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ENDOCRINE SURGERY
The deposition of calcium and phosphorus in
blood vessels in addition to arterial hypertension
induces atherosclerosis [23]. Hemodialysis
patients have a very high prevalence of vascular
calcification of up to 83% (Fig. 22.2).
Hyperphosphatemia and hypercalcemia
have been shown to promote calcification of
vasculature (coronary artery included),
myocardium, and cardiac valves [24]. Calcification of the electrocardiac conduction
fibersmayleadtovariabledegreeofatrioventricular block (Fig. 22.3). Left ventricular
hypertrophy (LVH) is seen frequently in uremic patients. It is the major cause of cardiac
mortality associated with myocardial fibrosis,
poor perfusion, and cell death [25]. Excessive
PTH could lead to the development of LVH
and reduced left ventricular ejection fraction
[26]. It is believed that human fetuin-A deficiency may contribute to a decrease in
vascular wall elasticity and is a potent cardiovascular risk factor [27].
Metastatic Pulmonary Calcification
Calcification of the lung leads to impaired
pulmonary function, pulmonary fibrosis,
pulmonary hypertension,rightventricular
hypertrophy, and right-sided chronic heart
disease. MPC was previously shown to be
primarily amorphous whitlockite in composition, rather than the crystalline hydroxyapatite [20, 28]. Whitlockite is more likely to
persist despite therapy, as opposed to
hydroxyapatite, which tends to dissipate
with appropriate therapy [28]. MPC could
be diagnosed by high-resolution CT with
high sensitivity [29], or Tc99m-MDP bone
scan [20] Autopsy study revealed the pulmonary calcification occurred in the alveolar septae, bronchi, and vessels.
Pruritus
Pruritus is a common (>50%) disturbing symptom among patients on hemodialysis[30]. Serum
phosphate, calcium, and magnesium and their
ionic products are related with its development.
The symptom may get dramatic improvement
after parathyroidectomy (PTX) [31].
Fig. 22.2. Remarkable calcification of the aorta, splenic artery,
etc., in a sHPT patient.
Calciphylaxis
Calciphylaxis (calcific uremic arteriolopathy) is
an uncommon syndrome of disseminated calcification, resulting in both vascular calcification
and skin necrosis (Fig. 22.4). The main histo-
pathological finding is calcium deposits within
arteriolar and small vascular walls, inducing
endovascular fibrosis associated with fat necrosis. Lesions are characteristically located over the
hands and fingers, lower extremities, and sometimes lower abdomen. The patients usually have
a high Ca P product but not necessarily extremely high PTH levels. Gangrene of distal limbs
can lead to sepsis and death [32]. The prognosis
for patients with calciphylaxis is poor with mortality approaching 50%. Some potential etiological factors have been identified including
reduced serum levels of a calcification inhibitory
protein ,2-Heremans-Schmid glycoprotein
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MANAGEMENT OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM
Fig. 22.3. Calcification of the electrocardiac conduction fibers may lead to variable degree of atrioventricular block. (a, b, c, d) first-
degree A-V block; (e) second-degree A-V block (Wenkebach type); (f) ECG on admission to hospital; (g) alternating RBBB and LBBB.
(Fetuin-A) and abnormalities in smooth muscle
cell biology in uremic patients [33].
Sexual Dysfunction
Sexual dysfunction is a common feature in both
men and women. Disturbances include erectile
dysfunction in men, menstrual abnormalities in
women, and decreased libido in both sexes [34].
Anemia
Normochromic, normocytic anemia is a common complication in hemodialysis patients.
Decreased erythropoietin production, aluminum toxicity, iron deficiency, infections, and
increased hemolysis are important contributing
factors [35]. Progressive HPT induces bone
marrow resistance and reduces its response to
erythropoietin treatment [36].
