Histol Histopathol (2000) 15: 619-627

Histology and
001: 10.14670/HH-15.619 Histopathology
From Cell Biology to Tissue Engineering
[Link]

Invited Review

Pathophysiology of primary hyperparathyroidism

P. Hellman 1, T. Carlingl, L Rask2 and G. Akerstrom 1
Departments of 'Surgery and 2Medical Chemistry, Uppsala University, Uppsala,Sweden

Summary. Parathyroid gland is the overall regulatory Introduction

organ within the systemic calcium homeostasis. Through
cell surface bound calcium-sensing receptors external The parathyroid glands, the overall regulatory organ
calcium inversely regulates release of parathyroid within the systemic calcium homeostasis, exert an
hormone (PTH). This mechanism, which is voltage exceptional control of its principal secretory product,
independent and most sensitive around physiologic parathyroid hormone (PTH). The most important and
calcium concentrations, is regulated through a 120 kDa rapid regulation is exerted by the ambient calcium
calcium sensing receptor, CaR. Inherited inactivation of concentration, and even minor changes in serum calcium
this receptor is the cause for familial hypocalciuric concentrations will cause significant changes in the PTH
hypercalcemia (FHH). Parallel research identified the release (Brown, 1982). Even though many substances
550 kDa glycoprotein megalin, which also is expressed have been found to influence PTH secretion, calcium is
on the parathyroid cell surface, as another potential the most potent one, exerting its effect through cell
calcium sensing protein. Although this protein expresses surface-bound calcium-sensing receptors, with the
numerous calcium binding sites on its external domain, ability to mediate signal to the cell interior (Brown and
its main function may be calcium sensitive binding and Hebert, 1996). The relation between external calcium
uptake of steroid hormones, such as 25-0H-vitamin D3 and PTH release is inversely sigmoidal, where the
(bound to vitamin D binding protein) and retinol. In calcium concentration that causes half-maximal
hyperparathyroidism (HPT), excessive PTH is secreted inhibition of the PTH release (e.g., the set-point) is
and the calcium sensitivity of the cells reduced, i.e. the situated in the steepest part of the curve corresponding to
set-point, defined as the external calcium concentration the physiological concentration ranges for ionized
at which half-maximal inhibition of PTH release occurs, calcium (Brown, 1983).
shifted to the right. Pathological cells have reduced Hyperparathyroidism (HPT) is caused by one or
expression of both CaR and megalin, and reduced several enlarged parathyroid glands with excessive
amount of intracellular lipids, possibly including stored release of PTH. PTH activates its peripheral receptor
steroid hormones. A number of possible genetic present in several organs including many without
disturbances have been identified, indicating multi- involvement in the classical calcium homeostasis
factorial reasons for the disease. In postmenopausal (Juppner et aI., 1991). In bone and kidney, however,
women, however, the individual group with highest PTH binding to its receptor yields increased levels of
incidence of disease, a causal relation to reduced effect plasma calcium, through increased reabsorption of
of vitamin D is possible. An incipient renal insufficiency kidney tubule calcium and increased osteoclast activity
with age, lack of sunshine in the Northern Hemisphere, causing mobilization of calcium from the bone (Habener
and an association to the baT haplotype of the vitamin D et aI., 1984). Thus, HPT is characterized by increased
receptor supports this theory. This review summarizes plasma levels of calcium and may be diagnosed by
data on regulation of PTH release, dysregulation in HPT, determination of relatively increased serum PTH levels
as well as proliferation of parathyroid cells. (Hellman et aI., 1994). This review summarizes aspects
on the current understanding of normal parathyroid cell
Key words: Parathyroid, Calcium receptor, Hyper- physiology, with special focus on the pathophysiology of
parathyroidism, Tumor, Hypercalcemia HP?:

Regulation of PTH release

Offprint requests to: Per Hellman, M.D., Ph.D., Associate Professor. Calcium sensing
Department of Surgery, University Hospital, S-751 85 Uppsala, Sweden.
Fax: +46-18·504414. e-mail: [Link]@[Link] The dose-response relationship between the external
620
Pathophysiology of HPT

calcium concentration and the PTH release is inversely reverse , knock-out experiment is performed in nature
sigmoidal but a non-suppressible component of the PTH itself, since point mutations or inserts of Alu-repeat in
secretion persists even at high externa! calcium levels the CaR gene cause variable degrees of inactivation in
(Brown et al., 1979 ; Wallfelt et al., 1988a,b). The rapid individuals with familia! hypocalciuric hyperca lcemia,
stimulatory effect of a reduced externa! calcium FHH. Thus , the hypercalcemia and hypocalciuri a of
concentration mainly affects the secretion of recently FHH are related to a reduced calcium-sensing function
synthesized PTH, while long-standing hypocalcemia from inactivation of the CaR, which leads to a right-
increases the release also of PTH stored in secretory shifted set-point for the urinary calcium clearanc e and
granules (Habener et al., 1984 ). On the other hand, acule the PTH release (Pollak et al., 1993, 1994). Inactivation
hypercalcemia rapidly inhibits the PTH release , and also of both alleles leads to neonat a l severe hyperpara -
increases the intracellular PTH degradation and reduces thyroidism (NSHPT), with substantial mortalit y unless
the PTH gene transcription (Habener et al., 1984 ; surgery is performed neonatally .
Okazaki et al., 1992). The concept of ce!! surface- Parallel research led to identification of the human
located calcium-sensing proteins, which monitors the version of a rat protein referred to as the rat Heymann
externa! calcium concentration, was proposed after nephritis antigen, gp330 or LRP-2 in the liter atu re
electrophysiological studies of bovine parathyroid cells, (Lundgren et al., 1994). The human version was initi ally
and studies of cytoplasmic calcium ([Ca2+¡¡), found to denoted CAS (CA!cium Sensor), while the subsequently
act as a principal intracellular messenger in parathyroid cloned rat protein was called mega lin , due to its large
cells (Lopez-Barneo and Armstrong , 1983; Gylfe et al., size (Saito et al., 1994). In thi s revi ew we apply the
1986; Nemeth and Scarpa, 1986). These studies revealed name mega lin also for the human version. This large ,
that a sudden increase in externa! calcium induces a 550 kDa glycoprotein, has been proposed as another
transient rise in [Ca2+]¡, presumably through releas e of candidate for a parathyroid calcium sensing receptor
intracellular stores of calcium, followed by influx of protein. Murine monoclonal antibodies directed agains t
calcium through opening of calcium channels (Larsson human parath yro id cells recognized the prot ein, and one
et al., 1984) . The associated depolarization was of the antibodies was found to functionally inhibit the
demonstrated to be caused by calcium itself, and the Ca2+ induced rise in [Ca 2+]¡ and reduction in PTH
calcium channels were found to be voltage-independent release (Juhlin et al., 1987a ,b) . Thes e results were
supported by findings that the L-ty12e calcium channel supported by studies in placenta! cytotrophoblasts, also
blocker verapamil did not affect [Ca2+]i (Lopez-Barneo demonstrating a potential calcium regulation of release
and Armstrong, 1983; Ridefelt et al., 1Y96). The rath er of PTH-related protein (PTHrP) from the se cells
unusual voltage-independent depolarization of these (Hellman et al., 1992). Further characterization revealed
cells was the basis for postulation of a cell surface- that the human sequence and structure closely resemble d
bound calcium-sensing receptor regulating PTH release rat meg alin (Juhlin et al., 1988 ; Lundgren et al., 1994;
(Gylf e et al., 1987). Recent studies using image analysis Hjalm et al., 1996). This prot ein has prev iously mainly
technology have revealed that increased externa! Ca2+ been identified as an endocytotic receptor for various
induces verapamil-sensitive [Ca2+]i oscillations, and that protein complexes or apolipoprotein B or J, and has been
the frequency of these oscillations relates to the externa! thought to function merely as a scavenger prot e in
Ca2+ concentration (Ridefelt et al., 1995) . Thus, both (Farquhar et al., 1994). Interestingly , recen! research has
voltage-independent and voltage-dependent calcium identified megalin as an uptake mechanism in the renal
channels seem to be expressed, and there may indeed be proximal tubule for intact or amino terminal fragments of
severa! mechanisms for regulation of [Ca2+]i in the PTH, 25 -0H-vitamin D 3 bound to the pla sma vitamin
parathyroid cell. The sensor mechanism(s) is not D-bindin g protein (DBP) , as well as retino! , which have
selective for calcium, but also senses other cations, like been filtrated through the glomerulus (Hilpert et al.,
magnesium and the polyvalent cation neomycin, which 1999; Nykja e r et al., 1999). Megalin ha s thus been
both induce transient rises in [Ca2+]i and inhibit PTH proposed as a receptor effectuating tissue selective
release (Ridefelt et al., 1992a,b). uptake of steroid hormones, with implication not only
Research using expression cloning in oocytes for local calcium homeostasis (Nykjaer et al., 1999).
resulted in the identification and cloning of a G-protein- These findings may explain physiological mechanisms
cou pled 120 kDa glycoprotein with a seven also in the parathyroid, where megalin may constitute a
transmembrane receptor-like structure (Brown et al., mechanism for vitamin D (and possibly vitamin A)
1993). This protein, denoted CaR (Calcium Receptor) , is regulation of parathyroid chief cell function. Ind ee d, a
expressed in various tissues with known or (yet) cell surface mechanism with receptor-like properties
unknown calcium sensing properties, l ike the recognizing vitamin D has been proposed in severa]
parathyroid and kidney tubular cells, keratinocyt es, cells, including the parathyroid (Baran et al. , 1991;
certain cerebral cells and thyroid C-cells (Garrett et al., Bouillon et al., 1995). Moreover, although the
1995; Ruat et al., 1995; Bikle et al., 1996) . Transient PTH / PTHrP receptor seems to be absent on the
expression experiments of full-length CaR cDNA have parathyroid cell surface (our own unpubli shed resu lts) ,
document e d its calcium rece ptor function a nd its aminoterminal PTH(l-34) inhibits PTH release in
coupling to [Ca2+]i as an intracellular messenger. The cultured parathyroid cells (Fujimi et al., 1991 ),
 62 1
Pathophys ío/ogy of HPT

