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300
ENDOCRINE SURGERY
ischemia in the graft-bearing arm compared with
the nongraft-bearing arm [95, 96].
Intraoperative Localization
1. Methylene blue: Abnormal parathyroid
glands take up blue stain when a preoperative
infusion of methylene blue (5 mg/kg in 5%
Dextrose) is given one hour before surgery
[97]. However recent reports because reports
suggest that methylene blue can precipitate
serotonin toxicity in patients taking selective
serotonin uptake inhibitors [98] and cause temporary adverse effects on the central nervous
system.
2. Intraoperative MIBI: Intraoperative sestamibi scanning in reoperative surgery is reported
better than preoperative scanning with sensitivity of up to 91% [99, 100].
3. Intraoperative bilateral jugular vein
sampling for PTH: Venous sampling from both
internal jugular veins for PTH at the start of
an exploration is particularly useful when
localization studies have not shown any
abnormality [101]. Differential elevation of the
PTH level will indicate the side of the neck
where hyperfunctioning parathyroid gland is
likely to be found, this side should be explored
first.
Generally, localization studies should begin
with USS and MIBI, if these are negative or
nonconcordant; selection of further tests as
mentioned above will be directed by the suspected location of the abnormal parathyroid
gland/s. Invasive tests should be performed
selectively, when noninvasive test is negative.
Reoperative Surgery
Reoperation should be exclusively performed
by an experienced endocrine surgeon, and frozen section pathology, reporting to confirm
parathyroid tissue, and intraoperative PTH
assay, to confirm biochemical cure, should be
available [102].
In ideal circumstances localization studies will
have provided sufficient information to guide a
planned unilateral/bilateral cervical or mediastinal exploration. There are however cases when
localization test is negative and bilateral cervical
exploration is therefore mandatory.
The surgeon should obtain informed consent from the patient regarding the proposed
intervention, taking time to reexplain the
indications and implications of reoperative
surgery, including the details of risks and
complications (bleeding, temporary or permanent damage to the RLN/s with risk of
tracheostomy, failure to achieve cure, and
hypoparathyroidism).
Adequate planning should include allowance
for prolonged operating time, and if required,
the availability of a surgeon to assist with
sternotomy.
Operative Strategy
The strategy in reoperative PHPT is as follows:
a) Perform localization directed cervical and/or
mediastinal exploration.
b) Excise abnormal parathyroid gland/s.
c) Perform additional procedures such as
thymectomy in patients with multiglandular
disease and or autotransplantation or cryo-
preservation of parathyroid tissue in RHPT/
MEN.
d) Confirm successful identification of para-
thyroid tissue with frozen section and con-
firm biochemical cure with intraoperative
PTH.
e) Minimize operative complications such as
damage to recurrent the laryngeal nerve/s
and hypoparathyroidism.
Positive Localization
The operative strategy will of course be influenced by the surgical and pathological findings
at initial surgery as well as the results of subsequent localization studies. When the latter have
identified the ‘expected’ abnormal parathyroid
gland/s as
1. Single gland disease: Unilateral neck
exploration is the operation of choice [103].
The techniques of first time unilateral neck
exploration can be equally applied to reoperative parathyroid surgery. A lateral incision
or conventional cervicotomy skin incision
can be used. A lateral approach obviates the
need for dissection through midline scar tissue, the plane between the medial border of
the sternomastoid muscle at the level of the
thyroid gland and the lateral border of the
301
REOPERATIVE PARATHYROID SURGERY
strap muscles is developed. The strap muscles
and thyroid gland are retracted medially and
the plane deepened until one can see and palpate the vertebral column posteriorly and the
esophagus medially. The inferior thyroid artery
and RLN should be identified. This procedure
can be carried out under local or general
anesthesia.
2. Multiglandular disease:Whenpreoperative
localization studies are positive for multiglandular disease or multiglandular enlargement is
suspected – hyperplasia was identified on histology from tissue excised at a previous operation; assessment of all residual parathyroid
tissue is required. A systematic approach should
be used to guide the surgeon to the parathyroid
glands [104]. The surgical options include excision of abnormal gland/s in case of multiple
adenomas, and subtotal parathyroidectomy
or total parathyroidectomy with or without
autotransplantation when the diagnosis is
hyperplasia/MEN.
