Nephrol Dial Transplant (1996) 11 [Suppl 3]: 125-129
Nephrology
Dialysis
Transplantation
Ultrasonographic intervention of parathyroid hyperplasia in chronic
dialysis patients: a theoretical approach
M. Fukagawa1, M. Kitaoka2 and K. Kurokawa1
'First Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo 113,2Showa General Hospital,
Kodaira, Tokyo 187, Japan
Abstract. Calcitriol pulse therapy has markedly
changed the management of secondary hyperparathyroidism in chronic dialysis patients. However, there
are still many patients even resistant to this therapy.
Our observation of parathyroid size by ultrasonography revealed that these patients usually have
enlarged parathyroid glands larger than 0.5 cm3. Such
large parathyroid glands are composed of nodular
hyperplasia with monoclonal cell proliferation, whose
calcitriol receptor density is lower than that of diffuse
hyperplasia, thus more resistant to calcitriol. Based on
such a pathophysiological model, we have shown that
destruction of the largest parathyroid gland was sufficient to restore the responsiveness to calcitriol therapy
in these refractory patients. By using colour Doppler
ultrasonography, we could also optimize the site and
volume of ethanol injection and could detect the recurrence of parathyroid cell growth easily, with lower risk
of complications. This selective route of drug delivery
to parathyroid glands can be also used for direct
injections of calcitriol solution as we have reported.
Thus, evaluation of parathyroid size by sensitive ultrasonography is an essential marker for the management
of parathyroid hyperfunction in chronic dialysis
patients. It is also suggested that ultrasonographic
intervention of parathyroid hyperplasia may not only
be a useful and safe adjunct to calcitriol pulse therapy,
but may also serve as a new therapeutic modality for
parathyroid diseases in future.
patients [1,2]. In addition to the development of intact
parathyroid hormone (PTH) assay and other markers
for bone metabolism, recent advancement has made
ultrasonographic technology sensitive and compact
enough for practical use for the assessment of parathyroid hyperplasia in these patients [3].
In this brief review, we first summarize the recent
progress in the pathogenesis of parathyroid hyperfunction with an emphasis on parathyroid hyperplasia [4].
Then, based on such observations, we introduce interventional ultrasonography of parathyroid glands as a
new tool for the better management of parathyroid
hyperfunction in chronic dialysis patients.
Parathyroid size is a critical marker for the
prognosis of vitamin D therapy
Marked hyperplasia of parathyroid glands is a unique
feature of parathyroid hyperfunction in chronic dialysis
patients [5]. The degree of hyperplasia is different in
each patient and it even varies among the four glands
in the same patient.
It has been demonstrated in chronic dialysis patients
who have undergone parathyroidectomy that larger
glands are seen in patients more refractory to medical
therapy and that they have greater proliferative potential than smaller glands [6,7]. We have observed
changes of parathyroid size during and after calcitriol
pulse therapy and found that the size of the largest
is a critical marker for the responsiveness to
gland
Key words: parathyroid hyperplasia; ultrasonography;
vitamin D therapy in chronic dialysis patients [8].
ethanol injection; calcitriol
Thus, it is always difficult to control parathyroid
hyperfunction in dialysis patients with at least one
enlarged parathyroid gland greater than 0.5-1 cm maximum diameter or about 0.5 cm3 in volume. In such
Introduction
patients, enlarged glands never regress to normal size,
and parathyroid hyperfunction always relapses even if
Parathyroid hyperfunction is a major target of the it initially responds to calcitriol pulse therapy. This
management of bone diseases in chronic dialysis 'cut-off point' in gland size is in good agreement with
surgical data in dialysis patients who have undergone
Correspondence and offprint requests to: K. Kurokawa, First subtotal parathyroidectomy in whom autoimplantation
Department of Internal Medicine, University of Tokyo School of
of tissue fragments from glands heavier than 0.5 g
Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
© 1996 European Dialysis and Transplant Association-European Renal Association
M. Fukagawa et al.
126
resulted in frequent relapse of parathyroid hyperfunction (Y. Tominaga, personal communication).
