Case Report

Laura E. Hinz, MD1; Gregory A. Kline, MD1; Valerian C. Dias, PhD2

ABSTRACT
Objective: To present a case of symptomatic autoimmune adrenal insufficiency with initially normal serum
cortisol and to caution about limitations of the current
diagnostic algorithm for adrenal insufficiency, which does
not reflect the pathophysiology of early disease.
Methods: We describe the clinical presentation and
relevant investigations of a patient ultimately found to
have Addisons disease, which is followed by a focused
review of the literature.
Results: A 41-year-old Caucasian woman with autoimmune hypothyroidism, premature ovarian failure, and
microscopic colitis presented with nausea, salt craving,
increased skin pigmentation, and postural hypotension.
Initial bloodwork revealed a normal morning cortisol of
level of 19.2 g/dL (normal, 7.2 to 25 g/dL) but an adrenocorticotropic hormone (ACTH) level 10 times normal,
at 513.6 pg/mL (normal, <52.5 pg/mL). Her potassium was
normal, but her aldosterone level was 4.12 ng/dL (normal,
12.3 to 62.5 ng/dL) and her renin activity was increased
(23.0 mg/dL/hour; normal, <6.0 mg/dL/hour). Six weeks
after initial presentation, she was found to have anti-adrenal antibodies. It was not until 10 weeks after her initial
symptomatic presentation that her morning cortisol level

Submitted for February 19, 2014

Accepted for publication June 15, 2014
From the 1Division of Endocrinology, and 2Division of Clinical Pathology,
University of Calgary, Calgary, Canada.
Address correspondence to Dr. Gregory A. Kline, Richmond Road Diagnostic
and Treatment Centre, 1820 Richmond Road SW, Calgary, AB T2T 5C7.
E-mail: gakline@ucalgary.ca.
Published as a Rapid Electronic Article in Press at http://www.endocrine
practice.org on August 6, 2014. DOI: 10.4158/EP14080.CR
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright 2014 AACE.

e176 ENDOCRINE PRACTICE Vol 20 No. 9 September 2014

was found to be subnormal and a formal diagnosis of adrenal insufficiency was made.
Conclusion: The present case and literature review
reveal that common diagnostic approaches will miss
patients with (possibly symptomatic) early adrenal insufficiency. We suggest that serum ACTH level testing or tests
of mineralocorticoid function be included in the initial
step of investigation for suspected primary adrenal insufficiency. (Endocr Pract. 2014;20:e176-e179)
Abbreviations:
AAs = adrenal autoantibodies; ACTH = adrenocorticotropic hormone; AD = Addisons disease; CBG =
cortisol-binding globulin
INTRODUCTION
Epidemiology of Addisons Disease

Disaster lurks when a patient has a life-threatening
disease that not only is rare but also presents with either
atypical or nonspecific symptoms and signs (1). Keljo and
Squires description of a 15-year-old girl with a delayed
diagnosis of adrenal insufficiency is an elegant summary of
the diagnostic difficulties of Addisons disease (AD). The
situation is further complicated when laboratory abnormalities do not evolve in the manner that common diagnostic
algorithms assume.

The prevalence of AD in developed nations has
increased over the last 30 years, from 39 to 60 cases per
million population in 1983 to current estimates of 143 cases
per million population (2-4). Approximately 1% of patients
with other autoimmune endocrine disorders develop AD
(3-5). Despite the increasing prevalence, the diagnosis of
AD often comes after considerable delay (5). Fifty percent
of patients experience symptoms for more than a year prior
to diagnosis due to nonspecific symptoms and an insidious
onset (6).

e177

Current Guidelines for Diagnosis

The values of serum cortisol that are required to diagnose AD vary according to author. Some suggest a combination of laboratory values, such as a simultaneously
low cortisol and elevated adrenocorticotropic hormone
(ACTH) levels (7,8). In general, the recommended diagnosis of AD varies from a single morning serum cortisol
level <3 g/dL to a combination of random cortisol <9.1
g/dL and 30-minute stimulated cortisol of <21.7 g/dL
(6,9). However, many of the tests may only have high diagnostic sensitivity for the patient presenting with late-stage
complete adrenal failure. Earlier, yet progressive phases in
disease evolution may require a different approach. The
ACTH stimulation test is now the gold standard in the diagnosis of complete primary adrenal insufficiency, but there
is debate as to appropriate interpretations or how various
stages in disease evolution may alter the results. In addition, it is known that ACTH stimulation may miss some
cases of partial adrenal insufficiency. A highly cited review
article suggests first ordering a morning serum cortisol test
(Fig. 1) (10). Values <3 g/dL are diagnostic of adrenal
insufficiency, whereas values >19 g/dL rule it out. If the
morning serum cortisol level falls between 3 and 19 g/

dL, the authors suggest a 250-g ACTH stimulation test.

