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M. Sakr
drugs is markedly diminished in patients with
hypothyroidism. Anecdotally, an entity called
“myxedematous psychosis” had been described,
characterized by hallucinations, elusions, behavioral alterations, and aggressiveness [68, 69].
16.3.3.3 Hypoventilation
Profound hypoventilation is common in patients
with myxedema coma and requires mechanical
ventilator assistance to relieve CO2 retention and
hypoxia. Although hypercapnia and loss of
hypoxic drive are the cardinal physiological
mechanisms involved, other factors such as macroglossia, edema of the vocal cords and pharynx,
bradycardia, reduced stroke volume, anemia,
pleural effusion, ascites, pericardial effusion,
weakness of respiratory muscles due to myopathy, superimposed pulmonary infection, and
administration of drugs that cause CNS depression, may all further suppress the respiratory
function [70–72].
16.3.3.4 Hyponatremia
Hyponatremia is common in severe hypothyroidism because thyroid hormone has an effect on
renal tubule sodium reabsorption and water excretion. Excess TSH causes hyper-production of
antidiuretic hormone (ADH) with the consequent
water retention [71]. An inappropriate plasma
vasopressin level has also been seen in myxedema
coma. Other factors such as concomitant adrenal
insufciency, uid overload, CHF, and inadequate
use of diuretics further contribute to hyponatremia. Mild hyponatremia has no clinical signicance, but severe hyponatremia leads to
deterioration of the patient’s level of consciousness and seizures, which occur in approximately
25% of patients with myxedema coma [71].
16.3.3.5 Hypoglycemia
Hypoglycemia is an uncommon nding in
patients with myxedema coma; it is present in
approximately 29% of cases [56]. Hypoglycemia
may indicate co-existent adrenal insufciency or
pan-hypopituitarism. It may also result from
impaired glycogenolysis and gluconeogenesis,
increased insulin sensitivity, and malnutrition
(due to fasting and gastric paresis) without hypo-
adrenalism [73–76]. It is noteworthy that hypoglycemia is also responsible for seizures in some
patients with myxedema coma.
16.3.3.6 Cardio-vascular Alterations
Cardiovascular alterations are considered the
main cause of mortality in the patients with myxedema coma and include bradycardia, hypotension, and decreased myocardial contractility and
cardiac output [67, 77]. Cases of CHF have been
reported [78, 79], and pericardial effusion is frequent and can be of large volume. An entity
known as “heart of myxedema” has been
described, represented by hemodynamic alterations, cardiomegaly, electrocardiographic (ECG)
changes, and enzymatic alterations (increase in
creatine phosphor-kinase [CPK], lactic dehydrogenase [LDH], and transaminases). In general,
the “heart of myxedema” has a reversible behavior with the specic treatment [67]. The management of these manifestations focuses on hormonal
supplementation, and in some cases, inotropic
and aminergic support.
16.3.3.7 Gastrointestinal Alterations
In myxedema coma, there is a decrease in peristalsis with frequent constipation, which can
even manifest as myxedematous megacolon [69].
“Myxedematous ileus” may also occur, which is
a gaseous distension of the abdomen accompanied by a clinical obstructive abdominal syndrome [70].
16.3.3.8 Renal Alterations
Renal alterations are the most frequent nding in
patients with MC being present in nearly 43% of
cases [56]. In general, these alterations result
from a fall in cardiac output and hypoperfusion,
due to a decrease in glomerular ltration, or as a
consequence of acute urinary retention. The presentation of acute renal injury caused by rhabdomyolysis secondary to hypothyroid myopathy
has also been described [80, 81].
16.3.3.9 Myxedema
Myxedema is described as hard, non-pitting, generalized edema, which involves the peri-orbital
and acral area. There is supra-ciliary madarosis,
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16 Thyroid andParathyroid Endocrine Emergencies
467
known as “Queen Anne’s sign” [80]. “Madarosis”
refers to loss of the eyelashes or eyebrows; it can
be unilateral or bilateral; incomplete or complete.
The skin is characteristically cold and dry due to
cutaneous vaso-constriction, pale yellowish due
to anemia and hyper-carotenemia and rough to
the touch [81, 82]. Myxedema is a serious disorder with high mortality. Most patients die from
GI bleeding, sepsis, or respiratory failure despite
optimal treatment. Poor prognostic factors
include advanced age, persistent hypothermia,
and altered mental status.
16.3.4 Diagnosis
A timely diagnosis and prompt and proper treatment can alter the natural course and fatal outcome of myxedema coma. A high index of
suspicion is based on history and physical examination. Measurement of serum TSH, T3 and T4
concentrations conrms the diagnosis of hypothyroidism [56, 57]. However, just as in thyrotoxic storm, the results of serum thyroid function
tests correlate poorly with the clinical severity of
myxedema coma, and many patients with hypothyroidism without coma have equally high TSH
and low T3 and T4 levels. In patients with central
or secondary hypothyroidism, serum TSH, T3,
and T4 levels are low.
