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210
ENDOCRINE SURGERY
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Section II
Parathyroid
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15
Embryology, Anatomy, and Physiology of the Parathyroid Glands
Johnathan G.H. Hubbard
Introduction
The parathyroid glands were first dissected and
described in the Indian Rhinoceros by Richard
Owen from an animal that died in the London
Zoological Gardens in 1850. This specimen can
still be viewed in the Hunterian Museum at the
Royal College of Surgeons in London. The
Swedish anatomist and medical student Sandstrom subsequently described and named the
glands in 1880.
There are usually four Parathyroid glands
close to the thyroid gland whose combined
weight is approximately 240 mg. They are yellow/brown in color and roughly the size of a
lentil. They can become significantly enlarged
in pathological conditions such as primary
hyperparathyroidism (HPT) (Fig. 15.1).
Embryology
Mesodermal condensations develop in the primitive pharynx of the human embryo to form
branchial arches in the 4th to 5th week of development [1]. These arches are separated by clefts
or pouches. The parathyroid glands develop
from the endoderm of the third and fourth
pouches. The fifth pouch, from which the ultimobranchial body is derived is atypical. It
shares a common entrance to the pharynx with
the fourth pouch and is usually considered as
part of the fourth pouch [1].
Inferior Parathyroid
The inferior parathyroid (PIII) develops from
the dorsal aspect of the third pouch while the
thymus develops from the ventral aspect. They
separate from the pharynx, and the thymus descends caudally pulling PIII with it. The thymus
descends to the thorax where it joins with the
contra lateral thymus to form the bilobed thymus gland. The tail portions become thin and
remain in the neck near the inferior pole of the
thyroid or may break up into fragments. PIII is
classically located at or posterior to the inferior
pole of the thyroid but is commonly found
within the thymic capsule in the neck or upper
mediastinum. PIII can be ectopically located at
any point on its path of descent (Fig. 15.2).
Rarely PIII is found cranial to the superior
pole of the thyroid, in the carotid sheath, or
very rarely around the heart or the aortopulmonary window.
The Superior Parathyroid
The superior parathyroid (PIV) derives from
the dorsal aspect of the fourth pouch and descends attached to the thyroid and is classically
located on the dorsal aspect of the thyroid frequently beneath the capsule of the thyroid,
within a 1 cm radius of the junction of the
inferior thyroid artery and recurrent laryngeal
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_15, Ó Springer-Verlag London Limited 2009
215
Fig. 15.1. 12.5-g parathyroid adenoma.
nerve (RLN) [2]. Due to the more limited pathway of descent of PIV glands, the ectopic locations are less numerous than with PIII
(Fig. 15.2). PIV can be located cranial to the
superior pole of the thyroid, in the para or
retro oesophageal space, or very rarely be
totally intrathyroidal. The ultimobranchial
body, derived from the fourth pouch, descends
with PIV and gives rise to the parafollicular
cells of the thyroid which have neural crest
origin and produce calcitonin. These cells
become embedded in the thyroid, often leaving
a small nodule within the thyroid at its posterior medial aspect, the Tubercle of Zuckerkandl.
This can be a guide to the RLN which passes
beneath and medially to it, with PIV frequently
situated in close proximity.
The upper and lower parathyroid glands take
their blood supply from the inferior thyroid
artery in most situations although when ectopically placed the superior thyroid artery or thyroid ima artery may be the arterial supply.
216
ENDOCRINE SURGERY
A capsular plane of dissection when performing
a thyroidectomy (Fig. 15.3) helps preserve the
parathyroid glands with their blood supply,
although some parathyroid glands take vessels
direct from the thyroid capsule without an
obviously identifiable main feeding vessel [16]
and may require autotransplantion to the sternocleidomastoid muscle.
Surgical Aspects
In the adult, PIII is typically located on a plane
anterior and medial to the RLN while PIV is
located posterior to this plane. As an adenoma
develops, the plane of descent of PIV is frequently posterior and caudally toward the mediastinum and it may lie at the same level as PIII
but in the posterior plane. Parathyroid localization techniques are therefore important in planning focused (MIV) surgical techniques.
Cadaveric studies have shown that 13% of
individuals may have either true supernumerary parathyroid glands (5%) or additional tiny
rests of parathyroid tissue that do not amount to
a full parathyroid gland (8%) [3]. This is important in planning surgery for patients with conditions where diffuse stimulation of the parathyroid tissue occurs such as secondary HPT or
primary HPT in MEN1. In these patients, resection of the cervical thymus and fatty tissue in the
central compartment of the neck is important to
remove the rest of parathyroid tissue and reduce
the risk of persistent or early recurrent HPT.
