MINI-REVIEW

Pri mary Hyperparathyroidism

John P. Bilezikianl
rDivision
of Endocrinology, Department of Medicine, college of physicians
and Surgeons, columbia
University, New york, New york 10032

Background: Primary hyperparathyroidism (PHpr),

the most common cause of hypercalcemia, is
most often identified in postmenopausal women.
The clinical presentation of pHpr has evotved
over the past 40 years to include three distinct clinical phenotypes,
each of which has been studied
in detail and has led to evolving concepts about target
oigan invotvement, natural history,
and management.

Methods: In the present review, I provide an evidence-based

summary of this disorder as it has been
studied worldwide, citing key concepts and data
that have herped to shape our concepts about
this disease.
Results: PHPT is now recognized to include
three clinical phenotypes: overt target organ in-
volvement' mild asymptomatic hypercalcemia, and
high prH leveis with persistently normal
albumin-corrected and ionized serum calcium values.
The factors that determine which oT these
clinical presentations is more likely to predominate
in a given country include the extentto which
biochemical screening is used, vitamin D deficiency
is present, and wiether parathyroid
levels are routinely measured in the evaluation hormone.
of low bone density or frank osteoporosis.
Guidelines for parathyroidectomy apply to all three
clinical forms of the disease. tf surgical
guidelines are not met, parathyroidectomy
can also be an appropriate option if no
contraindications are present. lf either the serum calcium medical
or bone mineral density is of concern
and surgery is not an option, pharmacological approaches
are available and effective.
conclusions: Advances in our knowredge of pHpT
have guided new concepts in diagnosis
and management. (-/ Clin Endocrinol Metab 103:3993_400C,
ZOtg)

IL ithin the lifetimes of many of us, primary hy_ progress to clinical symptoms. The
UI perparathyroidism (pHpT), the most common
given new insights into the surgical
decades have also
cause of hypercalcemia, has appeared and medical man_
to change in its agement of PHPI along with guidelines
clinical presenration regarding the inuolvement that have been
of classic periodically updated since 1991 (2_S).A
and nonclassic target organs. progress disease thatwas
in understanding worrhy of case reporrs in the 1930s (5), now
this disease has also been markeJ by has
the application of seen >5000 published reporrs in the pasr
technologies, nor available previously,
le#ing ro rec_ 20 years.
Moreover, it has spawned interest in the pTH
ognition of a disease that has the potential molecule
to be pervasive itself and its pleotropic cellular and molecular
even when discovered incidentally. mecha_
However, this dev_ nisms of actions (7,8). The disease has
astating potential to be pervasive, also catalyzed.
a feature that was interest and new insights into its counterpart
realized by thq famous aphorism but much
coined by Fuller more uncommon disorder of parathyroid
Albright as a disease of bones, stones, function,
(1), has a variable natural -";;; and groans namely hypoparathyroidism (9). The disease
has given
:

history that can remain us a greater appreciation of bone, as

conuolled by pfff
as
asymptomatic as it was when it was first discovered or
a

and other molecular regulators that work :

in concert with
D)N Print 0021-972X
lssN online 1945-7197 :
Fhted in usA Abbreviations: BMD, bone mineral density;
D)(A, dual energy X-ray absorptiometry; j
FHH,
familial hypocatciuri< hypercalcemia; HRpacT,
O 2018 Endocrine Society high-re;fi,l"^ i"irn""r quantitative
a

lgnStt
Keceived 5 June computed tomography; NpHpT, norrnocalcemic primary :ii!
2018. Accepted 24 July 2018. hyperparathyroidtm; pXpT,
nr$ Published
Online 27 July 2018
primary hyperparathyroidism; TBS,
trabecular bone score.
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 I Clin Endocrinol Metab. NovemDer 2018' 103(1 1):3993-4004
3994 Bilezikian PrimaryHyperparathyroidism

mutadons in the
circulating elements for the most common form of FHH (i'e''
each other to keep our skeleton and to be a
circumstances' C"Snl, it readily available iI FHH is considered
under exquisite iorruol undet normal plausible diagnosis.
ii r.r ,rti.'n.iro.*ive, I provide an update onwith PHPT
this
;;1, ;;t,';t mv investigative experience
lir.o. ,ftr, has extended for over four decades' '--epp-*i-*.tyPHPT
Normocalcemic
15 years ago, our group recognized a
PTH
ror-rriiiprnr tut was characterized by an elevated
albumin-
Diagnosis i.u.i *i tt p..tit,."tly normal concentrations of
se- ,Jirrst.d tot"l ionized calcium (17)' The explanation
PHPT is due to abnormal, incompletely-regulated "ttd
il;;i",lttt biochemical phenotype was discovered and
four Parathyroto
cretion of PTH from one or more of the is now rather common relates to our
proactive approach
disorder will be
;ilt (10, 11). In vimrallv all cases' the to the evaluation of osteoporosis or low bone mass
i.J"t *i f-t .*ft.. a single adenoma (80%) or muitiple svndromes. In these clinical settings'
the PTH measure-
fttperpllstic, disease (20%) responsble' part oi the
"f"."al*.t.*fft mant, ir, soma centers, has become a routine
;;rr:;;;;;;'i,.i bv hvp"'^l"mia and levels of
.""fr",i"t. ln hypercalcemic PHPT, the serum calcium
ffH U", "r. in"ppropriately high for the hypercalcemic it ."n o.."riorr"lly ie normal; however, in normocalcemic
r*..itof*fft, ifie PTH level is franklv elevated' but pnli tr'rpr{Prl, the albumin-adjusted and ionized-se-
."t U. *i.irio th" ttot*"l range' [n both situations'
"f.. elevated levels of PTH are clearly
or rn- ,"- .^f.io- levels will be consistently normal' The-
detectable
when the serum calcium is elevated'
Well- dtii;t;"i diagnosis of NPHPT requires exclusion of
,*ood"ty."t-rr.t of increased PTH' Vitamin D deficiency
"pp."ptf".
i'oiu-"ttt.a prfff has been reported with PTH levels to
as
causes to be ruled
range of is one of the most important secondary
low as 20 to 25 pglml, given a normal -1-0-
o* ,l,f*ouglt this point inevitably leads to a discussion
ti of hv-
lj JJ azl. uitto"ttv al.l other etiologies of the normal range of 2S-hydroxyvitamrn and rm-
;;';;;l;,;. PTH levei will be franklv suppressed -D^
deh$tlon oI
mediately recalls the Irstitute of Medicine's
such as biotin can cause the
i6. ;;;G."bstances l'iomin6 a"n i.n.y (18) as a level <20 nglnil (50 nmoyl-)'
iTH to ,."d loiu *ith cenain assavs (13)' $?hen biotin is that the Institute of Med-
level wru i;;;;* to
discontinued, the rePeated PTH measurement "pp..ci"tt normal
i.i""ti*p"i", *as-ii,ected ptimarily toward a disease'
i. -"t" ..*p",ille with the diagnosis of PTIPT i{ the bone
oo*f",i". with no known metabolic
to set the
Datient has the disease' i" irr. .o.,.*, .r NHPT, it seems reasonable
'- rft. arS.t.n,i"t diagnosis of PTHdepndent hyper- some
low threshold at 30 ng/ml (75 nmol'/L)' because
."ffi"-in lod.. the rie of thiazide diuretics or lithium e-pid.-iology ,t.tdies have associated levels
<30 ng/ml
(14. 15). If possible, these medications should be dis- in PTH (19' 20)' It is also
.ii f n."gt!*it. increases
.ott,in,-,.a. eltttougtt the serum calcium will
return to
per- ,.lron"Ui. in .o-e situations to aim for an even higher
normal in some Patients, most will demonstrate
level of 25-hydroxyvitmain D (e'g" 40 ng/ml-) to see
Uf*hemical hallmarks of PHPT' namelv
.jti."." "i ,ft. per- ;;il;. brn i.u.t would become normal' other
iuo.r."l...i" and elevated levels of PTH More Jl*.a"r, associated with a secondary increase in frlra-
pi.'*G ," some has been the distinction beween JJ ". .*"1 hsulficiency (estimated glomerular.
-PTH