impli ca tin g a poss ibl e ro le fo r mega lin in a negat ive PK C at low Ca 2+ leve ls dec reases PTH release, wh ile
feed-b ack mech anism. suc h ac ti vat io n at hi g h Ca2 + incre ases th e sec re tio n
In additi o n, the initi al studi es in parath yro id ce lls ( Rid efe lt et al. , 1992a, b ; Rac ke and Ne m eth , 199 3)-
and place nta! cytotroph oblasts menti oned above, as we ll Recent resea rch may enli ghten this area, since high Ca +
as the additi onal se lec tive tiss ue ex press io n of mega lin, has b ee n fo und to ph os ph orylate int race llu lar P KC-
(e.g. p ro xim a l tubul a r bru s h b o rd e r, pl ace nt a ! ac tiva tin g sites in Ca R, mainl y Thr 888, w hich in turn
cy totro ph obl asts, type II pn eum ocy tes and m amm ary m ay m e di a te a n inhibiti o n of th e intrac e llul a r Ca2+
e pith e lium ) s upp o rt it s ac ti o n as a ca lcium -se ns in g m o bili zat i o n b y bluntin g t h e s timul a ti o n o f
rece pt o r (Juhlin e t a l. , 1990; He llm a n e t a l. , 1992; ph os ph o lip ase C, a nd th e re b y in c reas in g th e PTH
Lund gren et al., 1997) . Howeve r, many tissues includin g sec re ti o n ( Ba i e t a l. , 1 998). In a dditi o n , rece nt
para th yro id ex pr ess Ca R and meg alin co nco mit antl y, di scove ri es hav e cl a rifi ed th at b es id es th e cl ass ica l
w hereby the ca lcium se nsing mec hanism may depend on PKCs , whi ch are ac tiva ted by both Ca2+ and DAG , the re
e xpr ess io n o f bo th prot e in s . H oweve r, th e re a re are the nove l PKCs acti va ted by DA G but not Ca2+, and
example s of tissues and cells ex press ing only one of the th e aty pi ca l PK Cs requirin g ne ith er of th ese stimuli
prot e in s, but s till d e m o ns tratin g c a lcium- se n s in g (Shivji et al., 1996).
properties . Th yroid C-ce lls ex press Ca R but not mega lin, Poss ible routes w hereby exte rna] Ca2+ stimul us may
but di spl ay c a lcium- se ns iti ve reg ul a ti o n of [Ca2 +Ji ac t vi a mega lin need to be clarified, but the amin o ac id
osc illations and ca lcitonin release (Garrett et al., 1995) . sequ ence in the int race llul ar tail in thi s large prot ein has
On the other hand , a subcl one of the rat prox imal tubul e bee n de monstrated to cont ain poss ibl e SH 2-, SH 3-, or
ce ll lin e IRPT C, exp resses mega lin but no t Ca R, and PTB-d o mains, thu s o ffe ring a pr e requi s ite for furth e r
th ese ce ll s d o in fa ct reac t w ith p a ra th y roid-lik e prot ein-p ro tein interactions (Hjalm et al., 1996) .
altera tions in [Ca2 +]i wh en ex po se d to ex tern a! cat ion
stimuli (He llm a n e t a l., 1995a, b ; Ta ng et a l. , 199 5 ). Vitamin A and O
Howeve r, althoug h seve ra! studi es indi ca te that mega lin
is in vo lv ed in th e ca lcium se ns in g, thi s is still no t A v itamin D-res ponsive elem ent (VDR E) consisting
pr ove n , s inc e prop e r tran sfe cti o n ex p e rim e nt s o f a s ingle hexa nu cleo tid e is pr ese nt in th e PTH ge ne
doc umenting its role as a Ca2+ se nso r have not ye t bee n prom o te r, whic h me di a les the inhib itor y effects of
perfor med, mainl y du e to tec hni ca l problem s with the vit amin D o n PTH mRN A transcripti o n (Demay et al.,
large cDNA (- 13 kb ). Th e mega lin knockout mic e may 1992). Th e inhibiti o n is doc um e nt ed in v ivo in rats
h e lp t o c la ri fy thi s iss u e, a lth o u g h mi ce wi t h (Sil ve r e t a l. , 1985) , as we ll as in v it ro in bovi ne
ho mozygo usly disrupt ed mega lin ge nes die perin atally para thyroid ce ll cultur es (Ca ntley et al., 1985).
due to res pir atory failur e (Willn ow et al., 1996). Vitamin D has antip ro liferat ive effec ts in many ce ll
A ll ava ilable data taken toge th er may thu s indi ca te sys t e m s (Ca rlb e rg a nd P o ll y, 1998) , a nd h as in
that Ca R is not the only ca lcium se nsing receptor o n the parath yroid cells also bee n demons trat ed to inh ibit ce ll
para th yro id ce ll surfa ce, and th at mega lin in addi tio n repli catio n, both in v ivo (Nave h-M any et al., 1995), and
m ay fun c ti o n as a poss ibl e se n s in g and / o r upt ake in v itro (Nyg ren et al. , 1988) . Furth e r, v it amin 0 3 is
mec hanis m fo r ste roid ho rm ones and PTH , alth o ug h kn ow n to exer t di ffe re nti a tin g eff ec ts on ma ny ce ll
their respec tive roles in hea lth and disease awa its furth er sys tems, includi ng the parathyroid (Delmez et al., 1989).
analys is. The rece ntl y demonstrated lin k bet wee n mega lin and 25-
0H- vitamin 0 3 , retin o ids and PT H upt ake in prox im al
lntracel/ular signaling tubul e ce ll s, m ay a lso h y po th e tic a ll y fun c t ion in
parath yro id ce lls (Hilp ert et al. , 1999; Nykj aer et al. ,
Seve ra] intracellul ar factors are invo lved in furth er 1999 ).
tr a n s p o rt o f th e ex t e rn a ] ca ti o n m essage in th e Parathyro id ce lls have been demon strated to express
para thyro id ce lls . Th e mos t studi ed of these is [Ca2+ ]¡, a co mpl ete set -up of prot eins req uir ed for int racel lula r
which relates to the ex terna! ca lcium co nce ntration in a handlin g of retin o! and re tino ic ac id (Liu et al. , 1996).
pos iti ve s ig mo ida l fas hi o n. T he m ec ha ni s m for th e Ind eed, ret ino! is metabolized in the parath yro id to all-
in c reased [Ca2+ Ji is a ttribut e d to ac ti va ti o n o f trans- and 9-c is-retinoic ac id (RA ), the ac tive ligands fo r
ph os ph o lipa se C a nd in c rease in ph os ph o in os it o l the nucl ea r rece ptors (Liu et al., 1996). Retin oic aci ds,
turn over with th e pro ducti o n of in os ito l triph os ph ate like active vitamin D, have been show n to inhibit PT H
(IP 3) and IP4 (Ep ste in e t a l. , 1985; Sh o b ac k e t a l. , mRN A ex pr ess io n, and also to affec t the PT H release
1988). In cells tra nsfec ted w ith Ca R, Ca2+ ac tiv ates thi s (M acDonald et al., 1994 ; Liu et al., 1996) . Furth er, all-
casca de ( Kifor e t a l. , 199 7 ) . H oweve r, Ca2+ a lso tra ns - , a nd 9-c is- RA we re demo ns t ra t e d to inhibí !
increases th e leve ls of d iacy lg lyce ro l (DA G), anoth e r proli fera tio n o f para th yro id ce lls to simil ar deg rees as
p ro du ct of th e ac ti va te d ph osp hoin os it o l turn ove r vitamin D (Hellm an et al., 1998). T he pr ese nce of the
(McKay and Mill er, 1996) . DAG ac tiva tes protein kin ase ce llul ar retin oid -bindin g proteins, the nucl ea r recepto rs,
C (PKC), but severa ! experim ents have substanti ated the and the RA metabo lism in parathyro id cells suppo rt the
so mewh at surpri sing findin g that Ca2 + decreases rather hyp othes is that norm al para thyro id cells may function as
than increases the PK C ac tivity, and that acti va tion of sto rage ce lls fo r lipid s, and medi ate v itamin D and A
622
Pathophysiology of HPT

