Subclinical Adrenal Insufficiency Research Articles

Adrenoleukodystrophy an Overview

Adrenoleukodystrophy (ALD) is a rare X-linked peroxisomal oxidation disease caused by mutations in ABCD1. It presents with various clinical manifestations, including cerebral ALD, myelopathy, and primary adrenal insufficiency. About 80% of ALD patients suffer from adrenal insufficiency, and cerebral ALD affects one-third of boys under twelve, progressing to total impairment and death without treatment. Hematopoietic stem cell transplantation (HSCT) is the only disease-modifying treatment for early-stage cerebral ALD, but it does not halt adrenal insufficiency progression and carries significant morbidity and mortality risks. A recent gene therapy clinical trial showed short-term MRI and neurological outcomes equivalent to past HSCT treatments without the adverse side effects. Additionally, over a dozen states have initiated newborn screening (NBS) for ALD, with the number expected to triple by 2020. Genetic testing of NBS-positive newborns has identified novel variations of unknown significance, raising questions about monitoring and treating preclinical or moderate adrenal insufficiency or cerebral involvement. This presents further opportunities for genetic characterization. The availability of matching donors, transplant centers, and specialists will impact prompt treatment for those diagnosed with ALD at birth. As NBS and gene therapy trials improve ALD's clinical management and prognosis, endocrine management of presymptomatic and subclinical adrenal insufficiency will become increasingly important.

Adrenocortical function in patients with Single Large Scale Mitochondrial DNA Deletions: a retrospective single centre cohort study.

Single Large Scale Mitochondrial DNA Deletions (SLSMDs), Pearson Syndrome (PS) and Kearns-Sayre Syndrome (KSS), are systemic diseases with multiple endocrine abnormalities. The adrenocortical function has not been systematically investigated with a few anecdotal reports of overt adrenal insufficiency (AI). The study aimed to assess the adrenocortical function in a large cohort of SLSMDs. A retrospective monocentric longitudinal study involved a cohort of 18 SLSMDs patients. Adrenocortical function was evaluated by baseline adrenocorticotrophic hormone (ACTH) and cortisol measurements and by high- (HDT) and low-dose (LDT) ACTH stimulation tests and compared with 92 healthy controls (HC). Baseline adrenocortical function was impaired in 39% of patients and by the end of the study, 66% of PS and 25% of KSS showed an insufficient increase after ACTH stimulation, with cortisol deficiency due to primary AI in most PS and subclinical AI in KSS. Symptomatic AI was recorded in 44% of patients. Peak cortisol levels after ACTH stimulation tests were significantly lower in patients than in HC (P < .0001), with a more reduced response to LDT vs HDT (P < .05). Our study highlights that cortisol deficiency due to primary AI represents a relevant part of the clinical spectrum in SLSMDs, with more severe impairment in PS than in KSS. Basal and after-stimulus assessment of adrenocortical axis should be early and regularly investigated to identify any degree of adrenocortical dysfunction. The study allowed the elaboration of a diagnostic process designed for the diagnosis, treatment, and follow-up of adrenocortical abnormalities in SLSMDs.

Clinical insights of pregnancy management, adrenal insufficiency as a possible cause of elevated TSH: a pilot study of case series

BackgroundThe upper limit for thyroid-stimulating hormone has been strictly defined for pregnancy management, at which point levothyroxine replacement therapy will been initiated. However, it is essential to exclude adrenal insufficiency, including subclinical adrenal insufficiency, when initiating levothyroxine replacement therapy. However, in pregnancy management, it has rarely reported the incidence, clinical course, and characteristics of adrenal insufficiency as a possible cause of elevated thyroid-stimulating hormone.MethodsThis case series study included pregnant patients undergoing thyroid-stimulating hormone management in a single-center diabetes endocrinology department between 2017 and 2020. The primary study outcome was the incidence of newly diagnosed adrenal insufficiency. We reported the clinical course and assessed the adrenal insufficiency characteristics at baseline and delivery and compared them with those of hypothyroidism.ResultFifteen pregnant women were included for thyroid-stimulating hormone management; and nine were below the basal serum cortisol level, and four were newly diagnosed as having adrenal insufficiency (26.7%) with the endocrinological stimulation test. Among them, two cases exhibited nausea and hypoglycemic symptoms after the start of levothyroxine replacement therapy. In cases of adrenal insufficiency, the patients were successfully treated with appropriate steroid coverage.ConclusionsIn the management of elevated thyroid-stimulating hormone levels during pregnancy, the frequency of adrenal insufficiency suspecting hypothyroidism may be higher than expected; therefore, we must be careful about starting levothyroxine replacement therapy for hypothyroidism. These clinical insights can have a significant impact on the pregnancy outcomes.

