The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Nancy Lee Harris, M.D., Editors
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 9-2017: A 27-Year-Old Woman

with Nausea, Vomiting, Confusion,
and Hyponatremia
Amulya Nagarur, M.D., Lloyd Axelrod, M.D., and Anand S. Dighe, M.D.​​

Pr e sen tat ion of C a se

Dr. Meaghan E. Colling (Medicine): A 27-year-old woman was admitted to this hospi- From the Departments of Medicine (A.N.,
tal because of nausea, vomiting, confusion, and hyponatremia. L.A.) and Pathology (A.S.D.), Massachu‑
setts General Hospital, and the Depart‑
The patient had been well until 1 week before admission, when she had nausea ments of Medicine (A.N., L.A.) and Pathol‑
and nonbloody, nonbilious emesis. She did not seek medical care, and her symptoms ogy (A.S.D.), Harvard Medical School
resolved after several hours. Two days before admission, she had nausea and sev- — both in Boston.

eral episodes of nonbloody, nonbilious emesis in the evening, after she had eaten N Engl J Med 2017;376:1159-67.
seafood. The day before admission, she had recurrent vomiting associated with DOI: 10.1056/NEJMcpc1616024
Copyright © 2017 Massachusetts Medical Society.
eating but was able to drink large amounts of water. Earlier that day, she had
normal interaction with friends and participated in sightseeing activities, including
long-distance walking. Early in the evening, she was noted to be slightly confused.
Later in the evening, her friend had difficulty arousing her from sleep, and she
was not able to follow directions or walk. She was carried to a car by two of her
traveling companions and taken to the emergency department of another hospital
for evaluation.
On examination, the temperature was 36.1°C, the blood pressure 94/64 mm Hg,
the pulse 100 beats per minute, the respiratory rate 16 breaths per minute, and the
oxygen saturation 100% while the patient was breathing ambient air. She was lethar-
gic and did not respond to questions or commands. Her speech was incoherent,
and she cried intermittently. The pupils were 8 mm in diameter and responsive to
light. She moved her arms and legs nonpurposefully. The remainder of the examina-
tion was normal. On repeat measurement, the blood pressure was 73/54 mm Hg.
Intravenous access was obtained, and 700 ml of normal saline was administered
intravenously before the laboratory test results were received.
The blood level of sodium was 104 mmol per liter (reference range, 135 to 145),
potassium 5.1 mmol per liter (reference range, 3.5 to 5.0), chloride 74 mmol per
liter (reference range, 98 to 107), carbon dioxide 19 mmol per liter (reference range,
24 to 32), and glucose 114 mg per deciliter (6.3 mmol per liter; reference range,
70 to 110 mg per deciliter [3.9 to 6.1 mmol per liter]) and the anion gap was 11 mmol

