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Adrenal Function in the Human Immunodeficiency Virus–Infected Patient
Jose Mayo, MD;
Julio Collazos, MD;
Eduardo Martínez, MD;
Sofía Ibarra, MD
Arch Intern Med. 2002;162:1095-1098.
ABSTRACT
| |
Although clinical manifestations of adrenal dysfunction are uncommon
in patients infected with human immunodeficiency virus (HIV), subclinical
functional abnormalities of the hypothalamic-pituitary-adrenal axis are frequent.
Patients infected with HIV usually have higher basal serum cortisol and lower
serum dehydroepiandrosterone concentrations than HIV-seronegative individuals.
This imbalance has been related to progression of the infection by inducing
a shift from TH1 to TH2 immunologic responses. Although,
adrenal reserve may be marginal in HIV-infected patients, clinically evident
adrenal insufficiency is uncommon and, when present, it is observed in advanced
stages of the infection. Hypocortisolemia should be treated regardless of
the existence of associated symptoms. On the contrary, hypercortisolemia in
the absence of features of Cushing syndrome is common and should not promote
treatment nor specific studies. The possible influence that alterations of
the adrenal function could have on the patients' immune status and the eventual
effect of antiretrovirals on these alterations merit further investigation.
INTRODUCTION
Adrenal gland involvement has been documented in as many as two thirds
of patients with acquired immunodeficiency syndrome (AIDS) at postmortem examination.1 However, adrenal insufficiency is seldom diagnosed
in clinical practice because symptoms do not appear until more than 80% of
the gland has been destroyed, and the extent of necrosis in the most frequent
autopsy finding, cytomegalovirus adrenalitis, rarely exceeds 60%.2-3 Nevertheless, 2 (3%) of 75 autopsies
performed in unselected patients with AIDS at a single center revealed greater
than 80% destruction of the adrenal cortex by cytomegalovirus4;
this is in agreement with the 3% of patients who had an antemortem diagnosis
of adrenal insufficiency in another necropsy series.1
Less common pathological processes include other opportunistic infections
(Mycobacterium tuberculosis and Mycobacterium avium–intracellulare, Cryptococcus neoformans, Histoplasma
capsulatum, Pneumocystis carinii, and Toxoplasma
gondii), neoplasms (Kaposi sarcoma and lymphoma), hemorrhage, fibrosis,
infarction, and more subtle abnormalities such as cortical lipid depletion,
a likely surrogate of long-lasting severe stress.2-3,5-6
Adrenocortical antibodies are detected in a substantial proportion of patients
with AIDS,3, 5 probably as an epiphenomenon
linked to nonspecific B-cell activation and devoid of clinical significance.
Finally, several drugs have been found to be responsible for adrenal insufficiency
by decreasing steroidogenesis (ketoconazole), enhancing cortisol metabolism
(rifampin), or suppressing pituitary secretion of corticotropin due to their
intrinsic glucocorticoid activity (megestrol acetate).3, 7
In fact, Cushing syndrome induced by continuous administration of megestrol
acetate has been reported.8
DYSFUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
Subclinical functional abnormalities of the hypothalamic-pituitary-adrenal
(HPA) axis are much more prevalent than clinical manifestations of these disturbances.
Basal serum cortisol levels seem to be higher in patients infected with human
immunodeficiency virus (HIV) than in controls,9-10
with a negative linear correlation between CD4 cell counts and cortisol found
in some,11 but not all,12
studies. This elevation is usually associated with normal levels of 17-deoxysteroids
(ie, corticosterone, deoxycorticosterone, and 18-OH-deoxycorticosterone),
subnormal increase of both 17-deoxysteroids9
and cortisol9, 13-15
in response to cosyntropin, and an altered circadian rhythm of pituitary and
adrenocortical hormone secretion.10, 16
These patients also have a normal suppression of cortisol synthesis by dexamethasone,
and lower levels of corticotropin10 and dehydroepiandrosterone
(DHEA),10-12,17
an adrenal androgen that has a positive correlation with CD4 cell counts.11-12,17
Although basal aldosterone levels tend to be lower in HIV-infected individuals,
and both hyporeninemic and hyperreninemic hypoaldosteronism have been reported,18 response of plasma aldosterone to angiotensin III
infusion and postural stimulation was normal in a study9;
these findings have been interpreted as a preferential involvement of the
zona fasciculata over the zona glomerulosa.2-3,5
There are 2 case reports of primary aldosteronism in HIV-infected patients,19 perhaps mediated through a reninlike activity of
the HIV aspartic protease, but the causal relationship is far from clear.