Calcium Physiology
The vast majorityof calcium in the bodyis stored
in bone as hydroxylapatite, and only 1% of calcium is present in the extracellular fluid. Half of
serum calcium is in the ionized form (Ca
remaining 50% is metabolically inactive and
bound to albumin (40%) or complexed with
anions such as phosphate and citrate (10%).
Therefore, total calcium levels in plasma are
affected by changes in protein concentration,
but Ca
level is controlled by the hormones PTH and
1,25-dihydroxycholecalciferol (DHCC) and
involves regulation of calcium exchange across
the gut, the bone, and renal tubule mediated via
the calcium-sensing receptor (CaSR).
2+
is unaffected. The ionized calcium
2+
). The
217
EMBRYOLOGY, ANATOMY, AND PHYSIOLOGY OF THE PARATHYROID GLANDS
Fig. 15.2. Pathways of descent of PIII and PIV showing area of ectopic locations.
Fig. 15.3. Plane of capsular dissection.
Table 1. Summary of actions of PTH, VIT D and Calcitonin on calcium homeostasis
PTH Vitamin D Calcitonin
Gastrointestinal Indirect effect via production Vitamin D Increased calcium/
phosphate
absorption
Bone Increases osteoclast resorption Increases osteoclast
resorption
Renal Stimulates resorption – fine tunes calcium uptake in
DCT. Inhibits Phosphate uptake PCT
No effect Inhibits calcium and
218
ENDOCRINE SURGERY
No effect
Inhibits resorption
phosphate resorption
Calcium-sensing receptor (CaSR) (Table 15.1).
The commonest causes of persistent hypercalcaemia are parathyroid dysfunction and malignancy
(Table 15.2).
Table 2. Some causes of Hypercalcaemia
Malignancy
Primary – multiple myeloma, lymphoma
Secondary with bone metastases
Endocrine
Pheochromocytoma, Thyrotoxicosis, Addisons,
Hyperparathyroidism
Familial Hypercalciuric hypercalcaemia(FHH)
Granulomatous disease
Sarcoid, Tuberculosis
Medication related
Lithium, Thiazide diuretics, Vitamin D, Vitamin A
Miscellaneous
Milk-Alkali syndrome, Pagets and immobilisation
Parathyroid Hormone
The endocrine function of parathyroid glands
has been recognized for many years. In 1925,
parathyroid extract was shown to prevent hypocalcemia in dogs that had undergone parathyroidectomy [4]. PTH is an 84 amino acid (aa)
peptide synthesized by the chief cells of the
parathyroid gland. Its gene is located on chromosome 11. It is secreted in a prepro-PTH form.
The presequence (23aa) and prosequence (6aa)
are removed by the endoplasmic reticulum and
Golgi apparatus before PTH is packaged into
secretory granules for secretion [5].
Intact (1–84aa) PTH has a half life of 2–4 min
and is broken down by the liver and kidney yielding amino and carboxy terminal fragments.
Carboxy terminal fragments are excreted via the
kidney and accumulate in renal failure. Early
radioimmunoassays to measure PTH were developed in the 1960s [6] however interpretation of
results was problematic as breakdown fragments
of PTH were detected. Current PTH assays measure intact PTH with either a two-site immunoradiometric assay (IRMA) or immunochemiluminescent assay (ICMA). In the late 1980s, alteration
of the incubation times and temperatures reduced
assay times (15 min) and enabled the quick measurement of PTH, which is today frequently used
to monitor adequacy of excision during focused
techniques of parathyroidectomy.
The main function of PTH is to control Ca
2+
PTH acts via the receptors, PTH-1, and PTH-2.
The first 34 amino acids are responsible for the
biologic effects of PTH. Amino acids 18–34 bind
the receptor with amino acids 1–6 required for
its activation. PTH-related peptide (PTHrP)
secreted by malignant tumurs produces hypercalcemia by activating the PTH-1 receptor [5].
The kidneys filter large amounts of calcium
(10 g/day). The majority (60–70%) is reabsorbed in the proximal tubule and thick ascending limb of Henle by passive paracellular
absorption. PTH stimulates reabsorption of calcium in the kidney and is particularly important
for fine tuning calcium active uptake in the
distal convoluted tubule. Active uptake of Ca
2+
occurs via the epithelial Ca2+channel TRPV5
(transient receptor potential vanilloid-5) on the
luminal side of the distal convoluted tubule
(DCT) and is the rate-limiting step in transcellular calcium reabsorption. New regulators currently under investigation that are implicated in
the regulation of renalcalcium uptake via TRPV5
expression include 1,25-DHCC, estrogen, tissue
kallikrein, and klotho (an anti aging protein)[7].