After Kidney Transplantation
tHPT may be difficult to be distinguished from
primary HPT clinically because of similar serum
chemistries; however, tHPT usually occurs in
patients with CRF who have undergone a
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ENDOCRINE SURGERY
5% met the combined targets for Ca, P, PTH,
and Ca P product [38]. Eventually, some
patients undergo parathyroid surgical intervention. When the parathyroid glands are enlarged
and weigh more than 500 mg or exhibit nodular
hyperplasia with monoclonal cell growth, vitamin
D therapy might not effectively inhibit PTH oversecretion [39]. Such severe sHPT frequently
causes hypercalcemia and hyperphosphatemia
that consequently increase the risk of cardiovascular morbidity and mortality.
Fig. 22.4. Calciphylaxis-induced bilateral hand skin blisters
and necrosis.
successful kidney transplantation. Both serum
calcium and PTH are elevated but phosphorous
may be low.
Management
In an attempt to improve the control of sHPT and
clinical outcomes, the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality
Initiative (K/DOQI) has recently published clinical practice guidelines for the management of
bone metabolism and disease in chronic kidney
disease [37] (Table 22.1). These evidence-based
guidelines propose challenging new target levels
for serum intact PTH (iPTH), calcium, phosphorus, and calcium–phosphorus product in
patients with advanced chronic kidney disease
mainly to avoid ectopic calcification and cardiovascular complications. However, most hemodialysis patients do not meet these goals. One large
study of uremic patients from seven countries
found that only 21% of patients satisfied the
guideline’s criteria for PTH concentration and
Table 22.1. National Kidney Foundation K/DOQI (Kidney
Disease Outcomes Quality Initiative) targets for intact parathyroid hormone(i-PTH), calcium, phosphorus, and calciumphosphorus (Ca P) product in uremic patients
Variable Target Range
Serum i-PTH 150–300 pg/ml (16.5–33.0 pmol/l)
Total serum calcium 8.4–9.5 mg/dl (2.10–2.37 mmol/l)
Serum phosphorus 3.5–5.5 mg/dl (1.13–1.78 mmol/l)
Ca P <55 mg
2
/dl2(<4.5 mmol2/l2)
Medical Treatment
The aim of medical treatment of sHPT is to
prevent progression from diffuse to nodular
hyperplasia. In order to avoid progression of
sHPT, pathogenetic factors should be sought
and eliminated [40]. Treatments of metastatic
pulmonary calcification (MPC) include the correction of Ca P product, parathyroidectomy,
and renal transplantation [20]. Biophosphonate
could be employed to stop the progressing of
calcification [41]. In patients with calciphylaxis
condition, the therapeutic strategy is to normalize the high Ca P products with phosphate
binders initially [42]. When calciphylaxis is
complicated with advanced renal hyperparathyroidism, PTX should be performed
promptly. A prospective study by Park et al.
confirmed the finding that PTH-suppressive
calcitriol therapy led to a regression in myocardial hypertrophy in dialysis patients [43].
Surgical Treatment
Prerenal Transplantation
Although sHPT could be effectively treated
medically, medical therapy does not always
work in achieving adequate control of serum
PTH, calcium, phosphorus, and Ca P product.
Surgical PTX is indicated for severe sHPT associated with hypercalcemia and/or hyperphosphatemia but not responsive to medical
approaches. The K/DOQI guideline (2003) [44]
proposes surgical treatment for severe sHPT as
follows: PTX is recommended for patients with
severe HPT (a persistent serum level of iPTH >
800 pg/ml, 88.0 pmol/l), associated with
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MANAGEMENT OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM
hypercalcemia and/or hyperphosphatemia that
are refractory to medical treatment. An additional indication for parathyroidectomy is the
presence of calciphylaxis with an elevated PTH
level of >500 pg/ml since it is a very serious
complication in uremic patients [45]. These
recommendations emphasize the avoidance of
ectopic calcification and cardiovascular complications resulting from hypercalcemia, hyperphosphatemia, and a persistent high PTH level
[46]. Besides, according to the algorithm of the
Association of European Dialysis Transplantation (EDTA), the size of the parathyroid gland is
one of the factors to be considered as the indications for surgery [47] (Table 22.2). Besides calciphylaxis, patients with high bone turnover,
osteitis fibrosa on X-ray, severe symptoms of
sHPT, progression of ectopic calcifications, progression of bone loss, and anemia resistant to
erythropoietin should be advised to have surgical intervention [48].
