Association Between Aldosterone and Hypertension Among Patients With Overt and Subclinical Hypercortisolism

Posted on December 20, 2022 by MaryO

Abstract

Introduction

Hypertension is one of the most common clinical features of patients with overt and subclinical hypercortisolism. Although previous studies have shown the coexistence of autonomous cortisol and aldosterone secretion, it is unclear whether aldosterone plays a role in hypertension among patients with hypercortisolism. Therefore, we examined the associations of plasma aldosterone concentrations (PACs) with hypertension among patients with overt and subclinical hypercortisolism.

Methods

This single-center retrospective cohort study included patients with adrenal tumor and serum cortisol levels after 1-mg dexamethasone suppression test >1.8 µg/dL (50 nmol/L). Using multivariable regression models adjusting for baseline characteristics, we investigated the association of PACs with systolic blood pressure and postoperative improvement of hypertension after the adrenalectomy.

Results

Among 89 patients enrolled in this study (median age, 51 years), 21 showed clinical signs of Cushing syndrome (overt hypercortisolism) and 68 did not show clinical presentations (subclinical hypercortisolism). We found that higher PACs were significantly associated with elevated systolic blood pressure among patients with subclinical hypercortisolism (adjusted difference [95% CI] = +0.59 [0.19-0.99], P = 0.008) but not among those with overt hypercortisolism. Among 33 patients with subclinical hypercortisolism and hypertension who underwent adrenalectomy, the postoperative improvement of hypertension was significantly associated with higher PACs at baseline (adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01).

Conclusion

These findings indicate that aldosterone may contribute to hypertension among patients with subclinical hypercortisolism. Further multi-institutional and population-based studies are required to validate our findings and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Cortisol production in the adrenal gland is regulated by the hypothalamus-pituitary-adrenal (HPA) axis. Subclinical hypercortisolism is a status characterized by the alteration of HPA axis secretion without typical signs or symptoms of overt hypercortisolism (eg, moon face, truncal obesity, easy bruising, thin extremities, proximal myopathy, cutaneous purple striae) [1, 2]. Although overt hypercortisolism can be detected by its clinical presentations or severe complications, it is sometimes challenging for clinicians to appropriately diagnose subclinical hypercortisolism because of the absence of such clinical presentations [2]. The 1-mg overnight dexamethasone suppression test (1-mg DST) measures the response of the adrenal glands to ACTH through the HPA axis and therefore has been widely used for screening and diagnosis of subclinical hypercortisolism [1, 3]. The European Society of Endocrinology Guideline has defined a partial suppression of the HPA axis (ie, serum cortisol levels after 1-mg DST [F-DST] > 1.8 µg/dL [50 nmol/L]) without clinical signs of overt cortisol hypersecretion as “possible autonomous cortisol secretion” and recommended screening these patients for metabolic disorders including hypertension and type 2 diabetes mellitus to offer appropriate treatment of these comorbidities [4].

Hypertension is one of the most common and distinguishing clinical features in patients with subclinical hypercortisolism [2] as well as overt hypercortisolism [5]. Although hypertension can be triggered by excess cortisol levels [5, 6], it is still unclear whether even slightly elevated cortisol levels among individuals with subclinical hypercortisolism contribute to the occurrence of hypertension. This raises another potential mechanism to cause hypertension such as the coexistence of hyperaldosteronism (ie, excess aldosterone that is an essential steroid hormone for sodium reabsorption, water retention, and blood pressure control) [7]. Previous studies have reported that 10% to 20% of primary aldosteronism is accompanied by cortisol-producing adenoma [8-10], and autonomous cortisol secretion was decreased after the resection of the aldosterone-producing adenoma (a subtype of primary aldosteronism) [11]. Furthermore, a previous mass spectrometry-based analysis revealed that cortisol secretion was frequently found in patients with primary aldosteronism [12]. Although these studies have examined cortisol biosynthesis in primary aldosteronism [13], evidence about whether aldosterone plays a role in the occurrence of hypertension among people with subclinical hypercortisolism is limited.

To address this knowledge gap, we performed a cohort study examining the association between aldosterone and hypertension among patients with adrenal tumor and F-DST >1.8 µg/dL, stratified by whether patients had clinical signs of Cushing syndrome or not. We first analyzed the cross-sectional association between aldosterone and blood pressure at baseline. Then, we analyzed the longitudinal association between aldosterone at baseline and the improvement rate of hypertension after the adrenalectomy. Last, to further clarify the role of aldosterone in the regulation of blood pressure in subclinical hypercortisolism, we described the difference in aldosterone response to ACTH after the adrenalectomy according to the postoperative improvement of hypertension.

Materials and Methods

Data Sources and Study Participants

A retrospective cohort study was designed to assess the clinical characteristics (focusing on aldosterone) among patients with hypercortisolism at the Yokohama Rosai Hospital from 2008 to 2017. We enrolled 89 patients with adrenal tumor and F-DST > 1.8 µg/dL (50 nmol/L) [3, 4, 14]. We then categorized them into 2 groups: (1) overt hypercortisolism (F-DST > 5.0 µg/dL [138 nmol/L]) and having clinical signs of Cushing syndrome (moon face, central obesity, dorsocervical fat pad [buffalo hump], purple striae, thin skin, easy bruising, and proximal myopathy] [15]) and (2) subclinical hypercortisolism (not having such clinical signs). All patients with overt hypercortisolism in this study showed F-DST > 5.0 µg/dL (138 nmol/L). The study was approved by the research ethics committee of the Yokohama Rosai Hospital, and all participants provided written informed consent.

Measurements

Demographic characteristics were self-reported, and body mass index (BMI) was calculated using measured weight and height. Systolic blood pressure was measured in the sitting position using a standard upper arm blood pressure monitor after a 5-minute rest in a quiet place [16]. The mean of 2 measurements was recorded. If the measurement was done only once on a given occasion, the level obtained was recorded. When the patients were already taking antihypertensives at enrollment, they were asked to report their blood pressure levels at the diagnosis of hypertension (ie, systolic blood pressure before starting antihypertensives). Blood samples were collected at 8:00 AM after the patient had rested in the supine position for 30 minutes. We measured F (µg/dL, × 27.6 for nmol/L) and ACTH (pg/mL, × 0.220 for pmol/L) using chemiluminescent enzyme immunoassay and electrochemiluminescent immunoassay, respectively. Plasma aldosterone concentrations (PACs; ng/dL, × 27.7 for pmol/L) and plasma renin activities (PRAs; ng/mL/h) were measured using radioimmunoassay. Any antihypertensive drugs were replaced with calcium channel antagonists (including dihydropyridine calcium channel antagonists) and/or α blocker several weeks before the measurement of PACs and PRAs according to the clinical guideline of the Japan Endocrine Society [17]. We also measured urine aldosterone (µg/day × 2.77 for nmol/d) and urine cortisol (µg/day, × 2.76 for nmol/d) using radioimmunoassay. The tumor size was estimated using contrast-enhanced thin-section computed tomography scans of the adrenal glands.

