Phosphodiesterases and cAMP pathway in pituitary diseases

© 2019 Bizzi, Bolger, Korbonits and Ribeiro-Oliveira. Human phosphodiesterases (PDEs) comprise a complex superfamily of enzymes derived from 24 genes separated into 11 PDE gene families (PDEs 1-11), expressed in different tissues and cells, including heart and brain. The isoforms PDE4, PDE7, and PDE8 are specific for the second messenger cAMP, which is responsible for mediating diverse physiological actions involving different hormones and neurotransmitters. The cAMP pathway plays an important role in the development and function of endocrine tissues while phosphodiesterases are responsible for ensuring the appropriate intensity of the actions of this pathway by hydrolyzing cAMP to its inactive form 5'-AMP. PDE1, PDE2, PDE4, and PDE11A are highly expressed in the pituitary, and overexpression of some PDE4 isoforms have been demonstrated in different pituitary adenoma subtypes. This observed over-expression in pituitary adenomas, although of unknown etiology, has been considered a compensatory response to tumorigenesis. PDE4A4/5 has a unique interaction with the co-chaperone aryl hydrocarbon receptor-interacting protein (AIP), a protein implicated in somatotroph tumorigenesis via germline loss-of-function mutations. Based on the association of low PDE4A4 expression with germline AIP-mutation-positive samples, the available data suggest that lack of AIP hinders the upregulation of PDE4A4 protein seen in sporadic somatotrophinomas. This unique disturbance of the cAMP-PDE pathway observed in the majority of AIP-mutation positive adenomas could contribute to their well-described poor response to somatostatin analogs and may support a role in tumorigenesis.We are grateful for the support by Fundação de Amparo à Pesquisa de Minas Gerais—Fapemig (AR-O), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (AR-O, MB) and the Medical Research Council UK (MK), and the NIH, USA (GB)

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

Eye and foot checks in patients with diabetes on haemodialysis: Are they done, and who does them?

AIM: To determine if retinal and foot checks are carried out on patients with diabetes receiving haemodialysis. METHODS: Eighty-four patients with diabetes receiving haemodialysis were asked if they recalled having eye and foot screening in the last year, and if so, by whom was the check done. RESULTS: Seventy-seven (91.7%) patients recalled having an eye check in the preceding 12 mo. Of these, 52 (67.5%) did so in an ophthalmology clinic, 17 (22%) in retinal screening, three (3.9%) in an optician clinic. Three patients (3.9%) went to both ophthalmology and retinal screening, and two (2.6%) attended an ophthalmology and optician. Seventy (83.3%) patients recalled having a foot check in the preceding 12 mo. Of these, 33 (47.1%) were done by practice nurse, 14 (20%) by a diabetes nurse, 11 (15.7%) by a general practitioner, eight (11.4%) by a chiropodist, and four (5.7%) were each checked by renal nurse, diabetes consultant, junior doctor, or unknown person at a foot clinic. CONCLUSION: Most patients with diabetes on haemodialysis are able to recall having an eye check in the last year, although 8.3% could not. A significant proportion of patients could not recall having a foot check (16.7%) in the last year. This baseline audit suggests that an improvement in the rate of foot screening is important to achieve in patients with diabetes on haemodialysis in our unit