Download Hypoparathyroidism: Pathophysiology and Diagnosis*

Article #2
CE
An In-Depth Look:
HYPOPARATHYROIDISM
Hypoparathyroidism:
Pathophysiology and Diagnosis*
Alicia K. Henderson, DVM
Orla Mahony, MVB, DACVIM
Tufts University
ABSTRACT:
Calcium plays a vital role in nearly all cells in the body. As a result, calcium
homeostasis is precisely regulated through the actions of parathyroid hormone (PTH), vitamin D, and calcitonin. Hypoparathyroidism is an
endocrine disorder characterized by a deficiency in PTH, resulting in
hypocalcemia and hyperphosphatemia. Causes include immune-mediated,
surgical gland destruction and hypomagnesemia, among other conditions
better defined in humans. Hypocalcemia results primarily in neurologic
and neuromuscular abnormalities, including generalized seizures. A diagnosis can be made based on the presence of hypocalcemia, hyperphosphatemia, and inappropriately low PTH levels as well as exclusion of other
causes of hypocalcemia, especially renal disease.
P
rimary hypoparathyroidism is an uncommon endocrine disorder that develops as
the result of an absolute or relative deficiency in parathyroid hormone (PTH).1,2
PTH deficiency causes various physiologic abnormalities, including hypocalcemia, hyperphosphatemia, decreased levels of vitamin D (i.e., calcitriol), and clinical
signs primarily involving neuromuscular disturbances.2–4
*A companion article
on treatment appears
on page 280.
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COMPENDIUM
CALCIUM HOMEOSTASIS:THE ROLES OF PTH,VITAMIN D,
AND CALCITONIN
Calcium circulates in three distinct fractions: ionized, protein bound, and complexed. About 50% of total calcium is ionized and serves as the biologically active portion.5,6 The protein-bound fraction is primarily bound to albumin and accounts for
40% of the total. Binding is affected by the pH of extracellular fluid. Acidemia
decreases protein binding and thereby increases the amount of ionized calcium in
serum. Alkalemia causes increased protein binding, resulting in less ionized calcium.5,6
About 10% of circulating calcium is complexed to anions such as lactate, bicarbonate,
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Pathophysiology and Diagnosis CE
citrate, and sulfate.5,6 The partitioning of calcium into
these three fractions is influenced by the amount of calcium in the extracellular fluid, the quantity of protein
and complexes available for binding, and the patient’s
acid–base status.6
Calcium concentration is regulated through the
actions of three hormones: PTH, vitamin D, and calcitonin.6 PTH is synthesized and secreted by the chief
cells of the parathyroid glands and is the principal hormone responsible for calcium homeostasis. It is secreted
at a rate that is inversely proportional to the serum ionized calcium concentration.7 A high serum calcium concentration inhibits secretion of PTH by the parathyroid
glands (i.e., negative feedback), whereas a low or falling
calcium concentration prompts the release of PTH.8,9
This is achieved by means of a calcium-sensing receptor
on the surface of the parathyroid cells.10 PTH performs
its functions by three main actions: It increases osteoclastic bone resorption of calcium and phosphorus, it
increases calcium and decreases phosphorus resorption
from renal tubules, and it stimulates conversion of vitamin D to its active metabolite, which increases calcium
absorption by the intestines.11 The net effect of PTH is
to increase the serum calcium concentration and decrease the serum phosphorus concentration.6
Vitamin D increases both serum calcium and phosphorus. Its primary action is to increase the absorption
of calcium, phosphorus, and magnesium from the intestines. It also has a permissive effect on the action of
PTH on bone and thereby stimulates bone resorption
and calcium mobilization.6 It also acts at the level of the
kidneys to increase renal tubular resorption of calcium
and phosphorus, although this is likely a minor effect.