To evaluate whether the patients had autonomous cortisol secretion, we performed 1-mg DST, in which dexamethasone (1 mg) was administered at 11:00 PM, and blood samples were drawn at 8:00 AM the following morning. F and ACTH were measured in 1-mg DST.

The total or partial adrenalectomy was performed in all cases with overt hypercortisolism. For patients with subclinical hypercortisolism, the adrenalectomy was recommended to those who showed F-DST > 5.0 µg/dL (138 nmol/L) accompanying metabolic disorders [3]. It was also recommended to those who were expected to improve their clinical symptoms and/or metabolic disorders by the tumor resection, which included patients with hypertension possibly resulting from autonomous aldosterone secretion as well as autonomous cortisol secretion from the adrenal gland. The adrenalectomy was conducted when patients agreed with the treatment plan through informed consent. To evaluate whether patients had autonomous aldosterone secretion, we used the screening criterion of primary aldosteronism (ie, PAC/PRA ratio; aldosterone-to-renin ratio [ARR] > 20), followed by the confirmatory tests of primary aldosteronism that included the saline infusion test, captopril challenge, and/or furosemide stimulation test [17].

For patients who were considered to receive a benefit by the adrenalectomy and who agreed with the examination, we performed the segment-selective adrenal venous sampling to assess the laterality of hyperaldosteronism [18-20]. First, blood samples were collected from the bilateral central adrenal veins before ACTH stimulation. Then, we collected samples from the superior, lateral, and inferior tributaries of the right central adrenal vein and the superior and lateral tributaries of the left central adrenal vein after ACTH stimulation. Aldosterone excess (ie, hyperaldosteronism) was considered when the effluent aldosterone concentrations were > 250 ng/dL before ACTH stimulation and 1400 ng/dL after ACTH stimulation, respectively [18-20]. We used the absolute value instead of the lateralization index because individuals included in our study had elevated cortisol concentrations given the inclusion criteria (ie, F-DST >1.8 µg/dL [50 nmol/L]). For 9 patients with subclinical hypercortisolism who showed bilateral adrenal nodules, the side of adrenalectomy was determined by the nodule size and the results of adrenal venous sampling (ie, laterality of hyperaldosteronism). The adrenalectomy was conducted when patients agreed with the treatment plan through informed consent. Immunohistochemical evaluation of aldosterone synthase cytochrome P450 (CYP11B2) was conducted for some resected nodules.

To evaluate the postoperative cortisol responsiveness to ACTH, we performed an ACTH stimulation test a year after the adrenalectomy, in which blood samples were collected and PAC and F were measured 30 and 60 minutes after ACTH administration. Postoperative improvement of hypertension was defined as blood pressure <140/90 mmHg without antihypertensives or the reduction of the number of antihypertensives to maintain blood pressure <140/90 mmHg after the adrenalectomy.

Statistical Analyses

We describe the demographic characteristics and endocrine parameters at baseline comparing patients with overt hypercortisolism and those with subclinical hypercortisolism using the Fisher exact test for categorical variables and Mann-Whitney U test for continuous variables. Second, for each group, we investigated the association between the baseline characteristics and systolic blood pressure using ordinary least-squares regression models. The model included age, sex, BMI, serum potassium levels, estimated glomerular filtration rate, tumor size, and F and PAC at 8:00 AM. Third, we estimated the risk difference and 95% CI of the improvement rate of hypertension after the adrenalectomy according to these baseline characteristics (including systolic blood pressure) using a modified least-squares regression model with a Huber-White robust standard error [21]. Last, to evaluate whether the improvement of hypertension is related to postoperative cortisol and aldosterone secretion, we compared PAC and F responsiveness to ACTH from peripheral blood samples between patients who improved hypertension and those who did not using the Mann-Whitney U test. The longitudinal and postoperative analyses were performed among patients with subclinical hypercortisolism because only 2 cases with overt hypercortisolism failed to show the improvement of hypertension after the adrenalectomy.

To assess the robustness of our findings, we conducted the following 2 sensitivity analyses. First, we replaced F at 8:00 AM with F after DST in our regression models. Second, we estimated the risk difference of the improvement rate of hypertension after the adrenalectomy according to the postoperative F and PAC levels after ACTH stimulation, adjusting for the baseline characteristics included in our main model.

We also conducted several additional analyses. First, to investigate the relationship of change in PAC after adrenalectomy with the improvement rate of hypertension, we included decrease in PAC between before and after adrenalectomy instead of PAC at baseline in the model. Second, to assess the relationship between aldosterone and hypertension among patients with subclinical hypercortisolism without primary aldosteronism, we reran the analyses excluding patients who met the diagnostic criteria of primary aldosteronism. Third, to understand the overall association, we reran the analyses using all samples as a single group to assess the relationship among people with overall (ie, overt and subclinical) hypercortisolism. Last, we compared PAC and F responsiveness with ACTH during adrenal venous sampling between patients with and without postoperative improvement of hypertension. All statistical analyses were performed using Stata, version 15.

Results

Among the 89 enrolled patients, 21 showed clinical signs of overt Cushing syndrome and 68 did not. The flow of the study population is shown in Fig. 1. Among 21 patients with overt hypercortisolism, 19 patients had hypertension. All patients underwent adrenalectomy, and 16 patients showed improved hypertension levels after the surgery (1 patient was referred to another hospital; therefore, no information is available). Among 68 patients with subclinical hypercortisolism, 63 had hypertension. After the evaluation of autonomous aldosterone secretion as well as autonomous cortisol secretion, of 33 patients who underwent adrenalectomy, 23 (70%) showed improved hypertension levels after the adrenalectomy (10 patients in the surgery group decided not to undergo adrenalectomy). Patients with subclinical hypercortisolism who underwent adrenalectomy showed lower PRA and higher ARR than those without adrenalectomy (Supplementary Table S1) [22].