n engl j med 376;12 nejm.org  March 23, 2017 1159

The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Laboratory Data.*

total bilirubin, and lipase were normal, as were
the results of renal-function tests. A urine test for
Reference Range, On Presentation, human chorionic gonadotropin and a urine drug
Variable Adults† This Hospital
screen were negative. The blood level of salicylate
Hematocrit (%) 41–53 33.9 was less than 0.2 mg per deciliter (0.01 mmol
Hemoglobin (g/dl) 13.5–17.5 12.8 per liter; reference range, 2.8 to 20.0 mg per
White-cell count (per mm3) 4500–11,000 12.2 deciliter [0.20 to 1.44 mmol per liter]), and acet-
Differential count (%)
aminophen 0 μg per milliliter. Intensive care
was not available at the other hospital, and the
Neutrophils 40–70 71
patient was transferred to this hospital by heli-
Lymphocytes 22–44 21 copter. During the flight, the patient was agitated
Monocytes 4–11 7 and unable to lie still. Ketamine was adminis-
Eosinophils 0–8 0.3 tered, along with normal saline and hypertonic
Basophils 0–3 0.2 saline.
Platelet count (per mm3) 150,000–400,000 229,000 On evaluation in the emergency department of
this hospital, the patient was unable to answer
Red-cell count (per mm3) 4,500,000– 4,340,000
5,900,000 questions, and further history was obtained from
Mean corpuscular volume (fl) 80–100 78.1
her family. She was healthy and used an etono-
gestrel implant. She was a graduate student, re-
Mean corpuscular hemoglobin (pg) 26–34 29.5
sided in the southern United States, and was
Mean corpuscular hemoglobin 31–37 37.8
­concentration (g/dl)
visiting New England with friends. She drank
alcohol occasionally and did not smoke tobacco
Sodium (mmol/liter) 135–145 106
or use over-the-counter medications. Her mother
Potassium (mmol/liter) 3.4–5.0 4.5 had had breast cancer, but there was no family
Chloride (mmol/liter) 98–108 75 history of autoimmune disease.
Carbon dioxide (mmol/liter) 23–32 19 On examination, the temperature was 36.7°C,
Calcium (mg/dl) 8.5–10.5 8.3 the blood pressure 102/57 mm Hg, the pulse 92
Glucose (mg/dl) 70–110 97 beats per minute, the respiratory rate 12 breaths
per minute, and the oxygen saturation 100%
Urea nitrogen (mg/dl) 8–25 12
while the patient was breathing ambient air. She
Creatinine (mg/dl) 0.6–1.5 0.6
was somnolent and did not respond to com-
Lactic acid (mmol/liter) 0.5–2.2 0.9 mands, but she opened her eyes and withdrew in
Osmolality in random urine (mOsm/ 150–1150 740 response to painful stimuli. The pupils were
kg of water) round, equal, and reactive to light. The mucous
Sodium in random urine (mmol/liter) NA 158 membranes were moist. The skin turgor was
Thyrotropin (μU/ml) 0.4–5.0 2.27 normal. The first and second heart sounds were
normal, without murmurs. The breath sounds
* NA denotes not available. To convert the values for calcium to millimoles per
liter, multiply by 0.250. To convert the values for glucose to millimoles per liter,
were normal in both lungs, without wheezing or
multiply by 0.05551. To convert the values for urea nitrogen to millimoles per rhonchi. Bowel sounds were present, and the
liter, multiply by 0.357. To convert the values for creatinine to micromoles abdomen was soft, nondistended, and nontender
per liter, multiply by 88.4. To convert the values for lactic acid to milligrams
per deciliter, divide by 0.1110.
on palpation. The edge of the liver was not pal-
† Reference values are affected by many variables, including the patient popu­ pable. There was no splenomegaly. The arms
lation and the laboratory methods used. The ranges used at Massachusetts and legs had no edema. The remainder of the
General Hospital are for adults who are not pregnant and do not have medi‑
cal conditions that could affect the results. They may therefore not be appro‑
examination was normal.
priate for all patients. Additional laboratory studies were performed,
and the results are shown in Table 1. Computed
tomography (CT) of the head, performed with-
per liter (reference range, 3 to 15). The blood out the administration of intravenous contrast
level of aspartate aminotransferase was 37 U per material, revealed no acute intracranial hemor-
liter (reference range, 10 to 32), and alanine rhage, infarction, or intracranial mass lesions.
aminotransferase 37 U per liter (reference range, Chest radiography revealed low lung volumes
7 to 35). The blood levels of total protein, albumin, without focal consolidation or pulmonary edema,