PATHOGENESIS
Several pathogenic mechanisms have been proposed to explain the relative
hypercortisolemia present in untreated HIV-positive individuals. First, the
shift of steroid metabolism from aldosterone, DHEA, and 17-deoxysteroids to
cortisol may represent an adaptive response to stress.2-3,5-6
Second, the cortisol-binding globulin of HIV-infected patients shows a higher
number of binding sites compared with controls.20
Some authors have also found increased plasma concentrations of cortisol-binding
globulin associated with progression of the disease,21
whereas others found normal levels of cortisol-binding globulin in all HIV
disease stages.22 Third, the increased cortisol
synthesis in the absence of an increase in corticotropin suggests that some
nonpituitary factors derived from infected immune cells, such as interleukin
(IL)-1 and IL-6,10, 23-24
might directly stimulate the adrenal cortex. In patients with hypercortisolemia
and increased corticotropin levels, these abnormalities may result from a
stimulatory effect of cytokines (eg, interferon- , IL-1, IL-2,
and IL-6)25 or the HIV envelope protein gp12026 on the hypothalamic corticotropin-releasing hormone
release. However, patients with advanced HIV disease often have reduced or
blunted pituitary-adrenal responsiveness to corticotropin-releasing hormone
infusion,27 and cases of secondary adrenal
insufficiency with normal corticotropin stimulation tests have been described.28 Fourth, some patients with AIDS have a syndrome of
peripheral cortisol resistance due to acquired abnormalities of the glucocorticoid
receptor (GR), characterized by an increase in GR density and a decrease in
GR affinity for the substrate.29 These individuals
have a high-cortisol, low-corticotropin state with paradoxical Addisonian
features, but it is conceivable that a clinical spectrum exists, ranging from
subclinical alterations to overt adrenal failure. Finally, the HIV vpr gene
product has been reported to act as a GR coactivator in human lymphoid and
muscle-derived cell lines,30 which could result
in an enhanced effect of glucocorticoids on the target cells.
It has been suggested that this pattern of high cortisol and low DHEA
levels could induce a worsening in immune status by shifting the cytokine
production from the so-called TH1 or cellular-type response (interferon- ,
IL-2, and IL-12) to the TH2 or humoral-type response (IL-4, IL-5,
IL-6, and IL-10),31 a hallmark of HIV disease
progression. In fact, cortisol suppresses interferon- and IL-2 production,
favors IL-4 production, and stimulates programmed cell death (apoptosis).31 In this regard, cortisol-resistant AIDS patients
have a type 1 cytokine profile.32 In contrast,
DHEA appears to enhance immune function,12
probably by antagonizing some effects of cortisol on lymphocytes3;
indeed, both decreased concentrations of DHEA33-34
and increased cortisol/DHEA ratio35 are independent
predictors of progression to AIDS in some studies.
EFFECTS OF ANTIRETROVIRAL TREATMENT
How and whether highly active antiretroviral therapy modifies this profile
is largely unknown. Shortly after the release of protease inhibitors (PIs)
for clinical use, disorders in the body adipose tissue distribution, including
truncal obesity, visceral fat deposition, peripheral wasting, breast hypertrophy,
and enlargement of the dorsocervical pad ("buffalo hump"), often associated
with hyperlipidemia, hyperinsulinemia, and insulin resistance, were recognized.36-37 The similarities in their phenotypic
characteristics led some authors to use the term pseudo-Cushing
syndrome to denominate this clinical picture,38
but soon it became clear that, unlike the pseudo-Cushing syndrome seen in
alcoholism or severe depression, the vast majority of PI-treated patients
had normal or slightly elevated cortisol levels in the morning serum or in
the 24-hour urinary determinations, and showed normal dexamethasone suppression
tests.37, 39-42
Due to a number of clinical and laboratory features shared with classic generalized
lipodystrophic syndromes, these changes in fat distribution and metabolic
profile have been commonly referred to as antiretroviral-associated lipodystrophy.
Lately, lipodystrophy has been linked to antiretrovirals other than PIs (eg,
nucleoside-analogue reverse-transcriptase inhibitors) or even to the HIV infection
itself,43 and ascribed to a large array of
pathogenic mechanisms, such as inhibition by the PIs of several host-cell
proteins involved in lipid and carbohydrate metabolism,44
PI-induced subcutaneous adipocyte apoptosis,45
mitochondrial damage attributable to nucleoside-analogue reverse-transcriptase
inhibitors,46 and cytokine dysregulation in
the setting of immune recovery,47 among others.
