- Email: [email protected]
Adrenal Cortisol Secretion Capacity in Children and Adolescents with New-Onset, Mild Crohn's Disease
Adrenal Cortisol Secretion Capacity in Children and Adolescents with New-Onset, Mild Crohn’s Disease Amnon Zung, MD, Michal Kori, MD, Gabriel Dinary, MD, Efrat Broide, MD, Baruch Yerushalmi, MD, and Arie Levine, MD Objectives To evaluate the integrity of the hypothalamic-pituitary-adrenal axis in active Crohn’s disease (CD) among children and adolescents.
Study design We retrieved data on patients with CD who participated in a prospective study where budesonide treatment was evaluated. Basal and adrenocorticotropic hormone and corticotropin–stimulated cortisol levels in 52 children and adolescents with CD were compared with levels obtained in 52 age-matched control subjects. Correlations of cortisol levels with pediatric CD activity index and C-reactive protein (CRP) as an inflammatory marker were also assessed. Results Both basal and stimulated cortisol levels in CD were significantly higher than in control subjects: 364 173 versus 290 122 nmol/L (P = .029) and 865 236 versus 738 148 nmol/L (P # .001), respectively. Cortisol levels were correlated with CRP but not with pediatric CD activity index. Unlike in the control group, stimulated cortisol levels in patients with CD were not correlated with basal levels but rather with CRP (positive correlation) and age at diagnosis (negative correlation). Conclusions Contrary to previous reports suggesting that dysregulation of the hypothalamic-pituitary-adrenal axis is implicated in the susceptibility to and severity of CD and other chronic inflammatory diseases, we demonstrated an adequate response of this axis in pediatric CD, in proportion to the inflammation severity. (J Pediatr 2010;156:296-301). rohn’s disease (CD) is characterized by increased intestinal permeability1 and a TH1 and TH17 cytokine response,2 leading eventually to chronic inflammation and to subsequent mucosal damage. The hypothalamic-pituitary-adrenal (HPA) axis may modify this inflammatory cascade because it has a regulatory role in the duration and extent of inflammatory processes by means of the release of cortisol.3 Glucocorticoids (GC) as final effectors of the HPA axis suppress the inflammatory cascade via the inhibition of NF-kB, a transcription factor for the expression of many cytokine genes in chronic inflammation.4 Data on the HPA axis in patients with CD are scarce and focused mainly on dehydroepiandrosterone sulphate (DHEAS), a corticotropin-stimulated adrenal–derived hormone with multiple immunomodulating effects.5,6 Several studies have shown lower levels of DHEAS in adults with CD compared with in the control group.7-9 Similarly, abnormally low serum levels of DHEAS were reported in other chronic inflammatory diseases such as systemic lupus erythematosus,10,11 systemic sclerosis,12 and rheumatoid arthritis.13-15 In 2 studies that evaluated HPA axis and cortisol secretion in CD, cortisol levels were assessed either during GC tapering phase16 or recently after cessation of therapy.7 As expected, cortisol levels were low compared with normative data16 or untreated patients with CD.7 The HPA axis was also evaluated in other chronic inflammatory diseases. Patients with rheumatoid arthritis have shown lower-than-normal spontaneous secretion of cortisol,17 attenuated diurnal cortisol rhythm of secretion18 failure to increase cortisol secretion after surgery18 and normal response of cortisol to corticotrophin-releasing hormone (CRH)18 and low-dose corticotropin (ACTH) stimulation.15 These seemingly normal stimulated cortisol levels were interpreted as inadequate in the setting of sustained inflammation. With the same line of evidence, patients with systemic lupus erythematosus have shown attenuated cortisol levels in response to insulin-induced hypoglycemia.19,20 In Sjogren syndrome, patients demonstrated low evening plasma ACTH and cortisol levels, and they also exhibited a blunted ACTH and cortisol response to CRH compared with control subjects.21 Taken together, these observations suggested that dysregulation of the HPA axis in CD and other chronic inflammatory diseases leads to reduced DHEAS and cortisol-restraining effect on the inflammatory process.
C
ACTH CD CRH CRP DHEAS GC HPA PCDAI
Adrenocorticotropic hormone, corticotropin Crohn’s disease Corticotropin releasing hormone C-reactive protein Dehydroepiandrosterone sulphate Glucocorticoids Hypothalamic-pituitary-adrenal Pediatric Crohn’s disease activity index
From Pediatric Endocrinology Unit, Kaplan Medical Center, Affiliated with the Hebrew University of Jerusalem (A.Z.), the Pediatric Gastroenterology Units of Kaplan Medical Center (M.K.), Schneider Children Hospital (G.D.), Asaf Harofe Hospital (E.B.), Soroka Medical Center (B.Y.), and Wolfson Medical Center, Tel Aviv University (A.L.), Israel. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.08.046
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Vol. 156, No. 2 February 2010 We aimed to assess the adrenal cortisol secretion capacity in a cohort of children and adolescents with CD who were off GC treatment for at least 1 year, as a measure of HPA axis integrity in this inflammatory disease. We also aimed to assess correlations between cortisol levels and indexes of inflammation severity and disease activity in these patients.
