JOURNAL OF BONE A N D MINERAL RESEARCH

Volume 6, Supplement 2, 1991

Mary Ann Liebert, Inc., Publishers

Pathophysiology of Primary Hyperparathyroidism

ALLEN M. SPIEGEL

ABSTRACT
Primary hyperparathyroidism (PHPT) is characterized by hypersecretion of parathyroid hormone (PTH)
leading to hypercalcemia and relative hypophosphatemia. PTH acts by binding to cell surface receptors cou-
pled to G proteins. Cyclic AMP is the classic second messenger of PTH action, but substantial evidence indi-
cates that PTH also acts to stimulate formation of the dual second messengers, inositol trisphosphate and di-
acylglycerol, thereby mobilizing intracellular calcium. The physiologic actions of PTH include (1) an in-
crease in extracellular fluid ionized calcium through direct actions on kidney and bone, the classic target
organs for PTH, and (2) a decrease in extracellular fluid phosphate primarily through renal action. The
pathophysiologic effects of PTH arise from (1) direct actions of PTH on bone and kidney, and possibly on
nonclassic target organs, and (2) indirect effects of altered mineral homeostasis. PTH hypersecretion in
PHPT can lead to bony demineralization, nephrolithiasis, and hypercalcemic crisis. PHPT may also be asso-
ciated with mental disturbances, neuromuscular disease, hypertension, and glucose intolerance.

INTRODUCTION
(PHPT) is character-
P RIMARY HYPERPARATHYROIDISM
ized by excessive secretion of parathyroid hormone
(PTH) leading to hypercalcemia and a tendency toward
hypophosphatemia. PTH-related protein (PTHrP), a re-
cently discovered polypeptide associated with hypercal-
cemia of malignancy, shares sequence homology and both
hypercalcemic and hypophosphatemic actions with PTH.
Messenger RNA for PTHrP has been found in some para-
thyroid tumors, but measurement of circulating PTHrP
argues against a role for this peptide in the hypercalcemia
of PHPT."' In the majority of cases of PHPT, hyperse-
cretion of PTH is caused by benign neoplastic growth of a
single parathyroid gland (adenoma). The etiology of para-
thyroid neoplasia and the basis for abnormal PTH secre-
tion in P H P T are discussed in the next paper, by Marx.
The present paper focuses on the mechanisms whereby hy-
persecretion of PTH disrupts mineral homeostasis and
causes disease.
MECHANISM OF PTH ACTION
PTH, like many other polypeptide hormones and mono-
amine neurotransmitters, binds to specific cell surface re-
ceptors on its target tissues. PTH receptors most likely be-
long to the G protein-coupled receptor gene superfamily.
Receptors in this family, upon activation by bound hor-
mone, interact with signal transducers termed G pro-
teins.'2' The latter, in turn, interact with membrane-bound
effector molecules, often enzymes that generate so-called
second messengers. Cyclic AMP is the classic second mes-
senger that mediates many of the actions of PTH,"' but it
is likely that the dual second messenger products of phos-
phoinositide breakdown also mediate certain effects of
PTH in both kidneyI4' and boneIs 6 , cells. Second messen-
gers mediate PTH action by mobilizing int racellular cal-
cium stores, as well as controlling protein phosphoryla-
tion.
Structure-activity studies indicate that the ability to
stimulate cyclic AMP production resides completely within
the 1-34 amino-terminal portion of the 84 amino acid
polypeptide.") Dissociation between the ability of certain
PTH analogs to increase cyclic AMP in vitro versus serum
calcium in vivo may reflect PTH receptor heterogene-
it^.'^,^' It is possible that distinct PTH receptors couple to
distinct G proteins to mediate stimulation of cyclic AMP
formation and mobilization of intracellular calcium, re-
spectively. The latter pathway may in fact be more relevant
than stimulation of cyclic AMP formation in mediating the
bone-resorbing action of PTH.[6)

