Adrenocortical dysfunction in liver disease: a systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.     

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods

CONTEXT: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. OBJECTIVES: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. DESIGN: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. SETTING: The study was conducted at an academic medical center. PATIENTS/PARTICIPANTS: Participants were critically ill subjects. Intervention: There was no intervention. MAIN OUTCOME MEASURE: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. RESULTS: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 microg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 microg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 microg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. CONCLUSIONS: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.     

Adrenal insufficiency in the critically ill: a new look at an old problem

Stress from many sources, including pain, fever, and hypotension, activates the hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of corticotropin and cortisol. Increased glucocorticoid action is an essential component of the stress response, and even minor degrees of adrenal insufficiency can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed disorder in the critically ill. We review the risk factors, pathophysiology, diagnostic approach, and management of HPA dysfunction in the critically ill.     

The hypothalamic–pituitary–adrenal axis in critical illness

Hypothalamic-pituitary-adrenal (HPA) axis function is crucial to maintain and restore homeostasis. The HPA axis does not function in isolation. Rather, the HPA axis modulates and reacts to signals from endocrine, neural, and immune systems. Cortisol is the major glucocorticoid secreted by the human adrenal cortex. Its actions are largely mediated by the glucocorticoid receptor. The potent anti-inflammatory actions of glucocorticoids led to their use in critically ill patients. Metaanalyses of these early studies (before 1985) concluded that large glucocorticoid doses had no effect and were potentially detrimental. More recently, the pendulum has swung in the opposite direction based on the concept that critically ill patients may have relative adrenal insufficiency and/or acquired glucocorticoid resistance. However, inconsistent diagnostic criteria, heterogeneity of subjects, variable nutritional status, and pre-existing conditions preclude formulating definitive conclusions regarding glucocorticoid use among critically patients. Diagnosing adrenal insufficiency in the critically ill patient remains challenging. To resolve the issue, our challenge is to develop physiologically relevant tools to assess glucocorticoid action and GR function at the cellular level.     

Update on adrenal insufficiency in patients with liver cirrhosis

Liver cirrhosis is a major cause of mortality worldwide,often with severe sepsis as the terminal event.Over the last two decades,several studies have reported that in septic patients the adrenal glands respond inappropriately to stimulation,and that the treatment with corticosteroids decreases mortality in such patients.Both cirrhosis and septic shock share many hemodynamic abnormalities such as hyperdynamic circulatory failure,decreased peripheral vascular resistance,increased cardiac output,hypo-responsiveness to vasopressors,increased levels of proinflammatory cytokines [interleukine(IL)-1,IL-6,tumor necrosis factor-alpha] and it has,consequently,been reported that adrenal insufficiency(AI) is common in critically ill cirrhotic patients.AI may also be present in patients with stable cirrhosis without sepsis and in those undergoing liver transplantation.The term hepato-adrenal syndrome defines AI in patients with advanced liver disease with sepsis and/or other complications,and it suggests that it could be a feature of liver disease per se,with a dif-ferent pathogenesis from that of septic shock.Relative AI is the term given to inadequate cortisol response to stress.More recently,another term is used,namely "critical illness related corticosteroid insufficiency" to define "an inadequate cellular corticosteroid activity for the severity of the patient’s illness".The mechanisms of AI in liver cirrhosis are not completely understood,although decreased levels of high-density lipoprotein cholesterol and high levels of proinflammatory cytokines and circulatory endotoxin have been suggested.The prevalence of AI in cirrhotic patients varies widely according to the stage of the liver disease(compensated or decompensated,with or without sepsis),the diagnostic criteria defining AI and the methodology used.The effects of corticosteroid therapy on cirrhotic patients with septic shock and AI are controversial.This review aims to summarize the existing published information regarding AI in patients with liver cirrhosis.     