Methods Children and adolescents with CD aged 9.5 to 19.7 years (n = 52) were included in the study and compared with 52 agematched and in most cases also sex-matched control subjects. The data were retrospectively obtained from a larger cohort of patients that participated in a prospective study aimed to evaluate oral budesonide treatment in CD.22 This study was conducted in 10 pediatric gastroenterology units throughout Israel between 2003 to 2006, and aimed to evaluate the efficacy of 2 regimens of budesonide, a GC with fewer side effects than prednisone.23 All patients in the prospective study (n = 71) underwent ACTH stimulation test before therapeutic intervention, and we retrieved the results (that were not reported yet) for our study. All patients had an established diagnosis of CD determined by a history of symptoms compatible with the disease, endoscopy and Histologic study, or definitive radiology.24 The inclusion criteria were negative stool culture result and test result for parasite for exclusion of infectious ileocolitis, a previous diagnosis of CD or newly diagnosed disease with symptoms for at least 1 month, and mild to moderately active CD defined by a pediatric CD activity index (PCDAI) at baseline $12.5 and #40.25 The exclusion criteria were macroscopic intestinal involvement above the ileum, short bowel syndrome, prior colostomy or ileostomy, abdominal abscess, intestinal fistula, small bowel obstruction, symptomatic stenosis or ileal structure, imminent surgery, evidence for infectious bowel disease, a serious secondary illness of an acute or chronic nature, a history of tuberculosis, human immunodeficiency virus, hepatitis B or C, impaired hepatic function (ALT $2 times upper normal limit), impaired renal function, and body weight less than 20 kg. Although GC therapy within 6 weeks before the study was considered an exclusion criteria in the prospective study, we excluded patients who were treated with GC within 1 year before the ACTH stimulation test to ensure full recovery of the HPA axis from any prior GC-suppressing effect.26 Nineteen of the original cohort of patients were excluded from our study: in 11 patients there were missing data, and 8 patients were treated with GC within a year before the ACTH stimulation test. The control group was comprised of subjects who underwent ACTH stimulation test for suspected hyperandrogenism or pubertal disorders between 2003 to 2006. All control subjects were followed-up and tested in the pediatric endocrinology unit in Kaplan Medical Center. Control subjects with isolated or multiple hormone deficiency, chronic
disease, and classical or nonclassical congenital adrenal hyperplasia were excluded from the study. Congenital adrenal hyperplasia was diagnosed on the basis of basal and ACTH-stimulated 17-hydroxyprogeterone levels.27 Because ACTH stimulation testing is commonly performed in children and adolescents with suspected hyperandrogenism, it enabled us to carefully select age- and sex-matched control subjects in whom normal adrenal function was confirmed by the same methods and assays as the patients with CD. Indeed, all control subjects had ACTH-stimulated cortisol levels above the minimal reference values reported in pubertal children (414 nmol/L)28 and adults (550 nmol/ L).29 Thirty-eight control subjects were sex- and age matched (3 months) to patients with CD, and 14 subjects were matched by age only, because ACTH stimulation test was infrequently performed in males. The clinical reason for ACTH stimulation test among control subjects were delayed puberty (n = 4), advanced bone age (n = 3), fast puberty (n = 3), acne (n = 2), small penile size (n = 2), gynecomastia (n = 1), male type balding (n = 1), acanthosis nigricans (n = 1), and premature pubarche (n = 1) in males, and hirsutism with or without dysmenorrhea (n = 25), dysmenorrhea alone (n = 5), acne (n = 2), and accelerated puberty (n = 2) in girls. The prospective study protocol was approved by the ethics committees of the participating institutes, and written informed consent was obtained from both parents of each participant. The retrospective data collection of the control subjects was approved by the ethics committee of Kaplan Medical Center. Study Design ACTH stimulation test (0.25 mg Synacten; Novartis, Basel, Switzerland) was performed both in subjects with CD at initial visit and in the control subjects, and cortisol levels were measured before and 60 minutes after ACTH injection. The tests were performed during morning hours after 9 AM, and not during early morning hours (0600 to 0800) when peak physiological level of cortisol is expected. Cortisol was measured by chemiluminescent enzyme immunoassay (Immulite 2000 analyzer; Siemens Healthcare, Deerfield, Illinois). C-reactive protein (CRP) as a measure of inflammation severity and pediatric CD activity index (PCDAI) were obtained in each patient at the time of ACTH stimulation test. Data are reported as mean SD. The t test was used for the comparison of basal, peak, and cortisol elevation (peak minus basal values) between patients with CD and control subjects, and Mann-Whitney rank sum test was applied for nonparametric data. Correlations between cortisol levels and some disease variables (CRP, PCDAI, age of patients, duration of CD) were performed by regression analysis. Variables that were correlated with a P value of less than .05 were analyzed by multiple regression. A P value of #.05 was considered significant. Statistical analysis was performed by SigmaPlot/SigmaStat software (Systat Software, San Jose, California). 297
