Karim Meeran

A Common and Recurrent 13-bp Deletion in the Autoimmune Regulator Gene in British Kindreds with Autoimmune Polyendocrinopathy Type 1

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.

The NPY Y1 receptor antagonist BIBP 3226 blocks NPY induced feeding via a non-specific mechanism.

We have previously shown that intracerebroventricular BIBP 3226 inhibits NPY induced feeding in rats. However, this was associated with abnormal behaviour, likely to be due to interaction with Y1 receptors involved in mechanisms other than the control of food intake. In order to minimise such interactions we investigated the effects of paraventricular nucleus (PVN) injections of BIBP 3226 and its inactive enantiomer BIBP 3435. Intra-PVN injection of NPY (0.1-2.5 nmol/animal) increased food intake, with an EC50 of approximately 0.15 nmol/animal. Injections of BIBP 3226 and BIBP 3435 (0.25-25 nmol) reduced NPY-induced food intake in a dose responsive manner, with BIBP 3226 reducing food intake by 95%, and BIBP 3435 by 65% at the highest dose tested. The reversibility of the effect of BIBP 3226 was investigated by measuring the feeding response to NPY (0.5 nmol) in animals 1 week after BIBP 3226 injection. The response to NPY was less in animals which had received high doses of BIBP 3226. Animals previously injected with saline vehicle alone showed a normal NPY feeding response. These results suggest that BIBP 3226 may be inhibiting NPY-induced food intake in a non-specific manner, not secondary to inhibition of the Y1 receptor. This does not, however rule out a role for the Y1 receptor in the control of food intake by NPY.

A tumour that secretes glucagon-like peptide-1 and somatostatin in a patient with reactive hypoglycaemia and diabetes

Glucagon-like peptide 1 (GLP-1), an insulinotropic hormone normally synthesised in the intestinal mucosa and released in response to a meal, is essential for normal glucose homoeostasis. There is much interest in the use of GLP-1 to treat diabetes, since the risk of hypoglycaemia is thought to be low. We report an instance of a 45-year-old woman with a GLP-1 and somatostatin secreting neuroendocrine tumour who presented with reactive hypoglycaemia and hyperglycaemia, but who was subsequently cured by surgery. This case, of a neuroendocrine tumour secreting GLP-1 and causing reactive hypoglycaemia, indicates a potential adverse effect of GLP-1 therapy for diabetes.

Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists

Background: Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy. Methods: In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured. Results: Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298±33 versus 204±30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups. Conclusion: This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy.

Measurement of basal growth hormone (GH) is a useful test of disease activity in treated acromegalic patients.

Background  Nadir GH during oral glucose tolerance test (OGTT) is the gold‐standard test of GH secretion in treated acromegaly. However, it was recently reported that variability in GH is reduced postradiotherapy, making basal GH a potential surrogate marker for nadir GH in such patients.

Weight loss in rats treated with intracerebroventricular cobalt protoporphyrin is not specific to the neuropeptide Y system

Cobalt protoporphyrin (CoPP) reduces food intake and body weight following intracerebroventricular (i.c.v.) administration in rats. We injected 0.2 mumol CoPP per kg body weight i.c.v. and monitored body weight and daily food intake for 7 days. The body weight and 24 h food intake of CoPP-treated animals was significantly lower than that of vehicle-treated animals in all studies (P < 0.01) from day 2 to day 7. The 2 h feeding response (CoPP vs. vehicle-treated) to 10 micrograms neuropeptide Y (NPY) (4.0 vs. 7.1 g; P < 0.05), the 1 h feeding response to 10 micrograms galanin (1.3 vs. 3.2 g; P < 0.05) and 30 micrograms norepinephrine (0.6 vs. 1.9 g; P < 0.05) in CoPP-treated animals were all reduced compared to the vehicle-treated group. In addition there was no change in hypothalamic NPY mRNA in CoPP-treated animals. I.c.v. CoPP decreases sensitivity to exogenous NPY, galanin and norepinephrine. The effect of CoPP is not specific to NPY as previously described.

Prednisolone 3 mg once daily should be the glucocorticoid replacement for hypopituitarism

Prednisolone is an alternative glucocorticoid that can be used for steroid replacement therapy1. It is structurally similar to hydrocortisone with the exception of a double bond between C1 and C2 on the first carbocyclic ring (Figure 1). This double bond gives prednisolone a longer half-life than prednisolone, permitting a one dose per day regimen. We herein present a case highlighting that prednisolone 3mg once daily can be used effectively in hypopituitarism.

Diagnosis and Preoperative Assessment (Algorithms) for Pancreatic NETs

PNETs arise from neuroendocrine cells within the pancreas. Most (up to 90 % in some series) do not secrete hormones (nonfunctioning) and may be an incidental finding on imaging. The rest are described as functioning. These exhibit hypersecretion of various hormones and are generally defined by their secretory products. They may produce one or more hormones, which subsequently give rise to a specific clinical picture (Table 8.1).

A man with anxiety, confusion, and red eyes

A 31 year old man presented with a four day history of anxiety, insomnia, and confusion. Over the past few months he had intermittently noticed red eyes and a “tummy ache.” A concomitant history from his parents revealed a previous episode of confusion and concern about excessive alcohol intake—he had been drinking 10 units of vodka a day for the past six years. He denied any medical history or current drugs. On examination, he was agitated, tachycardic (heart rate 110 beats/min), and he had bilateral conjunctivitis. Initial investigations showed a calcium concentration of 3.54 mmol/L (reference range 2.15-2.6) and metabolic alkalosis (table⇓). He was treated for acute hypercalcaemia with fluids and discharged when levels normalised. View this table: The patient’s biochemistry results at different time points Before further outpatient investigations were performed, he was readmitted two weeks later with confusion and a witnessed seizure. Investigations again showed a raised calcium (3.80 mmol/L), metabolic alkalosis, and new onset acute renal failure (table). Plasma glucose was normal. He was once again treated for acute hypercalcaemia and stabilised. On day three of admission, calcium carbonate tablets were discovered on his bedside table. He reported regularly ingesting up to three packets a day to treat symptoms of indigestion. ### 1 How do you explain this patient’s ocular symptoms? #### Short answer Bilateral conjunctivitis is a rare complication of severe hypercalcaemia. #### Long answer Although rare, hypercalcaemia can cause ocular complications, …