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476
M. Sakr
the chief cells, and mediating PTH- stimulated
bone reabsorption [176–179]. Vitamin D3 is synthesized by ultraviolet (UV) irradiation of
7-dehydro-cholesterol, which is present in the
skin or diet. Once vitamin D enters the circulation
from the skin or intestine, it is concentrated in the
liver where it is hydroxylated to form
25-hydroxyvitamin D3 (25-(OH)D3). It is then
transported to the kidney, where it is transformed
into active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The major action of the activated form
of vitamin D (calcitriol), is to increase the absorption of Ca and sensitize bone to the resorptive
actions of PTH.There is also recent evidence that
vitamin D controls parathyroid gland growth and
suppresses the synthesis and secretion of
PTH.The formation of calcitriol in the kidneys is
regulated by the feedback mechanism of plasma
Ca and phosphate levels. Calcitonin lowers Ca
level by targeting bone, renal, and GI losses.
The main function of PTH is to maintain the Ca
concentration of the ECF.It performs this function
by promoting the release of Ca from bone, increasing the activation of vitamin D as a means of
enhancing intestinal absorption of Ca, and stimulating Ca conservation by the kidney while increasing
phosphate excretion. The dominant regulator of
PTH is the plasma Ca concentration. The parathyroid gland has a remarkable sensitivity to ionized
serum calcium changes. These changes are recognized by the calcium- sensing receptor (CaSR), a
7-transmembrane receptor linked to G-protein with
a large extracellular amino-terminal region [176,
177]. Binding of calcium to the CaSR induces acti-
vation of phospholipase C and inhibition of PTH
secretion. On the other hand, a slight decrease in
calcium stimulates the chief cells of the parathyroid
gland to secrete PTH.The response to a decrease in
plasma Ca is prompt, occurring within seconds
[180].
Patients with a decrease in total serum Ca may
not have “true” hypocalcemia, which is dened
as a decrease in ionized Ca. A reduction in total
serum Ca can result from a decrease in albumin
secondary to liver disease, nephrotic syndrome,
or malnutrition.
Alkalemia induces tetany due to a decrease in
ionized Ca, whereas acidemia is protective. In
patients with renal failure who have hypocalce-
mia, rapid correction of acidemia or development
of alkalemia may thus trigger tetany [181–183].
16.5.3 Etiology ofHypocalcemia
Calcium homeostasis is maintained through
interactions involving the PTGs, kidneys, bones,
and vitamin D metabolism [168, 176, 177, 179].
There are a large number of recognized causes of
hypocalcemia and correct management depends
on appropriate diagnosis [176, 177].
Hypocalcemia occurs with either decreased
entry of Ca into the circulation or through sequestration and effective removal of Ca (Table16.9).
Table 16.9 Etiology of hypocalcemia
Reduced entry of Ca into
circulation
Parathyroid dysfunction
– Hypoparathyroidism
Autoimmune
Autoimmune
polyglandular
syndrome (APS)
Post-operative
Inltrative
– Hypo-magnesemia
– Hyper-magnesemia
– Congenital disorders
of PTGs
Di George
syndrome
Defects in Ca-SR
– Pseudo-
hypoparathyroidism
secondary to
G-protein defects
Vitamin D deciency
– Dietary or
malabsorption
– Lack of sunlight
exposure
– Renal impairment
Ca calcium, PTG parathyroid gland, Ca-SR calciumsensing receptor, EDTA ethylene diamine tetra acetic acid
Increased movement of Ca
out of circulation
Movement into bone
stores
– Hungry bone
syndrome
– Osteoblastic
metastases (e.g.,
prostatic cancer,
breast breast)
Chelation of ionized
calcium
– Acute pancreatitis
–
Hyperphosphatemia
Renal
impairment
Tumor lysis
syndrome
Rhabdomyolysis
– Citrate or EDTA
(transfusions/
phlebotomy)
Miscellaneous
– Sepsis
– Drugs such as
bisphosphonates
and denosumab
(both inhibit
osteoclastic bone
resorption),
chemotherapeutic
agents and
Foscarnet
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16 Thyroid andParathyroid Endocrine Emergencies
477
The most common cause of hypocalcemia in the
general population is vitamin D deciency.