 

Figure 1.

Enrollment and follow-up of the study population after the adrenalectomy. aThe prevalence of patients with overt hypercortisolism and hypertension among this study population may be higher than in the general population and therefore needs to be carefully interpreted given that the study institute is one of the largest centers for adrenal diseases in Japan. bAll patients in this category showed autonomous cortisol secretion (ie, serum cortisol levels >5.0 µg/dL [138 nmol/L] after a 1-mg dexamethasone suppression test). cOne case underwent adrenalectomy at another hospital and therefore no information was available after the adrenalectomy. dThe adrenalectomy was performed for 33 patients who were expected to improve their clinical symptoms and/or metabolic disorders, including hypertension. This assessment was mainly based on autonomous cortisol secretion evaluated by a 1-mg dexamethasone suppression test, complicated metabolic disorders, and autonomous aldosterone secretion evaluated by adrenal venous sampling for patients who were positive for the screening and confirmatory tests of primary aldosteronism. Details in the assessment can be found in the Methods section or elsewhere [18-20].

Demographic Characteristics and Endocrine Parameters Among Patients With Overt and Subclinical Hypercortisolism

The median age (interquartile range) was 51 years (46, 62 years), and 72% were female. Patients with overt hypercortisolism were relatively younger and showed a higher estimated glomerular filtration rate and larger tumor size compared with patients with subclinical hypercortisolism (Table 1). Other demographic characteristics were similar between these groups. Patients with overt hypercortisolism showed higher F with undetected low ACTH, higher F after DST, and higher urine cortisol levels compared with those with subclinical hypercortisolism who instead showed higher PAC and ARR. Among patients with subclinical hypercortisolism, 9/68 (13.2%) showed undetectable ACTH levels and 25/68 (36%) were positive for PA screening criterion (ie, ARR > 20) followed by at least 1 positive confirmatory test. Based on the results of adrenal venous sampling of these cases, 9 showed aldosterone excess in the right nodules, 6 showed aldosterone excess in the left nodules, and 7 showed aldosterone excess on both sides, respectively (3 cases did not show aldosterone excess on both sides). Immunohistochemical evaluation of CYP11B2 was examined for 6 resected adrenal glands, and all of them showed positive expression.

 

Patients’ characteristicsa Patients with overt hypercortisolism (N = 21) Patients with subclinical hypercortisolism (N = 68) P
Age, y 46 [38-52] 54 [47-63] 0.002
Female, n (%) 18 (85.7) 46 (67.7) 0.11
Body mass index, kg/m2 23.4 [20.6-26.2] 23.1 [21.7-25.1] 0.94
Systolic blood pressure, mm Hg 156 [140-182] 162 [151-191] 0.29
Diastolic blood pressure, mm Hg 98 [92-110] 100 [90-110] 0.73
Serum potassium, mEq/Lb 3.9 [3.5-4.0] 3.8 [3.6-4.0] 0.98
eGFR, mL/min/1.73 m2 86.7 [77.3-123.0] 82.1 [69.8-87.7] 0.02
Tumor size by CT scan, mm 28 [25-30] 22 [17-26] 0.001
ACTH, 8:00 AM − c 6.6 [2.4-11.8] —
F, 8:00 AM 16.6 [12.5-18.8] 9.5 [7.7-12.0] <0.001
PRA, 8:00 AM 0.7 [0.4-1.3] 0.5 [0.2-1.0] 0.10
PAC, 8:00 AM 8.3 [7.2-9.8] 9.2 [7.2-16.2] 0.09
ARR, 8:00 AM 10.0 [6.4-16.7] 21.0 [9.8-46.5] 0.02
F after DST 16.5 [14.4-18.7] 5.1 [3.2-7.5] <0.001
Urine cortisol 220.0 [105.0-368.0] 49.5 [37.4-78.5] <0.001
Urine aldosterone 5.7 [3.9-10.1] 7.2 [4.8-13.1] 0.16

Conversion to SI units: ACTH, pg/mL × 0.220 for pmol; F, µg/dL × 27.6 for nmol/L; PAC, ng/dL × 27.7 for pmol/L; urine aldosterone, μg/day × 2.77 for nmol/d; Urine cortisol, μg/day × 2.76 for nmol/d.

Abbreviations: ARR, aldosterone-to-renin ratio; CRH, corticotropin-releasing hormone; CT, thin-section computed tomography; DST, 1-mg dexamethasone suppression test; eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.

aData are presented as median (interquartile range) or count (proportions) unless otherwise indicated.

bSerum potassium levels were controlled using potassium supplement/tablets at enrollment.

cUndetected in all cases.

Association of Demographic Characteristics and Endocrine Parameters With Systolic Blood Pressure

Among patients with overt hypercortisolism, we did not find a significant association of demographic characteristics and endocrine parameters with systolic blood pressure (Table 2). However, among patients with subclinical hypercortisolism, we found that higher PACs at 8:00 AM were significantly associated with systolic blood pressure (adjusted coefficient [95% CI] = +0.59 [0.19-0.99], P = 0.008). The results did not change when we used F after DST instead of F at 8:00 AM (Supplementary Table S2) [22].

Table 2.

Cross-sectional association of demographic characteristics and endocrine parameters with systolic blood pressure among patients with overt and subclinical hypercortisolism

Outcome Systolic blood pressure at baseline
Groups Patients with overt hypercortisolism Patients with subclinical hypercortisolism
Parameters Adjusted coefficient (95% CI) P Adjusted coefficient (95% CI) P
Age, y +1.73 (0.17-3.30) 0.03 +0.49 (−0.13 to 1.10) 0.12
Female −7.48 (−76.75 to 61.79) 0.81 +15.38 (−0.83 to 31.59) 0.06
Body mass index +5.47 (−2.4 to 13.33) 0.15 +1.07 (−0.49 to 2.63) 0.17
Serum potassium +11.29 (−23.42 to 45.99) 0.48 −9.61 (−26.38 to 7.15) 0.26
eGFR −0.12 (−1.00 to 0.77) 0.77 −0.44 (−0.89 to 0.01) 0.06
Tumor size −2.39 (−6.92 to 2.14) 0.26 +0.40 (−0.46 to 1.26) 0.35
F, 8:00 AMa,b +1.96 (−1.27 to 5.18) 0.20 +1.26 (−1.00 to 3.52) 0.27
PAC, 8:00 AMa −2.86 (−7.38 to 1.66) 0.18 +0.59 (0.19-0.99) 0.008

Abbreviations: DST, 1-mg dexamethasone suppression test; eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.

aACTH and PRA were not included in the main model because they have strong correlation with F and PAC, respectively (ie, multicollinearity). The results did not change when additionally adjusting for ACTH and PRA.

bThe results did not change when we replaced F at 8:00 AM with F after DST (Supplementary Table S2).