Posttransplantation
Surgical treatment is the only curative therapy
for tHPT [49, 50, 51]. Successful surgical intervention for sHPT and tHPT significantly
reduces preoperative symptoms and leads to
recovery of bone disease. Surgery is usually
reserved for patients having symptoms of HPT
refractory to medical treatment [52, 53]. Indications for surgery include persistent symptoms
of hypercalcemia and/or renal graft calculi
Table 22.2. Overall Indications for PTX
K/DOQI guideline
1. High level of PTH (intact PTH > 800 pg/ml)
2. Hypercalcemia
3. And/or Hyperphosphatemia
4. Condition: calciphylaxis with elevated PTH levels
(>500 pg/ml)
EDTA (European Dialysis and Transplant Association):
Detection of enlarged parathyroid glands by
ultrasonography (volume of the largest gland > 500 mm3)
Other indications
1. High bone turnover, osteitis fibrosa
2. Severe symptoms of SHPT
3. Progression of ectopic calcification
5. Progression of bone loss
6. Anemia resistant to therapy
formation after a successful renal transplantation. Ultimately, 1.6–3% of all kidney recipients
may require parathyroidectomy, as the definitive treatment for tHPT [54].
The indication of PTX for asymptomatic
hypercalcemia alone after kidney transplantation is still controversial. Mild hypercalcemia
alone is not a serious threat to the patient.
Early reports showed that high PTH and
hypercalcemia have detrimental effects on
graft function and recommended early
aggressive PTX for posttransplant HPT, as
the association of renal stones with longstanding hypercalcemia [55]. Other studies
found that posttransplantation hypercalcemia, occurring early after the transplant,
mostly resolved spontaneously in the first
month after kidney transplantation [56].
Thus, many investigators recommended conservative approach to posttransplant hypercalcemia, with PTX reserved for patients with
progressive symptomatic disease and/or
roentgenographic findings, those with an
asymptomatic persistent hypercalcemia
(greater than 12.0 mg/dl) for more than
1 year after the transplant, or those with
acute hypercalcemia (calcium >12.5 mg/dl)
in the immediate posttransplant period [57].
Preoperative Care
Medication and Preoperative Image
Studies
The control of hyperkalemia, hypomagnesemia,
hypervolemia, hypertension, and cardiovascular disease in uremic patient is mandatory to
avoid perioperative complications.
Localization
Ectopic parathyroid glands may be pitfalls in
attempts to detect all parathyroid glands, especially over mediastinal, intrathyroidal, and
undescended glands. Ultrasound (US) is effective for detecting glands in the area around and
within the thyroid lobes. Glands weighing more
than 200 mg can be recognized by US. 99mTc
sestamibi-scan (mibi-scan) is positive in 88%
patients; however, it is difficult for a mibi-scan
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ENDOCRINE SURGERY
to visualize all the diseased glands. Usually, only
1–2 dominant glands are visualized [58]. A preoperative neck US study also helps to detect any
coexistent thyroid nodule or tumor disease.
Surgical Management
Type of Surgical Procedure
Three different surgical procedures are recommended in the K/DOQI guideline: subtotal PTX
(removal of three and a half glands and leaving
half a gland remnant in the neck), total PTX with
autotransplantation (TPTX+AT) of some of the
excised tissue into defined areas (forearm muscle, anterior tibialmuscle or subcutaneously, and
total parathyroidectomy without autotransplantation (TPTX). Not one technique appears to
provide superior outcomes [59, 60]. Mortality
and morbidity do not differ significantly between
TPTX+AT and subtotal PTX [61].
AlthoughTPTX alone providesa feasible therapeutic option, the procedure alone would carry
with the potential complication of adynamic
bone disease or severe hypocalcemia requiring
lifelong vitamin D and oral calcium medications.