In a cross-sectional study,48 the serum
steroid hormone concentrations of patients taking highly active antiretroviral
therapy who presented symptoms of lipodystrophy, according to a subjective
clinical score, were compared with those of nonlipodystrophic individuals.
Serum cortisol levels were elevated in patients compared with HIV-negative
controls, but no differences were found between individuals with or without
lipodystrophy. However, serum DHEA levels were significantly lower and cortisol/DHEA
ratio higher in patients with lipodystrophy, and cortisol/DHEA ratio correlated
positively with both dyslipidemia and the subjective clinical score. Christeff
et al48 speculated that the increased cortisol
and decreased DHEA concentrations were due to the effect of PIs on cytochrome
P450 isoforms involved in steroid metabolism, producing an imbalance between
lipolysis and lipogenesis that could account for the peripheral fat loss and
central fat accumulation.48
In another study,49 patients with antiretroviral-related
lipodystrophy, defined by changes in body shape and abdominal computed tomographic
scan findings, were compared with HIV-negative controls for multiple parameters
of the HPA axis; unfortunately, there was no group of untreated HIV-positive
individuals. Lipodystrophic patients showed normal values of serum cortisol
levels, cortisol response after corticotropin-releasing hormone stimulation,
cortisol-binding globulin concentration, and GR number and affinity, ruling
out hyperactivity of the HPA axis as a cause of lipodystrophy. However, basal
and corticotropin-releasing hormone–stimulated plasma corticotropin
concentration, as well as 24-hour urinary 17-OH-corticosteroid concentrations,
were significantly greater, whereas urinary free cortisol excretion was significantly
lower in patients than in controls. The authors hypothesized that 1 or more
of the antiretroviral drugs taken by these patients alter the metabolism of
cortisol by enhancing the renal 11-ketosteroid reductase activity or by partially
inhibiting the adrenal 11-hydroxylase. According to this study, lipodystrophy
cannot be attributed to hypercortisolism, and other possible mechanisms, such
as selective changes in the glucocorticoid sensitivity of different adipose
tissue depots, are worth exploring.49 We are
aware of a single study that compared serum cortisol levels in nucleoside-analogue
reverse-transcriptase inhibitor–treated and naive HIV-infected patients,
excluding therefore the effect of PI, and no difference was found between
the 2 groups.50
SUMMARY
Clinically evident adrenal insufficiency constitutes an uncommon event
in HIV infection. When present, it usually involves patients in advanced stages
of the infection, with cytomegalovirus disease or under treatment with drugs
that interfere with cortisol metabolism. Even in this setting, the rate of
adrenal insufficiency is probably lower than 5%. However, adrenal reserve
may be marginal, as suggested by a subnormal response to corticotropin stimulation
tests in many cases, and this diagnosis should be kept in mind whenever a
patient who undergoes stressing conditions, such as infection or trauma, develops
hypotension, profound weakness, untreatable fever, or electrolyte abnormalities.
Basal hypocortisolemia, even asymptomatic, should be treated with lifelong
substitutive glucocorticoids, but cortisol supplementation for only very stressing
situations (eg, surgery) is probably sufficient in patients with normal serum
cortisol levels and corticotropin hyporesponsiveness.
Hypercortisolemia without clinical features suggestive of Cushing syndrome
is frequent enough to not warrant a complete workup of adrenal disease. Antiretroviral-associated
lipodystrophy is usually distinguishable from Cushing syndrome on a clinical
basis. However, if lipodystrophy coexists with marked hypercortisolemia, measurement
of 24-hour free urinary cortisol level and a dexamethasone suppression test
would clarify this issue. The extent to which alterations in the HPA axis
are related to these patients' immune dysfunction, as well as the possible
changes induced by antiretroviral treatment, should be further investigated.
At present, no intervention for these subclinical abnormalities is likely
to be useful.
AUTHOR INFORMATION
Accepted for publication September 6, 2001.
Corresponding author and reprints: Julio Collazos, MD, Section of
Infectious Diseases, Hospital de Galdakao, 48960 Vizcaya, Spain.
From the Section of Infectious Diseases, Hospital de Galdakao, Vizcaya,
Spain.
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