In patients with multiglandular disease,
cervical thymectomy should be carried out in
addition to parathyroidectomy.
3. Mediastinal parathyroid gland:Mediastinal
exploration should only be performed when
there is evidence from localization studies that
the hyperfunctioning gland is in the mediastinum. In our center, mediastinal exploration is
not undertaken without positive preoperative
localization.
The mediastinum can be explored via a partial or complete sternotomy, or a thoracoscopic
approach can be employed if available, appropriate, and feasible. Mediastinal parathyroids
that are located at the level of the innominate
vein in the anterior superior mediastinum
may be retrievable via a cervical approach, but
if necessary can be removed using a partial
sternotomy. Parathyroid glands that are low in
the anterior mediastinum or in the middle
mediastinum require a complete sternotomy.
The potential complications and morbidity
associated with open sternotomy may be
reduced by the thoracoscopic approach, but
this has not been widely accepted as standard
treatment [105–110]. The UK National Institute
for Health and Clinical Excellence (NICE)
issued guidance in December 2007 which confirmed that there is limited evidence to support
the efficacy of thoracoscopic excision of mediastinal parathyroid lesions [111].
Negative preoperative Localization
The surgeon should have a clear plan prior to
the intervention as to the means by which the
abnormal parathyroid will be identified, e.g., if
two normal glands were found on one side of
the neck at the initial operation it is reasonable
to explore the contralateral side first. If an
enlarged parathyroid gland is found and excised
and a fall in PTH confirms cure, the operation is
terminated. If ‘cure’ is not confirmed then the
exploration is continued, if necessary exploring
both sides of the neck until biochemical cure is
confirmed.
Cryopreservation of parathyroid tissue for
future transplantation [112] or autotransplantation of parathyroid tissue should be considered
in patients having total parathyroidectomy.
If exploration is negative, a thyroid lobectomy
on the side of suspicion should be considered to
remove suspected/unidentified intrathyroidal
parathyroid lesions.
Hyperfunctioning Parathyroid
Autograft
Patients with confirmed hyperfunctioning
forearm autograft require excision of hyperfunctioning graft tissue and lifelong calcium
replacement therapy.
Parathyromatosis
Removal of all abnormal parathyroid tissue/
scattered nodules in the neck should be
attempted. Parathyromatosis may be difficult
to diagnose preoperatively and although color
Doppler sonography can easily identify scattered
deep and superficial hypoechoic, hypervascular
lesions, they do not conform to typical anatomic
locations of parathyroid glands [54]. Although
a rare cause of recurrent RHPT control of the
disease with surgical resection has been reported
[53, 113].
Angiographic Ablation
Angiographic ablation is a nonsurgical alternative to standard mediastinal exploration that
involves injection of ionic contrast material or
alcohol into a previously identified arterial
vessel feeding the abnormal parathyroid
ENDOCRINE SURGERY
Table 21.3. Anatomic location of abnormal parathyroid glands and results of reoperation for recurrent/persistent HPT
Jaskowiak
Wang
Locations
Eutopic 29 48 113 103 14 28 19
Ectopic 78 54 109 26 47 46 26
Supernumerary 4 – 0 – – 1 5
Multiglandular
disease (%)
RLN injury (%) 2.7 1 1.3 0.8 – – –
Permanent
hypocalcemia (%)
Cure rates (%) 91 95 96.8 88 98 97.6 98
Total number of patents 112 102 222 129 61 77 50
(1977) [37]
– 37 0 73 – 69 56
18 1 5 13 9 –
Shen
(1996) [119]
(1996)
[117]
Thompson
(1999) [77]
Feingold
(2000)
[57]
Arnalsteen
(2004) [81]
302
Gough
(2006)
[121]
gland [114]. The hyperosmolar contrast
material transudes into the interstitial spaces
of the parathyroid and leads to ischemic insult
and destruction of the gland. Angiographic
ablation can be used in patients who are poor
surgical candidates; however, experience with
this technique is limited and the failure rate is
as high as 40%, and tissue for histology cannot
be obtained [115].
Patients who are unfit to have any form of
surgical or interventional radiological procedure can be treated with medical therapy with
biphosphonates and calcimimetics. Cinacalcet
has been used successfully to lower PTH in
recurrent RHPT [57, 59].