Abstract 40: Adrenal insufficiency in patients with HbE/Beta thalassemia

Background: Adrenal insufficiency (AI) in HbE/Beta thalassemia is not well documented.Aims and Objectives: Prevalence of AI in HbE/Beta thalassemia. Difference in prevalence of AI according to severity of HbE/Beta thalassemia and dependence on transfusion.Results: In this observational, cross sectional study, one hundred four patients with HbE/Beta thalassemia were evaluated. Amongst them 57 and 47 were transfusion dependent (TD) and non-transfusion dependent (NTD) thalassemia. According to Mahidol criteria, patients were classified into mild (n=39), moderate (n=39) and severe (n=26) disease. Early morning (8 AM) serum cortisol, plasma ACTH, DHEAS, androstenidione and plasma aldosterone, renin were measured. Patients with baseline cortisol of 5-18 μg/dl underwent both 1 μg and 250 μg SST (Short Synacthen Test). Overt adrenal insufficiency was found in 41% (n= 43). Amongst them 72% (n= 31) had primary AI and 27% (n= 12) had secondary AI. Thirty three patients (31%) with normal or elevated ACTH, with low or normal aldostreone with high renin were diagnosed as subclinical adrenal insufficiency. There was no significant difference in prevalence of AI between TD and NTD (p = 0.56) nor was there was any difference in prevalence of AI according to disease severity (p=0.52).Conclusion: Adrenal insufficiency is common in HbE/Beta thalassemia and is independent of transfusion dependency and disease severity.

Pediatric Adrenal Insufficiency: Challenges and Solutions.

Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason.

Overt and Subclinical Adrenal Insufficiency in Pulmonary Tuberculosis

BackgroundTuberculosis of the adrenal glands may cause overt or subclinical adrenal insufficiency. An algorithm-based approach including assessment of paired basal cortisol and plasma adrenocorticotropic hormone (ACTH), short Synacthen, and plasma renin activity assays could be useful to diagnose all forms of adrenal insufficiency. MethodsThis cross-sectional study included consecutive, treatment-naive subjects diagnosed with pulmonary tuberculosis. Tuberculosis severity was classified by radiological criteria. Baseline parameters plus morning (8 am) serum cortisol and paired plasma ACTH were measured in all patients. Synacthen stimulation tests and plasma renin activity assays were performed as required. ResultsEighty-four treatment-naive consecutive cases of pulmonary tuberculosis were evaluated for adrenal insufficiency. Twenty-seven (32.14%) subjects had normal adrenocortical function and 8 (9.5%), 7 (8.3%), 40 (47.6%), and 2 (2.4%) subjects had stage 1, stage 2, stage 3, and stage 4 adrenal insufficiency, respectively. Serum cortisol was negatively correlated with radiological severity (P = .01) and duration of illness (P = .001). Adrenal dysfunction was present in 27.3%, 82.5%, and 80% of those with radiologically minimal, moderately advanced, and far-advanced disease, respectively. Mean cortisol was 19.74 ± 5.52, 17.42 ± 8.53, and 15.71 ± 7.14 (μg/dL) in the 3 groups, respectively (P = .042). Hyponatremia was present in 83.3% of the patients. Serum sodium was negatively correlated with severity but not with the duration of disease. ConclusionThe prevalence of overt and subclinical adrenal dysfunction in pulmonary tuberculosis was high and was correlated with disease severity and duration. An algorithmic approach may be useful to detect the same and may have important clinical implications.

