Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Early Marker of Remission

Posted on May 16, 2022 by MaryO

Abstract

Context

Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion.

Objective

Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD).

Design

Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission.

Results

Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], P = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], P = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), P = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status.

Conclusions

A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively.

Arginine vasopressin (AVP) and CRH act synergistically as the primary stimuli for secretion of ACTH, leading to release of cortisol [1, 2]. The role of AVP in the hypothalamic-pituitary-adrenal (HPA) axis is via release from the parvocellular neurons of the paraventricular nuclei (and possibly also from the magnocellular neurons of the paraventricular and supraoptic nuclei), the secretion of which is stimulated by stress [3-6]. AVP release results in both independent stimulation of ACTH release and potentiation of the effects of CRH [3, 7-9]. Additionally, there is evidence that glucocorticoids act by way of negative feedback to suppress AVP secretion [10, 11-20]. Further, parvocellular neurons of the hypothalamic paraventricular nuclei have been shown to increase AVP production and neurosecretory granule size after adrenalectomy, and inappropriately elevated plasma AVP has been reported in the setting of adrenal insufficiency with normalization of plasma AVP after glucocorticoid administration [21-24]. This relationship of AVP and its effect on the HPA axis has been used in the diagnostic evaluation of Cushing syndrome (CS) [14] and evaluation of remission after transsphenoidal surgery (TSS) in Cushing disease (CD) by administration of desmopressin [25].

Copeptin makes up the C-terminal portion of the AVP precursor pre-pro-AVP. Copeptin is released from the posterior pituitary in stoichiometric amounts with AVP, and because of its longer half-life in circulation, it is a stable surrogate marker of AVP secretion [26-28]. Plasma copeptin has been studied in various conditions of the anterior pituitary. In a study by Lewandowski et al, plasma copeptin was measured after administration of CRH in assessment of HPA-axis function in patients with a variety of pituitary diseases. An increase in plasma copeptin was observed only in healthy subjects but not in those with pituitary disease who had an appropriately stimulated serum cortisol, and the authors concluded that copeptin may be a sensitive marker to reveal subtle alterations in the regulation of pituitary function [7]. Although in this study and others, plasma copeptin was assessed after pituitary surgery, it has not, to the best of our knowledge, been studied as a marker of remission of CD before and after pituitary surgery [7, 29].

In this study, plasma copeptin levels were assessed as a surrogate of AVP secretion before and after TSS for treatment of CD. Because there is evidence that glucocorticoids exert negative feedback on AVP, we hypothesized that there would be a greater postoperative increase in plasma copeptin in those with CD in remission after TSS resulting from resolution of hypercortisolemia and resultant hypocortisolemia compared with those not in remission with persistent hypercortisolemia and continued negative feedback. In other words, we hypothesized that an increase in copeptin could be an early marker of remission of CD after TSS. We aimed to complete this assessment by comparison of the peak postoperative copeptin and change in copeptin from preoperative to peak postoperative copeptin for those in remission vs not in remission postoperatively.

Subjects and Methods

Subjects

Adult and pediatric patients with CD who presented at the Eunice Kennedy Shriver National Institute of Child Health and Human Development under protocol 97-CH-0076 and underwent TSS between March 2016 and July 2019 were included in the study. Exclusion criteria included a prior TSS within 6 weeks of the preoperative plasma copeptin sample or a preoperative diagnosis of diabetes insipidus, renal disease, or cardiac failure. Written informed consent was provided by patients aged 18 years and older and by legal guardians for patients aged < 18 years to participate in this study. Written informed assent was provided by patients aged 7 years to < 18 years. The 97-CH-0076 study (Investigation of Pituitary Tumors and Related Hypothalamic Disorders) has been approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development institutional review board.

Clinical and Biochemical Data

Clinical data were extracted from electronic medical records. Age, sex, body weight, body mass index (BMI), pubertal stage (in pediatric patients only), and history of prior TSS were obtained preoperatively during the admission for TSS. Clinical data obtained postoperatively included TSS date, histology, development of central diabetes insipidus (DI) or (SIADH), time from TSS to most recent follow-up, and clinical remission status at postoperative follow-up.

Preoperatively, serum sodium, 24-hour urinary free cortisol (UFC), UFC times the upper limit of normal (UFC × ULN), midnight (MN) serum cortisol, MN plasma ACTH, and 8 AM plasma ACTH were collected. Postoperatively, serum sodium, serum and urine osmolality, urine specific gravity, serum cortisol, and plasma ACTH were collected. For serum cortisol values < 1 mcg/dL, a value of 0.5 mcg/dL was assigned for the analyses; for plasma ACTH levels < 5 pg/mL, a value of 2.5 pg/mL was assigned.

Additionally, plasma copeptin levels were obtained preoperatively and on postoperative days (PODs) 1 through 8 after TSS at 8:00 AM. Peak postoperative copeptin was the highest plasma copeptin on PODs 1 through 8. The delta copeptin (Δcopeptin) was determined by subtracting the preoperative copeptin from the peak postoperative copeptin; hence, a positive change indicated a postoperative increase in plasma copeptin. Plasma copeptin was measured using an automated immunofluorescent sandwich assay on the BRAHMS Kryptor Compact PLUS Copeptin-proAVP. The limit of detection for the assay was 1.58 pmol/L, 5.7% intra-assay coefficient of variation, and 11.2% inter-assay coefficient of variation, with a lower limit of analytical measurement of 2.8 pmol/L. For those with multiple preoperative plasma copeptin values within days before surgery, an average of preoperative copeptin levels was used for analyses.

