Published by Bioscientifica Ltd. Printed in Great Britain © 2021 European Society of Endocrinology https://eje.bioscientifca.com https://doi.org/10.1530/EJE-21-0063 European Journal of Endocrinology 184:5 L17–L19 N Patel and R Mihai Phaeochromocytomas at high altitudes Relative hypoxia at high altitudes increases the incidence of phaeochromocytomas Neil Patel and Radu Mihai Department of Endocrine Surgery, Churchill Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK We read with great interest the recent paper reporting a high incidence of phaeochromocytomas and paragangliomas in an unselected population from the western region of Canada (1). All cases were identifed based on clinical data available over a 7 years period. Interestingly, Alberta has a higher altitude (3678 ft, https ://en -gb.t opogr aphic -map. com/m aps/l rg4/A lbert a/) compared with other geographical areas from where a lower incidence was reported in previous papers (Table 1). Similarly, detailed epidemiological data from multiple geographical area are not easily available. Previous reports involving the entire USA population cannot be scrutinised as they lack ‘granular details’ regarding states with different altitudes. There is, however, a convincing trend that suggests that high altitude (as in Alberta) and its associated relative hypoxia modulate the risk of development of phaeochromocytomas. In support of this hypothesis, in an analysis of 58 subjects from 23 families with SDHD mutations, subjects with phaeochromocytomas lived at higher altitudes and were exposed to higher altitude-years than those without them. Furthermore, those who were diagnosed with single tumours at their frst clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumours (7). Population-weighted elevations were approximately 260 m for the United States and 2 m for the central-Western Netherlands (P~0), suggesting that low altitudes in The Netherlands reduce penetrance and relax the natural selection on SDHD mutations (7). Previous basic research data provide a mechanism that could explain this relation through the pseudohypoxia model. Hypoxia-induced factor (HIF2α) is more intensely expressed in both noradrenergic sporadic and hereditary von–Hippel Lindau (VHL)-related tumours than in sporadic and familial adrenergic tumours . HIF-2α is also expressed in developing sympathetic neurones, where it regulates the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis (8). Such expression might confer onto these cells a susceptibility to VHL-associated tumorigenesis, thereby explaining both the development of such tumours and their associated noradrenergic phenotype (9). Robust data is available on the ability of hypoxia to modulate enzymatic activity needed for catecholamine production. Long-term hypoxia in ewes maintained at high altitude (3820 m) results in a selective reduction in plasma adrenaline following acute stress, due to a reduction in tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) expression (10). In animals conceived, born and raised at high altitude (3800 m, 13% PO 2 ), the activities of the synthesizing enzymes, TH, DDC and PNMT, were variably affected at some time during the perinatal period. The activities of the catabolizing enzymes, MAO and COMT, at high altitude were increased on the last days of gestation but depressed after birth (11). In laboratory settings, mouse pheochromocytoma cells (MP712 cells) showed a two-fold increase in PNMT mRNA after incubation in 5%O 2 , with an inverse relationship between PNMT gene reporter gene expression and O 2 concentration between 10 and 1%. Anoxia evokes the most pronounced response, detectable within 15 min, becoming maximal at 45 min then subsiding to normoxic levels by 120 min (12). Traditionally it is considered that noradrenaline (NA) and adrenaline (Adr) are stored in different types of intracellular granules. In a previous study using Correspondence should be addressed to R Mihai Email radumihai@doctors.org.uk Letter Downloaded from Bioscientifica.com at 01/13/2022 01:16:28PM via free access