Evaluation of Subclinical Adrenal Insufficiency in Patients with Active Tuberculosis

The existence of subclinical adrenal insufficiency in active tuberculosis is a matter of debate and little is known in this regard. This analytical cross-sectional study is contemplated to find out the association between active tuberculosis and subclinical adrenocortical insufficiency. Where 77 active tubercular patients have been included consecutively in the study along with 30 age and sex matched healthy controls for comparison. Nearly two-thirds (64.9%) of the cases ware diagnosed as pulmonary tuberculosis and rest 35.1% as extra pulmonary tuberculosis. In pulmonary tuberculosis 68.8% had subclinical adrenal insufficiency but 31.2% in extra pulmonary tuberculosis. It shows that 62.3% of the cases had sub-clinical adrenocortical insufficiency as opposed to none in the control group (p &lt; 0.001). Adrenal insufficiency appeared to be significantly associated with smear positivity, X-ray evidence of severe disease and multi-drug resistance. Therefore, physician ought to look for subclinical adrenal insufficiency among patients with active tuberculosis specially if they are sputum positive, X-ray evidence of severe disease and multidrug resistant TB.&#x0D; Faridpur Med. Coll. J. Jul 2019;14(2): 67-70

The Changing Face of Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).

Acute Statin Administration Reduces Levels of Steroid Hormone Precursors.

Cholesterol-lowering statin drugs are used by approximately 25% of US adults 45 years of age and older and frequency of use is even higher among the elderly. Cholesterol provides the substrate for steroid hormone synthesis and its intracellular concentrations are tightly regulated. Our aim was to evaluate whether statin use acutely changes the circulating levels of cortisol, other glucocorticoid precursor molecules and their metabolites. Fourteen subjects not taking statins were administered a single oral dose (2 mg) of pitavastatin. Blood samples collected at baseline and 24 h post-treatment were analyzed for plasma cholesterol and steroid hormone profile. A parallel study in mice entailed the administration of atorvastatin (10 mg/kg) via orogastric delivery for three consecutive days. Cholesterol and corticosterone levels were quantified at baseline and at 1-day and 1-week post-treatment. Several precursor molecules in the steroidogenic pathway (corticosterone, cortisone, and 11-deoxycortisol) were significantly decreased 24 h after administration of a single dose of pitavastatin in human study subjects. Their circulating cholesterol concentrations were unchanged. In mice, there were no significant differences in serum cholesterol or corticosterone at 1-day or 1-week post-treatment compared to both pre-treatment baseline levels and control group levels. We conclude that acute dysregulation of the production of certain glucocorticoid precursor molecules was observed after a single treatment with a lipophilic statin drug. This may be of clinical relevance for individuals with underlying or subclinical adrenal insufficiency.

SAT-316 MAX-Related Bilateral Pheochromocytoma Associated with Subclinical Adrenal Insufficiency: A Case Report

INTRODUCTION: Loss-of-function mutation in the MYC-associated factor X (MAX) gene causes hereditary pheochromocytoma (PCC) that are frequently bilateral or multifocal1. Adrenal insufficiency (AI) associated with unresected bilateral PCC has not been previously described. We hereby present a case of subclinical AI in a patient with bilateral PCC. CLINICAL CASE: An otherwise healthy 30-year-old woman was found to have a pathogenic MAX gene mutation (c.228delG) after undergoing genetic testing for a significant family history of PCC in 3 relatives. She participated in high-intensity interval training 5 times per week and denied episodes of palpitations, flushing, diaphoresis, or dizziness, but endorsed frequent pulsatile tinnitus and morning headaches. She had a history of hypertension in late pregnancy which had been presumed gestational. Exam was notable only for manual BP 152/110 mmHg, HR 110 bpm, and a faint resting tremor. Lab work was consistent with PCC: plasma norepinephrine 12417 pg/mL (ref <874) and normetanephrine 26 nmol/L (ref <0.9); urine norepinephrine 3378 mcg/24h (ref <135) and normetanephrine 16620 mcg/24h (ref <500). AM cortisol was 10.9 mcg/dL (ref 5-20) with a high normal ACTH of 46 pg/mL (ref 0-46) and low DHEA-S of 23 mcg/dL (ref 75-530). She had no prior history of glucocorticoid exposure, and thyroid studies were normal. CT imaging revealed bilateral contrast-enhancing heterogeneous adrenal masses (R: 3.5 x 2.2 cm; L: 4.6 x 4.5 cm). She was treated with alpha- then beta-adrenergic blockade and subsequently underwent surgical removal of both adrenal tumors with sparing of the superior adrenal cortices bilaterally. Plasma and urine catecholamines and metanephrines normalized a week post-operatively, and she began to report fatigue and dizziness. Two weeks post-operatively, midday plasma levels of cortisol, DHEA-S, and ACTH were 6.3 mcg/dL, <15 mcg/dL, and 118 pg/mL, respectively. Standard-dose 250mcg ACTH stimulation test confirmed AI with peak cortisol of 15.1 mcg/dL. Replacement hydrocortisone was initiated with prompt resolution of symptoms. CONCLUSIONS: Individuals with a pathogenic MAX mutation require prompt screening for PCC as symptoms may be subtle despite significant biochemical abnormalities. Large PCCs may also impact hormone synthesis by the adjacent adrenal cortex. Even prior to surgery, this patient had subclinical AI as evidenced by a high-normal plasma ACTH and clearly low DHEA-S. The latter is the earliest adrenal steroid to decline in patients with primary or central AI2. It is unclear whether her worsening adrenal function after surgery was a surgical complication or due to dramatic decline in circulating catecholamines. Regardless, loss of adrenal androgen production warrants close follow-up for development of AI. REFERENCES: (1) Burnichon N et al. Clin Cancer Res 2012;18:2828 (2) Sayyed Kassem L et al. JCEM 2012;97:3655