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

s15
S16
The classic target organs for PTH action are bone and
kidney. Within bone, PTH receptors have been convinc-
ingly identified on osteoblastic cells, but not on osteo-
clasts. In kidney, PTH receptors are found in the renal
cortex on proximal and distal tubular cells. Less clearly
proven is the occurrence of PTH receptors in various
"nonclassic" sites, including circulating lymphocytes and
monocytes, skin fibroblasts, liver, fat, and vascular endo-
thelium and smooth muscle.
PHYSIOLOGIC ACTIONS OF PTH
PTH raises serum calcium through direct actions on
bone and kidney and indirect action on the gut.'8' In bone,
PTH mobilizes calcium and phosphate into the extracellu-
lar fluid; in kidney, PTH enhances renal calcium reabsorp-
tion and stimulates the formation of 1,25-dihydroxyvita-
min D, the active metabolite that increases intestinal cal-
cium absorption. The phosphaturic action of PTH in the
kidney counteracts the rise in serum phosphate caused by
the skeletal action of the hormone and promotes relative
hypophosphatemia. PTH also increases renal bicarbonate
excretion. The net effect of PTH on renal calcium excre-
tion is a complex function of increased filtered load (de-
rived from skeletal calcium mobilization and/or enhanced
intestinal absorption) and the renal anticalciuretic action.
The net effect of PTH on bone is also complex and may be
a function of both frequency and amplitude of PTH secre-
tion, as well as other factors, such as vitamin D status.
PTH can clearly cause an increase in osteoclastic resorp-
tion, particularly in cortical bone, but under certain experi-
mental conditions PTH has also been found to stimulate
bone formation."'
PATHOPHYSIOLOGIC EFFECTS OF
PTH HYPERSECRETION
Adverse clinical effects of PTH hypersecretion may be
due to the hypercalcemia and/or hypophosphatemia
caused by the hormone or to additional effects of elevated
PTH itself. Normal cellular function depends on tightly
regulated serum ionized calcium concentration and, to a
lesser extent, serum phosphate concentration. Elevated
serum calcium in symptomatic P H P T may cause wide-
spread organ dysfunction. Symptoms include anorexia,
nausea, vomiting, polydipsia, polyuria, lethargy, and, with
extreme hypercalcemia, coma and death.
Extreme elevations of circulating PTH dramatically in-
crease osteoclastic bone resorption, culminating in "osteitis
fibrosa cystica," the classic presentation of the disease,
rarely seen t ~ d a y . ' ~Whether
.~' mild P H P T is associated
with a clinically significant loss of bone mineral and at
what sites (trabecular versus cortical), is controversia1.(9.'0'
This important question is discussed in detail in several
papers in this volume.
Increased urinary calcium excretion in P H P T can lead to
nephrolithiasis. Why certain patients with P H P T develop
hypercalciuria and nephrolithiasis and others with equiva-
SPIEGEL
lent hypercalcemia d o not is not clear. Earlier sugges-
tions") that patients with nephrolithiasis represent a sub-
group with higher serum 1,25-dihydroxyvitamin D causing
intestinal calcium hyperabsorption have recently been
questioned.'"l In the latter study, evidence of cortical
bone demineralization was found in patients both with and
without nephrolithiasis. Serum 1,25-dihydroxyvitamin D,
moreover, was not significantly higher in the subgroup
with nephrolithiasis. Nephrocalcinosis, or ectopic calcifica-
tion in other sites, appears to be rare in uncomplicated
PHPT, and progressive reduction in renal function due to
mild hypercalcemia has not been well documented.
Proximal muscle weakness, probably secondary to a
neuropathic loss of type I1 muscle fibers, is another mani-
festation of PHPT."'' There is objective evidence for an
increase in muscular strength following successful parathy-
roidectomy."." A variety of neuropsychiatric disorders, in-
cluding depression and other nonspecific symptoms, such
as fatigue and headache, are often encountered in individ-
uals with PHPT, but it is difficult to prove that these are
caused by PTH e x ~ e s s . ' ' ~Reports
' of increased incidence
of peptic ulcer disease in P H P T may be due primarily to
the association of Zollinger-Ellison syndrome with P H P T
in multiple endocrine neoplasia type I , although hypercal-
cemia clearly potentiates gastric acid secretion. Abnormal
glucose tolerance, possibly related to peripheral insulin re-
sistance, has been reported as a reversible consequence of
PHPT.l'sl The clinical significance of disturbed carbohy-
drate metabolism in PHPT, however, is unclear.
Reports of the increased incidence of hypertension in
P H P T are difficult to assess."6' Both diseases are rela-
tively common and could coincide on a chance basis. PTH
has been claimed to have a direct vasodilatory effect
There are also data suggesting abnormalities in circulating
calciotropic hormones in patients with some forms of hy-
pertension.'I8) There is substantial controversy, however,
as to the role of dietary calcium and calciotropic hormones
in the pathogenesis and treatment of hypertension. Some,
but not all, studies show reversibility of hypertension after
successful surgery for PHPT.L'9' This area clearly requires
further study.
Hypercalcemia in P H P T has also been suggested to be a
risk factor for the development of pancreatitis, atheroscle-
rotic cardiovascular disease, and malignancy.(14)The puta-
tive mechanisms involved are rather speculative, and proof
of a cause-and-effect relationship is lacking. Designing
studies to assess accurately the morbidity and mortality of
untreated "asymptomatic" P H P T and to determine the po-
tential reversibility of any morbidity after successful para-
thyroidectomy represents a significant
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