Cortisol response to critical illness: effect of intensive insulin therapy

CONTEXT: Both excessive and insufficient activation of the hypothalamic-pituitary-adrenal axis in response to critical illness is associated with increased mortality. OBJECTIVE: The objective of the study was to study the effect of intensive insulin therapy, recently shown to reduce mortality and morbidity of critically ill patients, on the cortisol response to critical illness. DESIGN: This was a preplanned subanalysis of a large randomized, controlled study measuring serum total cortisol, cortisol-binding globulin, and albumin and calculating free cortisol levels. SETTING: The study was conducted at a university hospital surgical intensive care unit. PATIENTS: Four hundred fifty-one critically ill patients dependent on intensive care for more than 5 d and 45 control subjects matched for gender, age, height, and weight participated in this study. INTERVENTION: The intervention was strict blood glucose control to normoglycemia with insulin. RESULTS: Total and calculated free cortisol levels were equally elevated upon admission in both patient groups and thereafter were lower in intensive insulin-treated patients. Lower cortisol levels statistically related to the outcome benefit of intensive insulin therapy. Cortisol-binding globulin levels and structure were affected by critical illness but not insulin therapy, and neither were albumin levels. Administration of hydrocortisone in so-called replacement dose resulted in severalfold higher total and free cortisol levels, indicating that reevaluation of the doses used is warranted. CONCLUSIONS: Lower serum cortisol levels in critically ill patients receiving intensive insulin therapy statistically related to improved outcome with this intervention. The lower cortisol levels were not related to altered cortisol-binding capacity.     

Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol

METHODS: Baseline and cosyntropin-stimulated serum (total and free) and salivary cortisol concentrations were measured, in the early afternoon, in 51 critically ill patients and healthy subjects. Patients were stratified according to their serum albumin at the time of testing: those whose serum albumin levels were 2.5 gm/dl or less vs. others whose levels were greater than 2.5 gm/dl. RESULTS: Baseline and cosyntropin-stimulated serum free cortisol levels were similar in the two groups of critically ill patients and were severalfold higher (P < 0.001) than those of healthy subjects. Similarly, baseline and cosyntropin-stimulated salivary cortisol concentrations were equally elevated in the two critically ill patient groups and were severalfold higher (P < 0.001) than those of healthy subjects. Salivary cortisol concentrations correlated well with the measured serum free cortisol levels. CONCLUSIONS: Salivary cortisol measurements are simple to obtain, easy to measure in most laboratories, and provide an indirect yet reliable and practical assessment of the serum free cortisol concentrations during critical illnesses. The concentrations of the two measures of unbound cortisol determined in two different body fluids correlated very well, regardless of the serum protein concentrations. Measurements of salivary cortisol can serve as a surrogate marker for the free cortisol in the circulation.     

Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality

Recent reports suggest adrenal insufficiency in critically ill patients is common. We found only one case of de novo adrenal insufficiency using admission ACTH injection in 70 selected intensive care unit (ICU) patients. Random serum cortisol levels correlated positively with illness severity in ICU patients using proven methods for assessing illness severity. Those with the highest random serum cortisol levels (greater than 60 micrograms/dl) had the greatest mortality, while those with lower random cortisol levels which stimulated to more than 18 micrograms/dl after ACTH injection had improved outcomes. Based on our results, routine screening for adrenal insufficiency in ICU patients is not warranted. If it is suspected, the cosyntropin test should be performed since low random cortisol levels (even to 5 micrograms/dl) are not diagnostic of adrenal insufficiency.     

Relative adrenal failure in intensive care: an identifiable problem requiring treatment?

Adequate adrenocortical function is essential to survive critical illness. Most critically ill patients display an elevated plasma cortisol level, reflecting activation of the pituitary-adrenal axis, which is considered to be a homeostatic adaptation. In the setting of critical illness, the failure of an appropriate neuroendocrine response can lead to the picture of vasopressor-dependent refractory hypotension. This state of relative or functional adrenal insufficiency is characterized by an inadequate production of cortisol in relation to an increased demand during periods of severe stress, particularly prolonged critical illness such as multi-organ failure. This clinical entity, however, lacks clear-cut diagnostic criteria. What are the appropriate cortisol concentrations in the critically ill? Should base-line and adrenocorticotropic hormone-stimulated cortisol concentrations be assessed? The classical adrenocorticotropic hormone stimulation test is often used, but there are problems with interpreting its results. Other diagnostic tools, such as the low-dose adrenocorticotropic hormone test and relative eosinophilia, are promising but also lack proper criteria. A prompt response to hydrocortisone treatment is a major clue to the diagnosis. Recent studies with stress doses of hydrocortisone in sepsis and septic shock have shown a marked haemodynamic improvement, but whether patients with relative adrenal dysfunction benefit most from this treatment and whether there is definitely an effect on outcome is still undecided.     