Study of adrenal function in patients with tuberculosis

Although subclinical adrenal insufficiency has been documented in tuberculosis but it has been neglected in mainstream management of TB due to inconclusive data on its prevalence in TB. The fact that adrenal insufficiency may result not only in poor general condition of the patient but also sudden death due to adrenal crisis, makes it all the more important to address this issue seriously. In this non-randomized interventional study comprising of 100 cases of TB, our aim was to assess the adreno-cortical functions in patients with pulmonary TB (50 cases) and extra-pulmonary TB (50 cases) in an attempt to determine if there is any compromise of adrenal function. In this study, 100 cases of active TB were investigated for adrenal insufficiency by measuring morning fasting basal serum cortisol levels, followed by low dose ACTH stimulation test using 1μg synacthen (synthetic ACTH analog). The post-stimulation serum cortisol levels were estimated. Basal serum cortisol levels<220nmol/L or post-stimulation test serum cortisol level increment<200nmol/L or post-stimulation serum cortisol levels<500nmol/L were suggestive of adrenal insufficiency. Basal serum cortisol level was low in 16% cases and after low dose ACTH stimulation test, cortisol response was subnormal in 76% cases. Incidence of adrenal insufficiency in pulmonary TB (74%) and extra-pulmonary TB (78%) were comparable. The number of females having adrenal insufficiency in both the groups was higher than the males (67.3% males and 83.3% females) but the difference was statistically significant only in extra-pulmonary TB group (p=0.011). On analysing the data, the sensitivity of basal serum cortisol level estimation in diagnosing adrenal insufficiency was observed to be 21.05% and its specificity was 100%. Positive predictive value was 100% and negative predictive value was 28.57%. Diagnostic accuracy of basal serum cortisol level estimation was observed to be 40%. The incidence of subclinical adrenal insufficiency in TB cases attending chest department at a tertiary care hospital was significantly high but comparable in both pulmonary and extra-pulmonary type of TB. Females in general and particularly those with extra-pulmonary TB were observed to be at increased risk of adrenal insufficiency. The low dose ACTH stimulation test was able to identify cases with adrenal insufficiency which had normal basal serum cortisol levels. Screening all TB cases for adrenal insufficiency by measuring both morning basal serum cortisol levels and low dose ACTH stimulation test can help identify cases at risk of fatal adrenal crisis and institute timely management, thus improving disease prognosis.

Status epilepticus in an adolescent patient with adrenoleukodystrophy

Adrenoleukodystrophy is a neurodegenerative disease with X-linked recessive inheritance, which rapidly leads to neurological dysfunctions in childhood. It could only be treated by bone marrow transplantation at early stage. Here we report a case of X-linked adrenoleukodystrophy who was admitted to our hospital with status epilepticus and subclinical adrenal insufficiency. A 13-year-old boy, who had initially presented to a local hospital with seizures, was transferred to our hospital upon having generalized tonic-clonic seizures, which were followed by focal seizures. He had been introverted and amnesiac for the previous 2 months; hence, he had been receiving medication for major depression. However, his clinical condition worsened despite the medication. Although the patient lacked typical symptoms, he was diagnosed as having adrenoleukodystrophy upon detection of hyperintense lesions in occipitoparietal white matter by brain magnetic resonance imaging and increased serum very long chain fatty acid concentrations. Thus, we would like to emphasize the importance of awareness of physicians, particularly the pediatricians, neurologists and psychiatrists for clinical and laboratory characteristics of adrenoleukodystrophy.

