INTRODUCTION:

Adrenal suppression is a condition in which cortisol level decrease under normal range cause of exogenous glucocorticoid exposure^1,2,3. Cortisol is the end product from HPA axis circuits that have functioned as insulin antagonists increasing glucose production for brain and red blood cells, maintaining blood pressure and metabolic enzyme concentration, anti-inflammation, and immunosuppressant^4,5. The aetiological factors of adrenal suppression include duration and dose of glucocorticoid, the administration of glucocorticoid, cumulative dose of glucocorticoid, and potency of glucocorticoid^6,7.

Adrenal suppression could be indicated by clinical manifestation and cortisol level. The clinical manifestation can be varied such as weakness/fatigue (64%), weight loss (30%), hypotension (32%), lost of appetite (29%), headache (45%), nausea and vomiting (21 – 24 %), abdominal pain (5%)^8,9.

Nephrotic syndrome is a renal disease characterized by heavy proteinuria (≥ 40mg/m²/h), hypoalbuminemia (≤ 2.5g/dl), oedema, and hyperlipidemia. The incidence of this disease in the world at least 1 – 7 per 100.000, especially in Indonesia the incidence of 6 cases per 100.000/year with a boy to a girl (2:1)^10,11,12. The recommended regiment for this disease, according to the KDIGO guidelines, is by giving glucocorticoid (prednisone) to control this disease^10,13,14. The dose of glucocorticoid (prednisone) is 60mg/m² for 3 – 4 weeks in divided dose or single dose at induction phase followed by the alternate day 40mg/m2 for 4 – 12 weeks^12,15,16,26. This treatment could suppress Hypothalamic-Pituitary-Adrenal (HPA) axis by negative feedback control mechanism as short-loop feedback and long loop feedback which suppresses corticotrophin-releasing hormone (CRH) neuron. The result of this condition is decreased Adrenocorticotropic Hormone (ACTH) synthesis and cortisol production^6,17,18. The prednisone regiment in this disease is a high-dose (supraphysiological steroid levels) and long term therapy so it potentials to develop adrenal suppression. Not only dose and duration were indicated adrenal suppression, but also total cumulative dose and potency of steroid used²⁵. In fact only a few studies in nephrotic syndrome patient which assess cortisol level, all of the studies showed that decreased cortisol level^19,20. Some study showed that the higher dose, the higher impact to down up cortisol level. On the other hand, the longer exposure of therapy, the longer it will take the effect on adrenal suppression²¹. Therefore by alternating regiment, cortisol is expected to reach normal range in the end of therapy.

Case Presentation:

A 2-year-old java boy has entered to emergency department initially with oedema since 2 two weeks ago and worsen, cough and flu, increased body temperature, and urine coloration (red). The laboratory studies in the emergency department showed hypoalbuminemia (1.55 g/dl), protein urine (+3), and clinical symptoms such as anasarca oedema were found in this patient. No other significant abnormality was noticed on examination. After admission, the oedema, protein urine, and hypoalbuminemia were under controlled. Then, the patient took prednisone for therapy his disease (10mg three times a day). Before taking prednisone, cortisol morning was measured (15.36μg/dl). A month later, the patient admitted to the hospital to do a routine examination. No significant abnormality found in clinical manifestation but cortisol level showed that there was a decrease in cortisol level (2.51μg/dl). The regiment of prednisone was changed to the alternate method as a single dose (20mg in the morning). A month later we did examine cortisol level in the morning. The result showed that the cortisol level of the patient was 1.18μg/dl. No other abnormal clinical manifestation was found.

DISCUSSION:

Though clinical manifestation such as hypotension, weakness/fatigue, nausea, vomiting, abdominal pain, lost appetite, weight loss, and headache were not found in this patient, the cortisol level decreased after initial treatment for a month and still decreased after alternate therapy for a month. It showed that adrenal suppression may be developed which indicated by decrease cortisol level under the normal range^1,2,21. Prednisone cause suppression of the HPA axis by decreasing corticotrophin-releasing hormone (CRH) synthesis and secretion. As the result, the synthesis of proopiomelanocortin, peptide are deceased significantly. The ability of adrenal cortex to produce cortisol fail in short term²². The Adrenal suppression occurred in this patient because prednisone took in a divided dose (morning, afternoon, and night). According to circadian rhythm, the peak cortisol production reaches in the morning more than at another time. So, when prednisone takes in another time except in the morning, it has a greater effect in the cortisol level^6,7. The mechanism of prednisone caused adrenal suppression could be explained by negative feedback in hypothalamic and hypophysis resulting in suppress proopiomelanocortin gene expression. As a result, the adrenocorticotropic hormone was inhibited and adrenal gland atrophy. Decreasing of ACTH level made the adrenal gland not able to produce cortisol appropriately^6,17. Lowering cortisol levels in the induction phase could be indicated adrenal suppression (below 3mcg/dl). To overcome this condition, prednisone should be given in the morning and a tapered dose of prednisone was needed. The adrenal examination should be done when prednisone tapered to physiologic dose². Meta-analysis study showed that adrenal insufficiency occurs frequently after cessation of glucocorticoid, while only few study examine cortisol level in clinical setting, almost patients having nonspecific symptoms of adrenal suppression²³. Another study in 37 children with nephrotic syndrome showed that they were associated with increased risk of developing adrenal suppression after steroid discontinuation²⁶. Those findings were reinforced by study involving 70 children with nephrotic syndrome found that 40% patient had low morning serum cortisol level²⁷.Albeit lowering morning serum cortisol level happened, it might not be specific to identify adrenal suppression. Further study with the number of subjects and longer observation was needed to evaluate when the cortisol level has reached the normal range and also single morning doses with ACTH stimulation are needed for more definitive diagnosis²⁷.

CONCLUSION:

Divided dose prednisone had a stronger effect in decreasing cortisol levels than a single dose. It is proven by lower cortisol levels in a patient with a divided dose even after an alternate phase.

ACKNOWLEDGEMENT:

The subjects are acknowledged for participating in this study. The authors also thank you to apt. Ana khusnul Faizah, M.Farm.Klin for supporting and giving chance to write this article.

CONFLICT OF INTEREST:

No conflicts of interest are declared by authors.

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Received on 29.06.2020 Modified on 22.01.2022

Research J. Pharm. and Tech 2023; 16(6):2601-2603.

DOI: 10.52711/0974-360X.2023.00426