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Results Although the time between CD diagnosis and ACTH test was variable among the patients, 31 of them (60%) were diagnosed less than 12 months prior to the test. In addition, our cohort of patients was characterized by a relatively mild to moderate disease, reflected by a CD activity index in the range of 15 to 40 (Table I). The vast majority of patients with CD (47 of 52) had never been treated with GC, and 5 of the patients have finished their last course of GC more than a year (1.2 to 4.5 years) before recruitment to the study. Some of the patients were treated with other therapeutic modalities, but none of them were treated with cyclosporine or methotrexate within 12 weeks or anti-tumor necrosis factor-a within 8 weeks before the beginning of the study. Both basal and particularly stimulated cortisol levels in patients with CD were significantly higher than corresponding levels in control subjects. Mean cortisol elevation also tended to be higher in patients with CD compared with control subjects, but this difference was not statistically significant (Figure 1). Cortisol indexes (basal, stimulated and elevation levels) in boys and girls were similar both in patients with CD and the control group (data not shown). By comparison to the expected values of morning serum cortisol levels in the assay used in our study, 4% and 6% of the patients and control subjects, respectively, had cortisol levels below the normal range, and 10% and 2% of the patients and control subjects, respectively, had levels above the normal range. All patients and control subjects had peak cortisol levels above the minimal reference values reported in pubertal children (414 nmol/L).28 Correlations between cortisol levels in CD (as dependent variable) and several disease characteristics are described in Table II. On the basis of the univariate regression analysis, we performed multiple regression analysis that included stimulated cortisol levels as dependent variable and CRP, age at diagnosis and length of time from diagnosis to study entry as independent variables. Only CRP and age at diagnosis appeared to account for the ability to predict ACTH-stimulated cortisol (Figure 2, R = 0.495; P = .001). Unlike control group where stimulated cortisol levels were positively correlated with basal cortisol levels (R = 0.556, P # .001), stimulated cortisol levels in the CD group were not correlated with basal levels but rather with CRP and age at diagnosis (Table II). There was no correlation between pediatric disease activity index (PCDAI) and CRP values.
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Table I. Characteristics of patients with Crohn’s disease and control subjects
Age (yr) Sex (M/F) Age at diagnosis (yr) Time from diagnosis to ACTH test (mo) Pediatric Crohn’s disease activity index C-reactive protein (mg/L)
Crohn’s disease (n = 52)
Control subjects (n = 52)
14.5 2.7 (9.5-19.7) 32/20 13.1 2.8 (8.0-17.8) 16.6 21.0 (1-80)
14.4 2.7 (9.3-19.9) 18/34 NA NA
27.3 7.2 (15-40)
NA
44.7 45.6 (2-248)
NA
Ranges of variables are in parentheses. NA, Not applicable.
the CD group compared with the control group suggest that the integrity of the HPA axis is preserved and the axis responds properly to the inflammatory condition. This conclusion is mainly supported by the higher basal cortisol levels in CD, levels that are exclusively regulated by the upper arms of the HPA axis. The positive correlations between cortisol levels and CRP, a marker of inflammatory activity, further supports an appropriate response of the HPA axis, in proportion to the magnitude of inflammation in CD. This observation corroborates a previous report by Straub et al7 that found a positive correlation between cortisol levels and both CRP and blood sedimentation rate in adults with CD.
Discussion Our study demonstrates an adequate, stress-related increase in spontaneous and ACTH-stimulated cortisol secretion in a cohort of children and adolescents with relatively recently diagnosed, nonsevere CD. Although we did not directly assessed CRH and ACTH secretion at the hypothalamus and pituitary levels respectively, the higher cortisol levels in 298
Figure 1. Basal and ACTH-stimulated cortisol levels and cortisol elevation (the difference between basal and stimulated levels) in patients with Crohn’s disease and control subjects. Data are displayed as 25-75th percentile boxes, with 5th and 95th percentiles displayed as error bars. NS, not significant. Zung et al
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Table II. Correlations between basal and ACTHstimulated cortisol levels and CD clinical and inflammatory-related variables Age (yr) Age at CD diagnosis (yr) Length of time from CD Diagnosis to study entry (mo) Pediatric CD activity index (PCDAI) C-reactive protein (mg/L)
Basal cortisol
Stimulated cortisol
NS NS NS
NS R = 0.303; (P = .029) R = 0.278; (P = .048)
NS
NS
R = 0.443; (P = .001)
R = 0.357; (P = .010)
Minus sign denotes negative correlation. NS, Not significant.
At the adrenal gland level, ACTH-induced cortisol elevation in patients with CD was similar to levels obtained in the control group. Therefore, in spite of sustained hypercortisolism in CD, there were no signs of exhausted adrenal reserve. Peak cortisol levels, however, were differently regulated in patients with CD, as reflected by correlations with CRP and age at diagnosis, rather than with baseline cortisol levels as found in control subjects. The observed correlation between cortisol levels and CRP may derive from a simultaneous effect of interleukin-6 on both variables. Interleukin-6, a key proinflammatory cytokine in the pathogenesis of CD, strongly correlates with CRP30 and was found to be an important stimulator of the HPA axis.31 It should be mentioned, however, that other proinflammatory and antiinflammatory cytokines, and even long-term administration of IL-6 might be involved in the attenuation, rather than stimulation of the HPA axis in patients with various chronic
Figure 2. Multiple regression between stimulated cortisol levels (dependent variable) and CRP and age at diagnosis (independent variables).