iamiliil hypocalciuric hypercalcemia (FHH)' agene)

rare
tion rate (60 mUmin) and malabsorption
syndromes
air*J* "i.ft. CASR (caicium-sensing recePtorthat FHH ]"J -"d.",io"t such as diuretics, lithiunL bisFhosPho-
and PHPT (15). It is important to recognize in-
denosumab should all be ruled out before
high
it^l .*" ai..tatr' It' additio"' FHH hasbesuch to
"L*, ".a
vokine the diagnosis of NPF{PT' Even after
known causes
**r."... that vimrally all patients will shown ".f.tations
years' bylne
of PTH have been ruled out'
irave hypercalcemia in their young
adult "i-*i"ta"tt secondary stim-
usually present' Ihe tha possibility of some unrecognized
of lb. e f"-ily history is also
ulua to for this presentation will rematn tn
"*. who develops bio*
o"r.**"i"ut"l *o*"nfirst decade after the
"aaorrnt
Jorn. ,i,r",ioot. It is also possible that
those whose
""tt."f- ,ig". oiprrpr in the FHH' p'I]g t.r,.tt are minimally elevated represent the outer
"'rr'.-i."i
*.".n""*lt ft,tnfy unlikely statistically to havewill.be ?Jg" ,ft. normal distribution curYe for PTH' Ap'
i"-rdrr, ,ft. z+ itour urinary calcium excretion "f 2'5L ot the normal populat'nn is likely
ti.y f"* *g) and the calcium clearancdcreatinine ".oii.""rt zone'
tafOO
<0'01' Btt"ote of PTH's calcium-
io have PTH levels in this outer, higher fringe.
.tit*..'."tio *ilibt excrli:1 A further consideration of NPHPT addresses
the oo-
calcium
.""r..vr*1."4 actions, low urinary <0'01)
calcium
;J;;t that an analyte such as the serum in an
l-ir.. .Ad]"- clearance/creatinine clearance ratio
with PHPT' especiallv for patients ;ii;;"; much narrower dav-to-day excursions
range' rt 15
:;; JJ;;n"tible testing individual than the normal population
*i".. iL,".t .ifa"* has been restricted' Genetic
 doi: 10.12104c.2018-01225
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possible, therefore, that some patients with NpHpT manifest as two and, very rarely, three adenomas.
actuaLly have hypercalcemia relativeto their historically Parathyroid carcinoma is rare, accounting for < 1% ofall
lower serum calcium values. An individual, for example, cases of PHPT (11). Suspicion for parathyroid cancer
whose serum calcium was ti?ically -9.0 mgldl, can be should be increased when patients, who are typically
considered to have become relatively hypercalcemic but younger by about one decade, present with much hieher
still technically normocalcemic if the calcium has increased serurn calcium and PTH levels. Invariably, renal and
to 10 mgldl. The 1-mg/dl- increase in serum calcium skeletal involvement will be readiiy apparent. The in_
would still be within the normal population range but for cidence of_parathyroid cancer appears to be increasing in
that given patient decidedly higher. The patienr would the United States and in China (2g, 34).
presenr ostensibly with NPHPT.
Most often, PHPT is a sporadic disease, with no familv
Although not the subject of the presint discussion, it is history and no evidence for other end.ocrine eland in_
noteworthy that the existence of a form of pHpT with a volvement. Genetic forms of pHpT, constirutinfno more
normal serum calcium and PTH concentfation that was than 10o/o of the hyperparathyroid population, can be
found only by pathological examination of abnormal limited to the parathyroid glands or be part of a mul-
parathyroid tissue has been proposed (21, 22). tigland endocrine syndrome (10). The girmline muta_
tions that have been associated with hereditary forms of
Epidemiology PHPT are numerous. At least six somatic mutations have
also been described (3.5, 35).
PH?T predomfurates among women, usually in their Environmental and modifiable risk factors thar have
postmenopausal years, with a female/male ratio of 3 to
been associated with pHpT include ihronically low
4:1. The prevalence varies by country and race. [n the calcium intake, reduced physical activity, higher body
United States, for example, the prevalence of pHpT has weight, frrrosemide, and hypertension (37_40). External
been 0.85% (23), with a racial predilection that seems
neck radiation (41, 42) and lithium and thiazide theraov
to favor blacks (24). Much wider prevalence estimates (14, 15) are also classic risk factors. Mor. ....rrt
have been reported for NPHpT, 0.4 % to 17"/. (25-27\. .*o._
rience with thiazide diuretics has suggested thai hyper_
Another determinant of the epidemiology of this disease calcemia in this setting is most likely unmaskini
is the extent to which (ourine biochemical screenins is the
underlying state of pHpT and is not likely to be rev-ersed
used in a country. ln North American and Westlrn when the diuretic is stopped (14).
European countries, where biochemical screening has
been used since the eady 7970s, pHpT became and
continues to be a relatively common disease (2g). In Specific Aspects of pHpT
countries such as India, where screening is not routine,
The signs and symptoms of pHpT can be due to hy_
PHPT is_ seen much less frequently. Overall, however, percalcemia itself, especially when the serum
the incidence and prevalence of pHpT have increasej calcium
is >12 mg/dl and/or if it has increased rapidly. Symp_
during the past several decades, even rn countries thar
toms include polyuria, polydipsia, .orr.tip"tiorr,
had established biochemical screening decades before
orexra, vomiting, dehydration, irrhythmias, and altered
"n_
(24). This could have resulted frorn the greater
recog_ mental stahls. More likely, however, the symptoms of
nition and diagnostic pursuit of mild hypercalcemla
PHPT are related not to the hypercalcemia i*elf but to
and the likelihood that biochemical s.reenine is even its
key target organs. Renal involvement can take the forms
more widespread than previously 124, 29: 30). ln
of hypercalciuria, nephrolithiasis, nephrocalcinosis, and./
countries where serum calcium has become routinelv
or reduced renal function (43). Although the incidence
measured, the incidence of pHpT has increased. of
A eood tlese overt renal manifestations has declined. in the
recent example is China, where the incidence
hi in_ context of appreciating in many countries a miJder
creased in concert with the greater use
of biochemical biochemical form of the disease, more recent systematic
screening (10,28,31). In Latin America,
the disease has , evaluarion of the kidneys among these asymptomatic
also seen a change in incidence as screening
has become patients has revealed that stones and/or nephrocalcinosis
routine (32, 33).
is actually present in 27y" to SSyo of patients with
asymptomatic PHPT (44, 45).
Etiology and Risk Factors Skeleal symptoms can take tle form of any combina_
tiol of lagiliry fracnues, skeletal deformities, and bone
I Most patients with pHpT have single ad.enomarous
pain.In the classic settng, osteitk
I (80%).or multiply hyperplastic (75;/o fibrosa cysrica describes
to 2OTol para- the radiograph features ofthis presentation in which
thyroid tissue. Multiglandular disease can brown
s
also be tumors, lytic lesions, subperiosteal bone resorption of
the
 2018' 103(1 1):3993-4004
J Clin Endocrinol Metab, November
3996 Bilezikian PrimaryHyperparathyroidism