However, the most commonly encountered cause
of acute hypocalcemia is postoperative hypoparathyroidism in the context of neck surgery.
Hypoparathyroidism can also less commonly be
due to autoimmune or inltrative conditions
[184]. Congenital disorders and pseudo-
hypoparathyroidism cause hypocalcemia through
defects in the calcium-sensing receptor or parathyroid receptor. Hypo- and hyper-magnesemia
both cause abnormal PTH production and secretion. Vitamin D deciency, which may be primary
in the context of dietary or environmental causes
or secondary due to hepatic or renal impairment,
can cause hypocalcemia or may exacerbate hypocalcemia caused by other processes [183].
Excessive movement of Ca into bone occurs
with “hungry bone syndrome” and osteoblastic
bone disease including metastatic cancer (e.g.,
breast or prostate cancer). Hyperphosphatemia,
most commonly seen in renal impairment, but also
a feature of tumor lysis syndrome and rhabdomyolysis, causes hypocalcemia through sequestration
and complexing of ionized Ca. Acute pancreatitis
is associated with the formation of Ca complexes
within the abdominal cavity. Calcium chelation
can occur with ethylene diamine tetra acetic acid
(EDTA), or citrate but is rare with normal renal
and hepatic function. Sepsis-related hypocalcemia
is multifactorial, but signicant factors include
renal impairment, Mg abnormalities, release of
inammatory cytokines, and frequent transfusions. Finally, a number of medications are associated with hypocalcemia [185].
16.5.4 Etiology
ofHypoparathyroidism/
PTH-Related Hypocalcemia
Hypoparathyroidism can be hereditary or
acquired; both varieties share the same symptoms, although hereditary hypoparathyroidism
tends to have a gradual onset [186]. Clinical manifestations of hypoparathyroidism can result from
either decreased secretion of parathyroid hormone (PTH) or target organ resistance to PTH.
The etiologies of inadequate PTH secretion
include (1) the destruction of the parathyroid
glands (PTGs) as a complication of neck surgery,
(2) genetic defects, such as mutations in the PTH
gene or the Ca-SR gene, (3) developmental
anomalies including DiGeorge’s syndrome, (4)
autoimmune destruction as in the polyglandular
autoimmune endocrinopathies, and (5) inltrative diseases including hemochromatosis and
Wilson’s disease. In contrast to true hypoparathyroidism, hypocalcemia, and hyperphosphatemia
in pseudo-hypoparathyroidism are accompanied
by an elevated serum level of PTH and result
from resistance to the action of PTH rather than
from PTH deciency.
Acquired hypoparathyroidism may result from
the following:
– Neck irradiation/radioactive iodine (RAI)
therapy [187].
– Post-parathyroidectomy in dialysis patients
[188].
– Inadvertent surgical removal as a complica-
tion of neck surgery (can be transient or
permanent).
– Inltrative disease (e.g., hemochromatosis,
Wilson’s disease, granulomatous disease [sar-
coidosis], thalassemia, amyloidosis, or meta-
static malignant inltration).
– Autoimmune destruction: late-onset hypopara-
thyroidism can be seen as a part of a complex
autoimmune disorder involving ovarian and
adrenal failure. Mucocutaneous candidiasis,
alopecia, vitiligo, and pernicious anemia are
associated with this disorder, known as “poly-
glandular autoimmune disease” (PGA I).
Hereditary hypoparathyroidism may be
familial or sporadic, and it can occur as an
isolated entity or can be associated with
other endocrine manifestations.
– The familial forms result from genetic defects,
such as mutations in the PTH gene or the
Ca-SR gene.
