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.

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.

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.

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

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.

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.

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.

Contact thermography of painful diabetic neuropathic foot.

OBJECTIVE: To investigate regional differences in skin blood flow (measured by contact thermography) in the diabetic neuropathic foot and to examine the effect of foot temperature on the severity of neuropathic pain. RESEARCH DESIGN AND METHODS: Thirty-five diabetic patients with painful polyneuropathy (PPN) and 33 healthy age- and sex-matched control subjects comprised the study. Mean foot temperature (MFT) in PPN (mean +/- SE 28.3 +/- 0.3 degrees C) was significantly higher (P less than 0.001) than in the control subjects (25.9 +/- 0.5 degrees C), with the highest temperatures over the metatarsal areas and heel. Visual analogue scale pain score (mean +/- SD 5.3 +/- 1.9 cm) did not correlate with MFT (r = -0.14, P = 0.52). In 10 patients with PPN followed for 2-8 mo (mean 4.6), MFT fell by 1.6 degrees C (P = 0.05), but pain scores did not alter. CONCLUSIONS: Neuropathic pain is unaffected by alterations in skin temperature. Elevated skin temperatures at recognized sites of weight bearing (metatarsal heads and heels) are common in the diabetic neuropathic foot and may indicate tissue injury or inflammation induced by pressure trauma or increased arteriovenous shunting. Follow-up studies will determine whether thermographic hot spots are more susceptible to ulceration.

The prediction of diabetic neuropathic plantar foot ulceration by liquid-crystal contact thermography.

OBJECTIVE: To assess whether the development of plantar foot ulceration could be predicted from the mean plantar foot temperature (MFT), as assessed by liquid-crystal contact thermography (LCT), in patients with peripheral neuropathy. RESEARCH DESIGN AND METHODS: Fifty patients with painful diabetic sensorimotor neuropathy were studied prospectively. Initially, 30 patients had no significant peripheral vascular disease (PVD) (ankle:brachial systolic blood pressure ratio > 1.0). LCT was used to assess the MFT from eight standard plantar sites. RESULTS: Initial MFT was higher in the patients without PVD (28.2 +/- 2.9 degrees C, mean +/- SD) than in patients with PVD (25.6 +/- 1.9 degrees C, P < 0.001) and in nondiabetic control subjects (25.7 +/- 2.1 degrees C, P < 0.001). At review, on average 3.6 (range 3.0-4.1) years later, 11 patients had died (6 of whom had PVD), and one was lost to follow-up. Six patients (seven feet) from the group without PVD had developed neuropathic plantar foot ulcers. The initial MFT was significantly higher in these seven feet (30.5 +/- 2.6 degrees C) than in the 38 feet of the 19 survivors in this group (27.8 +/- 2.3 degrees C, P < 0.01). Only one patient with PVD developed a plantar ulcer, although four required foot surgery for ischemic feet. CONCLUSIONS: LCT is a simple, inexpensive, and noninvasive method of identifying the neuropathic foot at increased risk of ulceration. Patients with high plantar foot temperatures are at increased risk of neuropathic foot ulceration. A normal or low MFT in the neuropathic foot is a marker of PVD, which confers an increased risk of ischemic foot disease.

Abnormal heart rate variability in adults with growth hormone deficiency.

GH-deficient (GHD) patients have increased risk of cardiovascular death and may have cardiac structural abnormalities. In non-GHD patients these are associated with cardiac autonomic dysfunction, and it is possible that autonomic dysfunction is also present in GHD patients. Power spectral analysis (PSA) of heart rate variability (HRV) indirectly measures cardiac autonomic tone and generates peaks at 3 frequency bands, very low frequency (VLF), low frequency (LF) and high frequency (HF). The area under the LF curve is considered to reflect predominantly cardiac sympathetic activity, whereas HF indicates parasympathetic activity. PSA of HRV was performed in 14 normotensive GHD patients (5 men and 9 women; mean age, 35.2 yr) and 19 healthy controls (9 men and 10 women; mean age, 38.3 yr). GHD patients had 26% lower normalized LF power (P < 0.004), 39% higher normalized HF power (P < 0.001), 28% lower normalized VLF power (P < 0.046), and 51% lower LF/HF ratio (an index of sympathovagal balance; P < 0.001) compared to controls. These data indicate that heart rate variability is abnormal in patients with GHD. The decreased sympathetic tone could be a consequence of reduced central sympathetic tone or altered cardiac responsiveness to autonomic control and may contribute to the increased cardiovascular risk in GHD patients.

