routine diabetes clinic attendance in achieving glycaemic and cardiovascular risk targets in patients with Type 1 diabetes. METHODS: Eighty-one patients (45 male, mean age 34.6 years, mean duration of diabetes 15 years) with an HbA(1c) ≥ 8% (64 mmol/mol) and at least one other risk factor for the development of cardiovascular disease were randomized to receive either routine care or intensive nurse-led cardiovascular risk factor intervention. HbA(1c) , non-fasting lipid profile, blood pressure, weight, BMI and insulin dose were recorded at baseline, 6, 12 and 24 months. RESULTS: At baseline there were no differences between the groups. At 12 months, there were significant improvements in the nurse-led cardiovascular risk factor group: HbA(1c) [10.1% (87 mmol/mol) vs. 9.3% (78 mmol/mol), P < 0.001], total cholesterol (5.8 vs. 4.3 mmol/l, P < 0.001), systolic blood pressure (127 vs. 115 mmHg, P < 0.001) and diastolic blood pressure (71 vs. 65 mmHg, P < 0.05). Improvements were maintained in all variables at 24 months except diastolic blood pressure. In the routine group, only total cholesterol improved significantly (5.8 vs. 5.2 mmol/l, P < 0.01) after 12 months and this was maintained at 24 months. CONCLUSION: A nurse consultant cardiovascular risk factor clinic has a beneficial effect on cardiovascular risk targets in Type 1 diabetes, probably attributable to the increased use of lipid-lowering and anti-hypertensive agents and this was maintained at 24 months. Glycaemic control also improved.

Improvement in the care of multiple endocrine neoplasia type 1 through a regional multidisciplinary clinic.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is associated with significant morbidity and mortality. Timely detection of MEN1 kindred, together with treatment of associated tumours, results in an improved outcome. We describe how the development of a dedicated multidisciplinary MEN clinic has improved the diagnosis and treatment of MEN1-associated endocrinopathies. DESIGN AND PATIENTS: A dedicated MEN clinic was developed at Aintree University Hospital, Liverpool in 2002 for patients living in Merseyside, Cheshire and North Wales. The multidisciplinary approach adopted, aimed to improve communication and continuity of care. Patients see all clinicians involved in their care (Consultant Endocrinologist, Paediatrician, Clinical Geneticist and Endocrine Surgeon) simultaneously, allowing for a unified, clear approach and a reduction in unnecessary attendances. The clinicians adopt a proactive approach to tracing the relatives of patients, with the aim of identifying kindred with previously asymptomatic disease. RESULTS: In 2002, 16 patients from 5 families were diagnosed clinically with MEN1. Twenty MEN1-associated endocrinopathies had been diagnosed and 21 surgical procedures had been performed. By the end of 2008, 45 patients from 15 families had been identified, with 83 endocrinopathies diagnosed and 50 surgical procedures performed. Ninety-four known relatives are awaiting screening for MEN1. CONCLUSION: The successful identification of patients with MEN1 has resulted in an exponential increase in the number of patients attending the clinic. As relatives undergo screening, the diagnosis of MEN is likely to increase. The ever increasing numbers of patients requiring screening, surveillance and treatment has implications in the planning of future service provision.

The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency.