– Sporadic, late-onset hypoparathyroidism is a
feature of several hereditary syndromes,
which include (1) DiGeorge syndrome (con-
genital heart disease, cleft palate/lip, and
abnormal facies), (2) Kearns–Sayre syndrome
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478
M. Sakr
(heart block, retinitis pigmentosa, and ophthalmoplegia), and (3) Kenny–Caffey
syndrome (medullary stenosis of the long
bones and growth retardation).
16.5.5 Post-Surgical
Hypoparathyroidism
The most common cause of hypoparathyroidism
is surgical destruction, devascularization, or
removal of the PTGs. Hypoparathyroidism can
occur after any surgical procedure involving the
anterior neck; however, it is most common after
thyroid and parathyroid surgery, or after extensive resection for head and neck cancer.
Estimates of the incidence of post-thyroidectomy hypoparathyroidism varied widely, ranging from 6.9% to 46% for transient and 0.4–33%
for permanent hypoparathyroidism [7]. A 1998
multicenter prospective trial of 5846 patients
who underwent total thyroidectomy (TT)
reported an incidence of transient hypoparathyroidism of 7.3% and permanent hypoparathyroidism of 1.5%.
Technical factors associated with development of postoperative hypocalcemia were central
rather than peripheral ligation of the inferior thyroid arteries (ITAs) and identication of <2
PTGs. Thyroidectomy for Graves’ disease was
also associated with increased risk when compared with other diagnoses. Following TT, more
experienced surgeons reported a lower incidence
of postoperative hypoparathyroidism and other
complications [8].
Post-surgical hypoparathyroidism is usually
apparent in the rst 24–48h after parathyroidectomy. Generally, calcium (Ca) values begin to
normalize within 1week after surgery. If the preexisting HPT resulted in excessive bone resorp-
tion or osteitis brosa cystica, then a more severe
and protracted form of hypocalcemia referred to
as “hungry bone syndrome” may ensue. Once the
chronic PTH-stimulated bone resorption is halted
by parathyroidectomy, Ca and phosphorous
deposit rapidly in the bones and can precipitate
symptomatic hypocalcemia and hypophosphatemia. An elevated serum PTH and a low phosphorous level distinguish hypocalcemia related to
hungry bone syndrome from hypocalcemia
resulting from true hypoparathyroidism
(Table 16.10). Among patients with PHPT, predictors of postoperative hungry bone syndrome
include increased adenoma size, advanced age,
elevated alkaline phosphatase, and elevated blood
urea nitrogen (BUN) [189] Hungry bone syndrome is typically associated with more severe
symptomatic hypocalcemia and may require
treatment for several weeks to months before
parameters normalize.
16.5.6 Clinical Manifestations
The clinical manifestations of hypocalcaemia
depend on the degree of hypocalcaemia (ionized
calcium level) and the rate of its development.
The typical signs and symptoms associated with
hypocalcemia are neuro-muscular irritability,
including peri-oral or acral paresthesias, muscle
cramps that may progress to carpo-pedal spasm,
laryngo-spasm, broncho-spasm, or even tetany (a
state of spontaneous tonic muscular contraction,
typically seen when the ionized Ca drops below
1.0mmol/L [<4 mg/dL]) (normally 4.5–5.5mg/
dL) [190, 191]. Tingling parasthesia in the ngers and around the mouth indicate overt tetany,
while carpo-pedal spasm indicates severe hypocalcemia and is considered the classic muscular
component of tetany. In carpal spasm, the typical
Table 16.10 Biochemical characteristics of selected hypocalcemic disorders
Disorder Calcium PTH Phosphorous
Hypoparathyroidism Low Low High
Hungry bone syndrome Low High Low
Pseudo-hypoparathyroidism Low High High
Pseudo-hypoparathyroidism Normal Normal Normal
PTH Parathyroid hormone
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16 Thyroid andParathyroid Endocrine Emergencies
479
“main d’accoucheur” posture is characterized by
thumb adduction, exion of metacarpophalangeal joints, extension of inter-phalangeal
joints, and exion of wrists (Fig.16.1). In pedal
spasm, there is big toe extension and exion of
metatarso-phalangeal joints of the lateral 4 toes
(Fig.16.2). These automatic muscle contractions
are painful. All muscles can participate in tetany,
but the most dangerous is the spasm of laryngeal
muscles resulting in stridor.
