TSH-secreting pituitary adenoma: benefits of pre-operative octreotide.

UNLABELLED: TSH-secreting pituitary adenomas are rare and the optimal investigation and management is uncertain. We describe a case of a 43 year-old woman with a TSH-secreting pituitary adenoma, highlighting diagnostic testing and our use, pre-operatively of somatostatin analogue therapy, which induced biochemical euthyroidism and a reduction in tumour size. LEARNING POINTS: The differential diagnosis of the syndrome of inappropriate TSH secretion is non-thyroidal illness, medications, assay interference due to heterophilic antibodies, thyroid hormone resistance and TSH-secreting pituitary adenoma.TRH stimulation test and triiodothyronine suppression test assist in differentiating thyroid hormone resistance and TSH-secreting pituitary adenoma.Somatostatin analogue therapy can induce biochemical euthyroidism and reduce tumour size.

Phaeochromocytoma crisis: two cases of undiagnosed phaeochromocytoma presenting after elective nonrelated surgical procedures.

Phaeochromocytoma is a catecholamine producing tumour and an uncommon cause of hypertension. We present two cases of relatively asymptomatic individuals, in which previously undiagnosed phaeochromocytoma was unmasked by elective nonadrenal surgical procedures, manifesting as postoperative hypertensive crisis and subsequent cardiogenic shock. The initial management in intensive care is discussed, in addition to the clinical and biochemical diagnostic challenges present. Successful adrenalectomy was performed in each case.

Adiponectin multimers, body weight and markers of cardiovascular risk in adolescence: Northern Ireland Young Hearts Project.

BACKGROUND: Research examining the relationship between adiponectin (AN) isoforms, body weight and cardiovascular (CV) risk factors is limited, particularly in younger populations. OBJECTIVES: To investigate the inter-relationships between AN isoforms and CV risk factors, and their dependence on body weight status, in adolescents. DESIGN: Blood samples from 92 obese, 92 overweight and 92 normal weight age- and sex-matched adolescents were analysed for traditional cardiovascular disease (CVD) risk biomarkers and also total, high molecular weight (HMW), medium and low molecular weight (LMW) AN. RESULTS: A significant inverse association was observed between total and HMW AN and waist-hip ratio (P=0.015, P=0.006, respectively), triglycerides (P=0.003, P=0.003, respectively) and systolic blood pressure (P=0.012, P=0.024, respectively) and a significant positive association with high-density lipoprotein (P<0.001, P<0.001, respectively) in multi-adjusted analyses. There was no evidence of a relationship between multimeric AN and high-sensitivity C-reactive protein. There was also little evidence of a relationship between LMW AN and CVD risk factors. There was a strong, body mass index (BMI)-independent, association between AN, CVD biomarkers and the hypertriglyceridemic waist phenotype. CONCLUSION: Prominent, BMI-independent associations between total and HMW AN, but not LMW AN, and CVD risk factors were already evident in this young population. This research in adolescents supports the contention that AN subfractions may have different biological actions. These associations in apparently healthy adolescents suggest an important role for AN and its subfractions in the pathogenesis of metabolic syndrome traits and indicate that the potential for total or HMW AN to act as early universal biomarkers of CV risk warrants further study.

100 cases of primary aldosteronism: careful choice of patients for surgery using adrenal venous sampling and CT imaging results in excellent blood pressure and potassium outcomes.

OBJECTIVE: Patients with primary aldosteronism (PA) who are suitable for surgery should undergo adrenal computerised tomography (CT) and adrenal venous sampling (AVS). A retrospective study was performed of 100 patients with PA. We determined the optimal AVS lateralisation ratio for unilateral disease and reviewed adrenalectomy outcomes evaluating which characteristics predicted hypertension cure. METHODS: AVS was performed in 93 patients. Lateralisation criteria were assessed using ROC curve analysis. The outcome of adrenalectomy was reviewed in 39 patients and predictive factors for cure determined using univariate and multivariate analysis. RESULTS: Of previously published criteria, ROC curve analysis found a cortisol corrected aldosterone affected to unaffected (Aldo/Cort A:U) cut-off of 2·0 was the best predictor of adenoma identifying 80·4% of patients. A novel ratio calculated by dividing the affected to unaffected ratio by the unaffected to peripheral ratio [(Aldo/Cort A:U)/(Aldo/Cort U:IVC)] was successful in identifying 87·0% of patients. Cure rate for blood pressure after adrenalectomy was 38·5% with improvement in 59·0%. On univariate analysis, predictors of post-operative hypertension were increased weight, raised creatinine, left ventricular hypertrophy (LVH) and male sex. On multivariate analysis, male sex and higher pre-operative systolic blood pressure were predictive. CONCLUSIONS: Patients with PA should have CT scanning and AVS. Aldo/Cort A:U >2·0 is the most accurate of previously published ratios in predicting unilateral disease. When patients were carefully selected for surgery, 97% had cure or improvement in blood pressure control. Further confirmatory work is required on a novel ratio which was even more predictive in our series.

