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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3029-3033
Copyright © 1997 by The Endocrine Society

Original Studies

The Hypothalamic-Pituitary-Adrenocortical Axis in Severe Falciparum Malaria: Effects of Cytokines1

Timothy M. E. Davis, Li Thi Anh Thu, Tran Quang Binh, Ken Robertson, John R. Dyer, Phan Thi Danh, Desiree Meyer, Miles H. Beaman and Trinh Kim Anh

University of Western Australia, Department of Medicine, Fremantle Hospital (T.M.E.D., J.R.D., D.M., M.H.B.), Western Australia, Australia; Tropical Diseases Research Center, Cho Ray Hospital (L.T.A.T., P.T.D., T.K.A.), Ho Chi Minh City, Vietnam; and Biochemistry Department, Royal Perth Hospital (K.R.), Perth, Western Australia, Australia

Address all correspondence and requests for reprints to: Professor T. M. E. Davis, University of Western Australia, Department of Medicine, Fremantle Hospital, P.O. Box 480, Fremantle, Western Australia 6160, Australia. E-mail: tdavis{at}cyllene.uwa.edu.au


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Patients with malaria can have features of adrenal insufficiency. Because of the pathophysiological and clinical implications of an Addisonian state, the hypothalamic-pituitary-adrenocortical axis was assessed in nine Vietnamese adults with complicated malaria. A CRH test was performed on admission (in convalescence in five cases) and in six healthy controls. Basal plasma ACTH concentrations in the patients and controls were similar [median (range): 2.9 (0.2–9.7) vs. 3.5 (1.9–13.4) pmol/L, respectively; P > 0.1]. Serum cortisol levels were greater in the patients [882 (294–1682) vs. 190 (110–676) nmol/L; P < 0.01], but three (33%) had values within the control range. Basal serum corticosteroid-binding globulin concentrations were similar in patients and controls (P = 0.23). The post-CRH rise in plasma ACTH was attenuated in the patients [peak: 6.1 (0.9–23.2) vs. 14.5 (6.2–21.5) pmol/L in controls; P < 0.05]; basal and peak plasma ACTH correlated with plasma interleukin-6 in this group (rs >= 0.60; P <= 0.04). Serum cortisol responses to CRH were depressed in acute illness [peak 990 (394–1, 805) nmol/L or 10 (0–50%) above baseline vs. 500 (429–703) nmol/L or 160 (10–380%) in controls; P < 0.05]. The median estimated serum cortisol t1/2 was 4.6 h in the patients and 1.6 h in the controls. These data suggest that, relative to a normal stress response, primary and secondary adrenal insufficiency can occur in severe malaria but may be attenuated by increased circulating interleukin-6 concentrations and impaired cortisol metabolism. The benefits of stress-dose corticosteroid replacement are unknown but could be considered in hypoglycemic patients or those with a serum cortisol within or below the reference range.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CLINICAL FEATURES of adrenal insufficiency and histological changes in the adrenal glands occur in falciparum malaria (1). In view of complications such as hypoglycemia arising from the infection or its treatment, hemodynamic instability including algid malaria, and fluid and electrolyte imbalance from dehydration and renal impairment (2), hypothalamic-pituitary-adrenocortical (HPA) dysfunction would have important implications in malaria. Published data on the HPA axis in human malaria are few. Brooks et al. (3) found raised plasma 17-hydroxycorticosteroids but normal diurnal variation and metyrapone response in patients of unspecified severity. Phillips et al. (4) found raised serum cortisol during hypoglycemia (4), but the range of values was wide, and there was no comparison with levels in euglycemic patients. The clinical state of the patients and methods used in these studies leave open the possibility that HPA dysfunction might complicate severe malaria.

The relatively recent developments of specific ACTH assay and the CRH test have facilitated HPA axis investigation in other diseases (5). Increased basal and CRH-stimulated plasma ACTH and cortisol are usually found in severe illness (6), but some patients have adrenal insufficiency (7, 8). Pharmacological corticosteroid doses do not benefit unselected patients with severe infections (9, 10) and have proved deleterious in cerebral malaria (11). Nevertheless, stress dose glucocorticoids may improve short-term survival in severely ill patients with a depressed cortisol response to ACTH stimulation (12).