allergic inflammatory disorders.32 Neither CRP nor cortisol levels were correlated with PCDAI, a disease activity index that integrates both clinical and laboratory markers. Apparently, the inflammatory process reflected by CRP is rapidly evolving and therefore synchronized with the rapid adaptation of the HPA axis, and CD activity index manifest some variables that are slower to respond such as anemia, weight, and height; hence, they are not directed entirely by the level of inflammation. Along the same lines of evidence, data from adult studies showed that the CD activity index was not correlated with DHEAS levels.7 We do not believe that sex may have influenced our analysis because we did not find sex-related differences in basal and stimulated cortisol levels neither in patients with CD nor in control subjects. Our main findings are in contrast to many previously reported studies that partly attributed the flare of several inflammatory diseases including CD to dysregulation of the HPA axis, with a subsequent failure to contain the inflammatory activity.3,7-15,17-21 Several explanations for this discrepancy can be suggested. First, in some of the previous reports, participants were probably under some suppressive effect because of prior GC treatment, which could have led to artificially reduced levels of adrenal steroids. Indeed, patients with CD with prior GC treatment have shown lower cortisol levels compared with naı¨ve patients.7 Exogenous corticosteroid therapy suppresses the production of CRH and ACTH and can induce adrenal atrophy. The magnitude of HPA suppression depends on the dose, duration and even the type of GC, as reflected for example by lower serum bioactivity (and subsequently milder suppressive effect) of budesonide compared with prednisolone in children and adolescents with inflammatory bowel disease.33 Budesonide, a non-halogenated GC has been shown to have a high ratio of topical to systemic activity, explained by a high first-pass metabolism in the liver and in the gut mucosa. Budesonide undergoes extensive first pass metabolism to nearly inactive metabolites and has a systemic bioavailability of about 10%, which leads to fewer side effects in comparison to systemic GC.22,34 The HPA suppression effect of GC should be anticipated in any patient who has been receiving more than 30 mg per day of hydrocortisone (or 7.5 mg of prednisone per day) for more than three weeks.35 Under these conditions, the HPA suppression may persists for months36 or up to 1 year26 after the cessation of GC treatment. When ACTH stimulation test was performed in patients with inflammatory bowel disease during the tapering phase of GC treatment, the mean duration for adrenal recovery was reported to be 7.2 1.3 months.16 In our study we excluded 8 patients who have been treated with GC (prednisone in a dose of 30 to 40 mg daily over 2 to 3 months) during the year before study entry to ensure a full recovery of the HPA axis. An exposure of our patients to other therapeutic modalities probably carries no effect on the HPA axis.7 In this study, among 179 patients with inflammatory bowel disease, DHES levels were similar in patients with or without therapeutic modalities such as budesonide, sulfasalazine, 5-ASA or azathioprine.
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Another possible explanation for the discrepancy between previous reports and our study may derive from differences in the methods by which the HPA axis was evaluated. In most of the studies in patients with CD and other chronic inflammatory diseases, the HPA axis activity was evaluated by serum levels of DHEAS rather than cortisol.7-15 Although both hormones are secreted under ACTH stimulation, only cortisol maintains a negative feedback at the hypothalamicpituitary level, therefore its secretion reflects the integrity of the HPA axis more comprehensively. A dissociation between cortisol and DHEAS levels was reported in critically ill patients37,38 and in patients with CD.7 Finally, we have studied young patients with CD with relatively recent disease (60% of them were diagnosed within a year before the study) and mild to moderate disease severity, as reflected by PCDAI. By comparison, in the 3 studies that assessed DHEAS levels in CD, the patients were adults with longer duration of the disease and variable levels of disease activity: some of them were in a quiescent state and other patients have shown different severity levels of active disease.7-9 Because stimulated cortisol levels in our study were negatively correlated with age at diagnosis, it is conceivable that some decline in adrenal functioning evolves over the years, leading to lower adrenal steroid levels in adults compared with children and adolescents with CD. Taken together, prior exposure to exogenous GC treatment, measurements of DHEAS and not cortisol, and inclusion of adult patients with long-standing CD may account for some HPA axis suppression in previous studies compared with ours. On the basis of our observations, we conclude that the HPA axis can mount an adequate response to the inflammatory process in children and adolescents with active CD and is not a contributing component in the disease flare-up, at least with a relatively short-term and mild to moderate disease. We cannot exclude the possibility that in older patients or in more severe clinical activity and longer duration of the disease, some interruption of HPA axis may exist. n We thank the members of Israeli pediatric study group, Dr. Gabriel Dinari, Dr. Ron Shaoul, Dr. Avi on, Dr. Esther Granot, Dr. Aaron Lerner, Dr. Ayala Yaron, Dr. David Wald, Dr. Yoram Bujanover, Dr. Zvi Wezman, Dr. Avi Pacht, Dr. Shimon Reif and Dr. Arie Silbermintz for recruitment of patients with Crohn’s disease to the study. Submitted for publication Feb 4, 2009; last revision received Aug 4, 2009; accepted Aug 26, 2009.
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Reprint requests: Amnon Zung, MD, Pediatric Endocrinology Unit, Kaplan Medical Center, Rehovot 76100, Israel. E-mail: [email protected].