In addition, vitamin D is absorbed in the intestine as an
inactive prohormone and requires a two-step hydroxylation in the body to become active. The inactive hormone is first transported to the liver, where it is
hydroxylated at the 25 position to 25-hydroxyvitamin
D—a partially active metabolite.12 Then it is transported
to the kidneys, where it is again hydroxylated at the 1
position via renal 1α-hydroxylase to produce the active
metabolite 1,25-dihydroxyvitamin D.12 Both PTH and
phosphorus play key roles in regulating the activity of
renal 1α-hydroxylase.12 Elevated PTH and low phosphorus concentrations increase this enzyme’s activity,
thus enhancing formation of active 1,25-dihydroxyvitamin D. Conversely, low PTH and high phosphorus levels decrease renal 1α-hydroxylase activity and therefore
production of the active vitamin D metabolite.12 ConseApril 2005
271
Cholecalciferol (Vitamin D3)
Liver
25-Hydroxycholecalciferol
Kidney
Activation
1,25-Dihydroxycholecalciferol
PTH
Inhibition
Increased plasma
calcium concentration
Increased intestinal absorption of calcium
Increased bone resorption and calcium mobilization
Increased renal resorption of calcium (minor effect)
Figure 1. Two-step hydroxylation of vitamin D to its
active form and its subsequent actions to increase the
serum calcium concentration.
quently, in patients with hypoparathyroidism (in which
PTH is low and phosphorus is high), deficiency of
active vitamin D also develops, contributing to the
hypocalcemia already present12 (Figure 1).
Calcitonin is a polypeptide secreted by the C cells of
the thyroid gland.6 Its rate of secretion increases with
increased calcium concentration. 6 Calcitonin blocks
bone resorption by inhibiting the release of calcium and
phosphorus from bone.6 It also decreases resorption of
calcium and phosphorus in the kidneys.6 The net effect
of calcitonin is to decrease both calcium and phosphorus
concentrations in the serum.
The precision of integrated control of PTH, vitamin
D, and calcitonin is such that the ionized serum calcium
concentration likely fluctuates by no more than 0.1
mg/dl from its “set” normal value in healthy animals.2
Bone resorption and distal renal tubular calcium resorption are the acute mechanisms that effect minute-tominute serum calcium homeostasis, with the effect of
the renal tubule being quantitatively more important.2
Conversely, changes in the rate of intestinal calcium
absorption via the calcium–PTH–vitamin D axis require
approximately 24 to 48 hours to become maximal.2
PATHOPHYSIOLOGY
Various disease mechanisms have been described as
causes of hypoparathyroidism. Iatrogenic, transient, or
permanent hypoparathyroidism is a well-recognized but
infrequent sequela to surgical treatment of the thyroid
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CE An In-Depth Look: Hypoparathyroidism
or parathyroid glands (such as in feline hyperthyroidism). 1,3,4,13 This is the most common cause of
hypoparathyroidism in cats4 and results not only from
excised parathyroid tissue but also when tissue has been
traumatized or its blood supply interrupted.2 In addition,
in cases of prolonged hypercalcemia from hyperparathyroidism or other parathyroid-independent causes, treating hypercalcemia can result in transient hypocalcemia
due to atrophy of normal parathyroid tissue.1,8 Given the
associated patient history, such causes of hypoparathyroidism are easy to recognize and the pathophysiology is
straightforward. Other causes include immune-mediated
destruction, congenital hypoplasia or aplasia, end-organ
resistance, and severe hypomagnesemia. The various disease mechanisms have been well defined in human medicine. However, in veterinary patients, when there is no
evidence of trauma or surgical destruction, an underlying
cause is rarely determined, and most cases in dogs are
classified as idiopathic.3,13
Detection of antibodies against parathyroid tissue in
humans has led to the theory that hypoparathyroidism
is an autoimmune process. 2,14 Antibodies have been
macytic infiltration in approximately 60% to 80% of
cases. 2,3,11,15,17 This has been used as support for an
immune-mediated cause of hypoparathyroidism,
although circulating autoantibodies directed toward parathyroid tissue have not been demonstrated in dogs.1,13,15,16
The cloning of the calcium-sensing receptor in 1993
and the subsequent discovery of mutations that make
the receptor more or less sensitive to calcium have
allowed a better understanding of several parathyroid
hereditary disorders in humans.18 The calcium-sensing
receptor is a low affinity, G protein–coupled receptor
found in high concentrations on the surface of parathyroid cells, calcitonin-secreting C cells of the thyroid, and
various sites along the nephron, brain, bone, and other
tissues.19 Activation of the receptor stimulates phospholipase C, resulting in increased inositol 1,3,5-triphosphate, which mobilizes cytosolic calcium.19 Activation of
the receptor also inhibits adenylate cyclase, thereby suppressing intracellular cAMP.19 The end result in the
parathyroid gland is suppression of PTH secretion.19
The receptor is activated by minute changes in ionized
calcium, which explains both the steep inverse relation-
The main diagnostic differentials for concurrent hypocalcemia
and hyperphosphatemia are hypoparathyroidism and renal
disease.These conditions can be easily differentiated via blood
urea nitrogen, serum creatinine, and urine specific gravity.