The “diagnostic scoring system for myxedema
coma” [56], developed in 2014, includes only
clinical parameters. A score of 60 points is considered diagnostic of myxedema coma, with a
sensitivity of 100% and specicity of 85%. This
score has the advantage of being based solely on
clinical parameters allowing early diagnosis and
hence prompt treatment, before laboratory results
are obtained. Another screening tool, published
in 2015 [57], includes, in addition to clinical
parameters, measurements of TSH and FT4, classies the diagnostic probability and issues a therapeutic recommendation according to the score
(Table16.5); however, it has lower sensitivity and
specicity of 80% each.
Elevation of serum CPK, LDH, and transaminase levels in severe hypothyroidism may help in
the differential diagnosis. The iso-enzyme pat-
Table 16.5 Diagnostic scoring system for myxedema
coma
Criteria Score
Glasgow
coma scale
0–10
11–13
14
15
TSH
>30Mu/L
15–30Mu/L21
T4 level
(<0.6ng/dL)
Hypothermia
(<95°F)
Bradycardia
(<60/min)
Precipitating
event
Total score Category Recommendation
8–10
5–7
<5
TSH thyroid-stimulating hormone, T4 thyroxin
4
3
2
0
1
1
1
1
– Most
likely
– Likely
– Unlikely
– Treat
– Treat if there are
no causes
– Consider
another
diagnosis
tern of increased CPK is predominantly MM,
consistent with skeletal muscle origin. In case of
a greatly elevated CK-MB fraction, concomitant
myocardial infarction is suggested, which may
not be evident clinically [83]. It is important to
document these tests and to obtain an ECG before
initiating treatment with thyroid hormone if chest
pain develops with treatment.
Computed tomography (CT) scan of the head
may demonstrate either a pituitary or hypothalamic lesion in most cases of central hypothyroidism: pituitary adenomas and
cranio-pharyngiomas are the most frequent
causes.
16.3.5 Dierential Diagnosis
The insidious onset of symptoms further impedes
the early recognition of this syndrome.
Myxedema coma should be considered in the
differential diagnosis of any patient who presents with an altered mental status, profound
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M. Sakr
hypothermia, and unexplained CO2 retention,
either alone or in combination. One should be
particularly alert to any hypothyroid patient who
has received RAI therapy or who has been
treated with total or subtotal thyroidectomy for
Graves’ disease.
16.3.6 Treatment
The goals regarding myxedema coma management should be directed at improving the neurological, cardiovascular, and pulmonary
manifestations [82, 84–87]. Management in an
ICU should be provided so that the patient
remains under monitoring of the cardiorespiratory status and receive the pertinent ventilatory
support, effective uid resuscitation, and correction of hypotension and electrolyte alterations.
Thus, the strategies for the treatment of myxedema coma are (1) maintenance of cardiopulmonary function, (2) institution of thyroid
hormone therapy, (3) treatment of metabolic
complications, (4) elimination of precipitating
factors or concurrent illnesses, and (5) provision
of general supportive care.
16.3.6.1 Maintenance
ofCardiopulmonary Function
Once the diagnosis of myxedema coma is
reached, prompt and close monitoring of cardiopulmonary function must be instituted since
death in such patients is frequently caused by
respiratory failure and/or cardiovascular collapse. CO2 retention and respiratory acidosis can
be conrmed by arterial blood gas analysis and
rapidly relieved by intubation and mechanical
ventilation.
Hypotension in myxedema coma is due to
blood volume depletion, intrinsic heart disease,
or pericardial effusion. Thyroid hormone therapy,
whole-blood transfusion, and administration of
hydrocortisone may correct the hypovolemia.
Pressor agents are rarely required. If CHF develops, the patient should be treated with digitalis
and diuretics or after load-reducing agents.
Concomitant myocardial infarction indicates a
poor outcome.
16.3.6.2 Thyroid Hormone
Replacement
Thyroid hormone replacement therapy is essential in the management of myxedema coma [88].
The initial dose of levo-thyroxine (L-T4) is
300–500 μg given IV. After the initial dose,
serum T4 and T3 levels gradually rise, and the
patient should be subsequently maintained on
50–100μg/day IV.The enteral route is less preferred in this situation due to the alterations in
intestinal absorption that these patients have, as
well as the need for immediate bioavailability of
thyroid hormone [58, 88, 89]. As soon as the
patient regains consciousness, oral L-T4 is
instituted.