Cosyntropin-stimulated salivary cortisol in hospitalized patients with hypoproteinemia

Analysis of adrenocortical function in acutely ill, hospitalized patients can be challenging due to changes in plasma binding proteins. This study used dynamic testing of salivary cortisol levels to evaluate adrenal function in hospitalized patients with low/low-normal plasma protein concentration in whom adrenal insufficiency was suspected. Twenty-eight patients with low serum albumin and proteins hospitalized for acute illness were evaluated for decreased adrenocortical function because of clinical presentations suspicious for adrenal insufficiency. Baseline and post cosyntropin-stimulated levels of serum total and salivary cortisol levels were assessed. Data were gathered by a retrospective analysis of medical records. Eight patients had normal peak serum total and salivary cortisol responses, consistent with intact adrenocortical function. Five patients had abnormal peak serum total and salivary cortisol responses indicating decreased adrenocortical function. Fifteen patients had subnormal peak serum total cortisol, but normal peak salivary cortisol responses indicating normal adrenal function. Salivary cortisol testing can identify hospitalized patients with apparently intact adrenal function in whom low serum protein confounded interpretation of serum total cortisol measurements. Salivary cortisol is a clinically useful surrogate for serum free cortisol in dynamic testing of adrenocortical function.     

Diagnosis of adrenal insufficiency in severe sepsis and septic shock

RATIONALE: Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard. OBJECTIVE: We used the overnight metyrapone stimulation test to investigate the diagnostic value of the standard cosyntropin stimulation test, and the prevalence of sepsis-associated adrenal insufficiency. METHODS: This was an inception cohort study. MEASUREMENTS AND RESULTS: In two consecutive septic cohorts (n = 61 and n = 40), in 44 patients without sepsis and in 32 healthy volunteers, we measured (1) serum cortisol before and after cosyntropin stimulation, albumin, and corticosteroid-binding globulin levels, and (2) serum corticotropin, cortisol, and 11beta-deoxycortisol levels before and after an overnight metyrapone stimulation. Adrenal insufficiency was defined by postmetyrapone serum 11beta-deoxycortisol levels below 7 microg/dl. More patients with sepsis (31/61 [59% of original cohort with sepsis] and 24/40 [60% of validation cohort with sepsis]) met criteria for adrenal insufficiency than patients without sepsis (3/44; 7%) (p < 0.001 for both comparisons). Baseline cortisol (< 10 microg/dl), Delta cortisol (< 9 microg/dl), and free cortisol (< 2 microg/dl) had a positive likelihood ratio equal to infinity, 8.46 (95% confidence interval, 1.19-60.25), and 9.50 (95% confidence interval, 1.05-9.54), respectively. The best predictor of adrenal insufficiency (as defined by metyrapone testing) was baseline cortisol of 10 microg/dl or less or Delta cortisol of less than 9 microg/dl. The best predictors of normal adrenal response were cosyntropin-stimulated cortisol of 44 microg/dl or greater and Delta cortisol of 16.8 microg/dl or greater. CONCLUSIONS: In sepsis, adrenal insufficiency is likely when baseline cortisol levels are less than 10 microg/dl or delta cortisol is less than 9 microg/dl, and unlikely when cosyntropin-stimulated cortisol level is 44 microg/dl or greater or Delta cortisol is 16.8 microg/dl or greater.     

Hyperreninemic hypoaldosteronism in the critically ill: a new entity

To define the changes in adrenal gland function during critical illness, we evaluated 28 severely ill patients with persistent hypotension who were hospitalized in a medical intensive care unit. The patients had increased plasma cortisol (mean +/- SE, 40.1 +/- 10.1 micrograms/dl). PRA was increased in all subjects (21.6 +/- 7.2 ng/ml.h); however, the plasma aldosterone concentration was inappropriately low in 18 of the subjects, with values ranging from 1-9 ng/dl, despite normal serum potassium concentrations (4.3 +/- 0.1 meq/liter) and increased concentrations of the aldosterone percursor, 18-hydroxycorticosterone. These 18 patients had hypotension associated with major infections and a high mortality rate (78%). Infusions of ACTH or angiotensin II were associated with a normal aldosterone response in only 2 of the 14 patients tested, also suggesting that the defect was probably at the level of the zone glomerulosa cell. Although infection was a common underlying illness, no other factors, such as dopamine administration, decreased angiotensin-converting enzyme activity, or increased aldosterone clearance, could be implicated as the cause of the phenomena. Thus, selective hypoaldosteronism in the presence of high renin levels exists in a substantial percentage of hypotensive critically ill patients.     

Adrenal insufficiency in patients with decompensated cirrhosis

Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal(HPA) axis are causes for adrenal insufficiency(AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics aswell. Both stable cirrhotics and liver transplant patients(early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels(the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI.     

What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy?

A new diagnosis of primary adrenal insufficiency (PAI) during pregnancy is extremely rare and difficult to recognize as signs and symptoms such as nausea, fatigue and hypotension may resemble features of normal pregnancy. However, if the diagnosis is overlooked and steroid replacement delayed, subsequent adrenal crisis triggered by hyperemesis gravidarum, fever or delivery can cause severe maternal and foetal morbidity and even mortality. In case of clinical suspicion of PAI, we recommend to measure paired samples of cortisol and ACTH and, if clinically feasible, a short synacthen test. We propose trimester‐specific pass cut‐offs for the short synacthen test that take into account the rise of total and also free cortisol during pregnancy. Empirical hydrocortisone treatment should never be delayed if the clinical suspicion is high. All pregnant women with PAI should be monitored by a team of endocrine and obstetric specialists. The third trimester is physiologically associated with a rise not only in total but also free cortisol and thus requires regular adjustment of the glucocorticoid dose. Mineralocorticoid requirements may change during pregnancy due to the anti‐mineralocorticoid properties of progesterone. As plasma renin physiologically increases in pregnancy, monitoring is limited to clinical assessment including blood pressure and serum electrolytes. It is crucial that a pregnant woman with PAI and her partner are well educated regarding the adjustment of glucocorticoid dose in intercurrent illness and that both are trained in hydrocortisone emergency injection techniques. The obstetric staff should be provided with clear and written guidance for hydrocortisone cover during labour and delivery. With the appropriate replacement therapy, PAI patients can expect to have an uneventful pregnancy and deliver a healthy infant.     

The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function

Dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) are corticotropin-dependent adrenal androgen precursors that are uniformly low in treated patients with corticotropin deficiency. There are no data investigating the diagnostic value of DHEA-S measurements in the prospective assessment of adrenal function. This study examined serum DHEA-S levels as possible markers for hypothalamic- pituitary-adrenal (HPA) function in patients with large pituitary adenomas. Patients were characterized to have normal HPA (n = 47) or abnormal HPA (ABN-HPA, n = 35) function based on their respective responses to insulin-induced hypoglycemia. Patients also underwent low-dose Cortrosyn (1 micro g, LDC) and standard-dose Cortrosyn stimulation testing. All patients with ABN-HPA had very low age- and gender-matched serum DHEA-S levels. When the normal response to LDC was set at a cortisol level of at least 18.1 micro g/dl, 10 of 31 patients with ABN-HPA exhibited normal responses. Receiver operating characteristic curves for baseline DHEA-S and for maximal cortisol responses to LDC had areas of 0.984 (confidence interval, 0.962-1.000) and 0.893 (confidence interval, 0.817-0.969), respectively. LDC- or SDC-stimulated serum cortisol levels have significant limitations in defining HPA function. A normal age- and gender-specific serum DHEA-S level makes the diagnosis of corticotropin deficiency extremely unlikely. However, when serum DHEA-S levels are low, further testing is necessary to define HPA function.     

Serum cortisol levels in patients admitted to the department of medicine: Prognostic correlations and effects of age, infection, and comorbidity

BACKGROUND: In contrast to healthy adults or critically ill patients, data on serum cortisol levels in noncritically ill patients admitted to general internal medicine wards has not been well characterized. We aimed to describe the distribution and range of serum cortisol levels in patients admitted to the department of medicine, to discover whether old age, severe infections, or comorbidity induced a blunted hypothalamic-pituitary-adrenal (HPA) response and whether initial serum cortisol value had a prognostic significance. METHODS: Morning (8 am) serum cortisol level together with epidemiologic, clinical, and laboratory data were analyzed for 252 consecutive adult (age > or = 18 yrs) patients admitted to the department of internal medicine during a 6-weeks period. RESULTS: The mean serum cortisol level (541 +/- 268 nmol/L) was within the normal range. Only one patient had a low serum cortisol level of 72 nmol/L, whereas the majority of patients had either normal (80%) or increased (19%) serum cortisol levels. Older age, sepsis, prolonged duration of fever, higher comorbidity score, and higher serum creatinine level were each associated with significantly higher serum cortisol level. In addition, a higher serum cortisol level was significantly related to longer hospitalization and higher in-hospital mortality rate. CONCLUSIONS: Serum cortisol level positively correlated with age, disease severity, and outcome. All admitted patients, except one, had normal to high serum cortisol. Whether this increased cortisol level is an adequate HPA response or less than required for the disease-induced stress should be investigated in further studies.     

The altered adrenal axis and treatment with glucocorticoids during critical illness

Critical illness is generally hallmarked by activation of the hypothalamic-pituitary-adrenal axis. The development of very high levels of cortisol has been associated with severe illness and a raised risk of death. Likewise, a response that is inadequate relative to the degree of stress, termed relative adrenal insufficiency (also known as critical-illness-related corticosteroid insufficiency) has been associated with increased mortality. Much controversy exists with regard to the definition and biochemical testing of an adequate adrenal response to critical illness, which hampers diagnosis. High doses of glucocorticoids have been shown to have no effect in this setting and might be harmful. Moderate doses have been advocated, however, for critically ill patients with inflammatory conditions, such as acute respiratory distress syndrome and septic shock syndrome. Initial results from proof-of-concept studies were promising but thus far have not been reproduced in large, multicenter trials, although the latter were underpowered to yield definite conclusions. The role of glucocorticoid therapy in intensive care, therefore, remains uncertain. Until the debate has been settled, we recommend that use of glucocorticoid therapy in critically ill patients should continue to be based on the clinician's judgment and that routine adjuvant use should be avoided.     

Serum free cortisol as an ancillary tool in the interpretation of the low-dose 1-μg ACTH test

Objective Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter‐subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic–pituitary–adrenal (HPA) assessment in noncritically ill subjects is unknown. Design, patients and measurements We performed the low‐dose 1‐μg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured. Results Mean fraction of free cortisol was 5·07 ± 4·08% (±SD; range 1·77–10·1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0·539 P = 0·01), as well as between peak ACTH‐stimulated total and free cortisol (R = 0·619; P = 0·01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH‐stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (≥500 nm ), the minimal ‘pass’ level for normal serum free cortisol response to 1 μg ACTH was set at 25·0 nm . Five of the 19 subjects showing subnormal TC response to 1 μg ACTH had normal serum free cortisol response. Conclusions Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH‐stimulated TC peaked between 440 and 580 nm . At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1‐μg ACTH.     

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.     

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.     

Adrenocortical insufficiency after pituitary surgery: an audit of the reliability of the conventional short synacthen test

BACKGROUND: Assessment of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery is important for appropriate decision making regarding replacement therapy. The synacthen test is often used but is questioned, as time has to elapse for adrenal atrophy to develop. OBJECTIVE: To audit the use of the 250 microg synacthen test after transsphenoidal adenomectomy. METHODS: A retrospective study of 110 patients submitted to first-time transsphenoidal adenomectomy. Anterior pituitary testing was performed preoperatively, 1 week and 1, 3, 6 and 12 months postoperatively. The adrenocortical function was tested by a synacthen test (250 microg synacthen i.v.). RESULTS: Thirty-two out of 71 patients with normal HPA function before surgery developed insufficiency postoperatively, seven patients presenting an insufficient test response after 1 week, 16 after 1 month and nine after 3 months, whereas none became insufficient during the remaining follow-up. Three patients presented symptomatic adrenal insufficiency during the first postoperative week despite a normal test. All of these developed an insufficient test 1 month postoperatively. A 1-week basal plasma cortisol > 400 nmol/l indicated HPA sufficiency, whereas a basal cortisol < or = 100 nmol/l indicated insufficiency when related to the diagnosis based on the 3-month synacthen test. CONCLUSION: This study confirms that the synacthen test is of limited use in the early postoperative phase, because out of 62 patients with normal 1-week postoperative synacthen responses, 23 patients developed a test that was indicative of adrenal insufficiency over 1-3 months. Our results indicate that a large proportion of patients should be considered for hydrocortisone replacement therapy up to 3 months postoperatively followed by reassessment of the HPA axis.     

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.     

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.     

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.