trabecular bone score (TBS), which can identify

some
patients
phalanges, and bone cyss are seen {46, 47)' \Fhen the lumbar spine DXA
PFIPT' in the early aspects of bone quality from
*.re fiirt des..ib.d with asymptomatic DXA instrument is
image, is available to anyone whose
1970s, the absence of these radiographic manifestations
or not iortiil.a *ith rsS software (58, 59)' The concept of the
was assumed to mean that the skeleton was spared
TBS ia ao-p"rutive one [r.e', the extent to which
the
yet involved. It took the advent of bone densitometry rt
"
textural micr;structural patterns of the lumbar spine fit
this
h. -ia-fSgO, to. us to appreciate the extent to which (homogeneous) or worse
Using more comfortably as better
mild form of the disease did not spare the skeleton' (60)
(D)(A), the distal one- (heterogeneous) bone qualityl. Using TBS, Silva etal'
dual energy X-ray absorptiometry more
showed that lower mean TBS scores were mucrr
third radi"us, a site of conical bone, was shown tote
low
evident in PHPT than in reduced BMD by DXA' Similar
(+S). Th. lu-U.t spine, a skeletal site in which trabecular
involvement' data were reported by Romagnoli et al' (51)' Such studies
Lone oredominateg showed lesser degrees of
reinforced the concept, documented with greater
pre-
of trabecular and
Th. lip ,.giot ., tttore even admixture
cision by HRpQCT, that the"trabecular compaftment
ts
" that were
*.ticai Uitt", showed densitometric values often irwolved in PHPT. Applying these new imaging
midwav between the relativdy well-preserved lumbar spine
panem' technologies, is now clear that in PHPT, the skeletal
it
and the affected disal one-third radius sites' This
most typical den- microstructur" in both cortical and trabecular com-
ftst desaibed in the 1980s, is still the partments is comfromised, observations that are now
the
sitometric profile and reinJorces the need to measure
h all patients with PHPT' The opPosite ion"ord"nt with epidemiology studies that have shown
distal forearm
an increased fracture risk at vertebral and nonvertebral
pattem, however' car also be seen in which the lumbar
with this disease. These observations have decision-
i"itt. it t.***ially reduced (49)' The early effects of sites
making implications because vertebral fracture
assess-
estrogen deficiency, before the onset of PHPT
in post-
can
t n, can explain the reduced lumbar spine ment ;d TBS are accessible to many clinicians and
*tJp"*"I*ot
'mineral the information available from DXA alone'
density (BMD) in at least some of these
supplement
'Slome
bo.re
bone loss can be seen in of the most vexing clinical aspects of PHPT are
Datients. Flowever, any Pattem of but
neurocognitive features that have been well described
irp. ,"tgittg fto- a uniformly low BMD to a uniformly
,
not cl"ar-ly ditectly attributable to the "modern" form of
normal BMD. cog-
the disease' Fatigue, anxiety, Poor concentration'
The pr"ferential involvement of the distal one-third
that the nitive decline, and reduced quality of life have all been
radius in PH?T was consistent with the notion
reponed with varying frequency, leading some to
ques-
fust at a
catabolic effecs of excessive PTH would be seen PHPT is
ftacture tion whether the terminology "asymptomatic"
cortical site. Beeuse DXA is a strong predictor of
be more an accurate descriptor of these patients' If these com'
risk, it was thought that in PIIPT, fracn:res would pa-
(i'e', cortical) skeleton' Two plaints can be direitly attributed to the disease, the
often seen in the nonvertebral
aI' iiens so afflicted are not asymptomatic' However' the
reports by Khosla ef aL (50) and Yignali et
(5.7\'
attribution is uncenain' Each of these features can be seen
Lo*.u.., ,ho*.d that vertebral fractures were seen with
a
in literally any cbronic disease. They lack specifrcity' Even
,ig.rii"*tly greater incidence than in the control Pop- mo.e problematic, the demonsuation of reversibility
after
ul-atior,s. A more incisive imaging technology'
dt :t-
of the ,rr...r.frrl parathyroid surgery in rigorously conducted
solving power that permitted direct assessment
clinical trials has been inconclusive (62-661'
;;;;t compartment of bone (52), was needed. to
paradox' namely that ftacture riskis The neuromuscular, cardiovascular' rheumatologic'
Jdr.", ,tti,
"pp"t.nt and gastrointestinal systems are additional putative
io"r."r.d at a site that the DXA resuks predicted would 'When the disease was typically symp-
targets of PHPT.
[. J",i*ty protected. Even histomorphometry of the tomatic' all tlese systems were described as common
iliac crest bone biopsy did not help to resolve this
isue
not
did, high-resolution perigf- manifestations of the disease; however, now they are
(53). The technology that
as a clinical problem, except in "classic"
.r"i qu"rrtit"tit" .omputed tomography (HnpQCT) (5+)' "fpr."l"t.d settings (11, 12' 43)'
PHPT or in specialized
.ho"r.d that both the cortical and the trabecular com-
(55-57)'
oarmrents of bone are adversely affected in PHPT
in the study by Stein el aL (55), trabecular microstructure A Summary of the variable clinical
*a, fioth.. analyzed using individual trabecular seg- Expressions of PHPT
indexes
mentation analysis' The topology of the trabecular
The symptomatic disorder
favored the vertically oriented rods, a spatial disposition wes
In tire era described between 1930 and 1970' PHPT
that is suboptimal for bone strength'
generally considered a symptomatic disorder with overt
Although HRpQCf is available only in research
the ik Lt"l'*d ..n"1 .omplications (57)' Radiologically' salt
centets a;, thus, not assessable to most clinicians'
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and pepper deganulation of the skull, distal tapering of the counEies to be an uncofiunon disease. India miehc be
clavicles, bone resorption of the phalanges, bone cysts, and
the best example of th.is form of pFIpT (77). In cointries
Drown tumors were common. Stones and nephrocalcinosis where biochemical screening is routine, such as in Western
constituted the renal manifestations, proximal muscle Europe, North Arnerica, and many other parts of the
weakness was due to impaied function of type 2 muscle
world, asymptomatic pFIpT is likely, and it will be ap_
fibers (58). preciated as a rather common disease. parentheticallv.
as
noted already, the use of the term asymptomatic prob;ly
The asymptomatic disorder requires some adjustment, if only semantically, because
In the 1970s, with widespread biochemical screening, with greater imaging tools applied to this population, it is
asymptomatic PHPT emerged as the predominant clin_ apparent that such patients can often be shown'to have
ical form. Because PHIT was beins discovered in_ involvement of the skeleton and./or kidneys. Finally, if
cidentally, the oven radiological feitures of pHpT PTH is routinely measured when patients with low BME
essentially disappeared and the incidence of kidnev are being evaluated, even in normocalcemic individuals.
stones plummeted. Proximal moscle weakness w"s no NPFIPT will emerge as an entity. Thus, all three forms of
longer seen (59). It was reasonable, with dre tools at our PHPT coexist with a relative incidence that is defined by
disposable in the 1970s, to describe these subiects with country- and practice-specific variables.
PHPT as asymptomaric, because they did not have any
classic organ signs or symptoms of the disease.