In the past, low-dose thyroid hormone replacement was recommended because of concern of
underlying cardiac disease; however, the mortality rate with low-dose replacement was as high as
80% [89, 90]. However, there has been considerable progress in supportive medical care in the
past decades. Yamamoto etal. (1999) suggested
that not every patient requires a high dose of thyroid hormone. They added that a bolus of 500μg
of levo-thyroxine orally or via an NGT is effective and can be tolerated by patients <55years of
age [91]. Reinhardt and Mann (1997) conducted
a survey of hospitals in Germany (1993–1995)
and identied a group of 24 patients with myxedema coma, treated initially with levo-thyroxine
in doses ranging from 25 to 500μg. They reported
a mortality rate of 25% (6 deaths) [79].
Some authors believe that myxedema coma is
partially related to decreased 5′-deiodinase activity with impairment in conversion of T4–T3 in
patients with non-thyroidal illnesses [92, 93].
They recommend using liothyronine (T3) hormone at an initial dosage of 25μg every 8h IV
for 1day followed by 12.5μg every 8h the next
day. As soon as the patient’s consciousness
improves, T3 is changed to oral L-T4 [84, 85].
Careful monitoring of cardiac function is required
during T3 replacement, as it is associated with
more cardiac arrhythmias and a higher mortality
rate [90, 94].
A survey that collected 87 cases of myxedema
coma published in English, French, German, and
Japanese since 1970 found that the incidence of
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16 Thyroid andParathyroid Endocrine Emergencies
469
death was highest after treatment with T3 of
≥75μg/day with or without levo-thyroxine [91].
In 2013, Wartofsky suggested an initial dose of
200–250-μg L-T4 IV followed by a dose of
100μg 24h later [63]. A maintenance dosage of
50μg/day is started on the third day either IV or
orally. Alternatively, T3 is initially given with a
dose of 10μg then the same dose every 8–12h
given IV until the patients can take oral dose of
T4. Continuous ECG monitoring in an ICU is
mandatory. In patients with cardiac arrhythmia
or myocardial ischemia, thyroid hormone
replacement is discontinued or dramatically
lowered.
16.3.6.3 Treatment ofMetabolic
Complications
Hypothermia usually improves after thyroid hormone replacement therapy. Generally, blankets to
prevent further heat loss would sufce. External
rewarming should be avoided as it can cause
vasodilation and vascular collapse. Because prolonged profound hypothermia suggests a poor
prognosis, active rewarming is sometimes recommended, accompanied by whole-blood transfusion in patients with a body temperature below
30°C [31].
Mild to moderate hyponatremia is usually corrected by uid restriction and thyroid hormone
therapy. Hypertonic saline and glucose are only
occasionally required to alleviate severe hyponatremia (sodium <110mEq/L) and hypoglycemia,
respectively. Seizures are prevented by correcting
the hyponatremia, hypoglycemia, hypercapnia,
and hypoxia. When seizures occur, they are
treated with anticonvulsants.
16.3.6.4 Elimination ofPrecipitating
Factors andConcurrent Illness
Bacterial infection is the most common precipitating factor of myxedema coma [95], and delay
in the diagnosis and treatment is associated with
a poor outcome [96]. A vigorous search for any
possible source of infection and its adequate
treatment with specic antibiotics should be conducted because fever, sweating, tachycardia, and
leukocytosis may be totally absent in patients
with myxedema coma and concurrent bacterial
infection. Nicoloff and LoPresti [61]
recommended broad-spectrum IV antibiotic coverage for patients until all cultures return to negative. One should also be alert to the presence of
other concurrent diseases such as cardiac and
cerebrovascular diseases and gastrointestinal
bleeding.
16.3.6.5 General Supportive Care
As in case of all comatose patients, frequent
changes in position, prevention of aspiration, and
bowel and bladder care should be undertaken.
Paralytic ileus is frequently found with myxedema coma and should be differentiated from
mechanical obstruction, which usually requires
surgical intervention. Ileus resulting from myxedema coma improves with thyroid hormone
therapy. Both thyroid and adrenocortical failure
may occur in patients with pan-hypopituitarism
and polyglandular autoimmune syndrome.
Treatment of such patients with thyroid hormone
without simultaneous administration of cortisol
results in adrenal crisis. Thus, several investigators recommend the administration of IV hydrocortisone, 100mg every 8h for the rst few days,
followed by 50 mg, IV every 6h for all myxedema coma patients [97, 98]. The dose can be
rapidly tapered or discontinued when the random
serum cortisol value is ≥18μg/dL and concomitant adrenal insufciency is ruled out [99].
16.3.7 Prognosis
Today, mortality from myxedema coma is still
relatively high, although it has declined due to
better knowledge of the pathology, the development of equipment that facilitate faster recognition, and a more adequate intensive therapy. In
the 1960s, mortality was up to 80% [89]. With the
beginning of the use of IV L-T4, in the 1990s, it
decreased signicantly, reporting gures of
20–25% [58]. In 2017, a retrospective observational study, which included 149 patients,
reported a mortality rate of approximately 29%
[100]. The main cause of death from myxedema
coma is cardiovascular disease [100, 101], followed by pneumonia and its complications [101].