upt ake in parall el to the Ita cells of the liver. Wh ether al., 1989; Naveh-M any et al., 1995). Active vitamin D3
megalin in additi on may effectu ate calcium reg ulation of has effec ts on the para thyro id ce ll pro lifera tion, poss ibly
retin o! (a nd vitamin D) upt ake in para thyro id (a nd other) v ia inhi b ition o f c-m yc express io n, w hic h indicates that
ce lls awaits furth er analysis. thi s transc ription fac tor is importa n! fa r the regula tion of
parathyro id ce ll grow th (Kremer et al., 1989). Defic ient
Hyperparathyroidism produ c t io n o f ac ti ve vit a m in D is c ru c ia l for th e
deve lo pm ent and pro g ress io n o f se c o nd ary HPT in
Clínica/ variants ur e mi a a nd ma y a lso sig nifi ca ntl y co ntri b ut e to th e
pa th oge nes is o f prim a ry HPT in e ld erl y indi v id uals
HPT is c h a racteriz e d b y h y p e rca lc e mi a du e to (Ma rtin and Sl atopo lsky , 1994). HPT is a lso the mos t
excess ive PT H secreti on fro m o ne or seve ra! d isease d co mm o n di s turb a n ce see n in multipl e e n doc rin e
a nd ge ne rall y e nl a rged parath yro id g la nd s . Wh ile neo pl asia ty p e 1 ( M EN - 1), b ut thi s varian t of HPT
se condary HPT is most frequ entl y assoc iated w ith renal de mo ns trates a d iff e re nt patho ph ys io log ical patte rn ,
fa ilur e, prim a ry HPT m ay b e s poradi c o r fa mili a !. charac terized mainl y by an increase d proli feration rate
P a rath y roid a d e nom a is th e m os t fre qu e nt (85 % ) and less fun cti o nal di sturb ance. Thi s co mb inatio n is
hi stopath o log ica l entit y in non- fa mili a ! HPT , and thi s reflec ted in a close to norm al se t-p oint fa r the [Ca2+]i
di sease is particularly pr eva len! in the elderly (fe male) reg ul at io n (a nd PTH re lease) and co mp arab ly hi g h
popul atio n. On th e cont ra ry, o nse t o f fa mili a! HPT is expr ess ion of Ca R and mega lin (Ca rlin g et al., 1995) .
earlier and mor e often ca use d by multi glandul ar disease.
Genetic disturbances
Pathophysiology
T he most likely imp ortan! reaso n far th e increase d
In the pathologic al parath yroid tissue, the reg ulation ce ll proli fera ti o n of parathyro id ade nom as is vario us
o f PT H re l ease is functi o n a ll y di s turb e d. Thi s ge net ic disturb ances, w hich may be famili a! inherite d or
d e ra nge m e nt , o r fun c ti o n a l d e di ffe re nti a ti o n , is acqu ired. Famili a) HPT may be asso ciated with ME N-1
charac terize d by a relative inse nsiti v ity of [Ca2 +]i and o r occ ur in kindr eds not suffe rin g fro m M EN -1. Th e
PT H sec retion to changes in th e ex terna! Ca 2+, w hich ME N-1 ge ne on chrom oso me 11ql 3 has rece ntl y bee n
res ult s in rig ht- shi fted dose -res po nse rel atio nship s ( o r identifi ed and fo und to enca de a put ative transc ripti on
se t-p o ints) (L arsso n et al., 1984). T he deg ree of rig ht- factor menin, apparently ac ting as a suppr esso r of JunD-
shift co rr e la tes and to a lar ge exte nt de termin es the indu ce d tra nscripti o n (Chandrase kh arapp a et al., 1997;
se rum Ca2 + va lue of the indi v idu al patient (Wall felt et Aga rw al et al. , 1999) . In non -MEN l fa m ilia! HP T, a
al., 1988a, b), and see ms to be va lid , albeit to a vari ab le tum o r s up presso r ge ne o n chro moso m e 1q has bee n
ex tent, fa r virtu ally ali the histopatho log ica l entiti es of id enti fie d (Sz abo e t a l. , 1995), alth o ug h th e re m ay
prim ary and seco ndary HPT. The lowered sensitiv ity to app arently be other dera ngements in other famili es .
externa! ca2 + m ar theo retica lly be ca use d by redu ce d A bout 30 % of sporad ic parath yro id adenomas are
ex pr ess ion o f Ca + se nsor s. Thi s is supp o rted by th e asso ci a ted with in c rease d ex pr ess io n of cy clin 01 ,
re duc e d e xpr ess io n of b o th Ca R a nd m eg alin , inducin g the ce lls to leave the Gl ph ase to enter S phase
de mon stra ted at th e mRNA as we ll as prot e in leve ls (Arn o ld, 1994). T his ove rexpress ion may result from an
(Juhlin et al., 1988; Kifar et al., 1996; Farn ebo et al. , inve rsion on chromoso me 11 ca using the PTH promoter
199 7 ; Lund g r e n e t a l. , 1997). A s imil a r t y p e o f to b e pl aced in fro nt of the cy clin D J ge ne (Arno ld ,
fun ctional dediff erentiation may be indu ced in cultur es 1994) . At prese nt there are no other types of discove red
of norm al bov in e para th yro id ce ll s, whi ch deve lop a gene ac tiva ti on in spora di c parath yro id tum ors , w hil e
gra dual right-shi ft in the se t-p oint fa r the PTH release in Ioss o f ge ne fun cti on has bee n dem onstrated bot h by
para lle l with redu ce d expr ess io n of Ca R and mega lin alle lic losses a nd in ac ti va ting po in t mut atio ns. Thu s ,
mRNA s (N yg re n e t al. , 1988; Ki fo r e t a l. , 1996). a ll e li c losses a nd mut a ti ons in th e M EN l ge ne a lso
Additi ons of vitamin 0 3 or RA durin g these cultur es fail comm only oc cur in spora dic HPT (Ca rlin g et al., 1998;
to inhibit the fun ctional dedi ffere ntiation as we ll as the F arnebo et al., 1998) . In additi o n, clona) allelic losses of
redu ced Ca R and mega lin mRN A levels (Nyg ren et al., loc i o n chro m oso m e lp h as b ee n observed in a
1988). Howeve r, c ulturin g of p a th o log ica l, a lr ea d y substantial subse t of para thyro id adenomas (Cryns et al.,
fun ctionally dedifferenti ated, hum an para th yro id ce lls, 1995) .
dem onstrat es m aint enance o f th eir deg ree of ca lcium Ce rt a in p o l y m o rphi s m s w ithin th e v it ami n D
sensitivit y for seve ra! wee ks (H ellm an et al., 1998) . rece pt o r (V DR ) ge ne we re initi all y de mo nstr ate d to
Whil e fun ction al dediff erenti ation is a ch aracteristic coupl e to the developm ent of osteo poro sis (Morriso n et
di s turb a n ce o f p a th o log ica l p ara th y roid ce ll s , th e al., 1994 ). A lth oug h fur ther analyses fa iled to suppo rt
pro lif era ti ve di sturb anc e is a no th e r. Alth o ug h rare ly thi s hypo th es is, th e sa m e po ly m o rphi sm s have bee n
e nco unt ered in the cl inica l situ at io n, w ith the poss ible assoc iated w ith in crease d ri s k fa r d eve lo p me nt of
exce pti o n of ea rl y s t ages o f r e n a l i n s u ff ic ie n cy, prim ary H PT in pos tmenopa usa l wo men (Carling et al.,
h y p ocalce m ia h as bee n d e m o ns t ra te d to s timul a te 1995). T hus, pos tm enopa usal wo men w ith the haplo type
proli feration of parath yro id ce lls in cultur e (Krem er et baT ex press redu ced VDR mR NA and probably pro tein
 623
Pathophysiology of HPT