A Case of Rathke's Cleft Cyst Associated with Transient Central Adrenal Insufficiency and Masked Diabetes Insipidus.

A 73-year-old woman admitted to our hospital because of headache, poor appetite, malaise, weight loss, and vomiting was found to have central adrenal insufficiency and thyrotoxicosis due to silent thyroiditis. Polyuria developed after replacement with glucocorticoid (masked diabetes insipidus), which was controlled with nasal administration of desmopressin. Magnetic resonance imaging of the brain showed a large cystic pituitary mass (18 × 18 × 12 mm) extending suprasellarly to the optic chiasm. Transsphenoidal surgery revealed that the pituitary tumor was Rathke's cleft cyst. Following surgery, replacement with neither glucocorticoid nor desmopressin was needed any more. Therefore, it is suggested that Rathke's cleft cyst is responsible for the masked diabetes insipidus and the central insufficiency. Furthermore, it is speculated that thyrotoxicosis with painless thyroiditis might induce changes from subclinical adrenal insufficiency to transiently overt insufficiency.

Adrenal gland dysfunction and myocardial Tissue Doppler echocardiographic abnormalities in Patients with Beta Thalassemia Major: cross sectional study

Background: Adrenal, parathyroid gland and myocardial echocardiographic abnormalities are recognized with variable outcomes in patients with transfusion dependent Beta-Thalassemia major (-TM). Aim: In this cross-sectional analytic study in patients with -TM, we evaluate the left ventricle systolic and diastolic function using Pulsed Doppler (PD) and Tissue Doppler (DT) echocardiogram with simultaneous measurement of serum level of cortisol and parathyroid hormone. Methods: The study was conducted on patients with ?-TM (n = 99, age 15.928.92 years) and compared with an age-matched controls (n = 98 age 15.798.94 years). In all participants echocardiographic indices of M mode and PD and TD were performed. Blood samples were withdrawn for measuring the serum cortisol, parathyroid and Ferritin. Correlation between the level of cortisol and ferritin level was evaluated. Results: Patients with ?-TM compared with controls, have significantly thicker LV septal wall index of 0.65 0.26 vs. 0.44 0.2190, P&lt;0.001 and LV posterior wall of 0.65 0.235 vs. 0.43 0.214, P&lt; 0.001, with no significant dilation of LV cavity in systole and diastole. The systolic function of LVFE% was normal of 51.95?5.5 vs. 5.0?5.6, p=0.23. Furthermore patients with ?-TM have higher E/A ratio (1.540.18 vs. 1.230.17, P&lt;0.01) and shorter deceleration time (DT) (170.5313.3 vs. 210.5019.20 m sec, P&lt;0.01). The ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em) was significantly higher in ?-TM group (19.682.81 vs. 13.861.41, P&lt;0.05). The tissue Doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in ?-TM group compared with controls with Sm, of 4.821.2 vs. 6.222.1 cm/sec, P&lt;0.05 and (Em) of 3.512.7 vs. 4.122.5 cm/sec P&lt;0.05, respectively). The tricuspid valve velocity was significantly higher in ?-TM patients compared with controls (2.850.56 vs. 1.7430.47 m/sec, respectively, P&lt;0.01). The prevalence of adrenal insufficiency in patients with -TM was 16 %, hypoparathyroidism of 4.5%. There was a weak negative correlation between serum level of cortisol and the serum Ferritin. Conclusion: Patients with ?-thalassemia major had a high prevalence of subclinical adrenal insufficiency of 16%, hypoparathyroidism of 4.5% with weak negative correlation between the low level of cortisol ?160 nmol/L and high serum ferritin. Echocardiographic Pulsed Doppler showed a restrictive LV diastolic pattern suggestive of advanced diastolic dysfunction but preserved left ventricle systolic function.

