PMID- 12412774
OWN - NLM
STAT- MEDLINE
DCOM- 20030513
LR  - 20131121
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 17 Suppl 2
DP  - 2002 Nov
TI  - The pathophysiology of primary hyperparathyroidism.
PG  - N24-9
AB  - The parathyroid glands play a key role in maintaining near constancy of the 
      extracellular calcium concentration ( Ca(o)2+) through their capacity to sense 
      even minute changes in the level of blood calcium from its normal level. The G 
      protein-coupled, Ca(o)(2+)-sensing receptor (CaSR) is the mechanism through which 
      the parathyroid chief cells senses changes in Ca(o)2+. In primary 
      hyperparathyroidism (PHPT), Ca(o)2+ is reset upward from its normal level. This 
      defect likely arises from increases in both the mass of pathological parathyroid 
      tissue as well as the set point for Ca(o)(2+)-regulated parathyroid hormone (PTH) 
      release. The former likely arises from somatic mutations that enhance parathyroid 
      cellular proliferation, although our understanding of the mechanism(s) underlying 
      the latter is incomplete. However, substantial insights have been achieved 
      through the study of inherited disorders caused by mutations in CaSR gene. In 
      familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations 
      in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in 
      neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations 
      cause severe hypercalcemia and hyperparathyroidism. Thus, the body's "calciostat" 
      is reset upward in FHH and NSHPT because of resistance of CaSR-expressing cells, 
      including the parathyroid cells, to Ca(o)2+. In FHH, there is a reduced 
      complement of normal CaSRs (e.g., haploinsufficiency) that likely provides an 
      explanation for the Ca(o)(2+)-resistance in this condition, whereas in NSHPT, 
      there are no normally functioning CaSRs, thereby engendering more severe Ca(o)2+ 
      resistance. Although somatic mutations in the CaSR gene could provide an 
      explanation for the Ca(o)(2+)-resistance in PHPT, no such mutations have been 
      found. Instead, in PHPT, the resistance of pathological parathyroid glands to 
      Ca(o)2+ results, at least in part, from a reduced expression of otherwise 
      apparently structurally normal CaSRs. Thus, PTH-dependent hypercalcemia can occur 
      in the setting of either inherited, generalized resistance to Ca(o)2+ (i.e., FHH 
      and NSHPT) or acquired tissue selective resistance of pathological parathyroid 
      glands to Ca(o)2+ (e.g., PHPT).
FAU - Brown, Edward M
AU  - Brown EM
AD  - Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts 02215, USA.
LA  - eng
GR  - DK41415/DK/NIDDK NIH HHS/United States
GR  - DK48330/DK/NIDDK NIH HHS/United States
GR  - DK52005/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Receptors, Calcium-Sensing)
RN  - 0 (Receptors, Cell Surface)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/*metabolism
MH  - Calcium Signaling
MH  - Disease Models, Animal
MH  - Homeostasis
MH  - Humans
MH  - Hypercalcemia/metabolism/physiopathology
MH  - Hyperparathyroidism/genetics/metabolism/*physiopathology
MH  - Infant, Newborn
MH  - Infant, Newborn, Diseases/metabolism/physiopathology
MH  - Mice
MH  - Receptors, Calcium-Sensing
MH  - Receptors, Cell Surface/metabolism
RF  - 51
EDAT- 2002/11/05 04:00
MHDA- 2003/05/14 05:00
CRDT- 2002/11/05 04:00
PHST- 2002/11/05 04:00 [pubmed]
PHST- 2003/05/14 05:00 [medline]
PHST- 2002/11/05 04:00 [entrez]
PST - ppublish
SO  - J Bone Miner Res. 2002 Nov;17 Suppl 2:N24-9.