level s, with an expected reduction in inhibition of the visualized, representing its origin in normal glandular
tran sc ription of severa! genes regulated by vitamin D tissue, and is often used to substantiate the adenoma
(Carling et al., 1998). Concomitantly right- shifted set- diagnosis. The pathological part of the gland expresses
points for the PTH release occur in pathological low amounts of the calcium-sensing proteins, both CaR
parathyroid glands from the individuals with the baT and megalin, substantiated both at mRNA and protein
haplotype when compared to thos e with other VDR levels , whereas the rim seems to exhibit high expression
haplotypes (Carling et al., 1997). In the older population comparable with the normal parathyroid glands (Juhlin
there is an increased incidence of nephrosclerosis , giving et al., 1988; Kifor et al., 1996; Lundgren et al., 1997) . X-
rise to mainly subclinical reduction of the vitamin D chromosome inactivation analyses of sporadic adenomas
lev e ls. This may , at least in the North European have revealed that these are monoclonal lesions,
countries, be aggravated by seasonal lack of sunshine, supporting the theory of development as a result of a
and cause insufficient inhibition of the vitamin D-related specific genetic hit (Arnold et al., 1988).
gene transcription (e.g. PTH and c-myc; Fig. 1). Primary parathyroid hyperplasia may be categorized
Intere s tingly, one of the genes that at Ieast in sorne as diffus e hyperplasia exhibiting a variable degree of an
tissue s is upregulated by vitamin D is VDR itself, increased number of chief cells in ali four parathyroid
whereby insufficient circulating vitamin D Ievels may glands, or as nodular hyperplasia with irregularly
aggravate the disturbance. distributed areas of apparently clonally expanding
nodules of chief cells often surrounded by more normal-
Histopathology a ppeari ng tissue. The slowly proliferating diffuse
hyperpla sia appears to be a polyclonal lesion , both in
Parathyroid glands consist of chief and oxyphil cells, sporadic (Arnold et al., 1988) and in familia! HPT
a fibrous stroma, and fat cells. The number of oxyphil (Friedman et al., 1989) , whereas the nodular hyperplasia
cells increases with age, and although they may maintain of both sporadic and MEN-1-associated HPT has been
sorne secretory function their role remains obscure. Fat proposed to arise from a background of polyclonal,
may be stored not only in fat cells, but also as lipid diffu se hyperpla sia, and to consist of severa) monoclonal
droplets of variable size within the parenchymal chief lesions (Friedman et al., 1989; Arnold et al., 1995). The
cells. The total amount of fat is related to the activity of prevailing theory is that the diffusely hyperplastic tissue
the gland and may thus relate to levels of ambient Ca2+. is more vulnerable to genetic hits, which favour the
A normal parathyroid gland (mean weight approx. 60 development of nodular hyperplasia after appearance of
mg) consists on average of 50 % fat, while a functionally different secondary genetic hits (Fig. 1) (Akerstróm et
active and proliferating adenoma may be more or less al., 1986 ; Arnold , 1994). Although beyond the scope of
totally depleted of fat. Oil red O staining for this review, there are many similar features between this
visualization of cytoplasmic fat in parathyroid chief cells type of primary hyperplasia and secondary HPT. Mild
is an important histopathological method which may be renal insufficiency consequently is characterized by a
use d to distinguish normal and pathological glands diffuse hyperplasia, whereas with increased duration and
(Grimelius et al., 1986). The functional parenchymal severity of the renal impairment a nodular growth
0

chief cells of normal parathyroid glands abundantly pattern emerges within the glands (Akerstróm et al.,
express both CaR and megalin. 1986; Wallfelt et al., 1988a,b; Hellman et al., 1989 ;
The size of parathyroid adenomas varíes Tominaga et al., 1996). These parenchymal cell nodules,
considerably from that jusi exceeding a normal gland to which may be conspicuously large and apparently
seve ra! grams. A rim of normal parenchyma situated at represen! severa) monoclonal lesions, may present

0
one end of the pathological gland may often be features s imilar to adenomas. The term oligoclonal
lesion has been suggested for this disease (Fig. 1). More
Rlm of norma! tissue or less impaired renal function within a nephrosclerotic ,
Normal gland
elderly population may, especially in individuals

~
harboring the baT haplotype of the VDR gene , constitute
baT VDR ¡¡olymorphlsm
Vitamin D def]c,ency
(lad< of sunshlne)
NephroscleroSis
=:> PTHgene activation
=:> prollferatlon
=:> Low VDR expression
\
. PRAD·
rearrangement
·LOH llq 13
·etc.
I
Adenoma