Macroprolactinomas presenting as nasal polyps: a series of three cases.

BACKGROUND: Pituitary tumours that present with nasal symptoms are uncommon. Management can be difficult due to their aggressive nature, location and extension. METHODS: We report a series of three cases of prolactinomas that enlarged inferiorly presenting initially as nasal polyps. RESULTS: Recurrence of symptoms (case 1) prompted testing for serum prolactin and examination of histology confirmed the presence of a prolactinoma. In cases 2 and 3, radiological evidence of a pituitary mass prompted testing for a prolactinoma. No patients exhibited clinical signs of hyperprolactinaemia. All three cases have residual tumour at 2-4 years after diagnosis, despite prolactin levels approaching the normal range on dopaminergic therapy. CONCLUSION: Pituitary tumours that invade the nasal cavity are rare and clinicians should be aware of their existence. A prolactinoma should be considered in the differential diagnosis of nasopharyngeal tumours. Measurement of serum prolactin can expedite a diagnosis and prevent delay of treatment with dopamine agonists.

Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma.

The aim of this study is to review the experience of the clonidine suppression test in a regional endocrine centre and to compare the diagnostic sensitivity and specificity using various previous published criteria. The design used is retrospective study. The subjects include 56 patients in whom clonidine suppression tests had been performed from 1995 to 2000: 15 with phaeochromocytoma and 41 patients in whom the diagnosis was excluded using a combination of biochemical testing, abdominal computed tomography scanning and clinical follow-up. Plasma catecholamines were measured by high pressure liquid chromatography on basal samples and at hourly intervals for 3 h after the administration of clonidine 300 µg orally and the following diagnostic criteria were applied: plasma noradrenaline+adrenaline>2.96 nmol l(-1) at 3 h post-clonidine or a baseline plasma adrenaline plus noradrenaline>11.82 nmol l(-1); plasma noradrenaline>2.96 nmol l(-1) at 3 h post-clonidine and plasma noradrenaline>2.96 nmol l(-1) and <50% fall in noradrenaline at 3 h post-clonidine. The results obtained is that mean plasma noradrenaline plus adrenaline fell across the test in 40/41 patients in the non-phaeochromocytoma patients and was lowest at 3 h (basal 2.28 ± 0.14 vs 1.36 ± 0.11 nmol l(-1), P<0.001). In the phaeochromocytoma group, clonidine had a variable effect on adrenaline plus noradrenaline levels with increases in 7/15. Using an abnormal result as a 3 h level of noradrenaline plus adrenaline>2.96 mmol l(-1) gave a sensitivity of 93% and specificity of 95%. When a 3 h noradrenaline>2.96 mmol l(-1) was used, sensitivity was 87% and specificity 95%. Using the former criteria, noradrenaline plus adrenaline>2.96 mmol l(-1), 1/15 in the phaeochromocytoma group had a normal result after clonidine suppression testing. Two of 41 in the non-phaeochromocytoma group had a false-positive result. Under carefully controlled conditions, the clonidine suppression test is well tolerated, safe and accurate for use in the investigation of patients with suspected phaeochromocytoma.

Is there value in routine screening for Cushing's syndrome in patients with diabetes?

CONTEXT: Subclinical Cushing's syndrome has been described among diabetic populations in recent years, but no consensus has emerged about the value of screening. METHODS: We enrolled 201 consecutive patients attending our diabetes clinic and 79 controls. Patients with at least two of the following three criteria were offered screening using a 2300 h salivary cortisol test: glycosylated hemoglobin of at least 7%, body mass index of at least 25 kg/m(2), and a history of hypertension or blood pressure of at least 140/90 mm Hg. Results are expressed as mean +/- sem. RESULTS: Mean nighttime salivary cortisol levels were similar in the two groups (8.5 +/- 1.0 nmol/liter for diabetic patients vs. 5.8 +/- 1.0 nmol/liter for controls). Forty-seven patients (23%) had a value of at least 10 nmol/liter, which was set as a conservative threshold above which further investigation would be performed. Thirty-five (75%) agreed to further testing with a 1-mg overnight dexamethasone test. Of the remaining 12 patients, 10 were followed up clinically for at least 1 yr, and no evidence was found of the syndrome evolving. In 28 patients, serum cortisol suppressed to 60 nmol/liter or less. Of the seven patients who failed this test, four agreed to a 2 mg/d 48-h dexamethasone test, with serum cortisol suppressing to 60 nmol/liter or less in all four. Three declined this test but had normal 24-h urinary free cortisol levels. No patient had clinical features of hypercortisolism. CONCLUSIONS: The 1-3% detection rates of three recently published series have not been realized at our center where we studied a group using criteria making patients more likely to have hypercortisolism. Our results do not support the validity of screening patients without clinical features of Cushing's syndrome in the diabetes clinic.

