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220
ENDOCRINE SURGERY
parathyroidectomy and the clinical importance is to differentiate FHH from other
forms of HPT that benefit from surgery.
Screening involves measuring the CCCR and
performing CaSR gene analysis when CCCR
is <0.02 [13].
Drug Modulators
in Parathyroid Disease
Type II calcimimetics drugs (e.g., cinacalcet
hydrochloride) are positive allosteric modulatorsoftheCaSRwhichenhancethesensitivity of the receptor to calcium resulting in a
decrease in PTH secretion [12, 14]. Cinacalcet
hydrochloride has therapeutic use in patients
with SHPT and is often used in conjunction
with selective VDR agonists [14], e.g., paricalcitol. Selective VDR agonists reduce PTH
levels in SHPT patients without the rise in
serum calcium and phosphate seen with calcitriol with the benefit of reducing vascular
calcification and complications seen in SHPT
[15].
References
1. Sadler TW. Langmans medical embryology. 5th ed.
London: Williams & Wilkins, 1985.
2. McMinn RM. Lasts Anatomy. 8th ed. Edinburgh:
Churchill Livingstone; 1990.
3. Akerstr¨om G, Malmaeus J, Bergstr¨om R. Surgical anatomy
of human parathyroid glands. Surgery. 1984;95:14–21.
4. Collip JB, The extraction of a parathyroid hormone
which will prevent or control parathyroid tetany and
which regulates the level of blood calcium. J Biol Chem.
1925; 63:395–438.
5. Shoback D, Sellmeyer D, Bikle D. Metabolic bone disease. In: Gardner DG, Shoback D, editors. Greenspan’s
basic & clinical endocrinology. 8th ed. New York:
McGrawHill; 2007.
6. Berson SA, Yalow RS, Aurbach GD, Potts JT. Immunoassay of bovine and human parathyroid hormone.
Proc Nat Acad Science U S A. 1963;49:613–7.
7. Renkema KY, Alexander RT, Bindels RJ, Hoenderop JG.
Calcium and phosphate homeostasis: concerted interplay of new regulators. Ann Med. 2008;40:82–91.
8. Krajisnik T, Bj¨orklund P, Marsell R, et al. Fibroblast
growth factor-23 regulates parathyroid hormone and
1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol. 2007;195:125–31.
9. Westerberg PA, Linde T, Wikstr¨om B, Ljunggren O,
Stridsberg M, Larsson TE. Regulation of fibroblast
growth factor-23 in chronic kidney disease. Nephrol
Dial Transplant. 2007;11:3202–7.
10. Brown EM, Pollak M, Herbert SC. Physiology and cell
biology update: sensing of extracellular Ca2+ by parathyroid and kidney cells: cloning and characterisation of
an extra-cellular Ca2+ -sensing receptor. Am J Kidney
Dis. 1995;25:506–13.
11. Conlin PR, Fajtova VT, Mortensen RM, LeBoff MS, Brown
EM. Hysteresis in the relationship between serum ionized
calcium and intact parathyroid hormone during recovery
from induced hyper- and hypocalcemia in normal
humans. J Clin Endocrinol Metab. 1989; 69:593–9.
12. Hu J, Speigel AM. Structure and function of the human
calcium-sensing receptor: insights from natural and
engineered mutations and allosteric modulators. J Cell
Mol Med. 2007;908–22.
13. Christensen SE, Nissen PH, Vestergaard P, Heickendorff L,
Brixen K, Mosekilde L. Discriminative power of three
indices of renal calcium excretion for the distinction
between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: A follow-up study on methods.
Clin Endocrinol (Oxf). 2008 Apr 10 [E-pub ahead of print].
14. Harrington PE, Fotsch C. Calcium sensing receptor activators: calcimimetics. Curr Med Chem. 2007;14: 3027–34.
15. Brancaccio D, Bommer J, Coyne D. Vitamin D receptor
activator selectivity in the treatment of secondary
hyperparathyroidism: understanding the differences
among therapies. Drugs. 2007;67:1981–98.
16. Johansson K, Ander S, Lennquist S, Smeds S. World
J Surg. 1994;18:417–20.