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kin 6 concentration in healthy humans. Eur J Endocrinol 2008;159: 649-52. Priftis KN, Papadimitriou A, Nicolaidou P, Chrousos GP. The hypothalamic-pituitary-adrenal axis in asthmatic children. Trends Endocrinol Metab 2008;19:32-8. Vihinen MK, Raivio T, Verkasalo M, Janne OA, Kolho KL. Circulating glucocorticoid bioactivity during peroral glucocorticoid treatment in children and adolescent with inflammatory bowel disease. J Clin Gastroenterol 2008;42:1017-24. Levine A, Broide E, Stein M, Bujanover Y, Weizman Z, Pacht A, et al. Evaluation of oral budesonide for treatment of mild and moderate exacerbation of Crohn’s disease in children. J Pediatr 2002;140: 75-80. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Eng J Med 2003;348:727-34. Salem M, Tainsh RE, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. Ann Surg 1994;219:416-25. Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985;60:947-52. Beishuizen A, Thijs LG, Vermes I. Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care 2002;6:434-8.
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Study design We retrieved data on patients with CD who participated in a prospective study where budesonide treatment was evaluated. Basal and adrenocorticotropic hormone and corticotropin–stimulated cortisol levels in 52 children and adolescents with CD were compared with levels obtained in 52 age-matched control subjects. Correlations of cortisol levels with pediatric CD activity index and C-reactive protein (CRP) as an inflammatory marker were also assessed. Results Both basal and stimulated cortisol levels in CD were significantly higher than in control subjects: 364 173 versus 290 122 nmol/L (P = .029) and 865 236 versus 738 148 nmol/L (P # .001), respectively. Cortisol levels were correlated with CRP but not with pediatric CD activity index. Unlike in the control group, stimulated cortisol levels in patients with CD were not correlated with basal levels but rather with CRP (positive correlation) and age at diagnosis (negative correlation). Conclusions Contrary to previous reports suggesting that dysregulation of the hypothalamic-pituitary-adrenal axis is implicated in the susceptibility to and severity of CD and other chronic inflammatory diseases, we demonstrated an adequate response of this axis in pediatric CD, in proportion to the inflammation severity. (J Pediatr 2010;156:296-301). rohn’s disease (CD) is characterized by increased intestinal permeability1 and a TH1 and TH17 cytokine response,2 leading eventually to chronic inflammation and to subsequent mucosal damage. The hypothalamic-pituitary-adrenal (HPA) axis may modify this inflammatory cascade because it has a regulatory role in the duration and extent of inflammatory processes by means of the release of cortisol.3 Glucocorticoids (GC) as final effectors of the HPA axis suppress the inflammatory cascade via the inhibition of NF-kB, a transcription factor for the expression of many cytokine genes in chronic inflammation.4 Data on the HPA axis in patients with CD are scarce and focused mainly on dehydroepiandrosterone sulphate (DHEAS), a corticotropin-stimulated adrenal–derived hormone with multiple immunomodulating effects.5,6 Several studies have shown lower levels of DHEAS in adults with CD compared with in the control group.7-9 Similarly, abnormally low serum levels of DHEAS were reported in other chronic inflammatory diseases such as systemic lupus erythematosus,10,11 systemic sclerosis,12 and rheumatoid arthritis.13-15 In 2 studies that evaluated HPA axis and cortisol secretion in CD, cortisol levels were assessed either during GC tapering phase16 or recently after cessation of therapy.7 As expected, cortisol levels were low compared with normative data16 or untreated patients with CD.7 The HPA axis was also evaluated in other chronic inflammatory diseases. Patients with rheumatoid arthritis have shown lower-than-normal spontaneous secretion of cortisol,17 attenuated diurnal cortisol rhythm of secretion18 failure to increase cortisol secretion after surgery18 and normal response of cortisol to corticotrophin-releasing hormone (CRH)18 and low-dose corticotropin (ACTH) stimulation.15 These seemingly normal stimulated cortisol levels were interpreted as inadequate in the setting of sustained inflammation. With the same line of evidence, patients with systemic lupus erythematosus have shown attenuated cortisol levels in response to insulin-induced hypoglycemia.19,20 In Sjogren syndrome, patients demonstrated low evening plasma ACTH and cortisol levels, and they also exhibited a blunted ACTH and cortisol response to CRH compared with control subjects.21 Taken together, these observations suggested that dysregulation of the HPA axis in CD and other chronic inflammatory diseases leads to reduced DHEAS and cortisol-restraining effect on the inflammatory process.
C
ACTH CD CRH CRP DHEAS GC HPA PCDAI
Adrenocorticotropic hormone, corticotropin Crohn’s disease Corticotropin releasing hormone C-reactive protein Dehydroepiandrosterone sulphate Glucocorticoids Hypothalamic-pituitary-adrenal Pediatric Crohn’s disease activity index
From Pediatric Endocrinology Unit, Kaplan Medical Center, Affiliated with the Hebrew University of Jerusalem (A.Z.), the Pediatric Gastroenterology Units of Kaplan Medical Center (M.K.), Schneider Children Hospital (G.D.), Asaf Harofe Hospital (E.B.), Soroka Medical Center (B.Y.), and Wolfson Medical Center, Tel Aviv University (A.L.), Israel. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.08.046
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Vol. 156, No. 2 February 2010 We aimed to assess the adrenal cortisol secretion capacity in a cohort of children and adolescents with CD who were off GC treatment for at least 1 year, as a measure of HPA axis integrity in this inflammatory disease. We also aimed to assess correlations between cortisol levels and indexes of inflammation severity and disease activity in these patients.
