Serum Cortisol and Cortisone as Potential Biomarkers of Partial 11β-Hydroxysteroid Dehydrogenase Type 2 Deficiency

Abstract

BACKGROUND Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11βHSD2 deficiency in those heterozygous subjects. METHODS We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21–3.69] and 2.54 [2.35–2.88], and in adults were 4.42 [3.70–4.90] and 2.23 [1.92–2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION Serum F/E ratio and cortisone allow to identify partial 11βHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure

“…THF and THE, is used to evaluate 11b-HSD2 genetic deficiency. 21,22 We therefore assessed the THF/THE ratios, and similar to the changes in absolute cortisol concentrations and F/E ratios, found that the THF/ THE ratio increased in 24/25 (96%) patients, 28/38 (74%) patients and 47/54 (87%) patients in study 1, study 2 and study 3, respectively. The cohorts in all three studies had a statistically significant rise in THF/THE (P < 0.001 for all studies).…”

GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome

“…These subtle RAAS abnormalities may reflect the degree of the HSD11B2 defect. Carvajal et al previously described some patients carrying HSD11B2 heterozygous mutations who were normotensive with normal kalemia but with a high serum cortisol/cortisone ratio, reflecting a decrease in 11β-HSD2 activity (53), and suggesting that partial 11β-HSD2 deficiency may not always lead to overt arterial hypertension. Another study showed that mice with 11β-HSD2 haploinsufficiency had a higher salt sensitivity of blood pressure (54), consistent with either a genetic susceptibility or a 'second hit' leading to a phenotype prone to develop hypertension or either a GR activation that could be excluded in GC-resistant patients owing to the deleterious consequences of GR loss-offunction mutations.…”

Genetics and pathophysiology of low-renin arterial hypertension

“…Однако в более легком варианте симптоматика сглажена, и болезнь практически неотличима от обычной эссенциальной гипертонии (Wilson et al, 1998). В качестве хорошего диагностического критерия рекомендуется оценивать величину соотношения кортизол/ кортизон (Carvajal et al, 2018). У детей это соотношение должно колебаться в пределах 2.21-3.69, а у взрослых -3.70-4.90.…”