Diagnosis of CD was based on guidelines published by the Endocrine Society and as previously described for the adult and pediatric populations [30, 31]; diagnosis was further confirmed by either histologic identification of an ACTH-secreting pituitary adenoma in the resected tumor specimen, decrease in cortisol and ACTH levels postoperatively, and/or clinical remission after TSS at follow-up evaluation. All patients were treated with TSS at the National Institutes of Health Clinical Center by the same neurosurgeon. Remission after surgical therapy was based on serum cortisol of < 5 μg/dL during the immediate postoperative period, improvement of clinical signs and symptoms of cortisol excess at postoperative follow up, nonelevated 24-hour UFC at postoperative follow-up, nonelevated midnight serum cortisol at postoperative follow up when available, and continued requirement for glucocorticoid replacement at 3 to 6 months’ postoperative follow-up.

Diagnosis of SIADH was based on development of hyponatremia (serum sodium < 135 mmol/L) and oliguria (urine output < 0.5 mL/kg/h). Diagnosis of DI was determined by development of hypernatremia (serum sodium > 145 mmol/L), dilute polyuria (urine output > 4 mL/kg/h), elevated serum osmolality, and low urine osmolality.

Statistical Analyses

Results are presented as median (interquartile range [IQR], calculated as 25th percentile-75th percentile) or mean ± SD, as appropriate, and frequency (percentage). Where appropriate, we compared results using parametric or nonparametric testing; however, the median (IQR) and the mean ± SD were both reported to allow for comparisons with the appropriate testing noted. Subgroup analyses were completed comparing those who developed water balance disorders included patients who developed DI only (but not SIADH), those who developed SIADH only (but not DI), and those with no water balance disorder; hence, for these subgroup analyses, those who developed both DI and SIADH postoperatively (n = 4) were excluded. Preoperative copeptin, peak postoperative copeptin, and Δcopeptin were compared between those with and without remission at follow-up, using either t test or Wilcoxon rank-sum test, depending on the distribution of data. These were done in all patients combined, as well as within each subgroup. The same tests were used for comparing other continuous variables (eg, age, BMI SD score [SDS], cortisol excess measures) between those with and without remission. Categorical data (eg, sex, Tanner stage) were analyzed using the Fisher exact test. Comparisons of copeptin levels among the subgroups (DI, SIADH, neither) were carried out using mixed models and the Kruskal-Wallis test, as appropriate. Post hoc pairwise comparisons were adjusted for multiplicity using the Bonferroni correction, and as applicable, only corrected P values are reported. Mixed models for repeated measures also analyzed copeptin, serum sodium, and cortisol data for PODs 1 through 8. In addition, maximum likelihood estimation (GENMOD) procedures analyzed the effects of copeptin and serum sodium on the remission at follow-up. Correlation analyses were done with Spearman ρ. All analyses were tested for the potential confounding effects of age, sex, BMI SDS, and pubertal status, and were adjusted accordingly. For plasma copeptin reported as < 2.8 pmol/L, a value of 1.4 pmol/L (midpoint of 0 and 2.8 pmol/L) was used; sensitivity analyses repeated all relevant comparisons using the threshold limit of 2.8 pmol/L instead of 1.4 pmol/L. Odds ratios (OR) and 95% CIs, other magnitudes of the effect, data variability, and 2-sided P values provided the statistical evidence for the conclusions. Statistical analyses were performed in SAS version 9.4 software (SAS Institute, Inc, Cary, NC).

Results

Patient Characteristics

Forty-four adult and pediatric patients, aged 7 to 55 years (77.2% were < 18 years old), with CD were included in the study. The cohort included 28 female patients (64%), and the median BMI SDS was 2.2 (1.1-2.5). Thirty-four percent (15/44) had prior pituitary surgery (none within the prior 6 weeks). Seventy-five percent (33/44) had postoperative follow-up evaluations available, with median follow-up of 13.5 months (11.3-16.0). Of those 33 patients, 85% were determined to be in remission at follow-up. Comparing those in remission vs no remission, there was no difference in age, sex, BMI SDS, pubertal status (in pediatric ages only), preoperative measures of cortisol excess (UFC × ULN, PM serum cortisol, MN plasma ACTH, AM plasma ACTH), duration of follow-up, or development of DI or SIADH. There was a lower postoperative serum cortisol nadir in those in remission at follow-up compared with those not in remission at follow-up, as expected, because a postoperative serum cortisol < 5 μg/dL was included in defining remission status. Postoperatively, 8/44 (18%) developed DI, 13/44 (30%) developed SIADH, 4/44 (9%) developed both DI and SIADH, and 19/44 (43%) developed no water balance disorder (Table 1). There were no differences by remission status when assessing these subgroups (ie, DI, SIADH, and no water balance disorder) separately.

 
Table 1.