found against the calcium-sensing receptor of the parathyroid gland in humans with acquired hypoparathyroidism. 14,15 The presence of concurrent immunemediated diseases in humans, such as autoimmune polyendocrinopathy, provides further circumstantial evidence
of an autoimmune cause.7,9,14 However, antiparathyroid
antibodies in humans have been found in only a relatively low percentage of patients with hypoparathyroidism, suggesting that other mechanisms are likely
involved.14,16
In dogs, lymphocytic, plasmacytic infiltration of the
parathyroid glands is a relatively common histologic finding. In dogs and cats in which surgical exploration is performed for histopathologic confirmation, the glands are
often difficult to locate grossly and show microscopic evidence of atrophy.3,11,13,15 Histologic evaluation reveals
fibrous connective tissue with diffuse lymphocytic, plasCOMPENDIUM
ship between PTH levels and small changes in calcium
and the sharp rise in urinary calcium that occurs when
serum calcium rises slightly above the “threshold”
value.19 Mutations affecting the calcium-sensing receptor, making it more or less sensitive to calcium, are
responsible for various clinical diseases in humans.8,9,19
More genetic research in veterinary patients is needed
before such disease states can be appreciated.
Magnesium also plays an important role in calcium
homeostasis. In humans, it is well-recognized that magnesium depletion can produce hypocalcemia and hyperphosphatemia by inducing a state of secondary
hypoparathyroidism.16,17,20 This phenomenon has also been
described in dogs, particularly those with protein-losing
enteropathy (PLE).20,21 Several case reports have described
severe hypomagnesemia, hypocalcemia, and inappropriately low PTH concentration in dogs with PLE.20,21
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Pathophysiology and Diagnosis CE
Hypomagnesemia may be the result of renal loss, GI
tract loss, decreased intake, or alterations in the distribution of magnesium.20 Severe magnesium depletion may
cause secondary hypoparathyroidism via three mechanisms: suppression of PTH secretion; interference with
the peripheral action of PTH, causing end-organ resistance; and impaired synthesis of the active form of vitamin D. 2,5,13 Magnesium plays a role in modulating
adenylate cyclase activity by competing for binding with
calcium. 20 A low magnesium concentration allows
increased calcium binding at the inhibitory site, exacerbating the inhibitory effect of calcium on adenylate
cyclase.20 This causes decreased cAMP generation and
blunted release of PTH.20 In addition to decreased production of PTH, decreased response to PTH in bone
and the kidneys has been demonstrated in hypomagnesemic humans and suspected in dogs.20 Magnesium
deficiency can also decrease serum 1,25-dihydroxyvitamin D concentration by lessening PTH release and
impairing renal vitamin D activation.20 The effect of
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SIGNALMENT
Primary hypoparathyroidism is most commonly seen
in middle-aged dogs (mean age: 4.8 years); however, a
wide age range of 6 weeks to 13 years of age has been
reported.2,3,6,13 Females are predisposed (approximately
65% of cases ).2 3,13 Breeds most frequently identified are
the toy poodle, miniature schnauzer, Labrador retriever,
German shepherd, dachshund, and terriers.3,6,8,17 However, this increased prevalence may merely reflect the
popularity of these breeds.13
Fewer cases of primary hypoparathyroidism have been
reported in cats compared with dogs; therefore, it is difficult to identify age, breed, and sex predisposition.2,6,13,14
Most reported cats have been young to middle aged
(i.e., 6 months to 7 years of age).11
CLINICAL SIGNS
The predominant clinical signs of hypoparathyroidism are directly attributable to the decreased concentration of ionized calcium in the blood. Calcium ions
The diagnosis of hypoparathyroidism is based on
an inappropriately low PTH level in the presence of
hypocalcemia rather than on an absolute PTH level.
