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

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Eric S. Rosenberg, M.D., Editor
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Case 24-2019: A 39-Year-Old Woman with

Palpitations, Abdominal Pain, and Vomiting
Victor Chiappa, M.D., Mark A. Anderson, M.D., Conor D. Barrett, M.D.,
Nikolaos Stathatos, M.D., and Melis N. Anahtar, M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. Kelsey Hills-Evans (Medicine): A 39-year-old woman with cyclic vomiting syn- From the Departments of Medicine
drome and polysubstance use disorder was seen in the emergency department of (V.C., C.D.B., N.S.), Radiology (M.A.A.),
and Pathology (M.N.A.), Massachusetts
this hospital because of abdominal pain and vomiting. General Hospital, and the Departments
Eleven weeks before the current presentation, the patient was admitted to a of Medicine (V.C., C.D.B., N.S.), Radiology
hospital affiliated with this hospital because of intractable nausea and vomiting. (M.A.A.), and Pathology (M.N.A.), Har‑
vard Medical School — both in Boston.
She also had loose stools and pain in the right lower abdomen in the presence of
menses. Her symptoms were similar to those in previous episodes that had been N Engl J Med 2019;381:567-77.
DOI: 10.1056/NEJMcpc1900142
attributed to cyclic vomiting syndrome. Testing for Clostridium difficile toxin and Copyright © 2019 Massachusetts Medical Society.
fecal leukocytes was negative, as was an examination of the stool for ova and
parasites; a stool culture showed normal enteric flora. A urine toxicology screen
was positive for cocaine and opiates. Imaging studies were obtained.
Dr. Mark A. Anderson: Computed tomography (CT) of the abdomen and pelvis,
performed after the administration of intravenous contrast material, revealed bi-
lateral, punctate, nonobstructing renal calculi without hydronephrosis. There was
no evidence of bowel obstruction or acute inflammation in the abdomen or pelvis,
including the appendix. Normal premenopausal ovaries that contained functional
follicles were noted.
Dr. Hills-Evans: Ondansetron, hydromorphone, and intravenous fluids were ad-
ministered. Nausea, vomiting, and abdominal pain resolved. On the second hos-
pital day, the patient was able to eat normally and was discharged home.
One day before the current presentation, the patient inhaled smoke from an
electrical fire in her basement. After the smoke inhalation, pain in the left lower
abdomen and severe fatigue developed, but she did not seek medical evaluation.
On the day of the current presentation, menses began, and she awoke with nausea
and profuse vomiting of dark-brown fluid. Her temperature at home was 39.4°C.
During the next 12 hours, she had persistent nausea and repeated episodes of
vomiting. Weakness, light-headedness, and dizziness developed, and she presented
to the emergency department of this hospital for evaluation.