Fig. 16.1 Carpal spasm: The typical “main d’accoucheur”
posture is characterized by adduction of the thumb, exion of the metacarpo-phalangeal joints, extension of the
interphalangeal joints, and exion of the wrists
Central nervous system (CNS) manifestations
of hypocalcemia range from mood lability to stupor to focal or generalized seizures. Simple bedside maneuvers such as the Chvostek’s sign and
Trousseau’s sign can reveal the presence of
neuro-muscular irritability. Chvostek’s sign is
described as circumoral twitching following tapping of the facial nerve. This sign is present in
10–30% of normal individuals; therefore, if it is
to be used as a post-operative marker of hypocalcemia it must be tested pre-operatively to verify
that it is not present [192]. Conversely, Chvostek’s
sign is negative in approximately 30% of those
with hypocalcaemia [192]. Trousseau’s sign is
carpal spasm that is elicited by ination of a
blood pressure cuff to 20 mmHg above the
patient’s systolic blood pressure for 3 min.
Trousseau’s sign is more sensitive (94%) and
specic for hypocalcaemia than Chvostek’s sign
and is positive in only 1% of normo-calcemic
patients [192].
Other clinical presentations of hypocalcemia
are pseudo-tumor cerebri, papilledema, confusion, lassitude, and organic brain syndrome.
Basal ganglia are often calcied in patients with
long-lasting hypocalcemia, and this can be
related to movement disorders. Other manifestations include cardiac effects (delayed repolarization, prolongation of QT on ECG, and refractory
CHF), ophthalmological effects (cataract), and
dermatological effects (dry skin and brittle nails).
Symptoms and signs of hypocalcemia are
summarized in Table16.11. They include muscu-
lar, dermatological, neuro-psychological, cardiac, and ophthalmological manifestations.
Fig. 16.2 Pedal spasm: Extension of the big toe and exion of the metatarso-phalangeal joints of the lateral 4 toes
t.me/Dr_Mouayyad_AlbtousH
16.5.7 Hypocalcemia Work-Up
16.5.7.1 Approach Considerations
Symptomatic patients with acute or severe hypocalcemia require immediate resuscitation and evaluation. However, most cases of hypocalcemia are
discovered by clinical suspicion and appropriate
laboratory testing. Albumin, liver function studies,
and coagulation parameters should be obtained to
assess liver dysfunction and hypo-albuminemia.
Blood urea nitrogen (BUN) and serum creatinine
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M. Sakr
Table 16.11 Symptoms and signs of Hypocalcemia
Symptoms
Neuro-muscular
[193]
Dermatological – Hair loss, coarse hair
Neuropsychological
[194]
Physical Signs
Neuro-muscular – Parasthesia (circumoral and
Cardiovascular
[195]
Ophthalmological – Subcapsular cataract
Dermatological – Dry skin (xeroderma),
– Muscle twitches, muscle
aches, or cramps.
– Change of voice (due to
laryngo-spasm)
– Wheezing (due to
broncho-spasm)
– Dysphagia
– Brittle nails
– Dry skin
– Chronic pruritus
– Psoriasis
– Anxiety, irritability,
depression
– Headache
– Impaired intellectual
capacity, memory loss
– Personality changes
– Weakness and fatigue
– Tingling in the lips, ngers,
or toes
extremities)
– Muscle spasms, seizures
(grand mal, petit mal, focal)
– Chvostic’s sign
– Trousseau sign
– Tetany (clinical or latent)
– Laryngo-spasm (stridor),
broncho-spasm (wheezing)
– Irritability, confusion,
hallucinations, dementia
– Coma
– Pseudo-tumor cerebri,
papilledema
– Dysrhythmia (bradycardia,
tachycardia), hypotension,
refractory CHF
– Papilledema
patches of psoriasis or
eczema, and excoriations
from pruritis (may be
present)
– Brittle nails, hair loss
– Surgical skin scar indicating
previous neck surgery, e.g.,
thyroidectomy
should be measured, as elevated levels may indicate kidney dysfunction. Other tests such as markers of bone activity (e.g., alkaline phosphatase),
should also be considered. In addition, assessment
of acid/base status is also warranted because alkalosis tends to decrease ionized Ca levels due to
increased binding to albumin.