1160 n engl j med 376;12 nejm.org  March 23, 2017

The New England Journal of Medicine

Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital
a normal cardiac silhouette, and no pleural effu-
sions.
The patient was admitted to the intensive care
unit (ICU), and diagnostic tests were performed.
Differ en t i a l Di agnosis
Dr. Amulya Nagarur: This young woman had traveled
to New England and presented with profound
hyponatremia and confusion. As far as we know,
she had been healthy until 1 week before admis-
sion, when she had several episodes of vomiting,
including one that occurred after she had eaten
seafood. She then had an acute and precipitous
decline in mental status. At the other hospital,
she had fluid-responsive hypotension. Laboratory
testing revealed severe hyponatremia with a high
urine osmolality and a high urine sodium level,
findings that appropriately led to admission to
the ICU.
Hyponatremia
Hyponatremia is the most profound and worri-
some feature of this patient’s presentation. In
cases such as this one, in which one laboratory
test result is markedly more abnormal than others,
an initial differential diagnosis can be construct-
ed by identifying the physiological disturbances
that can lead to the derangement. We can subse-
quently test our hypotheses by examining other
salient features of the presentation (Table 2) to
arrive at a diagnosis.
Volume Status
Central to evaluating this patient’s hyponatremia
is determining her volume status. Although re-
sults of a volume-status examination at the
other hospital are not provided, she had fluid-
responsive hypotension, which suggests initial
extracellular volume depletion. On transfer to this
hospital, she had normotension, moist mucous
membranes, and normal skin turgor, findings in-
dicative of euvolemia.
Urine studies performed after fluid resuscita-
tion revealed a high urine sodium level, which
reflects increased natriuresis. In the context of
this finding, the patient’s high urine osmolality
signifies increased circulating antidiuretic hor-
mone production. However, the interpretation of
the urine sodium level in this patient is limited
by the fact that she received intravenous saline
before urine was collected for this measurement.
n engl j med 376;12 nejm.org  March 23, 2017
The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
Table 2. Salient Features of This Patient’s Presentation.
Intermittent vomiting
Confusion and agitation
Hyponatremia with a high urine osmolality and a high
urine sodium level
Fluid-responsive hypotension
Mild, isolated hyperkalemia
Normal anion-gap metabolic acidosis
At this point, we can reframe the clinical pic-
ture as one of severe hyponatremia causing neu-
rologic abnormalities in a young woman with a
high urine sodium level and a high antidiuretic
hormone level despite restoration of euvolemia
after fluid resuscitation.
Hyponatremia with a High Urine Osmolality
and a High Urine Sodium Level
Given that the volume status in this patient is
dynamic, we can develop a differential diagnosis
for her hyponatremia that could explain both the
high circulating antidiuretic hormone level and
the high urine sodium level. This list is limited
and includes salt-wasting syndromes, drug or
toxin exposure, and hormonal alterations.1,2
Several diagnoses can be rapidly ruled out.
There is no evidence of a process that would
explain a cerebral salt-wasting syndrome, and a
CT scan of the head was unremarkable. There is
also no reason that she would have a salt-wasting
nephropathy. Pregnancy must be ruled out in a
young woman with a low blood sodium level,
but the degree of hyponatremia in pregnant
women is typically mild, and a pregnancy test
was negative. Although hypothyroidism can cause
hyponatremia, the exact mechanisms are un-
known; they may include increased antidiuretic
hormone release and disrupted sodium handling
in the renal tubules.3 In this patient, the thyro-
tropin level was normal. Finally, the syndrome of
inappropriate secretion of antidiuretic hormone
(SIADH) is a diagnosis of exclusion that I will con-
sider if an alternative diagnosis is not identified.
Diuretic Misuse and Hyponatremia
Given its association with eating disorders, di-
uretic misuse is an important consideration in
this young woman. Thiazides are the most com-
monly misused diuretics, and they are more likely
to cause hyponatremia than are loop diuretics,
1161
 The n e w e ng l a n d j o u r na l
owing to differences between the two drugs in
the renal tubular site of action. Thiazides pre-
vent sodium chloride reabsorption in the distal
convoluted tubule but leave the medullary con-
centration intact, whereas loop diuretics prevent