Association of Demographic Characteristics and Endocrine Parameters With Hypertension Improvement After the Adrenalectomy Among Patients With Subclinical Hypercortisolism

Among 33 patients with subclinical hypercortisolism and hypertension who underwent the adrenalectomy, we found that age and higher PAC were significantly associated with a higher improvement rate of hypertension after the adrenalectomy (age, adjusted risk difference [95% CI] = +2.36% [1.08-3.64], P = 0.001; PAC, adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01; Table 3). The results did not change when we used F after DST instead of F at 8:00 AM (Supplementary Table S3) [22]. Patients with improved hypertension after the surgery showed significantly lower PACs 60 minutes after a postoperative ACTH stimulation test than those without the improvement of hypertension (P = 0.05), although F and PAC/F ratio were not significantly different between these 2 groups (Table 4). The association between lower PACs after postoperative ACTH stimulation and higher improvement rate of hypertension was also found in the multivariable regression analysis adjusting for baseline characteristics (adjusted risk difference [95% CI] = −1.08% [−1.92 to −0.25], P = 0.01; Supplementary Table S4) [22].

Table 3.

Longitudinal association of demographic characteristics and endocrine parameters with hypertension improvement after the adrenalectomy among patients with subclinical hypercortisolisma

Outcome Hypertension improvement after the adrenalectomy
Parameters Adjusted risk difference (95% CI) P
Age +2.36% (1.08-3.64) 0.001
Sex (female) −11.32% (−61.37 to 38.73) 0.64
Body mass index −5.08% (−10.29 to 0.13) 0.06
Systolic blood pressure −0.67% (−1.77 to 0.43) 0.22
Serum potassium −0.06% (−31.84 to 31.71) 1.00
eGFR +0.53% (−0.36 to 1.42) 0.23
Tumor size +0.79% (−1.35 to 2.93) 0.45
F, 8:00 AMb,c −2.81% (−7.43 to 1.81) 0.22
PAC, 8:00 AMb +1.45% (0.35-2.55) 0.01

Abbreviations: eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.

aAnalysis was not performed for patients with overt hypercortisolism because only 2/18 cases failed to show improved hypertension after the adrenalectomy.

bACTH and PRA were not included in the main model because they have strong correlation with F and PAC, respectively (ie, multicollinearity). The results did not change when additionally adjusting for ACTH and PRA.

cThe results did not change when we replaced F at 8:00 AM with F after DST (Supplementary Table S3).

 

Table 4.

Aldosterone and cortisol response to ACTH a year after the adrenalectomy according to hypertension improvement status among patients with subclinical hypercortisolisma

Outcome: hypertension improvement status after the adrenalectomy Improvement (+) (N = 23) Improvement (−) (N = 10)
Parameters Median [IQR] Median [IQR] P
PAC 60 min after ACTH stimulation 13.6 [10.0-16.7] 15.5 [13.7-43.1] 0.05b
F 60 min after ACTH stimulation 16.9 [13.7-20.6] 18.5 [13.5-24.7] 0.61
PAC/F ratio 60 min after ACTH stimulation 0.70 [0.52-1.39] 1.27 [0.50-5.44] 0.26

Conversion to SI units: F, µg/dL × 27.6 for nmol/L; PAC, ng/dL × 27.7 for pmol/L.

Abbreviations: F, serum cortisol; PAC, plasma aldosterone concentration.

aAnalysis was not performed for patients with overt hypercortisolism because only 2/18 cases failed to show improved hypertension after the adrenalectomy.

bThe association was also observed after adjusting for baseline characteristics (eg, age, sex, body mass index, systolic blood pressure, serum potassium, estimated glomerular filtration rate, tumor size) and F 60 min after ACTH stimulation a year after the adrenalectomy (Supplementary Table S4).

Additional Analyses

Decreased PAC between before and after adrenalectomy was significantly associated with hypertension improvement (Supplementary Table S5) [22]. When we restricted samples to those without primary aldosteronism, PACs at baseline tended to be associated with systolic blood pressure but the 95% CI included the null (Supplementary Table S6) [22]. Decreased PAC after adrenalectomy was associated with hypertension improvement after the adrenalectomy, whereas PAC at baseline was not associated with that outcome (Supplementary Table S7) [22]. When we analyzed the entire sample (ie, both overt and subclinical hypercortisolism), PAC at baseline was associated with systolic blood pressure at baseline (Supplementary Table S8) [22] and hypertension improvement after the adrenalectomy (Supplementary Table S9) [22]. We also found the higher median value of PAC response to ACTH during adrenal venous sampling at the remained (ie, not resected by the adrenalectomy) side of adrenal gland among patients whose hypertension did not improve compared with those whose hypertension improved after the surgery, but the difference was not statistically significant (Supplementary Table S10) [22].

Discussion

In this retrospective cohort study, we found that higher aldosterone levels were associated with higher systolic blood pressure among patients with possible autonomous cortisol secretion and without clinical signs of overt Cushing syndrome (ie, subclinical hypercortisolism). In this group, higher aldosterone before the adrenalectomy was associated with the postoperative improvement of hypertension. Moreover, we found that patients with postoperative improvement of hypertension showed lower aldosterone response to ACTH after the adrenalectomy compared with those without the improvement of hypertension. Decrease in PACs after the adrenalectomy was associated with improved hypertension even among patients with subclinical hypercortisolism who did not have primary aldosteronism at baseline, whereas baseline PAC was not associated with that outcome. We found no evidence that aldosterone is associated with systolic blood pressure among patients with overt hypercortisolism. These findings indicate that elevated aldosterone may contribute to the presence of hypertension and its improvement rate after the adrenalectomy for patients with subclinical hypercortisolism.