Once the biochemical diagnosis of adrenal insufficiency is
made, one can then order imaging, ACTH levels, and tests
for adrenal autoantibodies (AAs).
CASE REPORT

A 41-year-old nonpregnant woman with autoimmune
hypothyroidism, premature ovarian failure, and microscopic colitis presented for assessment of low bone mass.
Written consent was obtained from the patient for the publication of this report. Further questioning revealed complaints of salt craving and increased skin pigmentation. Her
medications included Diclectin (doxylamine succinate and
pyridoxine hydrochloride, started 4 months prior to presentation) for chronic nausea, conjugated equine estrogens,
cyclic progesterone, levothyroxine, calcium, and vitamin
D. There was no exogenous glucocorticoid use. Physical
exam showed a body mass index of 16.7 kg/m2 and a postural rise in heart rate of 30 beats/minute, but there was
no classic pigmentation of skin folds or gingiva and no
hypotension or postural blood pressure drop. There was no
vitiligo.

Fig. 1. Biochemical diagnosis of adrenal insufficiency (10).

e178

Given her autoimmune history and symptoms, the
patient was presumed to have AD (possibly as part of autoimmune polyglandular syndrome) and was sent for initial
bloodwork. This revealed a surprisingly normal morning
serum cortisol level of 19.2 g/dL (normal, 7.2 to 25 g/
dL). No stimulation test was done because her basal cortisol level already exceeded the cut-off of 19 g/dL. Her
serum potassium level was normal, at 4.5 mEq/L. Thus,
AD was felt to be essentially excluded.

A few days later, the patients serum ACTH (drawn
concomitantly with the original serum cortisol) was
reported to be 10 times the upper limit of the reference
range (513.6 pg/mL; normal, <52.5 pg/mL). Investigation
of her mineralocorticoid function revealed a first morning,
upright, serum aldosterone level of 4.12 ng/dL (normal,
12.3 to 62.5 ng/dL), with concomitant high plasma renin
activity of 23 mg/dL/hour (normal, <6 mg/dL/hour on ad
libitum salt diet).

The elevated ACTH and low aldosterone levels with
high renin activity were in keeping with AD, but the normal cortisol level was unexpected. It was considered that
there might be an estrogen-induced elevation of cortisolbinding globulin (CBG) giving the falsely high total cortisol result. CBG testing was not available, but the patients
albumin level was normal, at 4.1 g/dL. Therefore, tests
of cortisol that are independent of CBG were ordered. A
24-hour urine free cortisol level was low-normal, at 20.6
g/24 hours (normal, 9.1 to 79.7 g/24 hours), and her first
morning salivary free cortisol level was <1.3 nmol/L (normal, 4.7 to 32.0 nmol/L), leading to the initial conclusion
that this was AD with falsely normal serum cortisol due to
estrogen-induced elevated CBG levels.

To confirm the hypothesis, a repeat morning serum total
cortisol was ordered, as were tests for AAs. However, this
result, drawn 10 weeks after initial bloodwork, revealed a
serum total cortisol level of <0.05 g/dL and positive tests
for anti-21-hydroxylase and anti-17-alpha-hydroxylase
antibodies. The fact that the patients serum total cortisol
level was low despite continued estrogen therapy argued
against elevated CBG as the sole explanation of the initially normal cortisol levels. During this time, her potassium level remained normal, with a maximum value of 5.1
mEq/L. As the patient remained clinically stable, no glucocorticoids were given until after all of the above testing
was completed.

A formal diagnosis of AD was made, and the patient
was started on hydrocortisone 10-mg twice a day and
fludrocortisone 0.05-mg daily. Four months after her first
visit, her symptoms had completely resolved, she had
gained 6 pounds, and she was normotensive.

Based on the definition of AD outlined by current
guidelines, we could have initially dismissed AD with our
patients first cortisol measurement, but ultimately, we
would have missed the correct diagnosis.

Preclinical AD and AAs

AD may proceed through a preclinical phase, with
laboratory abnormalities but no clinical symptoms. This
is analogous to autoimmune hypothyroidism, in which
elevation of thyroid-stimulating hormone levels is known
to precede clinical symptoms (11). It may be possible to
use these preclinical laboratory changes to make an earlier
diagnosis in high-risk individuals.