Methods Children and adolescents with CD aged 9.5 to 19.7 years (n = 52) were included in the study and compared with 52 agematched and in most cases also sex-matched control subjects. The data were retrospectively obtained from a larger cohort of patients that participated in a prospective study aimed to evaluate oral budesonide treatment in CD.22 This study was conducted in 10 pediatric gastroenterology units throughout Israel between 2003 to 2006, and aimed to evaluate the efficacy of 2 regimens of budesonide, a GC with fewer side effects than prednisone.23 All patients in the prospective study (n = 71) underwent ACTH stimulation test before therapeutic intervention, and we retrieved the results (that were not reported yet) for our study. All patients had an established diagnosis of CD determined by a history of symptoms compatible with the disease, endoscopy and Histologic study, or definitive radiology.24 The inclusion criteria were negative stool culture result and test result for parasite for exclusion of infectious ileocolitis, a previous diagnosis of CD or newly diagnosed disease with symptoms for at least 1 month, and mild to moderately active CD defined by a pediatric CD activity index (PCDAI) at baseline $12.5 and #40.25 The exclusion criteria were macroscopic intestinal involvement above the ileum, short bowel syndrome, prior colostomy or ileostomy, abdominal abscess, intestinal fistula, small bowel obstruction, symptomatic stenosis or ileal structure, imminent surgery, evidence for infectious bowel disease, a serious secondary illness of an acute or chronic nature, a history of tuberculosis, human immunodeficiency virus, hepatitis B or C, impaired hepatic function (ALT $2 times upper normal limit), impaired renal function, and body weight less than 20 kg. Although GC therapy within 6 weeks before the study was considered an exclusion criteria in the prospective study, we excluded patients who were treated with GC within 1 year before the ACTH stimulation test to ensure full recovery of the HPA axis from any prior GC-suppressing effect.26 Nineteen of the original cohort of patients were excluded from our study: in 11 patients there were missing data, and 8 patients were treated with GC within a year before the ACTH stimulation test. The control group was comprised of subjects who underwent ACTH stimulation test for suspected hyperandrogenism or pubertal disorders between 2003 to 2006. All control subjects were followed-up and tested in the pediatric endocrinology unit in Kaplan Medical Center. Control subjects with isolated or multiple hormone deficiency, chronic
disease, and classical or nonclassical congenital adrenal hyperplasia were excluded from the study. Congenital adrenal hyperplasia was diagnosed on the basis of basal and ACTH-stimulated 17-hydroxyprogeterone levels.27 Because ACTH stimulation testing is commonly performed in children and adolescents with suspected hyperandrogenism, it enabled us to carefully select age- and sex-matched control subjects in whom normal adrenal function was confirmed by the same methods and assays as the patients with CD. Indeed, all control subjects had ACTH-stimulated cortisol levels above the minimal reference values reported in pubertal children (414 nmol/L)28 and adults (550 nmol/ L).29 Thirty-eight control subjects were sex- and age matched (3 months) to patients with CD, and 14 subjects were matched by age only, because ACTH stimulation test was infrequently performed in males. The clinical reason for ACTH stimulation test among control subjects were delayed puberty (n = 4), advanced bone age (n = 3), fast puberty (n = 3), acne (n = 2), small penile size (n = 2), gynecomastia (n = 1), male type balding (n = 1), acanthosis nigricans (n = 1), and premature pubarche (n = 1) in males, and hirsutism with or without dysmenorrhea (n = 25), dysmenorrhea alone (n = 5), acne (n = 2), and accelerated puberty (n = 2) in girls. The prospective study protocol was approved by the ethics committees of the participating institutes, and written informed consent was obtained from both parents of each participant. The retrospective data collection of the control subjects was approved by the ethics committee of Kaplan Medical Center. Study Design ACTH stimulation test (0.25 mg Synacten; Novartis, Basel, Switzerland) was performed both in subjects with CD at initial visit and in the control subjects, and cortisol levels were measured before and 60 minutes after ACTH injection. The tests were performed during morning hours after 9 AM, and not during early morning hours (0600 to 0800) when peak physiological level of cortisol is expected. Cortisol was measured by chemiluminescent enzyme immunoassay (Immulite 2000 analyzer; Siemens Healthcare, Deerfield, Illinois). C-reactive protein (CRP) as a measure of inflammation severity and pediatric CD activity index (PCDAI) were obtained in each patient at the time of ACTH stimulation test. Data are reported as mean SD. The t test was used for the comparison of basal, peak, and cortisol elevation (peak minus basal values) between patients with CD and control subjects, and Mann-Whitney rank sum test was applied for nonparametric data. Correlations between cortisol levels and some disease variables (CRP, PCDAI, age of patients, duration of CD) were performed by regression analysis. Variables that were correlated with a P value of less than .05 were analyzed by multiple regression. A P value of #.05 was considered significant. Statistical analysis was performed by SigmaPlot/SigmaStat software (Systat Software, San Jose, California). 297