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It has been identied that the best predictors
of poor prognosis are the deterioration of the
level of consciousness, Glasgow scale equal to
or <5, and APACHE II score equal to or >20.
More recently, it was shown that the SOFA score
is more effective in prediction than other models;
a score of 6 points at presentation and at 3days is
highly predictive of mortality >60%, which
increases as the score increases.
16.4 Parathyroid (Hypercalcemic)
Crisis
16.4.1 Denition
Parathyroid crisis is currently dened as a “syndrome characterized by a serum calcium (Ca)
level of >3.5 mmol/L (>14.5 mg/dL) resulting
from marked elevation of parathyroid hormone
(PRH) with severe signs and symptoms of hypercalcemia” [102].
16.4.2 Synonyms
Hypercalcemic crisis secondary to primary
hyperparathyroidism (PHPT) has been referred
to in the literature as acute hyperparathyroidism,
parathyroid crisis, hyperparathyroid crisis, parathyroid poisoning, parathyroid intoxication,
para-thyrotoxicosis, and parathyroid storm
[103–107].
16.4.3 Incidence andEtiology
ofHypercalcemic Crisis
The incidence of hypercalcemic crisis has never
been determined. Bondeson etal. [108] reported
a 10% incidence of hypercalcemic crisis in 514
patients with PHPT. Hypercalcemic crisis secondary to PHPT is commonly caused by a large
parathyroid adenoma, and less commonly by carcinoma or hyperplasia [103, 105, 109].
Parathyroid carcinoma is usually associated with
much higher PTH and calcium levels than nonmalignant PHPT, and the incidence of
hypercalcemic crisis complications may be as
high as 14% [110]. Maselly etal. [111] reported
that 10 out of 325 (3.1%) consecutive patients
with PHPT developed hypercalcemic crisis and
that 9 of these 10 patients had a single adenoma.
The risk of developing hypercalcemic crisis
among patients with untreated PHPT is relatively
low. Corlew etal. [112] reported that only 1 out
of 47 patients (0.21%) followed over a 5-year
period developed a hypercalcemic crisis.
Moreover, only 1 out of 142 patients (0.7%) in a
prospective series at the Mayo Clinic followed
for 10years developed a hypercalcemic crisis as
a complication of PHPT [113].
Several authors reported that the patient age at
the time of presentation of a hypercalcemic crisis
was the same or slightly lower than the average
age of patients with PHPT at the time of presentation [105, 106, 114, 115]. The majority of
patients presenting with a hypercalcemic crisis
are in the sixth decade of life [103, 105]. The
male–female ratio (1.0:1.1) is similar to that of
the distribution of parathyroid carcinoma [110,
116, 117], but markedly different from the sex
ratio in a recent series of patients with PHPT
[114, 115].
Causes of hypercalcemia (Table 16.6) can be
divided into those that are PTH-dependent or
PTH-independent. The main causes of hypercalcemia are malignancy and PHPT, which are also
the most common causes of hypercalcemic crisis
in hospitalized and ambulatory patients, respectively, accounting for >90% of all patients [118].
Other causes of hypercalcemic crisis are listed in
Table 16.6. In granulomatous diseases, macrophages activated by the granulomas can metabolize 25-OH vitamin D (calcidiol) to the more
active 1,25(OH)2 vitamin D (calcitriol), leading
to endogenous elevated levels, and on rare occasions, can lead to hypercalcemic crisis [5]. Less
commonly, some lymphomas have been associated with excess endogenous calcitriol production, which sometimes causes hypercalcemic
crisis [119]. In hyperthyroidism, hypercalcemia
may be caused by the direct stimulatory effect of
thyroxine on osteoclastic bone resorption [104]
particularly in young, immobile patients with
hyperthyroidism.
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16 Thyroid andParathyroid Endocrine Emergencies
471
Table 16.6 Differential diagnosis of hypercalcemia
Cause Examples
Parathyroid
function
Malignancy – Solid tumor with metastasis
Vitamin-D
disorders
High
boneturnover
Renal
Failure
Other – Acromegaly
SCC squamous cell carcinoma, PTHrP PTH-related poly-
peptide, HHM humoral hypercalcemia of malignancy
– Primary hyperparathyroidism
(PHPT)
Solitary parathyroid adenoma
Primary parathyroid hyperplasia
Parathyroid carcinoma
Multiple endocrine neoplasia
(MEN1 and MEN2A)
Familial isolated HPT
– Lithium use
– Familial hypocalciuric
hypercalcemia/familial benign
hypercalcemia
(e.g., breast cancer, or SCC,
which can be PTHrP--mediated)
– Solid tumor with HHM (e.g.,
lung cancer, most commonly
nonsmall cell lung cancer, kidney
cancer, pheochromocytoma.