Long term effect of external pituitary irradiation on IGF1 levels in patients with acromegaly free of adjunctive treatment.

OBJECTIVE: It is established that external pituitary irradiation (EPI) effectively reduces serum GH levels in acromegaly. However, its effect in normalising serum IGF1 has been disputed. We looked at the number of our patients who achieved persistently normal IGF1 levels whilst free of adjunctive treatment for at least 1 year after EPI. PATIENTS AND DESIGN: We identified 63 acromegalic patients between 1964 and 2004 who received EPI. Six were excluded: three had surgery after EPI, two had no medical records available, and one had a pituitary Yttrium implant. MEASUREMENTS: Patients received 4500-5000 cGy in fractionated doses. IGF1 levels were correlated with their respective age-related reference ranges. RESULTS: After EPI, the number of patients with normal IGF1 and free of adjunctive medical treatment for at least 1 year were four patients by 3 years, nine patients by 5 years and seventeen by 10 years, with the current number of 25/57 (44%). Concordance between IGF1 levels and random GH dropped from 90% at the time of EPI to 65% at 3 years, 66% at 5 years and 71% at 10 years. CONCLUSIONS: We have demonstrated that, with time, EPI achieves a normal IGF1 in significant numbers of patients with acromegaly, thus obviating the need for life-long expensive medical therapy. For each patient this benefit has to be weighed against the possibility of new hypopituitarism as a result of the treatment. Any decision to use EPI is easier in the context of pre-existent hypopituitarism.

Poor responses to a test dose of subcutaneous octreotide predict the need for adjuvant therapy to achieve 'safe' growth hormone levels.

OBJECTIVE: Somatostatin analogues are an established treatment in acromegaly. This study was designed to evaluate whether the acute serum growth hormone (GH) response to a test dose of octreotide in acromegaly predicts longer-term response to the drug at 3 years. DESIGN AND METHODS: In 23 patients, GH responses across 8 h to a subcutaneous test dose (50 microg) of octreotide were compared with GH levels after 3 years of therapy. The majority had pituitary surgery as primary therapy and at 3 years were receiving at least 600 microg octreotide daily subcutaneously or 20 mg LAR monthly intramuscularly. RESULTS: Seven had a test day GH Nadir of 5 mU/l or less of whom 4 achieved GH < 5 mU/l at 3 years. Sixteen had a test day nadir GH of 10 mU/l or less and of these 8 achieved GH < 5 mU/l at 3 years. Seven of the 23 had a GH Nadir >10 mU/l and of these 3 had achieved GH <5 mU/l at 3 years. However all of these 3 had received external pituitary irradiation within 4 years of the 3 year assessment, as compared with 3 of the <5 mU/l nadir group and 5 of the <10 mU/l nadir group. CONCLUSIONS: In patients on optimal long-term doses of octreotide for acromegaly, absence of a nadir GH <10 mU/l in the 8 h after a test dose was associated with failure to achieve GH levels associated with a normal life expectancy (5 mU/l or less) unless adjunctive external pituitary irradiation was given. As well as testing tolerability a test dose of octreotide may help in determining which patients should be offered early external pituitary irradiation or therapy with a GH receptor antagonist if surgery has failed to achieve 'safe' GH levels.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3-independent mechanism.

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes of cno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3-independent mechanism critical to the biogenesis of lysosome-related organelles. (Blood. 2000;96:4227-4235)

Neuropeptide variability in man.

BACKGROUND: Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. METHODS: We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. RESULTS: Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery. CONCLUSIONS: The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E-21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin.