In sharp contrast to such patients, patients with
smaller glands usually respond to calcitriol pulse
therapy independent of the degree of PTH hypersecretion as assessed by plasma PTH, and can be controlled
with active vitamin D sterols in the long term. Thus,
assessment of parathyroid size is an important element
for the decision-making of management strategy for
parathyroid hyperfunction in chronic dialysis patients.
Role of calcitriol in the pathogenesis of parathyroid
hyperplasia
uremtc toxin
EFFECT*
Fig. 1. Vicious cycle of calcitriol receptor decrease in uraemia. In
What is the difference between large and small para- uraemia, calcitriol receptor number in parathyroid cell decreases,
which may be associated with disturbance of up-regulation of
thyroid glands in chronic dialysis patients? The fact calcitriol
receptor by calcitriol itself, leading to a further decrease in
that data on the regulation of parathyroid cell prolif- calcitriol receptor number. X denotes a step possibly disturbed
eration are scarce due to the lack of established para- in uraemia.
thyroid cell lines makes this question very difficult to
answer satisfactorily [5].
It has been shown that larger glands are usually with the surrounding tissue [11]. Thus, cells with a
composed of nodular hyperplasia which is considered more severe depletion of calcitriol receptors then prolifof a more advanced type than diffuse hyperplasia seen erate more vigorously to eventually form nodular
in smaller glands. Cells in nodular hyperplasia have hyperplasia. Although monoclonal proliferation had
more proliferative potential [6,7] and more abnormal been demonstrated only in highly advanced nodular
regulation of PTH secretion than those in diffuse hyperplasia [18], a recent report analysing individual
hyperplasia [9]. We have recently shown in dialysis nodules by Tominaga and associates demonstrated that
patients that calcitriol receptor number is reduced all nodules were monoclonal and that each nodule
more in nodular hyperplasia [10] than in diffuse hyper- may be of separate monoclonal origin [19]. In other
plasia [11]. Since calcitriol has been shown to suppress words, whole nodular hyperplastic glands are comparathyroid cell proliferation [12,13], such difference posed of several monoclonal nodules, one of which
in calcitriol receptor density may play a role in the may grow much more vigorously than others and may
development of parathyroid hyperplasia in chronic finally occupy the majority of the enlarged gland. Thus,
monoclonal proliferation may not be the result [20],
dialysis patients.
but
rather be the cause of nodular hyperplasia. The
Furthermore, calcitriol receptor density was also
biochemical
and molecular mechanisms responsible for
inversely correlated with the weight of enlarged glands
the
differences
of proliferative potency among these
[11]. Thus, the difference in the response to vitamin D
to be elucidated.
nodules
remain
therapy which seems dependent upon gland size may
a
small
number
of patients, gene rearrangement
In
be due, at least in part, to the difference of calcitriol
in
some
cells probably within nodular
may
occur
receptor number in nodular (i.e. larger) and diffuse
hyperplasia, leading to autonomous proliferation [21].
(i.e. smaller) hyperplastic parathyroid glands.
Such gene rearrangements in parathyroid glands in
dialysis patients have not been analysed in sufficient
depth to compare with those of primary hyperparathyProgression of parathyroid hyperplasia
roidism, such as PRADl/cyclin Dl oncogene and
In chronic renal failure, even from its early phase, multiple endocrine neoplasia type I (MEN-I) [22].
parathyroid cell growth is stimulated by several factors Analysis of gene rearrangements may reveal similar
such as decreased plasma concentrations of ionized abnormalities in dialysis patients.
calcium and calcitriol. In addition, recent data suggest
that phosphate retention may directly and indirectly
stimulate parathyroid cell growth [14]. Along with Destruction of parathyroid tissue by ethanol under
these stimuli, calcitriol receptor density in parathyroid ultrasonography
cells decreases, and calcitriol receptor up-regulation by
calcitriol may be impaired at several steps, leading to Obviously, prevention of parathyroid hyperplasia is
a vicious cycle in calcitriol action in parathyroid cells the most desirable management, but what is the best
[15,16] (Figure 1). Thus, parathyroid cells become treatment for patients with established marked pararesistant to calcitriol [17] and continue to grow, leading thyroid hyperplasia? Subtotal parathyroidectomy with
autoimplantation of tissue fragments from the least
to diffuse hyperplasia.