In a patient with hypocalcemia, measurement
of the serum albumin is essential to distinguish
true hypocalcemia (reduction in ionized serum
Ca), from factitious hypocalcemia (decreased
total Ca). Corrected Ca (mg/dL)=measured total
Ca (mg/dL)+0.8 (4.0−serum albumin [g/dL]),
where 4.0 represents the average albumin level.
Parathyroid hormone (PTH) level should be
checked as early as possible and vitamin D
should be measured if deciency is suspected. In
patients with PTH deciencies, alkaline phosphatase levels tend to be normal or slightly
decreased, whereas these levels frequently are
elevated in patients with osteomalacia and rickets. If the diagnosis of osteomalacia is suspected,
a bone biopsy can determine the nal diagnosis.
An electrocardiogram (ECG) is indicated in case
of hypocalcemia. Imaging studies may include
plain radiography or computed tomography (CT)
scans to detect or rule out rickets, osteomalacia, or
osteoblastic metastases from certain tumors (e.g.,
breast, prostate, and lung), which can cause hypocalcemia. CT scans of the head may show basal
ganglia calcication and extra-pyramidal neurological symptoms (in idiopathic hypoparathyroidism).
16.5.7.2 Serum Ionized Calcium
Ionized calcium is the denitive method for diagnosing hypocalcemia. A serum calcium
level< 2.0 mmol/L (<8.5mg/dL) or an ionized
Ca level<1.0mmol/L (<4mg/dL) is considered
“hypocalcemia” [176]. Analysis for the ionized
Ca level must be performed rapidly with whole
blood to avoid changes in pH and anion chelation. Blood should be drawn in an unheparinized
syringe for best results. Falsely elevated Ca levels
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16 Thyroid andParathyroid Endocrine Emergencies
481
may be seen with elevated acetaminophen levels,
alcohol, hydralazine, and hemolysis. Falsely
depressed levels can be seen with heparin, oxalate, citrate, or hyper-bilirubinemia.
16.5.7.3 Serum Electrolytes
Phosphate and Mg levels should be evaluated in
every patient with hypocalcemia. In healthy kidneys, PTH stimulates phosphate excretion. The
combination of hypocalcemia and elevated phosphorus levels typically suggests hypoparathyroidism or pseudo-hypoparathyroidism. Patients
with renal failure (RF) and hypocalcemia usually
present with hyper-phosphatemia and high PTH
levels. Hypophosphatemia develops in patients
with vitamin D deciency and hungry bone syndrome. Occasionally, inadequate Mg intake in
diet results in hypo-magnesemia, hypophosphatemia, and hypo-calcemia [196].
16.5.7.4 Parathyroid Hormone (PTH)
The PTH level should be checked by as early as
possible. Low-to-normal PTH levels occur in
patients with hereditary or acquired hypoparathyroidism and in patients with severe hypomagnesemia. Patients with ineffective PTH have
elevated PTH levels. The PTH elevation is a
result of hypocalcemia.
16.5.7.5 Vitamin D Metabolites
If vitamin D deciency is suspected, measurements of 25(OH) D and 1,25(OH)2 D should be
performed. A low 25(OH) D level suggests vitamin D deciency from poor nutritional intake,
lack of sunlight, or malabsorption. Low levels of
1,25(OH)2 D in association with high PTH suggest ineffective PTH from a lack of vitamin D, as
observed in patients with chronic RF and
pseudo-hypoparathyroidism.