The prevalence of AAs in AD patients ranges from 70
to >90% (4,11). In contrast, <5% of the general population
are positive for AAs, and the most common AA is an antibody directed against 21-hydroxylase (11).
Progression from Antibodies to Symptoms

Betterle et al (2) were the first to suggest that, in the
context of AAs, adrenal dysfunction proceeds through 5
stages, with a drop in serum cortisol as the last stage (summarized in Table 1). First to appear are AAs (stage 0), followed by mineralocorticoid dysfunction (stage 1). Stage 2
is characterized by decreased response to ACTH stimulation, followed by a rise in ACTH level in stage 3 and finally
a drop in cortisol level in stage 4. The commonly used clinical algorithms frequently involve a test applicable to stage
4 (or possibly stage 2, depending on the definition), which
means that most cases of early adrenal dysfunction could
be missed.
Diagnostic Implications

Our patient fit the well-established pattern of a partial
loss of mineralocorticoid function before glucocorticoid
function, and the grossly elevated ACTH level heralded an
eventual drop in cortisol level. However, our patient experienced classic symptoms (stage 4) prior to developing a
diagnostically subnormal cortisol level.

A possible explanation is that our patients symptoms were mediated by early mineralocorticoid dysfunction, which was clearly documented by elevated renin
and low aldosterone levels. Despite these abnormalities,
the patients electrolytes were normal. Myers et al (12)
Table 1
Stages of Loss of Adrenal Function in
Adrenal AntibodyPositive Patientsa
Stage
0
1
2
3
4

Laboratory findings
Adrenal autoantibodies
Increased renin with low or normal aldosterone
Decreased response to ACTH stimulation
Persistently elevated ACTH
Low cortisol

Abbreviation: ACTH = adrenocorticotropic hormone.

a From Betterle et al (2).

e179

described a similar case of classic symptoms of primary

adrenal insufficiency with normal electrolytes. They postulated that a deficiency of 11-hydroxysteroid dehydrogenase 2 could enable cortisol to act on mineralocorticoid
receptors, thus maintaining sodium and potassium levels
within the normal range despite undetectable aldosterone.
It may also be that hyperkalemia is not seen until there is
a profound deficiency of aldosterone accompanying dehydration, something that may not occur in early stage AD.

A common feature of the various algorithms is the
role of serum ACTH in determining the pathophysiology
of adrenal insufficiency (i.e., primary adrenal or hypothalamic/pituitary). Thus measurement of ACTH is only performed after stimulation testing in the common algorithm
outlined in Figure 1. None of the algorithms routinely
incorporate mineralocorticoid testing, but two papers suggest that high renin may sometimes be useful (13,14).
Based on a growing body of literature concerning the natural history of AD, it becomes clear that these common
clinical approaches probably do not detect the early stages
of AD.

There are several other cases in the literature demonstrating a significantly delayed diagnosis owing to apparently normal cortisol tests. Kong (15) summarized 86
cases of confirmed AD and found 2 patients with a normal
response to ACTH stimulation at presentation. Butcher et
al (16) treated a 70-year-old man presenting with vomiting, tachycardia, hyponatremia, and hyperkalemia. He
had a normal 250-g ACTH stimulation test, with cortisol
increasing from 11.1 to 23.7 g/dL after 60 minutes but
an elevated random ACTH level of 220 pg/mL. He was
discharged home but presented 6 months later hypotensive
with a stimulated cortisol response of 10.1 g/dL. AA testing was negative. The authors suggested that the patient
had an initial mineralocorticoid deficiency (which would
explain the symptoms) but normal stimulation test, then
later proceeded to glucocorticoid deficiency (16).
CONCLUSION

In summary, we describe a case of autoimmune AD
that was unique because classic symptoms and signs preceded a drop in morning serum cortisol level. The case
illustrates a pitfall of current diagnostic algorithms that
focus on late-stage disease and total cortisol levels, since
the elevated ACTH was the only initial laboratory clue that
AD was present. We suggest using basal ACTH or measures of mineralocorticoid function to monitor for disease
progression in those at high risk, such as AA-positive
patients or those with other diseases known to cause progressive loss of adrenal function, such as X-linked adrenoleukodystrophy. Morning or random cortisol measurements may have very poor sensitivity for early stage AD,
and ACTH stimulation may not be helpful if cortisol is
already within normal range. Further studies are needed to

clarify the predictive power and role of mineralocorticoid

measures, but they may be useful when measured along
with ACTH and cortisol. A diagnosis of AD should not be
excluded based upon cortisol measures alone where there
is a high suspicion of disease.
DISCLOSURE

The authors have no multiplicity of interest to disclose.

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