– Hematological Cancers (multiple
myeloma, lymphoma, and
leukemia)
– Ovarian small cell carcinoma of
the hypercalcemic type
– Hypervitaminosis D (vitamin D
intoxication)
– Elevated 1,25(OH)2D levels (e.g.
sarcoidosis and other
granulomatous diseases such as
tuberculosis, berylliosis,
histoplasmosis, Crohn’s disease,
and granulomatosis with
polyangitis).
– Idiopathic hypercalcemia of
infancy
– Rebound hypercalcemia after
rhabdomyolysis
– Hyperthyroidism
– Multiple myeloma
– Prolonged immobilization (with
or without Paget’s disease)
– Paget’s disease of bone
– Thiazide use
– Vitamin A intoxication
– Tertiary hyperparathyroidism
– Aluminum intoxication
– Milk alkali syndrome
– Adrenal insufciency (Addison
disease)
– Zollinger-Ellison syndrome
(ZES)
– Williams syndrome
(developmental disorder)
There are three separate syndromes in which
malignant tumors can result in a life-threatening
hypercalcemic crisis: (1) humoral hypercalcemia of malignancy (HHM) caused by endocrine
and paracrine mediators, (2) hypercalcemia
associated with localized osteolytic disease, and
(3) hypercalcemia associated with multiple
myeloma and related hematological malignancies. HHM results from the increased production
of the bone-resorbing PTH-related polypeptide
(PTHrP). This 146 amino acid polypeptide is
homologous to PTH in 8 of its rst 13 aminoterminal residues, and it binds to the PTH receptor and produces the same hypercalcemic effects
as PTH on end organs (bone, gut, and kidney)
[5]. In addition, it is not subject to the feedback
regulation via serum calcium that occurs with
PHPT.Humoral mediators of hypercalcemia in
malignancy lead to increases in bone resorption
by increasing osteolytic activity, and possibly by
disturbing calcium homeostasis in the kidney
and gut. Solid tumors of the lung, head, neck,
kidney, pancreas, and ovary are often associated
with humorally mediated hypercalcemia and
produce factors, including PTHrP, that are potent
activators of osteoclastic bone resorption and
cause hypercalcemia invivo [5]. Hematological
malignancies, most notably multiple myeloma,
secrete a number of cytokines that act locally in
the bone marrow to stimulate osteoclastic bone
resorption [104].
16.4.4 Clinical Features
ofHypercalcemic Crisis
A serum Ca level of 14.5mg/dL or higher should
be considered a medical emergency, and most
patients are symptomatic [5]. However, Frame
et al. (1981) reported that some patients are
asymptomatic with a serum Ca of 20 mg/dL,
while others with levels <14.5mg/dL may present with hypercalcemic crisis [120]. Thus, serum
Ca level should not be considered the sole marker
used to dene hypercalcemic crisis [121]. The
severity of hypercalcemia is usually proportional
to the increase in the PTH level [5], which is
almost always at least twice the upper limit of
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normal in patients with hypercalcemic crisis, and
as many as 40–50% have a palpable mass on
physical examination [122, 123].
The clinical manifestations of mild-tomoderate hypercalcemia include anorexia, malaise, weakness, osteoporosis, and renal stones.
These manifestations may only be recognized
retrospectively after a parathyroidectomy for
mild PHPT [3, 124]. As may be seen in Table16.7,
anorexia, polyuria, nausea, and vomiting caused
by hypercalcemia can result in dehydration [5].
The renal symptoms of hypercalcemic crisis are
polyuria and polydipsia with or without acute
renal failure (ARF). Neurological symptoms are
less characteristic and include depression, anxiety, and psychosis. Gastrointestinal (GI) symptoms include nausea, vomiting, constipation,
peptic ulcer disease (PUD), and pancreatitis.
Gastric acid secretion and pancreatic enzyme
secretion are also increased [10]. The cardiac
symptoms associated with hypercalcemic crisis
are also nonspecic. A shortened QT-interval and
tachycardia have been reported. The mechanism
of hypertension attributable to PHPT is still
unclear [6]. Thus, hypercalcemic crisis is a constellation of the above signs and symptoms,
including psychological disturbances (ranging
from drowsiness to stupor or coma), renal insufciency, and cardiac dysrhythmias (bradyarrhythmias, bundle-branch blocks, complete
heart blocks, and cardiac arrest) [5]. Grossman
etal. [5] suggested that hypercalcemia associated
with malignancy must be considered in patients
Table 16.7 Clinical manifestations of hyper-calcemic
crisis
System involved Manifestations
Renal Polyuria and polydipsia (with or
without ARF) and renal stones
Musculoskeletal Muscle weakness, decreased
reexes, bone aches, and joint pain
Gastrointestinal Loss of appetite, nausea, vomiting,
constipation, PUD, and pancreatitis
Cardiac Cardiac dysrhythmias,
hypertension, shortened
QT-interval on ECG
Neurological Drowsiness, confusion, stupor, or
coma
Psychological Depression, anxiety, and psychosis
with a history of breast cancer, for example, in
women and lung or renal cancer or myeloma in
both sexes [6].