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Results Although the time between CD diagnosis and ACTH test was variable among the patients, 31 of them (60%) were diagnosed less than 12 months prior to the test. In addition, our cohort of patients was characterized by a relatively mild to moderate disease, reflected by a CD activity index in the range of 15 to 40 (Table I). The vast majority of patients with CD (47 of 52) had never been treated with GC, and 5 of the patients have finished their last course of GC more than a year (1.2 to 4.5 years) before recruitment to the study. Some of the patients were treated with other therapeutic modalities, but none of them were treated with cyclosporine or methotrexate within 12 weeks or anti-tumor necrosis factor-a within 8 weeks before the beginning of the study. Both basal and particularly stimulated cortisol levels in patients with CD were significantly higher than corresponding levels in control subjects. Mean cortisol elevation also tended to be higher in patients with CD compared with control subjects, but this difference was not statistically significant (Figure 1). Cortisol indexes (basal, stimulated and elevation levels) in boys and girls were similar both in patients with CD and the control group (data not shown). By comparison to the expected values of morning serum cortisol levels in the assay used in our study, 4% and 6% of the patients and control subjects, respectively, had cortisol levels below the normal range, and 10% and 2% of the patients and control subjects, respectively, had levels above the normal range. All patients and control subjects had peak cortisol levels above the minimal reference values reported in pubertal children (414 nmol/L).28 Correlations between cortisol levels in CD (as dependent variable) and several disease characteristics are described in Table II. On the basis of the univariate regression analysis, we performed multiple regression analysis that included stimulated cortisol levels as dependent variable and CRP, age at diagnosis and length of time from diagnosis to study entry as independent variables. Only CRP and age at diagnosis appeared to account for the ability to predict ACTH-stimulated cortisol (Figure 2, R = 0.495; P = .001). Unlike control group where stimulated cortisol levels were positively correlated with basal cortisol levels (R = 0.556, P # .001), stimulated cortisol levels in the CD group were not correlated with basal levels but rather with CRP and age at diagnosis (Table II). There was no correlation between pediatric disease activity index (PCDAI) and CRP values.
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Table I. Characteristics of patients with Crohn’s disease and control subjects
Age (yr) Sex (M/F) Age at diagnosis (yr) Time from diagnosis to ACTH test (mo) Pediatric Crohn’s disease activity index C-reactive protein (mg/L)
Crohn’s disease (n = 52)
Control subjects (n = 52)
14.5 2.7 (9.5-19.7) 32/20 13.1 2.8 (8.0-17.8) 16.6 21.0 (1-80)
14.4 2.7 (9.3-19.9) 18/34 NA NA
27.3 7.2 (15-40)
NA
44.7 45.6 (2-248)
NA
Ranges of variables are in parentheses. NA, Not applicable.
the CD group compared with the control group suggest that the integrity of the HPA axis is preserved and the axis responds properly to the inflammatory condition. This conclusion is mainly supported by the higher basal cortisol levels in CD, levels that are exclusively regulated by the upper arms of the HPA axis. The positive correlations between cortisol levels and CRP, a marker of inflammatory activity, further supports an appropriate response of the HPA axis, in proportion to the magnitude of inflammation in CD. This observation corroborates a previous report by Straub et al7 that found a positive correlation between cortisol levels and both CRP and blood sedimentation rate in adults with CD.
Discussion Our study demonstrates an adequate, stress-related increase in spontaneous and ACTH-stimulated cortisol secretion in a cohort of children and adolescents with relatively recently diagnosed, nonsevere CD. Although we did not directly assessed CRH and ACTH secretion at the hypothalamus and pituitary levels respectively, the higher cortisol levels in 298
Figure 1. Basal and ACTH-stimulated cortisol levels and cortisol elevation (the difference between basal and stimulated levels) in patients with Crohn’s disease and control subjects. Data are displayed as 25-75th percentile boxes, with 5th and 95th percentiles displayed as error bars. NS, not significant. Zung et al
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Table II. Correlations between basal and ACTHstimulated cortisol levels and CD clinical and inflammatory-related variables Age (yr) Age at CD diagnosis (yr) Length of time from CD Diagnosis to study entry (mo) Pediatric CD activity index (PCDAI) C-reactive protein (mg/L)
Basal cortisol
Stimulated cortisol
NS NS NS
NS R = 0.303; (P = .029) R = 0.278; (P = .048)
NS
NS
R = 0.443; (P = .001)
R = 0.357; (P = .010)
Minus sign denotes negative correlation. NS, Not significant.
At the adrenal gland level, ACTH-induced cortisol elevation in patients with CD was similar to levels obtained in the control group. Therefore, in spite of sustained hypercortisolism in CD, there were no signs of exhausted adrenal reserve. Peak cortisol levels, however, were differently regulated in patients with CD, as reflected by correlations with CRP and age at diagnosis, rather than with baseline cortisol levels as found in control subjects. The observed correlation between cortisol levels and CRP may derive from a simultaneous effect of interleukin-6 on both variables. Interleukin-6, a key proinflammatory cytokine in the pathogenesis of CD, strongly correlates with CRP30 and was found to be an important stimulator of the HPA axis.31 It should be mentioned, however, that other proinflammatory and antiinflammatory cytokines, and even long-term administration of IL-6 might be involved in the attenuation, rather than stimulation of the HPA axis in patients with various chronic
Figure 2. Multiple regression between stimulated cortisol levels (dependent variable) and CRP and age at diagnosis (independent variables).