Uncoupling of sympathetic nervous system and hypothalamic-pituitary-adrenal axis in cirrhosis

Background and Aim: The hypothalamic‐autonomic nervous system (HANS) axis and the hypothalamic‐pituitary‐adrenal (HPA) axis are stimulated in parallel in response to stress factors under healthy conditions. This physiological synergism of the axes aims at optimizing anti‐inflammatory actions. Therefore, we investigated whether this synergism is altered in patients with liver cirrhosis. Methods: As a typical marker of the HANS axis neuropeptide Y (NPY is a neurotransmitter of the sympathetic nerve terminal) and of the HPA axis, cortisol together with adrenocorticotropic hormone (ACTH) and cortisol‐binding globulin (CBG), were measured in samples from control subjects and patients with liver cirrhosis. Results: Plasma NPY was found to be increased in cirrhotic patients compared to control subjects (P < 0.01). This increase was observed to be independent of the severity of liver disease (Child class). Serum cortisol was decreased in cirrhotics, particularly in patients with Child A cirrhosis. Plasma NPY was positively correlated with serum cortisol in control subjects (r = 0.32, P < 0.05) reflecting the parallel activation of both axes under the normal condition. However, serum cortisol was not correlated with plasma NPY in cirrhotic patients. For the subgroup of Child A patients, even a negative correlation between NPY and cortisol was observed (r = ?0.43, P < 0.05). No significant change in serum levels of ACTH and its positive correlation with serum cortisol was observed in cirrhotic patients. Conclusions: The present study demonstrates that the two stress axes seem to act in parallel fashion in control subjects but are uncoupled in liver cirrhosis. We discuss how uncoupling of the two anti‐inflammatory axes can occur and may contribute to the increased susceptibility for infections and lethal complications in cirrhotic patients.     

Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.     

Transient adrenal insufficiency in diffuse large B cell lymphoma patients after chemotherapy with short-course,high-dose corticosteroids

Data on the rate of adrenal insufficiency (AI) in patients receiving short-course and high-dose corticosteroids are limited. In this study, we aimed to determine the incidence of AI in newly diagnosed, diffuse large B cell lymphoma (DLBCL) patients after receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or prednisolone] (R-CHOP/CHOP) regimen. We enrolled newly diagnosed DLBCL patients who were scheduled to receive 6–8 cycles of R-CHOP/CHOP regimen. One-microgram adrenocorticotropic hormone (ACTH) stimulation tests were performed at the study entry and 3 weeks after each cycle of chemotherapy (CMT). AI was defined by a peak-stimulated serum cortisol of less than 18 μg/dL. For patients who had AI after completing a course of CMT, 1-μg ACTH stimulation tests were carried out at 60 and 90 days after the last CMT cycle to assess the duration of hypothalamic-pituitary-adrenal (HPA) axis recovery. Ten DLBCL patients were included in this study, with a total of 84 1-μg ACTH stimulation tests. Their mean age was 52 years. AI occurred in 3 out of the 10 patients (30%). The first occurrence of AI was after the third CMT cycle, and the incidence was highest after the fifth cycle. Adrenal function recovered completely 3 to 5 weeks after completing the course of CMT, except for 1 patient, whose HPA axis suppression persisted 90 days after the last CMT cycle. Receiver operating characteristic (ROC) analysis revealed that a basal cortisol level of <?8.7 μg/dL was predictive of AI, with a sensitivity and specificity of 80% and 72.2%, respectively. Transient HPA axis suppression can occur in DLBCL patients receiving R-CHOP/CHOP regimen. We strongly encourage careful observation and examination for potential adrenal insufficiency in such patients, particularly after the fifth cycle of chemotherapy.     

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy

Glucocorticoids (GCs) are steroid hormones, which are essential for life. They are secreted by the adrenal cortex under the control of the hypothalamic‐pituitary‐adrenal (HPA) axis. Glucocorticoids are essential for the normal function of most organ systems and, in both, excess and deficiency can lead to significant adverse consequences. Adrenal insufficiency (AI) is a rare, life‐threatening disorder characterized by insufficient production of corticosteroid hormones. Primary AI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids despite normal or increased adrenocorticotropin hormone (ACTH). Secondary AI is adrenal hypofunction due to insufficient amount of ACTH produced by the pituitary gland. Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. The role of cortisol deficiency and the impact of hydrocortisone replacement on morbidity and mortality in this patient group are under increasing scrutiny. Established glucocorticoid replacement regimens do not completely mirror endogenous hormonal production, and their monitoring to ensure optimum therapy is hampered by the lack of reliable biomarkers of hormone sufficiency. A further confounding issue is the tissue‐specific regulation of glucocorticoid through the two isozymes of 11β‐hydroxysteroid dehydrogenase (11β‐HSD) with research focusing on the role of this prereceptor regulation in the development of adverse metabolic features in patients. This review defines the factors influencing glucocorticoid action in patients with adrenal insufficiency receiving glucocorticoid therapy.     