It is not the procedure of choice in patients who
may subsequently receive a kidney transplant.
Therefore, subtotal PTX or TPTX+AT, both supplemented with thymectomy, are currently considered as the standard procedures in the treatment of sHPT [61, 62]. If a subtotal PTX is
planned, the smallest parathyroid is selected to
preserve. An approximately 50–70 mg remnant
would beleft with its blood supply and is marked
with nonabsorbable material, e.g., hemoclips. If a
total PTX with autotransplant would be
arranged, all the glands over neck (usually four
glands) are resected and the most suitable gland
(one less likely to have severe nodular hyperplasia) is selected for immediate autotransplant. A
100-mg portion of the gland is sliced into 1-mm
fragments and 10–20 fragments are placed into
several separate intramuscular or subcutaneous
pockets in the nondominant forearm. These
pockets are closed with nonabsorbable material.
Subtotal Parathyroidectomy (SPTX)
Theoretically, SPTX has the advantage of less
postoperative hypocalcemia. The risk of persistent hypocalcemia is less than 1% [63].
However, since the pathophysiological condition of CRF and maintenance dialysis continues,
the growth stimulus persists and may cause
recurrent sHPT of the remnant, which increases
with time [64]. The success of SPTX depends on
size and pathology of the remnant. Nodular
remnant is likely to grow recurrently. An adequate mark on the parathyroid remnant facilitates the resection of the target lesion during
reoperation.
Total Parathyroidectomy and
Autotransplantation (TPTX+AT)
The advantage of total PTX with forearm autograftisthattherecurrentparathyroidtissue
can be removed from the forearm with less
morbidity and can be performed under local
anesthesia. Besides, the function of grafted
parathyroid tissue can be detected by comparing the PTH levels at grafted and nongrafted
arms, and the parathyroid function can be
easily controlled by changing the amount of
parathyroid tissue used for the autograft [48].
Therefore, total PTx with a forearm autograft is
considered a preferable operative procedure in
sHPT patients who continue with hemodialysis
for a long time [48, 65]. Since the graft function
does not build up immediately, a period of
postoperative hypocalcemia usually occurred
after TPTX+AT. Appropriate graft function is
generally delayed several days to 3 months postoperatively. Normocalcemic patient just after
operation should be considered as having an
incomplete total PTX with supernumerary
glands in the neck or mediastinum [66]. Some
preferred grafting the parathyroid chips in the
four quadrants of a subcutaneous pocket to
avoid the disadvantage of muscle damage
if graft-dependent HPT occurs and graft
debulking is needed. It remains a problem to
differentiate a supernumerary gland from a
graft-dependent HPT or a combination of
both for patients undergoing TPTX+AT. A US
or mibi-scan of the graft site may visualize the
hyperfunctioning graft especially if there are
palpable subcutaneous nodules at the graft
site. To avoid persistent HPT, detecting and
removing all parathyroid glands at initial
operation is essential but may be difficult
to accomplish for supernumerary or ectopically located parathyroid glands. Routine
315
MANAGEMENT OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM
exploration and excision of the fat tissue surrounding the glands, removal of as much bilateral thymic tongue, and opening bilateral carotid sheaths to detect any glands around the
carotid artery, trachea, and esophagus are
recommended [65].
Surgical Intervention for tHPT
The surgical procedure for tHPT remains controversial. Some surgeons prefer bilateral neck
exploration with subtotal or total parathyroidectomy and autotransplantation based on the
belief that tHPT is usually due to multiple
hyperplastic parathyroid glands and patients
who have initial limited parathyroidectomy
have a higher risk of persistent or recurrent
tHPT [67, 68]. However, some investigators
have reported that 2.6–32% of tHPT may have
disease limited to single or double adenomas,
and propose resection of only the enlarged
glands after a bilateral neck exploration [69,
70]. Meanwhile, recent advances in radioguided
parathyroidectomy, advanced imaging, and
intraoperative PTH testing have facilitated a
focused surgical approach as in the management of patients with primary HPT. PTX by
unilateral approach under local anesthesia may
be of value when preoperative localization studies show a single gland enlargement [70, 71].