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II. The GH response to hypoglycaemia was impaired and plasma levels of both IGF-I and the GH-dependent IGF binding protein (IGFBP-3) were low. A recently described unextracted assay directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II) allows direct plasma estimation (plasma E-21) of larger molecular forms of IGF-II without interference from normal IGF-II and IGF binding proteins. Basal values were grossly elevated (23.7 and 23.8 nmol/l). Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4.25 +/- 0.21 mol/l (mean +/- SEM) before treatment, compared with 4.86 mmol/l +/- 0.17 following GH (P < 0.01)) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP-3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change in plasma glucose levels or insulin-like growth factors. Two courses of intrahepatic adriamycin restored elevated levels of E-21 to normal. Total IGF-II remained normal and IGF-I increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of bupivacaine instillation and inguinal field block for control of pain after herniorrhaphy.

In a single-blind, randomised trial, 50 consecutive adult patients for inguinal herniorrhaphy under general anaesthesia received either an inguinal field block or bupivacaine instilled into the wound to provide postoperative analgesia. Bupivacaine instillation was found to be simple, safe and effective. The method is particularly appropriate for day-case surgery.

Primary malignant melanoma of the oesophagus. Report of a case with flow cytometric DNA analysis.

Primary malignant melanoma is a very rare tumour of the oesophagus, and although this is the first case reported in a black patient in South Africa, the clinical, radiographic and histopathological features were characteristic of this malignancy. Primary oesophageal melanoma is a highly lethal tumour--fewer than 2% of patients are surviving 5 years after diagnosis. Flow cytometric DNA analysis of the resected specimen in this case revealed two populations of malignant cells, one of which had grossly abnormal DNA. Existence of two clones of malignant melanoma cells supports the observations that this tumour is biologically aggressive, radioresistant and almost always incurable.

DNA ploidy in oesophageal cancer. A preliminary report.

Prognosis in oesophageal cancer is directly related to depth of invasion and lymph node metastases. However, without surgical exploration, assessment of the spread of oesophageal cancer is notoriously inaccurate and there is a need for another objective measurement of prognosis. In this study, the relationship of DNA-ploidy status to tumour length, histological appearance, extra-oesophageal spread and survival was examined in 42 patients with squamous oesophageal cancer. No correlation was found between DNA-ploidy status and tumour length or histological appearance. But the DNA-aneuploidy rate in cancers with extra-oesophageal spread was significantly greater than the rate in tumours localised to the oesophagus (P = 0.038). Short-term survival was poorer in patients with DNA-aneuploid cancers than in those with a DNA-diploid pattern. DNA analysis may prove to be a more accurate guide to prognosis in oesophageal cancer than either clinical or operative staging.

Gastric mucosal lesions induced by hemorrhagic shock in baboons. Role of oxygen-derived free radicals.

In this study we sought to define the role of oxygen-derived free radicals during ischemia and reperfusion in the production of acute damage to the gastric mucosa of baboons. The protective effect of the xanthine oxidase inhibitor, allopurinol, the superoxide scavenger, superoxide dismutase (SOD), and a long-acting SOD-albumin was determined. Mucosal damage was evaluated using light and scanning electron microscopy. Evidence for oxidative insult to the gastric mucosa was sought by measuring tissue concentrations of reduced (GSH) and oxidized (GSSG) glutathione. Gastric mucosal blood flow was estimated using the microsphere technique. A similar pattern of tissue damage was found at the end of ischemia in all three groups. Thirty minutes after reperfusion, severe mucosal damage (grade 3) increased only in the untreated control. In the two treated groups, grade 3 damage remained unchanged during reperfusion and a decrease in the percentage of moderate damage (grade 2) was seen. Both GSH and GSSG tissue concentrations were lower in the untreated controls as compared to the scavenger-treated groups, making it questionable whether GSH/GSSG tissue levels adequately reflect oxidative stress. We conclude that in our ischemia-reperfusion model the generation of oxygen-derived free radicals produces mucosal damage and prevents the restitution of moderate mucosal damage during reperfusion. In ischemia, factors other than free radicals seem to be responsible for mucosal damage. The protective effect of allopurinol and SOD was not mediated by changes in gastric mucosal blood flow.

Propofol for inpatient dental anaesthesia. A comparison of propofol as sole anaesthetic agent with thiopentone and halothane for inpatient dental anaesthesia.

The induction, maintenance and recovery characteristics of propofol anaesthesia were compared with thiopentone induction and halothane maintenance in 51 spontaneously breathing, intubated patients who underwent dental surgery. Induction with thiopentone produced fewer side effects than propofol, notably pain on injection. Control of the depth of anaesthesia was better in patients who breathed halothane than in those who received intermittent bolus doses of propofol. Recovery characteristics of the two groups were similar.