Demographic and clinical characteristics of subjects

All subjects, n = 44 All subjects by remission status, n = 33 All subjects by remission status, excluding those with DI or SIADH, n = 13
Remission, n = 28 No remission, n = 5 P Remission,
n = 10		 No remission, n = 3 P
Age, median (range), y 14.5 (7-55) 17.4 ± 10.7
14.5 (12.5-17.5)		 15.6 ± 13.2
11.0 (9.0-12.0)		 0.11 13.7 ± 3.1
14.0 (13.0-15.0)		 19.7 ± 16.8
11.0 (9.0-39.0)		 0.60a
Sex
Female		 28 (64%) 22 (78.6%) 3 (60.0%) 0.57 9 (90.0%) 2 (66.7%) 0.42
BMI SDS 2.2 (1.1-2.5) 1.7 ± 1.0
2.0 (0.9-2.5)		 2.2 ± 0.4
2.2 (2.1-2.3)		 0.70 1.7 ± 1.1
2.0 (0.7-2.5)		 2.0 ± 0.4
2.1 (1.5-2.3)		 0.65a
Pubertal status
Female (n = 19) (n = 15) (n = 2) 0.51 (n = 8) (n = 1) 0.44
  Tanner 1-2 6 4 (26.7%) 1 (50.0%) 3 (37.5%) 1 (25.0%)
  Tanner 3-5 13 11 (73.3%) 1 (50.0%) 5 (62.5%) 0
Male (n = 14) (n = 5) (n = 2) (n = 1) (n = 1) —
Testicular volume < 12, mL 10 4 (80.0%) 2 (10.00%) 1 (100.0%) 1 (100.0%)
Testicular volume ≥ 12, mL 4 1 (20.0%) 0 1.0 0 0
Preoperative UFC ULN 3.3 (1.2-6.1) 4.9 ± 6.1
2.6 (1.0-7.6)		 3.2 ± 1.3
3.7 (3.0-3.9)		 0.70 7.2 ± 8.4
3.9 (1.8-9.1)		 3.8 ± 0.7
3.9 (3.0-4.4)		 0.93
Preoperative PM cortisol 11.9 (9.2-14.8) 13.3 ± 4.7
12.2 (9.2-16.8)		 10.8 ± 2.1
11.5 (9.0-11.6)		 0.30 13.3 ± 6.0
11.2 (8.4-16.5)		 11.1 ± 2.6
11.6 (8.3-13.6)		 0.57a
Preoperative MN ACTH 43.4 (29.3-51.6) 44.2 ± 25.5
46.1 (27.6-50.5)		 40.9 ± 15.3
11.5 (9.0-11.6)		 0.74 36.6 ± 16.6
37.4 (29.1-48.8)		 34.0 ± 9.4
39.3 (23.1-39.5)		 0.67
Preoperative AM ACTH 44.6 (31.4-60.5) 46.9 ± 28.9
44.0 (29.8-56.2)		 48.6 ± 28.8
58.7 (21.7-60.5)		 0.84 35.2 ± 16.2
40.3 (28.0-44.0)		 45.4 ± 24.6
58.7 (17.0-60.5)		 0.41a
Postoperative cortisol nadir 0.5 (0.5-0.5) 0.7 ± 0.7
0.5 (0.5-0.5)		 7.8 ± 6.6
5.2 (2.2-12.3)		 <0.001 0.6 ± 0.3
0.5 (0.5-0.5)		 8.1 ± 7.9
5.2 (2.1-17.0)		 0.003
Duration of follow-up 13.5 (11.3-16.0) 15.3 ± 7.9
14.0 (12.0-16.5)		 14.0 ± 13.0
11.0 (6.0-14.0)		 0.30 18.6 ± 11.2
15.5 (12.0-27.0)		 16.7 ± 17.2
11.0 (3.0-36.0)		 0.82a
DI only 8 (18%) 7/8 (87.5%) 1/8 (12.5%) 0.91 — — —
SIADH only 13 (30%) 8/9 (88.9%) 1/9 (11.1%)
Neither DI/SIADH 19 (43%) 10/13 (76.9%) 3/13 (23.1%)
Both DI and SIADH 4 (9%) 3/3 (100%) 0/3

Demographic and clinical characteristics of all subjects (n = 44) with Cushing disease. Data are also presented by remission status for all subjects with postoperative follow-up (n = 33) and by remission status after excluding those who developed DI or SIADH postoperatively with postoperative follow-up (n = 13). Both median (IQR) and mean ± SD reported to allow for comparisons, with P value provided using appropriate testing depending on distribution of data sets. Data are mean ± SD, median (25th-75th IQR), or frequency (percentage) are reported, except for age, which is presented as median (range).

Abbreviations: AM, 7:30-8 PM; BMI, body mass index; DI, diabetes insipidus; IQR, interquartile range; MN, midnight; N/A, not applicable; SDS, SD score; SIADH, syndrome of inappropriate antidiuresis; UFC, urinary free cortisol; ULN, upper limit of normal. p-values below the threshold of 0.05 are in bold.

aP value indicates comparison using parametric testing, as appropriate for normally distributed data.

Preoperative copeptin levels were higher in males (7.0 pmol/L [5.1-9.6]) than in females (4.0 pmol/L [1.4-5.8], P = 0.004) (Fig. 1). Age was inversely correlated with preoperative copeptin (rs = -0.35, P = 0.030) and BMI SDS was positively correlated with preoperative copeptin (rs = 0.54, P < 0.001) (Fig. 2).

 

Figure 1.

Preoperative plasma copeptin and sex. Preoperative plasma copeptin in all patients, comparing by sex. A higher preoperative plasma copeptin was found in males (7.0 pmol/L [5.1-9.6]) than in females (4.0 pmol/L [1.4-5.8], P = 0.004). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

Preoperative plasma copeptin and sex. Preoperative plasma copeptin in all patients, comparing by sex. A higher preoperative plasma copeptin was found in males (7.0 pmol/L [5.1-9.6]) than in females (4.0 pmol/L [1.4-5.8], P = 0.004). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

 

Figure 2.

Preoperative plasma copeptin and BMI SDS. Association of preoperative plasma copeptin and BMI SDS in all patients. A BMI SDS was positively associated with a preoperative plasma copeptin (rs = 0.54, P < 0.001). Shaded area = 95% confidence interval.

Preoperative plasma copeptin and BMI SDS. Association of preoperative plasma copeptin and BMI SDS in all patients. A BMI SDS was positively associated with a preoperative plasma copeptin (rs = 0.54, P < 0.001). Shaded area = 95% confidence interval.