BACKGROUND: Adult GHD syndrome is associated with clustering of adverse cardiovascular (CV) risk factors such as abnormal body composition, dyslipidemia, insulin resistance and abnormal haemostatic factors. There is a wealth of evidence linking CV events with elevated levels of inflammatory markers (hs-CRP and IL-6) in the general population; however data on their abnormalities in GHD and specially the effects of GH replacement (GHR) on these inflammatory markers are limited. OBJECTIVE: To study the effects of GHR on inflammatory markers, glucose homeostasis and body composition in a cohort of adults with recently diagnosed severe GHD due to hypothalamic pituitary disease. DESIGN: Fifteen hypopituitary adults (11 males, mean age 48.5 years) with recently diagnosed, severe GHD were recruited. Patients received GHR (in addition to other pituitary hormone replacements) titrated to clinical response and to normalize age and gender adjusted IGF-1 levels. Weight, waist hip ratio (WHR), body composition, fasting plasma glucose and insulin, insulin resistance index (HOMA-IR), fasting serum lipid levels, hs-CRP, IL-6 and TNF-alpha were measured at baseline and following a minimum 6 months of stable maintenance GHR. RESULTS: GHR resulted in a physiological increase in IGF-1 SDS [median -0.6 to +0.39, P<0.0001], improved quality of life (mean pre-treatment AGHDA score 16 vs. post-treatment score 7, P<0.0001) and reduction in WHR (0.94 vs. 0.92, P=0.01). There were no significant changes in body weight and composition. Levels of hs-CRP (log transformed, mean (SD)) were significantly reduced following GHR (pre 1.21 (0.9) vs. post 0.27 (0.9), P<0.0001) but TNF-alpha and IL-6 levels remained unchanged. Fasting glucose (mmol/L) [4.6 (0.1) vs. 5.1 (0.1), P=0.003], fasting insulin (muU/mL) [9.4 (8.1) vs. 12.1 (9.2), P=0.03] and HOMA-IR [1.2 (1.0) vs. 1.5 (1.1) P=0.02] (all pre-GHR vs. post-GHR and mean (SD)) significantly increased following GHR indicating increased insulin resistance. Significant improvements were noted in fasting LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) levels following GHR [3.4 (0.9) vs. 2.9 (0.7), P=0.03 and 1.2 (0.2) vs. 1.3 (0.2), P=0.02, respectively] (all pre-GHR vs. post-GHR and mean (SD)). Levels of total cholesterol and triglycerides did not change following GHR. CONCLUSIONS: Physiological GHR for at least 6 months in hypopituitary adults with recently diagnosed severe GHD resulted in favourable changes in hs-CRP, WHR, fasting LDL-C and HDL-C levels all of which are recognised CV risk markers. However, there remains a high prevalence of obesity in this population and given the worsening of insulin sensitivity in the short term with GHR, monitoring and aggressive treatment of established CV risk factors is essential to reduce premature atherosclerotic CVD in this patient population.

The d3/fl-GH receptor gene polymorphism does not influence quality of life and body composition in GH-deficient adults receiving GH replacement therapy.

CONTEXT: The growth response to recombinant human growth hormone (rhGH) in GH deficient (GHD) patients may be influenced by polymorphisms in the growth hormone receptor (GHR) gene. OBJECTIVES: To investigate adults with GHD who have been treated with rhGH for more than 1 year to determine the relationship between genomic deletion of exon 3 in the GHR gene and quality of life (QoL), body composition (BC) and serum IGF1 levels, and to compare these variables to a healthy adult control population. DESIGN: Cross-sectional study. METHODS: A total of 100 healthy adult controls and 131 patients were studied. Deletion of exon 3 in the GHR gene was determined in DNA that was isolated from peripheral blood. QoL was determined using the adult GHD assessment scale and three other validated QoL instruments. RESULTS: In the control population, the frequency of the genotypes was 53% fl/fl, 40% d3/fl and 7% d3/d3, and in the patient population, 55, 39 and 6% respectively. There was no significant difference in QoL scores and BC in control subjects with the fl/fl genotype compared with those with the d3/d3 or fl/d3 genotype. There was no difference in the rhGH dose required to optimize serum IGF1, QoL or BC in patients with the fl/fl genotype compared with those with the d3/d3 or d3/fl genotype. CONCLUSION: Deletion of exon 3 in the GHR gene does not influence adult height, QoL or BC of the normal adult population nor does it influence rhGH dose, QoL and BC in GHD adults treated with rhGH for more than 1 year.

Improvements in glycaemic control and cardiovascular risk factors in a cohort of patients with type 1 diabetes over a 5-year period.