Urinary cyclic adenosine monophosphate
(cAMP) may help differentiate hypoparathyroidism from pseudo-hypoparathyroidism types I and
II.Urinary cAMP levels are generally elevated in
hypoparathyroidism.
16.5.7.6 Electrocardiogram (ECG)
Acute hypocalcemia causes prolongation of the
QT-interval, which may lead to ventricular dys-
rhythmias. It also causes decreased myocardial
contractility, which can lead to CHF, hypotension, and angina. Cardiomyopathy and ventricular tachycardia may be reversible with
treatment.
16.5.8 Emergency Treatment/Acute
Intervention
Symptomatic patients (e.g., tetany, seizures,
laryngospasm or cardiac arrhythmias, or dysfunction) or those with a corrected Ca below
2 mmol/L (<8 mg/dL) should prompt urgent
intervention with IV Ca supplements [197].
Intermittent IV dosing may be associated with
signicant uctuations in Ca level, and continuous infusion is preferable in severe cases. This
treatment should be given in hospital and Ca levels carefully monitored (usually every 1–2h). A
recommended approach includes using 10–12
ampules of 10% Ca gluconate, infused slowly in
50–100 mL 0.9% saline (or 5% dextrose) over
10–20min (with cardiac monitoring). Ca gluconate is the preferred formulation for acute Ca
replacement and should be repeated until the
patient is symptom free. The infusion should then
be titrated to maintain a serum Ca level in the low
normal range (2.0–2.1mmol/L [8–8.5mg/dL]).
This continuous infusion may then be converted
to an oral regimen of Ca and calcitriol once the
patient is stabilized [197].
Patients who are asymptomatic or minimally
symptomatic with mild hypocalcemia
(7.5–8.5mg/dL) may be treated with oral therapy
consisting of up to 1000 mg of elemental Ca
every 6h and 0.25–2.0μg/day of calcitriol [1,25-
(OH)2]. The dose should again be titrated to keep
the serum Ca in the low normal range.
Magnesium levels should also be monitored
and repleted, as hypomagnesemia may result in
PTH resistance and impaired PTH secretion.
Empirical administration of Mg is recommended
if there is likely to be a delay in acquiring a magnesium level. The preferred infusion is Mg sulfate 2g (8mmol) in 5% dextrose over 10–20min.
This can be followed by a further 4g (16mmol)
in the next 4h if necessary.
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482
M. Sakr
16.5.9 Maintenance Therapy
Oral Ca replacement should be initiated as soon
as possible along with vitamin D replacement.
Calcitriol (1,25-(OH)2D3) is the preferred
preparation of vitamin D for patients with severe
acute hypocalcemia because of its rapid onset of
action. Calcitriol should be started immediately
at a dose of 0.5–1mg/day. The doses of calcitriol
and oral Ca should be adjusted to maintain serum
Ca levels in the low normal range. For most other
patients, the choice of vitamin D preparation will
depend on the cause of the hypocalcemia and the
desired pharmacological properties (i.e., rapid
acting vs. long acting, oral vs. parenteral, etc).
While 1,25-(OH)2D3 has a half-life of approximately 6h, 25-(OH)2D3 preparations have halflives of weeks to months. Repeat assessment of
vitamin D levels when using these longer-acting
products should be delayed until 3months have
elapsed since commencement [179].
Another consideration in patients with decient of PTH action at the renal tubule is the
resultant unopposed calciuria. Urinary Ca excretion should be measured once a satisfactory Ca
level has been achieved, either with a 24-h collection of urine or calculated on a spot urine with a
Calcium: creatinine ratio. If excessive excretion
is detected, a lower serum Ca target should be set.