Evaluation
The normocalcemic disorder
It took another four decades before the normocalce- The curent recommendations for evaluation ofa Datient
mic variant of PHPT was described in the first decade of with PHPT are surnraarized in Table 1 (5). tn contrast to
the 21st cenrury (17). It was discovered in patients being the approaches for many disorders of bone and mineral
evaluated for low bone mass or frank osteoporosis (17, metabolism, in which only the lumbar spine and hip
70-75). However, when MHPT was first described, it regions are measured, DXA measurements shbuld in-
was not asymptomatic but rather associated w.ith overt ciude the distal one-third radius (7g). tn addition to
bone loss, an observation that spoke to the proactive DXA, further evaluadion of the skeleton is now recom_
approach to bone loss syndrbrnes in which the pTH mended because of the recent evidence that many patients
became a stendard part of the evaluation. Since the early with asymptomatic PHPT have vertebral involvement.
descriptions of MHPT, an asymptomatic vatiant has been Thus, in addition to DXA, X-rays, vertebral fracture
described when unsuspecting populations are screened assessment, or TBS should be pan of the skeletal eval_
with serum calcium and PTH levels (75). Thus, MHpT uation. In those centers in which HRpeCT is available,
can be asymptomatic gr symptomatic (53). .These two its use also should be seriously considered. Additional
forms of NPHPT, symptomatic and asymptomatic, match imaging should extend also to the kidneys, because of the
the two forms of tIrc more traditional hypercalcemic
variant of the disease.
Table 1. Evaluation of patients With
Primary Hyperparathyroidism
A World View oi How pHpT Can present
Recommended
These three different presentations of pFIpT have.fol-
lowed a timeline with the symptomatic form described
first, followed by asymptomatic pHpT, and, most re-
BlvlD.by (lumbar spine, hip, distal one-third radius)
cendy, MHPT. Although this historical perspective is ,D)(A
v,eneDrat sptne.€ssessment (radiography, CT or VFA by DXA)
valuable, it is imporrant to recognize that these three srone nsk prottte (it urinary calcium >400 moy'dav)
forms of PIIPT exist concurrently in the wodd today. One Abdominal imaging by radiography, uttrason6gra'phy, or CT
scan
could state that these three forms of pHpT have always Optional
coexisted. The preponderance ofone variant over another HRpQcI
willdepend on seyeral factors that tend to vary by TBS by D)(A
Bone turnover markers
countrf. In countries where biochemical screening is still
not a regular part of the health care system, symptomatic lAdapted with permission from Bilezikian Jp, Brandi ML, Eastell R, et al.
PHPT is likely to be the most common form oi the dis- Consensus Statement: Guidelines ior the management of asympiomatic
primary hyperparathyroidism: Summary Stalement from the Fourth
ease. Because hypercalcemia will be discovered In_
only in the temationat Workshop. J Clin Endocrinol [4etab 2014;99i3561_3569.]
context of symptoms, PHPT wlll be considered in those Abbreviation; VFA, vertebral fracture assessment.
 1):3993-4C04
I Clin Endocrinol Metab, November 2018' 103(l
3998 Bilezikian PrimaryHyperparathyroidism