To the best of our knowledge, this is one of the first studies to assess the potential role of aldosterone in hypertension among patients with overt and subclinical hypercortisolism, during both pre- and postoperative phases. Since aldosterone- and cortisol-producing adenoma was reported in 1979 [23, 24], several studies have assessed the cortisol production in aldosterone-producing adenoma clinically and histologically [8-10, 25] and showed the correlation between the degree of glucocorticoid excess levels and metabolic markers including BMI, waist circumference, blood pressure, insulin resistance, and high-density lipoprotein [12]. Prior research suggested that aldosterone-producing adenoma might produce cortisol as well as aldosterone even when serum cortisol levels after DST is less than 1.8 µg/dL (50 nmol/L) [11]. Although these studies have focused on cortisol synthesis among patients with aldosterone-producing adenoma, little is known about aldosterone synthesis among patients with cortisol-producing adenoma. Given that patients with hypercortisolism tend to have therapy-resistant hypertension and electrolyte disorders [8], our findings may generate the hypothesis that aldosterone contributes to the incidence and severity of hypertension in patients with possible autonomous cortisol secretion; this warrants further investigation.

There are several mechanisms by which cortisol excess leads to hypertension, such as regulating endothelial nitric oxide synthase expression modulated by 11β-hydroxysteroid dehydrogenases [26], activating the mineralocorticoid receptor [27] and upregulating vascular endothelin-1 [28]. Moreover, hypercortisolism impairs the production of endothelial vasodilators, including prostacyclin, prostaglandins, and kallikreins [29]. Despite these potential mechanisms, the direct effect of cortisol may not be sufficient to explain hypertension in patients with hypercortisolism, particularly subclinical hypercortisolism, and the presence of cortisol and aldosterone coproducing adenoma indicates another potential pathway to induce hypertension through aldosterone excess. Aldosterone is a steroid hormone not only promoting sodium reabsorption and volume expansion but also activating the mineralocorticoid receptor in the kidney and nonepithelial tissues (eg, adipose tissue, heart, endothelial cells, and vascular smooth muscle cells) [30]. It also induces oxidative stress, inflammation, fibrosis, vascular tone, and endothelial dysfunction [31]; therefore, aldosterone excess could induce hypertension even when it is slightly elevated [32]. A recent multiethnic study showed that aldosterone levels within the reference range were associated with subclinical atherosclerosis partially mediated through elevated blood pressure [33]. These mechanisms support our results indicating the potential contribution of aldosterone to hypertension among patients with subclinical hypercortisolism.

This study had several limitations. First, we did not have information on the duration of cortisol excess and therefore the estimated effect of cortisol on hypertension in our study might have been underestimated. The duration of exposure to mild hypercortisolism may be one of the important drivers of cardiovascular and metabolic disorders including irreversible vasculature remodeling in patients with subclinical hypercortisolism [2]. Second, we did not have the genetic information of adrenal tumors including aldosterone-producing adenoma. Given the heterogeneity of aldosterone responsiveness to ACTH [34] and postoperative hypertension resolution rate across genetic mutations (eg, KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1) [35], such information might affect our findings. Third, because of the nature of an observational study, we cannot rule out the unmeasured confounding. Fourth, because aldosterone and cortisol levels were measured at a single point, we may have a risk of mismeasurement. Moreover, when evaluating aldosterone levels, we used dihydropyridine calcium channel blockers to control hypertension based on the clinical guideline of primary aldosteronism in Japan; this might lower serum aldosterone levels. Fifth, because the present study was conducted at a single center, selection bias is inevitable [13]. Given that primary aldosteronism—one of the major causes of secondary hypertension—has still been underdiagnosed, partially because of insufficient recognition of clinical guidelines [36], our findings may indicate the importance of considering aldosterone when evaluating patients with subclinical hypercortisolism accompanied by hypertension. However, we need to carefully interpret the observed “prevalence” in this study because individuals potentially having subclinical hypercortisolism were likely to come to our hospital, which specializes the adrenal disorders, and thus the numbers do not reflect the prevalence in general population. The small number of resected adrenal glands with the evaluation of CYP11B2 expression in this study cohort also limits the prevalence estimation of primary aldosteronism. Finally, as we only followed up 1 year after the adrenalectomy, we could not evaluate the long-term resolution rate of hypertension. To overcome these limitations and generalize our findings, future molecular studies and multicenter longitudinal studies with sufficient individual datasets and longer follow-up are required.

In conclusion, plasma aldosterone concentrations were associated with systolic blood pressure and improvement rate of hypertension after the adrenalectomy among patients with subclinical hypercortisolism—possible autonomous cortisol secretion without clinical signs of overt Cushing syndrome. Our findings underscore the importance of considering aldosterone when patients have an adrenal tumor with possible autonomous cortisol secretion complicated with hypertension. Future molecular and epidemiological studies are warranted to identify the potential role of aldosterone in hypertension among patients with subclinical hypercortisolism, clarify how often these patients also have primary aldosteronism, and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Funding

K.I. was supported by the Japan Society for the Promotion of Science (JSPS; 21K20900 and 22K17392) and The Japan Endocrine Society. Study sponsors were not involved in study design, data interpretation, writing, or the decision to submit the article for publication. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflicts of Interest

All of authors confirm that there is no conflict of interest in relation to this work.

Data Availability

Restrictions apply to the availability of some data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

Abbreviations

 

  • ARR

    aldosterone-to-renin ratio

  • BMI

    body mass index

  • DST

    dexamethasone suppression test

  • F

    serum cortisol level

  • HPA

    hypothalamus-pituitary-adrenal

  • PAC

    plasma aldosterone concentration

  • PRA

    plasma renin activity

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
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© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

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Eyelid Edema Due to Cushing’s Syndrome

Posted on July 25, 2022 by MaryO

Abstract

Cushing’s syndrome (CS) shows diverse signs such as centripetal obesity, moon face, and buffalo hump, which can complicate the diagnosis. Facial features including eyelid edema, as an underrecognized sign, can be diagnostic clues for an excess of corticoids in a CS patient.