magnesium depletion on PTH and calcium is further
supported by the fact that supplementation of magnesium rapidly normalizes the PTH concentration and
ionized calcium concentration and alleviates clinical
signs.2,13, 20
Regardless of the underlying cause, the absence of
PTH in patients with hypoparathyroidism results in
hypocalcemia secondary to increased urinary loss (i.e.,
hypercalciuria), decreased bone mobilization, and
decreased intestinal absorption of calcium. Hyperphosphatemia occurs from decreased urinary loss, which
overcomes decreased bone mobilization and decreased
intestinal absorption of phosphorus.4 PTH is a potent
stimulator and phosphorus a potent inhibitor of the
25(OH)-cholecalciferol–1α-hydroxylase system in the
renal tubules; consequently, the absence of PTH and the
presence of hyperphosphatemia work together to
decrease renal synthesis of calcitriol.4 Decreased levels of
calcitriol contribute to hypocalcemia through decreased
intestinal calcium absorption.4
April 2005
are integral to the function of nearly all cells in the body.
Calcium is essential for muscle contraction and serves as
a nerve cell membrane stabilizer by decreasing nerve cell
permeability to sodium.2,3 When the extracellular concentration of calcium ions declines to subnormal levels,
the nervous system becomes progressively more excitable because of increased neuronal membrane permeability.2–4 This increase in excitability occurs in both the
peripheral system and central nervous system (CNS),
although most clinical signs are manifested peripherally.2,12 Nerve fibers may become so excitable that they
begin to discharge spontaneously, initiating impulses to
peripheral skeletal muscles, where they elicit tetanic
contraction.2,3 As a result, hypocalcemia causes tetany.
The duration and magnitude of the calcium depression
as well as the rate of calcium decline interact to determine the severity of clinical signs.4
Clinical signs of hypocalcemia tend to occur intermittently. By the time of diagnosis, most patients have
illustrated occasional signs anywhere from 1 day to 12
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CE An In-Depth Look: Hypoparathyroidism
months.2,3 Clinical tetany typically occurs when the total
calcium concentration declines to 6 mg/dl or less. 2
However, episodes of clinical tetany are interspersed
with “normal” periods despite persistent hypocalcemia.2,4,13 It is not entirely understood why this occurs.
It indicates adaptation to hypocalcemia and suggests
that relatively minor changes in calcium concentrations
in a state of hypocalcemia result in obvious clinical
problems.2 For example, a serum calcium decline of 0.3
mg/dl with a serum concentration of 10 mg/dl has no
effect, but the same decrease when the serum calcium
concentration is 6 mg/dl could result in clinical tetany.2
A state of latent tetany likely exists in these hypocalcemic patients that appear “normal” between episodes of
clinical tetany.2 This condition is described as one in
which patients can progress from appearing clinically
normal to becoming “tetanic” with minimal stimulation.2 The fact that owners frequently describe signs as
occurring after exercise, excitement, or stress supports
the notion of latent tetany.1,2,13,17 Such activity may induce respiratory alkalosis and therefore reduction in the
ionized fraction of calcium.4
A study examining plasma and cerebrospinal fluid
(CSF) total and ionic calcium concentration in postthyroparathyroidectomized dogs may help explain latent
tetany and the episodic nature of this disease. It was
shown that the calcium concentration within the CSF
does not decrease as rapidly as the serum concentration.22 Thus the concentration of calcium ions in the
CSF is relatively constant despite large fluctuations in
plasma concentrations, suggesting a homeostatic protective function.22 However, when changes do occur, relatively small changes in CSF calcium concentration may
also result in dramatic clinical signs.2
The signs of hypocalcemia are similar regardless of
the cause. Signs vary from hardly discernible lameness
to severe, generalized seizures and can be abrupt or
gradual in onset. As already discussed, clinical signs are
typically intermittent and predominantly involve neurologic or neuromuscular disturbances.2 Common clinical signs include focal or generalized muscle tremors
and seizures. Generalized convulsions, resembling those
of an idiopathic seizure disorder, are the predominant
CNS manifestation of hypoparathyroidism, occurring
in 80% of dogs in one study.3,12 Unlike classic grand mal
convulsions, however, hypocalcemic seizures are not
reliably associated with loss of consciousness or incontinence.3,12 It is not uncommon for a dog to present with
a prior presumptive diagnosis of a seizure disorder and
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to have been given anticonvulsant medication.17 Common muscular signs include cramping, tonic spasm or
fasciculations of leg muscles, and a stiff, stilted, or rigid
gait.23 Other clinical signs include nervousness, ataxia,
disorientation, weakness and lethargy, facial rubbing,
and excessive panting.2,3,13,17 Intense facial rubbing is
thought to result from pain associated with masseter
and temporal muscle cramping or from a “tingling”
sensation around the mouth. 3 Owners occasionally
notice behavioral changes, including aggression, restlessness, irritability, decreased playfulness, slow movement, or painfulness.2,4 Aggressive behavior is assumed
to be caused by pain associated with muscle cramping.2
Polydipsia and polyuria, vomiting, diarrhea, and inappetence are less commonly noted.1,6,13 Severe hypocalcemia with total calcium concentrations less than 4
mg/dl can cause death secondary to hypotension,
decreased myocardial contractility, and paralysis of respiratory muscles.4
The clinical features of cats with chronic hypocalcemia secondary to primary hypoparathyroidism are
similar to those in dogs.3,4 In cats, however, seizure
activity has not been noted to be induced by excitement.4 Anorexia and lethargy are also commonly seen
and appear more frequently in cats than in dogs.4 Panting and raised nictitating membranes are also commonly
noted.2,3
PHYSICAL EXAMINATION
The most common physical examination abnormalities are attributed to tetany and include muscle rigidity
and fasciculations, stiff gait, and a tense splinted
abdomen.3,13,17 Fever, panting, nervousness, depression,
weakness, and dehydration are also noted.2,13 Cardiac
abnormalities include paroxysmal tachyarrhythmias and
muffled heart sounds with weak pulses. 3,13 Cataracts
have been detected in both dogs and cats with primary
hypoparathyroidism. 2,13 It is also possible to find no
physical examination abnormalities in patients with
hypoparathyroidism; therefore, a normal physical examination does not rule out the disease.
ELECTROCARDIOGRAM
Hypocalcemia prolongs the duration of the action
potential in cardiac cells.2,3,24 On an electrocardiogram,
this is most consistently associated with deep, wide T
waves, prolonged Q-T intervals, and bradycardia. 2,3
These abnormalities rapidly return to normal after
hypocalcemia has been corrected.15
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DIAGNOSIS
To diagnose primary hypoparathyroidism, clinicians should obtain a complete database, including history, physical examination, complete blood
count, chemistry profile with ionized calcium and magnesium, and a PTH
level. Through this information, the diagnosis can be made based on
hypocalcemia and hyperphosphatemia, inappropriately low PTH, and
exclusion of other causes of hypocalcemia2,25 (Table 1).
The ionized fraction of serum calcium is the biologically active form that
regulates PTH production.8 Therefore, it is the preferred form to measure.
Ionized calcium is measured in serum or heparinized plasma by an instrument using a calcium-specific electrode with a simultaneous measurement
of pH.8 pH has an effect on the binding of calcium to protein in an inverse
relationship. 8 Serum samples collected in EDTA tubes are unsuitable
because EDTA binds available ionized calcium.8
In general, nonhypoparathyroid-induced hypocalcemic conditions are associated with secondary hyperparathyroidism and a normal or high serum PTH
level. In addition, as long as the glomerular filtration rate is not severely
decreased, the serum phosphorus concentration will be normal or low in these
disorders. 12 Both hypocalcemia and hyperphosphatemia occur only in
hypoparathyroidism and renal insufficiency, and these conditions can usually
be easily differentiated by routine evaluation of renal function via blood urea
nitrogen, creatinine level, and urine specific gravity.12 The exceptions to these
disease trends are disorders causing severe hypomagnesemia; therefore, a magnesium concentration should be checked with a chemistry panel.13
A presumptive diagnosis of hypoparathyroidism can be made based on
hypocalcemia, hyperphosphatemia, normal renal function, and the absence of
an obvious alternative diagnosis.4,12,13 However, because primary hypoparathyroidism is a permanent condition requiring lifelong treatment, confirmation
of the diagnosis with PTH measurement is highly recommended.4,12 The
PTH concentration may be in the low-normal range. However, this finding
would not be normal in a hypocalcemic animal that has healthy parathyroid
glands because hypocalcemia provides a strong stimulus to the normal parathyroid gland to secrete PTH at a high level.3,4,6 Therefore, the definitive diagnosis
is made based on an inappropriately low rather than absolute PTH level.
The serum PTH concentration must be interpreted in conjunction with
the serum calcium concentration while the patient is still hypocalcemic;
therefore, blood samples for PTH determination should be obtained before
initiating therapy.13 Serum or EDTA plasma may be used to measure the
PTH concentration.8 Assays that detect the intact hormone are important.11,13 The molecule is readily broken down into inactive fragments that
are excreted by the kidneys.6 Therefore, with renal disease, elevations in
inactive fragments in the bloodstream may overrepresent the amount of biologically active PTH if a different assay is used.6
CONCLUSION
Calcium plays a vital role in cell function, especially in the neuromuscular
system. Essential to its role in the body is the precision of calcium homeostasis through PTH, vitamin D, and calcitonin. Primary hypoparathyroidism is a
rare endocrine disease in which this homeostasis is altered, causing significant
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Pathophysiology and Diagnosis CE
277
Table 1. Differential Diagnosis of Hypocalcemia
Condition
Hypoalbuminemia
Comments
There is a decreased protein-bound fraction with normal ionized calcium.
Correcting formula for dogs:
Corrected total Ca++ = Serum Ca++ – Serum albumin + 3.5
Renal failure
Acute renal failure resulting in hyperphosphatemia causes secondary
hypocalcemia. Chronic renal failure can cause hypocalcemia or
hypercalcemia.
Acute pancreatitis
Mild hypocalcemia occurs.
Coexisting acidosis increases ionized calcium.
The mechanism is unknown. The theory is that it is caused by
saponification of peripancreatic fat.
Puerperal tetany (eclampsia)
Lactating bitches and queens are affected.
Small dogs are most often affected.
The condition is acute and severe.
Ethylene glycol toxicosis
Ethylene glycol metabolites chelate calcium ions.
Phosphate enemas
Acute elevation in phosphorus causes reciprocal hypocalcemia.
Use of EDTA anticoagulant
EDTA chelates calcium.
Hypomagnesemia
There is decreased synthesis and secretion of PTH.
There is increased PTH resistance.
It occurs with PLE.
Nutritional secondary
hyperparathyroidism
Transient hypocalcemia occurs.
It induces PTH secretion.
It occurs in animals fed diets with low calcium:phosphorus ratios.
Laboratory error
Always recheck the calcium concentration if it is unexpectedly high or low.
Malabsorption syndrome
It is uncommon in dogs.
It occurs secondary to hypoalbuminemia with or without decreased
absorption of dietary calcium, vitamin D, and magnesium.
Transfusion with citrated blood
Citrate chelates calcium.
Bone tumors
They most often cause hypercalcemia; however, hypocalcemia occurs in
humans.
Soft tissue trauma
—
Vitamin D deficiency
—
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biochemical and clinical abnormalities. Clinicians should
be readily able to identify primary hypoparathyroidism
through clinical signs and laboratory abnormalities.
REFERENCES
1. Monroe W: Diseases of the parathyroid gland, in Morgan R (ed): Handbook of
Small Animal Practice, ed 3. Philadelphia, WB Saunders, 1997, pp 457–459.
2. Feldman EC, Nelson RW: Hypocalcemia and primary hypoparathyroidism,
in Feldman EC, Nelson RW (eds): Canine and Feline Endocrinology and
Reproduction, ed 2. Philadelphia, WB Saunders, 1996, pp 497–515.
3. Feldman EC: Disorders of the parathyroid glands, in Ettinger SJ, Feldman
EC (eds): Textbook of Veterinary Internal Medicine, ed 3. Philadelphia, WB
Saunders, 2000, pp 1392–1399.
4. Chew D, Nagode L: Treatment of hypoparathyroidism, in Bonagura JD (ed):
Kirk’s Current Veterinary Therapy XIII. Philadelphia, WB Saunders, 2000, pp
340–345.
5. Bushinsky DA, Monk RD: Calcium. Lancet 352(9124):306–311, 1998.
6. Carothers M, Chew D, Van Gundy T: Diseases of the parathyroid gland and
calcium metabolism, in Birchard SJ, Sherding RG (eds): Saunders Manual of
Small Animal Practice, ed 2. Philadelphia, WB Saunders, 1994, pp 248–258.
7. Ding C, Buckingham B, Levine MA: Familial isolated hypoparathyroidism
caused by a mutation in the gene for the transcription factor GCMB. J Clin
Invest 108(8):1215–1220, 2001.
8. Refsal KR, Provencher-Bollinger AL, Graham PA, Nachreiner RF: Update
on the diagnosis and treatment of disorders of calcium regulation. Vet Clin
North Am Small Anim Pract 31(5):1043–1061, 2001.
9. Marx ST: Medical progress: Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 343(25):1863–1875, 2000.
10. Brown EM, Vassilev PM, Quinn S, Hebert SC: G-protein-coupled, extracellular Ca2+-sensing receptor: A versatile regulator of diverse cellular functions. Vitam Horm 55:1–71, 1999.
11. Ruopp J: Primary hypoparathyroidism in a cat complicated by suspect iatro-
genic calcinosis cutis. JAAHA 37:370–373, 2001.
12. Peterson ME: Hypoparathyroidism, in Kirk RW (ed): Current Veterinary
Therapy IX. Philadelphia, WB Saunders, 1986, pp 1039–1045.
13. Nelson RW: Disorders of the parathyroid gland, in Nelson RW, Couto CG
(eds): Small Animal Internal Medicine, ed 3. St. Louis, Mosby, 2003, pp 686–689.
14. Rose N: Is idiopathic hypoparathyroidism an autoimmune disease? J Clin
Invest 97(4):899–900, 1996.
15. Forbes S, Nelson RW, Guptill L: Primary hypoparathyroidism in a cat.
JAVMA 196:1285–1286, 1990.
16. Peterson ME, James KM, Wallace M, et al: Idiopathic hypoparathyroidism in
five cats. J Vet Intern Med 5(1):47–51, 1991.
17. Bruyette DS, Felman EC: Primary hypoparathyroidism in the dog. J Vet
Intern Med 2:7–14, 1988.
18. Urena P, Frazao J: Calcimimetic agents: Review and perspectives. Kidney Int
63:91–96, 2003.
19. Coburn JW, Elangovan L, Goodman WG, Frazao JM: Calcium-sensing
receptor and calcimimetic agents. Kidney Int Suppl 56:S52–S58, 1999.
20. Bush WW, Kimmel SE, Wosar MA, Jackson M: Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing
enteropathy. JAVMA 219:1732–1734, 2001.
21. Kimmel SE, Waddell LS, Michel KE: Hypomagnesemia and hypocalcemia
associated with protein-losing enteropathy in Yorkshire terriers: Five cases
(1992–1998). JAVMA 217:703–706, 2002.
22. Kirk GR, Breazile JE, Kenny AD: Pathogenesis of hypocalcemic tetany in
the thyroparathyroidectomized dog. Am J Vet Res 35:407–408, 1974.
23. Platt SR: Neuromuscular complications in endocrine and metabolic disorders. Vet Clin North Am Small Anim Pract 32(1):125–146, 2002.
24. Lehmann G, Deisenhofer I, Ndrepepa G, Schmitt C: ECG changes in a 25year-old woman with hypocalcemia due to hypoparathyroidism. Chest 118(1):
260–262, 2000.
25. Peterson ME: Hypoparathyroidism and other causes of hypocalcemia in cats,
in Kirk RW (ed): Current Veterinary Therapy XI. Philadelphia, WB Saunders,
1992, pp 376–379.
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1. Calcium circulates as ___% ionized, ___% protein
bound, and ___% complexed.
c. 40, 50, 10
a. 50, 40, 10
b. 60, 30, 10
d. 10, 30, 60
2. PTH
a. is secreted at a rate that is directly proportional to
the serum ionized calcium concentration.
b. decreases osteoclastic bone resorption of calcium
and phosphorus.
c. increases calcium and phosphorus resorption from
the renal tubules.
d. stimulates conversion of vitamin D to its active
metabolite.
3. Calcitonin
a. is secreted by the C cells of the parathyroid gland.
b. is secreted when the calcium concentration decreases.
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c. inhibits the release of calcium and phosphorus from
bone.
d. increases resorption of calcium and phosphorus in
the kidneys.
4. Which statement regarding vitamin D is incorrect?
a. It increases intestinal absorption of calcium and phosphorus.
b. It increases renal resorption of calcium and phosphorus.
c. Its activation is decreased by elevated PTH and low
phosphorus levels.
d. It requires two-step hydroxylation to become active.
5. Clinical tetany typically occurs when the serum
calcium concentration declines to __ mg/dl.
c. 7
a. 9
b. 8
d. 6
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Pathophysiology and Diagnosis CE
6. Which statement regarding ionized calcium is
incorrect?
a. It is the biologically active form of calcium.
b. It regulates PTH production.
c. It is the preferred form of calcium to measure.
d. Blood should be collected in EDTA tubes to measure
ionized calcium.
7. Which condition is most likely to result in tetany
secondary to hypocalcemia?
a. acute pancreatitis
c. eclampsia
b. hypoalbuminemia
d. malabsorptive disease
8. Which statement regarding calcium and clinical
signs in patients with hypoparathyroidism is true?
a. Signs often occur after exercise, excitement, or
stress.
b. Calcium stabilizes nerve cell membranes by increasing cell permeability to sodium.
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c. Most clinical signs are manifested in the CNS.
d. Calcium concentration within the CSF rapidly equilibrates with the plasma concentration.
9. Which clinical sign is commonly seen in patients
with hypoparathyroidism?
a. polydipsia and polyuria c. inappetence
b. focal tremors
d. vomiting
10. Which statement regarding hypoparathyroidism
is true?
a. The PTH level must be less than 0.5 pmol/L for a
diagnosis of hypoparathyroidism.
b. The main differentials for hypocalcemia and hyperphosphatemia are hypoparathyroidism and pancreatitis.
c. The physical examination may be completely normal
in a patient with hypoparathyroidism.
d. Hypoparathyroidism has been diagnosed in cats only
secondary to surgical trauma.
COMPENDIUM