Several cytokines influence HPA function and, in malaria, plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor-{alpha} (TNF-{alpha}) are raised in proportion to clinical severity (13). IL-6 stimulates the HPA axis (14), TNF-{alpha} may inhibit cortisol production (15), and both mediate lipopolysaccharide-induced ACTH release (16). Nitric oxide, which is induced by TNF-{alpha}, may have a neutral (17) or inhibitory (18) effect on the HPA axis. However, before interventions such as glucocorticoid replacement and cytokine modulation are considered, HPA function and the cytokine millieu need careful evaluation.

We have used the CRH test to investigate the HPA axis and its relationship to selected cytokines in Vietnamese patients with severe malaria. The results suggest that some patients have an inappropriately low serum cortisol caused by corticotroph and adrenocortical dysfunction, and that IL-6 has an important role in modulating HPA function.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and patients

Nine patients with severe malaria (2) and six healthy volunteers were studied (see Table 1Go). The patients were admitted to Cho Ray Hospital, Ho Chi Minh City after an inadequate response to rural hospital care but within 7 days of the onset of symptoms. No patient or volunteer had a history of chronic illness or had received recent corticosteroid therapy. Three patients had cerebral malaria, four were in renal failure, two were jaundiced, and two had severe anemia (hematocrit <15%). The controls were hospital staff or relatives or friends of patients. Each subject or, in the case of comatose patients, a relative, gave informed consent to study procedures, which were approved by the Ministry of Health, Vietnam.


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  		Table 1. Details of patients and controls at time of study

 
Methods

After initial clinical assessment and laboratory tests, patients received parenteral quinine or artesunate, and complications were managed as described previously (2, 19). Once the patient was hemodynamically stable and had not eaten for >4 h, a CRH test was performed either between 0800 and 1000 h on the admission day or, if patients were stabilized after 1000 h, the next morning. Dextrose-containing iv fluids were started to maintain euglycemia before and during testing. A venous cannula was inserted, and a baseline sample drawn. After 15 min, a second sample was taken (0 min), and 100 µg human CRH (Bachem, Bubendorf, Switzerland) in 1.0 mL 0.02% (vol/vol) HCl in sterile normal saline was injected as an iv bolus. Further samples were taken at 15, 30, 45, 60, and 120 min. Patients remained supine throughout. Samples were kept on ice, centrifuged promptly, and serum and plasma stored below -20 C until assay. Patients were asked to undergo a CRH test when they were afebrile and slide-negative for malaria. The same protocol was used in convalescent patients and controls.

Assays

Plasma ACTH was measured by specific chemiluminescence immunometric assay (Nichols Institute, San Juan Capristrano, CA). Interassay precision was 10.0% at 0.6 pmol/L, 7.5% at 7.2 pmol/L, and 8.1% at 72 pmol/L. Serum cortisol was assayed by fluorometric enzyme immunoassay (Stratus, Baxter Diagnostics, Deerfield, IL). Interassay precision was <5.0% over the range 116-1074 nmol/L. Serum corticosteroid-binding globulin (CBG) was measured by RIA (Medgenix, Biosource, Camarillo, CA) with intrassay precision 7.1% at 25 mg/L and 3.6% at 106 mg/L. Serum-free T4 and TSH were measured by enzyme immunoassay and two-site immunoenzymometric assay, respectively (Tosoh, Tokyo, Japan). Other biochemical tests were performed using Chem-1 methods (Bayer Diagnostics, Tarrytown, NY). Plasma cytokines were assayed by double-sandwich two-site enzyme-linked immunosorbent assay (20). Detection limits were 9.5 pg/mL for IL-6, 19 pg/mL for soluble IL-6 receptor, and 39 pg/mL for TNF-{alpha}. Serum nitrates (including nitrite) were measured by copper-plated cadmium reduction and the Griess reaction, with a detection limit of 3 µmol/L.