Applications of the
Intraoperative PTH Assay
Intraoperative measurement of PTH (IOPTH)
using a quick assay 15–30 min after removing
all parathyroid glands is performed to assess the
completeness of parathyroid surgery [72]. The
use of IOPTH has been controversial in the
application of PTX for renal HPT. The major
cause could exist in the variable PTH degradation kinetics with renal disease. There were studies that revealed no correlation between
IOPTH and the PTH obtained on postoperative
Day 1 [73]. However, others showed an average
of 85% decline from the baseline for those with
complete TPTx [74].
Due to high risk of recurrent laryngeal nerve
injury in reoperation procedures and for the more
accurate localization, jugular venous sampling for
PTH determination is advised to regionalize the
hypersecreting parathyroid tissue to one side of
neck during reexploring operations [75].
Other Invasive Treatment
Intraparathyroid Injection of Alcohol
or Vitamin D
Ultrasound-guided percutaneous ethanol or
active vitamin D analog injection into parathyroid glands has been performed [76] in
recent few years in few institutions. Repeated
active vitamin D injections into parathyroid
glands were reported to be effective in suppressing PTH secretion. Percutaneous injection of ethanol or active vitamin D analogs
could also reduce the size of enlarged parathyroid glands. The induction of apoptosis of
hyperplastic parathyroid cells and the upregulation of VDR on parathyroid cells by
exposure to extremely high vitamin D concentrations have been shown to be the
mechanisms underlying the reduced volume
of parathyroid glands [77].
However, advanced sHPT is often associated
with multiple parathyroid hyperplasia and is not
easily controlled by alcohol injection. Besides,
palsy of the recurrent laryngeal nerve is not a
negligible complication of this procedure. As
alcohol injection gives rise to adhesions of
fibrous tissue, the identification of parathyroid
tissue and the recurrent laryngeal nerve would be
difficult in subsequent exploration [78]. Alcohol
injection could be considered only for selected
patients in whom only one gland is substantially
enlarged, and those with high surgical risk or
severe deformity of the cervical vertebrae limiting an extensive neck exploration [79].
Complications of
Parathyroidectomy
The mortality after PTX for sHPT is from 0.15 to
3.1%. Short-term postoperative mortality rate
after PTX is about 3.1%, and long-term-related
risks of death among patients after PTX is estimated to be 10–15% [80]. Much mortality was
related to chronic heart failure [79, 80]. The
injury of recurrent laryngeal nerve was less
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ENDOCRINE SURGERY
than 2%, and wound bleeding was less than
0.3% [63]. After PTX, there are dramatic reductions in PTH, calcium, and phosphate levels in
more than 95% of patients [81, 82]. There are
some important conditions that could be
encountered:
Transient Hypocalcemia
Hypocalcemia occurs in 20–85% uremic
patients with sHPT after PTX. Numbness,
paresethesia, and tetany cramp could be
the symptoms related. After PTX, the
serum calcium will drop rapidly, as autografted parathyroid tissue does not function
well immediately. Usually patients have
severe hungry bone syndrome, because calcium and phosphorus would move from the
blood for bone formation [83].
In the K/DOQI guideline the method of calcium supplementation was described in detail.
Calcium-replacement therapy is advised in the
condition of transient hypocalcemia. Vitamin-D
as well as intravenous and oral calcium replacement should be administered in severe hypocalcemia patients.
Permanent Hypocalcemia
(hypoparathyroidism)
The prevalence of permanent hypoparathyroidism is from 4 to 12%. Nonfunctioning of autograft parathyroid tissue is the major cause of
permanent hypoparathyroidism. We could
recognize the functioning by comparing serum
PTH levels from both antecubital veins. A PTH
gradient over 1.5 times between the grafted and
the nongrafted arm indicates a functioning graft
[83]. Re-transplantation with cryopreserved
parathyroid tissue is limited in success rate.
Patients with permanent hypocalcemia should
be provided with vitamin D and calcium supplement for life.