Success rates in seven published series of
parathyroid reoperations for PHPT between
1977 and 2006 are 82–98%, with multiglandular
disease identified in 37–73% of cases. The incidence of RLN injury varies between 0 and 2.7%
and permanent hypocalcemia rates of 1–18%
[40, 60, 77, 81, 116-118] (Table 21.3). A high
number of missed glands wre found in eutopic
sites [10, 81, 116–124].
Summary
The chances of cure are highest at the first
operation, and it is therefore important to ‘get
it right the first time’ [6]. Parathyroid surgeons
should be familiar with the operative algorithm
when an abnormality is not found at initial
parathyroid exploration [104]. Confirmation of
the biochemical diagnosis of HPT, examination
of initial parathyroid localization studies, in
conjunction with review of the operative findings and pathological examination of tissue
removed at initial surgery are the initial key
steps in the evaluation of a patient with recurrent/persistent HPT.
Further localization studies should be car-
ried out if there are indications for reoperation.
The indications, risks, and benefits of reoperation should be weighed carefully against the
patient’s comorbidity.
Reoperation can be targeted to remove
abnormal gland/s when localization tests are
positive but more extensive exploration may
be necessary if localization tests are negative
or there is suspicion of multiglandular disease.
At surgery, the removal of all hyperfunctioning parathyroid tissue should be confirmed with
frozen section and intraoperative PTH.
Reoperative parathyroid surgery can be a
technically demanding procedure and should
be undertaken by experienced endocrine surgical teams to maximize the rate of success [74].
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22
Management of Secondary and Tertiary Hyperparathyroidism
Jui-Yu Chen, Ling-Ming Tseng and Chen-Hsen Lee
Introduction
Secondary hyperparathyroidism (sHPT) is a
condition that occurs when external factors
stimulate the parathyroid glands to increase
the secretion of parathyroid hormone (PTH),
and develop mostly hyperplasia and/or adenomas of the parathyroid. The most common
external factor is chronic renal failure (CRF)
(i.e., renal hyperparathyroidism) [1]. Renal
hyperparathyroidism could cause osteitis
fibrosa, and other varieties of extra-osseous
manifestations. Some consequences would
bring patient poor life quality and even mortality [2].
Tertiary hyperparathyroidism (tHPT) is a
state of autonomic excessive secretion of PTH
developing from the secondary hyperplasia that
occurs despite after restoration of renal function by dialysis or kidney transplantation [3].
tHPT is not a common disease process in the
kidney transplant population, but it can cause
damage of graft function that is not easily
detected.
Pathogenesis
The major factors in the pathogenesis of sHPT
consist of hypocalcemia, hyperphosphatemia,
reduced 1,25 dihydroxyvitamin D3 (1,25-[OH]
2D3, calcitriol) production, altered PTH
metabolism, skeletal resistance to PTH, and
changed set-point in PTH production.
Before Kidney Transplantation
Hypocalcemia, resulting from phosphorus
retention [4] and reduced calcitriol synthesis
[5], has been regarded as the classic cause of
sHPT. Besides, phosphorus retention directly
promotes PTH synthesis and secretion [6]. Dietary phosphate load is found to affect the parathyroid cell cycle [7] and the responsiveness of
parathyroid cells to extracellular Ca
tration. The resistance of bone to PTH also plays
a part in the pathogenesis of sHPT due to low
level of calcitriol, phosphate retention, and
downregulation of PTH bone receptors [8].
The PTH set point is dependent on the serum
calcium concentration which can decrease the
maximal PTH level by 50%. In uremic patient,
there is a shift in the PTH set point rendering the
parathyroid insensitive to the suppressive effects
of calcium [9], and excessive PTH is secreted
without moderate control mechanism. A novel
phosphaturic hormone, fibroblast growth factor23 had been reported to be implicated in the
pathogenesis of renal osteodystrophy (ROD)
[10]. The decreased responsiveness of parathyroid glands to vitamin D is also found in the
pathogenesis of sHPT. It could in part be
explained by the reduced vitamin D receptor
(VDR) [11] and reduced calcium-sensing receptor (CaSR) expression in the patients [11, 12].