Data analysis

Basal plasma ACTH and serum cortisol were taken as the average of -15 and 0 min concentrations. Peak ACTH and cortisol were the maximum concentrations over 2 h. The peak increment (peak minus basal) was expressed as a proportion of the basal value. A rate constant describing a monoexponential decline in serum cortisol from 60–120 min was estimated by regression analysis. Statistical analysis was by nonparametric tests, and data are medians and ranges unless otherwise stated. Two-sample comparisons were by Wilcoxon-Mann-Whitney tests. Spearman rank correlation was used to assess associations between variables.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical course

All patients responded to treatment and were discharged after a median of 15 (range, 7–24) days. Of five patients consenting to a repeat CRH test, three had a mildly raised serum creatinine and/or bilirubin but all were afebrile, ambulant, and eating normally when restudied. No patient or control had side-effects after CRH apart from mild flushing.

Plasma ACTH

Plasma ACTH profiles during the CRH test are shown in Fig. 1Go. Measures of response are summarized in Table 2Go. There was no significant difference between the basal plasma ACTH concentrations in the patients and controls, nor between basal values in acute illness and convalescence. The peak ACTH level was significantly depressed in the patients in absolute terms and as a proportion of basal (see Table 2Go), and there was a significant correlation between basal and peak plasma ACTH (rs = 0.87, n = 9; P = 0.002).



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  		Figure 1. Median plasma ACTH concentrations before and after administration of 100 µg human CRF in healthy controls ({blacksquare}) and in patients with severe malaria in acute illness ({blacktriangleup}) and in convalescence ({blacktriangledown}). Vertical bars represent absolute range of values in each group at each time point.

 

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  		Table 2. Parameters derived from serial serum cortisol and plasma ACTH concentration profiles after CRH administration

 
Serum cortisol

Serum cortisol concentrations are shown in Fig. 2Go and response parameters in Table 2Go. Basal concentrations in the patients during acute illness were significantly higher than those of the controls. However, there was a wide scatter of values, and three patients had levels within the control range. Basal serum cortisol concentrations in convalescence were largely intermediate between values in controls and acute illness. There was no significant association between basal plasma ACTH and serum cortisol in the severe malaria group (rs = 0.30, n = 9; P = 0.22). However, the patient with the lowest basal serum cortisol (294 nmol/L) had the lowest basal plasma ACTH of any subject (0.2 pmol/L), and minimal ACTH (0.7 pmol/L) and cortisol (10 nmol/L) responses to CRH.



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  		Figure 2. Median serum cortisol concentrations before and after administration of 100 µg human CRF in healthy controls ({blacksquare}) and in patients with severe malaria in acute illness ({blacktriangleup}) and in convalescence ({blacktriangledown}). Vertical bars represent absolute range of values in each group at each time point.

 
The post-CRH rise in serum cortisol in the patients was significantly less than that in the controls when expressed in absolute terms or as a proportion of basal, whereas there was an intermediate cortisol response in convalescence (see Fig. 2Go and Table 2Go). In the severe malaria group, the serum cortisol increment expressed as a ratio of basal correlated significantly with the equivalent measure for ACTH (rs = 0.57, n = 9; P = 0.05). However, a median post-CRH increase in plasma ACTH of 1.4 times basal resulted in a median rise in serum cortisol of 0.1 basal (ACTH/cortisol incremental ratio, 14:1; see Table 2Go). In the controls, the equivalent figures were 4.0 and 1.6, respectively (ratio, 2.5:1).

Estimated rate constants for cortisol metabolism were lower in the patients than in controls and convalescents (see Table 2Go). There was a significant correlation between the rate constant and serum bilirubin in acute illness (rs = -0.60, n = 9; P = 0.05) but not with serum aspartate transaminase, albumin, or creatinine (P > 0.2 in each case). The median rate constants in controls and in patients with severe malaria and in convalescents corresponded to elimination t1/2 values of 1.6, 4.6 and 1.9 h, respectively.

Serum CBG

There were no significant differences in serum CBG concentrations between controls and patients (P = 0.23) or between patients with acute illness or convalescents (P = 0.18; see Table 2Go).

Cytokines and nitrates

The patients had significantly greater baseline plasma concentrations of IL-6, IL-6 receptor, and TNF-{alpha}, and serum nitrate concentrations than controls. Convalescent values were intermediate between these two groups (see Table 3Go). IL-6 and TNF-{alpha} were unmeasurable in almost all controls. There was a significant positive association between basal plasma TNF-{alpha} and serum nitrates in the patients (rs = 0.72, n = 9; P = 0.02) but not between IL-6 and IL-6 receptor (P > 0.5).