BACKGROUND: Management of patients with type 1 diabetes in the UK has changed over the past 20 years. The targets for glycaemic control, blood pressure and cholesterol are lower. We examined a cohort of patients with type 1 diabetes who have been through these changes to assess their effects. DESIGN AND METHODS: A cohort of patients with type 1 diabetes who attended a secondary care outpatient diabetes clinic between 1991 and 1996 were reviewed in 2001 and 2006. Comparison is made between current biophysical markers and those obtained in 2001. RESULTS: Only 81.9% (n = 214) of the original cohort attended in 2006. These patients had an average duration of diabetes of 23.46 (SD +/- 8.06) years. There were 134 male patients (62.62%). In these patients HbA1c had reduced by 0.4% (absolute reduction); a relative reduction of 4.41% (P = 0.0001). Statistically significant reductions in diastolic blood pressure (74-68 mmHg) and total cholesterol (5.37-4.62 mmol/l) occurred. However, weight (75.04-82.31 kg) and BMI (25.32-27.72 kg/m(2)) significantly increased. There was no statistically significant change in insulin dose (units/kg), serum creatinine, urinary ACR or systolic blood pressure. CONCLUSION: An urban setting, mobile population and patient non-attendance can complicate modern diabetes care. Despite these difficulties, input by the diabetes team working with the patients can achieve small improvements in Hba1c and cardiovascular risk factors by increased use of long acting insulins, metformin, statins and blood pressure medication.

Growth hormone and changes in energy balance in growth hormone deficient adults.

BACKGROUND: Adults with growth hormone deficiency (AGHD) have an adverse body composition with an increased prevalence of obesity. It is not known whether growth hormone replacement (GHR) results in alterations in energy intake (EI) and/or energy expenditure (EE). The aim of the study was to investigate the effects of GHR on EI and EE. MATERIALS AND METHODS: Nineteen hypopituitary adults (14 males, 5 females, mean age 46.2 years) with severe GHD (peak GH response to glucagon

Aerobic fitness and hand grip strength in Type 1 diabetes: relationship to glycaemic control and body composition.

AIM: To clarify the relationship of aerobic fitness and handgrip strength with glycaemic control (HbA1c), body composition and lipid profile in Type 1 diabetes. METHODS: Aerobic capacity (Chester Step Test), handgrip strength and body composition (bioelectrical impedance) were measured in 141 patients with Type 1 diabetes. RESULTS: Aerobic capacity correlated positively with HbA1c and lean body mass and negatively with body mass index and fat mass. Handgrip strength correlated positively with aerobic capacity and negatively with HbA1c and fat mass. In addition, there was a positive correlation between HbA1c and total cholesterol. CONCLUSION: Patients with Type 1 diabetes who have good aerobic capacity have poorer glycaemic control. However, this was an observational study and the results must be interpreted with caution. Further investigation into how these patients manage blood glucose during exercise is required.

Cardiovascular disease, hypertension, dyslipidaemia and obesity in patients with hypothalamic-pituitary disease.

OBJECTIVE: Adults with hypothalamic-pituitary disease have increased morbidity and mortality from cardiovascular disease (CVD). Therefore, the prevalence of CVD and adequacy of treatment of cardiovascular risk factors (according to current treatment guidelines) was studied in a large group of patients with hypothalamic-pituitary disease. STUDY DESIGN: In 2005, 152 consecutive adult patients with hypothalamic-pituitary disease attending our neuro-endocrine centre were clinically examined and blood pressure (BP), lipid profile, type 2 diabetes mellitus, body composition and smoking status were assessed. RESULTS: Of the 152 patients, 36.8% had treated hypertension and 28.2% had treated dyslipidaemia. Many of these patients had inadequate BP control (BP >140/85 mm Hg, 44.6%) and undesirable lipid levels (total cholesterol >4.0 mmol/l, 69%). Also, many of the untreated patients had BP and lipid levels which should have been considered for treatment (26 patients (27%) and 83 patients (76%), respectively). Smoking was admitted in 18% of patients. Central adiposity was present in 86% and obesity (body mass index > or =30) was present in 50%. CONCLUSIONS: Cardiovascular risk factors are highly prevalent and often inadequately treated in adult patients with hypothalamic-pituitary disease. Aggressive treatment of these factors is essential to reduce mortality and morbidity from CVD in these patients.

Ablative thyroid treatment for thyrotoxicosis due to thyrotropin-producing pituitary tumours.

