The role of the melanocortin receptors in adrenal growth, development and stem cell maintenance

PhDThe adrenal gland is a highly dynamic organ with the ability to respond to changes in its environment with rapid changes in hormone production, and dramatic remodelling of its structure. Our understanding of the role of the melanocortin peptides in this process has been mostly restricted to the anterior pituitary hormone ACTH, via the melanocortin 2 receptor MC2R. The presence of additional melanocortin receptors and their antagonists has been demonstrated in rat and bovine adrenals, but the role of these in humans has not been well explored. An intensive clinical and biochemical work-up of a single patient with ACTH-independent Cushing’s syndrome and a gastrointestinal stromal tumour (GIST) was performed. The data presented are consistent with the possibility that her disease was caused by release of some bioactive molecule released from the GIST. We propose that alpha-MSH is a possible candidate for this molecule, on the basis that the GIST immuno-stained for alpha- MSH but not ACTH, that alpha-MSH but not ACTH was present in supernatant from a primary culture, and that alpha-MSH has the potential to stimulate cortisol production from adrenal cells. The precise mechanism for alpha-MSH secretion from the tumour is not fully elucidated, and further work is required to corroborate this hypothesis. The patient had both pigmented skin and pigmented adrenal nodules, and we further demonstrated the presence of the alpha-MSH receptor MC1R was demonstrated with her excised adrenal gland. The pigment was identified as melanin, and we went on to show that same pattern in primary pigmented nodular adrenal disease, and to demonstrate that the zona reticularis in normal adrenal gland contains melanin, and has additional features in common with melanocytic tissues elsewhere in the body. The role of alpha-MSH in normal adrenal function, and the possibility that melanin is also playing an important role, perhaps for its antioxidant properties, is an exciting area for future study.Barts and The London Charity Dunhill Medical Trus

The diagnostic certainty levels of junior clinicians: a retrospective cohort study

Background: Clinical decision-making is influenced by many factors, including clinicians’ perceptions of the certainty around what is the best course of action to pursue. Objective: To characterise the documentation of working diagnoses and the associated level of real-time certainty expressed by clinicians and to gauge patient opinion about the importance of research into clinician decision certainty. Method: This was a single-centre retrospective cohort study of non-consultant grade clinicians and their assessments of patients admitted from the emergency department between 01 March 2019 and 31 March 2019. De-identified electronic health record proformas were extracted that included the type of diagnosis documented and the certainty adjective used. Patient opinion was canvassed from a focus group. Results: During the study period, 850 clerking proformas were analysed; 420 presented a single diagnosis, while 430 presented multiple diagnoses. Of the 420 single diagnoses, 67 (16%) were documented as either a symptom or physical sign and 16 (4%) were laboratory-result-defined diagnoses. No uncertainty was expressed in 309 (74%) of the diagnoses. Of 430 multiple diagnoses, uncertainty was expressed in 346 (80%) compared to 84 (20%) in which no uncertainty was expressed. The patient focus group were unanimous in their support of this research. Conclusion: The documentation of working diagnoses is highly variable among non-consultant grade clinicians. In nearly three quarters of assessments with single diagnoses, no element of uncertainty was implied or quantified. More uncertainty was expressed in multiple diagnoses than single diagnoses. Implications: Increased standardisation of documentation will help future studies to better analyse and quantify diagnostic certainty in both single and multiple working diagnoses. This could lead to subsequent examination of their association with important process or clinical outcome measures

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course