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 The n e w e ng l a n d j o u r na l
In the emergency department, the patient re-
ported ongoing nausea, vomiting, and pain in the
left lower abdomen. She reported recent use of
cannabinoids but no other drugs. Other medical
history included nephrolithiasis, asthma, allergic
rhinitis, chronic back pain, depression, gastro-
esophageal reflux disease, and severe dysmenor-
rhea. Past surgeries included shoulder replace-
ment, reduction mammoplasty, and removal of
an ovarian cyst. Medications included acetamino-
phen, intranasal fluticasone, inhaled fluticasone
propionate, albuterol, promethazine, ondansetron,
polyethylene glycol, and a multivitamin. She had
no known allergies. She did not know of any
medical problems in her family. Three years
before presentation, she had moved to New En­
gland from the northwestern United States after
marrying her husband. She had worked in the
pharmaceutical industry but had stopped work-
ing 3 months previously because of cyclic vomit-
ing syndrome. She did not use tobacco or alcohol.
She had a history of using cocaine, heroin,
marijuana, and 3,4-methylenedioxymethamphet-
amine (MDMA).
The temperature was 37.2°C, the pulse 165 beats
per minute, the blood pressure 152/70 mm Hg,
the respiratory rate 22 breaths per minute, and
the oxygen saturation 100% while the patient was
breathing ambient air. The weight was 52.5 kg; at
the affiliated hospital 11 weeks earlier, it had
been 59.3 kg. She was alert and oriented but had
a labile affect, with alternating periods of laugh-
ing and crying. Her gaze was noted to be in-
tense, and her speech was rapid, pressured, and
at times slurred. She was agitated and was seen
thrashing in her bed, pulling at equipment and
clothing. Her face and chest were erythematous,
and her skin was warm to the touch. A fine
tremor was noted in her hands, but no tongue
fasciculations were seen. She did not cooperate
during a neck examination. The heart sounds
were rapid and regular; a systolic ejection mur-
mur was noted. The abdomen was soft, with
normal bowel sounds and no distention; there
was tenderness on palpation of the left lower
abdomen.
Shortly after arrival in the emergency depart-
ment, the patient vomited “coffee grounds”
material. Twenty-five minutes later, the pulse in-
creased from 165 beats per minute to 210 beats
per minute.
Dr. Conor D. Barrett: A 12-lead electrocardio-
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of m e dic i n e
Figure 1 (facing page). Electrocardiograms and Rhythm
Strip.
A 12-lead electrocardiogram obtained on the current
presentation (Panel A) shows supraventricular tachy‑
cardia; the electrocardiogram also showed a long RP
interval (see Fig. S1 in the Supplementary Appendix,
available at NEJM.org). A rhythm strip obtained after the
administration of adenosine (Panel B) shows termina‑
tion of supraventricular tachycardia. After a ventricular
ectopic beat and a brief episode of atrial ectopy, sinus
tachycardia emerged. A subsequent 12-lead electrocar‑
diogram (Panel C) confirms ongoing sinus tachycardia.
gram obtained in the emergency department
showed supraventricular tachycardia with a long
RP interval (Fig. 1A, and Fig. S1 in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). Adenosine was admin-
istered intravenously, and after a ventricular ec-
topic beat and a brief episode of atrial ectopy,
sinus tachycardia emerged. It is important to
note that the last observed event on cessation of
this patient’s supraventricular tachycardia was a
QRS complex and not a P wave, and the previ-
ously observed P wave was of high-to-low atrial
activation, as seen in lead II (Fig. 1B). A subse-
quent 12-lead electrocardiogram confirmed on-
going sinus tachycardia (Fig. 1C).
Dr. Hills-Evans: The alkaline phosphatase level
was 165 U per liter (reference range, 27 to 129);
the results of other tests of liver function were
normal. A urine test for beta human chorionic
gonadotropin was negative. Urinalysis showed a
specific gravity of 1.013, with 2+ ketones and 2+
blood per high-power field, as well as 2 leuko-
cytes per high-power field (reference range, 0 to 4).
A urine toxicology screen was positive for fen-
tanyl, oxycodone, and cannabinoids. The results
of other laboratory tests are shown in Table 1.
Additional imaging studies were obtained.
Dr. Anderson: A chest radiograph showed clear
lungs, a normal cardiac silhouette, no pulmo-
nary edema, and no mediastinal or hilar lymph-
adenopathy. A CT scan of the abdomen and
pelvis, obtained after the administration of in-
travenous contrast material, showed bilateral,
punctate, nonobstructing renal calculi without
hydronephrosis. During the portal venous phase,
the liver attenuation level was 27 Hounsfield
units lower than the splenic attenuation level, a
finding consistent with hepatic steatosis. There
was no bowel obstruction or acute inflammation
 Case Records of the Massachuset ts Gener al Hospital

A Initial 12-Lead Electrocardiogram

I aVR V1 V4

II aVL V5

V2

III aVF V6

V3

II

B Rhythm Strip Obtained after the Administration of Adenosine

II

V5

C Subsequent 12-Lead Electrocardiogram

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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 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.*

11 Wk before
Presentation,
on Discharge, On Presentation,
Variable Reference Range† Affiliated Hospital This Hospital
Hematocrit (%) 34.9–44.5 27.9 36.9
Hemoglobin (g/dl) 12–15.5 9.5 12.7
White-cell count (per mm3) 4000–11,000 3730 10,030
Differential count (%)
Neutrophils 40–70 83.3 84.7
Immature granulocytes 0–0.9 0.3 0.4
Lymphocytes 22–44 11.6 9.5
Monocytes 4–11 4.7 5.4
Basophils 0–3 0.0 0.0
Eosinophils 0–8 0.1 0.0
Platelet count (per mm3) 135,000–400,000 209,000 413,000
Red-cell count (per mm3) 3,900,000–5,030,000 3,420,000 4,640,000
Mean corpuscular volume (fl) 80.0–100.0 81.6 79.5
Red-cell distribution width (%) 11.9–14.8 12.4 13.2
Prothrombin time (sec) 9.4–12.5 12.8
Prothrombin-time international 0.9–1.1 1.2
normalized ratio
Troponin T (ng/ml) 0–0.01 <0.01
Lactate (mmol/liter) 0.5–1.9 0.9 1.3
Sodium (mmol/liter) 136–145 144 139
Potassium (mmol/liter) 3.5–5.2 3.7 3.5
Chloride (mmol/liter) 95–106 108 90
Carbon dioxide (mmol/liter) 20–31 24 19
Anion gap (mmol/liter) 3–17 12 30
Urea nitrogen (mg/dl) 8–25 4 12
Creatinine (mg/dl) 0.60–1.50 0.31 0.51
Estimated glomerular filtration rate >60 >60 >60
(ml/min/1.73 m2)‡
Glucose (mg/dl) 70–110 108 94
Calcium (mg/dl) 8.7–10.4 8.7 9.4

* To convert the values for lactate to milligrams per deciliter, divide by 0.1110. To convert the values for urea nitrogen
to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
To convert the values for glucose to millimoles per liter, multiply by 0.05551.
† Reference values are affected by many variables, including the patient population and the laboratory methods used.
The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical con­
ditions that could affect the results. They may therefore not be appropriate for all patients.
‡ If the patient is black, multiply the results by 1.21.

in the abdomen or pelvis. The appendix ap- pantoprazole, fentanyl, and lorazepam were ad-
peared normal, and the ovaries were premeno- ministered. The patient was admitted to the in-
pausal, containing functional follicles (Fig. 2). tensive care unit (ICU), and a diagnostic test was
Dr. Hills-Evans: Intravenous fluids, ondansetron, performed.

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 Case Records of the Massachuset ts Gener al Hospital

A B

27 mm

C D

60 HU

87 HU

Figure 2. CT Scan of the Abdomen and Pelvis.

A CT scan of the abdomen and pelvis was obtained after the administration of intravenous contrast material. Coronal
reconstruction images (Panels A through D) show normal‑appearing premenopausal ovaries that contain functional
follicles (Panel A, arrows), as well as bilateral, punctate, nonobstructing renal calculi (Panels B and C, arrows) without
hydronephrosis (Panel D). An axial image (Panel E) shows that, during the portal venous phase, the liver attenuation
level is 27 Hounsfield units (HU) lower than the splenic attenuation level (see circles), a finding consistent with
hepatic steatosis.

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 The n e w e ng l a n d j o u r na l
Differ en t i a l Di agnosis
Dr. Victor Chiappa: This 39-year-old woman with
nausea, abdominal pain, and agitation had a
sudden episode of tachycardia with a narrow
QRS complex, with a heart rate of more than
200 beats per minute. My first step in construct-
ing a differential diagnosis is to define the pre-
cise type and anatomical origin of the tachycar-
dia in order to determine the mechanism of the
arrhythmia and hence the underlying disease
that is driving this process. In addition, to reach
a single unifying diagnosis, I need to consider
several other features of this patient’s presenta-
tion, including recurrent abdominal pain, pro-
found weight loss over an 11-week period, and
the development of odd behavior characterized
by agitation and pressured speech.
Approach to Supraventricular Tachycardia
The patient’s rhythm strip showed rapid tachy-
cardia with a narrow QRS complex, a finding
consistent with supraventricular tachycardia. The
regular rhythm makes atrial fibrillation and
multifocal atrial tachycardia unlikely. The abrupt
onset makes sinus tachycardia unlikely. In sinus
tachycardia, I would expect there to be a ramp-
up phase, as opposed to an abrupt escalation of
the heart rate to more than 200 beats per min-
ute. I suspect that this patient’s supraventricular
tachycardia with regular rhythm is one of three
types: atrioventricular nodal reentrant tachycar-
dia; atrioventricular reentrant tachycardia, which
is due to retrograde conduction through an ac-
cessory pathway; or focal atrial tachycardia.
Distinguishing among these types requires
assessment of the P waves, but at high ventricu-
lar rates such as the rate seen in this patient, the
P waves can be obscured by, buried within, or
superimposed on the T waves or QRS complexes.
This patient received adenosine to slow the ven-
tricular rate and unmask any P waves in order to
allow assessment of their rate, morphologic fea-
tures, and position in the cardiac cycle. However,
the administration of adenosine also terminated
the supraventricular tachycardia, which can hap-
pen in patients with atrioventricular nodal re-
entrant tachycardia, atrioventricular reentrant
tachycardia, and some forms of atrial tachycar-
dia. Before it terminated the supraventricular
tachycardia, the administration of adenosine
resulted in slowing of the ventricular rate and
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of m e dic i n e
revealed what I suspect are P waves at the end of
the T wave, with a long RP interval. Overall, I
think atrial tachycardia is the most likely mech-
anism of her supraventricular tachycardia.
Regardless of the specific mechanism, I know
that this patient is susceptible to supraventricu-
lar tachycardia. What triggered the supraven-
tricular tachycardia in this case?
Underlying Causes of Supraventricular
Tachycardia
Ischemia, electrolyte abnormalities, or changes
in heart rate, autonomic tone, or the pH of local
tissue can lead to premature atrial or ventricular
beats, which in turn can trigger supraventricular
tachycardia in susceptible patients. Cardiac ische­
mia is unlikely in this patient, since she is young
and did not have chest pain, ischemic changes
on electrocardiography, or elevated troponin
levels. Despite her history of cyclic vomiting
syndrome and recent nausea and vomiting, the
results of laboratory tests did not show clini-
cally significant electrolyte or pH abnormalities.
An underlying increase in heart rate appears to
be the most likely trigger of supraventricular
tachycardia in this patient. The initial vital signs
were indicative of tachycardia, and after the ad-
ministration of adenosine, the supraventricular
tachycardia resolved, revealing underlying sinus
tachycardia.
Underlying Causes of Sinus Tachycardia
Common drivers of sinus tachycardia to consid-
er in this patient include pain, infection, bleed-
ing, and hypovolemia. She reported abdominal
pain and had tenderness on palpation, but her
tachycardia appears to be out of proportion to
the reported abdominal pain and to the findings
on clinical examination and imaging studies.
Although pain can cause a clinically significant
rise in the heart rate, the pain she described
would be unlikely to result in this degree of
tachycardia.
Tachycardia related to the onset of an infec-
tion, such as sepsis and shock due to bowel
perforation or bowel ischemia, is unlikely in the
absence of hypotension, localizing signs on phys-
ical examination, leukocytosis, and persistent
fever. Furthermore, chest radiography and CT of
the abdomen did not reveal a source of infec-
tion, and an intraabdominal process would not
explain the other features of her presentation,
 Case Records of the Massachuset ts Gener al Hospital
including agitation, pressured speech, and some-
what odd behavior.
The normal response to profound hypovole-
mia due to bleeding or dehydration is tachycar-
dia; the heart rate increases to compensate and
to maintain hemodynamic stability. This patient
had no history of bleeding and the hematocrit
was above the baseline level, so an acute bleed is
unlikely to be the driver of her tachycardia. Hypo-
volemia due to vomiting and dehydration is pos-
sible, but the normal sodium and creatinine
levels and only mildly elevated lactate level argue
against the presence of hypovolemia severe
enough to lead to this degree of tachycardia.
Up to this point, I have focused on identify-
ing the cause of this patient’s tachycardia. How-
ever, to arrive at the correct diagnosis, I need to
consider several other features of this case, in-
cluding abdominal pain, reported fever, weight
loss, and agitation.
Nephrolithiasis
This patient had a history of nephrolithiasis.
Could her presentation be due to the passage of
a kidney stone? The pain associated with a kid-
ney stone can certainly be severe and, depending
on the location of the stone, can sometimes
mimic acute abdominal pain. When a stone
causes obstruction and hydronephrosis, urosep-
sis may develop and vomiting can be a promi-
nent presenting feature. Several aspects of this
patient’s presentation are suggestive of this di-
agnosis. First, she had a known history of neph-
rolithiasis, with nonobstructing kidney stones
visualized on multiple CT scans. Second, she
had 2+ blood in her urine, which could be due
to menses but is also consistent with the pas-
sage of a kidney stone. However, the imaging
studies did not show evidence of urinary ob-
struction; there was no hydronephrosis. There-
fore, the diagnosis of nephrolithiasis as the
cause of her tachycardia and other presenting
features is unlikely.
Substance Use
The patient had a history of using multiple sub-
stances, including cocaine, MDMA, opiates, and
tetrahydrocannabinol. Her presenting symptoms
of tachycardia and agitation could be consistent
with intoxication from either cocaine or MDMA,
but a toxicology screen did not detect these sub-
stances. Withdrawal from opiates could explain
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tachycardia, agitation, nausea, vomiting, and ab-
dominal pain. However, she did not have dia-
phoresis, yawning, goose bumps, or dilated pu-
pils, findings consistent with opiate withdrawal.
The toxicology screen was positive for fentanyl
and cannabinoids, either of which could have
been laced with an unknown substance that
could not be detected by means of current toxi-
cologic testing methods. Although I cannot rule
out the possibility that intoxication or with-
drawal led to tachycardia, I want to avoid an-
choring on her history of substance use disorder
in order to avoid premature narrowing of the
differential diagnosis.
Serotonin Syndrome
Serotonin syndrome is an important consider-
ation in this patient, since she reportedly had a
fever while at home and had a tremor and agita-
tion. Opiates, ondansetron, MDMA, and cocaine
have all been implicated in this syndrome.1 How-
ever, even if I assume that she had taken a sero-
tonergic agent, according to the Hunter criteria
(a decision rule developed to assist in the diag-
nosis of serotonin syndrome), the absence of
hyperreflexia and of clonus rules out serotonin
syndrome.2
Ovarian Teratoma
Although the patient was alert and oriented, her
speech was rapid and pressured and her affect
was labile. Also, she had lost approximately 7 kg
of body weight since the initial hospital admis-
sion, which took place 11 weeks before her cur-
rent presentation. The combination of weight
loss, abdominal pain, and behavioral change in
a 39-year-old woman arouses concerns about
cancer, possibly an ovarian teratoma causing
limbic encephalitis. However, this diagnosis
would not explain the tachycardia, and although
the patient had a known history of cystic disease
of the ovaries, the presence of a teratoma or
another mass lesion of the ovaries was ruled out
on imaging studies.
Hyperthyroidism
The combination of tachycardia3,4 and weight
loss,5 the two most prominent features of this
patient’s presentation, suggests hyperthyroid-
ism. When I consider the weight loss and tachy-
cardia in the context of agitation, vomiting,6 and
neuropsychiatric signs and symptoms7 — such
573
 The n e w e ng l a n d j o u r na l
as a labile affect, intense gaze, pressured speech,
fine tremor, and skin erythema and warmth —
the diagnosis of hyperthyroidism rises to the top
of my differential diagnosis. Furthermore, supra-
ventricular tachycardia triggered by underlying
tachycardia3,4 occurring in the context of thyro-
toxicosis would provide a single unifying diag-
nosis in this case. In geographic regions in
which patients typically have sufficient iodine
intake, hyperthyroidism is most commonly due
to either Graves’ disease or nodular thyroid dis-
ease. To establish the diagnosis, I would per-
form thyroid-function tests as well as antibody
tests for autoimmune thyroid disease. If these
tests are not diagnostic of Graves’ disease, ad-
ditional studies to look for other, less likely
causes of hyperthyroidism may be needed.
Dr . V ic t or Chi a ppa’s Di agnosis
Hyperthyroidism.
Pathol o gic a l Discussion
Dr. Melis N. Anahtar: Thyroid-function tests were
performed. The blood thyrotropin level was un-
detectable, and the free thyroxine (T4) and total
triiodothyronine (T3) levels were both above the
upper limit of quantification; these findings are
consistent with the diagnosis of overt hyperthy-
roidism. To evaluate for autoimmune thyroid
disease, testing for antibodies to thyroid peroxi-
dase and thyrotropin receptors was performed.
The thyroid peroxidase antibody level was nor-
mal, and the thyrotropin receptor antibody level
was 29 U per liter (reference range, 0 to 1.75).
The thyrotropin receptor antibody assay, which
detects any antibody that binds within a region
of the thyrotropin receptor, has approximately
97% sensitivity and specificity for untreated
Graves’ disease.8,9
Additional testing was performed to specifi-
cally determine the presence of thyroid-stimulat-
ing immunoglobulin (TSI), a type of thyrotropin
receptor antibody that directly activates thyro-
tropin receptor signaling and is thought to cause
the clinical manifestations of Graves’ disease
(Fig. 3). TSI is measured with a sensitive bio­
assay that uses an engineered cell line that ex-
presses a human thyrotropin receptor and a cyclic
adenosine monophosphate–induced luciferase
reporter gene.9 A TSI index of more than 1.8
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of m e dic i n e
(reference range, ≤1.3) has nearly 100% sensitiv-
ity and specificity for untreated Graves’ disease.
This patient’s TSI index was 7.5, confirming the
diagnosis of Graves’ disease. This degree of eleva-
tion of the TSI index is associated with a poor
response to treatment with antithyroid drugs, an
increased risk of fetal thyrotoxicosis if the pa-
tient were to become pregnant, and an increased
risk of Graves’ ophthalmopathy.10
Dr. Anderson: In addition to thyroid-specific
laboratory tests, ultrasonography of the thyroid
was performed to help distinguish diffuse thy-
roiditis from a hyperfunctioning nodule or multi-
nodular goiter. On transverse and sagittal gray-
scale and color Doppler ultrasound images of
the thyroid, the sagittal dimension was at the
upper limit of the normal range and there was
mildly heterogeneous parenchymal echotexture
(Fig. 4). On color Doppler images, there was
marked hyperemia throughout the entire gland,
a pattern characteristic of Graves’ disease and
referred to as the “inferno sign.”11 This pattern
of Doppler flow has been shown to have high
specificity (88 to 95%) and sensitivity (95%) for
Graves’ disease, and the peak systolic velocity is
higher in patients with Graves’ disease than in
patients with other causes of thyroiditis.12-16 The
adjacent nonthyroid structures did not show ran-
dom or artifactual Doppler flow. The heteroge-
neity and prominent size of the gland are non-
specific findings but are consistent with a
diagnosis of Graves’ disease.
Discussion of M a nagemen t
Dr. Nikolaos Stathatos: This patient met the criteria
for severe thyrotoxicosis (thyroid storm),17 a diag-
nosis associated with a mortality of up to 30%.
Because of the severity of her presentation with
neurologic, cardiovascular, and gastrointestinal
symptoms, she was admitted to the ICU for fur-
ther treatment. In addition to receiving support-
ive care with beta-blockers and intravenous fluids,
she was initially treated with propylthiouracil,
which was transitioned to methimazole within
24 hours. She responded quickly to treatment,
with improvement in her clinical symptoms and
in the results on thyroid-function tests within
the first 4 to 5 days.
The patient’s quick response was probably re-
lated not only to the establishment of the diag-
nosis of hyperthyroidism and to the initiation of
 Case Records of the Massachuset ts Gener al Hospital

Thyrotropin receptor activation causes

unregulated T4 and T3 production

T H Y R O ID
E P IT H E L IA L C E L L

+
AC
Autoreactive B cells Gs
produce antibodies T H Y R O ID ATP cAMP
that stimulate the
thyrotropin receptors T3
Thyrotropin T4
receptor
+

Increased free
T4 and T3

Tachycardia, palpitations, Nausea, vomiting, Anxiety Marked suppression of thyrotropin

and weight loss and abdominal pain and agitation release from the anterior pituitary gland

Figure 3. Production of Thyroid-Stimulating Immunoglobulin and Clinical Manifestations of Graves’ Disease.

Thyrotropin receptor antibodies known as thyroid‑stimulating immunoglobulins directly activate thyrotropin receptor signaling and cause
the clinical manifestations of Graves’ disease. The plus signs indicate stimulation, and the minus sign inhibition. AC denotes adenylyl
cyclase, cAMP cyclic AMP, and GS stimulatory G protein.

antithyroid medications but also to the adminis-
tration of iodinated contrast material for ab-
dominal CT. The large iodine load probably in-
duced a Wolff–Chaikoff effect (a decrease in
thyroid hormone production due to the adminis-
tration of a large amount of iodine, such as that
given during imaging studies)18 in her thyroid
gland, resulting in the acute shutdown of thy-
roid hormone synthesis. Then, the initiation of
antithyroid medications provided long-term con-
trol of the hyperthyroidism. In contrast, during
her admission 11 weeks earlier, after she pre-
sented with similar symptoms that were proba-
bly related to undiagnosed hyperthyroidism, she
received a large iodine load through the admin-
istration of intravenous contrast material for
abdominal CT, which probably induced a similar
effect. However, because she did not receive anti-
thyroid medications after admission, her thyroid
gland probably escaped the short-term suppres-
sive effect of the iodine load and severe hyper-
thyroidism again developed, leading to the cur-
rent presentation and hospitalization.
During the current hospitalization, the pa-

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

A B

C D

E F

Figure 4. Ultrasound Images of the Thyroid.

On grayscale sagittal images (Panels A and C) and a grayscale transverse image (Panel E), the dimensions are at the
upper limit of the normal range and there is mildly heterogeneous parenchymal echotexture. On corresponding color
Doppler images (Panels B, D, and F), there is marked hyperemia throughout the entire gland, a pattern characteris‑
tic of Graves’ disease and referred to as the “inferno sign.” The adjacent nonthyroid structures show no random or
artifactual Doppler flow.

tient responded well to treatment and was dis-
charged home; she had follow-up visits with her
endocrinologist. However, the results of thyroid-
function tests performed a few months later
were suggestive of poor adherence to treatment,
with high free T4 and total T3 levels. The patient
was subsequently lost to follow-up.
A physician: What type of supraventricular
tachycardia did the treating physicians think this
patient had?
Dr. Barrett: Atrial tachycardia was thought to
be most likely. The P-wave morphologic features
and timing were not consistent with atrioven-
tricular nodal reentrant tachycardia. Although
termination of supraventricular tachycardia in
an accessory pathway with adenosine is possible,
it is far more likely that this patient’s supraven-
tricular tachycardia was an adenosine-sensitive
atrial tachycardia. In such an atrial tachycardia,
adenosine terminates the supraventricular tachy-

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 Case Records of the Massachuset ts Gener al Hospital

cardia in the atrial tachycardia focus; the last
observed beat conducts to the ventricles, produc-
ing a QRS complex with no subsequent focal
atrial ectopic activity, which was responsible for
the supraventricular tachycardia.
A physician: Was the patient treated with gluco-
corticoids when she presented with thyroid storm?
Dr. Stathatos: Although glucocorticoids reduce
the peripheral conversion of T4 to T3 and can be
used in the treatment of thyroid storm, gluco-
corticoids were not used in this patient because
she was hemodynamically stable and responded
quickly to treatment with propylthiouracil.
A physician: Do you think there is a connection
between the patient’s history of nephrolithiasis
and her diagnosis of hyperthyroidism?
Dr. Stathatos: Hyperthyroidism is a well-known
cause of hypercalcemia. This is particularly rel-
evant in patients with biochemically severe hyper-
thyroidism. However, this patient did not have
hypercalcemia at any time during this hospital-
ization. There is no known association between
nephrolithiasis and hyperthyroidism, even in
the context of hyperthyroidism-induced hyper-
calcemia.
Fina l Di agnosis
Hyperthyroidism due to Graves’ disease.
This case was presented at the Medical Case Conference.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Iqbal MM, Basil MJ, Kaplan J, Iqbal
MT. Overview of serotonin syndrome. Ann
Clin Psychiatry 2012;​24:​310-8.
2. Dunkley EJ, Isbister GK, Sibbritt D,
Dawson AH, Whyte IM. The Hunter Sero-
tonin Toxicity Criteria: simple and accu-
rate diagnostic decision rules for serotonin
toxicity. QJM 2003;​96:​635-42.
3. Klein I, Danzi S. Thyroid disease and
the heart. Circulation 2007;​116:​1725-35.
4. Wustmann K, Kucera JP, Zanchi A,
et al. Activation of electrical triggers of
atrial fibrillation in hyperthyroidism.
J Clin Endocrinol Metab 2008;​93:​2104-8.
5. Nordyke RA, Gilbert FI Jr, Harada AS.
Graves’ disease: influence of age on clini-
cal findings. Arch Intern Med 1988;​148:​
626-31.
6. Rosenthal FD, Jones C, Lewis SI. Thy-
rotoxic vomiting. Br Med J 1976;​2:​209-
11.
7. Stern RA, Robinson B, Thorner AR,
Arruda JE, Prohaska ML, Prange AJ Jr. A sur-
vey study of neuropsychiatric complaints in
patients with Graves’ disease. J Neuropsy-
chiatry Clin Neurosci 1996;​8:​181-5.
8. Schott M, Hermsen D, Broecker-Preuss
M, et al. Clinical value of the first auto-
mated TSH receptor autoantibody assay
for the diagnosis of Graves’ disease (GD):
an international multicentre trial. Clin En-
docrinol (Oxf) 2009;​71:​566-73.
9. Thyretain TSI Reporter BioAssay.
Athens, OH:​Diagnostic HYBRIDS, 2009
(package insert).
10. Barbesino G, Tomer Y. Clinical utility
of TSH receptor antibodies. J Clin Endo-
crinol Metab 2013;​98:​2247-55.
11. Ralls PW, Mayekawa DS, Lee KP, et al.
Color-flow Doppler sonography in Graves
disease: “thyroid inferno.” AJR Am J
Roentgenol 1988;​150:​781-4.
12. Aldasouqi S, Sheikh A, Klosterman P.
Doppler ultrasonography in the diagnosis
of Graves disease: a non-invasive, widely
under-utilized diagnostic tool. Ann Saudi
Med 2009;​29:​323-4.
13. Arslan H, Unal O, Algün E, Harman
M, Sakarya ME. Power Doppler sonogra-
phy in the diagnosis of Graves’ disease.
Eur J Ultrasound 2000;​11:​117-22.
14. Cappelli C, Pirola I, De Martino E,
et al. The role of imaging in Graves’ dis-
ease: a cost-effectiveness analysis. Eur J
Radiol 2008;​65:​99-103.
15. Chaudhary V, Bano S. Thyroid ultra-
sound. Indian J Endocrinol Metab 2013;​
17:​219-27.
16. Saleh A, Cohnen M, Fürst G, Gode-
hardt E, Mödder U, Feldkamp J. Differen-
tial diagnosis of hyperthyroidism: Doppler
sonographic quantification of thyroid
blood flow distinguishes between Graves’
disease and diffuse toxic goiter. Exp Clin
Endocrinol Diabetes 2002;​110:​32-6.
17. Burch HB, Wartofsky L. Life-threaten-
ing thyrotoxicosis: thyroid storm. Endocri-
nol Metab Clin North Am 1993;​22:​263-77.
18. Markou K, Georgopoulos N, Kyriazo-
poulou V, Vagenakis AG. Iodine-induced
hypothyroidism. Thyroid 2001;​11:​501-10.
Copyright © 2019 Massachusetts Medical Society.

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