sodium, chloride, and potassium reabsorption in
the thick ascending limb of the loop of Henle.
Patients who are taking thiazides have relatively
preserved urinary concentrating ability and a nor-
mal response to antidiuretic hormone to retain
free water.4 Thiazide-induced hyponatremia typi-
cally develops within 1 or 2 weeks after initia-
tion of the diuretic and is common in elderly
women with a lean body mass. Patients with
thiazide-induced hyponatremia often appear to
have euvolemia.5 Given this patient’s age, sex,
volume status, and laboratory findings, surrepti-
tious diuretic use will continue to be included in
my differential diagnosis, and I will need to
further test this hypothesis as I consider other
features of this case.
Adrenal Insufficiency and Hyponatremia
Hyponatremia can occur in all forms of adrenal
insufficiency, although it tends to occur most
prominently in primary adrenal insufficiency
(Addison’s disease). Primary adrenal insufficiency
is caused by impairment of the adrenal glands,
whereas secondary adrenal insufficiency is the
result of corticotropin deficiency caused by either
pituitary or hypothalamic disease. In a patient
with primary adrenal insufficiency, a low blood
sodium level can stem from two major biochem-
ical pathways. The first pathway involves cortisol
deficiency. Cortisol deficiency disrupts the neg-
ative feedback loop that inhibits antidiuretic
hormone release and may result in increased
corticotropin-releasing hormone production, which
promotes antidiuretic hormone release.6-8 The
second pathway involves aldosterone deficiency.
Because aldosterone regulation is independent
of the hypothalamic–pituitary axis, aldosterone
deficiency is seen only in patients with primary
adrenal insufficiency. Decreased aldosterone
secretion causes several changes in the renal
tubules that affect sodium balance and result
in hyponatremia.9 Patients with adrenal insuf-
ficiency can have either hypovolemia or eu-
volemia. In assessing the cause of this patient’s
severe hyponatremia, adrenal insufficiency is a
compelling diagnosis that warrants further evalu-
ation.
1162 n engl j med 376;12 nejm.org  March 23, 2017
The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
3,4-Methylenedioxymethamphetamine (MDMA)
Use and Hyponatremia
The recreational drug MDMA (also known as
“ecstasy” or “molly”) is a synthetic serotonergic
amphetamine. Complications caused by use of
this drug include hypertension, tachycardia, rhab-
domyolysis, the serotonin syndrome, and severe
hyponatremia leading to coma or death. Pro-
posed mechanisms for MDMA-related hypona-
tremia include drug-induced antidiuretic hormone
release and excessive consumption of free water
for increased thirst and in an effort to prevent
hyperthermia. Patients who take MDMA typical­
ly have hypovolemia due to volume loss, although
some patients can present with euvolemia.10
MDMA-related hyponatremia and its associated
complications disproportionately affect premeno-
pausal women,11 and thus it is a possible diag-
nosis in this case. However, this patient would
have had hypertension in the presence of cate-
cholamine excess. Furthermore, MDMA should
be detectable in most urine drug screens for 1 to
3 days after use. Thus, even though this patient
is of the right demographic, was agitated, and
reportedly drank large amounts of water in the
days before her presentation, the negative drug
screen and absence of a history of recreational-
drug use point to an alternative diagnosis.
Iterative Hypothesis Testing
The two remaining diagnoses that have not been
ruled out are diuretic misuse and adrenal insuf-
ficiency. Do either of these diagnoses explain the
other salient features of this case, such as fluid-
responsive hypotension, mild isolated hyperkale-
mia, and normal anion-gap metabolic acidosis?
Diuretic-induced hypotension can be caused
by profound volume depletion, which would be
fluid-responsive. The blood-pressure derange-
ments seen in patients with adrenal insufficiency
may be caused by vasoplegia due to cortisol de-
ficiency or by volume depletion due to vomiting
(or aldosterone deficiency in patients with pri-
mary adrenal insufficiency).12 Although the cor-
nerstone of hypotension management in patients
with adrenal insufficiency is glucocorticoids and
fluid resuscitation, this patient’s hypotension
improved after fluid resuscitation alone, which
suggests that volume depletion had an influence
on her blood pressure that was disproportionate
to other factors. Although the presence of hypo-
tension has not helped to narrow my differential
 Case Records of the Massachuset ts Gener al Hospital
diagnosis, the mild hyperkalemia and normal