If use of a lower target is associated with hypocalcemic symptoms, a thiazide diuretic can be
benecial due to the reduced tubular Ca excretion
produced by this class of medicines. Even in stable patients, serum and urinary calcium levels
should be monitored every 6months to check for
hypercalcemia and hypercalciuria [197].
16.5.10 Emerging Therapies
Due to the limitations of treatment with Ca and
calcitriol, recombinant PTH is being investigated
as a potential therapy in patients with permanent
hypoparathyroidism [198–200]. Teriparatide
[human PTH (1–34)] and NPSP558 [human PTH
(1–84)] are the two forms of recombinant PTH
currently in clinical use. Both are administered
by subcutaneous (SC) injection. Typically,
patients are treated with 20mg teriparatide subcutaneously, twice a day, or up to 2mg/kg/day. In
a 3-year randomized controlled trial, patients
treated with PTH (1–34) twice daily demonstrated decreased hypercalciuria and improved
bone turnover markers when compared with
patients receiving oral Ca and calcitriol [201].
There are also some data to suggest that quality
of life in patients with hypoparathyroidism is
improved by treatment with recombinant PTH
instead of calcitriol [198]. Of the two available
formulations, PTH (1–84) offers the advantage of
less frequent (every other day) dosing. Use of
continuous SC infusion of PTH by pump, as is
available for insulin administration, has been
investigated in at least one small trial [202]. Cost
remains a major disincentive to use of PTH therapy versus calcitriol, and the injection route
poses an additional barrier. At present, recombinant PTH is available for the treatment of osteoporosis, but it is not FDA-approved for the
treatment of hypoparathyroidism.
Drugs that antagonize the calcium-sensing
receptor (termed calcilytics), thereby increasing
PTH secretion, are in development and may also
have a role in the management of hypoparathyroidism [203].
An additional emerging area of research is
stem cell therapy for hypoparathyroidism. Areas
of investigation have included animal studies of
hematopoietic stem cells transfected with the
human PTH gene [204] and invitro embryonic
stem cells differentiated into parathyroid-like
cells [205]. Generated cells express the calciumsensing receptor and secrete PTH.Ideally, cells
collected from individual patients could be differentiated invitro to parathyroid-like cells, then
auto-transplanted to treat hypoparathyroidism.
However, this approach is likely still some years
away from clinical use.
16.5.11 Pseudo-Hypoparathyroidism
Pseudo-hypoparathyroidism is a heterogeneous
group of disorders characterized by PTH resistance. Typically, these patients present with
hypocalcemia and hyperphosphatemia due to
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16 Thyroid andParathyroid Endocrine Emergencies
483
impaired target tissue responsiveness to PTH
rather than to inadequate PTH production.
Two genetically distinct forms of pseudohypoparathyroidism type 1 have been described.
The more common variant, termed
pseudo- hypoparathyroidism type 1a, is an autosomal dominant disorder with resistance to multiple hormones (PTH, STH, luteinizing hormone,
gonadotropin hormone-releasing hormone) and a
constellation of development defects termed
Albright’s hereditary osteodystrophy (AHO)
tance and have normal Ca, phosphorous, and
PTH levels. Conrmation of the diagnosis of
pseudo-hypoparathyroidism 1a or 1b can be
accomplished by monitoring urinary cyclic adenosine monophosphate and phosphate excretion
following infusion of PTH [211]. Although a reliable diagnosis of pseudo-hypoparathyroidism 1a
may be made on clinical grounds, the molecular
genetic diagnosis requires inactivating mutation
of GNAS1. There is currently no commercially
available genetic test for PHP 1b.
[206].
These defects include short stature, obesity,
round facies, brachy-metacarpia, SC ossication,
and mental deciency. Patients with pseudohypoparathyroidism type 1a have mutations in
maternal GNAS1 alleles that abrogate expression
or activity of Gs, the hetero-trimeric G protein
that couples receptors to activation of adenylyl
cyclase [207]. Identical mutations in paternal
ment of pseudo-hypoparathyroidism are similar
to those for postoperative hypoparathyroidism
causing hypocalcemia, with the mode of treatment dictated by the severity of hypocalcemia
and the presence of symptoms. Long-term therapy consists of oral administration of Ca and
vitamin D, while acute hypocalcemic crisis
requires IV infusion of Ca.
alleles are associated with AHO and normal hormonal responsiveness, a variant termed pseudopseudo- hypoparathyroidism (PPHP) [208].