Apo E phenotype and changes in serum lipids in adult patients during growth hormone replacement.

OBJECTIVE: To determine whether apo E phenotype influences changes in lipid profiles induced by growth hormone replacement in growth hormone (GH)-deficient adults. DESIGNS: Patients were treated for 6 months with recombinant human GH (hGH), given in a dose of 0.125 U/kg per week for 4 weeks followed by 0.25 U/kg per week thereafter. The effects on serum lipids and the influence of apo E phenotype were examined. METHODS: Thirty patients (aged 35.1+/-11.8 years: mean +/- S.D.) with adult growth hormone deficiency with included in the study. Fasting serum samples were analysed for apo E phenotype total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, lipoprotein (a) (Lp(a)) and IGF-I. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedwald formula. RESULTS: Six months of replacement treatment with hGH resulted in a reduction in HDL-cholesterol from 0.90+/-0.10 to 0.68+/-0.08 mmol/l (P<0.01), and a small, non-significant reduction in total cholesterol from 6.14+/-0.40 to 5.99+/-0.35 mmol/l (P = 0.06). There was no significant change in the other lipid parameters. The decrease in HDL-cholesterol concentration was greater in patients carrying the apo E2 allele (0.40+/-0.07 mmol/l, P<0.05) than in patients homozygous for the apo E3 allele (0.23+/-0.04 mmol/l) and patients carrying the apo E4 allele (0.15+/-0.36 mmol/l). Patients with the apo E4 allele had lower baseline cholesterol concentrations than patients lacking the apo E4 allele, and this persisted after treatment with hGH (P<0.05). CONCLUSIONS: Apo E phenotype may be a determining factor in the response of HDL-cholesterol to hGH in GH-deficient adults.

Oncogenic hypophosphataemia and ectopic corticotrophin secretion due to oat cell carcinoma of the trachea.

A case of oat cell carcinoma causing Cushing's syndrome and oncogenic hypophosphataemic osteomalacia is reported. The association of the two disorders in one patient is believed to be unique and this is the second reported case of oncogenic osteomalacia caused by oat cell carcinoma.

Glycaemic control in a type 1 diabetes clinic for younger adults.

BACKGROUND: In the Diabetes Control and Complications Trial (DCCT, 1993) tight diabetes control (HbA1c <7%) was associated with significantly less microvascular complications compared to 'conventionally' treated type 1 patients. AIM: To assess the effectiveness of a dedicated young-adult type 1 diabetes clinic in achieving HbA1c levels <7% between 1991 and 2001. DESIGN: Retrospective review of case-notes. METHODS: All patients who attended the clinic in the first six years (1991 to 1996) were studied. All were offered at least two appointments per year. Case-notes were reviewed up to December 2001. RESULTS: We treated 386 type 1 patients (59.8% male, mean age 28.7 years, mean duration diabetes 9.5 years). After a mean follow-up of 7.7 years, 261 (67.6%) had attended in the past 2 years, 22 (5.8%) were known to have died, 11 (2.8%) had transferred to another clinic and 92 (23.8%) had repeatedly failed to attend appointments for 2 years. Over 11 years, the total mean (SD) HbA1c was 9.19% (1.3). Only 3.4% of patients achieved an average HbA1c of <7% during the study period, and 80% of patients had average HbA1c levels of >8%. DISCUSSION: Despite regular specialist physician, specialist diabetes nurse and dietician input, encouragement of multiple daily insulin injections and repeatedly following-up failed appointments (including home visits), fewer than 1:20 patients achieved the DCCT target of mean HbA1c <7%. Tight diabetes control is rare in a routine clinic setting.

Diabetic peripheral neuropathy and quality of life.