Persistent and Recurrence
Hyperparathyroidism
The incidence of persistent or recurrent hyperparathyroidism is from 2 to 12% [84, 85, 86].
Most are due to the incomplete PTX in the
initial operation. There are many possible
causes considered, including the origins from
autograft (graft dependent HPT), supernumerary gland in the neck or mediastinum, metastasis of parathyroid tissue in the lung, and cell
implantation due to ruptured grand surrounding the thyroid gland (parathyromatosis) [78].
Before a second operation, recognition of the
origin is important. At first, we should determine whether the recurrence is graft dependent
or nondependent, for which Casanova’s procedure is a useful test [87]. When the PTH level
does not drop significantly by blockade of the
blood stream in the grafted arm, we can assume
that the origin of PTH hypersecretion is not
from the autografted tissue but more likely
from the residual parathyroid tissue in the
neck or mediastinum. The recurrence after
TPTX+AT is mostly graft dependent. Partial
resection of the graft is advised after ultrasound
or mibi-scan of the graft. On the other hand, if
the recurrence is notgraft dependent, residual
parathyroid tissue should be localized or regionalized before reexploration of neck or mediastionotomy. US and mibi-scan can be employed
initially. If the two imagings fail, CT and MR
imaging should be considered. Occasionally, a
selective angiography or selective venous sampling for PTH is needed in difficult cases.
Clinical Course after
Successful Parathyroidectomy
After PTX, symptoms such as bone and joint
pain, irritability, sleeplessness, and pruritus
decrease overnight in our experience and also
others [31, 65]. The improvement of muscle
weakness depends on the degree of preoperative
muscle wasting.
Bone Disease (Osteoporosis)
Rapid decrease in PTH after PTX would suppress bone resorption and cause a transient
marked increase in bone formation, and an
increase in normal lamellar osteoid seams [88].
The bone mass density of the lumbar spine can
be significantly increased with timely postoperative supplementation with vitamin D and
calcium [89]. The mineral content in trabecular
bone measured by X-ray absorptiometry
increases about 10% after PTX, but in cortical
bone the increase is only 2–3% [90]. Biopsy
317
MANAGEMENT OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM
studies have shown that bone resorption is
immediately suppressed and bone formation is
accelerated after PTX [91].
Anemia
As increased PTH levels may have some direct
effects on erythropoiesis, red cell survival, and
induce bone marrow fibrosis. Zingraff first
reported that parathyroidectomy improved the
anemic status of CRF patients by surgical suppression of PTH secretion. Medical suppression
of PTH oversecretion by intravenous calcitriol
supplement has similar effects on the anemia
observed in dialysis patients. It is therefore
early control of PTH secretion is crucial for
preventing worsening of anemic status [92, 93].
Cardiovascular Condition
The benefit for hypertension control after surgery is controversial. PTX has been found to
lower blood pressure in a significant proportion
of sHPT patients, but there was no pressure
change observed in the study of Ifudo et al.
[94]. Successful PTX could improve nonvisceral
calcification in 50–60%, but the change of vascular calcification is definitive [95]. Bleyer and
his colleagues observed decrease in vascular
calcification [96] but, on the contrary, no benefit or even worsening was reported by de
Francisco etal. [97]. PTX rarely affects vascular
calcification but usually diminishes nonvascular calcium deposits [96]. It is therefore important that PTX should be performed at an early
stage before the calcification has become progressive [48, 98]. PTX in uremic patients with
sHPT has led to a significant improvement of
left ventricular ejection fraction and function
[98].
Summary
Poor control of renal HPT would bring serious
outcomes from the skin itching to cardiovascular impairment. Parathyroidectomy should be
considered as early as possible if the sHPT progresses despite medical treatment. After successful parathyroidectomy, sHPT-related symptoms usually improve. It is believed that early
intervention should be performed if progressive
hyperparathyroidism is suspected after a successful kidney transplantation to avoid further
renal osteodystrophy, extra-osseous calcification, and failure in renal graft function.
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