anion-gap metabolic acidosis are more infor-
mative.
Unless the patient was taking a potassium-
sparing agent, diuretic use would be expected to
cause hypokalemia and metabolic alkalosis due
to hyperaldosteronism, as well as possible con-
traction alkalosis. Primary adrenal insufficiency,
however, could cause this patient’s metabolic
derangements. Among patients with adrenal in-
sufficiency, hyperkalemia occurs only in those
with the primary form, owing to aldosterone
deficiency. This patient’s mild and isolated hyper-
kalemia may be attributed to her intercurrent
vomiting, which most likely prevented a more
marked increase in the potassium level. Hyper-
kalemia occurs in only 50 to 60% of patients
with primary adrenal insufficiency,13 perhaps
because of aldosterone-independent regulatory
mechanisms in the distal nephron that maintain
eukalemia.14 A diagnosis of primary adrenal in-
sufficiency would also explain this patient’s mild
normal anion-gap metabolic acidosis (despite the
vomiting), which would result from a hypoaldo-
steronism-associated renal tubular acidosis caus-
ing defective urinary acidification.
Primary Adrenal Insufficiency
Primary adrenal insufficiency is a rare entity,
and in high-income countries, autoimmune ad-
renalitis is the most common cause. The signs
and symptoms are nonspecific and include fa-
tigue, dizziness, gastrointestinal illness, salt crav-
ing, and hyperpigmentation. In this patient, we
could posit a unifying diagnosis of chronic auto-
immune primary adrenal insufficiency, perhaps
with decompensation, given the presence of a
gastrointestinal illness. However, some typical
features are missing.
Hyperpigmentation is almost always present
in chronic primary adrenal insufficiency, but skin
changes were not reported in this patient. Since
hyperpigmentation can be prominent in the
flexural areas, it may be easily missed on initial
assessment. There are also some case reports of
chronic primary adrenal insufficiency in which
hyperpigmentation is absent, most likely because
there are adequate resting levels of plasma cor-
tisol, which would prevent increased corticotro-
pin secretion and subsequent melanocyte stimu-
lation.15 Eosinophilia can also be a manifestation
of adrenal insufficiency, but only a fraction of
n engl j med 376;12 nejm.org  March 23, 2017
The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
patients with adrenal insufficiency have a periph-
eral eosinophilia, so its absence in this case is
not surprising.16
In summary, I suspect this patient has pri-
mary adrenal insufficiency, and my recommend-
ed diagnostic tests would be measurement of the
baseline corticotropin level and a cosyntropin
stimulation assay.
Dr. Meridale Baggett (Medicine): Dr. Colling,
what was your impression when you evaluated
this patient?
Dr. Colling: When we evaluated this young
woman, we were most concerned about her pro-
found hyponatremia. The team in the emergency
department thought that she might have adrenal
insufficiency and administered a dose of intra-
venous hydrocortisone. When she arrived in the
ICU, we considered the diagnosis of adrenal
insufficiency but were admittedly more focused
on other causes of hyponatremia, such as an
ingestion complicated by excess water intake or
SIADH as a diagnosis of exclusion.
Cl inic a l Di agnosis
Severe symptomatic hyponatremia due to an in-
gestion, the syndrome of inappropriate secretion
of antidiuretic hormone, or adrenal insufficiency.
Dr . A muly a Nag a rur’s Di agnosis
Primary adrenal insufficiency.
Pathol o gic a l Discussion
Dr. Anand S. Dighe: The initial diagnostic test in
this case was measurement of the blood total
cortisol level, which was performed at 4:30 a.m.,
shortly after the patient arrived in the emergency
department. The cortisol level was 7.2 μg per deci-
liter (198 nmol per liter; reference range, <10.0 μg
per deciliter [<276 nmol per liter]). The reference
range for cortisol is based on the ranges seen in
healthy patients and incorporates diurnal varia-
tion. However, in the presence of critical illness,
the cortisol level would be expected to be sub-
stantially elevated, because critical illness acti-
vates the hypothalamic–pituitary axis to stimu-
late corticotropin release from the pituitary
gland, which in turn promotes cortisol release
from the adrenal cortex. The low blood cortisol
level in the context of this patient’s critical illness
1163
 The n e w e ng l a n d j o u r na l
is thus presumptive evidence for a diagnosis of
adrenal insufficiency.
The cosyntropin stimulation test was used to
further evaluate this patient for adrenal insuffi-
ciency. Cosyntropin, an active fragment of cortico-