16.4.5 Diagnosis/Work-Up
A complete history and physical examination and
a review of the patient’s medical records are the
most important elements in the emergency diagnosis of hypercalcemic crisis [5]. Patients with
PHPT rarely experience a hypercalcemic crisis,
and those who do usually have a long-standing
history of progressive symptoms of hypercalcemia. Most patients presenting with hypercalcemia
secondary to malignancy have an antecedent
diagnosis of malignancy, and many are already
hospitalized when severe hypercalcemia develops [104].
Grossman et al. (1997) recommended that a
serum ionized Ca assay be performed in all
patients who present with psychological disturbances, renal insufciency, cardiac dysrhythmias, or neurological abnormalities [5]. If an
ionized Ca assay is not available, the total serum
Ca level may be measured and the value corrected for the measured albumin level.
The most specic laboratory test in the differential diagnosis (DD) of hypercalcemia is the
serum intact PTH assay [125]. An increased
intact PTH level and Ca level are almost pathognomonic for PHPT. The quick (10 min) intact
PTH assay popularized by Irvin etal. [126]; however, has allowed a rapid DD of hypercalcemic
crisis. Other than PHPT, conditions with an
increased level of intact PTH include hypocalcemia, secondary HPT (with low to low normal
serum Ca), and tertiary HPT (with normal to
increased serum Ca) after a history of longstanding renal insufciency [5].
The majority of patients who present with
non-parathyroid hypercalcemia have malignant
disease. The paraneoplastic production of ectopic
PTH can occur, but is extremely rare [127]. If
familial hypocalciuric hypercalcemia (FHH) is
suspected, an above normal 24-h urine Ca or a Ca
clearance-to-creatinine ratio of >0.01in patients
who have never been documented as being
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16 Thyroid andParathyroid Endocrine Emergencies
473
normo-calcemic can rule out FHH [1]. Patients
with FHH rarely, if ever, have profound hypercalcemia. The serum 25-OH vitamin D level may be
checked if excessive vitamin D intake is suspected. The serum 1,25(OH)2 vitamin D level is
normally high or mildly elevated in patients with
PHPT.A cost-effective and accurate diagnosis of
HPT can be made by documenting increased calcium and intact PTH levels in patients who are
not hypocalciuric.
16.4.6 Hypercalcemic Crisis
inPregnancy
Although the exact incidence of PHPT during
pregnancy is still unknown, it is considered to be
a rare condition [128–130]. The incidence in
women of child-bearing age is estimated to be
approximately eight cases per 100,000 population/year [131]. During pregnancy, maternal PTH
levels increase to enhance gastrointestinal (GI)
absorption and hence placental transport of Ca to
the fetus [132]. Maternal hypercalcemia accompanying maternal HPT causes depression of the
fetal parathyroid gland (PTG) function [132].
After birth, the neonate no longer has access to
maternal serum Ca and is unable to adequately
mobilize Ca from bone because of depressed
PTG function, resulting in a risk of neonatal tetany. The placental delivery of Ca to the fetus is
greatest during the third trimester and is protective for the mother [128, 133]. Since this protection is lost with the delivery, the neonate is at the
greatest risk for tetany several hours after birth,
while the mother is at the greatest risk of developing a hypercalcemic crisis during the same
period [132, 134].
The incidence of fetal complications has been
reported to be 53% for treated mothers [130, 135]
and 80% for untreated mothers [135], and
between 27% and 31% among those whose
infants die during the neonatal period [130, 135].
Complications include intrauterine growth
restriction, a low-birth weight, preterm delivery,
and intrauterine fetal demise [128, 130, 135–137].
The diagnosis of HPT in pregnant patients is
most commonly made postpartum once the infant
develops neonatal tetany [132], which has been
reported to occur in nearly 50% of infants born to
untreated mothers [107].
The diagnosis and management of PHPT during pregnancy is imperative since it poses a signicant risk to the fetus as well as to the mother.