are oosidve attention. Centers vary by what *odaliry

o'
recent evidence that stones and/or nephrocalcinosis true
in- combination of modalities are preferred (77)' As is
;;;; p;.; among those with PHPT discovered
for most procedural endeavors, surgeons wlto frequently
.id.n The recommendations include abdominal
"lly. perform parathyroidectomy and centers that are highly
iloy' oi."ro.oetaphy, or CT (44)' The 24-hour test for '.*p.ri.rr..d in preoperative localization are most likely
calcium is also sttongly recomrnended' with
guidelines
tnese
to have positive outcomes. The success rates among
io. .or. biochemical urinary stone risk pro-
complete (791' The use of intra-
surgeons and cente$ exceed 95%
filing if marked hypercalciuria is present' with a rapid duoughput
ooerative PTH measurements .
of cur.e
aisay has given assurance regarding the likelihood
Treatment of PHPT aftei remoial of the single or multiply involved parathyroid
exceed
tiss,re. The intraoperative reduction in PTH should
-
Surgical management
cure 50% of the immediate preoperative PTH concentraton
SLeerv in PfPI offers the promise of definitive to 30 minutes
and should be in the normal range within 15
to those who meet any one of
-J trt""Ji u. recomrnended >1 mg/dl after the procedure.
,h. oi oi" fo. rutgo'" hypercalcernia consistendy
nor-"l; f.-"cture;;enal stones' hypercalciuria' and
other stone risk factors; T-score <-2'5 at any
"bot" srte; and -Ciu.tt-Ot management
Nonsurgical
.*gi.al-guidelines' it is obvious that those who
:
aee (50 (Table 2)' Surgery can also be pursued for
vears
do not meet such guidelines will not necessarily be
en-
tio.. *ho do not *eet any of these indications as long.as patients
ulanuruty couraged to undergo parathyroidectomy' In t}'ese
no medical contraindications ale Present and monitoring
who are not to undergo surgery, a reasonable
has been reached among the endocrinologist' surgeon'
protocol includes semiannual testing of the serum calcium
and patient about this course of action' 'and
P[FI; an t ,al or biannual DXA testing (I prefer annual
testing); annual urinary calcium measurements as
clinically
Preoperative parathyroid localization indica'i"d; and further skeletal and renal irnaeing testing as
It ls an axiom in our field that the most important a
the exPert clinically indicated (Table 3) (5)' If the patient develops
aspect of parathyroid localization is locating surgery should be seriously considered'
s*gioi guid.litt.,
p"r"thyroid surgeon. Although this is clearly true' vtr-
'"t"Ut paratf,yroid surgeons depend on successful
"ff Nutritional guidelines
or.oo.r"aiu. localizatio" of the abnormal parathyroid patients
ii.roi- Utr..tonography and technetium-99m-labeled Calcium intake. The intrinsic logic among many
Dietary
,.st"-ibi have be-err-the most popular approaches.for and some physicians is to restrict calcium intake'
calcium ristriction' however, can be perceived by
recenuy' mgn- the
DreoDerative localization; however, more
abnormal parathyroid tissue, which still mahtains some
;;itil CT and four-dimensional CT have received
,.roonriu.ln.r, to fluctuations in the serum calcium-
higher level-to further increase PTH levels
z. rnai."tio"t t*
r"u-.....--r" s*gery in Asymptomatic "iU"i ", "
Primary HyPerParathYroidism
TableT Gu'ld"lines f"r Medical Monitoring in
Parameter Criteria f or Parathyroidectomy With Asymptomatic Prlmary
Patients
'H;;E;ihi;;iAii'n
A9e <50 vears tuE19ggg c'^'"*"ti'"lv
Serum calcium tilriJoi auou" upper limit of normal
skeletal i"oJ.6o eMo by DXA to a T-score of Parameter Frequency of Evaluation
manifestations I<-2.5 (lumbar spine, hip, or
iite (luml
-l.s at any sfie Serum calcium Annually
distal one-third radlus) Three-site D)(A every 1-2 yeas
ve-rteUiat tricture Uy X-ray, CT, magnetic ii.i"tut
imaglng of spine to iccess vertebral fradure
resonance or VFA if-clin-ically suspected (e 9 ' height loss'
Renal Creatinine clearance. <60.mumin, back pain)
manifestations Kidnev stone or nephrocalclnosls oy Serum creatinine and eGFR annually
abciominal imaging lf renal stones are clinically suspected:
Hvgercalciuria (>400 mg/day) 24-hour biochemical stone prolrle'
'iciompanied by biochemical $one risk
abdominal imaging bY X+aY,
orofile placing patient at risk ot Kloney ultrasonograPhY, or CT
stones
aI
ML'iastell R' et
ML' Eastell R' et al IAdaoted with permission from Bilezikian lP, Brandi
lAdaoted with permrssion from Bilezikian JP' Brandr A-J;;;;i";;;i, cuidelines for the management or asvmptomatc
a""T;;;il;;;i, Guidelines for rhe manasernent of asvmptomatic
Statement from the Fourth In- il"il;;dil;;djism: summary sutenient from the Fourth-|ft
i irn1" fn*ipi",nv.idism: summary
l i"i""t i,"jiwir*tnob. I clin Endocrinol Metab 20 l4; 99:3561-3559J
"-lil""ili3iiii,tfr",li. i clin Endocrinol Metab 2014; ee:3s61-3s6e
Abbreviation: eGFR, estimated glomerular liltration
rate'
Abbreviation: VFA. vertebral fracture assessmenl
0or: r u. r1104c.2018-01225 https//academic.oup.corn4cem 3999