16
Presentation and Diagnosis of Primary Hyperparathyroidism
Jenny Gough and F. Fausto Palazzo
Introduction
The term hyperparathyroidism was first coined in
the 1920s to describe a syndrome characterized by
bone disease, renal stones, fatigue, hypercalcemia,
and hypercalciuria [1]. The diagnosis was dependent on symptoms related to ‘‘bones, stones,
abdominal groans and moans’’ which often correlated with osteitis fibrosa cystica, advanced kidney
disease, psychiatric, and neuromuscular disorders,
respectively. The clinical features were often associated with radiological evidence of subperiosteal
erosion of the phalanges, brown tumors, and salt
and pepper erosions on the skull radiograph
(Figs. 16.1 and 16.2). With Rasmussen and Craig’s
isolation and characterization of parathyroid hormone (PTH) in 1959 and Berson and Yalow’s
development of an immunoassay for PTH in 1963
[1] our understanding of calcium metabolism
and the definition of primary hyperparathyroidism(pHPT) improved. It is appropriate that
the definition, like the current commonest
presentation of pHPT, is biochemical: hypercalcemia in the presence of an unsuppressed and
therefore relative or absolute inappropriately
elevated PTH level. The disease now covers a
spectrum that has extremes as diverse as asymptomatic normocalcemic hyperparathyroidism
and hypercalcemic crises.
The arrival of the multichannel-automated
serum electrolyte analysis machine in the
1970s made symptoms no longer a prerequisite
for the diagnosis of pHPT. The routine measurement of serum calcium unearthed a large
number of previously unrecognized patients
with hypercalcemia. Since pHPT is the commonest cause of hypercalcemia in the community [2], the prevalence of pHPT, or rather the
prevalence of its diagnosis, increased in
parallel, resulting in a fivefold increase in the
incidence of pHPT [3]. In North America, the
incidence of pHPT is now 4.3/1000 per annum
[4] with an estimated 100,000 new cases diagnosed each year in the USA alone [5]. The
incidence across Europe is thought to be
3/1000 [6], although a Swedish populationbased study suggests the prevalence of pHPT
rises to 2.1% of postmenopausal women aged
55–75 [7] or to 3.4% for those aged 65–84 [8].
Overall, the incidence of pHPT is twice as high
in females as in males and increases with advancing age in both sexes [6].
Most patients with pHPT present sporadically
with no apparent risk factors. The known risk
factors for pHPT include radiation exposure [9],
long-term lithium use [10], and a family history of
hyperparathyroidism [11] or multiple endocrine
neoplasia syndromes (MEN1 and MEN2A). Parathyroid disease in MEN1 is usually multiglandular
and occurs in 95% of patients making pHPT the
major feature of the syndrome [12]. In patients
with MEN2A, hyperparathyroidism is a less common component of the syndrome, is less frequently multiglandular, and is usually a milder
disease than in MEN1 [13].
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_16, Ó Springer-Verlag London Limited 2009
221
Fig. 16.1. Browns tumor of tibia due to hyperparathyroidism.
Fig. 16.2. Subperiosteal bone erosion of proximal phalanges
and metacarpals in hyperparathyroidism.
Clinical Features
Primary hyperparathyroidism in its classic symptomatic form, with severe skeletal and renal complications and in extreme cases mortality, is today
seen only in patients in or from developing countries [14]. Elsewhere, the disease is most commonly diagnosed following the investigation of
an incidentally identified hypercalcemia, usually
222
ENDOCRINE SURGERY
in an apparently asymptomatic patient [5]. A
small proportion of patients may have traditional
symptoms including renal calculi [15] and pancreatitis [16]. Less common presentations include
recurrent miscarriages and neonatal tetany in an
undiagnosed hypercalcemic mother [17]. Primary
hyperparathyroidism may also be detected by
focussed screening programs in patients known
tocarrytheMEN1,MEN2A,orHRPT2genesorto
be directly related to a gene carrier.
‘‘Asymptomatic’’ Primary
Hyperparathyroidism
Whilst most patients currently diagnosed with
pHPT are described as asymptomatic [5], this
refers to theabsence of theovert clinic symptoms
of advanced parathyroid disease. If the myriad of
subtle clinical symptoms such asmalaise,fatigue,
depression, memory loss, poor concentration,
polydipsia, polyuria, constipation, and nonspecific bone and joint aches are taken into consideration, the incidence of truly asymptomatic disease may be lower than 5%, with no correlation
between degree of hypercalcemia and the extent
of these symptoms [18] (Table 16.1).