Small nodules formed within diffuse hyperplasia tend proliferative gland may be the best treatment currently
to have a lower density of calcitriol receptors compared available [1,2]. In addition, direct ethanol injection
127
Ultrasonography for parathyroid hyperplasia
into parathyroid glands has been gaining popularity
as an alternative to surgery.
Percutaneous ethanol injection into parathyroid
glands under ultrasonography was first introduced as
a practical procedure by an Italian group [23,24] and
there have been several case reports its success. We
further improved this technique based on recent clinical
and experimental observations and on the advancement of technology [25]. The principles of our
improvement are demonstrated in our protocol shown
in Figure 2.
The first principle is to destroy the smallest number
of parathyroid glands necessary for the management
of secondary hyperparathyroidism. This is important
to avoid unnecessary parathyroid tissue destruction
that may lead to adynamic bone disease due to relative
hypoparathyroidism. Since larger glands are more resistant to calcitriol therapy than smaller glands, presumably due to more severe decrease of calcitriol receptors
[11], we select the largest gland as the initial target for
ethanol injection. Only when the destruction of the
largest gland is not sufficient to control PTH hypersecretion do we destroy the next largest gland as shown
in the flow chart (Figure 2).
The second principle is to optimize the site of ethanol
injection. For this purpose, we have opted to use colour
Doppler ultrasonography which can detect the tissue
with ample blood supply due to marked proliferation.
As shown in Figure 3, tissue destruction can be confirmed by the disappearance of blood flow.
Furthermore, recurrence of parathyroid cell proliferation can be identified by the same technique.
The third principle is to avoid complications by
ethanol leakage from injected glands, such as recurrent
nerve palsy and fibrosis of surrounding tissue. Thus,
we developed a new injection needle which has holes
( Secondary Hyperparathyroidism ^
^Resistant to Calcitriol Pulse Therapy J
(Detection of Enlarged Glands)
Ettinnol I n j e c t i o n s
into the L n r s « c t Gland
on its side [25]. In addition, the volume of ethanol to
be injected should be about 70% of the calculated
gland volume. The volume should be further decreased
for glands larger than 1 cm in diameter, and the site
for additional injections should be optimized by the
help of Doppler ultrasonography.
The last principle is to continue proper vitamin D
therapy and to watch for relapse after ethanol injection.
Since it is assumed that the gland most resistant to
calcitriol therapy has been destroyed, the control of
parathyroid hyperfunction should be much easier either
with calcitriol pulse therapy or with conventional oral
active vitamin D therapy. However, excess suppression
of parathyroid function should be avoided to prevent
adynamic bone disease [26,27]. Thus, as suggested by
some groups [28,29], serum intact PTH should be
maintained between 150 and 200pg/ml and serum
alkaline phosphatase activity within the normal range.
Interventional ultrasonography as a new tool for
the modification of parathyroid hyperfunction
With the progress of ultrasonography, direct injection
can be a practical route of drug delivery to parathyroid
glands. As we have preliminarily tested, direct injection
of calcitriol solution into enlarged parathyroid glands
suppressed PTH hypersecretion and restored the
responsiveness to calcitriol in chronic dialysis patients
[30]. These results may have been derived not only
from the very high local concentration of calcitriol,
but also from the up-regulation of calcitriol receptor.
This direct route of administration of test agents may
also be suitable for selective gene therapy of parathyroid glands in the future [31].
Genetic analysis of samples obtained by aspiration
biopsy may be another possible example of practical
interventional ultrasonography of parathyroid gland.