A 49-year-old woman presented with amenorrhea and weight gain that had continued for 2 years. Her medical history was dyslipidemia, hypertension, and osteoporosis. Physical examination revealed eyelid edemas (Figure 1A), moon face, buffalo hump, abdominal purple striae, and centripetal obesity (body mass index (BMI), 30.8 kg/m2). Basal plasma adrenocorticotropin was undetectable and serum cortisol level was high (16.9 μg/dl) without circadian rhythms. Free cortisol level in a 24-h urine collection was elevated (158.7 μg/day). Overnight administration of dexamethasone (1 mg) did not reduce serum cortisol level (17.4 μg/dl). Magnetic resonance imaging suggested bilateral adenomas. We made a diagnosis of adrenal Cushing’s syndrome (CS). Since 131l-adosterol scintigraphy showed specific uptake in the left adrenal gland, left adrenalectomy was laparoscopically performed. Histopathology of the tumor was compatible with adrenocortical adenoma. Three months after surgery, her BMI decreased to 25.0 kg/m2 and eyelid edemas were ameliorated (Figure 1B).

Details are in the caption following the image

(A) Bilateral eyelid edemas due to Cushing’s syndrome are shown. (B) These findings were improved three months after surgery for left adrenal adenomas

Eyelid edema, in addition to centripetal obesity, moon face, and buffalo hump, is also a significant sign of CS; however, it has scarcely been reported in countries other than Japan.1, 2 Increased capillary permeability, insufficient venous return due to muscle atrophy, and sodium retention due to mineralocorticoid actions conceivably cause edema in CS.

AUTHORS’ CONTRIBUTIONS

KY wrote the first draft and managed all the submission processes. KO and KH contributed to the clinical management of the patient. FO organized the writing the manuscript.

ACKNOWLEDGMENT

None.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

ETHICAL APPROVAL

Written informed consent was obtained from the patient to publish this case report.

  • 1Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015; 386: 913- 927.
  • 2Komiya I, Takasu N, Ohara N, et al. Forty-one cases of Cushing’s syndrome: a comparison between Cushing’s syndrome (adrenal adenoma) and Cushing’s disease (adrenal hyperplasia). Nihon Naibunpi Gakkai Zasshi. 1992; 68: 607- 622.

https://doi.org/10.1002/ccr3.5940

From https://onlinelibrary.wiley.com/doi/10.1002/ccr3.5940

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COVID-19 and Cushing’s syndrome: recommendations for a special population with endogenous glucocorticoid excess

Posted on March 3, 2021 by MaryO

Rosario Pivonello,a,b Rosario Ferrigno,a Andrea M Isidori,c Beverly M K Biller,d Ashley B Grossman,e,f and Annamaria Colaoa,b

Over the past few months, COVID-19, the pandemic disease caused by severe acute respiratory syndrome coronavirus 2, has been associated with a high rate of infection and lethality, especially in patients with comorbidities such as obesity, hypertension, diabetes, and immunodeficiency syndromes.

These cardiometabolic and immune impairments are common comorbidities of Cushing’s syndrome, a condition characterised by excessive exposure to endogenous glucocorticoids. In patients with Cushing’s syndrome, the increased cardiovascular risk factors, amplified by the increased thromboembolic risk, and the increased susceptibility to severe infections, are the two leading causes of death.

In healthy individuals in the early phase of infection, at the physiological level, glucocorticoids exert immunoenhancing effects, priming danger sensor and cytokine receptor expression, thereby sensitising the immune system to external agents. However, over time and with sustained high concentrations, the principal effects of glucocorticoids are to produce profound immunosuppression, with depression of innate and adaptive immune responses. Therefore, chronic excessive glucocorticoids might hamper the initial response to external agents and the consequent activation of adaptive responses. Subsequently, a decrease in the number of B-lymphocytes and T-lymphocytes, as well as a reduction in T-helper cell activation might favour opportunistic and intracellular infection. As a result, an increased risk of infection is seen, with an estimated prevalence of 21–51% in patients with Cushing’s syndrome. Therefore, despite the absence of data on the effects of COVID-19 in patients with Cushing’s syndrome, one can make observations related to the compromised immune state in patients with Cushing’s syndrome and provide expert advice for patients with a current or past history of Cushing’s syndrome.

Fever is one of the hallmarks of severe infections and is present in up to around 90% of patients with COVID-19, in addition to cough and dyspnoea. However, in active Cushing’s syndrome, the low-grade chronic inflammation and the poor immune response might limit febrile response in the early phase of infection. Conversely, different symptoms might be enhanced in patients with Cushing’s syndrome; for instance, dyspnoea might occur because of a combination of cardiac insufficiency or weakness of respiratory muscles. Therefore, during active Cushing’s syndrome, physicians should seek different signs and symptoms when suspecting COVID-19, such as cough, together with dysgeusia, anosmia, and diarrhoea, and should be suspicious of any change in health status of their patients with Cushing’s syndrome, rather than relying on fever and dyspnoea as typical features.

The clinical course of COVID-19 might also be difficult to predict in patients with active Cushing’s syndrome. Generally, patients with COVID-19 and a history of obesity, hypertension, or diabetes have a more severe course, leading to increased morbidity and mortality. Because these conditions are observed in most patients with active Cushing’s syndrome, these patients might be at an increased risk of severe course, with progression to acute respiratory distress syndrome (ARDS), when developing COVID-19. However, a key element in the development of ARDS during COVID-19 is the exaggerated cellular response induced by the cytokine increase, leading to massive alveolar–capillary wall damage and a decline in gas exchange. Because patients with Cushing’s syndrome might not mount a normal cytokine response, these patients might parodoxically be less prone to develop severe ARDS with COVID-19. Moreover, Cushing’s syndrome and severe COVID-19 are associated with hypercoagulability, such that patients with active Cushing’s syndrome might present an increased risk of thromboembolism with COVID-19. Consequently, because low molecular weight heparin seems to be associated with lower mortality and disease severity in patients with COVID-19, and because anticoagulation is also recommended in specific conditions in patients with active Cushing’s syndrome, this treatment is strongly advised in hospitalised patients with Cushing’s syndrome who have COVID-19. Furthermore, patients with active Cushing’s syndrome are at increased risk of prolonged duration of viral infections, as well as opportunistic infections, particularly atypical bacterial and invasive fungal infections, leading to sepsis and an increased mortality risk, and COVID-19 patients are also at increased risk of secondary bacterial or fungal infections during hospitalisation. Therefore, in cases of COVID-19 during active Cushing’s syndrome, prolonged antiviral treatment and empirical prophylaxis with broad-spectrum antibiotics,  should be considered, especially for hospitalised patients (panel ).