Health-related qualityoflifescoressuchas
SF36 (Medical Outcomes Study Short-Form
Health Survey) [19] are reduced in asymptomatic patients [20] and they improve following
parathyroidectomy [21]. Pasieka has designed a
disease-specific visual analog questionnaire to
quantify the subtle symptoms of pHPT, the Parathyroidectomy Assessment of Symptoms (PAS)
score (Table 16.2). The higher the PAS score the
more symptomatic the patient. This assessment
tool has been validated by comparing the pre- and
postoperative scores of patients with pHPT and
control patients undergoing surgery for euthyroid thyroid disease [22]. Quality of life assessed
with this tool improved following parathyroidectomy, with high preoperative PAS scores which
decreased significantly postoperatively compared
to controls. The validity of the PAS scoring system
is further supported by the fact that it also correlates with SF-36 scores in patients undergoing
parathyroidectomy for pHPT [23]. The consistent
improvements in PAS and SF-36 scores following
parathyroidectomy underline the tenuous nature
of the ‘‘asymptomatic’’ label attached to many of
such patients [24, 25].
223
PRESENTATION AND DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM
Table 16.1. Symptoms and signs of primary hyperparathyroidism
Musculoskeletal Renal Neuropsychiatric
Muscle weakness Renal calculi/renal colic Impaired concentration
Myalgia Nephrocalcinosis Memory loss
Bone aches/pains Thirst/dehydration Anxiety
Osteoporosis Polyuria/oliguria/anuria Depression
Osteitis fibrosa cystica Renal failure Confusion
Brown’s tumors Dementia/paranoia
Gastrointestinal Cardiovascular Other
Nausea/vomiting Hypertension Visual changes
Abdominal pain Vascular calcification Band keratopathy (corneal
Anorexia Shortened Q-T interval Conjunctivitis
Peptic ulcer disease Bradycardia Pruritus
Pancreatitis Heart block
Constipation Lethal arrhythmias
Weight loss
Ataxia
Hyporeflexia
Coma
calcification)
Table 16.2. Pasieka’s parathyroidectomy assessment of symptoms (PAS) score [19]
Not experiencing the
Symptoms
Pain in the bones
Feeling tired easily
Mood swings
Feeling ‘‘blue’’ or depressed
Pain in the abdomen
Feeling weak
Feeling irritable
Pain in the joints
Being forgetful
Difficulty getting out of a
chair or car
Headaches
Itchy skin
Being thirsty
symptom 0
Even if patients have what may be considered
asymptomatic or paucisymtomatic disease, pHPT
is clearly not innocuous. Various studies have
demonstrated higher rates of hypertension, dyslipidemia, insulin resistance, unfavorable body fat
distribution [26], cardiac and vascular dysfunction, and morbidity from cardiovascular diseases
Experiencing the most
extreme aspect of the
symptom 100
in patients with mild pHPT [27]. Twenty-five-year
follow up of pHPT patients with untreated
hypercalcemia demonstrates an excess number
of premature cardiovascular deaths compared
to age-matched normocalcemic controls [28].
In addition to increased cardiovascular morbidity, decreased bone mineral density (BMD)
224
ENDOCRINE SURGERY
has been reported in patients with mild or
‘‘asymptomatic’’ pHPT, and both appear to
normalize after parathyroidectomy [27]. Five
years following parathyroidectomy, a Swedish
population study demonstrated increased BMD in
L2–L4 to the level of matched controls, increased
femoral neck BMD in patients <67 years of age,
and preservation of femoral neck BMD in the
elderly population [29]. There is also evidence of
improvement in dyslipidemia [30] and glucose
tolerance [31] following surgery, which may
explain the improvement in cardiovascular morbidity. Retrospective data seem to indicate that
early surgery for mild pHPT normalizes cardiovascular risk and offers a survival advantage, but
long-term follow-up is required to either prove or
disprove this. A randomized, controlled trial of
191 patients has compared the morbidity and
quality of life of parathyroidectomy and medical
observation in mild asymptomatic pHPT. Asymptomatic patients with mild pHPT have decreased
quality of life and more psychological symptoms
than normal controls. However, at 2-year follow
up a benefit of operative treatment, compared
with medical observation, has not yet been proven
utilizing these parameters [32].
