ORIGINAL RESEARCH |
https://doi.org/10.5005/jp-journals-10002-1448 |
Clinical and Biochemical Pertinence of Glucocorticoid-induced Adrenal Insufficiency in Glomerular Disease Conditions
1Department of Physiology, Chettinad Academy of Research and Education, Kanchipuram, Tamil Nadu, India
2Department of Nephrology, Coimbatore Medical College and Hospital, Coimbatore, Tamil Nadu, India
3Department of Nephrology, Kilpauk Medical College and Hospital, Chennai, Tamil Nadu, India
Corresponding Author: Brinda Srinivasagopalane, Department of Physiology, Chettinad Academy of Research and Education, Kanchipuram, Tamil Nadu, India, Phone: +91 9500463307, e-mail: brindmbbs22@gmail.com
Received on: 08 March 2023; Accepted on: 15 July 2023; Published on: 31 August 2023
ABSTRACT
The cardinal treatment modality for any glomerular disease is glucocorticoids. The glucocorticoids cause an imbalance in the hypothalamus–pituitary–adrenal axis by altering the endogenous cortisol levels. The low levels of cortisol result in a clinical syndrome called adrenal insufficiency (AI). The occurrence of iatrogenic AI by the glucocorticoids among glomerular disease is evaluated in this study by both biochemical cortisol assay and clinical evaluation, and also, the value of salivary cortisol over serum cortisol is correlated.
Materials and methods: This cross-sectional study was done on 30 biopsy-proven glomerular disease patients on glucocorticoid treatment. Clinical implications were noted using a detailed questionnaire, and serum and salivary cortisol assays were analyzed by enzyme-linked immunosorbent assay (ELISA) technique.
Results: On clinical evaluation, 78% of the study population did not show signs of AI. However, 15% of the patients exhibited cushingoid symptoms. Biochemical assay with serum cortisol showed 45% with low serum cortisol levels, suggesting AI and only 3% of the study population had low salivary cortisol levels. There was no linear correlation between serum and salivary cortisol levels.
Conclusion: The evidence of AI among glucocorticoid-treated glomerular disease patients is established with serum cortisol assay. The value of salivary cortisol is not marked as the other confounding factors, such as drugs and cross-reactivity with antibodies, could alter the assay values. Overall, the suppression of the hypothalamic–pituitary–adrenal (HPA) axis is evident in our study, and a monitored glucocorticoid therapy is vital so as to prevent the tendency of AI and its complications.
How to cite this article: Srinivasagopalane B, Somasundaram K, Thoppalan B. Clinical and Biochemical Pertinence of Glucocorticoid-induced Adrenal Insufficiency in Glomerular Disease Conditions. World J Endoc Surg 2023;15(1):1–5.
Source of support: This study was partially funded by ACS Medical College and Hospital, Chennai.
Conflict of interest: None
Keywords: Adrenal insufficiency, Glomerular disease, Glucocorticoids, Hypothalamic–pituitary–adrenal axis, Salivary cortisol
BACKGROUND
The glomerular disease includes a wide array of disease conditions with injury to the glomerular membrane of the kidney due to infection, autoimmune mechanism, genetic mutation, toxin exposure, hypertension, atherosclerosis, diabetes mellitus, or idiopathic. Glucocorticoids form a baseline treatment for most glomerular diseases and to minimize the risk, the doses of glucocorticoids are kept low and tapered accordingly. The treatment regimen varies with the disease pattern and the patient profile. Chronic treatment with glucocorticoids results in the inhibition of the hypothalamic–pituitary axis by a negative feedback mechanism, this led to endogenous suppression of cortisol levels.1 A marked decrease in serum cortisol level could lead to adrenal insufficiency (AI), which is life-threatening and may go unnoticed in several cases. The prevalence of AI among glucocorticoid-treated individuals is significant, with a median prevalence of 37%. The insulin tolerance test and cosyntropin stimulation test adrenocorticotropic hormone (ACTH) are suggested to be the gold standards in diagnosing AI. In addition, studies have shown to associate serum and salivary cortisol as a convenient alternate marker in identifying AI. The measurement of salivary cortisol has its own advantages over serum cortisol as it is easier, noninvasive to measure, and it reflects an unbound steroid concentration.2 It was also evident that AI was seen even with the smallest treated doses of steroids and persistence of AI for 3 years after the glucocorticoid withdrawal.3 A meta-analysis study has shown that the risk of AI is not varied with differences in steroid mode of administration, dose, or treatment duration.4 The evidence of AI among glucocorticoid-treated glomerular disease patients with serum and salivary cortisol measurements is sparse, especially among the Indian population. Hence, in our study, we would like to:
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Assess the percentage distribution of AI among glomerular disease patients treated with glucocorticoids by cortisol assay estimation.