Panel

Risk factors and clinical suggestions for patients with Cushing’s syndrome who have COVID-19

Reduction of febrile response and enhancement of dyspnoea

Rely on different symptoms and signs suggestive of COVID-19, such as cough, dysgeusia, anosmia, and diarrhoea.

Prolonged duration of viral infections and susceptibility to superimposed bacterial and fungal infections

Consider prolonged antiviral and broad-spectrum antibiotic treatment.

Impairment of glucose metabolism (negative prognostic factor)

Optimise glycaemic control and select cortisol-lowering drugs that improve glucose metabolism. Hypertension (negative prognostic factor) Optimise blood pressure control and select cortisol-lowering drugs that improve blood pressure.

Thrombosis diathesis (negative prognostic factor)

Start antithrombotic prophylaxis, preferably with low-molecular-weight heparin treatment.

Surgery represents the first-line treatment for all causes of Cushing’s syndrome,,  but during the pandemic a delay might be appropriate to reduce the hospital-associated risk of COVID-19, any post-surgical immunodepression, and thromboembolic risks. Because immunosuppression and thromboembolic diathesis are common Cushing’s syndrome features,,  during the COVID-19 pandemic, cortisol-lowering medical therapy, including the oral drugs ketoconazole, metyrapone, and the novel osilodrostat, which are usually effective within hours or days, or the parenteral drug etomidate when immediate cortisol control is required, should be temporarily used. Nevertheless, an expeditious definitive diagnosis and proper surgical resolution of hypercortisolism should be ensured in patients with malignant forms of Cushing’s syndrome, not only to avoid disease progression risk but also for rapidly ameliorating hypercoagulability and immunospuppression; however, if diagnostic procedures cannot be easily secured or surgery cannot be done for limitations of hospital resources due to the pandemic, medical therapy should be preferred. Concomitantly, the optimisation of medical treatment for pre-existing comorbidities as well as the choice of cortisol-lowering drugs with potentially positive effects on obesity, hypertension, or diabates are crucial to improve the eventual clinical course of COVID-19.

Once patients with Cushing’s syndrome are in remission, the risk of infection is substantially decreased, but the comorbidities related to excess glucocorticoids might persist, including obesity, hypertension, and diabetes, together with thromboembolic diathesis. Because these are features associated with an increased death risk in patients with COVID-19, patients with Cushing’s syndrome in remission should be considered a high-risk population and consequently adopt adequate self-protection strategies to minimise contagion risk.

In conclusion, COVID-19 might have specific clinical presentation, clinical course, and clinical complications in patients who also have Cushing’s syndrome during the active hypercortisolaemic phase, and therefore careful monitoring and specific consideration should be given to this special, susceptible population. Moreover, the use of medical therapy as a bridge treatment while waiting for the pandemic to abate should be considered.

Acknowledgments

RP reports grants and personal fees from Novartis, Strongbridge, HRA Pharma, Ipsen, Shire, and Pfizer; grants from Corcept Therapeutics and IBSA Farmaceutici; and personal fees from Ferring and Italfarmaco. AMI reports non-financial support from Takeda and Ipsen; grants and non-financial support from Shire, Pfizer, and Corcept Therapeutics. BMKB reports grants from Novartis, Strongbridge, and Millendo; and personal fees from Novartis and Strongbridge. AC reports grants and personal fees from Novartis, Ipsen, Shire, and Pfizer; personal fees from Italfarmaco; and grants from Lilly, Merck, and Novo Nordisk. All other authors declare no competing interests.

References

1. Kakodkar P, Kaka N, Baig MN. A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19) Cureus. 2020;12 [PMC free article] [PubMed] []
2. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611–629. [PubMed] []
3. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17:233–247. [PubMed] []
4. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing’s syndrome. Trends Endocrinol Metab. 2020 doi: 10.1016/j.tem.2020.04.004. published online May 6, 2020. [PubMed] [CrossRef] []
5. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;80:607–613. [PMC free article] [PubMed] []
6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–1099. [PubMed] []
7. Isidori AM, Minnetti M, Sbardella E, Graziadio C, Grossman AB. Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur J Endocrinol. 2015;173:R101–R113. [PubMed] []
8. Nieman LK, Biller BM, Findling JW. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:2807–2831. [PMC free article] [PubMed] []
9. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36:385–486. [PMC free article] [PubMed] []
10. Newell-Price J, Nieman L, Reincke M, Tabarin A. Endocrinology in the time of COVID-19: management of Cushing’s syndrome. Eur J Endocrinol. 2020 doi: 10.1530/EJE-20-0352. published online April 1. [PubMed] [CrossRef] []

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Cushing’s syndrome in a child

Posted on February 3, 2021 by MaryO

Abstract

Cushing’s syndrome is a rare entity in children. Adrenal tumour is the common cause of this syndrome in young children, whereas, iatrogenic causes are more common among older children. We report a 4 year old male child diagnosed with Cushing syndrome due to a right adrenal adenoma; the child presented with obesity and increase distribution of body hair. After thorough investigation and control of hypertension and dyselectrolytemia, right adrenalectomy was performed. The patient had good clinical recovery with weight loss and biochemical resolution of Cushing’s syndrome.

1. Introduction

Cushing’s syndrome (CS) is rarely encountered in children. The overall incidence of Cushing syndrome is approximately 2–5 new cases per million people per year. Only approximately 10% of the new cases each year occur in children [1]. Unlike in adults, a male-to-female predominance have been observed in infants and young toddlers [[1], [2], [3]]. Although iatrogenic causes are common in children above seven years of age, adrenal causes (adenoma, carcinoma or hyperplasia) are common in children of younger age [4]. We report a 4 year old boy diagnosed with Cushing syndrome caused by a right adrenal adenoma, who had presented with obesity and increase distribution of body hair. Right adrenalectomy was performed and clinical stabilization resulted in weight loss and biochemical resolution of Cushing’s syndrome. (see Fig. 5)

2. Case report

A 4 years old boy presented with complaints of excessive weight gain of 5 months duration and increase frequency of micturition and appearance of body hair for 4 months. There was no history of any other illness, medication or steroid intake. The child was first born at term by normal vaginal delivery and birth weight of 3 kg. Physical examination revealed a chubby boy with moon face, buffalo hump, protruding abdomen, increase body hair and appearance of coarse pubic hair (Fig. 1). His intelligent quotient (IQ) was appropriate for his age and sex. His younger sibling was in good health and other family members did not have any metabolic or similar problems.