Symptomatic Primary
Hyperparathyroidism
Amongst patients with unequivocally symptomatic disease, nephrolithiasis is the commonest
clinical feature [33]. Renal stones and ureteric
colic are significantly more frequent in younger
patients where hypercalciuria is commoner due to
the higher levels of activevitamin D [15]. However,
nephrolithiasis may also occur in the absence of
symptoms, thus justifying ultrasonographic renal
assessment in patients with proven pHPT.
Bone disease culminating in pathological fractures in pHPT is now uncommon, indeed the earlier data suggesting increased fracture risk [34] has
not been supported by the outcomes of more
recent studies [35, 36]. One study even suggested
thattheincreaseinboneturnoverinmildpHPT
protected against the loss of cancellous bone structure that normally follows menopause [37]. These
data, however, do not correlate entirely with the
more recent large study that demonstrates parathyroidectomy to be independently associated
with a decreased fracture risk in age-matched
patients [38]. As bone disease may only present
clinically and radiologically at an advanced stage,
bone densitometry of cortical bone is therefore
required to demonstrate osteoporosis in patients
with general aches in the context of pHPT.
Gastrointestinal symptoms resulting from
smooth muscle relaxation include constipation,
anorexia, nausea, and vomiting. The high incidence of peptic ulcers and abdominal pain from
other causes in patients with pHPT has been
recognized for many years. Hypercalcemia
increases gastric acid secretion and may account
for associated ulcer disease and the ulcer-like
pain in pHPT. The mechanisms causing the
other gastrointestinal symptoms in hypercalcemia remain to be elucidated [39]. The association
of pHPT withpeptic ulcer disease is variable with
series showing no association contrasting with
others where as many as 12 of 20 patients with
pHPT are affected. Selection bias and the context
of the diagnosis is likely to explain these contrastingfindings. Of significance, however, is that
the majority of patients with abdominal symptoms thought to be secondary to pHPT experience complete resolution of their symptoms following parathyroid surgery [40, 41].
Pancreatitis is believed to bemore common in
pHPT and directly related to the hypercalcemia
of pHPT, but the molecular mechanism bywhich
this occurs remains unknown. In the 1980s, the
Mayo clinic audited their patients with pancreatitis in the presence of proven pHPT and found
an incidence of 1.5%, which was the same as for
patients without pHPT [42]. The natural and
often quoted conclusion was that there was no
direct causal correlation between the two diseases. However, once again selection bias is the
likely culprit for this finding since the patients
involved in this series all had asymptomatic and/
or mild pHPT. Indeed, subsequent studies from
Australia, Germany, and France have all demonstrated an increased prevalence of pancreatitis in
patients with pHPT – 5.1, 5.6, and 3.2%, respectively [43, 16, 44]. Furthermore, a study from
India, where pHPT is still seen in its more florid
form with more marked hypercalcemia, demonstrated an incidence of up to 8% [16].
The effects of pHPT on the cardiovascular
system include hypertension, vascular calcification, shortened Q-T interval, and arrhythmias
[45]. Whilst subtle neurological symptoms are
common, severe manifestations such as confusion, hypotonia, muscle weakness, and coma
are present only in hypercalcemic crises (vide
infra).
225
PRESENTATION AND DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM
Clinical examination of patients with pHPT
is usually unremarkable and serves to exclude
pathologies that represent an alternative cause
of hypercalcemia. Corneal calcification may be
present but may equally be an unrelated coexistent feature.
Hypercalcemic Crisis
A hypercalcemic crisis is an uncommon condition that occurs in no more than 1–2% of pHPT
[46]. It is characterized by a serum calcium
greater than 3.5 mmol/l (14 mg/dl) and is typically associated with a rapid deterioration in
central nervous system, cardiac, gastrointestinal, and renal function. The majority of cases
are due to pHPT and are therefore also known
as parathyrotoxic crises. The hypercalcemia of
advanced malignancy whilst being the next
most frequent cause of severe hypercalcemia
tends to present more indolently [47].
The presentation of the parathyrotoxic crisis
may be insidious and initially subtle or overt
and acute with confusion, delirium, abdominal
pain (sometimes with pancreatitis), vomiting,
dehydration and anuria, and occasionally with
a palpable parathyroid adenoma in the neck
[48]. The severe presentation is a consequence
of untreated advanced pHPT combined with
dehydration or another condition causing
fluid shifts out of the intravascular compartment. Life-threatening arrhythmias may occur
due to a prolongation of the Q-R interval and
shortening of the Q-T interval. Coma and cardiac arrest are possible in particular when
serum calcium levels reach 3.75–4 mmol/l
(15–18 mg/dl).
The priority in hypercalcemic crises is prevention rather than cure. This relies on avoiding
dehydration by maintaining a fluid intake of 3 L
or more a day especially in patients with hypercalcemia greater than 2.8 mmol/l.
If prevention has failed or the serum calcium
is >3 mmol/l, admission to hospital for inpatient management is adviseable [49] since
hypercalcemic crisis in its acute form represents
a medico-surgical emergency. The management
strategy focuses on maintaining an adequate
airway and breathing, aggressive rehydration
aimed at generating calciuresis, whilst also
decreasing calcium release from skeletal stores.
The in-patient rehydration should commence with intravenous normal saline titrated
to achieve a urine output of 100 ml/h. Following
adequate rehydration, loop diuretics may be
introduced to stimulate both calciuresis, and
these drugs present the additional advantage
of inducing diuresis, thus preventing fluid
overload. The frequently coexisting cardiac
and renal comorbidities in these patients
make an appropriate monitoring environment
(i.e., high dependency or intensive care unit),
essential and regular serum electrolyte estimation is required to prevent electrolyte
imbalances, in particular hypokalemia and
hypomagnesemia. Usually, serum calcium
levels can be reduced by 1.6–2.5 mg/dl within
24 h with only rehydration and loop diuretics
[50]. However, these measures alone are insufficient to normalize calcium in extreme cases
and additional agents alone or in combination
may beused to achieve normocalcemia including bisphosphonates, calcitonin, steroids, and
dialysis (Table 16.3).
Bisphosphonates are pyrophosphate analogs
that have a high affinity for hydroxyapatite in
bone. They are potent inhibitors of osteoclast
activity and can act for months. In hypercalcemia secondary to malignancy, they are extremely effective normalizing serum calcium in
most patients [51]. However, their prolonged
action is not favored for the management of
patients with pHPT awaiting surgery as a troublesome profound and prolonged hypocalcemia
may follow postoperatively. Calcitonin can be
used as a temporizing measure until the more
sustained effects of other agents begin. It has the
advantage of acting within 24–48 h to lower
serum calcium levels [52], by increasing calciuresis and decreasing osteoclast activity. The
duration of action of calcitonin, however, is
limited to a few days and it is most effective
when used in combination with steroids [53],
although long-term use even in combination is
limited by tachyphylaxis and allergic reactions
[54]. Glucocorticoids lower serum calcium by
several mechanisms including the inhibition of
the effects of vitamin D [55], inhibition of osteoclast-activating factor [56], and by decreasing
the intestinal absorption and increasing the
renal excretion of calcium [57]. However, glucocorticoids are more effective for hypercalcemia from granulomatous disease and malignancy than pHPT and so are rarely used in this
context. Another agent, gallium nitrate which
inhibits bone resorption, is now also less commonly used due to its nephrotoxicity, the need
Table 16.3. Management of hypercalcemia
Onset
Treatment
Intravenous
normal saline
Loop diuretics
Frusemide
Bisphosphonates
Etidronate
Pamidronate
Zoledronic acid
Calcitonin Hours 2–3 days Inhibition of osteolysis Fast onset
Hemodialysis Hours During use Removal of calcium from blood Rapid onset Treatment for
Glucocorticoids 5–7 days Days–weeks Increase calciuresis
of action
Hours During use Increase in calciuria Hemodilution Rehydration Fluid overload in congestive
Hours 2–6 h 20–500 mg/day induces diuresis and
1–2 days
1–2 days
Rapid
Duration
of action Mechanism of action Advantages Disadvantages
Rapid onset Electrolyte abnormalities
calciuria 100 mg/h infusion directly
stimulates calciuria
5–7 days
10–14 days
20–28 days
(twice as long
as
pamidronate)
Inhibition of osteolysis Antiresorptive Intermediate onset
High potency
Medium duration
Rapid action Long
duration
Used as a bridge until
intermediate action
drugs take effect
renal failure
Oral therapy
Decrease intestinal absorption of
calcium
Tumoricidal effect on
hematological and
breast malignancies
heart failure Hypokalemia/
hypomagnesemia
Dehydration
Renal impairment
Hyperphosphatemia 3-day
infusion
Fever (20%)
Hypophosphatemia
Hypomagnesemia
Hypocalcemia (can be
profound if
parathyroidectomy performed
soon after treatment)
Renal impairment
Tachyphylaxis
Flushing
Nausea/vomiting
Dialysis complications (catheter
related, hypotension)
Only effective in vitamin D excess
or granulomatous disease
Immunosuppression
Cushing’s syndrome
Effectiveness
% normalized
0–10
0–10
30–80
70–100
Unknown,
not yet
licensed
for use
10–20
Very effective
if tolerated
Variable
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226
227
PRESENTATION AND DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM
for continuous infusion, and lack of clinical data
to support its use [50]. Parathyrotoxic patients
with renal failure who cannot tolerate largevolume resuscitation may require dialysis with
low calcium dialysate, and such a strategy may
remove up to 250 mg of calcium/h.
Concurrent investigations should proceed in
parallel during the management of the hypercalcemic crisis, and surgical treatment should follow
once the patient has been rendered safe. The high
mortality associated with hypercalcemic crises
appears to have been related to a failure to make
the diagnosis and delays in appropriate management. Urgent parathyroidectomy remains the
most expedient method of restoring normocalcemia [58] and has minimal morbidity and mortality, with long-term success rates similar to elective
parathyroidectomy [59]. In contrast, the hypercalcemiccrisisofadvancedmalignancyimpliesa
very limited life expectancy, often only a matter
of weeks, and palliative management is usually
appropriate [45].
Normocalcemic
Hyperparathyroidism
As parathyrotoxic crises have become a rare
occurrence, its place is being taken by a disease
that represents the other end of the pHPT spectrum, namely normocalcemic hyperparathyroidism. These patients are normocalcemic but
with a consistently inappropriately elevated PTH
in the absence of secondary causes of hyperparathyroidism (Table 16.4). The significance of this
condition is controversial, but growing evidence
suggests that it may represent the earliest form of
pHPT, a phase characterized by elevated PTH
that leads to a reduced cortical bone density but
without hypercalcemia. The second phase of
pHPT is defined by the development of hypercalcemia and therefore leads to the investigation
and diagnosis.
Normocalcemic pHPT is being increasingly
diagnosed in the context of early bone disease
due to the increasing awareness of this problem.
Indeed many skeletal health physicians consider the measurement of PTH as a part of the
routine assessment of decreased bone density
[60]. Normocalcemic pHPT is a new disease,
being first described by Mather [61] in 1953.
He treated a 33-year-old normocalcemic
Table 16.4. Secondary causes of PTH elevation
Secondary causes of PTH elevation
Chronic renal failure
Vitamin D deficiency
Dietary
Lack of sun exposure
Familial hypocalciuric hypercalcemia
Liver disease
Gastrointestinal malabsorption
Vitamin D and calcium
Medications
Lithium
Thiazide diuretics
Bone disease
Osteoporosis
Osteomalacia
Rickets
woman with osteitis fibrosa cystica, whose
symptoms resolved following removal of a
parathyroid adenoma. The true incidence of
the condition, however, in the past has been
confounded by secondary causes of hyperparathyroidism, mainly vitamin D deficiency [62]
and by the inclusion of patients with intermittent hypercalcemia [60]. Vitamin D is a fat
soluble substance which is prevalent in dairy
products. It is absorbed from the gastrointestinal tract and hydroxylated in the liver to
25-hydroxyvitamin D. Once activated by the
kidneys, 1,25-dihydroxyvitamin D increases
resorption of phosphorus in the kidneys and
absorption of calcium from the gastrointestinal
tract. A deficiency of Vitamin D can lead to
raised PTH levels in normocalcemic patients
and possibly lead to the misdiagnosis of primary hyperparathyroidism.
Where secondary causes of PTH elevation
have been excluded, normocalcemic pHPT
increasingly probably represents the earliest
manifestation of parathyroid autonomy. There
is also growing evidence that normocalcemic
pHPT, like the hypercalcemic variant, is not
truly asymptomatic as previously thought. The
classic subtle symptoms and signs typical of
pHPT may be present, and one series of 37
patients that were investigated showed that
14% had nephrolithiasis, 57% osteoporosis,
and 11% fragility fractures. Over an 8-year of
follow up 19% developed hypercalcemia, 5%
228
ENDOCRINE SURGERY
marked hypercalciuria, and 29% progressive
cortical bone loss [63]. The same group of normocalcemic hyperparathyroid patients also had
elevated glucose, serum lipoprotein fractions,
and a raised BMI compared to matched controls. Importantly, this metabolic cluster of
increased cardiovascular risk factors converged
toward the controls group following parathyroidectomy and remained abnormal in those
managed conservatively [64].
Nevertheless, the treatment of normocalcemic pHPT remains controversial because the
emergence of clinical features of pHPT is unpredictable as is the evolution to a hypercalcemic
state. The fact that some patients remain normocalcemic despite the clinical manifestations
of pHPT inevitably raises the question of the
definition of a ‘‘normal’’ serum calcium level
for an individual patient. In other words, is it
possible that a serum calcium result within the
normal range for the population may represent
hypercalcemia for a specific individual?
The symptomatic patients with normocalcemic hyperparathyroidism tend to present with
renal calculi and hypercalciuria. Care must be
taken in such patients to exclude idiopathic
hypercalciuria which is the most common
cause of renal calculi, especially problematic
since idiopathic hypercalciuria patients may also
have raised PTH levels making differentiation
of the two conditions difficult. Several tests are
useful to distinguish between the two diseases, but
none alone is conclusive, thus a combination of
two or more are used to make the diagnosis.
Thiazide diuretic administration, which decreases
urinary calcium excretion, will normalize PTH
levels in patients with idiopathic hypercalciuria,
but not in those with normocalcemic pHPT [65].
Calcium loading (350–1000 mg orally) results in
hypercalcemia and hypercalciuria in those with
pHPT, due to increased intestinal absorption [66].
Serum-ionized calcium is often elevated in those
with normocalcemia on routine bloods [67] and
can also aid in the diagnosis of pHPT.
Differential Diagnosis
of Hypercalcemia
The appropriate differential diagnosis of hypercalcemia requires an appropriate understanding of calcium metabolism. Physiologically
active serum calcium in the free or ionized form
accounts for 50% of total serum calcium. Forty
percent of calcium is bound to plasma proteins,
(predominantly albumin) and the remaining calcium is complexed to anions including bicarbonate, lactate, phosphate, and citrate. Alterations in
serum albumin levels may therefore alter the
amount of calcium measured in serum assays, so
a calculation is required to establish a calcium
level that is ‘‘corrected’’ for this potential confuting
variable and that represents a standard against
which other calcium values can be reliably measured. Previously, the calculation had to be performed manually but now formulae such as that
shown below are automatically performed by the
machines used for automated blood sampling
although the reference range and therefore the
exact formula varies between laboratories [68].
Formula for calculating the calcium level cor-
rected for plasma albumin concentration:
Corrected Ca ¼ total Ca ðmmol=lÞ
þ 0:02 ½40
serum albumin ðg=lÞ
Calcium homeostasis is tightly regulated by
calcium-sensing receptors (CaSRs) in the parathyroid glands that are sensitive to fluctuations
in calcium via a negative feedback loop. CaSRs are
sensitive to fluctuations in calcium via a negative
feedback loop such that under normal circumstances, hypercalcemia inhibits PTH production
whereas hypocalcemia inactivates the CaSRs leading to release of the sequestered PTH [69]. CaSRs
are also located in the kidneys and gastrointestinal tract, placenta, pancreas, and brain, where
they also contribute to calcium homeostasis. In
the kidneys, the CaSR regulates renal calcium
excretion so that in the presence of a rise in
serum calcium, the excess calcium is excreted. In
the gastrointestinal tract, the CaSRs are present
in the gastrin-secreting G-cells and acid-secreting
parietal cells and provide one of the links between
hypercalcemia and acid secretion.
The dysfunction of CaSRs is responsible for
three uncommon genetically inherited conditions of calcium dysregulation: familial benign
hypocalciuric hypercalcemia (FHH), neonatal
severe hyperparathyroidism, and autosomal
dominant hypercalciuric hypocalcemia (ADHH)
which are amongst the important differential
diagnoses for disregulation of calcium hemostasis (see below) [70]. An alteration in CaSR
229
PRESENTATION AND DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM
function also lays at the heart of pHPT since
in this condition the parathyroid chief cells
erroneously interpret the calcium levels as low
leading to a lack of inhibition of PTH production
and release and therefore hypercalcemia [71].
In vivo studies have confirmed the existence
of a calcium-sensing deficit [71], as well as
immunohistochemical findings of decreased
numbers of CaSRs by 30–70% in parathyroid
adenomas [72].
Hypercalcemia is defined as a serum-corrected calcium >1 mg/ml above the normal
range (usually 8.5–10.2 or 2.2–2.5 mmol/l)
[73]. Whilst hypercalcemia has many causes,
the vast majority of patients have either primary
hyperparathyroidism or malignancy [53]
(Table 16.5). The distinction between pHPT and
malignant hypercalcemia is based on the clinical findings – absence of symptoms or signs of
malignancy – typically coupled with
biochemical findings such as low serum phosphate, normal serum alkaline phosphatase, normal vitamin D, and high 24-h urinary calcium.
However, key to ruling out malignancy is the
coexistence of an unsuppressed intact PTH
(iPTH), indicative of an alteration of the physiological feedback that suppresses PTH release
as the serum calcium climbs. The emphasis on
iPTH is required to avoid the misleading results
that previously occurred due to the cross-reaction
with PTH-related protein (PTHrP) secreted by
nonparathyroid malignancies although very
occasionally iPTH has been reported to be produced by nonparathyroid tumors [74]. In the
absence of this exceptional event the presence of
hypercalcemia with an unsuppressed iPTH narrows the diagnosis to two conditions: pHPT and
familial hypocalciuric hypocalcemia (FHH).
Familial Hypocalciuric
Hypercalcemia
Familial hypocalciuric hypercalcemia is an
autosomal dominant disorder, with virtually
100% penetrance. It is characterized by hypercalcemia, hypophosphatemia, unusually low
renal clearance of calcium, and typically is
accompanied by parathyroid hyperplasia [75].
Most cases of FHH are caused by a loss-offunction mutation in the calcium-sensing receptor gene which can now be confirmed on genetic
analysis.Typically,patientswith FHH have moderate hypercalcemia from an early age but
relatively low urinary calcium excretion. PTH
levels tend to be normal or mildly elevated but
always relatively unsupressed by the patient’s
hypercalcemia. To exclude FHH it is essential
to calculate the calcium/creatinine clearance
ratio (below). Failure to exclude FHH can lead
to erroneous diagnosis of primary hyperparathyroidism which can lead in turn to one or
more unnecessary parathyroid operations.
Urine calcium ðmmol=lÞ½plasma creatinine ðmol=lÞ=1000
Plasma calcium ðmmol=lÞurine creatinine ðmmol=lÞ
A ratio <0.01 is diagnostic of FHH and ratios
of >0.01 confirm pHPT.
Investigation of Severity
Primary Hyperparathyroidism
Once a diagnosis of primary hyperparathyroidism has been confirmed, an assessment of end
organ disease should be undertaken including
functional and anatomical kidney evaluation
and an assessment bone density. These assessments are important since they identify those
patients who even in the absence of symptoms
have end organ damage and who are therefore
most likely to objectively benefit from
parathyroidectomy.
Abdominal radiography for the diagnosis of
renal and ureteric calculi has been superseded
by unenhanced helical computer tomography
(CT) in patients with acute renal colic [76].
However, the radiation dose received during
an abdominal CT cannot be justified in asymptomatic patients with pHPT, thus renal ultrasound (USS) is the screening investigation of
choice. Ultrasound identifies calculi and
nephrocalcinosis with a sensitivity of 64% and
specificity of 100% [77, 78]. Renal function is
assessed by measuring serum urea and creatinine combined with the calculation of the
patients glomerular filtration rate.
Bone mineral density assessment using dualenergy X-ray absorptiometry (DEXA) is useful
in assessing the presence and degree of osteoporosis in patients with pHPT. Criteria for
osteopenia and osteoporosis based on DEXA
scan results have been published by the World
Health Organization (WHO) and are widely
accepted [79]. DEXA calculates the bone
mineral content divided by the area or volume