The Prevalence of Adrenal, Parathyroid and Cardiac Dysfunction in Patients with Beta Thalassemia Major

Background: Adrenal and parathyroid insufficiency are uncommon in patients with transfusion dependent Beta Thalassemia (β-TM). Further, myocardial echocardiographic abnormalities are recognized but with a variable outcomes Aim: The aim is to determine the prevalence of adrenal and parathyroid insufficiency in patient with transfusion dependent β-TM. And to assess left ventricle systolic and diastolic function using Pulsed Doppler (PD) and Tissue Doppler (DT) echocardiogram. Methods:The study was conducted on patients with β-TM (n = 99, age 15.92 ± 8.92 years) and compared with an age-matched controls (n = 98 age 15.79 ± 8.94 years). In all participants echocardiographic indices of M mode and PD and TD were performed. Blood samples were withdrawn for measuring the serum cortisol, parathyroid and Ferritin. Correlation between the level of cortisol and ferritin level was evaluated. Results: Patients with β-TM compared with controls, had significantly thicker LV septal wall index of 0.65 ± 0.26 vs 0.44 ± 0.2190, p 0.001 and LV posterior wall of 0.65 ± 0.235 vs 0.43 ± 0.214, p ± 5.5 vs 5.0 ± 5.6, p = 0.23. Furthermore patients with β-TM had higher E/A ratio (1.54 ± 0.18 vs 1.23 ± 0.17, p 0.01) and shorter deceleration time (DT) (170.53 ± 13.3 vs 210.50 ± 19.20 m sec, p 0.01). The ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em) was significantly higher in β-TM group (19.68 ± 2.81 vs 13.86 ± 1.41, p 0.05). The tissue Doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in β-TM group compared with controls with Sm, of 4.82 ± 1.2 vs 6.22 ± 2.1 cm/sec, p 0.05 and (Em) of 3.51 ± 2.7 vs 4.12 ± 2.5 cm/sec p 0.05, respectively). The tricuspid valve velocity was significantly higher in β-TM patients compared with controls (2.85 ± 0.56 vs 1.743 ± 0.47 m/sec, respectively, p 0.01). The prevalence of adrenal insufficiency in patients with β-TM was 16%, hypoparathyroidism of 4.5% weak negative correlation between serum level of cortisol and the serum Ferritin. Conclusion: Patients with β-thalassemia major had a high prevalence of subclinical adrenal insufficiency of 16%, hypoparathyroidism of 4.5% with weak negative correlation between the low level of cortisol ≤160 nmol/L and high serum ferritin. Echocardiographic Pulsed Doppler showed a restrictive LV diastolic pattern suggestive of advanced diastolic dysfunction but preserved left ventricle systolic function.

A Case of Acute Adrenal Insufficiency Unmasked During Sunitinib Treatment for Metastatic Renal Cell Carcinoma

Sunitinib has recently become a standard treatment for metastatic renal cell carcinoma. However, various adverse events have been reported. We present the first case of clinically evident adrenal insufficiency during sunitinib therapy. A 72-year-old man began sunitinib therapy for bilateral lung and adrenal metastases of renal cell carcinoma. His adrenocorticotrophic hormone level was 93.6 pg/ml (7.2-63.3 pg/ml) before sunitinib treatment, indicating that subclinical adrenal insufficiency already existed. Fatigue, which is a frequently seen adverse effect of sunitinib treatment, emerged acutely on Day 24 of the second cycle. Adrenocorticotrophic hormone and free T4 were high and thyroid-stimulating hormone was suppressed. Under the clinical diagnosis of acute adrenal insufficiency with thyrotoxicosis, a low dose of steroid was administered. Fatigue was completely ameliorated by the following morning, although free T4 was still high and thyroid-stimulating hormone was still low. Therefore, hypermetabolism due to thyrotoxicosis unmasked adrenal insufficiency in our case. Physicians should be aware of this rare but potentially fatal complication when severe acute fatigue develops in patients with subclinical adrenal insufficiency.