MonodonaJles,on
a similar prerequisite for the development of a diffuse
primary hyperplasia , with the increased risk of emerging
nodules, including possibly also large nodules
mimicking adenomas (Fig. 1). In other terms, this
abnormality in both "primary" and secondary HPT may
possibly relate to genetic instability associated with
impaired vitamin D action.
The calcium receptor expression in hyperplastic
tissue varíes. In sporadic hyperplasia different nodules
Severa!genetk hlts1
oligodonat lesion, i.e. severa!
within the same gland have been found to express
monoclonal [Link]>ns strikingly different levels of megalin , which indeed
Fig. 1. Schemat ic drawing of suggested development of parathyroid
supports the development of different monoclonal
hyperplasia and adenoma in postmenopausal women. lesions (Juhlin et al., 1988). In general , the non-
624
Pathophysiology of HPT

nodulated tissue maintains higher expression than the may also be used to attain these goals . A third nov e l
nodules. Similar differences in dístributíon have been alternative is usage of calcímimetícs , whích actívate CaR
reported for CaR, and consequently deficient expression and thereby ínhíbít PTH release (Nemeth et al. , 1998).
of calcium-sensing molecule(s) may constitute the The definíte way of treatment , how eve r, re main s
nec essary molecular pre-requisite for a ríght-shífted set- surgical. Skilled surgeons of today perform , with a
point seen in hyperplastic as well as adenomatous minor d eg ree of complications , varíous operations
parathyroid tissu e (Larsson et al. , 1984; Juhlin et al. , aímíng at and achíeving the goal of life-long
1988; Farnebo et al. , 1997). normocalcemi a in over 90 % of the patíent s.
The proliferation per se, however, could as a general
feature of dedífferentiation result in reduced expressíon Acknowledgements . The finan cia ! support of the Swed ish Medica !
of severa ) cell surface proteins , sínce other surface Society , The Swedish Cancer Foundation. Seland er's Foundation and
bound proteins also are altered in pathological the Swed ish Medical Research Council are greatly acknowledged. as
parathyroid glands (Hellman et al. , 1995a,b , 1996). well as the critical reading of the manuscript by Prof . Jonas Rastad.
However , the often highly variable ex pres s ion of th e
sa me surfac e protein s within the same gland mak es this
explanation unlikely , and MEN-1 , which is characterized References
by a subst anti a l proliferative capacity, tends to exhibit
almost normal ex pres s ion of megalin as well as Agarwal S.K .. Guru S.C ., Heppner C., Erdos M.R., Collins R.M., Park
reaso nab ly maint ained Ca2+ regulation (Carling et al., S.Y., Saggar S., Chandrasekharappa S.C ., Coll ins F.S. , Spiegel
1995). A .M., Marx S.J. and Burns A.L. (1999). Menin interacts with the AP1
transcription factor JunD and represses JunD -activated transcription .
Treatment Cell 96, 143-152.
Ákerstróm G .. Malmaeus J., Grimelius L., Ljunghall S. and Bergstrom R.
The only definite tr ea tment for primary HPT is (1984). Histological changes in parathyroid glands in subclinical and
surgery, but bi sphosfonates and calcitonin have been clinical renal diseas e. Scand. J. Urol. Nephrol. 18, 75-81 .
used, especially in patients with severe hyp ercalcemia , Ákerstróm G., Rudberg C., Grimelius L., Bergstróm R., Johansson H.,
e.g. hypercalcemic crisis (Grossman and Jossart , 1997). Ljungha ll S . and Rastad J . ( 1986 ). Histologic parathyro id
The operation of HPT aims to reduce the risk for abnormalities in an autopsy series. Hum. Pathol. 17, 520-527.
consequences of untreated HPT. The classical ones, but Arnold A. (1994) . Molecular basis of primary hyperparathyroidism. In:
nowadays seldom seen in Western countries, are bone The parathyroids . Lev ine M.A . and Bilezikian J .P. (eds). Rav en
disease (osteitis fibrosa cystica) and renal stones. Press , Ud . New York , NY. pp 407-421.
However , recen! studies have emphasízed other signs Arnold A., Brown M .. Urena P., Gaz R., Sarfati E. and Drueke T . (1995).
and sy mptom s, such as mental disturbance s like Monoclona lity of parathyro id tumors in chron ic renal failure and in
confusion, depres sion and dementia , muscl e weakness primary parathyroid hyperplasia. J. Clin. lnvest. 95, 2047-2053.
and joint pain , and increa se d risk of cardiovascular Arnold A ., Staunton C.E. , Kim H.G., Gaz R.D. and Kronenberg H.M.
diseases (Lundgren et al., 1998). Due to the dev elopment (1988). Monoclonality and abnorma l parathyroid hormone genes in
of sensitive method s to measure intact PTH in recent parathyroid adenomas . N. Engl. J. Med. 318, 658-662.
years , and reductions in peroperative complications, Bai M ., Trivedi S., Lane C.A., Yang Y., Quinn S.J. and Brown E.M.
patients toda y tend to be operated at les s extensive (1998) . Protein kinase C phosphorylation of threonine at position
hypercalcemia. In add ition , HPT is a common disorder, 888 in ca2+o-sens ing receptor (CaR) inhibits coupling to ca2 + store
s triking up to 2 % of postmenopausal women, and release. J. Biol. Chem. 273, 21267 -21275.
parathyroid pat~ology can be found in 10 % at post Baran D., Sorensen A. , Shalboub V., Owem T. , Oberdorf A., Stein G.
mortem studies (Akerstrom et al., 1984). Altogether this and Lían J. (1991 ). 1o,2 5-dihydroxyvitamin o3 rapidly increases
accounts for a considerable numb er of patients, where cytoso lic calcium in clonal rat osteosarcoma cells acking the vitamin
the majority hav e mild HPT accompanied by mild or no D receptor . J . Bone Min. Res. 6, 1269-1275.
overt symptoms and an increa se d Iong-term risk for Bikle D.D., Ratnam A., Mauro T., Harris J . and Pillai S. (1996). Changes
cardiovascular diseases (Hedback et al., 1990). To treat in calcium responsiveness and handling during keratinocyte
this large popul a tion, severa! alternative medical differentiation . Potential role of the calc ium receptor. J. Clin . lnvest.
trea tments have been suggested. Estrogens have been 97, 1085-1093.
discussed, but they exert comparably minor effects on Bouillon R ., Okamura W .H. and Norman A .W. (1995). Structure -
the parathyroid , although are beneficia) on bone loss . Function relationships in the vitamin D endocrine system . Endocrine
Vitamin D has a promi sing therapeutic potential , but also Rev. 16, 200-257 .
major s íde-effect s, includíng hypercalcemía , hyper- Brown E. (1982) . PTH secret ion in vivo and in vitro . Regu lation by
calcíuría and sof t tís s ue calcífícation caused by its calcium and other secretagogues . Miner Electrolyte Metab. 8. 130-
intestinal and skeletal effects (Vieth, 1990). How eve r, 150.
vítamin D analogues have bee n developed , which can Brown E.M. (1983) . Four-parameter model of the sigmoidal relationship
ínhíbít PTH gene tran sc riptíon and the parath yro id cell between parathyroid hormona ralease and extracellular calc ium
proliferation , but without the hy pe rcalcemic effect. concentration in normal and abnormal parathyroid tissue . J . Clin.
Retínoíd s or retínoíd analogues wíth selective effects Endocrinol. Metab . 56, 572-581 .
 625
Pathophysiology of HPT