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  		Table 3. Plasma cytokine and serum nitrate concentrations at baseline

 
Plasma IL-6 correlated positively with both basal and peak plasma ACTH in the severe malaria group (rs = 0.60 and 0.70, n = 9; P = 0.04 and 0.02 respectively) but not with basal or peak serum cortisol (P > 0.2). Parametric regression analysis indicated that plasma IL-6 accounted for a quarter of the variability in basal, and a third of that in peak, plasma ACTH (r2 = 0.25 and 0.34 respectively). Plasma IL-6 receptor, plasma TNF-{alpha}, and serum nitrates showed no significant associations with basal and peak ACTH and cortisol (P > 0.2). The product of IL-6 and IL-6 receptor showed stronger associations with basal and peak plasma ACTH (rs = 0.73 and 0.71, respectively; P < 0.02) than plasma IL-6 alone.

Serum TSH and free T4

Serum TSH and free T4 tended to be lower in acute illness than in controls (0.2 > P > 0.07; see Table 1Go). There was a significant inverse correlation between basal serum cortisol and free T4 in the severe malaria group (rs = -0.51; P = 0.04).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Serum cortisol is usually increased in stress states, primarily because of activation of the HPA axis (6, 21). However, clinically inappropriate concentrations within or below reference ranges can be found (7, 8, 12). Basal serum cortisol concentrations were distributed widely in our patients, from levels within the control range to those at least as a high as in other severe illnesses (6, 7, 8). However, simultaneous serum CBG concentrations were similar to those of controls and to published values in healthy Caucasians (22). Because CBG binds more than 90% of cortisol in the physiological range (23), these data imply that the 33% of patients in our sample with a total serum cortisol comparable with those of the controls had a free serum cortisol concentration that was also within the control range and thus inappropriate to the stress of the infection. At increased total serum concentrations, cortisol binding to albumin becomes more important (23). The remaining patients had raised serum cortisol and depressed albumin concentrations, suggesting that the free serum cortisol was appropriately raised.

In other severe illnesses, basal and peak ACTH levels after CRH are typically increased (6). All our patients had a basal plasma ACTH within or below the control range. Most had normal or blunted ACTH responses to CRH in absolute and relative terms, even in those with a normal basal cortisol. Thus, our data suggest that there is a pituitary contribution to relative adrenal insufficiency in severe malaria. This might reflect an altered set point for cortisol inhibition of ACTH secretion analogous to that found in depression (24), or of more globally impaired corticotroph function caused by parasitized erythrocyte sequestration (25) within the hypothalamic-pituitary portal system or parasite production of a somatostatin-like peptide (26). Nevertheless, the present results parallel those of a previous study in which the TSH response to TRH was attenuated in Thai patients with severe malaria (27).

ACTH stimulation testing has shown that primary adrenal insufficiency contributes to inappropriately low serum cortisol levels in sepsis (12). The significant correlation between the rises in plasma ACTH and serum cortisol after CRH in our patients, a physiological surrogate for administration of synthetic ACTH, indicates that the adrenal glands respond quantitatively to pituitary stimulation. Although the concentration-response relationship between ACTH and cortisol is nonlinear (28), there was a more than 5-fold greater relative increase in serum cortisol after the CRH-induced rise in plasma ACTH in our controls than in the patients. These data suggest that there is adrenocortical and corticotroph hyporesponsiveness to ACTH and CRH, respectively, in severe malaria. Delayed, exaggerated increases in plasma ACTH after CRH found in tertiary adrenal insufficiency (5) were not seen in our patients, but corticotroph dysfunction would mask such a response.

Circulating IL-6 concentrations correlated with both basal and peak plasma ACTH in our patients. This is consistent with known effects of IL-6 on the human HPA axis (14, 29) and an association between low plasma IL-6 and adrenal insufficiency in sepsis (12). Regression analysis suggested plasma IL-6 and ACTH were linearly related in our patients. As mentioned above, malaria-specific factors, combined with negative feedback where the serum cortisol is raised, may depress corticotroph function. Cytokines such as IL-6 have the opposite effect. Although synergism between ACTH and IL-6 on adrenal function has been reported in an animal model (16), this was not evident in the present study.