Copeptin Before and After Transsphenoidal Surgery for CD

Among the 33 patients with postoperative follow-up, there was no difference in peak postoperative copeptin for patients in remission vs those not in remission (6.1 pmol/L [4.3-12.1] vs 7.3 pmol/L [5.4-8.4], P = 0.88). There was also no difference in the Δcopeptin for those in remission vs not in remission (2.3 pmol/L [-0.5 to 8.2] vs 0.1 pmol/L [-0.1 to 2.2], P = 0.46) (Fig. 3). Including all subjects, the mean preoperative copeptin was 5.6 pmol/L (±3.4). For patients with follow-up, there was no difference in preoperative copeptin for those in remission (4.8 pmol/L [±2.9]) vs no remission (6.0 pmol/L [±2.0], P = 0.47). POD 1 plasma copeptin ranged from < 2.8 to 11.3 pmol/L.

 

Figure 3.

(A) Peak postoperative plasma copeptin in all patients, comparing those in remission with no remission (6.1 pmol/L [4.3-12.1] vs 7.3 pmol/L [5.4-8.4], P = 0.88). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) in all patients, comparing those in remission with no remission (2.3 pmol/L [-0.5 to 8.2] vs 0.1 pmol/L [-0.1 to 2.2], P = 0.46). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

(A) Peak postoperative plasma copeptin in all patients, comparing those in remission with no remission (6.1 pmol/L [4.3-12.1] vs 7.3 pmol/L [5.4-8.4], P = 0.88). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) in all patients, comparing those in remission with no remission (2.3 pmol/L [-0.5 to 8.2] vs 0.1 pmol/L [-0.1 to 2.2], P = 0.46). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

When those who developed DI or SIADH were excluded, there was no difference in peak postoperative copeptin in those in remission vs no remission (10.2 pmol/L [6.9-21.0] vs 5.4 pmol/L [4.6-7.3], P = 0.20). However, because the distribution of the peak postoperative copeptins was borderline normally distributed, parametric testing was also completed for this analysis, which showed a higher peak postoperative copeptin in remission (14.6 pmol/L [±10.9]) vs no remission (5.8 [±1.4], P = 0.03). There was no difference in the Δcopeptin for those in remission vs not in remission (5.1 pmol/L [0.3-19.5] vs 1.1 pmol/L [-0.1 to 2.2], P = 0.39) (Fig. 4). Preoperative copeptin was not different for those in remission (4.7 pmol/L [±2.4]) vs no remission (4.9 pmol/L [±20.3], P = 0.91). There was no association between serum cortisol and plasma copeptin over time postoperatively (Fig. 5).

 

Figure 4.

(A) Peak postoperative plasma copeptin excluding those who developed DI or SIADH, comparing those in remission with no remission (10.2 pmol/L [6.9-21.0] vs 5.4 pmol/L [4.6-7.3], P = 0.20). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) excluding those who developed DI or SIADH, comparing those in remission with no remission (5.1 pmol/L [0.3-19.5] vs 1.1 pmol/L [-0.1 to 2.2], P = 0.39). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

(A) Peak postoperative plasma copeptin excluding those who developed DI or SIADH, comparing those in remission with no remission (10.2 pmol/L [6.9-21.0] vs 5.4 pmol/L [4.6-7.3], P = 0.20). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) excluding those who developed DI or SIADH, comparing those in remission with no remission (5.1 pmol/L [0.3-19.5] vs 1.1 pmol/L [-0.1 to 2.2], P = 0.39). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges.

 

Figure 5.

Plasma copeptin and serum cortisol vs postoperative day for patients who did not develop DI or SIADH. Plasma copeptin (indicated by closed circle) and serum cortisol (indicated by “x”). Results shown as (median, 95% CI).

Plasma copeptin and serum cortisol vs postoperative day for patients who did not develop DI or SIADH. Plasma copeptin (indicated by closed circle) and serum cortisol (indicated by “x”). Results shown as (median, 95% CI).

All analyses here were repeated adjusting for serum sodium, and there were no differences by remission status for preoperative, peak postoperative, or Δcopeptin for all subjects or after excluding those who developed a water balance disorder (data not shown).

Copeptin and Water Balance Disorders

As expected, peak postoperative copeptin appeared to be different among patients who developed DI, SIADH, and those without any fluid balance disorder (P = 0.029), whereas patients with DI had lower median peak postoperative copeptin (4.4 pmol/L [2.4-6.9]) than those who developed no fluid abnormality (10.0 pmol/L [5.4-16.5], P = 0.04), the statistical difference was not present after correction for multiple comparisons (P = 0.13). Peak postoperative copeptin of patients with SIADH was 9.4 pmol/L (6.5-10.4) and did not differ from patients with DI (P = 0.32) or those with no fluid abnormality (P = 1.0). There was a difference in Δcopeptin levels among these subgroups (overall P = 0.043), which appeared to be driven by the lower Δcopeptin in those who developed DI (-1.2 pmol/L [-2.6 to 0.1]) vs in those with neither DI or SIADH (3.1 pmol/L [0-9.6], P = 0.05). However, this pairwise comparison did not reach statistical significance, even before correction for multiple comparisons (P = 0.16) (Fig. 6). Preoperative copeptin levels were also not different among the subgroups (P = 0.54).

 

Figure 6.

(A) Peak postoperative plasma copeptin, comparing those who developed DI, SIADH, or neither (P = 0.029 for comparison of all 3 groups). (B) ∆ Copeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin), comparing those who developed DI, SIADH, or neither (P = 0.043 for comparison of all 3 groups). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. Top brackets = pairwise comparisons. P values presented are after Bonferroni correction for multiple comparisons.