tropin, was administered intravenously; the blood
cortisol and corticotropin levels were measured
at baseline (before the injection), and the blood
cortisol level was again measured 30 minutes and
60 minutes after the injection. The baseline corti-
sol level was low (4.5 μg per deciliter [124 nmol
per liter]), and the baseline corticotropin level
was very high (896 pg per milliliter [197 pmol per
liter]; reference range, 6 to 76 pg per milliliter
[1 to 17 pmol per liter]). These results provided
strong evidence for the presence of primary ad-
renal insufficiency. This diagnosis was further
confirmed with the cortisol levels obtained at 30
minutes and 60 minutes (4.6 and 4.5 μg per deci-
liter [127 and 124 nmol per liter], respectively),
which showed no increase in the cortisol level in
response to the cosyntropin injection.
The laboratory abnormalities and clinical symp-
toms may be explained by a diagnosis of primary
adrenal insufficiency with decreased glucocorti-
coid and mineralocorticoid production (Fig. 1).
The cortisol deficiency causes a reduced stress
response and disrupts the negative feedback loop
that inhibits corticotropin production; these
effects lead to high levels of corticotropin and
other proopiomelanocortin-derived peptides and
may lead to an increase in skin pigmentation.
The cortisol deficiency also results in increased
antidiuretic hormone production, which leads to
hyponatremia. The lack of aldosterone further
contributes to hyponatremia and also results in
metabolic acidosis, mild hyperkalemia, and an
inappropriately high urine sodium level, findings
observed in this patient.
Discussion of M a nagemen t
Dr. Lloyd Axelrod: We had the advantage of meet-
ing this patient when her blood sodium level was
119 mmol per liter and she was more awake and
conversant. On the basis of the additional his-
tory she provided, we were able to characterize
her illness as chronic instead of acute; we asked
simple questions, such as “When is the last time
you felt completely well?” and “What was the
first thing that went wrong?” We found that this
1164 n engl j med 376;12 nejm.org  March 23, 2017
The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
lifelong runner had had months of fatigue that
had limited her ability to run. She reported weeks
of nausea. She had striking hyperpigmentation
both on areas that had been exposed to the sun
and on areas that had not — including the pal-
mar creases, the skin over the metacarpophalan-
geal joints, and the knees — that was most likely
missed on the initial examination. She had only
mild hyperkalemia, probably because she had
been vomiting.
After glucocorticoids became part of the treat-
ment for primary adrenal insufficiency, patients
began to have dramatic initial improvement with
fluid resuscitation, electrolyte repletion, and glu-
cocorticoids, and the hope was that such patients
would have a normal life expectancy; however,
they do not. Before 1930, primary adrenal insuf-
ficiency was almost invariably fatal.17 Patients
with adrenal insufficiency have a mortality rate
that is 2 or 3 times the normal rate, and they
have an increased incidence of certain cancers.18
Morbidity is considerable. Patients often have ab-
sences from school or work, frequent hospital-
izations, and alterations in work life, social life,
family life, and physical activity.19
There are still many aspects of the treatment
of adrenal insufficiency that remain challenging.
We often do not take into account the variations
in glucocorticoid sensitivity from patient to pa-
tient that are related to polymorphisms of the
glucocorticoid receptor.20 Some polymorphisms
cause decreased tissue sensitivity; others cause
increased sensitivity. In addition, we do not know
how to simulate the pulsatile secretion of corti-
cotropin and cortisol, with more and larger peaks
in the early morning and fewer and smaller
peaks later in the day. We also do not have a
precise way to individualize the initial dose of
the replacement glucocorticoid for each patient.
The average cortisol production rate is 14.5 mg
per day (range, 4.9 to 29.0).21 We usually start
with 15 to 25 mg per day in divided doses; we
tend to start on the lower side of that range.
How do we evaluate patients in the ambula-
tory setting after the initial diagnosis of primary
adrenal insufficiency? We look for overtreatment
or undertreatment with glucocorticoids or min-
eralocorticoids (Table 3). We also ensure that the
patient has adequate salt intake, which is some-
times difficult, given the emphasis on salt re-
striction in other circumstances (e.g., as part of
 Case Records of the Massachuset ts Gener al Hospital