BACKGROUND: Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are rare tumours that can be invasive. It has been suggested that thyroid surgery or radioiodine treatment should not be considered in patients with such tumours as these treatments may facilitate rapid and aggressive tumour expansion. AIM: To study the effects of thyroid ablative treatment on tumour size and thyroid status in two patients with TSHomas in whom the size of the adenoma was clearly documented before treatment was started. METHODS: Patients studied were: (1) a female patient with a TSHoma who declined to undergo pituitary surgery and underwent a total thyroidectomy instead and (2) a male patient who opted for radioiodine treatment for his recurrent TSHoma. Changes in tumour size on serial magnetic resonance imaging scans, and restoration of euthyroidism were studied. RESULTS: No marked changes in tumour size or features of aggressiveness occurred in these patients over periods of 8 and 12 years. Euthyroidism was restored and maintained in both patients. CONCLUSIONS: Ablative thyroid treatment can be a safe and successful option to treat TSHomas, but long-term and close follow-up of these patients is mandatory to ensure that the size and behaviour of the tumours do not change markedly.

The natural history of chronic painful peripheral neuropathy in a community diabetes population.

AIMS: To examine the natural history of chronic painful diabetic neuropathy (CPDN). METHODS: A cross-sectional study of 350 people with diabetes was performed during 1998-1999 to assess the prevalence of CPDN in the community. Fifty-six patients with CPDN were identified and were followed up an average of 5 years later. RESULTS: From the original cohort, 12 patients had died and 14 had moved away or were unable to participate in the follow-up study. Thus 30 patients with CPDN [21 male, mean (SD) age 68.6 years (9.4), mean (SD) duration of diabetes 15.4 years (8.7)] were re-assessed. Seven (23%) had been pain free for at least 12 months and 23 continued to report neuropathic pain of similar quality and severity [total McGill Pain Questionnaire Score median (interquartile range) at follow-up 22 (16-39) vs. 20 (16-33) at baseline, P = 0.3; mean (SD) visual analogue scale (VAS) score for pain over the preceding 24 h 5.3 cm (2.9) vs. 4.6 cm (2.5) at baseline, P = 0.1]. Only 65% had ever received treatment for CPDN despite 96% (22/23) reporting pain to their physician; 43.5% had received antidepressants, 17.4% anticonvulsants, 39% opiates and 30% had tried complementary therapies. CONCLUSIONS: The neuropathic pain of CPDN can resolve completely over time in a minority (23%). In those in whom painful neuropathic symptoms had persisted over 5 years, no significant improvement in pain intensity was observed. Despite the improvement in treatment modalities for chronic pain in recent years, patients with CPDN continue to be inadequately treated.

Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors.

AIMS: To determine the prevalence of overweight and obesity among patients with type 1 and type 2 diabetes mellitus attending a secondary care diabetes clinic in the United Kingdom, and to assess the impact of overweight and obesity on glycaemic control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: 3637 patients with diabetes were identified from the hospital electronic diabetes register, 916 with type 1 diabetes (mean (SD) age 40.4 (15.1) years, 496 male) and 2721 with type 2 diabetes (mean (SD) age 62.5 (11.8) years, 1436 male). Data on body mass index (BMI), glycaemic control, lipid profiles, and blood pressure were extracted. RESULTS: Of patients with type 1 diabetes, 55.3% were overweight (BMI >or=25 kg/m(2)), 16.6% were obese (BMI >or=30 kg/m(2)), and 0.4% had morbid obesity (BMI >or=40 kg/m(2)). In contrast, 86% of patients with type 2 diabetes were overweight or obese, 52% were obese, and 8.1% had morbid obesity. Obese patients with type 2 diabetes were younger, had poorer glycaemic control, higher blood pressures, worse lipid profiles, and were more likely to be receiving antihypertensive and lipid lowering drugs compared with patients with BMI <30 kg/m(2). CONCLUSIONS: Obesity is the rule among patients attending this hospital diabetes clinic, with 86% of those with type 2 diabetes overweight or obese. Obesity is associated with significantly worse cardiovascular risk factors in this patient group, suggesting that more active interventions to control weight gain would be appropriate.