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Assess the clinical outcome of AI among glomerular disease patients treated with glucocorticoids.
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To correlate the value of salivary cortisol level with serum cortisol in diagnosing AI among glomerular disease patients on glucocorticoids.
MATERIALS AND METHODS
Design and setting—this was a cross-sectional study, and the data was collected directly from the participants.
Participants and recruitment—a total of 32 patients with biopsy-proven glomerular disease on steroid medication, patients on maintenance dose, and those on withdrawal regimen were recruited for this study. Among the 32 participants, two patients withdrew from the study, and hence 30 patient parameters were used for analysis. Patients with any other medical condition affecting the adrenal function or history of any adrenal surgery were excluded from the study.
Data collection—the complying participants of both genders and ages between 18 and 65 years, attending the nephrology department, were selected without bias, and informed consent will be obtained. The study was performed after institutional ethical committee clearance in accordance with the ethical principles in the Declaration of Helsinki, which are consistent with good clinical practice and applicable regulatory requirements. The subject’s signed and dated informed consent was obtained before conducting the study. A detailed questionnaire on the history of the disease, treatment protocol, and clinical complications was noted. The patients were advised to stop their current steroid medication for 24 hours and later were asked to report for blood and saliva sampling to estimate cortisol levels at 8 AM. Both saliva and serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) technique for cortisol levels. The data were entered and analyzed by using Statistical Package for the Social Sciences (SPSS) software.
RESULTS
The parameters were statistically analyzed using SPSS software (version 21). The results of the analysis are summarized in Tables 1 and 2 and Figures 1 and 2.
Variables | N | % | |
---|---|---|---|
Age | ≤25 years | 8 | 25.00 |
26–40 years | 14 | 43.75 | |
>40 years | 10 | 31.25 | |
Gender | Male | 13 | 40.63 |
Female | 19 | 59.38 | |
Native kidney disease | Lupus nephritis | 15 | 46.88 |
Membranous nephropathy | 6 | 18.75 | |
Minimal change disease | 3 | 9.38 | |
Antineutrophil cytoplasmic antibody-associated vasculitis | 3 | 9.38 | |
Focal segmental glomerulosclerosis | 2 | 6.25 | |
Immunoglobulin A nephropathy | 1 | 3.13 | |
Immunoglobulin A vasculitis | 1 | 3.13 | |
Membranoproliferative glomerulonephritis | 1 | 3.13 | |
Parenteral steroids | Yes | 21 | 67.74 |
No | 10 | 32.26 | |
Complications | Weight gain | 3 | 9.38 |
Diabetes | 3 | 9.38 | |
Diabetes and weight gain | 3 | 9.38 | |
Cushingoid | 2 | 6.25 | |
Striae | 1 | 3.13 | |
Skin infections and weight gain | 1 | 3.13 | |
AVN femur, cushingoid, striae, and weight gain | 1 | 3.13 | |
No | 18 | 56.25 | |
Tapering | 10 mg at 3 months | 10 | 32.26 |
10 mg at 4 months | 7 | 22.58 | |
10 mg at 5 months | 1 | 3.23 | |
10 mg at 6 months | 3 | 9.68 | |
Medrol at >7 years | 1 | 3.23 | |
Tapered after 2 months | 1 | 3.23 | |
No | 8 | 25.81 | |
Relapses | Yes | 6 | 19.35 |
No | 25 | 80.65 | |
Clinical symptoms of AI | Cushingoid | 5 | 15.63 |
Obesity | 1 | 3.13 | |
Striae | 1 | 3.13 | |
No | 25 | 78.13 | |
Biopsy finding–glomerular disease | Lupus nephritis | 13 | 41.94 |
Membranous nephropathy | 5 | 16.13 | |
