Penny J. Hunt

Immunoreactive amino‐terminal pro‐brain natriuretic peptide (NT‐PROBNP): a new marker of cardiac impairment

Human brain natriuretic peptide‐32 (BNP) (i.e. proBNP(77–108)), the mature form of BNP and secreted predominantly by the cardiac ventricle, is formed from a high molecular weight precursor, proBNP(1–108). We have recently identified the aminoterminal form proBNP(1–76) (NT‐proBNP) in human plasma but its source, metabolism and production in circulatory disorders are unknown. We have investigated the relationship between immunoreactive (IR) NT‐proBNP and BNP‐32 in normal and hypertensive subjects and in patients with cardiac impairment, as well as the regional plasma concentrations in patients undergoing routine cardiac catheterization.

Association of the TSHR gene with Graves' disease: the first disease specific locus

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD ‘blocks’ and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 × 10−6, OR 1.7) with Graves’ disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1366 AITD cases and 1061 controls (GD, P=2 × 10−6, OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.

Mortality and morbidity in Cushing’s syndrome in New Zealand

Objectiveu2002 Untreated Cushing’s syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population‐based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand.

The Effects of Pathophysiological Increments in Brain Natriuretic Peptide in Left Ventricular Systolic Dysfunction

Plasma levels of brain natriuretic peptide (BNP) are raised in patients with left ventricular impairment and may play a role in the adaptation to left ventricular impairment. Manipulation of BNP levels may have therapeutic potential. The effects of BNP have not been well studied in patients with left ventricular impairment. We studied the effects of low-dose BNP infusion, reproducing the increment in plasma BNP seen with progression from mild to severe heart failure in patients with impaired left ventricular systolic function. BNP was infused in a placebo-controlled, single-blind, crossover design at a rate of 3.3 pmol x kg(-1) x min(-1) over 4 hours to 8 patients with a history of congestive heart failure and persistent impairment of left ventricular systolic function (left ventricular ejection fraction <35%). Endocrine, renal, and hemodynamic effects were measured. Compared with time-matched placebo-control, BNP infusion decreased mean systemic arterial pressure (peak decrease, 17.1 mm Hg; P=.04), mean pulmonary artery pressure (peak decrease, 6.1 mm Hg; P=.007), mean pulmonary capillary wedge pressure (peak decrease, 5.5 mm Hg; P=.04), and systemic vascular resistance (peak decrease, 1400 dyne s(-1) cm(-5); P=.015), but cardiac output and heart rate were unchanged. Urinary volume and urinary excretion of sodium and potassium were not altered. BNP infusion increased plasma cGMP (2.3-fold change, P=.002). Plasma atrial natriuretic peptide levels were increased for the first hour of BNP infusion (peak increase, 11.5 pmol/L; P=.005). Plasma aldosterone levels were unchanged during but increased over time-matched control levels after the end of the BNP infusion (peak increase, 90 pmol/L; P=.02). Plasma renin activity and cortisol and catecholamine levels were unchanged. Low-dose infusion of BNP causes favorable hemodynamic changes and relative neurohormonal suppression but has attenuated renal effects in patients with impaired left ventricular systolic function.

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

Objectiveu2002 Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects.

Intermittent severe, symptomatic hyponatraemia due to the nephrogenic syndrome of inappropriate antidiuresis

A 20-year-old fit male soldier presented on two separate occasions 16 months apart with severe, symptomatic hyponatraemia and a clinical and biochemical picture consistent with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In the intervening period, repeated plasma sodium values were in the reference range. Intensive investigation failed to reveal a cause for SIADH that was initially considered idiopathic. The description of a family comprising several adults with intermittent or water load induced-hyponatraemia associated with an activating mutation in the arginine vasopressin (AVP) receptor type 2 (AVPR2) raised the question of whether our patient could have a similar ‘nephrogenic syndrome of inappropriate antidiuresis’. Mutational screening of AVPR2 in our patient revealed a single missense mutation (R137C) in the second intracellular loop, which has been associated with constitutive activation of the AVPR2. In conclusion, adults with intermittent, severe hyponatraemia may have a constitutively activating mutation in the AVPR2 with resultant nephrogenic syndrome of inappropriate antidiuresis. Patients with idiopathic SIADH, particularly those with unmeasurable circulating AVP concentrations, should be considered for mutational screening of AVPR2.