Fig. 1

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Fig. 1. The child with moon face, protruded abdomen and coarse body hair.

The patient’s body length was 92cm (between -2SD to -3SD), weight 20kg (between 1 SD and 2 SD), weight for height >3SD, and BMI was 23.6 (BMI for age >3 SD). His blood pressure on right arm in lying position was 138/76 mm Hg (above 99th percentile for height and age).

Investigations: Morning 8am serum cortisol level – 27.3 μg/dl (normal: 6–23 μg/dl).

with a concurrent plasma ACTH level of < 5 pg/ml (n value < 46 pg/ml).

His serum cortisol following low dose dexamethasone suppression test (1mg dexamethasone at 11pm) at 8 am next morning was 22.1 μug/dl and his 24 hours urine catecholamine fraction was within normal limit.

HB % — 10.3 gm/dl; LDDST — 25 μg/dl; FBS — 106 mg/dl.

Serum Na+ – 140.6mmol/l; K+ – 2.83mmol/l; Ca+ – 8.7 mg/dl.

S. Creatinine −0.3 mg/dl.

Ultrasonography of abdomen revealed a heterogenous predominantly hypoechoic right supra renal mass. Contrast enhanced CT abdomen revealed well defined soft tissue density lesion (size −5.2 cm × 5.2 cm x 5.7cm) in right adrenal gland with calcifications and fat attenuations showing mild attenuation on post contrast study (Fig. 2).

Fig. 2

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Fig. 2. CECT shows right adrenal mass with calcification and mild attenuation on post-contrast study.

The child was started on oral amlodipine 2.5mg 12hourly; after 5days blood pressure became normal. For hypokalemia oral potassium was given @20 meq 8 hourly and serum potassium value became normal after 4 days. Right laparoscopic adrenalectomy was planned. but due to intra operative technical problems it was converted to an open adrenalectomy with right subcostal incision. A lobulated mass of size 9 cm × 5 cm x 4 cm with intact capsule was excised. The tumour weighed 230 gm. There was no adhesion with adjacent organs, three regional nodes were enlarged but without any tumour tissue. Inferior vena cava was spared. Histopathology report was consistent with adrenal adenoma (Fig. 3) (see Fig. 4).

Fig. 3

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Fig. 3. Cut section of tumour shows fleshy mass with fatty tissue.

Fig. 4

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Fig. 4. Microphotograph (100 × 10) showing intact capsule and adrenal tumour cells, which are larger in size with nuclear pleomorphism, inconspicuous nucleoli, cytoplasm of the tumour cells are abundant, eosinophilic and vacuolated.

Fig. 5

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Fig. 5. Physical appearance 4 months after adrenalectomy.

Post operative management: during post operative period hypokalemia and flaxuating blood sugar level was managed with oral potassium and oral glucose supplement. patient developed mild cough and respiratory distress on post op day 2, it was managed with salbutamol nebulization and respiratory physio therapy. Patient developed minor ssi and discharged on 10 th post operative day with oral prednisolone supplementation.

Follow up: the patient was followed up 2week after discharge and then every monthly, the oral prednisolone was gradually tapered and completely withdrawn on 2nd month after surgery.The patient experienced no post-surgical complications. After 4 months of surgery he reduces 6 kgs of his body weight with BMI of 16.5 (between median and 1SD) & BP 100/74 mm hg (within normal range), the moon face, buffalo hump, central obesity disappeared, morning 8am serum cortisol level was found within normal range 14 μg/dl (n value 6–23 μg/dl).

3. Discussion

Cushing’s syndrome is caused by prolonged exposure to supraphysiological levels of circulating glucocorticoids, which may be endogenously or exogenously derived. During infancy, CS is usually associated with McCune-Albright syndrome; adrenocortical tumours most commonly occur in children under four years of age and Cushing’s disease (ACTH dependent) is the commonest cause of CS after five years of age [5]. Primary adrenocortical tumours (ACTs) account for only 0.3–0.4% of all childhood neoplasms. Almost a third of these tumours manifests as Cushing syndrome and over 70% of the unilateral tumours in young children are often malignant [2,3,6,7]. There seems to be a bimodal incidence of these tumours, with one peak at under 5 years of age and the second one in the fourth or fifth decades of life. ACTs may be associated with other syndromes, such as, Li-Fraumeni syndrome, Beckwith-wiedemann syndrome, isolated hemihypertrophy, or even a germline point mutation of P53 tumour suppressor gene as reported in a series from Brazil [8]. In comparison to adult CS, growth failure with associated weight gain is one of the most reliable indicators of hypercortisolaemia in pediatric CS. The parents often fail to notice facial changes and growth failure and hence the diagnosis is often delayed. In one study, the mean time from appearing symptoms to diagnosis in 33 children with Cushing’s disease was 2.5 years [5]. More recently the comparison of height and BMI SDS measurements provided a sensitive diagnostic discriminator in pediatric patients with CD and those with simple obesity [9]. In the present case, the parents observed noticeable changes in his face and presence of body hair, which made them to bring the child to medical attention. A review of 254 children on the International Pediatric Adrenocortical Tumour Registry identified virilization as the most common manifestation [10]. About 10% of the tumours can be non-functional at presentation, and approximately one third of pediatric patients present with hypertension. Majority of patients (192/254) in the Registry had localized disease and metastatic disease was found in less than 5% of cases. Older children with CS or mixed androgen and cortisol secreting adrenocortical tumours had a worse prognosis compared to younger children [10]. The present case had mild hypertension as well as dyselectrolytemia at presentation, which could be controlled with medication. He had a single adenoma confined to the adrenal gland and there was no evidence of malignancy. After surgical excision of the tumour and the right adrenal gland, the patient made rapid improvement in clinical condition and has been on follow up for last 7 months.

4. Conclusion

Pediatric adrenocortical tumours (ACTs) are most commonly encountered in females and in children less than four years. But our case being an 4-year-old boy forms a rare presentation of endogenous Cushing’s syndrome due to adrenal adenoma. Cushing’s syndrome in this child was controlled after right adrenalectomy.

Patient consent

Informed written consent was taken.

Funding

No funding or grant support.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

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Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

Posted on September 25, 2019 by MaryO

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

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