Minimal change disease | 3 | 9.68 | |
Antineutrophil cytoplasmic antibody-associated vasculitis | 3 | 9.68 | |
Membranoproliferative glomerulonephritis | 1 | 3.23 | |
Immunoglobulin A vasculitis | 2 | 6.45 | |
Focal segmental glomerulosclerosis | 2 | 6.45 | |
Lupus nephritis 4 | 1 | 3.23 | |
Lupus nephritis 4 + 5 | 1 | 3.23 |
Variables | Mean ± standard deviation |
---|---|
Height (cm) | 159 ± 10 |
Weight (kg) | 61 ± 13 |
Systolic blood pressure (BP) | 127 ± 11 |
Diastolic BP | 80 ± 7 |
Pulse rate (PR) | 80 ± 6 |
Duration of steroid (months) | 39 ± 39 |
No. of cycles of steroid | 2 ± 2 |
Hemoglobin | 11.3 ± 1.7 |
Total count (TC) | 7487 ± 2014 |
Blood urea nitrogen (Bun) | 33 ± 19 |
Creatinine (Cr) | 1.14 ± 0.45 |
Sugar | 103 ± 34 |
Sodium (Na) | 138 ± 5 |
Potassium (K) | 4.4 ± 0.5 |
Salivary cortisol | 7.696 ± 5.201 |
Serum cortisol | 116.905 ± 43.770 |
DISCUSSION
Adrenal insufficiency (AI) is a clinical syndrome due to disturbance in the HPA axis with many etiological factors.5 In this study, we have focused on the iatrogenic cause of AI. Glomerular disease patients are commonly treated with glucocorticoids, and thereby, glucocorticoid-induced AI is less commonly studied, especially among the Indian population. The pathophysiological mechanism behind this phenomenon is the suppression of the HPA axis by the exogenous glucocorticoid administration which could alter the endogenous cortisol levels resulting in relative AI.6,7
The study was designed to identify the percentage distribution of AI clinically and by biochemical assays and also to validate the value of salivary cortisol as an efficient marker of AI. The study participants were 30 in number, and the characteristics of the study population are described in Table 1. The patients were all biopsy-proven on different glomerular diseases and were initiated on steroid medications and tapered gradually; 81% of the subjects had no relapse in the glomerular disease. The likely clinical features of AI were evaluated clinically and 78% of the study population had no significant clinical signs of AI; however, 15% of the study population exhibited cushingoid features. A similar low incidence in the clinical outcome was reported by Laugesen et al.8 Relatively, a low outcome on the clinical manifestation of AI is perceived when compared to the biochemical assay.
Biochemical evaluation of AI was done with serum and salivary cortisol assays. The biologically active cortisol is the unbound fraction and it can be measured both in the serum and saliva.9 It has been evident from several studies that cortisol values are an essential marker for AI.10 In our study, the mean salivary and serum cortisol values were 7.696 ± 5.201 and 116.905 ± 43.770, respectively. Figure 1 demonstrates that 45% had low serum cortisol values and 3% of the study population had low salivary cortisol levels. These low serum cortisol levels signify evidence of biochemical AI. The 45% distribution of AI evident with low serum cortisol levels is comparable to the study by Karangizi, who has shown 46% AI among glomerular disease patients on glucocorticoid therapy with short synacthen stimulation test.1 Studies have shown a strong outcome in the possibility of AI11 with glucocorticoid therapy. The hallmark aspect of our study is that direct serum cortisol measurement shows a similar distribution of AI. Thereby we could understand that serum cortisol measurements would be of much more benefit while investigating AI than subjecting the patients to stimulation tests.