(A) Peak postoperative plasma copeptin, comparing those who developed DI, SIADH, or neither (P = 0.029 for comparison of all 3 groups). (B) ∆ Copeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin), comparing those who developed DI, SIADH, or neither (P = 0.043 for comparison of all 3 groups). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. Top brackets = pairwise comparisons. P values presented are after Bonferroni correction for multiple comparisons.

Association of Sodium and Copeptin

Longitudinal data, adjusting for subgroups (ie, DI, SIADH, neither), were analyzed. As expected, there was a group difference (P = 0.003) in serum sodium over time (all DI was missing preoperative serum sodium), with the difference being driven by DI vs SIADH (P = 0.007), and SIADH vs neither (P = 0.012). There was no group difference in plasma copeptin over POD by water balance status (P = 0.16) over time (Fig. 7). There was also no effect by remission status at 3 to 6 months for either serum sodium or plasma copeptin.

 

Figure 7.

(A) Serum sodium and (B) plasma copeptin by POD and water balance status longitudinal data, adjusting for subgroups (ie, DI, SIADH, neither). Data points at point 0 on the x-axis indicate preoperative values. As expected, there was a group difference (P = 0.003) in serum sodium over time (all with DI were missing preoperative serum sodium), with the difference being driven by DI vs SIADH (P = 0.007), and SIADH vs neither (P = 0.012). There was no group difference in plasma copeptin over POD by water balance status (P = 0.16) over time.

(A) Serum sodium and (B) plasma copeptin by POD and water balance status longitudinal data, adjusting for subgroups (ie, DI, SIADH, neither). Data points at point 0 on the x-axis indicate preoperative values. As expected, there was a group difference (P = 0.003) in serum sodium over time (all with DI were missing preoperative serum sodium), with the difference being driven by DI vs SIADH (P = 0.007), and SIADH vs neither (P = 0.012). There was no group difference in plasma copeptin over POD by water balance status (P = 0.16) over time.

Higher serum sodium levels from PODs 1 through 8 itself decreased the odds of remission (OR, 0.56; 95% CI, 0.42-0.73; P < 0.001) in all CD patients. Copeptin levels from these repeated measures adjusting for serum sodium did not correlate with remission status at 3 to 6 months’ follow-up (P = 0.38). There were no differences in preoperative, peak postoperative, or delta sodium levels by remission vs no remission in all patients and in those with no water balance disorders.

Discussion

AVP and CRH act synergistically to stimulate the secretion of ACTH and ultimately cortisol [1, 2], and there is evidence that glucocorticoids act by way of negative feedback to suppress AVP secretion [10, 11-20]. Therefore, we hypothesized that a greater postoperative increase in plasma copeptin in those with CD in remission after TSS because of resolution of hypercortisolemia and resultant hypocortisolemia, compared with those not in remission with persistent hypercortisolemia and continued negative feedback, would be observed. Although a clear difference in peak postoperative and Δcopeptin was not observed in this study, a higher peak postoperative copeptin was found in those in remission after excluding those who developed DI/SIADH when analyzing this comparison with parametric testing, and it is possible that we did not have the power to detect a difference by nonparametric testing, given our small sample size. Therefore, postoperative plasma copeptin may be a useful early marker to predict remission of CD after TSS. The utility of this test may be limited to those who do not develop water balance disorders postoperatively. If a true increase in copeptin occurs for those in remission after treatment of CD, it is possible that this could be due to the removal of negative feedback from cortisol excess on pre-pro-AVP secretion, as hypothesized in this study. However, it is also possible that other factors may contribute to an increase in copeptin postoperatively, including from the stress response of surgery and postoperative hypocortisolism and resultant stimulation of pre-pro-AVP secretion from these physical stressors and/or from unrecognized SIADH.

It was anticipated that more severe hypercortisolism to be negatively correlated with preoperative plasma copeptin because of greater negative feedback on AVP. However, no association was found between preoperative plasma copeptin and markers of severity of hypercortisolism (MN cortisol, AM ACTH, UFC × ULN) in this study. Similarly, we would expect that the preoperative plasma copeptin would be lower compared with healthy individuals. However, comparisons of healthy individuals may be difficult because the fluid and osmolality status at the time of the sample could influence the plasma copeptin, and depending on those factors, copeptin could be appropriately low. A healthy control group with whom to compare the preoperative values was not available for this study, and the thirsted state was not standardized for the preoperative copeptin measurements. Future studies could be considered to determine if preoperative plasma copeptin is lower in patients with CD, or other forms of CS, compared with healthy subjects, with all subjects thirsted for an equivalent period. Further, if preoperative plasma copeptin is found to be lower in thirsted subjects with CS than a thirsted healthy control group, the plasma copeptin could potentially be a diagnostic test to lend support for or against the diagnosis of endogenous CS.

In the comparisons of those who developed DI, SIADH, or neither, no difference was found in the Δcopeptin. Peak copeptin was lower in DI compared with those without DI or SIADH (but not different from SIADH). Again, it is possible that there is a lower peak postoperative copeptin and change in copeptin in those with DI, but we may not have had the power to detect this in all of our analyses. These comparisons of copeptin among those with or without water balance disorders postoperatively are somewhat consistent with a prior study showing postoperative copeptin as a good predictor of development of DI, in which a plasma copeptin < 2.5 pmol/L measured on POD 0 accurately identified those who developed DI, and plasma copeptin > 30 pmol/L ruled out the development of DI postoperatively [29]. In the current study, 3 of 6 subjects with DI had a POD 1 plasma copeptin < 2.5 pmol/L, and none had a POD 1 plasma copeptin > 30 pmol/L. However, the study by Winzeler et al found that copeptin measured on POD 0 (within 12 hours after surgery) had the greatest predictive value, and POD 0 plasma copeptin was not available in our study. Further, we used the preoperative, peak, and delta plasma copeptin for analyses, so the early low copeptin levels may not have been captured in our data and analyses.