There were stronger associations between the product of IL-6 and its receptor and basal and stimulated plasma ACTH compared with those of IL-6 alone, consistent with cytokine-receptor synergism found in other contexts (30). Plasma IL-6 and IL-6 receptor levels in our patients were higher than in controls. In sepsis, very high IL-6 and low receptor levels have been reported (31), suggesting greater immune activation and either greater receptor binding or reduced receptor expression than in malaria. Glucocorticoids up-regulate human epithelial cell IL-6 receptor expression (32), but there was no association between serum cortisol and plasma IL-6 receptor levels our patients.

Consistent with TNF-{alpha} induction of nitric oxide synthesis, plasma TNF-{alpha} correlated significantly with serum nitrate in acute illness, but neither was associated with HPA dysfunction. Furthermore, plasma ACTH responses to CRH in convalescence were similar to those of controls despite elevated plasma TNF-{alpha} concentrations. Although convalescent cortisol responses were attenuated, studies of basal and ACTH-stimulated adrenal function in sepsis (12) suggest that TNF-{alpha} does not, as found in vitro (15), inhibit adrenocortical function. However, other cytokines such as IL-1 and IL-2 may be important modulators of HPA function (21), and further studies are needed to delineate their involvement in what could prove to be a complex system in malaria.

Despite racial differences in body composition, diet, activity levels, and stress, cortisol and ACTH responses to CRH in our Vietnamese controls were similar to those in Caucasians (33). Plasma ACTH peaked at around 2.5 times basal 30–45 min after CRH and, consistent with a 5-min t1/2 (34), had returned to near baseline by 60 min. There was typically a greater than 2-fold increase in serum cortisol by 45 min, followed by a consistent decline from 60–120 min. Cortisol kinetics have been modeled adequately using a single compartment and first-order clearance (35). Under this scheme, the median cortisol t1/2 in our controls was 1.6 h, a value within the normal range (1.4–3.0 h) (34). Cortisol elimination was slower in our patients than in controls or convalescents, and there was an inverse correlation with serum bilirubin. These findings provide evidence that, as suggested previously (3), hepatic dysfunction in malaria results in reduced cortisol metabolism. A prolonged cortisol t1/2 has also been reported in sepsis (36).

Basal pituitary-thyroid axis function in our patients was consistent with that found previously in severe malaria (27). Both serum TSH and free T4 tended to be lower than in the controls, suggesting a dysfunctional feedback loop. The inverse association between basal serum cortisol and HPA function parallels the situation in Cushing’s syndrome, in which low serum TSH and T4 normalize after treatment (37). Thus, a raised serum cortisol could contribute to the sick euthyroid syndrome seen in malaria and other infections.

The significance of HPA dysfunction in malaria is illustrated by considering the patient with the lowest basal serum cortisol and a minimal response to CRH. This patient would have a seriously impaired ability to maintain fluid and electrolyte balance and to mount a counterregulatory response to hypoglycemia. Consistent with this hypothesis is the observation that total serum cortisol levels reported previously in malaria-associated hypoglycemia (mean ± SD, 941 ± 394 nmol/L) (4) were similar to those in our euglycemic patients (860 ± 387 nmol/L).

Whether cortisol replacement benefits patients with malaria is unknown. Pharmacological glucocorticoid doses prolong coma and increase bleeding in cerebral malaria (11) and do not improve survival in unselected patients with sepsis (9, 10). Unspecified stress doses may improve short-term but not long-term survival in septic patients with adrenal insufficiency (12), but patients with malaria are generally younger than those in intervention studies in sepsis and have no other illnesses. There may, therefore, be a stronger case for stress level replacement in malaria, especially when the serum cortisol is within or below the reference range or when hypoglycemia develops.


   Acknowledgments
 
We are grateful to clinical and laboratory staff at Cho Ray Hospital for their cooperation during the study. We thank Andrew St. John, Sandy Musk, Peter O’Leary, and other staff in the Endocrinology Section of the Royal Perth Hospital Biochemistry Department for their assistance with assays, and Wayne Johnston for logistic help.


   Footnotes
 
1 This study was supported by the Fremantle Hospital Physicians-University Department of Medicine Research Fund. Back

Received September 6, 1996.

Accepted May 27, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals