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Original Article

Geanina Popoveniuc, MD1,2; Tanu Chandra, MD3,4; Anchal Sud, MD1;


Meeta Sharma, MD1; Marc R. Blackman, MD2,4,5; Kenneth D. Burman, MD1;
Mihriye Mete, PhD6,7; Sameer Desale, MS6,7; Leonard Wartofsky, MD1

ABSTRACT MC patients had a score of 60, whereas 6 of 7 non-MC


patients had scores of 25 to 50. A total of 16 of 22 MC
Objective: To develop diagnostic criteria for myx- patients whose data were retrieved from the literature had
edema coma (MC), a decompensated state of extreme a score 60, and 6 of 22 of these patients scored between
hypothyroidism with a high mortality rate if untreated, in 45 and 55. The odds ratio per each score unit increase as a
order to facilitate its early recognition and treatment. continuum was 1.09 (95% confidence interval [CI], 1.01 to
Methods: The frequencies of characteristics associ- 1.16; P = .019); a score of 60 identified coma, with an odds
ated with MC were assessed retrospectively in patients ratio of 1.22. The area under the ROC curve was 0.88 (95%
from our institutions in order to derive a semiquantitative CI, 0.65 to 1.00), and the score of 60 had 100% sensitivity
diagnostic point scale that was further applied on selected and 85.71% specificity.
patients whose data were retrieved from the literature. Conclusion: A score 60 in the proposed scoring
Logistic regression analysis was used to test the predic- system is potentially diagnostic for MC, whereas scores
tive power of the score. Receiver operating characteristic between 45 and 59 could classify patients at risk for MC.
(ROC) curve analysis was performed to test the discrimi- (Endocr Pract. 2014;20:808-817)
native power of the score.
Results: Of the 21 patients examined, 7 were reclas- Abbreviations:
sified as not having MC (non-MC), and they were used APACHE II = Acute Physiology and Chronic Health
as controls. The scoring system included a composite of Evaluation; CI = confidence interval; EKG = electro-
alterations of thermoregulatory, central nervous, cardio- cardiogram; MC = myxedema coma; OR = odds ratio;
vascular, gastrointestinal, and metabolic systems, and ROC = receiver operating characteristic; TSH = thy-
presence or absence of a precipitating event. All 14 of our roid-stimulating hormone; T3 = triiodothyronine; T4 =
thyroxine

INTRODUCTION
Submitted for publication November 6, 2013
Accepted for publication January 16, 2014
From the 1Division of Endocrinology, Department of Medicine, MedStar Myxedema coma (MC) is a rare form of extreme
Washington Hospital Center, Washington DC, 2Division of Endocrinology, hypothyroidism, with a mortality rate that may approach
Department of Medicine, Georgetown University Hospital, Washington
DC, 3Division of Endocrinology, Department of Medicine, Veterans Affairs 60% (1). The condition represents a state of decompen-
Medical Center, Washington DC, 4Division of Endocrinology, Department sated hypothyroidism that usually occurs after a period of
of Medicine, George Washington University Hospital, Washington, DC, longstanding, unrecognized, or poorly controlled thyroid
5Research Service (151), Veterans Affairs Medical Center, Washington

DC, 6Department of Biostatistics and Bioinformatics, Medstar Health hypofunction and is often precipitated by a superimposed
Research Institute, Hyattsville, Maryland, and 7Georgetown-Howard systemic illness. Such precipitating or exacerbating factors
Universities Center for Clinical and Translational Sciences, Washington, DC include infection, trauma, certain medications, hypother-
(GHUCCTS-CTSA).
Address correspondence to Dr. Geanina Popoveniuc, 110 Irving Street NW, mia, cerebrovascular accident, congestive heart failure,
2A72, Washington, DC, 20010-2975. metabolic disturbances, and electrolyte abnormalities (1-3).
E-mail: Geanina.Popoveniuc@medstar.net. If left untreated, the clinical course is one of multiorgan dys-
Published as a Rapid Electronic Article in Press at http://www.endocrine
practice.org on February 11, 2014. DOI:10.4158/EP13460.OR function, with characteristic lethargy progressing to altered
To purchase reprints of this article, please visit: www.aace.com/reprints. sensorium (stupor, delirium, and coma). Hypothermia is a
Copyright 2014 AACE. key early manifestation in most patients and may be quite

808 ENDOCRINE PRACTICE Vol 20 No. 8 August 2014


809

profound (less than 26C). Respiratory depression lead- Hospital Center (MWHC), Washington, DC and to the
ing to hypoventilation and hypercapnia may necessitate Veterans Affairs Medical Center (VAMC), Washington,
intubation and mechanical ventilation. Decreased cardiac DC from 1989 to 2009 with an admitting or discharge diag-
contractility, bradycardia, cardiomegaly, and arrhythmias nosis of MC.
may lead to hypoperfusion and cardiogenic shock. Other
common abnormalities seen in patients with MC include Definitions
gastrointestinal dysfunction, renal impairment, hyponatre- The following definitions and grading systems were
mia, hypoglycemia, hypoxemia, and anemia (1). employed: hypothermia was defined as a temperature
The diagnosis of MC is usually based on clinical mani- lower than 35C. Bradycardia was defined as heart rate
festations, a history of moderate to severe hypothyroidism, 60 beats per minute and hypotension as blood pressure
and is confirmed by laboratory testing, with elevated serum less than 90/60 mm Hg or a mean arterial pressure less than
thyroid-stimulating hormone (TSH) and decreased total 70 mm Hg. Neurological findings were graded based on
and free thyroxine (T4) and triiodothyronine (T3). Early the severity of mental status changes, from somnolence to
diagnosis, supportive care, and treatment with intrave- obtundation, stupor, and coma. Obtundation was defined
nous T4 have been shown to improve outcomes (4). Recent as less than full mental capacity but still easily arousable,
reports including prospective studies (2,3,5) have focused with persistence of alertness for brief periods of time (1).
on establishing predictors of poor outcome in patients with Stupor was applied to the state of a lack of critical cogni-
MC. tive function and level of consciousness, responsiveness
Coma on admission, lower Glasgow Coma Scale only to painful stimuli, and coma was considered to be a
(GCS) score, and an Acute Physiology and Chronic Health state of complete lack of responsiveness. Hypoglycemia
Evaluation (APACHE II) score of <20 were demonstrated was defined as a blood glucose level <60 mg/dL, and hypo-
to be reliable predictors of higher mortality in the prospec- natremia was classified as a serum sodium <135 mEq/L.
tive study of Rodriquez et al (2) involving 11 patients with To define hypoxemia, we used a threshold for oxygen satu-
MC. The authors of that study also noted that the mean ration at room temperature of <88% or pO2 <55 mm Hg,
age of survivors was lower than that of nonsurvivors, albeit whereas hypercapnia was indicated by a pCO2 of 50 mm
not significantly. Heart rate, body temperature, mean free Hg. The diagnosis of primary hypothyroidism was based on
T4, and mean TSH did not differ between survivors and levels of total or free T4 below the reference range together
nonsurvivors. Dutta et al (3), in a report of 23 patients with with an elevated serum TSH level. Reference ranges were
MC, found hypotension and bradycardia on admission, as follows: total T3, 71 to 180 ng/dL; total T4, 4.5 to 12 g/
need for mechanical ventilation, hypothermia unrespon- dL; free T4, 0.8 to 1.7 ng/dL; and TSH, 0.45 to 4.5 mIU/L.
sive to treatment, sepsis, intake of sedative drugs, lower
GCS score, and high APACHE II and Sequential Organ Methodology
Failure Assessment scores highly predictive of a poor out- Each chart was retrospectively reviewed (by G.P.
come. Results from a Medline search of 82 cases of MC and T.C.) to note patient demographics and the clinical
revealed that older age, cardiac complications (such as manifestations of MC in each patient on presentation. The
hypotension and sinus bradycardia with low-voltage QRS), following characteristics were recorded for each patient:
and high-dose thyroid hormone replacement during treat- demographics (gender, age, race, and past medical history,
ment for MC are associated with a fatal outcome after 1 to include history of hypothyroidism, or thyroid surgery,
month of therapy (5). There was no significant difference medications, and medication noncompliance), vital signs
in mortality based upon the APACHE II score and the pres- at the time of MC diagnosis (temperature, heart rate, respi-
ence of pulmonary complications. ratory rate, blood pressure, oxygen saturation), respiratory
The diagnosis of MC is primarily clinical, with no status (supplemental oxygen, mechanical ventilation), neu-
clear-cut criteria that might distinguish either hypothyroid- rologic status (somnolence, lethargy, obtundation, stupor,
ism alone or coma of other etiologies from true MC. In coma, seizures), gastrointestinal manifestations (anorexia,
view of the high morbidity and mortality of MC (2), the abdominal pain, constipation, decreased/absent intestinal
development and application of criteria for its identifica- motility), laboratory findings (complete metabolic panel,
tion could allow earlier diagnosis and treatment that may TSH, free T4 and total T3, blood cultures, urine cultures),
have a salutary effect on prognosis for recovery and out- electrocardiographic findings, chest X-ray reports, and his-
come (4). tory of precipitating insults, if present.
The frequency of various factors distinguishing MC
METHODS from hypothyroidism without coma or nonthyroidal causes
of coma was assessed and weighted to further develop a
Study Population diagnostic point scale in order to enable a semiquantita-
Our study population was based on all patients age tive distinction between uncomplicated hypothyroidism,
18 years and older who presented to MedStar Washington severe hypothyroidism, and MC. The potential utility of
810

the diagnostic scoring system was assessed by application Table 1


to selected patients reported in the literature. Frequency of Events in 21 Patients with and without
Myxedema Coma Presenting Between 1989 and 2009 at
Statistical Analysis MWHC and VA Medical Center, Washington, DC
Microsoft Excel spreadsheet software was used to note
MC Non-MC P
the frequency of clinical events. Baseline characteristics n (%) n (%) value
between the two groups (MC vs. non-MC) were compared
Patients 14 7
by using Fishers exact test for categorical variables and
two-sample t test for continuous variables. A P value <.05 Gender
was considered statistically significant. Logistic regression Male 8 (57) 3 (43) .659
analysis was used to test the predictive power of the MC Female 6 (43) 4 (57)
score. Results are expressed as the odds ratio (OR) and
Age (mean SD ) 68 15 66 23 .812
95% confidence interval (CI). Further, receiver operating
characteristic (ROC) curve analysis was performed to test Date of admission (Nov-Feb) 6 (43) 3 (43) >.99
the discriminative power of the score. The discriminative History of hypothyroidism 12 (86) 4 (57) .28
power was measured using the area under the ROC curve. Hypothermia (temp. <35C) 7 (50) 2 (29) .642
Sensitivities and specificities were calculated for all val- Central nervous system
ues of the score, and the cutoff point was identified the left
topmost point on the ROC curve (representing the highest Somnolence/lethargy 5 (36) 1 (14) .613
sensitivity and specificity). Obtunded 4 (29) 1 (14) .624
Statistical analyses were performed using SAS 9.3 Stupor 1 (7) 2 (29) .247
(SAS Institute, Cary, NC). Coma 4 (29) 0 (0) .255
The study protocol was approved by the Institutional
Cardiovascular system
Review Boards of MWHC and the VAMC.
Bradycardia (heart rate <60) 5 (36) 2 (29) >.99
RESULTS Hypotension 7 (50) 1 (14) .174
Prolonged QT 3 (21) 1 (14) >.99
Chart review identified 21 patients who had been diag-
Nonspecific ST-T changes 3 (21) 0 (0) .521
nosed with MC by an endocrinologist. We reclassified 7
patients as non-MC, as we believed they were misdiag- Low voltage complexes 1 (7) 0 (0) >.99
nosed, and we used these patients as a control group. The Bundle branch blocks 1 (7) 0 (0) >.99
demographic and clinical characteristics of the patients Pericardial effusion 1 (7) 0 (0) >.99
in each group are presented in Table 1, and patient clini- CXR findings
cal characteristics are detailed in Tables 2 and 3. Reasons
Cardiomegaly 5 (36) 3 (43) >.99
for reclassification of the 7 patients as non-MC (Table
3) included normal free T4 and only marginally elevated Pleural effusions 5 (36) 2 (29) >.99
serum TSH levels (patients 1, 2, 4, and 7) or the absence of Pulmonary edema 3 (21) 3 (43) >.99
any degree of mental status change (patients 3, 5, and 6), Pulmonary infiltrates 2 (14) 2 (29) .574
as mental status alteration was a criterion historically used
Gastrointestinal symptoms
to diagnose MC in patients with hypothyroidism.
As noted in Table 1, there were no statistically sig- Anorexia, abdominal pain, 2 (14) 2 (29) .574
constipation
nificant differences between the two groups in terms of
patient clinical characteristics to distinguish patients with Decreased bowel sounds 2 (14) 0 (0) .533
MC from those with other forms of hypothyroidism. The Distended, quiet abdomen 1 (7) 0 (0) >.99
age (mean SD) at presentation was 68 15 years in Metabolic disturbances
the MC group versus 66 23 years in the non-MC group
Decrease in GFR 6 (43) 1 (14) .337
(P = .81), with men comprising 57% of the MC group ver-
sus 43% of the non-MC group (P = .66). The distribution Hypoxemia 5 (36) 2 (29) >.99
of neurologic alterations in the MC group was relatively Hypercarbia 5 (36) 2 (29) >.99
similar throughout the entire spectrum of neurocognitive Hyponatremia 5 (36) 0 (0) .123
dysfunction, with 36% of the patients described as somno-
Hypoglycemia 4 (29) 0 (0) .255
lent or lethargic and with coma being present in 29% of the
subjects (Table 1). The most common clinical manifesta-
tions in MC patients were hypothermia (50% in MC vs. (Continued on next page)
811

encountered in more than one category (i.e., precipitat-


Table 1 (Continued)
Frequency of Events in 21 Patients With and Without ing event and metabolic disturbance), the condition was
Myxedema Coma Presenting Between 1989 and 2009 at counted once.
MWHC and VA Medical Center, Washington, DC When applied to the 14 patients with MC, a score of
60 or higher (60 to 120) was calculated as being diagnostic
MC Non-MC P
n (%) n (%) value of MC (Table 2). Six of the seven patients with non-MC
had scores ranging between 25 and 50 (Table 3). A single
Precipitating event
patient from this latter cohort had a score of 110, but he
Infection 5 (36) 4 (57) .397 was excluded because of a normal free T4 level (1.14 ng/
Medication noncompliance 4 (29) 3 (43) .651 dL) and only mild TSH elevation.
Furosemide use 4 (29) 1 (14) .624 Univariate logistic regression analysis identified the
Cold exposure 4 (29) 1 (14) .624
score as a continuum to be predictive of the outcome, with
an OR of 1.09 per score unit (95% CI, 1.01 to 1.16; P =
Medications 3 (21)a 0 (0) .521 .019). A score of 45 predicted coma with a probability of
Hypoglycemia 2 (14) 0 (0) .533 0.27 and an OR of 0.37, whereas a score of 60 had a pre-
Gastrointestinal bleeding 2 (14) 0 (0) .533 dictive probability of 0.55, with an OR of 1.22. The model
Congestive heart failure 2 (14) 0 (0) .533 overall was significant (chi-square test, P value = .0006).
The area under the ROC curve of the prediction score
Hypercapnia 1 (7) 0 (0) >.99
was 0.88 (95% CI, 0.65 to 1.00) (Fig. 1). The cutoff point
Cerebrovascular event 1(7) 0 (0) >.99 on the ROC curve corresponded to a score of 60, which had
Treatment the highest sensitivity (100%) and specificity (85.71%),
Levothyroxine IV with steroids 9 (64) 1 (14) .064 with a positive likelihood ratio of 7.0 and negative likeli-
hood ratio of zero. A score of 45 had 100% sensitivity but
Levothyroxine IV without 3 (21) 0 (0) .521
steroids a lower specificity of 42.86%, whereas a score of <25 had
0% specificity (Fig. 1).
Levothyroxine PO 1 (7) 6 (86) <.001
When applied to patients described in the literature for
Abbreviations: CXR = chest X-ray; GFR = glomerular whom enough clinical data were available, the diagnostic
filtration rate; IV = intravenous; MC = myxedema coma; scoring system identified 16 out of 22 patients as having
MWHC = MedStar Washington Hospital Center; PO = by
MC (score 60) (Table 5). The remaining 6 patients would
mouth; VA = Veterans Affairs.
a Amiodarone (n = 2); amitriptyline (n = 1). have been classified as being at risk for MC (scores ranged
between 45 and 55) but did not quite meet the criteria for
a diagnosis of MC. None of the 22 patients examined from
29% in non-MC; P = .64) and hypotension (50% in MC the literature had scores at presentation that qualified them
vs. 14% in non-MC; P = .17). A wide spectrum of electro- as being unlikely to have MC.
cardiogram (EKG) alterations was noted in patients with
MC, with bradycardia present in 36% of the cases. MC DISCUSSION
patients had more frequent and wider distribution of EKG
alterations, metabolic disturbances, and gastrointestinal Although it is generally accepted that a diagnosis of
manifestations than did non-MC patients, although none of MC should rely on some degree of mental status alteration,
these differences reached statistical significance (Table 1). impaired thermoregulatory response, and the presence of
Each patient was noted to have had one or more identifi- a precipitating event (6), clear-cut diagnostic criteria to
able precipitating events. define MC have not been established. Moreover, uncer-
Based on the above findings, we constructed a diag- tainty of diagnosis is suggested by the numerous hypothy-
nostic scoring system to enable a semiquantitative distinc- roid patients with presumed MC reported in the literature
tion between uncomplicated hypothyroidism, severe hypo- in whom at least one of these features was minor or absent.
thyroidism, and MC (Table 4). The lack of statistically Although altered mental status was a prominent aspect
significant differences between all of the clinical charac- of the presenting clinical picture in all of our patients, it
teristics of the two groups, combined with the wide and would be tenuous to base a diagnosis on this alone. There
relatively similar distribution of events in each category, may be innumerable etiologies for mental status change,
led to the construction of a comprehensive multisystemic but it is through combination with other signs and symp-
diagnostic scale, in which points were assigned using a toms of our scoring system, along with thyroid function
stratified approach based on the severity of each condition test results, that the mental status changes allow a more
in a particular system. The highest weighted description precise focus on the diagnosis of MC.
applicable in each category was considered and scores To our knowledge, there have been no previous reports
were totaled. When a given descriptive characteristic was of clinical algorithms to define diagnostic criteria for MC,
812

Table 2
Features and Variables in 14 Patients With Myxedema Coma
TSH
History of (mU/L)/ Free T4 Change
hypothyro- Tempera- Neuro- Precipitating (ng/dL)/ Total T3 Heart Hypo- Hypo- Hyper- Sodium Glucose in GFRc EKG CXR GI
Patient Age Gender idism ture (C) cognition events (ng/dL)a rateb tension xemia carbia (mEq/L) (mg/dL) () findings findings Symptoms Score
1 49 M Yes 33.3 Obtunded Hypoglycemia 53.4/0.68/50.6 87 Yes No No 137 42 no QT No Decreased 90
Cold exposure prolong intestinal
motility
2 67 F Yes 36.4 Coma Infection (PNA) 28.6/0.59/56.3 65 No No Yes 104 147 Yes (35) No Pleural Decreased 95
Hypercarbia effusion intestinal
Infiltrates motility
3 84 M Yes 33.6 Coma Infection (UTI) 125/<0.3/N/A 62 No No No 146 50 Yes (9) No No No 70
GI bleeding
4 41 F Yes 36.4 Lethargic Amitriptyline 122/0.56/N/A 130 Yes No No 138 58 Yes (64) No Pleural No 95
effusions
Pulmonary
edema
5 76 M No 36.2 Obtunded Infection (UTI) 170/0.49/66.3 54 No No No 132 102 Yes (27) No No Constipation 60
Amiodarone
Cold exposure
6 82 F Yes 36.3 Lethargic Infection (UTI) 71/<0.2/<40 59 Yes Yes Yes 142 88 Yes (13) No Cardiomegaly No 95
7 67 F Yes 36.3 Obtunded Hypoglycemia 326/0.39/<40 83 Yes Yes No 133 <20 No QT Cardiomegaly No 105
prolong Pulmonary
edema
8 49 F Yes 37 Lethargic GI bleeding 57/0.42/<40 61 No No No 133 81 Yes (19) No Cardiomegaly No 65
Furosemide Pleural
effusions
9 74 M Yes 34.4 Coma Amiodarone 45/0.2/N/A 70 Yes Yes No 135 109 N/A No Cardiomegaly Abdominal 100
Cold exposure pain
10 65 M Yes 35 Coma CHF 58d/0.6d/N/A 56 No No No 136 135 N/A No No Ileus 90
Furosemide
11 64 M Yes 35 Lethargic ? (died at 128.8/0.9/N/A 46 Yes No No 133 71 N/A No No No 80
presentation)
12 89 M No 33.8 Stupor CHF 84/0.3/N/A 61 No No Yes 156 128 N/A No Pleural No 60
Furosemide effusions
Cold exposure
13 83 F Yes 34.4 Obtunded Infection (PNA, 116/0.59/N/A 67 Yes Yes Yes 145 175 Yes (15) QT Pleural No 120
UTI) prolong effusions
Pulmonary
edema
Infiltrates
14 61 M Yes 36.9 Lethargic/ CVA 107/0.44/41.2 56 No No No 138 145 No No Cardiomegaly No 75
seizures Furosemide

Abbreviations: CHF = congestive heart failure; CVA = cerebrovascular accident; CXR = chest X-ray; EKG = electrocardiogram; F = female; GFR = glomerular filtration rate; GI = gastrointestinal; M = male; N/A = not available;
PNA = pneumonia; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; UTI = urinary tract infection.
a SIconversion factors: To convert freeT4 to nmol/L, multiply by 12.8717; to convert total T3 to pmol/L, multiply by 15.361.
b Heart rate in beats per minute.
c GFR in mL/min.
d Thyroid function tests obtained 1 month prior.
Table 3
Features and Variables in 7 Patients Without Myxedema Coma
TSH
(mU/L)/
Free T4
History of Cold Tempe- (ng/dL)/ Change
hypothy- season rature Neuro- Precipitating Total T3 Heart Hypo- Hypo- Hyper- Sodium Glucose in GFRb EKG CXR GI
Patient Age Gender roidism (Nov-Feb) (C) cognition events (ng/dL) ratea tension xemia carbia (mEq/L) (mg/dL) () findings findings symptoms Score
1 32 M No Yes 31.3 Lethargic Infection 5.67/0.62/56.2 50 No No N/A 140 75 No QT N/A No 50
(bacteremia) (on HD) prolong.
2 73 M No No 36.8 Stupor Infection 5.83/1.06/N/A 85 No Yes No 137 80 No No Pleural No 50
(PNA) (on HD) effusions/
infiltrates
3 52 F Yes Yes 37 Normal Non- 80.6/0.39/N/A 87 No No No 140 263 No N/A Cardio- No 25
compliance megaly
4 77 F Yes No 37 Obtunded Non- 9.0/1.3/N/A 102 No Yes Yes 145 86 No No No No 45
compliance
5 94 F Yes No 36.6 Normal Infection 7.2/2.03/N/A 72 No No No 144 96 No No Cardio- No 25
(UTI) megaly
6 45 F Yes No 36.6 Normal Non- 145/0.28/N/A 57 No No No 140 127 No No No constipation 25
compliance
7 90 M No Yes 34.4 Stupor Infection 11.9/1.4/70.8 72 Yes No Yes 145 80 Yes (15) Atrial Cardio- Nausea/ 100
(PNA) flutter megaly, vomiting/
Cold exposure pleural constipation
Furosemide effusions,
infiltrates

Abbreviations: CXR = chest X-ray; EKG = electrocardiogram; F = female; GFR = glomerular filtration rate; GI = gastrointestinal; HD = hemodialysis; M = male; N/A = not available; PNA = pneumonia; T3 = triiodothyronine;
T4 = thyroxine; TSH = thyroid-stimulating hormone; UTI = urinary tract infection.
a Heart rate in beats per minute.
b GFR in mL/min.
813
814

Table 4
Diagnostic Scoring System for Myxedema Comaa
Thermoregulatory dysfunction (temperature, C) Cardiovascular dysfunction
>35 0 Bradycardia
32-35 10 Absent 0
<32 20 50-59 10
Central nervous system effects 40-49 20
Absent 0 <40 30
Somnolent/lethargic 10 Other EKG changesb 10
Obtunded 15 Pericardial/pleural effusions 10
Stupor 20 Pulmonary edema 15
Coma/seizures 30 Cardiomegaly 15
Gastrointestinal findings Hypotension 20
Anorexia/abdominal pain/constipation 5 Metabolic disturbances
Decreased intestinal motility 15 Hyponatremia 10
Paralytic ileus 20 Hypoglycemia 10
Precipitating event Hypoxemia 10
Absent 0 Hypercarbia 10
Present 10 Decrease in GFR 10
Abbreviations: EKG = electrocardiogram; GFR = glomerular filtration rate.
a A score of 60 or higher is highly suggestive/diagnostic of myxedema coma; a score of 25 to 59 is suggestive of risk for

myxedema coma, and a score below 25 is unlikely to indicate myxedema coma.


b Other EKG changes: QT prolongation, or low voltage complexes, or bundle branch blocks, or nonspecific ST-T changes, or

heart blocks.

Fig. 1. ROC curve of the scoring system for myxedema coma.


Table 5
Features and Variables in 22 Patients Described in the Literature Who Were Diagnosed With Myxedema Coma
Temp Neuro- Precipi-tating Conco- Heart EKG Hypo- Hyper- Sodium TSH Free T4
Ref Pt Age Gender (C) cognition events mitant disorder Ratea MAP changes xemia carbia (mEq/L) (mU/L) (ng/dL) Score
2 1 84 M 34.5 Obtunded Urinary infection Pleural effusion 39 110 N/A No N/A 133 51.3 0.46 85
2 2 75 F 34.4 Coma Pneumonia, sepsis Anemia, DIC, 124 108 N/A Yes N/A 122 0.43 0.25 90
ARDS, septic
shock
2 3 70 F 33.9 Coma Abdominal surgery Respiratory failure, 38 115 N/A Yes N/A 144 71 0.18 110
shock
2 4 65 F 34.9 Obtunded Urinary infection Pericardial 104 74 N/A No N/A 124 2.4 0.23 55
effusions
2 5 20 F 34.2 Obtunded Typhoid fever Anemia, 114 72 N/A No N/A 128 76.04 0.28 45
pneumonia
2 6 81 F 34.8 Coma Ileus Respiratory failure, 38 68 N/A Yes N/A 126 28 0.17 130
pleural effusion,
shock
2 7 63 F 35.0 Obtunded Urinary infection Anemia, respiratory 124 88 N/A No N/A 110 38 0.15 55
failure
2 8 83 F 35.0 Coma Urinary infection None 65 95 N/A No N/A 122 60.6 0.15 60

2 9 79 F 34.8 Obtunded Respiratory None 52 128 N/A No N/A 120 153 0.15 55
infection
2 10 47 F 34.9 Obtunded Urinary infection Anemia, 144 112 N/A No N/A 126 9.85 0.37 55
Respiratory failure
2 11 82 F 33.6 Obtunded Pneumonia Respiratory failure, 38 80 N/A Yes N/A 120 78.2 0.5 105
shock
7 12 84 F 30.0 Global amnesia N/A 33 60 N/A No No 135 63.2 0.17 85
8 13 62 M 35.3 Delayed Non-compliance Pleural effusions 50 74 Low volt N/A N/A 134 >60 Undetectable 60
response
9 14 47 F 33.2 Lethargic None Pericardial effusion 88 73 None N/A N/A Low 6.09 0.83 40->80
10 15 88 F 36.1 Lethargic Bok choy 58 119 N/A Yes Yes 132 74.4 Undetectable 60

11 16 68 F 29.1 Changes in MS Sunitinib 46 107 N/A No No 115 41.4 Undetectable 75


12 17 27 F 36.6 Changes in MS Diabetic None 40 98 Low volt N/A N/A 132 48 0.4 45
ketoacidosis
13 18 64 F 30.1 Changes in MS Urinary infection None 60 84 N/A No Yes 138 >200 <0.35 70
14 19 33 F 35 Coma Non-compliance Hypoglycemia 50 76 N/A No N/A 138 >100 0.24 60
15 20 74 F 34.8 Stupor CVA 59 50 Low volt Yes No 121 30.12 0.05 100
Prol QT
16 21 78 M 35.5 Coma N/A Hypoactive BS 52 70 N/A N/A Yes 106 61.24 <0.3 75
17 22 60 F 37.7 Altered sepsis Ogilvies syndrome bradic 125 Junctional N/A N/A 122 341.57 1.6b 75
sensorium (ileus) rythm
(obtunded)
Abbreviations: ARDS = acute respiratory distress syndrome; BS = bowel sounds; CVA = cerebrovascular accident; DIC = disseminated intravascular coagulation; EKG = electrocardiogram; F = female;
M = male; MAP = mean arterial pressure; MS = mental status; N/A = not available; Pt = patient; Ref = reference; T4 = thyroxine; TSH = thyroid-stimulating hormone.
a Heart rate in beats per minute.
815

b Total T : 1.6 g/dL (5.6-13.7 g/dL).


4
816

likely due to the paucity of cases and consequent lack of confusion, cognitive dysfunction, minimal responsive-
studies to address this issue. Accordingly, we have devel- ness, or coma. The decompensated neurologic state may
oped a diagnostic scoring system for MC, and we assessed be primary, such as from a cerebrovascular event or due
its potential utility in a cohort of patients from our two to a drug overdose with sedatives or hypnotics, whereas
institutions and applied it to selected patients identified in sepsis, hyponatremia, or other metabolic disturbances are
the literature (2,7-17). Our hope is that this scoring system secondary events, which may worsen the patients cogni-
will enable earlier diagnosis and treatment of patients with tive function.
MC. Homeostatic dysfunction resulting from thyroid hor-
Importantly, most of the patients that we evaluated mone deficiency is generally insufficient to cause MC, as
from the literature were likely underscored due to lim- the body can compensate through neurovascular mecha-
ited clinical data. Thus, an assigned score of 60 could eas- nisms. A triggering event is usually required to overcome
ily have been achieved with one or two more variables the compensatory mechanisms in a hypothyroid patient
being present, such as a lack of details of metabolic abnor- (18). Infection, cerebrovascular or cardiovascular events,
malities, EKG changes, and/or gastrointestinal manifesta- cold temperature exposure, medications such as amioda-
tions. Patient 14 (Table 5) (9) was of particular interest, as rone, beta blockers, lithium, narcotics, sedatives, diuretics,
she initially presented to the hospital with biochemical evi- and metabolic derangements are examples of such insults
dence of subclinical hypothyroidism and clinical features (2,3). Each patient had at least one identifiable precipitat-
that would not have diagnosed her with MC, given a score ing event, and the frequency of these events was in concor-
of 40. Shortly after admission, her clinical status deterio- dance with the findings reported in other studies (3).
rated and she was diagnosed with MC, achieving a score of Prolonged untreated hypothyroidism coupled with a
80 based on our diagnostic scale. Of note, the patients bio- triggering event may lead to cardiovascular collapse and
chemical markers continued to reflect a state of subclinical shock, which may not be responsive to vasopressor ther-
hypothyroidism throughout her hospitalization, showing apy alone until thyroid hormone is also administered (19).
that a reliance on thyroid function tests alone could have Electrocardiographic abnormalities, such as bradycardia,
potentially missed the development of MC, thereby delay- low voltage, nonspecific ST wave inversion, QT prolonga-
ing diagnosis and treatment of this patient. tion, as well as rhythm abnormalities, may be seen (20).
The predictive power of the score as a continuum Hypotension was commonly seen in our MC cases, and the
showed an OR of 1.09 (95% CI, 1.01 to 1.16; P = .019), frequency of electrocardiographic abnormalities was simi-
suggesting that with each unit increase in the score within lar to that reported in the literature (3).
the range of available data, the odds of MC increase by a An impaired ventilatory response and a need for
factor of 1.09, or by 9%. For instance, a change in score mechanical ventilation are common manifestations in
from 50 to 51 would change the predictive probability of patients with MC. Decreased respiratory center sensitiv-
coma from 0.35 to 0.37, or from an OR of 0.54 to an OR of ity to hypercarbia and hypoxemia may lead to hypoven-
0.58. The score of 60 represented a turning point and pre- tilation, which may be aggravated further by impaired
dicted coma with a high accuracy, given its predicted prob- respiratory muscle function, obesity, and other obstructive
ability of 0.55, which conferred an OR of 1.22. The odds processes of the airways, such as macroglossia, myxedema
of coma for a score of 45 was approximately 1 in 3 (0.37), of the larynx and nasopharynx, intrinsic processes such as
which corresponded to a predicted probability of 0.27. pneumonia, reduced lung volume, or extrinsic compressive
The discriminative power of the scoring system was processes such as pleural effusions (1,21,22).
high, with area under the ROC curve of 0.88 (95% CI, 0.65 A reduction in glomerular filtration rate in hypothy-
to 1.00). The score of 60 had the highest sensitivity (100%) roid patients is a result of decreased renal plasma flow,
and specificity (85.71%) of the scores calculated, which with water retention and hyponatremia usually being con-
makes it a good screening tool. The score of 45 had 100% comitant findings in these patients (23). Fluid extravasation
sensitivity but a lower specificity (42.86%). Given the resulting from altered vascular permeability may present as
above considerations, we propose that with application of effusions, nonpitting edema, and anasarca. Effects of pro-
the recommended scoring system, a score of 60 or higher found thyroid hormone deficiency on the gastrointestinal
will be highly suggestive of MC, a score between 45 and system may include decreased intestinal motility with con-
59 will represent risk for MC, and a score of less than 45 is stipation and may progress to paralytic ileus with a quiet
unlikely to indicate MC. Given the small sample size, our and distended abdomen, anorexia, nausea, and abdomi-
model was not capable of producing a threshold score for nal pain (17). In our patients, the metabolic abnormalities
patients at risk for MC; therefore, scores between 45 and occurred with relatively equal frequencies but independent
59 are only our suggestion of representing patients in this of each other, suggesting the importance of appreciation of
category, based on the given probabilities. the multisystemic basis for development of MC.
Neurocognitive dysfunction in patients with MC may The ultimate diagnosis of MC should be made with
vary from disorientation and lethargy to slow mentation, biochemical evidence of low levels of serum free T4 and
817

T3 and elevated TSH in patients with primary hypothyroid- 2. Rodrguez I, Fluiters E, Prez-Mndez LF, Luna R,
ism, whereas in secondary hypothyroidism, the biochemi- Pramo C, Garca-Mayor RV. Factors associated with
mortality of patients with myxoedema coma: prospec-
cal diagnosis should rely on low or normal TSH and low tive study in 11 cases treated in a single institution. J
free T4 and total T3 levels and evidence of pituitary dys- Endocrinol. 2004;180:347-350.
function. None of our patients had biochemical evidence 3. Dutta P, Bhansali A, Masoodi SR, Bhadada S, Sharma
of secondary hypothyroidism. N, Rajput R. Predictors of outcome in myxoedema coma:
Particular attention should be given to patients with a study from a tertiary care centre. Crit Care. 2008;12:R1.
4. Jordan RM. Myxedema coma. Pathophysiology, ther-
biochemical evidence of secondary hypothyroidism that apy, and factors affecting prognosis. Med Clin North Am.
could be difficult to distinguish from the sick euthyroid 1995;79:185-194.
state. The latter entity represents a physiologic adaptive 5. Yamamoto T, Fukuyama J, Fujiyoshi A. Factors asso-
response of the thyrotropic feedback control to severe ill- ciated with mortality of myxedema coma: report of eight
ness and is reflected by biochemical evidence of normal, cases and literature survey. Thyroid. 1999; 9:1167-1174.
6. Nicoloff JT. Thyroid storm and myxedema coma. Med
low, or slightly elevated TSH, depending of the severity Clin North Am. 1985;69:1005-1017.
of the illness, and low free T4 and T3. Therefore, in order 7. Kogan A, Kassif Y, Shadel M, et al. Severe hypothermia
to avoid misclassifying patients with sick euthyroid syn- in myxoedema coma: a rewarming by extracorporeal circu-
drome as having MC in the setting of commonly present lation. Emerg Med Australas. 2011;23:773-775.
8. Pearse GS, D Dahdal M, Grocott-Mason R, W Dubrey
multiorgan dysfunction, we suggest that appropriate diag-
S. Myxoedematous pre-coma and heart failure. Br J Hosp
nosis of secondary hypothyroidism should be done first, Med (Lond). 2011;72:52-53.
either from history of hypothalamic-pituitary dysfunction 9. Mallipedhi A, Vali H, Okosieme O. Myxedema coma in a
or through imaging studies reflecting organic hypothalamic patient with subclinical hypothyroidism. Thyroid. 2011;21:
or pituitary disease. 87-89.
10. Chu M, Seltzer TF. Myxedema coma induced by ingestion
This study is limited by virtue of its retrospective of raw bok choy. N Engl J Med. 2010;362:1945-1946.
design and relatively small sample size, which precluded 11. Chen SY, Kao PC, Lin ZZ, Chiang WC, Fang CC.
accurate comparison between groups due to a lack of sta- Sunitinib-induced myxedema coma. Am J Emerg Med.
tistical power. Also, due to insufficient published data in all 2009;27:370.e1-370.e3.
the case reports of MC assessed from the literature, it was 12. Cappelli C, Stanga B, Paini A, et al. Myxoedema coma
precipitated by diabetic ketoacidosis and neuroleptic drugs:
not possible to fully validate the scoring system. However, case report in an intensive care unit. Intern Emerg Med.
the score demonstrated positive predictive value and a high 2007;2:147-149.
discriminative power. 13. Sheu CC, Cheng MH, Tsai JR, Hwang JJ. Myxedema
coma: a well-known but unfamiliar medical emergency.
CONCLUSION Thyroid. 2007;17:371-372.
14. Yu CH, Stovel R, Fox S. Choreaan unusual manifesta-
In conclusion, considering the complex, multisystemic tion in a woman recovering from myxedema coma. Endocr
manifestations of hypothyroidism in patients with MC and Pract. 2012;18:e43-e48.
the high mortality associated with delays in therapy, a 15. Ahn JY, Kwon HS, Ahn HC, Sohn YD. A case of myx-
edema coma presenting as a brain stem infarct in a 74-year-
practical guide to earlier diagnosis could be of value. We
old Korean woman. J Korean Med Sci. 2010;25:1394-1397.
propose a diagnostic scoring system for MC that is based 16. Kargili A, Turgut FH, Karakurt F, Kasapoglu B,
upon data from retrospective cases diagnosed at our insti- Kanbay M, Akcay A. A forgotten but important risk fac-
tutions as well as data from selected case reports culled tor for severe hyponatremia: myxedema coma. Clinics (Sao
from the literature. This scoring system assessed an array Paulo). 2010;65:447-448.
17. Yanamandra U, Kotwal N, Menon A, Nair V. Ogilvies
of the diagnostic features associated with MC and found a syndrome in a case of myxedema coma. Indian J Endocrinol
similar frequency of findings in our cohort of patients as in Metab. 2012;16:447-449.
those assessed from the literature (2,3,5). 18. Fliers E, Wiersinga WM. Myxedema coma. Rev Endocr
This scoring system should be considered in the clini- Metab Disord. 2003;4:137-141.
cal context of the patient. Further large, prospective, well- 19. Gardner DG. Endocrine emergencies. In: Gardner
DG, Shoback D, eds. Greenspans Basic and Clinical
controlled studies are needed to confirm the current find- Endocrinology. 8th ed. New York, NY: McGraw-Hill;
ings and to inform whether such a diagnostic approach 2007.
to patients with MC will enable earlier recognition and 20. Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid
more effective treatment of this potentially fatal endocrine and the heart. Circulation. 1993; 87:1435-1441.
21. Zwillich CW, Pierson DJ, Hofeldt FD, Lufkin EG, Weil
emergency.
JV. Ventilatory control in myxedema and hypothyroidism.
DISCLOSURE N Engl J Med. 1975;292:662-665.
22. Ladenson PW, Goldenheim PD, Ridgway EC. Prediction
The authors have no multiplicity of interest to disclose. and reversal of blunted ventilatory responsiveness in
patients with hypothyroidism. Am J Med. 1988;84:877-883.
REFERENCES 23. Montenegro J, Gonzlez O, Saracho R, Aguirre R,
1. Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergen- Martnez I. Changes in renal function in primary hypothy-
cies. Med Clin North Am. 2012;96:385-403. roidism. Am J Kidney Dis. 1996;27:195-198.