Since some types of genetic abnormality can be
detected by polymerase chain reaction, aspiration
biopsy can be used for the source of DNA analysis.
Such information will be very important for advancement of our understanding of the pathophysiology and
biology of parathyroid hyperplasia and development
of further therapy.
£tti(]i»el I n j e c t i o n s
into the Qaloipasd Gland
(PTH<200pg7mP)
(j>TH>200pg/mf)
Check by
Color Oopple
Conventional
Oral Vitamin O
Calcitriol
Pulse Therapy
Etanael Injection into
theftant Loresst Gland
Fig. 2. Protocol for ethanol injection into parathyroid glands based
on our theory. Ethanol is injected into the largest gland first. Only
when this is not sufficient to control PTH hypersecretion is the
second largest gland destroyed by ethanol. Colour Doppler ultrasonography is used to confirm tissue destruction and recurrence.
Prevention and management of parathyroid
hyperplasia from early phase of chronic renal
failure
Prevention of parathyroid hyperplasia should be one
of the most important goals of the management strategy of renal osteodystrophy. This should be aimed at
from the early phase of chronic renal failure prior to
dialysis, when parathyroid hyperfunction is already
seen in many patients. Mild dietary phosphorus restriction is the first step, with, the subsequent use of
phosphate binders as necessary. Early use of active
vitamin D in pre-dialysis patients has been reviewed
recently and recommended for the prevention of secondary hyperparathyroidism without adverse effects
M . Fukagawa et al.
-.m-
6/
2/0
7/5
55/2
7/ 84.
. OCa
Fig. 3. Use of Doppler ultrasonography for ethanol injection. Blood supply to proliferate tissue (red, left panel) disappeared at 5min
after successful ethanol injection (right panel). Injected tissue became brighter (high echogenicity) as shown in the right panel suggesting
the necrosis of the injected gland.
Parathyroid Hyparfunction in Urainic Patents
•[Conventional Calcitrlol Therapy!
PTrl:(.)or<*)
PTH:(+)
> 0.5 cm'
(-) or < 0.5 cm
on residual renal function [32]. Nevertheless, a new
problem of adynamic bone disease and hypoparathyroidism has emerged in dialysis patients [26,27].
Although the contribution of pre-dialysis vitamin D
therapy to such a new disease entity has not been fully
elucidated, precise care with proper monitoring should
be given to each patient during the therapy. Thus,
markers of bone metabolism which reflect bone histology more precisely need to be developed.
ttrwrapyj
• »piitsaThfapy|.<-
Concluding remarks
PTH:<-)or(*|
Gland Sin: (-) or (±)
PTH:(*)
Gland S4z»: (•)
<•)
(-)or(±)
T&oH—'
| Convantional Tharapyj
I
! land I|
of the Largest Gland
or Parathyroidactom
wny J
ObMrvation
(•>-<(>
Our management strategy for parathyroid hyperfunction in chronic dialysis patients is summarized in
Figure 4. As can be seen, selection of each therapeutic
modality should be based on the degree of parathyroid
hyperplasia. Ethanol injection into the largest gland
can be an option for patients with severe hyperparathyroidism and responsiveness to active vitamin D therapy
can be restored by this therapy. Further manipulation
of parathyroid function by ultrasonography may
become practical in the near future, improving patient
management.
Fig. 4. Management protocol of parathyroid hyperfunction based Acknowledgements. This work was supported in part by the Program
on the degree of hyperplasia in chronic dialysis patients (modified Project Grant from the Ministry of Health and Welfare of Japan.
from [4]). Prognosis of medical therapy can be predicted by the size
of the largest parathyroid gland. Ethanol injection into the largest
gland may restore responsiveness to • active vitamin D therapy.
Response of PTH: (+) suppressed to less than 200pg/ml; (±) References
suppressed, but not to less than 200 pg/ml; (—) not suppressed.
Response of gland size: (+) regressed to normal size (not detectable
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