Schnatz and Curry (2002) recommended that if
hypercalcemia is not controlled medically, a
parathyroidectomy performed by an experienced
surgeon should be performed despite advanced
gestation, though preferably during the second
trimester [134]. Advances in surgical technology
have greatly improved the safety of parathyroidectomy [138–140]. Preoperative localization
studies including ultrasound, which is safely used
during pregnancy, offer the theoretical advantage
of maximizing surgical efcacy while minimizing the invasiveness and operative time [141,
142]. An alternative option is medical control,
such as with bisphosphonates and calcitonin, but
such therapy should only be used as part of the
preparation for a parathyroidectomy in patients
with profound hypercalcemia.
16.4.7 Treatment
The rst goal in the management of a hypercalcemic crisis is to lower the serum Ca level, and
next, to identify the etiology. Therapy should be
directed toward increasing Ca urinary excretion
and decreasing bone resorption [5, 104].
Increasing Ca excretion during a hypercalcemic
crisis using hydration and loop diuretics (furosemide) is quicker and easier than decreasing bone
resorption [121]. Symptomatic treatment is summarized in Table16.8.
Immediate therapy includes rapid and complete volume re-expansion [104], with continuous monitoring to avoid uid overload [121]. The
IV infusion of normal saline is indicated to promote renal Ca excretion and to restore cardiovascular function [143]. A 500 mL IV bolus of
normal saline should be administered initially
[5]. Usually, the goal should be 2–8L/day, and
once the kidneys have begun to respond to rehydration, a loop diuretic may be administered to
accelerate calciuresis [144]. Loop diuretics have
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474
Table 16.8 Symptomatic treatment of hypercalcemic crisis
Type Substance Indication
Diuretic – Normal saline
– Loop diuretics (furosemide)
Antirestorative
biphosphonates
Extractive – Hemodialysis – Renal insufciency
– Clodronate, Pamidronate, Ibandronate,
Risedronate
– Calcitonin
– Plicamycin (mithramycin)
– Universal
– Universal in cases of uid retention
– Universal (in preference in humoral
hypercalcemia of malignancy)
– Universal (adjuvant drug)
– Rare
M. Sakr
a profound effect on sodium (Na) and water
excretion [145]. Lower doses stimulate natriuresis, which is accompanied by calciuresis [6], but
if Na excretion exceeds the rate of replacement
with IV normal saline, renal sodium-conserving
mechanisms are activated, limiting Ca excretion
and aggravating the hypercalcemia [145]. A
direct calciuretic effect of loop diuretics can be
expected at high doses of 100 mg/h [144], and
aggressive uid hydration in combination with
loop diuretics is effective in lowering serum Ca
by 1.5–2.0mg/dL in 24–48h [104].
Many patients with a hypercalcemic crisis and
those with concurrent cardiac or other illness
require treatment in the ICU for the cautious
monitoring of vital signs, CVP, urine output
(UOP), and serum and urine electrolyte levels.
Chan et al. [145] advised the administration of
moderate doses of loop diuretics to older patients
with mildly impaired cardio-vascular function
when there is concern about volume overload
[55]. Thiazide diuretics should not be used, as
they increase the distal tubular reabsorption of Ca
and may exacerbate hypercalcemia [3].
The routine approach of saline solution
administration is ineffective in patients with
severely impaired renal function, and hemodialysis against a zero or a low Ca dialysate concentration may be necessary [5]. Some cases of
hypercalcemia caused by HPT are refractory to
hydration and diuresis, and thus inhibitors of
osteoclastic bone resorption are indicated when a
24-h to 48-h period of treatment has failed to
lower the blood Ca level [5]. The recognition of
this clinical entity and a subsequent urgent
parathyroidectomy has recently been shown to be
associated with low morbidity and an excellent
long-term outcome [146, 147]. Parathyroidectomy
is the denitive treatment of PHPT and should
not be delayed once a patient in hypercalcemic
crisis has recovered in response to treatment.
Ultrasonography is essential as a preoperative
localization test and is generally positive in
patients with a hypercalcemic crisis, since the
parathyroid masses of such patients are usually
large. However,
99m
Tc-SestaMIBI scintigraphy
may be required for localization, although it is
not recommended during pregnancy. Both CT
scan and MRI are more expensive and less accurate in preoperative localization. An intraoperative quick PTH assay biochemically conrms
that the adenomas have been completely excised
[126, 148]. Radio-guided parathyroidectomy,
which can be performed quickly using a lessinvasive procedure, has been developed [149],
with improved outcomes [150–152].