The quality of life (QOL) of 79 people with type 1 and type 2 diabetes and 37 non-diabetic controls was assessed using the Nottingham Health Profile (NHP). The NHP consists of six domains assessing energy, sleep, pain, physical mobility, emotional reactions and social isolation. Symptomatic diabetic neuropathy was present in 41 of the patients. The neuropathy patients had significantly higher scores (impaired QOL) in 5/6 NHP domains than either the other diabetic patients (p < 0.01) or the non-diabetic (p < 0.001) controls. These were: emotional reaction, energy, pain, physical mobility and sleep. The diabetic patients without neuropathy also had significantly impaired QOL for 4/6 NHP domains compared with the non-diabetic control group (p < 0.05) (energy, pain, physical mobility and sleep). This quantification of the detrimental effect on QOL of diabetes, and in particular of chronic symptomatic peripheral diabetic neuropathy, emphasizes the need for further research into effective management of these patients.

CSF enkephalins in diabetic neuropathy.

CSF methionine and leucine enkephalins were measured by high performance liquid chromatography and radioimmunoassay in diabetic patients with painful neuropathy (n = 22) and painless neuropathy (n = 5), and non-diabetic subjects with low back pain (n = 11). Wide variations in CSF enkephalin levels were found and they were often below the limit of detection (less than 0.1 pmol/l) in the diabetic and non-diabetic groups. The origin of CSF enkephalins is unknown and CSF levels may not reflect tissue concentrations. In conclusion, CSF enkephalin levels are difficult to interpret and do not provide useful information on the function of enkephalinergic pathways.

Nicotine administration reduces neuropeptide Y and neuropeptide Y mRNA concentrations in the rat hypothalamus: NPY may mediate nicotine's effects on energy balance.

Neuropeptide Y (NPY) is synthesized in arcuate (ARC) neurons which project principally to the paraventricular nucleus (PVN). NPY injected into the PVN causes hyperphagia, reduced energy expenditure and eventually obesity, effects which are opposed by nicotine. We aimed to investigate whether nicotine's effects on energy balance might be mediated by inhibition of hypothalamic NPYergic neurons. Nicotine or saline was given for 1 or 12 days using osmotic minipumps, and additional groups of rats were food-restricted to the intake of the nicotine-treated groups to allow for the effects of hypophagia on hypothalamic NPY. One day's nicotine treatment (12 mg/kg/day) reduced food intake by 30% (P < 0.001) and body weight by 2% (P < 0.01 vs. controls). NPY mRNA levels were significantly reduced by 40% (P < 0.05) and NPY concentrations fell significantly by 33% in the ARC and PVN (both P < 0.01). Matched food restriction also reduced NPY levels significantly in the ARC and PVN (P < 0.02 vs. controls) but had no effect on NPY mRNA. 12 days' nicotine treatment (12 mg/kg/day) lowered cumulative food intake by 8% (P = 0.02) and body weight by 10% (P < 0.05). NPY mRNA levels rose by 40% (P < 0.05), while NPY levels again fell in the ARC and PVN (both P < 0.05). Food restriction, which induced weight loss comparable with that during nicotine treatment, increased NPY mRNA to levels that were 100% above controls (P < 0.01) and also significantly higher than in the nicotine-treated group (P < 0.05). Food restriction also reduced NPY peptide levels in the PVN (P < 0.02), but did not affect those in the ARC. In addition, 12 days' nicotine treatment significantly reduced plasma insulin levels compared with controls (P < 0.05). We suggest that nicotine may inhibit NPY synthesis in the hypothalamus, independently of any effects due to altered energy balance. Reduced activity of NPYergic neurons in the ARC-PVN projection may mediate the effects of nicotine on energy balance.

Longitudinal changes in serum fructosamine do not parallel those in glycated haemoglobin in young adults with insulin-dependent diabetes.

In 93 adolescent and young adult patients with type 1 diabetes (163 paired comparisons) changes in fructosamine concentration correlated poorly with changes in HbA1 (r = 0.53); this correlation was no better if fructosamine values were adjusted for serum albumin by calculating a fructosamine/albumin index, F.A.I. (155 pairs, r = 0.50). These correlation coefficients were lower than those for cross-sectional comparisons (HbA1 vs. fructosamine, r = 0.74; HbA1 vs. F.A.I., r = 0.80). One-way analysis of variance showed that values of HbA1, fructosamine and F.A.I. all tended to increase as glycaemic control, judged by the clinician, worsened (P less than 0.001). HbA1 correlated better with clinical assessment than did either uncorrected fructosamine or F.A.I. We conclude that changes in fructosamine from one clinic visit to the next do not provide a basis for changing therapy. Clinical assessments tend to agree with values for HbA1, which may be more reliable than fructosamine because of its longer biological half life.