allergic inflammatory disorders.32 Neither CRP nor cortisol levels were correlated with PCDAI, a disease activity index that integrates both clinical and laboratory markers. Apparently, the inflammatory process reflected by CRP is rapidly evolving and therefore synchronized with the rapid adaptation of the HPA axis, and CD activity index manifest some variables that are slower to respond such as anemia, weight, and height; hence, they are not directed entirely by the level of inflammation. Along the same lines of evidence, data from adult studies showed that the CD activity index was not correlated with DHEAS levels.7 We do not believe that sex may have influenced our analysis because we did not find sex-related differences in basal and stimulated cortisol levels neither in patients with CD nor in control subjects. Our main findings are in contrast to many previously reported studies that partly attributed the flare of several inflammatory diseases including CD to dysregulation of the HPA axis, with a subsequent failure to contain the inflammatory activity.3,7-15,17-21 Several explanations for this discrepancy can be suggested. First, in some of the previous reports, participants were probably under some suppressive effect because of prior GC treatment, which could have led to artificially reduced levels of adrenal steroids. Indeed, patients with CD with prior GC treatment have shown lower cortisol levels compared with naı¨ve patients.7 Exogenous corticosteroid therapy suppresses the production of CRH and ACTH and can induce adrenal atrophy. The magnitude of HPA suppression depends on the dose, duration and even the type of GC, as reflected for example by lower serum bioactivity (and subsequently milder suppressive effect) of budesonide compared with prednisolone in children and adolescents with inflammatory bowel disease.33 Budesonide, a non-halogenated GC has been shown to have a high ratio of topical to systemic activity, explained by a high first-pass metabolism in the liver and in the gut mucosa. Budesonide undergoes extensive first pass metabolism to nearly inactive metabolites and has a systemic bioavailability of about 10%, which leads to fewer side effects in comparison to systemic GC.22,34 The HPA suppression effect of GC should be anticipated in any patient who has been receiving more than 30 mg per day of hydrocortisone (or 7.5 mg of prednisone per day) for more than three weeks.35 Under these conditions, the HPA suppression may persists for months36 or up to 1 year26 after the cessation of GC treatment. When ACTH stimulation test was performed in patients with inflammatory bowel disease during the tapering phase of GC treatment, the mean duration for adrenal recovery was reported to be 7.2 1.3 months.16 In our study we excluded 8 patients who have been treated with GC (prednisone in a dose of 30 to 40 mg daily over 2 to 3 months) during the year before study entry to ensure a full recovery of the HPA axis. An exposure of our patients to other therapeutic modalities probably carries no effect on the HPA axis.7 In this study, among 179 patients with inflammatory bowel disease, DHES levels were similar in patients with or without therapeutic modalities such as budesonide, sulfasalazine, 5-ASA or azathioprine.
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Another possible explanation for the discrepancy between previous reports and our study may derive from differences in the methods by which the HPA axis was evaluated. In most of the studies in patients with CD and other chronic inflammatory diseases, the HPA axis activity was evaluated by serum levels of DHEAS rather than cortisol.7-15 Although both hormones are secreted under ACTH stimulation, only cortisol maintains a negative feedback at the hypothalamicpituitary level, therefore its secretion reflects the integrity of the HPA axis more comprehensively. A dissociation between cortisol and DHEAS levels was reported in critically ill patients37,38 and in patients with CD.7 Finally, we have studied young patients with CD with relatively recent disease (60% of them were diagnosed within a year before the study) and mild to moderate disease severity, as reflected by PCDAI. By comparison, in the 3 studies that assessed DHEAS levels in CD, the patients were adults with longer duration of the disease and variable levels of disease activity: some of them were in a quiescent state and other patients have shown different severity levels of active disease.7-9 Because stimulated cortisol levels in our study were negatively correlated with age at diagnosis, it is conceivable that some decline in adrenal functioning evolves over the years, leading to lower adrenal steroid levels in adults compared with children and adolescents with CD. Taken together, prior exposure to exogenous GC treatment, measurements of DHEAS and not cortisol, and inclusion of adult patients with long-standing CD may account for some HPA axis suppression in previous studies compared with ours. On the basis of our observations, we conclude that the HPA axis can mount an adequate response to the inflammatory process in children and adolescents with active CD and is not a contributing component in the disease flare-up, at least with a relatively short-term and mild to moderate disease. We cannot exclude the possibility that in older patients or in more severe clinical activity and longer duration of the disease, some interruption of HPA axis may exist. n We thank the members of Israeli pediatric study group, Dr. Gabriel Dinari, Dr. Ron Shaoul, Dr. Avi on, Dr. Esther Granot, Dr. Aaron Lerner, Dr. Ayala Yaron, Dr. David Wald, Dr. Yoram Bujanover, Dr. Zvi Wezman, Dr. Avi Pacht, Dr. Shimon Reif and Dr. Arie Silbermintz for recruitment of patients with Crohn’s disease to the study. Submitted for publication Feb 4, 2009; last revision received Aug 4, 2009; accepted Aug 26, 2009.
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Reprint requests: Amnon Zung, MD, Pediatric Endocrinology Unit, Kaplan Medical Center, Rehovot 76100, Israel. E-mail: [email protected].
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