Once initial therapy has been instituted, the
administration of inhibitors of osteoclastic bone
resorption such as bisphosphonates, calcitonin, plicamycin (mithramycin), glucocorticoids, and gallium
nitrate should be considered [104]. The choice of the
agent is based on its pharmacodynamics, onset and
duration of action, route of metabolism, and potential side effects, as well as the etiology of hypercalcemia [104, 121]. The administration of
bisphosphonates should be considered early in
patients with HHM.Bisphosphonates are chemical
analogs of pyrophosphate and directly inhibit osteoclast function. Available agents include etidronate,
clodronate, pamidronate, ibandronate [107], and
risedronate, and each member of the bisphosphonate
family appears to have its own mechanism of osteoclast inhibition [145]. Bisphosphonates are administered IV, since they are poorly absorbed when
administered orally. Multiple infusions of the second-generation bisphosphonate pamidronate (Aredia) in conjunction with volume replenishment may
decrease the serum Ca level to normal within 7days
in nearly 75% of patients with hypercalcemia of
malignancy [153, 154] Pamidronate therapy may be
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16 Thyroid andParathyroid Endocrine Emergencies
475
complicated by mild hyperthermia, GI symptoms,
hypophosphatemia, hypokalemia, and hypomagnesemia. Pamidronate is a more potent and possibly
less toxic bisphosphonate than etidronate, a rstgeneration bis-phosphonate that is often used in the
treatment of Paget’s disease of bone.
Calcitonin (salmon, human) is a polypeptide
secreted by the C-cells of the thyroid and is a
potent inhibitor of osteoclastic bone resorption. It
promotes calciuresis at pharmacological doses
[155], and its hypocalcemic effect is the most
rapid of the agents, occurring within 2h in most
patients and lasting for up to 1week [156]. This
early loss of effectiveness is thought to result from
the downregulation of calcitonin receptors on the
surface of osteoclasts and has been termed the
“escape phenomenon” [157]. Nevertheless, it may
be overcome by the concomitant use of glucocorticoids [158, 159]. Calcitonin is best used as an
adjunct therapy with other antiresorption agents or
calciuric agents [104, 121, 145]. Combining the
rapid hypocalcemic effects of calcitonin with the
more delayed effect of a bisphosphonate has been
reported by several researchers to be a reasonable
approach for patients with severe hypercalcemic
crisis [160–163]. The onset of the antihypercalcemic effect is observed within 2h after combination
therapy consisting of a single IV injection of pamidronate and serial intramuscular (IM) injections of
calcitonin, and the effect is of sufcient duration
[162, 163]. Pamidronate and calcitonin do not
interfere with each other, and their combined use
to treat hypercalcemia is rapid, effective, and safe.
This combined treatment aids the safe performance of surgery in PHPT patients, appears to be
useful for improving quality of life, and is therapeutically effective in patients with malignancyassociated hypercalcemia.
16.5 Acute Hypocalcemic
Crisis—Tetany
16.5.1 Introduction
Calcium (Ca) is a bivalent cation that is essential
for a number of physiological processes that
include neuro-muscular activity, endocrine and
exocrine secretion, coagulation, immunity, and
bone metabolism. Plasma Ca concentration is
maintained within a narrow range of approximately, 2.2–2.6 mmol/L (8.5–10.5mg/dL) despite
large movements of Ca across the kidney, bone,
gut, and cells. Hypocalcemia is a common electrolyte disturbance complicating approximately
26% of hospital admissions and is found in as
many as 88% of patients admitted to (ICU) [164].
Chronic hypocalcemia may be asymptomatic
even at low levels of serum Ca, but severe (or
acute) hypocalcemia, dened by a serum
Ca<1.9 mmol/L (7.6 mg/dL), is often considered
an emergency because of the potential risk of
life-threatening cardiac arrhythmias or seizures
(neuro-muscular dysfunction) [165–170]. Severe
hypocalcemia has also been considered an independent risk factor of mortality among patients
admitted to the emergency department (ED) and
ICUs [171–174], particularly from sudden cardiac arrest [175].
16.5.2 Pathophysiology
The total Ca concentration in the plasma is
4.5–5.1mEq/L (9–10.2 mg/dL) with 50% being
“ionized,” 40% “protein-bound” (90% of which
binds to albumin), and 10% circulating “bound to
anions” (eg, phosphate, carbonate, citrate, lactate, sulfate). Ionized Ca is the necessary plasma
fraction for normal physiological processes. In
the neuro-muscular system, ionized Ca facilitates
nerve conduction, muscle contraction, and muscle relaxation. Calcium is necessary for bone
mineralization and is an important co-factor for
hormonal secretion in endocrine organs. At the
cellular level, Ca is an important regulator of ion
transport and membrane integrity [176].
Calcium (Ca), phosphate, and magnesium
(Mg) are ingested in the diet, absorbed from the
intestine, ltered in the glomerulus of the kidney,
reabsorbed in the renal tubules, and eliminated in
urine. Only a small, but vital, amount of these
three ions is present in extra-cellular uid (ECF)
and is directly or indirectly regulated by vitamin
D and parathyroid hormone (PTH) [176, 177].
Vitamin D acts to sustain normal plasma levels
of Ca and phosphate by increasing their absorption from the intestine, regulating PTH release by
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