(80). This does not mean that the serum calcium level operations, an inability to locate abnormal parathyroid
fluctuates perceptively as a function of calcium intake, tissue, and patient preference.
but that the paratlyroid tissue could well perceive a
'deficient calcium diet and be further stimulated to syn- Lott bone density. The bisphosphonate, alendronate,
thesize and secrete PTH. For these reasons, a normal improves the lumbar spine BMD without any changes in
calcium intake, in
accordance with the Institute of the serum calcium (93-97). Alendronate has also been
Medicine's general recommendations for calcium intake shown to increase BMD in MHPT (98). Very few data
(18) should be adopted by patients with PHPT. are available for other bisphosphonates in pFIpT (99).
Although an increase in bone density would be welcome
Vitamin D. Mtchevidence has suggested that vitamin D in these patients, alendronate was associated with an
deficiency in PHPT is an inciting facror to fu_rther in- increase in fracture risk in a large retrospective cohort
creases in PTH (29, 80-82) and greater expression of
study using an insurance database. The comparison was
disease activity (82-84). Moreover, in countuies .where among those who underwent parathyroidectomy, those
symptomatic PHPT has been well described, severe who were treated with dlendronate, and those who were
vitamin D deficiency is common (8S, 86), In .pHpT, simply observed witlout any intervention (100). The ret-
vitamin D deficiency is more likely because pTH rospective nature of that nonrandomized survey in which
stimulates the conversion of 2S-hydroxyvitamin D to major differences in age, baseline BMD, comorbidities,
1,2S-dihydroxyvitamin D. Although this might seem median T-score, and incidence of osteoporosis were
paradoxical, namd that viamin D deficiency is a clinical present among these duee groups render the conclusion
problem when the 25-hydroxyvitanin D level is low and uncertain. Selection bias could well have predetermined
active vitamin D is normal or higlr, it is the case. Earh who would receive parathyroid surgery or alendronate, or
cohore of patients with PHPT tlpically described vitamin neither, and, thus, have influenced the results.
D deficiency. However, more recent observations have Very recently, denosumab has been evaluated in a
shown that 2S-hydroxt'vitamin D levels are more likely to comparative study of older postmenopausal women with
be normal. This is undoubtedly because the general pop- PHPT or osteoporosis. After 2 years, the grJup with
ulation much more commonly uses vitamin D supplements PHPT showed greater increases in BMD at the lumbar
(83,87). Some studies have even equated seasonal vari- spine, total hip, and femoral neck than did the group with
abi.lity in the biochemical indexes of PHpT as a function of osteoporosis (101).
the seasonal variability in 2S-hy&oxyvitamin D levels (gg).
Although the clinical observarions that related greatC! Hypercahemia. In patients who are not going to have
biochemical indexes of PHPT to low 2S-hydroxyvitimin parathyroid surgery but in whom the serum calcium
D levels, the structural skeletal indexes as measured by is >1 mgldl- above normal or symptomatic hypercal_
TBS (89, 90), quantitative CT (90), or HRpeCT (91) cemia is present, control by pharmacological means
are not as clearly related. To restole vitamin D ade- could be indicated. Cinacalcet is a calcirnimetic agent that
can accomplish this goal by virtue of i* properry to bind
quacy, vitamin D3 or D2 should be used in rnodest
amounts, starting with 1000 IU daily (5). In a ran_
to the_ calcium-sensing receptor. Its calcimimetic prop-
erties lead to an intracellular effect to reduce pTH syn_
domized clinical trial, Rolighed et at. (92\ showed that
thesis and secretion. The serum calcium level will bec#e
vitamin D at 2800 ru daily for 6 months led to an
normal in >707o of patients (102). Although the primary
increase in 25-hydroxyvitamin D from 20 ng/ml to.
effect of cinacalcet is to affect pTH synthesis, circulating
38 nglml-. The restoration of vitamin D to normal was
levels of PTH levels will decrease but only modestly. Irr a
associated with lower serum pTH and C-telooeotide
wide range of clinical presentations of pHlT from mild to
levels and improved lumbar spine BMD. Vitamin D
severe disease, cinacalcet has been shown to be effective
supplementation was not associated with any changes as a calcium-lowering agent (80, 103-105). The S_year
in serum or urinary calcium (92). data have not shown any change in BMD (105).

Pharmacolog ica! g uidel i nes Hypercahemia and re&tczd BMD. Because medications
The reasons to consider a pharmacological agent for in PHF| appear to increase BMD or reduce the serum
-PHPT relate virnrally always to patients who meeithe ci- calcium level, but not both, it seems reasonable to con_
teria for surgery but lvho choose not to undergo parathyroid
sider combination ttrerapy with alendronate or denosu-
surgery. The reasorx for not undergoing parathyroid
sur- mab and cinacalcet for these patients. Vith the limited
Eery when the guidelines have been met include medical experience available to date, this approach has shown
contraindicadons, previous and,/or multiple previous neck
promise (106, 107).
4000 Bilezikian PrimaryHyperparathyroidism J Clin Endocrinol Metab, November 2018, 103(1 t )i399t-4004

Natural History of PHPT With and after parathyroidectomy helps to substantiate the
Without Surgery guidelines that do not include these features amone the
indications for surgery.
The long-term outcomes of those who do or do not
undergo parathyroid su.rgery are available for <15 years
of prospective monitorhg 15, 64, 65,78, 108, 109). Conclusions
Among those who do not undergo parathyroid surgery
During the past 40 years, we have gained progressively
(108), all relevant biochemical indexes remained stable,
greater insights in presentations, involvement of target
with only an upward trend between years 13 and 15 in
organs and the management of PHPT. New imaging
the serum calcium. The BMD was stable at all three sites
technologies have helped to define involvement among
until year 8 when the femoral neck and distal one-third
those who are discovered incidentally in the course of
radius began to decline. These small declines became
biochemical screening. Among those who present with .
more evident and were markedly evident between years
10 and 15.
classic symptoms, the lack of population-based bio-
chemical screening, along with vitamin D deficiency ap-
Among those who undergo successfi parathyroid
pear to be key determinants. NPHPT. can be discovered
surgery, the biochemical indexes will prompdy normalize
among those who are evaluated for a reduced bone mass
and the BMD will improve at all sites. BMD increases fust
but can aiso be discovered incidentally. Although suc-
in the lumbar spine, followed chronologically by irn-
cessful parathyroidecromy cures the disease, the guidelines
provements in the hip and distal one-third radius sites.
are usefrrl because of the benign natural history in many
Parathyroidectomy also leads to improvements in skeletal
who do not meet the criteria for sugery. In those who do
microstructure and bone stengdr as determined by
meet the surgical guidelines, but in whom surgLry is not to
HRpQCT and finite element analysis (110-112). However,
be performed, pharmacological approaches are available
within a relatively short follow-up period, during which
to reduce the serum calcium and/or improve the BMb.
high-resolution imaghg showed improvements, no changes
were found in the TBS (110). In the sening of a randomized
clinical trial (113), successfuI parathyroidectomy was as- Acknowledgments
sociated, not only with improvements in BMD, but also
During the past 40 years, I have worked with a large number of
with a reduction in fracture incidence (100, 109, 113). Even colleagues who individually and in the aggregate have conuib-
in NPHPT, when the surgical guidelines are applied, as uted much to the new knowledge we have gained and to whom I
recommended, parathyroidectomy has been associated am most grateful: Sanchita Agarwal, Claude funaud, Andrew
often, but not always, with beneficial outcomes such as an Arnold, Gerald Aubach, Francisco Bandeira, Leonardo Ban-
increase in BMD (11,t-115). deira, Victoria Borba, Joao Borges, Stephanie Boutroy, Maria
The renal system appears to be stable over time among Luisa Braldi, Robert Canfield, Filomena Cerani, Fred Chan,
those who have not undergone parathyroidectomy, at least Silvia Chiavistelli, Cristiana Cipriani, Ban Clarke, Aline Costa,
regarding serum creatinine and urinary calcium excretion. Serge Ctemers, Natalie Cusano, Hector Deluca, David Demp-

However, the recurrence of kidney stones was cofllmon ster, fuchard Eastell, Ghada El Haj Fuleihan, piene D'Amore,
(108). Surgery has been associated wirh a reduction in Lorraine Fitzpatrick, Arrdrea Giustina, David Golaman, Luiz
Griz, Ed Guo, Didier Hans, Hunter Heath, Andrew Ho, Thomas
urinary calcium excretion and kidney stones (117). Clini-
Jacobs, Elias Kazam, Aliya Khan, Klaus Klaushofu, Michael
cally, the risk of kidney stones appears to be substantially
Kleerekoper, Stavroula Kousteni, Henry Kronenberg, Annie
reduced after surgery (54,55, 100, 108, 109). Kung, Jennifer Kuo, Etah Kurland, Marise Lazareni-Casro,
The irnprovements in skeletal and renal parameters in
James lee, David K. ku.ng, M.ichael kvine, Michael
patients who demonstrate compromise in these two Lewiecki, Uri Libermao, Paul LoGerfo, Marjorie .Luckey,
target organs give dhect evideite for the guidelines that MichaelMcClung, PaulMiller,JianminLiu,She!ryLiu,Rukshana
recommend surgery for these padents. However, it has Majeed, Robert Marcus, Claudio Marcocci, Jasna Markovac,
not been possible to show with any consistency that Stephen Marx, Gherardo Mazzioni, Xunwu Meng, Salvatore
neurocognitive and cardiovascular features, should they Minisola, Carolina Moreira, Don McMahon, Ralph Muller,
be present, improve witl surgery (43). Summarizing the Kazuhide Ogino, Beatriz Omeragig Lefteris pascalis, Monika
experience in this regard, a recent meta-analysis of both Pawlowska, Muruo Peacock, John Potts, Dan Rao, pau.l
Roschger, Clifford Rosen, Michael Rosen, Mishaela Rubin, Ego
randomized clinical trials and observational studies of
Seeman, Markus Seibel, Monica Skarulis, Elizabeth Shane,
asymptomatic patients with PFIPT did not show any
Dolores Shoback, Barbara Silva, Shonni Silverberg, Ethel Siris,
improvem€nts in quality of life, neuropsychiatic AJlen Spiegel, Ernily Stein, Ronald Staron, Gaia Tabacco,
symptoms, or cardiovascular events (118). The lack of Donovan Ta6 Robcrt Udelsman, Marcclla Walker, Nelsor
evidence for substantial improvements in these areas Vats, John Villians, Randy Yeh, aod Ro get Z.ebaze.

.t
 dot: 10.1 21 qc.2O18-O1 225 https//academic.oup.co.ry'jcem 4001

Fiflancial Support: This work was supported, in part, by 15. Marx SJ. Famfial hypocalciuric hypcrcalcemia as an aq,pical
cortinuous funding since 1984 flom National Institutes of form of primary hyperparathyroidism. ,J Borrz Miner Res. i}lg;
Health (Grant DK 32333). 33trt27-3r:
Qorrespondence and Repritrt Requests: Joha p. Bilezikian, 17. Silverberg SJ, Bilezikian JP. "lncipient" primary hyperparathy_
roidism: a "forme fruste,' of an old disease. I Clin Endocrinol
MD, Departrnent of Medicine, College of Physicians and
M€t r. 2003j88{1t):j348-j3.52.
Surgeons, University of Columbia, 630 West 168rh Street, New 18. Rosen CJ, Gallaghcr JC. The 2011 IOM report or viramir D aod
York, New York 10032. E-mail: jpb2@columbia.edu. calcium rcquircments for Nortlr America: ciinical implications for
Discbsure Summary: The author has nothins to providers treating patien* with low bone mineral densirv, I Clir
disclose. D ensitoftt. 20 | 1 ;1 4 (2)j 9 -84.
19. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC. Deraska
DJ, Kirch BT, Vamvakas C, Dick lM, priace RL, Fin_kehrein IS.
References Hypoviraminosis D in medical inparienrs .
N Engl J Med. l99g;
338112):77 8-7 83 .
1. Albright F. A page out oI the history of hypcrparathyroidism. 20. Bendz H, Sjiidin I,Tos G, Bergluud K. Hyperparathyroidism and
J Clin Efldoctinol Metab. 194818 8).:637-657. lorlg-term lithium th€rapy-a c_ross-sectional study and the effect
2, Consensus Devclopment Conference panel. Diagnosis and roan- of lithium vithdrawal. J Intem Med. 1996;Z4OGBi7_365.
agement of
asymptomatic primary hyperparathyroidism. Azz 21. Lavryk OA, Siperstein AE. Usc of calcium and parathvroid
Iateit Med. 199 1:714: 59 3-597, hormone no&ogram to distinguish betweeu atypical prirnary
3. Bilezikiao JP, Potts }f Jr, Fuleihan Gel-t{, K.leerekoper M, Neer R, hyperpararhyroidism and nordal patienrs. World I Surg.2017;
Peacock M, Rastad J, Silverberg SJ, Udelsman R, Vells SA 47(1\122-128.
Jr.
Surffnary statement ftom a workshop on asymptomatic primary 22. Ros6rio Plf. Pdmary hyperparathyroidis& with normal calciun
hyperpanthyroidism: a perspcctive for the 21st ccntury. I gor? and PlH. World J Surg. 2OLZ;41(6):1649_L650.
Mifler 2}'2;tTlsuppl 2):N2-N11.
Res. 23. Press DM, Sipcrstein AE, Berber E, Shin JJ, Metzger R, Mooteiro
4. Bilezikian JP, Khan AA, pofts If Jr; Third Irtematioral Work_ R, Mino J, Swagel V, Mitchell JC. The prevalence of undiagnosed
.hgl oo y1"C:-enr of tuymptomaric primary Hypcnhy_ and unrecognized primary hyperparathyroidism: a popJation_
S:
forotsm, !,urctetrn€s lor the managcment of asymptomatic pri4ary
based analysis from the electror c medicalrecord, Suigiry. ZO|S;
hyperparathyroidism: sununary sktemcnt from rhe third in_ 15 4(6)t1232_1238.
tcrnational workshop. I Clit Endoninol Meub. 2009;94(2)t 24. Y-ch MV, Ituane PH, Zhou HC, Nshinoto S, Uu IL, Harari
335-339. A,
Haigh PI, Adams AL. Incidencc and prevalence of primary hy-
5- Bilezikian J[, Brandi ML, Eastell R" Silverbery SJ, Udelsman R,
perparathyroidism in a racially mixcd populati"". Ctin
.Marcocci C, Potts If Jr. Guidclines for the manasement
oi crinol Metab..20 13 ;9 8(3)t71ZZ-1129.
f A"ao-
asymptomatic primary hyperparathyroidisnr.: srxnmary-statedenr
25. Kontogeorgos c, Tlimpou p, Lainc Ctr{, Oleriid G, Lindahl
from the Fourth Intcrnational Vorkshop. / Clin-Endoctixol
landin-Wilhelrnsen K. Normocalcacmic, vitaEin D-sufficient
d
Metab. 2014 p9 110|:3 s 61-3 s 69.
6. AJbright F, Aub J, Baucr V. Hyperparathyroidism: comrnon and hypcrparathyroidism-high prevaleocc and low morbidity in t[e
polymorphic conditioD
general populatior: a long-term follow_up srudy, the !0HO
as illu.strated by seventcen proven cases in
one cf inic. /AMA. t934i1}2lt6)t1276. !!{!f nroiect, Cothcnbug, Swcden. Ciit Enioctb,ot (Oxf).
7. Revollo 2075:83121277--284.
ICivitelli R. Moleculat actions ofparathyroid hormorrc.
In: 8_ilezikian JP, cd. Tl e parctlryroids. 3d, id,. San biego: Elsevicr; 26. Vignali \ Cetani F, Chiavistelli S, Meola A, Saponaro F, Centori
2015:119-126. R, Cian-fcrotti L, Marcocci C. Nornocalccmic primary hypcr-
.8. Silva B, Kousteni S. Cellular actions of pTH: parathyroidism: a suwey in a small village Sorrd.in iaty,
osteoblasts. osteo-
clas6, and osrcocyrcs.ln: Bilezikian Endocr Connea. 2015 i4l3ltt7}-17 6. "f
Jp, cd. Tle p arath.yro;ds.3td
cd. San Diego: Elsevicr; 201\127-138, 27. Crrsano_N4 Maalouf NM, Wang py, Zhang C, Cremers SC,
9.
!:"$ {! Bilezikian Jp, Shoba& D, Bouilon R, Clarke BL, Harey ElvI" Bauer Dg Orwoll ES, Bilczikian lp. Normocalccmii
Thakler RV, Khan AA, potts IfJr, Managemun, hyperparathyroidism and hypoparathyroidism in two cornmuniry_
bypop","l if
tbyrordlirD: sununary statemeot and guidelines. Clin Endocrinol basrd norueferral populaaors. Ctin Endoainot Metfub. 2O1
I
I 3 i98l;)l
Meta b. 2Ot 6 ;10 tl6\.227 3-228 3. 2734-2741.
10, Bilezikian-JP, Bandeira L, Khan A" Cusano NE. Hyperparathy- 28. Ud:lsrm R, Akastritm c, Biagini g Duh ey, Miccoli p, Medcrle
roidism. Lancet. 2Ot8;391{10116):168-178. Tooelti
Th9 surdcal management of asympromatic primary
11. Bilezikian JP, Cusano NE, Khan A-A, Liu P, J.
JM, Marcocci C, Eyperparathyrod$m: proceedings of dre Fourth Intemational
Bandeira F. Primary hyperparathyroidism. Nai R- Dk pr;-ni. 'Workshop.
/ CJiz Ezlo6inol Metab. 2014;991 t0):359j_3605.
20162.16033. 29. Abood A, Vestergaard p. Increasing incidence of primary hy-
12. Bilezikian JP. Primary hyperpa.rathyroidism. In: DeGroot L, perparathyroidism in Dewnatk. Dan Med
www.ENDOTEXT.org (vcrsion of 2017); Singer F, Section-Ed-
ed. l. 2013;6-0(2),Ai55i.
30. Collicr d ?onclli M, Ghosh S, Nowell S, -Cf"rt fi. f.i-rr1t y_
itor. Sourh Daltmouth, MA: MDTEXT.COM, Inc.; 2017. perparathyroidism: increasing prevalencc, social deprivation,
_ ^ and
13. Piketry.M! Prie D, Scdel F, Bernard D, Hercend C,
Chanson p, sutgcry. Endocr Res. 20 17;42 (l ):3 1_3j.
Souberbielle JC, High-dose biotin therapy leading io false
biol ' 31. Liu JM, Cusano NE" Sllva BC, Zhao
chemical cndocrinc proiles: validation o( a simllc method to
! He Xy, Tao B, Sun LH,
ZhaoFIY, FanWW, Romano ME" Ning G, BilezikiaaJp. primary
overcome biotin interfcrcncc. Clin Chem Lab Med, 2017;5516): hyperparariyroidism: a tale of two citics revisitcd_New york
I 8t7-825. and Shanghai, Boze R cs. 2073;112)tt62_169,
) 14. Griebdc_r_Ml, Kearns A-E, Ryu E, Thapa p, Hathcock
MA, 32, Bandeira F, Griz L, Caldas G, Bandeira C, Freesc
E. From mild ro
M€lton LJ III, Vcrmers furi. Thiazidc-associatcd hypercalceoia: s:vcr: pnTary hyperparathyroidism: the Brazilian experience.
incidence and association with primary hyperparathyioidism
ovcr Atq Bras End.octinol Metdbol. 2006;5014)1657463.
two dccadcs. J Cirn Endocrhol Metab.21l6i7}1l3l.t1l6(-{173, ^^
-
r).
" Szalat A, Mazeh H, Freund HR. Lithium-assorciaEd byperDara-
33. Eufiazino C, Veras A, Bandeira F. Epiierniology of primary
hyperpararhyloidisr and its non-classical manifeitations
tltyroidism: rcpon of four cascs and review of the literanuc. in the
irrr_f City of Recif€, Rtail. CIin Med Insights Exd,ocrhol Diabet*.
Ettd o cr in o l. 200 9 ;t 60 12\ 1377 -323. 2073:6:69--7 4-