Additionally, this study revealed that increasing levels of serum sodium have lower odds of remission. Those who have an ACTH-producing adenoma that is not identified by magnetic resonance imaging and visual inspection intraoperatively have lower rates of remission and are more likely to have greater manipulation of the pituitary gland intraoperatively [32-36], and the latter may result in greater damage to the pituitary stalk or posterior pituitary, increasing the risk for development of DI and resultant hypernatremia.

A higher preoperative copeptin was associated with male sex and increasing BMI SDS. Increasing preoperative copeptin was also found in pubertal boys compared with pubertal girls, with no difference in copeptin between prepubertal boys and girls. It is particularly interesting to note that these associations were only in the preoperative plasma copeptin levels, but not the postoperative peak copeptin or Δcopeptin. Because the association of higher plasma in adult males and pubertal males in comparison to adult females and pubertal females, respectively, have been reported by others [26, 37-40], it raises the question of a change in the association of sex and BMI with plasma copeptin in the postoperative state. An effect of BMI or sex was not found by remission status, so it does not seem that the postoperative hypocortisolemic state for those in remission could explain this loss of association. However, this study may not have been powered to detect this.

Strengths of this study include the prospective nature of the study. Further, this is the first study assessing the utility of copeptin to predict remission after treatment of CD. Limitations of this study include the small sample size because of the rarity of the condition, difficulty in clinically diagnosing DI and SIADH, potential effect of post-TSS fluid balance disorders (particularly for those who may have developed transient partial DI or transient SIADH), lack of long-term follow-up, lack of any postoperative follow-up in 11 of the 44 total subjects, as well the observational nature of the study. Further, it is possible that pubertal status, sex, and BMI may have affected copeptin levels, which may have not been consistently detected because of lack of power. Lack of data on the timing of hydrocortisone replacement is an additional limitation of this study because postoperative glucocorticoid replacement could affect AVP secretion via negative feedback. Additional studies are needed to assess to further assess the role of vasopressin and measurement of copeptin in patients before and after treatment of CD.

A clear difference in peak postoperative plasma copeptin as an early marker to predict remission of CD after TSS was not found. Further studies with larger sample sizes are needed to further evaluate postoperative plasma copeptin as an early marker to predict remission of CD, though the utility of this test may be limited to those who do not develop water balance disorders postoperatively. Future studies comparing copeptin levels before and after treatment of adrenal CS would be of particular interest because this would minimize the risk of postoperative DI or SIADH which also influence copeptin levels. Additionally, comparison of thirsted preoperative plasma copeptin in those with endogenous CS and thirsted plasma copeptin in healthy controls could potentially provide evidence of whether or not preoperative plasma copeptin is lower in patients with CD, or other forms of CS, compared with healthy subjects. Further, if this is found to be true, it could potentially be a diagnostic test to lend support for or against endogenous CS.

Abbreviations

 

  • AVP

    arginine vasopressin

  • BMI

    body mass index

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • DI

    diabetes insipidus

  • HPA

    hypothalamic-pituitary-adrenal

  • IQR

    interquartile range

  • MN

    midnight

  • OR

    odds ratio

  • POD

    postoperative day

  • SDS

    SD score

  • SIADH

    syndrome of inappropriate antidiuresis

  • TSS

    transsphenoidal surgery

  • UFC

    urinary free cortisol

  • ULN

    upper limit of normal

Acknowledgments

The authors thank the patients and their families for participating in this study.

Funding

This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health.

Disclosures

C.A.S. holds patents on technologies involving PRKAR1A, PDE11A, GPR101, and related genes, and his laboratory has received research funding support by Pfizer Inc. for investigations unrelated to this project. C.A.S. is associated with the following pharmaceutical companies: ELPEN, Inc., H. Lunbeck A/S, and Sync. Inc.

Clinical Trial Information

ClinicalTrials.gov registration no. NCT00001595 (registered November 4, 1999).

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Published by Oxford University Press on behalf of the Endocrine Society 2022.
This work is written by (a) US Government employee(s) and is in the public domain in the US.

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , | Leave a comment »

Diagnostic pitfalls in Cushing’s disease impacting surgical remission rates; test thresholds and lessons learned in 105 patients

Posted on September 7, 2021 by MaryO

This article was originally published here

J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print.

ABSTRACT

CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection.

OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD.

DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD.

MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI.

RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion.

CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

PMID:34478542 | DOI:10.1210/clinem/dgab659

Filed under: Cushing's, Diagnostic Testing, Treatments | Tagged: , , , , | Leave a comment »

Thyroid dysfunction highly prevalent in Cushing’s syndrome

Posted on February 9, 2021 by MaryO

Central hypothyroidism is prevalent in about 1 in 2 adults with Cushing’s syndrome, and thyroid function can be restored after curative surgery for most patients, according to study findings.

“Our study findings have confirmed and greatly extended previous smaller studies that suggested a link between hypercortisolism and thyroid dysfunction but were inconclusive due to smaller sample size and short follow-up,” Skand Shekhar, MD, an endocrinologist and clinical investigator in the reproductive physiology and pathophysiology group at the National Institute of Environmental Health Sciences, NIH, told Healio. “Due to our large sample and longer follow-up, we firmly established a significant negative correlation between hypercortisolemia measures — serum and urinary cortisol, serum adrenocorticotropic hormone — and thyroid hormones triiodothyronine, free thyroxine and thyrotropin.”