The normal serum cortisol values (55%) could be attributed to several reasons, such as measured glucocorticoid treatment modality, tapered dosages, quick recovery response, and a smaller number of disease relapses. Though clear evidence of the outcome of AI could be noted, the outcome is influenced by several other factors, such as treatment dose and duration, route of administration, and the nature of the disease.4 Among those with higher doses and longer duration of corticosteroids, a higher percentage of AI is exhibited.12 The route of steroid administration has also played a vital role in the development of AI. In our study, 68% of patients were initiated with parenteral steroids and then tapered to oral steroids and the remaining 32% were only on oral steroids as their treatment regimen. Our study further supports the evidence that AI is more pronounced with the use of oral corticosteroids as oral steroids reach higher systemic levels than the other routes of usage.13 Our study supports the evidence of suppression of HPA axis14 among patients on glucocorticoid therapy, especially among the Indian population.
The utility of salivary cortisol as a better marker than serum cortisol has been evident.15,16 The higher interest in the use of salivary cortisol is because it represents the circulating level of cortisol and the sample collection is easier and cost-effective.17 Our study was planned to identify on correlation between the serum and salivary cortisol values. The correlation, as shown in Figure 2, demonstrates no signification linear relationship between both values. Even though saliva cortisol is a quicker marker, there are several limitations to its measurement validity as it could be altered with other pharmacological drugs or cross-reactions with antibodies used to detect cortisol by immunoassay.18 Hence the exact validity of salivary cortisol over serum cortisol could not be ascertained in our study. The negative association between serum and salivary cortisol assays in our study could be due to the small sample size. Our study highlights that on the valuation of both the clinical outcomes and cortisol assay measurements concomitantly, serum cortisol assay gives a valid and expeditious outcome on AI, which is beneficial for early identification.
Strengths—firstly, in our study, we asked our patients to stop taking the glucocorticoid medication 24 hours prior to the estimation of cortisol levels. Studies have reported a half-life of 0.5–4.0 hours for the glucocorticoid agents to have cross-reactivity with the assay measurements.19 Hence the influence of the medication effect on the assay levels is considered to be minimal. Secondly, to the best of our knowledge, our study is the first of its kind to study the iatrogenic AI among glomerular disease patients in the Indian population. Thirdly, both clinical outcomes and cortisol assay measurements are concomitantly observed in this study.
Limitations
A few limitations have been considered—(1) low sample size, (2) duration of glucocorticoid treatment, and (3) ACTH stimulation test as confirmatory evidence to diagnose AI.
CONCLUSION
The use of glucocorticoids among glomerular disease patients is inevitable. The risk of AI to prolonged exposure to glucocorticoids is highly possible. This study has shown a possibility of AI among glucocorticoid-treated glomerular disease patients in the Indian population and it adds to the evidence of the other population sets. We could also affirm the fact of suppression of the HPA axis with exogenous glucocorticoid administration; hence, a judicious watch for the signs of AI is vital. The importance of a simple marker such as salivary cortisol in diagnosing AI among glucocorticoid-treated glomerular diseases could not be entrenched in our study. Also, serum cortisol assay can be done regularly as a marker to identify and confirm AI among glucocorticoid-treated glomerular disease patients. In addition, slow monitored tapering of glucocorticoid doses is essential so that the HPA axis can regain its function according to the desired levels.
ORCID
Brinda Srinivasagopalane https://orcid.org/0000-0003-1960-6814
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