HYPOTHALAMUS
FRONTAL
PVN
LOBE

PONS
Corticotropin-releasing
hormone
TEMPORAL LOBE

PITUITARY
GLAND

Corticotropin

Cortex
Cortisol deficiency
Reduced stress response (e.g., hypotension) Cortisol Medulla
Disruption of the negative feedback loop that
inhibits corticotropin production, leading to Aldosterone
a high corticotropin level, which causes
and androgens ADRENAL
increased skin pigmentation
GLAND
Hyponatremia caused by increased antidiuretic
hormone production (due to a low cortisol
level, a high corticotropin-releasing
hormone level, and hypotension)

Aldosterone deficiency
Hyponatremia (due to renal salt-wasting and
volume depletion, leading to increased
antidiuretic hormone secretion) KIDNEY
Hyperkalemia
Metabolic acidosis
High urine sodium level

Figure 1. Laboratory Abnormalities in Primary Adrenal Insufficiency.

In patients with primary adrenal insufficiency, deficiencies in the adrenal production of cortisol and aldosterone
may result in certain laboratory abnormalities. PVN denotes paraventricular nucleus of the hypothalamus.

a healthy diet or as part of treatment for hyper-

Table 3. Findings in Patients with Primary Adrenal Insufficiency That Suggest
tension or an edematous disorder). Overtreatment or Undertreatment with a Glucocorticoid or Mineralocorticoid.
We saw this patient 1 month after discharge,
and she was receiving treatment with hydrocorti- Treatment Overtreatment Undertreatment
sone (10 mg at 8 a.m. and 5 mg at 3 p.m. daily) Glucocorticoid Hypertension Fatigue
and fludrocortisone (0.1 mg daily). She had fa- (hydrocortisone) Round face Poor appetite
Mood or personality Nausea
tigue in the morning, and we suspected the first changes Hyperpigmentation
dose of hydrocortisone was being taken too late Insomnia
in the morning. Her hands were puffy; we attrib- Weight gain
uted this new finding to an excessive dose of Mineralocorticoid Hypertension Salt craving
fludrocortisone. In 1 month, easy bruising, mus- (fludrocortisone) Hypokalemia Dizziness
Weight gain Orthostatic hypotension
cle loss, and weight gain had developed; her Edema Hyperkalemia
weight was 6.4 kg (14 lb) higher than her base- Hyponatremia
line weight, which had been obtained before the

n engl j med 376;12 nejm.org March 23, 2017 1165

The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

onset of her illness, without any change in intake
or exercise. We attributed these findings to the
administration of too much hydrocortisone. We
instructed her to continue taking her current
morning dose of hydrocortisone (10 mg), but to
take it at 7 a.m. (on awakening), and to take a
reduced dose (2.5 mg) in the afternoon. We also
instructed her to omit fludrocortisone on two
nonconsecutive days each week (Wednesday and
Sunday).
The patient returned 3 months later, after tak-
ing a lengthy vacation abroad with her friends in
the summer heat, which can be a challenge for
a patient with primary adrenal insufficiency be-
cause of the salt and water loss. She was well.
All the symptoms that were present at her 1-month
visit had resolved in response to the seemingly
modest changes we made. She had taken 30-km
hikes without difficulty and had resumed run-
ning at her previous baseline level.
Dr. Jeffrey L. Greenwald (Medicine): Once you have
made the diagnosis of primary adrenal insuffi-
ciency, how do you differentiate between auto-
immune and other causes?
Dr. Axelrod: To start, one must determine
whether there is a personal or family history of
primary adrenal insufficiency or autoimmune dis-
ease. Has the patient emigrated from or traveled
to an area in which she may have contracted
tuberculosis, histoplasmosis, or another infec-
tious disease that may cause primary adrenal
insufficiency? Is the patient receiving anticoagu-
lant agents? Has she had any symptoms of bilat-
eral adrenal hemorrhage, including severe back
and abdominal pain beyond the pain she might
have with primary adrenal insufficiency? If the
patient comes from certain parts of the world,
the probability that she has contracted tubercu-
losis or another infectious disease can be quite
high. If the patient comes from the United States,
autoimmune disease is strongly favored as the
cause.
Since autoantibodies are commonly seen in
patients with autoimmune primary adrenal insuf-
ficiency, the next step is to obtain the results of a
21-hydroxylase antibody test, which was ordered
for this patient during hospitalization. After her
discharge, the test was reported as negative. What
do we make of this? The test is approximately
60 to 75% sensitive, so a positive test would in-
dicate an autoimmune cause, but a negative test
does not rule it out. Other antibodies have been
identified in patients with autoimmune primary
adrenal insufficiency, such as antibodies against
the steroid 17α-hydroxylase and side-chain cleav-
age enzymes. These tests are not widely available
and are not specific.
The question we then faced was whether to
order an abdominal CT scan that might show
findings of tuberculosis or another granuloma-
tous disease, cancer, bilateral adrenal hemor-
rhage, or some other rare infiltrative disorders.
We elected not to do that because there was no
evidence to suggest these diagnoses and the
patient was doing remarkably well. Although we
may further investigate these diagnoses in the
future, we decided to pursue a strategy of watch-
ful waiting.
Fina l Di agnosis
Primary adrenal insufficiency (Addison’s disease).
This case was presented at Medicine Case Conference.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. van der Hoek J, Hoorn EJ, de Jong GM,
Janssens EN, de Herder WW. Severe hypo-
natremia with high urine sodium and os-
molality. Clin Chem 2009;​55:​1905-8.
2. Adrogué HJ, Madias NE. Hyponatre-
mia. N Engl J Med 2000;​342:​1581-9.
3. Schrier RW, Goldberg JP. The physiol-
ogy of vasopressin release and the patho-
genesis of impaired water excretion in ad-
renal, thyroid, and edematous disorders.
Yale J Biol Med 1980;​53:​525-41.
4. Szatalowicz VL, Miller PD, Lacher JW,
Gordon JA, Schrier RW. Comparative ef-
fect of diuretics on renal water excretion
in hyponatraemic oedematous disorders.
Clin Sci (Lond) 1982;​62:​235-8.
5. Fichman MP, Vorherr H, Kleeman CR,
Telfer N. Diuretic-induced hyponatremia.
Ann Intern Med 1971;​75:​853-63.
6. Papanek PE, Raff H. Physiological in-
creases in cortisol inhibit basal vasopres-
sin release in conscious dogs. Am J Physi-
ol 1994;​266:​R1744-R1751.
7. Oelkers W. Hyponatremia and inap-
propriate secretion of vasopressin (antidi-
uretic hormone) in patients with hypopi-
tuitarism. N Engl J Med 1989;​321:​492-6.
8. Kalogeras KT, Nieman LK, Friedman
TC, et al. Inferior petrosal sinus sampling
in healthy subjects reveals a unilateral
corticotropin-releasing hormone-induced
arginine vasopressin release associated
with ipsilateral adrenocorticotropin se-
cretion. J Clin Invest 1996;​97:​2045-50.
9. Schrier RW. Body water homeostasis:
clinical disorders of urinary dilution and
concentration. J Am Soc Nephrol 2006;​17:​
1820-32.
10. Campbell GA, Rosner MH. The agony
of ecstasy: MDMA (3,4-methylenedioxy-
methamphetamine) and the kidney. Clin J
Am Soc Nephrol 2008;​3:​1852-60.