Brown E.M. and Hebert S.C. (1996). Ca2•-receptor-mediated regulation pools by inositol trisphosphat e. FEBS Lett. 188, 141-144.
of parathyroid and renal function. Am. J. Med. Sci. 312, 99-109. Farnebo F.. Enberg U., Grimelius L., Báckdahl M., Schalling M., Larsson
Brown E.M., Gamba G., Riccardi D., Lombard i M., Butters R., Kifor O., C. and Farnebo L.-0 . (1997) . Tumor specific decreased expression
Sun A., Hediger M.A., Lytton J. and Hebert S.C. (1993). Cloning and of calc ium sensing receptor message ribonucl eic acid in sporadic
characterization of an extracellular Ca ¡2•)-sensing receptor from primary hyperparathyroidism . J. Clin. Endocrino!. Metab. 82, 3481 -
bovine parathyroid. Nature 366, 575-580 . 3486.
Brown E.M., Gardner D.G., Brennan M.F., Marx S.J., Spiegel A.M ., Attie Farnebo F., Teh B.T., Kytéilá S., Svensson A., Phelan C., Sandelin K.,
M.F., Downs Jr R.W ., Doppman J.L. and Aurbach G .D. (1979 ). Thompson N.W., HéiéigA., Weber G., Farnebo L.-0. and Larsson C.
Ca lci um-regulated parathyroid hormone re lease in pr im a ry (1998 ) . A lterations of th e MEN 1 gene in sporadic parathyroid
hyperpa rathyroidism : Studies in vitro with dispersad parathyro id tumors. J. Clin. Endocrino! . Metab. 83, 2627-2630 .
cells. Am . J. Med. 66, 923-931. Farquha r M.G., Kerjaschki D., Lundstrom M. and Orlando A.A. {1994).
Cantley L.K ., Russel J., Lettieri D. and Sherwood L.M. (1985) . 1,25- Gp330 and RAP: The heymann nephritis antigenic complex . Ann .
dihydroxyvitam in 0 3 suppresses parathy roid hormone secretion from NY Acad . Sci. 737, 96-113 .
bovine parathyro id cells in tissue culture . Endocrinology 117, 2114- Friedman E., Sakaguchi K., Bale A., Falchetti A. , Streeten E., Zimering
2119. M., Weinstein L., McBride W., Nakamura Y. and Brandi M. (1989).
Carlberg C. and Polly P. (1998). Gene regula tion by vitam in 0 3 [In Clonality of parathyroid tumors in familia ! multiple endocrina
Process Citation]. Crit. Rev. Eukaryot . Gene Expr. 8, 19-42. neoplasia type 1. N. Engl. J. Med. 321, 213 -218.
Carling T. , Correa P., Hessman O., Hedberg J., Skogseid B., Lindberg Fujimi T ., Baba H., Fukase M. and Fujita T . (199 1). Direct inhibi tory
D., Rastad J ., Westin G. and Akerstrom G. (1998) . Parat hyroid effect of aminoterminal parathyroid hormone fragment [PTH(1-34))
MEN 1 gene mutations in relat ion to cl inical characteristics of on PTH secretion from bovine parathyroid primary cultured cells in
nonfamilial primary hyperparathyroidism [see comments]. J. Clin . vitro . Biochem. Biophys. Res. Commun. 178, 953-958 .
Endocrino!. Metab. 83, 2960-2963. Garrett J.E., Tamir H., Kifor O., Simin A .T ., Rogers K.V. , Mithal A.,
Carling T., Kindmark A., Hellman P., Lundgren E., Ljunghall S., Rastad Gagel R.F. and Brown E.M. (1995). Calcitonin -secret ing cells of the
J., Ákers tréim G. and Melhus H. (1995) . Vitam in D genotypes in thyroid exp ress an ex tr ace llular calcium receptor gene .
hyperparathyroidism . Natura Med. 1, 1309-1311 . Endocrinology 136, 5202-5211 .
Carling T., Rastad J., Ridefelt P., Gobl A., Hellman P., Óberg K., Rask Grimelius L., Ákerstréim G., Johansson H., Ljunghall S. and Rastad J.
L., Larsson C., Juhlin C., Ákerstréim G. and Skogseid B. (1995) . (1986). The role of pathology in diagnosis and surg ical decision-
Hyperparathyro idism of multiple endocrina neoplas ia type 1: making . In: Progress in surgery . Eh H. (ed). S. Karger . Basal. pp 80-
Cand idata gene and parathyroid calcium sensing prote in 92.
expression . Surgery 118, 924-931 . Grossman R.F. and Jossart G.H. (1997). Hyp ercalcemic cr isis. In:
Carling T. , Rastad J., Ákerstréim G. and Westin G. (1998). Vitam in O Textbook of endocrine surgery . Cla rk O.H. and Duh Q .-Y. (eds) .
receptor (VDR) and parathyroid hormona mess enger ribonucle ic W .B. Saunders Company. Philadelphia, PA. pp 432-438.
acid leve ls correspond to polymorp hic VDR alleles in human Gylfe E., Joha nsson H., Larsson R., Nygren P., Rastad J., Wallfelt C.
parathyroid tumors . J. Clin. Endocrino !. Metab. 83, 2255-2259 . and Ákerstréim G. {1987). Activation of Ca2+ influx into parathyroid
Carling T ., Ridefelt P., Hellman P., Rastad J. and Ákerstréim G. (1997). cells by exte rna! cation binding . In: Calc ium regulation and bone
Vitamin D receptor polymo rphisms correlata to parathyro id cell metabolism: Basic and clinical aspects . Cohn O.V., Martín T .J. and
function in primary hyperparathyroidism . J. Clin. Endocrino!. Metab. Meunier P.J. (eds). Elsevier . Amste rdam. pp 33-38 .
82, 1772-1775. Gylfe E., Larsson R., Johansson H., Nygren P., Rastad J., Wallfelt C.
Chandrasekharappa S.C ., Guru S.C ., Manickam P. , Olufemi S.-E ., and Ákerstréim G. (1986). Calcium-act ivated calcium permeabili ty in
Collins F.S., Emmert -Buck M.R. , Debelenko L.V. , Zhuang Z ., parathyroid cells. FEBS Lett. 205, 132-136.
Luben sky I.A ., Liotta L.A. , Crabtree J .S ., Wang Y ., Roe B.A ., Habene r J.F., Rosenb latt M. and Potts Jr J.T . {1984) . Para thyroid
Weisemann J., Boguski M.S., Agarwal S.K., Kester M.B., Kim Y.S., hormone : Biochemical aspects of biosynthesis, secretion , action and
Heppner C., Dong Q., Spiegel A .M .. Burns A .L. and Marx S.J. metabo lism. Physiol. Rev. 64 , 985-1053.
{1997) . Posit ional clon ing of the gene far multiple endocrine Hedb áck G., Tisell L.-E., Bengtsson B.-A ., Hedman l. and Oden A.
neoplasia-type 1. Science 276, 404-407 . (1990) . Pr ema ture death in pati e nts operated on far primary
Cryns V .L., Yi S .M., Tahara H ., Gaz R.O. and Arnold A. (199 5) . hyperparat hyroidism . World J. Surg. 14, 829-835.
Frequent loss of chromosome 1p DNA in parathyroid adenomas . Hellman P., Ákerstréim G., Ljunghall S. and Rastad J. (1989). Surgical
Gene. Chromosome Canear 13, 9-17. fínding s and results of subtotal an d total par athyroide ctomy in
Delmez J.A ., Tindira C ., Grooms P., Dusso A ., Windus D.W . and hypercalcemic patients with uremic hyperparathyroidism . Acta Chir.
Slatopolsky E. (1989) . Parathyroid ho rmona suppression by Scand . 155, 573-582.
intravenous 1,25-dihydroxyvitamin D. A role far increased sensitivity Hellman P., Ridefelt P., Juhl in C., Ákerstréim G., Rastad J . and Gylfe E.
to calcium. J. Clin. lnvest. 83, 1349-1355. (1992). Parathyroid-like regulation of parathyroid hormone-related
Demay M.B., Kiernan M.S., Deluca H.F. and Kronenberg H.M. (1992). protein ralease and cytoplasmi c calcium in cytotrophoblast cells of
Sequences in the human parathyroid hormo ne gene that bind the human placenta . Arch . Biochem. Biophys 293, 174-180.
1,25-dihydro xyvitamin o3 receptor a nd mediata tran scr iption al Hellman P., Ákerstréim G., Juhlin C., Ridefelt P. and Rastad J. (1994).
repression in respo nse to 1 ,25- dihydroxyvitamin 0 3 . Proc. Natl. Pathophysiology of hyperpara thyroidism . In: Curren! controversy in
Acad. Sci. USA 89, 8097-8101. parathyro id operation and reoperat ion. Ákerstréim G., Juhlin C. and
Epstein P., Prentki M. and Attie M. (1985) . Modulation of intracellular Rastad J. (eds). R.G. Landes Company . Austin , TX , USA. pp 9-22 .
Ca2• in the parathyroid cell. Release of Ca2+ from non-mitochondria l Hellman P., Juhlin C., Karlsson-Parra A ., Klareskog L., Ridefel t P. ,
626
Pathophysiology of HPT

Rastad J . and Ákerstróm G. (1995a) . Expression and function of a patient s with hyperparathyro idism. Bioscience Rep. 4, 909-9 15.
CD 3-like molecule on normal and abnormal human parathyroid cells . Liu W ., Hellma n P., Li Q., Yu W .-R. , Juhlin C., Nordlinder H., Rollman
Surgery 118, 1055-1062. O., Ákerstróm G., Tórmii H. and Melhus H. (1996) . Biosynthesis and
Hellman P., Ridefelt P., Bjórklund E., Yu W. , Liu W., Tang S.-S., Juhlin function of all-trans- and 9-cis- retinoic acid in parathyro id cells .
C., Rastad J ., Gylfe E., Lundgren S., Rask L., lngelf inger J . and Biochem . Biophys. Res. Commun . 229 , 922 -929.
Ákerstróm G. (1995b) . Cation sensing in a transformed rat proxima l Lopez -Barneo J. and Armstrong C.M. (1983) . Depolar izing response of
tubule cell line. Bone 16, S139. rat parathyro id cells to diva lent cations . J . Gen . Physiol. 82 , 269-
Hellman P., Juhlin C ., Karlsson-Parra A ., Klareskog L., Lundgren S., 294 .
Ridefelt P., Rastad J . and Ákerstrom G. (1996 ) . Express ion and Lundgren E ., Lj unghall S., Ákers t róm G., Hetta J ., Mall min H. and
function of a CD4 -like molecule in normal and abnormal parathyroid Rastad J . (1998) . Case -contro l study on symptoms and signs of
cells - Relat ion to a calcium sensor molecule . Surgery 120, 985-992 . "asymptom atic " primary hyperparat hyroid ism . Surgery 124, 980-986 .
Hellman P., Liu W ., Tórmii H. and Ákerstróm G. (1998) . Parathyro id Lundgren S., Carling T ., Hjiilm G., Juhlin C., Rastad J ., Pihlgren U.,
cells are targets for retinoids . Bone 23, S452 . Rask L., Ákerstrom G. and Hellman P. (1997) . Tissue distribution of
Hilpert J., Nykjaer A. , Jacobsen c. Wallukat G .. Nielsen R., Moest rup human gp330/megalin , expressing putative Ca2+ sensing properties
S.K., Haller H., Luft F.C., Christensen E.I . and Willnow T.E. (1999). the 550 kDa calcium sensor protein . J. Histochem . Cytochem. 45,
Megalin antagon izes activation of the parathyroid hormone receptor. 383 -392 .
J. Biol. Chem . 274 , 5620-5625 . Lundg ren S ., Hjiilm G ., Hellman P., Ek B ., Juhl in C ., Ras tad J .,
Hjiilm G., Murray E., Crumley G., Harazim W. , Lundgren S., Onyango l., Klares kog L.. Ákerstróm G. and Rask L. (1994). A protein involved in
Ek B.. Larsson M., Juhlin C., Hellman P., Davis H., Áke rstróm G., cal c iu m sensing of the human parathy ro id a nd plac e nta !
Rask L. and Morse B. (1996) . Cloning and sequencing of human cytotrophoblast cell s belonging to the LDL-r ecep tor superfam ily .
gp330, a Ca2+ binding receptor with potent ial intracellular signalling Exp. Cell Res. 212 , 344-350 .
properties . Eur. J . Biochem . 239 , 132-137 . MacDonald P .N., Ritter C ., Brown A .J . and Sla top os lky E. (1994 ).
Juhl in C., Holmdahl R. , Johansson H., Rastad J., Ákerstróm G. and Retinoic acid suppresses parathyro id hormone (PTH) secretion and
Klareskog L. (1987a) . Monoclonal antibod ies with ex clusiv e preproPTH mRNA levels in bovine parathyroid cell cultu re. J . Clin.
reactivity against parathyroid cel ls and tubule cells of the kidney . lnvest. 93 , 725-730 .
Proc. Natl. Acad . Sci. USA 84, 2990-2994 . Martín K .J . and Slatopolsky E . (1994 ). The parathyro ids in rena l
Juhlin C., Johansson H., Holmdahl R., Gylfe E., Larsson R., Rastad J., dis ease. Pathophysio logy . In: The parathyro ids . Bilezekian J .P.,
Ákerstróm G. and Klareskog L. (1987b). Monoclonal ant iparathyroid Levina M.A . and Marcus R. (eds). Raven Press Ud . New York. pp
antibodies interfering with a Ca2•-sensor of human parathyroid cells. 711-719 .
Biochem . Biophys. Res. Commun . 143, 570-574 . McKay C . and Miller A . (1996 ). Re lat ionship am on g ce llular
Juhlin C., Klareskog L., Nygren P., Ljungha ll S., Gylfe E., Rastad J . and diacy lglycerol, sphingos ine format ion. protein kinas e C activity, and
Ákerstróm G . (1988) . Hyperparathy ro idism is associated with parathyroid hormone sec retion from dispersed bovine parathyroid
reduced expression of a parathyroid ca lcium receptor mechanism cells . Endocrinology 137, 2473-2479 .
defined by monoclonal antiparathyroid antibodi es . Endocrin ology Morrison N.A .. Cheng Qi J., Tokita A ., Kelly P.J ., Crofts L., Nguyen T.V.,
122, 2999 -3001 . Samb rook P.N. and Eisman J.A. (1994) . Prediction of bone density
Juhlin C., Lundgren S., Johansson H., Lorentzen J., Rask L., Larsson from vitam in D receptor alleles . Nature 367 , 284-287 .
E., Rastad J., Ákerstrom G. and Klareskog L. (1990). 500-kilodalton Naveh - Many T ., Rahamimov R ., Liv ni N . and Sil v er J . (1 995 ).
calcium senso r regulating cytoplasmic Ca2+ in cytotrophoblast cells Parathyroid cell proliferation in normal and chronic renal failure rats .
of human placenta . J. Biol. Chem . 265 , 8275 -8279 . The effect of calcium , phosphate and vitamin D. J. Clin. lnvest. 96,
Jüppner H., Abou -Samr a A.-B ., Freeman M., Kong X .F., Schipan i E., 1786-1793.
Richards J., Kolakowsk i Jr L.F., Hock J., Potts Jr J .T., Kronenberg Nemeth E.F. and Scarpa A . (1986). Cytosolic Ca2• and the regulation of
H .M . and Seg re G .V . (1991 ) . A G prote in-link ed receptor for secretion in parathyroid cells. FEBS Lett. 203, 15-19.
parathyroid hormone and parathyroid ho rmon e- relat ed peptid e . Nemeth E., Steffey M.E .. Hammer land L.G., Hung B.C., van Wagenen
Science 254 , 1024-1026. B.C ., DelMA r E.G. and Baland rin M.F. (1998) . Calcimimetics with
Kifor O., Moore F.D., Wang P., Goldstein M., Vass ilev P., Kifor l., Hebert poten! and sele ctive activity on the parathyroid calcium receptor .
S .C . and Brown E.M . (1996) . Reduc ed immunostain ing for the Proc. Natl. Acad. Sci. USA 95, 4040-4045 .
ex1racellular Ca2+.sensing receptor in primary and urem ic secondary Nygren P., Larsson R., Johansson H., Ljunghall S ., Rastad J . and
hyperparathyroidism . J . Clin. Endocrino!. Metab . 81, 1598- 1606. Ákerstr om G. (1988) . 1,25(0H)2D 3 inhibits hormone secretion and
Kifor O., Diaz R., Butters R. and Brown E. (1997). Th e Ca2•-sens ing pro liferat ion but not functi onal dedifferenti ation of cultured bovine
receptor (CaR ) activates phospholipas es C, A2, and D in bov ine parathyroid cells. Calcif. Tissue lnt. 43, 213-218 .
parathyroid and CaR -transfected , hum a n e mbryonic kidn ey Nykja er A ., Drag un D., Walther D., Vo rum H., Jacob sen C., Herz J .,
(HEK293) cells . J . Bone Miner. Res. 12, 715-725 . Melsen F .. Christensen E.I. and Willnow T .E. (1999). An endocytic
Kremer R., Bolívar l., Goltzman D. and Hendy G.N. (1989) . lnfluence of pathway essential for renal uptake and activation of the stero id 25-
calcium and 1,25-dihydroxycholecalciferol on proliferation and proto- (0H ) vitamin 0 3. Cell 96, 507-15.
oncogene expression in primary cultur es of bovine parathyroid cells. Oka z ak i T ., Ando K ., lgarsh i T ., Oga ta E . and Fuj ita T . (1 992) .
Endocrinology 125, 935 -941. Conserv ed mechanism of negative gene regulation by extracellular
Larsson R .. Wallfelt C., Abrahamsson H., Gylfe E., Ljunghall S ., Rastad calcium . J. Clin. lnvest. 89, 1268-1273.
J ., Rorsman P ., Wide L. and Ák e rstrom G. (1984 ). Detectiv e Pollak M .R., Brown E .M., Wu Cho u Y. -H., Heb ert S .C., Marx S.J .,
regulation of the cytosolic Ca2+ activity in parathyroid cells from Steinmann B., Levi T ., Seidman C.E. and Seidman J .G. (1993).
 627
Pathophysiology of HPT

Mutations in the human Ca2•-sensing receptor gene cause familia! Shoback D., Membreno L. and McGhee J. (1988) . High calcium and
hypocalciuric hypercalcemia and neonatal severe hyperpara - other divalent cations inc rease inositol triphosphate in bovine
thyroidism. Cell 75, 1297-1303. parathyroid cells. Endocrinology 123, 283-289 .
Pollak M.R., Wu Chou Y.-H., Marx S.J., Steinmann B., Cole D.E.C., Silver J ., Russell J. and Sherwood L.M. (1985). Regulation by vitamin D
Brandi M.L., Papapoulos S.E., Men ko F.H ., Hendy G.N., Brown metabol ites of messenger ribonucle ic acid for preproparat hyroid
E.M., Seidman C.E. and Seidman J.G. (1994). Familia! hypocalciuric hormone in isolated bovine parathyroid cells. Proc. Natl. Acad. Sci.
hypercalcemia and neonatal severe hyperparathyroidism . Effects of USA 82, 4270-4273.
mutant gene dosage on phenotype. J. Clin. lnvest. 93, 1108-1112. Szabo J., Heath B., Hill V.M., Lackson C.E., Zarbo R.J., Mallette L.E.,
Racke F.K. and Nemeth E.F. (1993). Protein kinase C modulates Chew S .L. , Besser G .M ., Thakker R.V . and Huff V . (1995).
hormone secretion regulated by extracellular polycations in bovine Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine
parathyroid cells. J. Physiol. 468, 163-176. tumor gene HRPT2 maps to chromosome 1q21-q31. Am. J. Hum.
Ridefelt P., Hellman P., Wallfelt C., Ákerstróm G., Rastad J. and Gylfe Genet. 56, 944-950.
E. (1992a) . Neomycin interacts with Ca2+ sensing of normal and Tang S.-S., Jung F., Diamant D., Brown D.. Bachinsky D., Hellman P.
adenomatous parathyroid cells. Mol. Cell. Endocrino!. 83, 211-218. and lngelfinger J . (1995). Tempe rature-sensitive SV40 immortalized
Ridefelt P., Nygren P., Hellman P., Larsson R., Rastad J., Ákerstróm G. rat proximal tubule cell line has functional renin-angiotensin system.
and Gylfe E. (1992b). Regulation of parathyroid hormone release in Am . J. Physiol. 268, F435-F446.
normal and pathological parathyroid cells exposed to modulators of Tominaga Y., Kohara S., Namii Y., Nagasaka T ., Haba T., Uchida K.,
protein kinase C. Acta Endocrino!. 126, 505-509. Numano M., Tanaka Y. and Takag i H. (1996). Clonal analysis of
Ridefelt P., Bjórklund E., Ákerstróm G., Olsson M.J ., Rastad J. and nodular parathyroid hyperplasia in renal hyperparathyro idism. World
Gylfe E. (1995). Ca2•-i nduced Ca2+ oscillations in parathyroid cells. J . Surg . 20, 744-752.
Biochem. Biophys. Res. Commun . 215, 903-909. Wallfelt C., Gylfe E., Larsson R., Ljunghall S., Rastad J . and Ákerstróm
Ridefelt P., Hellman P., Rastad J., Larsson R., Ákerstróm G. and Gylfe G. (1988a). Relationship between external and cytoplasmic calcium
E. (1996). Effects of calcium channel modulators on the regulation of concentrat ions, parathyro id hor mona release and we ig ht of
cytoplasmic Ca2• and hormone secretion of parathyro id cells . parathyroid glands in human hyperparathyro idism . J. Endocr ino!.
Pharmacol. Toxico!. 78, 147-153. 116, 457-464.
Ruat M., Molliver M.E ., Snowman A .M . and Snyder S.H . (1995) . Wallfelt C., Larsson R., Gylfe E., Ljunghall S., Rastad J. and Ákerstróm
Calcium sensing receptor: molecular cloning in rat and localization to G . (1988b ). Secretory dis turbance in hyperplast ic parathyroid
nerve terminals . Proc. Natl. Acad. Sci. USA 92, 3161-3165. nodules of uremic hyperparathyroidism: lmplications for parathyroid
Saito A. , Pietromonaco S., Kwor -Ch ieh Loo A. and Farquhar M.G . autotransplantation . World J. Surg. 12, 431-436.
(1994). Complete cloning and sequencing of rat gp330/"megalin' , a Vieth R. (1990). The mechanisms of vitamin D toxicity. Bone Miner. 11,
distinctive member of the low density lipoprotein receptor gene 267-272.
family. Proc. Natl. Acad. Sci. USA 91, 9725-9731. Willnow T., Hilpert J., Armstrong S., Rohlmann A., Hammer R., Burns D.
Shivji F., Cheng H., Zwiers H., Hollenberg H. and Hanley D. (1996). and Herz J. (1996). Defective forebrain development in mice lacking
ldentification of classical , novel , and atypical prote in kinase C gp330/megalin. Proc. Natl. Acad. Sci. USA 93, 8460-8464.
isoenzymes in the bovine parathyroid. Endocrinology 137, 3777 -
3783. Accepted November 18, 1999