16.5.12 Complications andPrognosis
Pseudo-hypoparathyroidism type 1b is a less
common and clinically distinct variant of hypoparathyroidism that has been linked to the
GNAS1 locus [209]. Patients with pseudohypoparathyroidism 1b lack features of AHO,
show renal resistance to PTH as the only manifestation of hormone resistance, and have normal
Gsa activity in tissue. Pseudo-hypoparathyroidism
type 1b arises as a result of imprinting defect that
affects expression of GNAS1 in the proximal
renal tubule and is the basis for this disorder.
The overall prognosis of hypocalcemia is good as
it can be easily corrected. In rare cases, patients
with complete parathyroidectomy require very
high doses of calcium and vitamin D supplements to maintain calcium in the normal range.
Patients who have undergone gastric bypass surgery usually have malabsorption and may also
require very high doses of calcium and vitamin D
to correct hypocalcemia.
Specically, patients with pseudohypoparathyroidism 1b have paternal-specic
patterns of cytosine methylation [210]. The specic genetic mutation that accounts for this methylation defect is unknown. Biochemically,
pseudo-hypoparathyroidism 1a and 1b leads to
functional hypoparathyroidism. Laboratory tests
show hypocalcemia, hyperphosphatemia, and
elevated levels of PTH.
In addition, individuals with pseudohypoparathyroidism 1a may also manifest symptoms of hypothyroidism, gonadotropin resistance,
and growth hormone deciency. In contrast, individuals with PPHP do not exhibit hormone resis-
threatening cardiac complications such as reversible heart failure, ventricular tachycardia, and
ventricular brillation, with hypocalcemia [212].
However, these case reports often attribute the
rhythm change to hypocalcemia when a perfectly
valid differential diagnosis is present [212, 213].
Recently, Yarmohammadi etal. (2017) evaluated
the role of hypocalcemia in the occurrence of
SSCA. They compared Ca levels (measured
within 90days of SCA) in 267 patients who presented an out-of-hospital cardiac arrest and 445
controls. They suggested that other unreported
factors may be involved such as the existence of
The basic principles associated with the treat-
ofHypocalcemia
Numerous case reports have associated life-
t.me/Dr_Mouayyad_AlbtousH
484
M. Sakr
elevated parathyroid hormone, thyroid disease,
use of QT-modifying medications, or abnormal
magnesium levels [175].
An early study by Gupta in 1989 [214]
reported that 27% of his patients with severe
hypocalcemia developed seizures; However,
Maxime etal. [215], in their recent retrospective observational study on 155 patients with
severe hypocalcemia, found a 10% incidence of
neurological complications (8% seizures, 2%
coma).
Other studies have focused on hypocalcemic
patients with hypoparathyroidism (post-surgical
and or idiopathic) [216–219] and vitamin D deciency [220–222]. The prevalence of seizures in
patients with hypoparathyroidism ranges from
30% to 70% [216–219], and in patients with vitamin D deciency it ranges from <5% to 16%
[220–222]. These studies concerned almost
exclusively young children and neonates.
Maxime etal. (2018) reported an in-hospital
mortality of 18% of patients with severe hypocalcemia, which increased to 35% when they only
considered the patients with life-threatening cardiac or neurological complications. The causes of
death were mainly uncontrolled cardiovascular
disease and sepsis leading to multiple organ dysfunction syndrome [215]. Whether calcium levels and mortality are associated is still a major
cause of debate. Reports have found conicting
results with either no association of calcium levels with mortality or both high and low levels of
Ca reported to be associated with an increase in
mortality [171–174, 223].
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