1166 n engl j med 376;12 nejm.org  March 23, 2017

The New England Journal of Medicine

Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital

11. Moritz ML, Kalantar-Zadeh K, Ayus
JC. Ecstacy-associated hyponatremia: why
are women at risk? Nephrol Dial Trans-
plant 2013;​28:​2206-9.
12. Oelkers W. Adrenal insufficiency.
N Engl J Med 1996;​335:​1206-12.
13. Soule S. Addison’s disease in Africa
— a teaching hospital experience. Clin
Endocrinol (Oxf) 1999;​50:​115-20.
14. Gagnon RF, Halperin ML. Possible
mechanisms to explain the absence of
hyperkalaemia in Addison’s disease.
Nephrol Dial Transplant 2001;​16:​1280-
4.
15. Fellows RE, Buchanan JR, Peterson
RE, Stokes PE. Chronic primary adrenal
insufficiency without hyperpigmentation.
N Engl J Med 1962;​267:​215-8.
16. Spry C. Eosinophilia in Addison’s dis-
ease. Yale J Biol Med 1976;​49:​411-3.
17. Thorn G. The diagnosis and treatment
of adrenal insufficiency. 2nd ed. Spring-
field, IL:​Charles C Thomas, 1951.
18. Bensing S, Brandt L, Tabaroj F, et al.
Increased death risk and altered cancer
incidence pattern in patients with isolated
or combined autoimmune primary adre-
nocortical insufficiency. Clin Endocrinol
(Oxf) 2008;​69:​697-704.
19. Forss M, Batcheller G, Skrtic S,
­Johannsson G. Current practice of gluco-
corticoid replacement therapy and patient-
perceived health outcomes in adrenal in-
sufficiency — a worldwide patient survey.
BMC Endocr Disord 2012;​12:​8.
20. Quax RA, Manenschijn L, Koper JW,
et al. Glucocorticoid sensitivity in health
and disease. Nat Rev Endocrinol 2013;​9:​
670-86.
21. Purnell JQ, Brandon DD, Isabelle LM,
Loriaux DL, Samuels MH. Association of
24-hour cortisol production rates, cortisol-
binding globulin, and plasma-free corti-
sol levels with body composition, leptin
levels, and aging in adult men and wom-
en. J Clin Endocrinol Metab 2004;​89:​281-
7.
Copyright © 2017 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

n engl j med 376;12 nejm.org  March 23, 2017 1167

The New England Journal of Medicine
Downloaded from nejm.org at The University Of Illinois on February 8, 2018. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.