Intraosseous lipoma of the body of the sphenoid bone

A case of intraosseous lipoma arising from the body of the sphenoid bone with intrasellar and suprasellar components is reported. This is the first report of this uncommon tumour occurring in an atypical intracranial site, producing the locally invasive and pressure effects of visual failure and hypopituitarism. The diagnosis was based on computed tomographic (CT) and magnetic resonance (MR) imaging with histological confirmation following frontal craniotomy.

Impact of Month of Birth on the Development of Autoimmune Thyroid Disease in the United Kingdom and Europe

CONTEXTnViral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves disease (GD) and Hashimotos thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life.nnnOBJECTIVEnMonth of birth effects were investigated in three independent European Caucasian AITD datasets.nnnDESIGNnVariation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test.nnnSETTINGnThe study was conducted at a research laboratory.nnnPATIENTSnNational UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent).nnnMAIN OUTCOME MEASURESnCase-control and family-based association studies were measured.nnnRESULTSnNo consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walters test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort.nnnCONCLUSIONnOur results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Another cause of 'pseudophaeochromocytoma'--quetiapine associated with a false positive normetanephrine result.

We report a case of elevated plasma and urinary normetanephrines in a patient with a pararenal mass treated with quetiapine. A 31-year-old woman was referred for assessment of a left pararenal mass. She had borderline personality disorder with depression and psychosis treated with quetiapine (SeroquelTM, AstraZeneca, Wilmington, DE) 200 mg mane and 800 mg nocte. She had epilepsy, asthma and chronic idiopathic neutropenia. Her other medications were lamotrigine 200 mg bd, budesonide inhaler 200 μ g 2 puffs bd, turbutaline inhaler 250 μ g 2 puffs prn, zopiclone 7·5 mg nocte and clonazepam 0·5 mg prn. She also had endometriosis and a pelvic ultrasound incidentally identified the left pararenal mass. A computed tomography (CT) scan showed a 32 × 25 × 39 mm mass adjacent to the left renal hilum with heterogenous enhancement, flecks of calcification and an unenhanced density reading of 14 hounsfield units. Biochemical investigation revealed increased urinary normetanephrine excretion (1·7–2·8 × upper limit normal), increased plasma normetanephrine concentration (2 × upper limit normal) and on one occasion, increased urinary metanephrine excretion (see Table 1). Urine metanephrines and normetanephrines were analysed in the local hospital laboratory using high performance liquid chromatography with electrochemical detection (HPLC-EC) (Bio-Rad Laboratories, Richmond, CA). Plasma metanephrines and normetanephrines were analysed at Princess Alexandra Hospital, Brisbane, Australia using in-house HPLC-EC. At clinical assessment there were no symptoms or signs to suggest a hormonally active lesion and specifically no hypertension, headaches or ‘spells’ to suggest phaeochromocytoma. Chronic neutropenia was noted with a neutrophil count of 0·9 × 10 9 /l and other biochemical tests, including creatinine and electrolytes, were normal. Alpha blockade with phenoxybenzamine was initiated and the patient was referred to an endocrine surgeon for removal of the possible extra-adrenal phaeochromocytoma. The mass was successfully removed and histology showed spindle cells with an eosinophilic cytoplasm. Immunostaining was strongly positive for S100 consistent with a schwanoma. Two weeks postoperatively the urinary normetanephrine excretion remained elevated. To evaluate this further, quetiapine was withheld for one week and the tests repeated (Table 1). The plasma and urinary normetanephrine concentrations normalized off quetiapine with corresponding levels of metanephrine also lower, strongly suggesting that the increased values were secondary to the psychotropic drug. Her other medications were unchanged. Of note, during these assessments the patient was not using the inhaled beta-agonist as her asthma was well controlled on inhaled corticosteroids. A radiologically evident but clinically inapparent adrenal mass is present in 0·5–2% of the general population and in about 7% of those over 70 years old. 1 Current guidelines recommend screening these patients for possible phaeochromocytoma with measurement of metanephrine and normetanephrine. 1

Management of hypertension and heart failure in patients with Addison's disease

Addisons disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin‐angiotensin‐aldosterone axis in Addisons disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addisons disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy.