Prevalence and Risk Factors for Adrenal Insufficiency in Patients with Multiple Myeloma Receiving Long-Term Chemotherapy including Corticosteroids: A Retrospective Cohort Study

Multiple myeloma (MM) is the second most common hematologic malignancy and requires long-term and high-dose corticosteroid-based chemotherapy. The aim of this study was to investigate the prevalence and clinical predictors of corticosteroid-associated adrenal insufficiency (AI) in patients with MM receiving long-term chemotherapy. This retrospective study included patients with MM who were administered corticosteroid-based chemotherapy and underwent a rapid adrenocorticotropic hormone (ACTH) stimulation test between 2005 and 2018. AI was determined by a peak cortisol value < 18 μg/dL after ACTH stimulation. Demographic, clinical, and laboratory parameters were evaluated, and the prevalence and clinical risk factors of AI were examined. Of 282 patients with MM who received corticosteroid-based chemotherapy, 142 patients (50.4%) were classified as having AI. There were no differences in age, sex, body mass index, comorbidities, and laboratory findings, including serum sodium levels between the AI and no-AI groups. In univariate analysis, the cumulative dose of corticosteroid ( odds ratio OR = 0.99 , 95% confidence interval (CI) 0.98–0.99; P = 0.020 ) and megestrol acetate use ( OR = 2.63 , 95% CI 1.48–4.67; P = 0.001 ) were associated with the occurrence of AI. Cumulative duration and cumulative dose per duration of corticosteroid use were not associated with the occurrence of AI. However, in the multivariate analysis, only megestrol acetate use was associated with an increased risk of AI ( OR = 2.54 , 95% CI 1.41–4.60; P = 0.002 ). Approximately 95.8% of patients with AI had suspicious symptoms or signs of AI. Although clinical symptoms and signs are usually nonspecific, symptomatic patients with MM receiving long-term corticosteroid therapy have sufficient potential for developing AI, particularly when receiving megestrol acetate. These findings can help alert clinicians to consider adrenal suppression following corticosteroid-based chemotherapy in patients with MM.

Localized alopecia and suppression of hypothalamic-pituitary-adrenal (HPA) axis in dogs following treatment with difluprednate 0.05% ophthalmic emulsion (Durezol®)

Background Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited. Results Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2–3 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550 days (453–1160 days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced HPA axis suppression compared to dogs with no integumentary changes. Skin biopsies demonstrated follicular atrophy and follicular keratosis. When topical difluprednate was reduced to unilateral therapy, the hair regrew on the untreated side of the face. In addition to the affected research dogs, a 7-year old female spayed Chihuahua that was being treated as a clinical patient with long-term difluprednate 0.05% ophthalmic emulsion developed generalized hypotrichosis on the head and body and a potbellied appearance. ACTH stimulation testing revealed suppression of the HPA axis with a mild increase in serum alkaline phosphatase (ALP) activity and a urine specific gravity of 1.016. The combination of clinical signs and laboratory abnormalities was supportive of iatrogenic hyperadrenocorticism. Conclusions In dogs long-term use of difluprednate ophthalmic emulsion results in HPA axis suppression and in some cases iatrogenic hyperadrenocorticism. A novel pattern of localized alopecia is suspected to be related to dermal absorption and local action due to superior potency and penetration compared to other commonly utilized ophthalmic corticosteroids.

Hypercortisolism in patients with cholestasis is associated with disease severity

Background Cholestasis might lead to an impairment of adrenal function as suggested by in vitro and in vivo data as well as by clinical findings. Bile acid and adrenal steroid metabolism not only share the receptors farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5), but supraphysiological bile acid levels were found to stimulate steroidogenesis independent of FXR and TGR5. Our previous experimental findings revealed that mice fed bile acids or subjected to common bile duct ligation develop hypercortisolemia. We thus aimed to assess adrenal gland function in patients with cholestasis. Methods Adrenal gland function was assessed in 36 patients with cholestasis and in 32 patients without cholestasis by measuring total serum cortisol, adrenocorticotropic hormone (ACTH), as well as the increase of cortisol 20 and 30 min after administration of 1 µg of ACTH. Bile acid levels and bile acid pool composition were determined by high-resolution mass spectrometry. Results Patients with cholestasis per definition had markedly elevated levels of alkaline phosphatase (AP), bilirubin and serum bile acids. Baseline cortisol and maximum cortisol after ACTH stimulation were significantly higher in patients with cholestasis compared to controls. Increase of cortisol after ACTH stimulation and ACTH did not differ. In the cholestasis group, baseline cortisol correlated with bilirubin but not with AP, total serum bile acids and levels of conjugated and unconjugated bile acid species. Patients with duration of cholestasis < 6 months (n = 30) had significantly higher baseline cortisol levels than those with long standing cholestasis (> 6 months), together with higher bilirubin levels. Conclusions We find no evidence of adrenal insufficiency in non-cirrhotic patients with cholestasis. In contrast, patients with cholestasis show hypercortisolism associated with disease severity as mirrored by levels of bilirubin. Lack of ACTH increase in cholestasis suggests a direct effect of cholestasis on adrenals and not on the pituitary gland. Further studies are needed to elucidate the mechanism of cortisol elevation in patients with cholestasis and its clinical significance.

Comparison of Bolus and Continuous Infusion of Adrenocorticotropic Hormone During Adrenal Vein Sampling

BackgroundAdrenocorticotropic hormone (ACTH) is widely used in adrenal vein sampling (AVS) and can be administered as a bolus injection or continuous infusion. The optimal administration method has not been determined. We aimed to compare the effects of ACTH bolus with infusion on cannulation success, lateralization assessment and adverse events (AEs).MethodsRetrospectively collected data from patients with primary aldosteronism who underwent AVS with ACTH at a tertiary hospital in China. Rate of successful cannulation, lateralization index (LI), complete biochemical remission and AEs related to AVS were analyzed.ResultsThe study included 80 patients receiving ACTH bolus and 94 receiving infusions. The rate of successful cannulation was comparable between bolus and infusion groups (75/80, 93.4% vs 88/94, 93.6%). In those with successful cannulation, the bolus group had a higher selectivity index than the infusion group, while LI [6.4(1.8-17.5) vs. 7.6(2.0-27.8), P=0.48] and rate of complete biochemical remission (43/44, 97.7% vs 53/53, 100%, P=0.45) did not significantly differ between the two groups. One in the bolus and one patient in the infusion group had adrenal vein rupture but they recovered with conservative treatment. The bolus group reported more transient AEs such as palpitation (52.9% vs 2.2%) and abdominal discomfort (40.0% vs 2.2%) than the infusion group.ConclusionsDue to their similar effects on cannulation success and lateralization, but a lower rate of transient AEs in the infusion group, the continuous infusion method should be recommended for ACTH stimulation in AVS.

Septo-Optic Dysplasia Diagnosed in a Newborn Infant with Normoglycemia: The Importance of Thorough Physical Examination

A newborn male infant was admitted to the neonatal intensive care unit due to suspected sepsis. He was clinically stable with normal electrolyte levels on admission. However, he was noted to have micropenis and bilateral nonpalpable testes. Ultrasound imaging confirmed the presence of both gonads in the inguinal canal, with no Müllerian structures visualized. Laboratory examination revealed an undetectable random plasma cortisol level; subsequent ACTH stimulation testing confirmed adrenal insufficiency. Further testing revealed additional pituitary hormone deficiencies, and the infant was started on multiple hormone replacement therapies. Magnetic resonance imaging identified absent septum pellucidum, pointing of the frontal horns, and optic nerve hypoplasia. A diagnosis of septo-optic dysplasia was made based on this combination of findings. This case highlights the importance of thorough physical examination in newborn infants, which may reveal the only sign of underlying pathology in the absence of other concerning findings.

Evaluation of adrenal reserve in patients with differential thyroid cancer receiving thyroid hormone suppression therapy- case-control comparative study

Background Patients with differentiated thyroid cancer (DTC) are exposed to subclinical exogenous hyperthyroidism for the suppression of thyroid-stimulating hormone (TSH). In this study, we aimed to evaluate the adrenal reserve in DTC patients receiving suppression therapy. Materials and Methods The study included 55 DTC patients on suppression therapy and 32 healthy volunteers. Basal serum cortisol of all participants and adrenocorticotropic hormone (ACTH) of the patient group were measured. A standard-dose ACTH test (0.25 mg) was performed in patients with a basal cortisol < 14.5 mcg/dL. Results In the patient group, TSH was lower, free thyroxine (fT4) was higher, and free triiodothyronine (fT3) was similar to those of the control group (p < 0.01, p < 0.01, p = 0.140, respectively). The serum cortisol of the patient group was significantly lower than the control group (12.14 ± 5.12 mcg/dL vs 18.00 ± 5.56 mcg/dL, p < 0.001). 34 (61.8%) patients with DTC had a basal cortisol < 14.5 mcg/dL. Prolonged TSH suppression (≥ 5 years vs < 5 years) was associated with lower basal cortisol (7.46 ± 2.63 mcg/dL vs 9.48 ± 2.65 mcg/dL, p = 0.022). The ACTH stimulation test showed that 2 (5.8%) patients had a cortisol response < 18 mcg/dL. The rate of adrenal insufficiency was 3.6% in DTC patients. A moderate negative correlation was found between ACTH and fT3 of patients with low basal cortisol (r = − 0.358, p = 0.038) Conclusion Patients with DTC receiving TSH suppression therapy are at risk for adrenal insufficiency. The duration and severity of suppression might increase this possibility. Dynamic testing with synthetic ACTH can be used to reveal insufficient cortisol response in case of clinical suspicion.

Emergence of Autoimmune Type 1 Diabetes and Acute Adrenal Crisis Following COVID-19

Objective: Several case reports have indicated a possible link between Coronavirus Disease 2019 (COVID-19) and new-onset autoimmune disorders while co-precipitation of autoimmune type 1 diabetes and Addison’s disease has never been reported to date. Case Description: A 60-year-old male presented with extreme fatigue and weight loss three weeks after testing positive for COVID-19. The course of COVID-19 was mild, without pulmonary involvement. The patient showed symptoms and laboratory signs of new-onset diabetes without ketoacidosis and acute primary adrenal insufficiency, latter of which was confirmed with an ACTH stimulation test. GAD-65 antibody and antibodies to the adrenal cortex were positive in high titers, and the patient also had primary hypothyroidism associated with autoimmune thyroiditis. Previous medical records of the patient revealed no hyperglycemia or electrolyte abnormalities prior to current admission, but an earlier test result compatible with primary hypothyroidism. The patient was diagnosed with autoimmune polyglandular syndrome type II (APS II). Clinical and laboratory findings improved after starting appropriate hormone replacement therapies along with insulin. Conclusions: Evidence mostly obtained from case reports suggests that COVID-19 may induce a variety of autoimmune disorders in susceptible subjects. In our case, COVID-19 might have simply precipitated T1D and adrenal crisis in whom autoimmune thyroiditis may have been the first manifestation of an undiagnosed APS II. Or, COVID-19 may have triggered autoimmunity in the patient who was possibly predisposed to autoimmune disorders, and led to the development of APS II. Anyhow, more research is required to evaluate the possible link between COVID-19 and autoimmune disorders.

Pituitary

This chapter covers the pituitary gland. It starts with the anatomy and physiology, then moves on to imaging, and pituitary function. It then covers common tests, including ITT, glucagon, ACTH stimulation, arginine, clomiphene, hCG, and TRH. It then begins to cover disorders of pituitary function, with treatment, hormone replacement, and investigation all included. Pituitary tumours are described, along with investigation, diagnosis, and treatment. Other disorders, including Cushing’s disease, cysts, inflammatory conditions are all included. Complications from other conditions are also described.

Prevalence of adrenal insufficiency among patients with euvolemic hyponatremia

Background: The diagnosis of SIAD requires the exclusion of secondary adrenal insufficiency (AI) among patients with euvolemic hyponatremia (EuVHNa). Studies have suggested about 2.7% to 3.8% of unselected patients presenting to the emergency room with EuVHNa have undiagnosed AI and it is as high as 15% among patients admitted to specialized units for evaluation of hyponatremia. Objective: To study the prevalence of AI among inpatients with EuVHNa in a general medical ward setting Methods: This was a prospective, single centre observational study conducted among general medical inpatients with EuVHNa, defined as patients with a serum Na <135 mmol/L, clinical euvolemia and urine spot sodium >30mmol/L. Additionally patients with recent vomiting, current renal failure, diuretic use and those with uncontrolled hyperglycemia were excluded. Adrenal functions were assessed by a modified ACTH stimulation test called Acton Prolongatum™ stimulation test (APST). A cut off cortisol value of <18mg/dl after 60 minutes of ACTH injection was used to diagnose AI. Results: One hundred and forty-one (141) patients were included and underwent an APST. APST suggested 20/141 (14.2%) had undiagnosed AI. The most common cause of AI (9/20) was secondary AI because of the use of steroids including inhaled steroids and indigenous medicines contaminated with steroids. In 5 (3.5%) patients hypopituitarism was newly diagnosed. Despite primary adrenal insufficiency not commonly presenting as EuVHNa, 2/20 patients had primary adrenal insufficiency. Conclusions: AI is much commoner in our country among inpatients with EuVHNa primarily driven by exogenous steroid use and undiagnosed hypopituitarism.

Assessment of Neuroendocrine Changes and the Hypothalamo-Pituitary Autoimmunity in Patients With COVID-19

Purpose: The SARS-CoV-2 may affect the hypothalamic-pituitary axis and pituitary dysfunction may occur. Therefore, we investigated neuroendocrine changes, particularly, secondary adrenal insufficiency using a dynamic test and the role of autoimmunity in pituitary dysfunction in the patients with COVID-19.Methods: The single-center, prospective, case-control study included PCR-confirmed COVID-19 patients and healthy controls. Basal hormone levels were measured and ACTH stimulation test was performed. Anti-pituitary (APA) and anti-hypothalamic antibodies (AHA) were also determined. Results: We examined a total of 49 patients with COVID-19 and 28 healthy controls. The frequency of adrenal insufficiency in patients with COVID-19 was found as 8.2%. The patients with COVID-19 had lower free T3, IGF-1, total testosterone levels, and higher cortisol and prolactin levels when compared with controls. We also, demonstrated the presence of APA in three and AHA in one of four patients with adrenal insufficiency. Conclusions: The COVID-19 may result in adrenal insufficiency, so the routine screening of adrenal functions is these patients is needed. Endocrine disturbances in COVID-19 are similar to those seen in acute stressful conditions or infections. Also, pituitary or hypothalamic autoimmunity may play a role in neuroendocrine abnormality in COVID-19.