PTH indirectly stimulates gut uptake of calcium by stimulating renal production of active
vitamin D (1,25-DHCC). Absorption of calcium
.
219
EMBRYOLOGY, ANATOMY, AND PHYSIOLOGY OF THE PARATHYROID GLANDS
occurs throughout the small and large intestine
with maximum absorption occurring in the
duodenum and jejunum, via active and passive
means. Active uptake is regulated via the epithe-
2+
lial Ca
resorption and elevation of serum calcium but
in the longer term also stimulates new bone
formation.
effect by inhibiting the reabsorption of phosphate
in the proximal convoluted tubule. In renal failure, GFR is reduced and phosphate is retained,
both factors are reported to induce fibroblast
growth factor 23 (FGF23) [7, 8, 9]. FGF23 is a
bone-derived circulating factorthat has an important role in phosphate and vitamin D regulation.
FGF23 inhibits phosphate reabsorption in the
kidney and inhibits the production of vitamin D.
PTH levels rise secondary to reduced vitamin D
levels and possibly as a direct consequence of
raised levels of FGF23. Retained phosphate complexes with calcium and contributes to the hypocalcemia of renal failure, which further stimulates
the production of PTH by the parathyroid glands.
channel, TRPV6 [7].
PTH activates osteoclasts causing bone
In the kidney, PTH has a marked phosphaturic
Vitamin D
Vitamin D is obtained from the diet and is
formed in the epidermis of the skin with exposure toadequate sunlight. It is metabolized in the
liver to 25-hydroxycholecalciferol (HCC) and
further in the kidney. The main active form is
1,25-DHCC, produced via the action of the
1–hydroxylase enzyme on 25-HCC in the kidney. The actions of vitamin D are mediated via
the nuclear vitamin D receptor (VDR). Production of 1,25-DHCC is stimulated by PTH, IGF-1,
and is inhibited by high levels of calcium, phosphate, and FGF23. Vitamin D has an important
role in regulating calcium homeostasis with PTH,
particularly the gut absorption of calcium and in
regulating bone formation particularly bone
resorption mediated by osteoclasts.
The Calcium Sensing Receptor
The calcium sensing receptor (CaSR) was cloned
in 1993[10]. The CaSR is a 1078aa cell surface
protein and member of the G-protein-coupled
receptor family. The CaSR gene is located on
chromosome 3 (3q13.3–21). The CaSR is widely
found throughout the body including the parathyroid glands, C cells of the thyroid, kidney,
intestine, bone, and brain. The CaSR enables
the parathyroid glands to sense Ca
adjust the amount of parathyroid hormone
secreted. There is negative feedback between
2+
Ca
and PTH. The steep section of the sigmoid
relationship lies within the normal range of
serum Ca
tionship between PTH and serum Ca
this range [11].
resulting in a suppression of PTH levels, while
low levels of calcium inactivate the CaSR resulting in high levels of PTH. The mechanism by
which this occurs remains poorly understood
and under investigation [12].
2+
, such that there is an inverse rela-
High levels of calcium activate the CaSR
2+
levels and
2+
within
Calcitonin
The CaSRs in the C cells of the thyroid are
set up in an opposite fashion to those in the
parathyroid glands, such that activation with
calcium results in secretion of calcitonin
which lowers calcium and inactivation due
to low levels of calcium suppresses calcitonin
secretion. Calcitonin is a 32aa peptide coded
by the CALC-1 gene. Calcitonin inhibits
osteoclast activity in bone and inhibits reabsorption of phosphate in the kidney and
increases renal excretion of calcium.
Although it has actions to lower serum calcium, calcitonin is relatively unimportant as
an acute regulator of calcium homeostasis in
humans as demonstrated by the lack of complications following total thyroidectomy. It is
an important tumor marker in MTC.
GeneticmutationsoftheCaSRhavebeen
linked with clinical disorders such as familial
hypocalciuric hypercalcemia (FHH) and neonatal severe HPT. FHH is rare and caused by
a heterozygous inactivating mutation of the
CaSR. This autosomal dominant disorder is
characterized by hypercalcemia with low
urinary calcium excretion. The calcium clearance to creatinine clearance ratio (CCCR) is
<0.01.Typically, individuals have a normal
(inappropriate) PTH and mild hypermagnesemia. These patients do not benefit from