The potential role of increased adrenal volume in the pathophysiology of obesity-related type 2 diabetes

The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in obesity and Type 2 diabetes (DM). The aim of the present study was to determine the adrenal volume in obese patients with DM in comparison to obese non-diabetic patients. Eleven diabetic obese and 19 non-diabetic obese women were sequentially invited to take part in the study. Computed tomography (CT) scan of the abdomen was performed to determine adrenal volume, visceral (VF) and sc fat (SCF). Daily urinary free cortisol (UFC) was used as a measure of integrated cortisol production. In the diabetic patients, hemoglobin A1c was measured as an index of metabolic control. Compared to nondiabetic controls, patients with diabetes had a significantly higher total adrenal volume (4.29+/-1.50 vs 2.95+/-1.64; p=0.03). A highly significant correlation was detected between VF and VF/SCF ratio and total adrenal volume in the whole group (r=0.36, p=0.04 and r=0.48, p=0.008, respectively). This study, therefore, suggests an association between abdominal obesity, enlarged adrenals and Type 2 diabetes. These findings support the hypothesis that an increased activity of the HPA axis in obese subjects may be involved in the pathogenesis of Type 2 diabetes.     

Immediate postoperative cortisol levels accurately predict postoperative hypothalamic–pituitary–adrenal axis function after transsphenoidal surgery for pituitary tumors

Accurate assessment of the hypothalamic–pituitary–adrenal (HPA) axis is critical for the appropriate management of patients with pituitary adenoma after transsphenoidal surgery. We examine the role of immediate postoperative cortisol levels to assess hypothalamic–pituitary–adrenal axis (HPA) axis function post-operatively. We performed preoperative cortrosyn stimulation test (CST) and measured immediate postoperative serum cortisol levels in 100 patients undergoing 104 transsphenoidal surgeries. These results were compared to those of the CST at 4–6 weeks postoperatively, which served as a measure of HPA axis function. The ability of immediate postoperative, day of surgery (DOS) cortisol levels to predict normal HPA axis function was determined using standard predictive analytic methods and confusion matrix calculations. We found that postoperative, DOS cortisol level ≥15 μg/dL is a sensitive and accurate predictors of normal postoperative HPA axis function, with a sensitivity of 98%, an accuracy of 97%, and a positive predictive value of 99%. Our data suggest that an immediate, postoperative, DOS cortisol level ≥15 μg/dL predicts distant, normal, post-operative HPA axis function following transsphenoidal surgery.     

The hypothalamic-pituitary-adrenal axis in asthmatic children.

Reduced responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in patients with various chronic allergic inflammatory disorders and a blunted HPA axis response of poorly controlled asthmatics before long-term treatment with inhaled corticosteroids (ICS) have been reported. It seems that pro- and anti-inflammatory cytokines might be involved in the attenuation of cortisol and adrenocorticotropic hormone (ACTH) responses to stress in these patients. Although long-term ICS treatment might produce mild adrenal suppression in some asthmatic children, improvement of adrenal function has been detected in the majority of cases. We postulate that the anti-inflammatory effects of ICS result both in asthma remission and HPA axis improvement. Adrenal suppression of some asthmatic patients on maintenance ICS seems to be a separate phenomenon, possibly constitutionally or genetically determined.     

The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function

Tuberculosis may affect many of the endocrine glands including the hypothalamus, pituitary, thyroid and adrenals. The most commonly involved endocrine organ in tuberculosis is the adrenal gland. Adrenal glands may be directly or indirectly affected by tuberculosis. Tuberculous Addison's disease is still an important cause of primary adrenocortical insufficiency particularly in the developing countries. Recent improvements in imaging techniques and modern endocrinological tests for the investigation of adrenal function have given us greater insight into the endocrinology of adrenal tuberculosis. Hypothalamo-pituitary-adrenal (HPA) axis is also involved in tuberculosis and recent findings revealed that HPA axis is activated rather than underactivated in active pulmonary tuberculosis. Activated HPA axis in tuberculosis causes increased cortisol secretion which results in a shift in the Th1/Th2 balance towards Th2. T cell dysfunction due to high cortisol and low DHEAS levels may be responsible for immunologically-mediated tissue damage in tuberculosis. In this review, recent findings concerning the adrenocortical function, radiological changes in adrenal glands and HPA axis involvement in tuberculosis are discussed.     

Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis

A growing number of animal data strongly suggest that a hyporeactive hypothalamus-pituitary adrenal (HPA) axis may be pathologically significant by increasing the susceptibility to chronic inflammation. Following this line of evidence, the specific goal of the present study was to investigate the HPA axis in patients with atopic dermatitis (AD), a chronic allergic inflammatory disease. In addition, the sympathetic adrenomedullary (SAM) system as a second potent immunoregulatory and anti-inflammatory stress-response system has been examined. AD patients (n = 36) and nonatopic control subjects (n = 37) were exposed to a standardized laboratory stressor consisting of a free speech and mental arithmetic task in front of an audience. Cortisol, ACTH, and catecholamine concentrations were assessed before and after the stressor. To investigate feedback sensitivity of the HPA axis, a low dose (0.5 mg) dexamethasone suppression test was also performed. AD patients showed significantly attenuated cortisol and ACTH responses to the stressor, whereas catecholamine levels were significantly elevated in atopic patients. No difference between the experimental groups was found in basal cortisol and ACTH concentrations, whereas basal catecholamine levels were significantly elevated. Analysis of cortisol levels after dexamethasone treatment suggested an intact feedback sensitivity in AD sufferers at the pituitary level. The present findings suggest that patients with AD demonstrate a blunted HPA axis responsiveness with a concurrent overreactivity of the SAM system to psychosocial stress. Considering the important immunoregulatory role of the HPA axis and the SAM system, especially under stressful conditions, an aberrant responsiveness of these neuroendocrine systems may increase the susceptibility to (allergic) inflammation and may be one psychobiological mechanism of stress-related aggravation of the disease.     

Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency

The hypothalamic-pituitary-adrenal (HPA) axis, including hypothalamic corticotropin-releasing hormone (CRH) and pituitary corticotropin, is one of the first endocrine systems to develop during fetal life, probably because glucocorticoid secretion is necessary for the maturation of many essential fetal organs. Consistent with this, pregnant mice with an inactivating mutation in the Crh gene deliver CRH-deficient offspring that die at birth with dysplastic lungs, which can be prevented by prenatal maternal glucocorticoid treatment. But children lacking the ability to synthesize cortisol (because of various genetic defects in adrenal gland development or steroidogenesis) are not born with respiratory insufficiency or abnormal lung development, suggesting that the transfer of maternal glucocorticoid across the placenta might promote fetal organ maturation in the absence of fetal glucocorticoid production. We used pregnant mice with a normal HPA axis carrying fetuses with CRH deficiency to characterize the relative contributions of the fetal and maternal adrenal to the activity of the fetal HPA axis, and related these findings to fetal lung development. We found that in the presence of fetal adrenal insufficiency, normal fetal lung development is maintained by the transfer of maternal glucocorticoid to the fetus, specifically during the circadian peak in maternal glucocorticoid secretion.     

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.     

The relation between hypothalamic-pituitary-adrenal (HPA) axis activity and age of onset of alcohol use

Aims Hypothalamic–pituitary–adrenal (HPA) axis activity may prove a viable biomarker for identifying those susceptible to alcohol use disorders. The purpose of this study was to examine the relation of the age at which adolescents begin drinking with diurnal and stress cortisol. Design Adolescents' diurnal cortisol levels on a normal day and cortisol levels during a stress procedure were examined in relation to the age of onset of alcohol use. Setting and participants All adolescents (aged 14–20 years) were part of a general population study in the Netherlands (n = 2286). Measurements Ten assessments of salivary cortisol taken on a normal day (diurnal cortisol), as well as during a social stress procedure (stress cortisol) were used as indicators of HPA axis activity. Findings The age at which the first alcoholic drink was consumed varied as a function of cortisol levels at the onset of as well as during the stress procedure. Those who began drinking at an earlier age showed lower cortisol levels at the onset of the stressful tasks (r² = 0.14, P < 0.001) and during the stressful tasks (r² = 0.10, P < 0.05), although not after the tasks (cortisol recovery). Effects were strongest for anticipatory pre‐task cortisol levels. Differences in diurnal cortisol levels did not explain variance in the age at which adolescents had begun drinking. Conclusions Lessened activity of the hypothalamic–pituitary–adrenal axis at the onset of and during a stress procedure is present in adolescents who begin drinking at an early age.     

A case of aldosterone-producing adrenocortical adenoma associated with a probable post-operative adrenal crisis: histopathological analyses of the adrenal gland.

We describe a case of aldosterone-producing adrenocortical adenoma (APA) associated with a probable post-operative adrenal crisis possibly due to subtle autonomous cortisol secretion. The patient was a 46-year-old female who suffered from severe hypertension and hypokalemia. CT and MRI scans revealed a 2-cm diameter adrenal mass. The patient's plasma aldosterone level was increased, and her plasma renin activity was suppressed, both of which findings were consistent with APA. Cushingoid appearance was not observed. Morning and midnight serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were all within the normal range. Her serum cortisol level was suppressed to 1.9 microg/dl as measured by an overnight 1-mg dexamethasone suppression test, but was incompletely suppressed (2.7 microg/dl) by an overnight 8-mg dexamethasone suppression test. In addition, adrenocortical scintigraphy showed a strong uptake at the tumor region and a complete suppression of the contra-lateral adrenal uptake. After unilateral adrenalectomy, she had an episode of adrenal crisis, and a transient glucocorticoid replacement improved the symptoms. Histopathological studies demonstrated that the tumor was basically compatible with APA. The clear cells in the tumor were admixed with small numbers of compact cells that expressed 17alpha-hydroxylase, suggesting that the tumor was able to produce and secrete cortisol. In addition, the adjacent non-neoplastic adrenal cortex showed cortical atrophy, and dehydroepiandrosterone sulfotransferase immunoreactivity in the zonae fasciculata and reticularis was markedly diminished, suggesting that the hypothalamo-pituitary-adrenal (HPA) axis of the patient was suppressed due to neoplastic production and secretion of cortisol. Together, these findings suggested that autonomous secretion of cortisol from the tumor suppressed the HPA axis of the patient, thereby triggering the probable post-operative adrenal crisis. Post-operative adrenocortical insufficiency should be considered in clinical management of patients with relatively large APA, even when physical signs of autonomous cortisol overproduction are not apparent.     

Experimentally challenged reactivity of the hypothalamic pituitary adrenal axis in patients with recently diagnosed rheumatoid arthritis

OBJECTIVE: There is evidence that the hypothalamic pituitary adrenal (HPA) axis is subresponsive in patients with rheumatoid arthritis (RA). We assessed HPA axis responses to experimental stressors mimicking daily life challenges in patients with RA to determine whether HPA axis activity is associated with Th1 and Th2 activity. METHODS: ACTH and cortisol responses in reaction to the succession of a bicycle ergometer task, a cold pressor task, and a computerized Stroop Color-Word interference test, as well as basal Th1 and Th2 cell activity, were assessed in 29 patients (21 female, 8 male) with recently diagnosed RA (mean disease duration 29 wks, range 5-69), mean age 55.7 years, none receiving glucocorticoid treatment, and 30 (20 female, 10 male) healthy age and sex matched controls (mean age 54.1 yrs). RESULTS: Mean ACTH and cortisol levels did not differ between the groups (p > 0.10). Patients tended to have a less pronounced ACTH response (F2.50 = 2.7, p = 0.08) and had a significantly smaller cortisol response (P F2.50 = 6.1, p < 0.01) than healthy controls in reaction to the stressors. This difference in cortisol response was reduced, but remained significant when ACTH responsiveness was accounted for by entering it as a covariate (P F2.49 = 3.7, p = 0.03). ACTH and cortisol levels and responses were not associated (all p > 0.19) with basal interferon-gamma and interleukin 4 as reflections of Th1 and Th2 cell activity, respectively. HPA axis activity was not linked to current disease activity. CONCLUSION: Our findings show reduced HPA axis responsiveness in RA patients with recent diagnosis receiving longterm medication that is suggested to be located both at a hypothalamic/pituitary and at an adrenal level. It appears that common HPA axis activity accomplishes low amounts of cortisol release, which makes it difficult to determine an influence of endogenous cortisol changes on the Th1/Th2 balance.