2+
concen-
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_22, Ó Springer-Verlag London Limited 2009
307
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ENDOCRINE SURGERY
After Kidney Transplantation
sHPT usually regresses after successful kidney
transplantation due to the reversion of abnormalities in mineral metabolism attributing to
parathyroid proliferation. Continuous hyperfunction of hyperplastic parathyroid glands is
the main reason for hypercalcemia after kidney
transplantation. Parathyroid autonomy, slow
involution of parathyroid glands, nonsuppressible PTH secretion, abnormal PTH set point,
and insufficient calcitriol secretion are important factors that may prevent the involution of
the hyperplastic parathyroid gland even with a
well-functioning kidney transplant.[13, 14, 15]
The prevalence of persistent sHPT after kidney
transplantation is seen in approximately
8.5–53% [13, 14]. Only few required operative
reduction of parathyroid gland mass as a definitive treatment.
Clinical Manifestations
Classical clinical manifestations of sHPT consist
of many varieties of skeletal and nonskeletal
complications. ROD includes either osteitis
fibrosa or mixed uremic bone-type disease,
and nonskeletal toxicity includes the metastatic
calcifications and skin lesions due to the disturbance of PTH and mineral metabolism.
Skeletal Disease
reduced bone mass, increased nonlamellar bone,
osteopenia, and fractures [17] (Fig. 22.1). A con-
sequence of this is the release of calcium and
phosphorus into the systemic circulation. In
addition to the bone manifestation, ongoing
absorption of calcium from the gastrointestinal
tract during treatment with calcium-based drugs
would lead to the propensity for metastatic calcification in soft tissues.
After the long-term use of aluminum-based
phosphorus-binding agents, uremic patients
would present with adynamic bone disease or
osteomalacia [18]. Aluminum is absorbed by
the intestines and rapidly transported into
bones. Under those circumstances, aluminum
accumulates in the mineralization front and
prevents osteoid mineralization. Fortunately,
the incidence of aluminum toxicity has been
decreased because of the use of water purification for dialysate solutions and absence of aluminum in phosphate-binding agents.
Diagnosis of Uremic Osteodystrophy
Patients with high-turnover hyperparathyroid
bone disease and low-turnover aluminumassociated bone disease display similar clinical
and laboratory features. A misdiagnosis of osteitis fibrosa could lead to the decision of parathyroidectomy, and then worsen the bone condition
of truly aluminum-related low-turnover bone
disease [19]. It is important to differentiate
these different conditions, and bone biopsies
remain the most rational approach.
ROD-inducing bone loss remains the major
cause of morbidity in uremic patients [16] and
occurs as a consequence of bone-remodeling
dysregulation. The severity varies and comprises pain, deformities to fractures. Bone pain
is usually located at the lower back, hips, and
legs while fractures commonly occur in long
bones, vertebras, and ribs. The deformity manifestation arises mainly from vertebral fractures
leading to kyphosis and lumbar scoliosis. Shortening of body height is usually a result of compression fractures of the vertebras.
Elevated levels of PTH would stimulate bone
demineralization and lead to high bone turnover characterized by an enhanced number and
activity of osteoclasts, resulting in increasing
bone resorption. The classical histological
pathology is osteitis fibrosa accompanied with
Extraskeletal Disease (Tissue
Calcification)
There are two types of tissue calcification: metastatic and dystrophic calcification. Metastatic
calcification occurs when calcium salt deposits
in normal tissue whereas dystrophic calcification occurs in previously damaged tissue [20].
There are three major types of extra-skeletal
calcification: visceral, periarticular, and vascular calcification. Visceral calcification includes
lungs, myocardium, mitral valve, kidney, skeletal muscle, breast, and stomach. Periarticular
calcification manifests as calcific periarthritis,
and small-joint effusions. Vascular calcification
involves small and large vessels, and calcification of penile artery may induce impotency.
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MANAGEMENT OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM
Fig. 22.1. Severe kyphoscoliosis in a patient with severe sHPT due to compression fracture of thoraco-lumbar vertebrae.
Cardiovascular Problems
Elevated PTH has been shown to exacerbate
changes in cardiovascular structure and function. It is contributory to the high cardiovascular
morbidity and mortality rates in uremic patients
[21]. Besides, prolonged exposure to elevated
PTH has been linked to high arterial blood pressure [22] and increasing levels of intracellular
calcium attributes to the underlying mechanism.