Shekhar and colleagues conducted a retrospective review of two groups of adults aged 18 to 60 years with Cushing’s syndrome. The first group was evaluated at the NIH Clinical Center from 2005 to 2018 (n = 68; mean age, 43.8 years; 62% white), and the second group was evaluated from 1985 to 1994 (n = 55; mean age, 37.2 years; 89% white). The first cohort was followed for 6 to 12 months to observe the pattern of thyroid hormone changes after surgical cure of adrenocorticotropic hormone-dependent Cushing’s syndrome. The second group underwent diurnal thyroid-stimulating hormone evaluation before treatment and during remission for some cases.

Urinary free cortisol and morning thyroid hormone levels were collected for all participants. In the second group, researchers evaluated diurnal patterns of TSH concentrations with hourly measurements from 3 to 7 p.m. and midnight to 4 p.m. In the first group, adrenocorticotropic hormone and serum cortisol were measured.

In the first cohort, seven participants were receiving levothyroxine for previously diagnosed primary or central hypothyroidism. Of the remaining 61 adults, 32 had untreated central hypothyroidism. Thirteen participants had free T4 at the lower limit of normal, and 19 had subnormal levels. There were 29 adults with subnormal levels of T3 and seven with subnormal TSH.

Before surgery, 36 participants in the first group had central hypothyroidism. Six months after surgery, central hypothyroidism remained for 10 participants. After 12 months, the number of adults with central hypothyroidism dropped to six. Preoperative T3 and TSH levels were negatively associated with morning and midnight cortisol, adrenocorticotropic hormone and urinary free cortisol. In post hoc analysis, a baseline urinary free cortisol of more than 1,000 g per day was adversely associated with baseline and 6-month T3 and free T4 levels.

In the second group, there were 51 participants not on thyroid-modifying drugs who had a thyroid function test 6 or 12 months after surgery. Before surgery, free T4 levels were subnormal in 17 participants, T3 levels were subnormal in 22, and TSH levels were in the lower half of the reference range or below in all but one participant.

After surgery, two participants had below normal free T4, one had subnormal T3, and TSH levels were in the lower half of the reference range or below in 23 of 48 participants. Before surgery, there was no difference in mean TSH between daytime and nighttime. A mean 8 months after surgery, the second group had a normal nocturnal TSH surge from 1.3 mIU/L during the day to 2.17 mIU/L at night (P = .01). The nocturnal TSH increase persisted as long as 3 years in participants who had follow-up evaluations.

“We found a very high prevalence of thyroid hormone deficiency that appears to start at the level of the hypothalamus-pituitary gland and extend to the tissue level,” Shekhar said. “Some of these patients may experience thyroid hormone deficiency symptoms, such as fatigue, depression, cold intolerance, weight gain, etc, as a result of systematic and tissue-level thyroid hormone deficiency. We also noted a strong correlation between hypothyroidism and hypogonadism, which implies that hypothyroid patients are also likely to suffer adverse reproductive effects. Thus, it is imperative to perform thorough thyroid hormone assessment in patients with Cushing’s syndrome, and thyroid hormone supplementation should be considered for these patients unless cure of Cushing’s syndrome is imminent.”

Researchers said providers should routinely screen for hypothyroidism in adults with Cushing’s syndrome. Even after thyroid function is restored, regular follow-up should also be conducted.

Further research is needed to investigate thyroid dysfunction in iatrogenic Cushing’s syndrome and the impact of these findings on euthyroid sick syndrome, Shekhar said.

For more information:

Skand Shekhar, MD, can be reached at skand.shekhar@nih.gov.

From https://www.healio.com/news/endocrinology/20210208/thyroid-dysfunction-highly-prevalent-in-cushings-syndrome

Filed under: Cushing's | Tagged: , , , , , , , , , , , , , | 1 Comment »

COVID-19 May Be Severe in Cushing’s Patients

Posted on January 23, 2021 by MaryO

A young healthcare worker who contracted COVID-19 shortly after being diagnosed with Cushing’s disease was detailed in a case report from Japan.

While the woman was successfully treated for both conditions, Cushing’s may worsen a COVID-19 infection. Prompt treatment and multidisciplinary care is required for Cushing’s patients who get COVID-19, its researchers said.

The report, “Successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia,” was published in Endocrine Journal.

Cushing’s disease is caused by a tumor on the pituitary gland, which results in abnormally high levels of the stress hormone cortisol (hypercortisolism). Since COVID-19 is still a fairly new disease, and Cushing’s is rare, there is scant data on how COVID-19 tends to affect Cushing’s patients.

In the report, researchers described the case of a 27-year-old Japanese female healthcare worker with active Cushing’s disease who contracted COVID-19.

The patient had a six-year-long history of amenorrhea (missed periods) and dyslipidemia (abnormal fat levels in the body). She had also experienced weight gain, a rounding face, and acne.

After transferring to a new workplace, the woman visited a new gynecologist, who checked her hormonal status. Abnormal findings prompted a visit to the endocrinology department.

Clinical examination revealed features indicative of Cushing’s syndrome, such as a round face with acne, central obesity, and buffalo hump. Laboratory testing confirmed hypercortisolism, and MRI revealed a tumor in the patient’s pituitary gland.

She was scheduled for surgery to remove the tumor, and treated with metyrapone, a medication that can decrease cortisol production in the body. Shortly thereafter, she had close contact with a patient she was helping to care for, who was infected with COVID-19 but not yet diagnosed.

A few days later, the woman experienced a fever, nausea, and headache. These persisted for a few days, and then she started having difficulty breathing. Imaging of her lungs revealed a fluid buildup (pneumonia), and a test for SARS-CoV-2 — the virus that causes COVID-19 — came back positive.

A week after symptoms developed, the patient required supplemental oxygen. Her condition worsened 10 days later, and laboratory tests were indicative of increased inflammation.

To control the patient’s Cushing’s disease, she was treated with increasing doses of metyrapone and similar medications to decrease cortisol production; she was also administered cortisol — this “block and replace” approach aims to maintain cortisol levels within the normal range.

The patient experienced metyrapone side effects that included stomach upset, nausea, dizziness, swelling, increased acne, and hypokalemia (low potassium levels).

She was given antiviral therapies (e.g., favipiravir) to help manage the COVID-19. Additional medications to prevent opportunistic fungal infections were also administered.

From the next day onward, her symptoms eased, and the woman was eventually discharged from the hospital. A month after being discharged, she tested negative for SARS-CoV-2.

Surgery for the pituitary tumor was then again possible. Appropriate safeguards were put in place to protect the medical team caring for her from infection, during and after the surgery.

The patient didn’t have any noteworthy complications from the surgery, and her cortisol levels soon dropped to within normal limits. She was considered to be in remission.

Although broad conclusions cannot be reliably drawn from a single case, the researchers suggested that the patient’s underlying Cushing’s disease may have made her more susceptible to severe pneumonia due to COVID-19.

“Since hypercortisolism due to active Cushing’s disease may enhance the severity of COVID-19 infection, it is necessary to provide appropriate, multidisciplinary and prompt treatment,” the researchers wrote.

From https://cushingsdiseasenews.com/2021/01/15/covid-19-may-be-severe-cushings-patients-case-report-suggests/?cn-reloaded=1

Filed under: Cushing's, symptoms, Treatments | Tagged: , , , , , , , , , , , , , , , , , , , , | Leave a comment »

Muscle Weakness Persists in Cushing’s Syndrome Despite Remission

Posted on October 3, 2020 by MaryO

People with Cushing’s syndrome experience muscle weakness that persists even when the disorder is in remission, a new study shows.

The study, “Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission,” was published in The Journal of Clinical Endocrinology and Metabolism.

Cushing’s syndrome is characterized by abnormally high levels of the hormone cortisol. This can result in a variety of symptoms, including muscle weakness. However, it’s unclear the extent to which treatment of the underlying syndrome affects muscle weakness in the long term.

In the new study, researchers analyzed data for 88 people with endogenous Cushing’s syndrome diagnosed between 2012 and 2018 who had undergone regular muscle function tests. The data were collected as part of the German Cushing’s Registry, and the assessed group was mostly female (78%), with an average age of 49.

Of note, not all individuals had data available for every time point assessed — for example, at four years of follow-up, data were available for only 22 of the people analyzed.

Of the 88 individuals assessed, 49 had Cushing’s disease (a form of Cushing’s syndrome driven by a tumor on the pituitary gland). All 88 underwent curative surgery. The median time between diagnosis and remission was two months.

The researchers measured muscle strength in two ways: by grip strength and the chair rising test.

On average, and after statistical adjustments for age and sex, grip strength at diagnosis was 83% (with 100% reflecting the average for people without Cushing’s syndrome). Six months after surgery, average grip strength had decreased to 71%. A year after surgery, average grip strength was 77%. At all time points measured, up to four years after surgery, grip strength was significantly lowered in people with Cushing’s syndrome.

The chair rising test (CRT) involves measuring how quickly a person can rise from a seated position. Generally, being able to do so more quickly indicates greater muscle strength. People with Cushing’s syndrome showed improvement in the CRT six months after treatment (median 7 seconds), compared to the beginning of the study (8 seconds).

However, no further improvement was observed at subsequent time points up to four years, and compared to controls, CRT remained abnormal over time (7 seconds in Cushing patients at three years of follow-up vs 5 seconds in controls).

“The main finding of our study is that muscle strength remains impaired even after years in remission,” the researchers wrote.

“Another interesting finding is that at 6 months follow-up grip strength and CRT performance show opposite effects. Whereas grip strength has worsened, CRT performance has improved,” they added.

The investigators speculated that this difference is probably due to changes in body weight. Cushing’s syndrome commonly results in weight gain, and treatment resulted in significant decreases in body mass index in the analyzed group. As such, it may have been easier for individuals to stand up because there was less mass for their muscles to move, not necessarily because their muscles were stronger.

“Why patients with CS in remission showed a temporary worsening in grip strength 6 months after surgery remains unclear in terms of pathophysiology,” the researchers wrote.

They speculated that this could be due to treatment with glucocorticoids, which may affect muscle strength, but added that, “Whether the necessity of a long-term glucocorticoid replacement influences muscle strength or myopathy [muscle disease] outcome remains controversial.”

The researchers also conducted statistical analyses to determine what patient factors were associated with poorer muscle function outcomes. They found statistically significant associations between poor muscle function and older age, higher waist-to-hip-ratio, and higher levels of HbA1c (a marker of metabolic disease like diabetes).

“Influencing factors for myopathy outcome are age, waist-to-hip-ratio and HbA1c, suggesting that a consistent and strict treatment of diabetic metabolic state during hypercortisolism [high cortisol levels] is mandatory,” the investigators wrote.

The study was limited by its small sample size, the researchers noted, particularly at longer follow-up times, and by the fact that only a few measurements of muscle strength were used. Additionally, since all the data were collected at one of three centers in Germany, the analyzed population may not be representative of the worldwide population of people with Cushing’s syndrome.

Adapted from https://cushingsdiseasenews.com/2020/09/30/muscle-weakness-persists-in-cushings-syndrome-despite-remission-study-finds/

Filed under: Cushing's, symptoms | Tagged: , , | Leave a comment »

Next Page »
%d bloggers like this: