Q J Med 2000; 93: 603-609
© 2000 Association of Physicians
Primary hypoadrenalism assessed by the 1 µg ACTH test in hospitalized patients with active pulmonary tuberculosis
From the Endocrine-Diabetes Unit, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
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Summary |
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Primary hypoadrenalism, assessed by 250 µg ACTH stimulation, is uncommon in patients with active pulmonary tuberculosis (PTB). Since 1 µg ACTH produces an equivalent +30 min cortisol response to 250 µg in control subjects, the 250 µg dose is supraphysiological and may lack sensitivity for the diagnosis of hypoadrenalism. Furthermore, the impact of coexistent HIV infection on the prevalence of primary hypoadrenalism in PTB is uncertain. We thus determined the cortisol response to an intravenous bolus of 1 µg ACTH in 21 controls, 18 HIV-positive (BMI 19.5±0.9 kg/m2, albumin 24±1.4 g/l, CD4 count 192±47/mm3) and 22 HIV-negative (BMI 19.3±0.8 kg/m2, albumin 29±1 g/l, CD4 count 652±76/mm3) patients with active PTB. The mean basal cortisol was greater in patients than in controls (559 vs. 373 nmol/l, p=0.0009). The mean cortisol after 1 µg ACTH stimulation did not, however, differ significantly when comparing either patients and controls or patients who were HIV-positive and -negative (p>0.05). Using the minimum +30 min cortisol derived from the 21 controls as a marker of normal adrenal function (414 nmol/l), a single patient was classified as hypoadrenal. In conclusion, primary hypoadrenalism, as assessed by the 1 µg ACTH test, is uncommon in a cohort of ill, hospitalized patients with active PTB, irrespective of HIV status.
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Introduction |
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The incidence of tuberculosis (TB) is increasing worldwide as a result of the immune compromise induced by the human immunodeficiency virus (HIV). In South Africa, where the prevalence of HIV in women attending antenatal clinics approaches 25%, TB mortality increased by 44% from 1994 to 1995.1 Hypoadrenalism in TB is of potential relevance, as cortisol deficiency could account for occasional sudden unexpected deaths in these patients.2 Furthermore, adrenal insufficiency is increasingly recognized in AIDS patients, and correlates with stage of progression of HIV infection.3 Although clinical adrenal insufficiency occurs in <5% of these patients, the incidence in the subgroup co-infected with TB has not been clearly established. Accurate evaluation of adrenal function in HIV-positive patients is essential in order to avoid the inappropriate use of steroids, which may aggravate opportunistic infections.
A number of studies have assessed the prevalence of hypoadrenalism in TB, with widely varying results (0–55%) reported.4–7 The methods and criteria used for evaluation of normal adrenal function are crucial determinants of the observed prevalence. Earlier workers regarded a rise in serum cortisol of 200 nmol/l above baseline as indicative of normal adrenal reserve.6 ACTH may, however, fail to further stimulate maximally stimulated adrenals, thus diminishing the diagnostic value of the cortisol increment. A cortisol concentration of 550 nmol/l at any time during testing may therefore be a more appropriate criterion for a normal response. Post et al. used the latter criterion as the determinant of adequate adrenal reserve and demonstrated a normal response in 100% of 50 ill patients with active pulmonary TB.8
Recently it has become evident that 250 µg ACTH does not represent a physiological stimulus to cortisol release. Even doses of 500 ng/1.73 m2 of ACTH produce an equivalent +30 min serum cortisol response in control subjects when compared with the standard 250 µg dose.9 Consequently, it has been proposed that low-dose (1 µg) ACTH stimulation may provide a more sensitive method of investigating adrenal function and unmask subtle changes in cortisol secretion. The normal adrenal response to ACTH stimulation demonstrated by Post et al. may thus have been a false negative result due to the supraphysiological dose of ACTH (250 µg) administered.8
Our aims, therefore, were: (i) to re-evaluate the prevalence of adrenal insufficiency in patients with active pulmonary TB by determining the cortisol response to low dose (1 µg) ACTH stimulation; (ii) to establish the prevalence of hypoadrenalism in the cohort of TB patients co-infected with HIV.
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Patients and controls
Forty hospitalized patients (16 male, 24 female; mean age 39.7 years, range 18–79, and mean BMI 19.4 kg/m2, range 13.3–28.8) with newly diagnosed sputum-positive TB and compatible radiographic changes were studied prospectively. Twenty-two patients (55%) had bilateral pulmonary disease on chest radiography, one with a miliary pattern. Cavitating disease was present in 18 patients (45%). No patient had received anti-tuberculous therapy for more than 24 h. Patients who were pregnant, alcoholic, diabetic or on steroids were excluded from the study. Twenty-one healthy subjects (six male, 15 female; mean age 33.5 years, range 21–46, and mean BMI 23.6 kg/m2, range 17.2–37.3) recruited from the University of Cape Town Medical School were used as a control group. Informed consent was obtained from all subjects, and the study was approved by the University of Cape Town Ethics and Research Committee.
Protocol
Information was collected relating to current anti-tuberculous therapy and CXR findings, and supine and erect blood pressures were taken. Thereafter, each patient had an intravenous ACTH (1 µg) stimulation test between 0830 and 1000 h. A dilute solution of ACTH was prepared by adding 250 µg to 49 ml 0.9% saline, from which 0.2 ml was added to 0.8 ml 0.9% saline (1 µg ACTH/ml). ACTH (1 µg) was then administered as an intravenous bolus within 15 min of preparation, directly into a three-way tap to reduce adsorption. Blood samples were drawn for cortisol at –15, 0, 20, 30, 40 and 60 min. Additional samples were drawn at baseline for HIV antibodies (ELISA) and CD4 count, serum electrolytes and osmolality, serum albumin, haemoglobin (Hb), thyroid stimulating hormone (TSH), free T4 (fT4), free T3 (fT3), FSH, LH, testosterone (in males) and ACTH. A spot urine sample was taken for estimation of electrolytes and osmolality.
A normal response to 1 µg ACTH stimulation was defined as a +30 min serum cortisol 
414 nmol/l. This figure was derived from the 21 controls in whom the minimum +30 min serum cortisol was 414 nmol/l. The results were further analysed using a cut-off value of 600 nmol/l.10 The sick euthyroid syndrome was defined as a serum fT3 concentration <3.4 pmol/l in the absence of clinical or biochemical features of primary or secondary hypothyroidism. A diagnosis of secondary hypogonadism was made in males when a subnormal total serum testosterone was accompanied by a normal or low serum LH concentration. Inappropriate ADH secretion (SIADH) was suggested by the combination of hyponatraemia (Na+<130 mmol/l) with low plasma osmolality (<280 mOsm/kg), inappropriately high urine osmolality and urinary sodium >20 mmol/l in the absence of clinical volume depletion or biochemical evidence of hypothyroidism, hypoadrenalism or renal impairment. Volume depletion was defined as postural hypotension (postural reduction in systolic and/or diastolic BP by >20 mmHg and/or >10 mmHg respectively), with urinary sodium <10 mmol/l.
Assays
Serum cortisol was measured using an ACS 180 analyser (Ciba Corning). The inter- and intra-assay CVs were 8.4% and 6.1%, respectively. Serum ACTH was measured using an RIA (Nichols Institute Diagnostics with inter- and intra-assay CVs 6.8% and 3.0%, respectively). Serum osmolality (mOsm/kg) was measured using an osmometer (Osmomat) which uses the principle of freezing point depression. TSH (normal range 0.35–5.5 mU/l), free T4 (normal 11–24 pmol/l), fT3 (normal 3.4–7.2 pmol/l), FSH (normal 0–16.4 U/l) and total testosterone (normal 8.4–28.7 nmol/l) were measured using IRMA methodology on the automated chemilumescent immunoassay instrument (ACS 180, Ciba Corning). LH was assayed using Maiaclone (Serono). The inter- and intra-assay CV for TSH, fT4 and fT3 were 5.5 and 4.1%, 4.6 and 3.9%, and 7.6 and 4.4%, respectively. The inter- and intra-assay CV for FSH, LH and testosterone were 5.7 and 4.4%, 5.8 and 3.3%, and 8.7 and 6.8% respectively.
Statistical analysis
A statistical software package (Statistica) was used for data analysis. The cortisol response to ACTH was compared in the control and patient groups, and the HIV positive and negative subgroups, by one-way ANOVA. Results were expressed as mean±SE. Significance was accepted at the p<0.05 level.
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Results |
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Demographic data
The sample consisted of 40 patients, 22 HIV-negative and 18 HIV-positive. There were no significant differences between the HIV-positive and -negative groups with respect to age, sex, BMI, systolic or diastolic BP, while the mean Hb, serum albumin and CD4 counts differed significantly (Table 1
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Cortisol response to 1 µg ACTH stimulation
The mean basal cortisol concentration was 559 nmol/l in the patient group and 373 nmol/l in the control group (p=0.0009). The mean cortisol concentrations after low dose (1 µg) ACTH stimulation did not, however, differ significantly between the patient and control groups at any timepoint (Figure 1). Plasma cortisol concentrations did not differ at any timepoint in patients who were HIV positive and negative (Figure 2). Using the +30 min serum cortisol cut-off (<414 nmol/l) derived from the results of the 21 control subjects, only one patient (HIV-negative) fulfilled the diagnostic criterion for hypoadrenalism. Nineteen patients (48%) were defined as having inadequate adrenal reserve using the +30 min cortisol cut-off value of 600 nmol/l suggested by Abdu et al.10 (Figure 3 ). It is, however, relevant to emphasize that only one of these 19 patients was hyponatraemic, and none were hyperkalaemic or had an elevated basal ACTH concentration (mean ACTH 14.4 pg/ml, range 0–36.3, normal 9–52).
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Thyroid and gonadal function
The mean±SE serum fT3 concentration was 3.66±0.15 pmol/l, and 36 patients (42%) had biochemical evidence of the sick euthyroid syndrome. Three patients, all of whom had low fT3 concentrations, also had a low serum fT4 concentration. There was a moderate elevation of TSH in two patients, both of whom had a normal fT4 and low fT3 concentration. There was no significant difference between HIV-positive and -negative patients with respect to fT3 and fT4 values, but TSH levels were significantly lower in the HIV-positive group (1.57 vs. 3.39 mIU/l, p=0.006) Fourteen (88%) of the males had biochemical evidence of secondary hypogonadism with mean±SE serum testosterone 4.35±0.93 nmol/l (range 0.85–14.4). There was no significant difference in serum testosterone between HIV-positive and -negative patients.
Serum and urinary electrolytes
No patient had clinical or biochemical evidence of volume depletion, and none was hyponatraemic with an inappropriate natriuresis. Four patients (10%) were hyponatraemic (Na+ range 128–129 mmol/l), all of whom had features of SIADH with mean serum osmolality 270 mOsm/kg (range 261–279) and mean urine osmolality 720 mOsm/kg (range 642–861).
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Discussion |
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Despite previous work suggesting that the prevalence of hypoadrenalism in acute pulmonary tuberculosis may approximate 55%,5 our study of 40 hospitalized patients with active PTB revealed that adrenal insufficiency, as assessed by the low dose (1 µg) ACTH stimulation test, was remarkably uncommon. This low prevalence occurred despite the fact that 45% of the patients were HIV-positive with a mean CD4 count of only 192/mm3. Moreover, the patient group was at particularly high risk of adrenal insufficiency in view of the severity of their illness, as evidenced by the extent of hypoalbuminaemia (mean 27 g/l) and the fact that both the sick euthyroid state (42%) and secondary hypogonadism (88%) were common associated features.
Previous studies of hypoadrenalism in active tuberculosis have produced variable results.4–7 Early studies used 250 µg intramuscular or intravenous ACTH stimulation tests. Ellis and Tayoub regarded a serum cortisol increment <300 nmol/l above baseline as suboptimal, and reported abnormal responses in 55% of 41 patients with acute pulmonary TB.5 Barnes et al., defining a cortisol increment >200 nmol/l as a normal response to 250 µg ACTH, described hypoadrenalism in 8% of 90 patients with active TB.6 Basal cortisol concentrations were, however, increased in 39% of their patients, potentially blunting the incremental cortisol response, with a resultant false-positive diagnosis of adrenal insufficiency. An intramuscular preparation of ACTH was used by Mugusi et al., who defined hypoadrenalism as a 60-min cortisol response <600 nmol/l and/or an increment <300 nmol/l, and found an impaired response in 32% of 50 patients with chronic pulmonary TB.7 Post et al. found no evidence of hypoadrenalism in their study of 50 hospitalized patients with newly diagnosed pulmonary TB, where adequate adrenal reserve was defined as a peak cortisol concentration exceeding 550 nmol/l after 250 µg ACTH.8 The issue of the optimal dose of ACTH is of particular relevance in view of the work of Crowley et al., which demonstrated that only 500 ng/1.73 m2 ACTH results in a 30-min cortisol response equivalent to that achieved after the standard 250 µg dose.9 We were thus interested to evaluate whether use of a more physiological dose of ACTH would unmask subtle but potentially important changes in adrenal function in patients with active tuberculosis.
The issue of the optimal cortisol cutoff value for the low-dose ACTH stimulation test remains contentious. A +30-min cortisol response to ACTH of <414 nmol/l was used in our study, based on the minimum concentration achieved in a group of 21 normal controls (Soule et al., in press). In their study of 42 patients with suspected pituitary disease who underwent both an ITT and a 1 µg ACTH stimulation test, Abdu et al. concluded that if the cortisol cutoff for the low-dose test was empirically set at 600 nmol/l, the test had 80% specificity and 100% sensitivity for the diagnosis of ACTH deficiency.10 Zarkovic et al., using a 15-min cortisol increment of >100 nmol/l after 1 µg ACTH, achieved a sensitivity of 100% for the diagnosis of secondary hypoadrenalism in 14 patients presumed hypoadrenal following 6 months of high-dose steroid treatment.11 These criteria for hypoadrenalism are certainly useful for screening for ACTH deficiency in view of their high sensitivity, although the limited specificity demands the subsequent use of a gold-standard test for definitive diagnosis. We suggest that the use of a 600 nmol/l cortisol cutoff is an inappropriately stringent criterion for the diagnosis of primary hypoadrenalism, since the limited specificity of this cutoff would result in a high false-positive rate of diagnosis of this condition. Using the 600 nmol/l cutoff, 48% of our patients would be classified as hypoadrenal, a prevalence we regard as an overestimate for the following reasons. Firstly, none of these patients manifested hyperkalaemia or hyponatraemia with inappropriate natriuresis, despite the fact that these metabolic disturbances are evident in 53% and 78%, respectively, of patients with acute primary hypoadrenalism admitted to our hospital.12 Secondly, none of the patients had an increase in ACTH concentration, the earliest biochemical feature of primary hypoadrenalism. We therefore propose that the cutoff of 414 nmol/l is a valid criterion for the diagnosis of primary hypoadrenalism in our study. It is noteworthy that the single patient classified as hypoadrenal according to this criterion was not treated with glucocorticoid supplementation, yet recovered uneventfully after 6 months of anti-tuberculous therapy with a drug regimen that included the enzyme inducer rifampicin.
There are several potential criticisms of our study. The first issue relates to the apparently low plasma cortisol cutoff (414 nmol/l) derived from our control group of healthy subjects in response to 1 µg ACTH. The dose of ACTH was prepared within 15 min of administration via a 2 ml syringe directly into a three-way tap, to prevent adsorption of ACTH to plastic.13 Furthermore, the cortisol responses elicited by our control group are comparable with those reported by Hudson et al. in response to 1 µg ACTH, as the peak cortisol in their normal control group was 486±141 nmol/l.14 Method-related differences using various cortisol assays represent the most plausible explanation for the relatively low plasma cortisol responses reported in our control subjects.15 The second contentious issue concerns the use of the cortisol increment rather than the peak cortisol after ACTH as an indicator of adrenal integrity. Since the increment is inversely proportional to the basal cortisol level we consider it an unreliable screening test for hypoadrenalism.16 This point was emphasized by a study in which one third of normal subjects exhibited a rise in cortisol 
200 nmol/l.17 Furthermore, hospitalized patients acutely ill with active PTB frequently have high basal cortisol levels, as noted in our study, and are thus liable to produce a blunted increment after ACTH administration—73% of our patients thus had a cortisol increment of <200 mmol/l. A further contentious issue concerns the pre-treatment of patients with rifampicin, an established enhancer of glucocorticoid metabolism, which may reduce the plasma cortisol concentration in patients with compromised adrenal function and may even precipitate an adrenal crisis.18,19 However, no patient in our study received more than a single dose of rifampicin prior to ACTH stimulation testing. Furthermore, the fact that only one patient had a blunted cortisol response to ACTH stimulation despite exposure to rifampicin provides further support for our contention that adrenal function is intact in the vast majority of patients with active tuberculosis with or without coexistent HIV infection. The final issue requiring clarification is the potential impact of a reduction in the corticosteroid-binding globulin concentration (CBG) on the interpretation of our results. There is now ample data confirming a decrease in CBG in the setting of severe acute illness, specifically septic shock, open heart surgery and burn injury.20–22 The reduction appears to be mediated by a combination of increased interleukin-6 and glucocorticoids and may, in HIV-positive patients, be accompanied by a reduction in the affinity of cortisol for CBG.23,24 It is therefore possible that in our cohort of acutely ill TB patients, the CBG concentration is reduced, thereby reducing the measured total cortisol which represents the combination of free and CBG-bound cortisol. We are unaware of any study specifically examining quantitative or qualitative changes in CBG in patients with active tuberculosis. Moreover, a falsely low reading of plasma cortisol secondary to an unmeasured reduction in CBG would tend to bias the study toward a higher prevalence of hypoadrenalism (false positives). The fact that there was a negligible prevalence of hypoadrenalism in this study therefore strengthens the conclusion, namely that hypoadrenalism is distinctly uncommon in patients with active PTB.
Clinical adrenal insufficiency occurs remarkably infrequently in patients with AIDS (<5%), and is most commonly secondary to cytomegalovirus infection, although hypoadrenalism due to TB has been described.3,25 It is clearly important to establish that adrenal reserve is intact in AIDS patients because of the risks associated with glucocorticoid treatment in immunocompromised subjects.25,26 The issue is confounded by the fact that AIDS patients with inadequate adrenal reserve do not necessarily demonstrate the classical clinical features of hypoadrenalism.26 Furthermore, AIDS itself may produce a clinical picture resembling primary adrenocortical insufficiency in patients with intact adrenal function.27–29 Hyponatraemia, for example, the commonest electrolyte abnormality in AIDS, is usually due to SIADH rather than adrenal insufficiency.26,30 Our study, which included 18 ill patients with advanced retroviral disease (mean CD4 192/mm3) and coexistent active tuberculosis, suggests that hypoadrenalism is an unusual feature in these patients and supports the need to evaluate adrenal function only in patients with strongly suggestive clinical features. The remarkably low incidence of adrenal insufficiency in AIDS patients may be explained by the shift in the metabolism of adrenal pregnenolone away from mineralocorticoid and androgen production toward glucocorticoid production.31 Furthermore, cortisol metabolism is altered, with a reduction in 11-ß-hydroxysteroid dehydrogenase and increased 11-ß reductase activity which may contribute to the alteration of cytokine subsets from TH1 to TH2 predominance, a change associated with a reduction in macrophage activation and CD4 count.2,32
In conclusion, we have demonstrated that adrenal insufficiency is rare in hospitalized patients with active pulmonary tuberculosis using a low-dose ACTH stimulation test. This low prevalence was found irrespective of HIV status, and despite a high frequency of thyroid and gonadal dysfunction.
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Acknowledgments |
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We would like to acknowledge the assistance of the Microbiology, Combined Endocrine and Chemical Pathology Laboratories at Groote Schuur Hospital, and Ciba Geigy-Novartis for supplying the Synacthen.
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Notes |
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Address correspondence to Dr S.G. Soule, Department of Medicine, UCT Medical School, Observatory 7925, Western Cape, South Africa. e-mail: ssoule{at}uctgsh1.uct.ac.za
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References |
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