Primary adrenal lymphoma: a case series study

Dear Editor, Non-Hodgkin’s lymphoma affects the adrenal gland, usually in the advanced stage of the disease. In 30% to 50% of patients with primary adrenal lymphoma (PAL), there are signs compatible with subclinical adrenal insufficiency only detected by laboratory tests [2, 3]. Autopsy series show that 25% of patients present gland involvement, in some degree, during disease course [1]. PAL is a rare form of primary adrenal neoplasia, and the Englishlanguage medical literature has reported 70 cases of PAL; the Chinese has only 30 cases [3]. We had three cases, and they will be presented below. Case 1: An 80-year-old man, reporting abdominal pain, nausea, and loss of weight for 5 months. Physical examination: pale, hyperpigmentation of the skin, and cardiac arrhythmia. Abdominal magnetic resonance imaging: ovalshaped bilateral mass of the adrenal gland, swollen on its left side (5.5 cm). Laboratory tests: Table 1. The patient started glucocorticoid and mineralocorticoid therapy and went through CHOP chemotherapy regimen (cyclophosphamide, Adriamycin or hydroxydoxorubicin, vincristine, and prednisone) associated to rituximab. The clinical outcome was the patient’s death due to respiratory failure 2 months after the diagnosis. Case 2: A 62-year-old man presenting a history of asthenia, anorexia, loss of weight, postural hypotension for 6 months, associated with severe abdominal pain. Physical examination: blood pressure 110×80 mmHg (seating) and 80×70 mmHg (standing); ungual hyperpigmentation. Insulin resistance test with no cortisol enhancement; abdominal tomography: bilateral mass lesions of the adrenal gland, swollen on its right side (10 cm), with renal capsule invasion. Laboratory tests: Table 1. He started chemotherapy but died 6 months after due to pulmonary thromboembolism. Case 3: A 73-year-old woman, with diabetes, reporting hypoglycemia and decreased consciousness, using chlorpropramide. After having discontinued medication, she presented hyponatremia and hypoglycemia over 7 days (drug half-life). Physical examination showed disorientation and obnubilation. Laboratory exams disclosed bicytopenia (Table 1). Under suspicion of hematological neoplasia, she had an abdominal tomography that disclosed bilateral diffuse adrenal hyperplasia. She started chemotherapy associated with corticotherapy, making the full endocrine investigation impossible. The glycemic level and the natremia were normalized. Currently, the patient is under chemotherapy regimen (CHOP and rituximab) with a 14-month survival. Literature indicates that adrenal insufficiency is the most common clinical manifestation of PAL cases [5, 6] identified in the first two reported cases. Regarding case 3, unfortunately, there has not been enough time to make a more detailed investigation. Case 1 presented elevated serum levels of adrenocorticotropic hormone (ACTH), upholding the presence of skin hyperpigmentation. All the studied cases presented low levels of dehydroepiandrosterones (DHEAs), not confirming adrenal carcinoma. The radiological investigation of the three cases pointed out bilateral and heterogeneous images, which are the most typical forms described in literature. The fine-needle aspiraAnn Hematol (2008) 87:859–861 DOI 10.1007/s00277-008-0492-x

Megestrol acetate-induced adrenal insufficiency

Megestrol acetate is a synthetic progestin that has been used since the 1970s for the treatment of advanced cancer and subsequently to treat anorexia, cachexia and weight loss in AIDS patients. It has been shown that high doses or prolonged treatment with this drug may cause Cushing's syndrome, new-onset diabetes and suppression of plasma ACTH and cortisol levels. Megestrol acetate may cause suppression of the pituitary-adrenal axis due to the affinity of this compound for the glucocorticoid receptor. Recognising the glucocorticoid-like activity of megestrol and its effects at the axis level is important for the diagnosis of sub-clinical adrenal insufficiency. We present the case of a 74-year-old woman with infiltrating ductal breast carcinoma refractory to prolonged hormonal treatment with megestrol acetate, presenting with adrenal insufficiency.

PARADOXICAL RESPONSES DURING ANTITUBERCULOUS TREATMENT IN PATIENTS WITH RESPIRATORY TUBERCULOSIS AND RELATIVE ADRENAL INSUFFICIENCY

PURPOSE: Although adrenal insufficiency in tuberculosis is mostly caused by adrenal tuberculosis, it may occur without direct adrenal involvement. During antituberculous treatment, enhanced metabolism of adrenal hormones also can be the cause of adrenal insufficiency. It is not known that subclinical adrenal insufficiency in tuberculosis without direct adrenal involvement could make some differences in clinial progress.

Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure

To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis. Controlled, prospective. Tertiary research center. Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure. Ovarian biopsy in 10 women. Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers. We obtained a histologic diagnosis of autoimmune oophoritis in four women who tested positive for adrenal cortex autoantibodies and excluded this diagnosis in ovarian biopsies from six women who tested negative for adrenal cortex autoantibodies (4/4 vs. 0/6). Women with histologically confirmed autoimmune oophoritis had a greater total ovarian volume as assessed by transvaginal sonography (11.4 +/- 5.6 mL vs. 1.5 +/- 0.4 mL) (mean +/- SEM). They were also more likely to have subclinical adrenal insufficiency and clinical signs of androgen deficiency (3/4 vs. 0/6). Overall, 10/266 women tested positive for adrenal cortex autoantibodies (3.8%, 95% confidence interval: 1.8%-6.5%). In women who present with 46,XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis.