Nephrol Dial Transplant (2003) 18: III23-III26
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Role of parathyroid intervention in the management of secondary hyperparathyroidism
Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe, Japan
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Abstract |
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Measurement of the size of the parathyroid glands is mandatory for the selection of the optimal therapy for secondary hyperparathyroidism. Surgical parathyroidectomy or parathyroid intervention is indicated for patients with nodular hyperplasia as this form is seldom responsive to medical therapy. Selection of the intervention should be determined by the number, size and location of the parathyroid glands with nodular hyperplasia, including ectopic glands.
Keywords: hyperparathyroidism; parathyroid hyperplasia; parathyroid intervention; parathyroidectomy; percutaneous ethanol injection therapy; ultrasonography
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Introduction |
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Control of secondary hyperparathyroidism is one of the main targets in the management of uraemic bone disease [1]. Although calcitriol pulse therapy [2] has been revolutionary in the management of this condition, we still have difficulty choosing the most suitable therapy for this abnormality, and patients whose condition cannot be controlled by calcitriol pulse therapy are a challenge.
Options recently added to the management strategy for secondary hyperparathyroidism include vitamin D sterols [3,4], calcimimetics [5], phosphate binders [6] and several methods of surgical intervention (Figure 1
). Further clinical and experimental data on parathyroid hyperplasia have added to therapeutic decision making [7], and we review the optimal combination of therapeutic modalities.
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Pathogenesis and assessment of parathyroid hyperplasia |
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The serum concentration of intact parathyroid hormone (i-PTH) is the main method used to assess the severity of hyperparathyroidism, together with serum markers for bone turnover such as serum alkaline phosphatase activity [8]. In addition, it has been suggested recently that evaluation of parathyroid hyperplasia is very useful for the establishment of management strategy [9].
The two types of parathyroid hyperplasia observed in uraemic patients are diffuse and nodular [10], with the latter developing from the former. Cells with a marked reduction of calcitriol receptor [11] in diffuse hyperplasia proliferate and form nodules that progress to nodular hyperplasia. Parathyroid cells in nodular hyperplasia are usually resistant to medical therapy, so it is critical to distinguish diffuse from nodular hyperplasia on the basis of size.
Our clinical observations show that patients with at least one parathyroid gland larger than 0.5 cm3, or 1.0 cm in diameter, usually do not respond to calcitriol pulse therapy in the long term [12], and others have reported that transplanted parathyroid fragments derived from glands heavier than 0.5 g often relapse [13]. This critical size has a significant pathological basis. A recent study of resected parathyroid glands has shown that >90% of parathyroid glands heavier than 0.5 g had nodular hyperplasia [14]. In future, this critical size may be reduced by vitamin D sterols and/or calcimimetics.
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Management of patients without detectable parathyroid hyperplasia or with suspected diffuse hyperplasia |
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The selection of therapeutic modalities depends on the pattern of parathyroid hyperplasia.
The initial treatment of patients with suspected diffuse hyperplasia (patients 1–3; Figure 2) is physiological doses of active vitamin D sterols, followed by intravenous vitamin D pulse therapy. Suppression of PTH secretion is usually prompt, and is maintained in the long term (Figure 2). In these patients, the aim is to prevent progression from diffuse to nodular hyperplasia. As high phosphate concentration per se stimulates PTH secretion and synthesis, control of phosphate, as well as the use of active vitamin D sterols, can achieve this. Such direct effects of phosphate are more evident in parathyroid tissue with diffuse hyperplasia than in nodular hyperplasia [15]. It has also been suggested that phosphate loading leads to parathyroid cell proliferation and a decrease in calcium-sensing receptors. This can be reversed by early phosphate restriction, which is more effective in the early phase of parathyroid hyperplasia than in more advanced stages [16].
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) circles, diffuse hyperplasia; filled (•) circles, nodular hyperplasia. Patient 1, no enlarged glands detectable; patient 2, single, small gland suggestive of diffuse hyperplasia; patient 3, multiple, small glands suggestive of diffuse hyperplasia; patient 4, one small gland, suggestive of nodular hyperplasia; patient 5, one ectopic gland with nodular hyperplasia; patient 6, single, large gland suggestive of nodular hyperplasia; patient 7, two large glands suggestive of nodular hyperplasia; patient 8, four large glands suggestive of nodular hyperplasia; patient 9, one large gland suggestive of nodular hyperplasia and one ectopic gland with nodular hyperplasia.If patients do not respond significantly to calcitriol pulse therapy within 3 months, there are two possibilities that should be eliminated. First, the development of nodular hyperplasia in relatively small glands (e.g. patient 4; Figure 2
). Data showed that 50% of the glands weighing between 0.25 and 0.5 g had developed nodular hyperplasia [14], and blood supply within the glands detected by colour Doppler ultrasonography also indicated the presence of nodular hyperplasia. Secondly, there may be one or more additional glands with nodular hyperplasia that have not been found by ultrasonography (e.g. patient 5; Figure 2) [17,18], and such glands can usually be located using scintigraphy and/or CT/MRI imaging techniques [19].
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Management of patients with suspected nodular hyperplasia |
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Calcitriol pulse therapy is seldom effective in patients with at least one gland with nodular hyperplasia (e.g. patients 6–8; Figure 2
), and surgical parathyroidectomy or parathyroid intervention is indicated [20]. There are three surgical approaches: (i) total parathyroidectomy with or without autotransplantation [21]; (ii) subtotal parathyroidectomy; and (iii) minimally invasive surgery [22]. Parathyroid interventions include ethanol, calcitriol and maxacalcitol [23–26]. The first difference between parathyroidectomy and parathyroid intervention is the selection of target glands. Total parathyroidectomy aims to excise all glands and to transplant fragments from the smallest gland. Because nodular hyperplasia is resistant to medical therapy, these are the glands targeted for parathyroid intervention, so that the other glands can be controlled by medical therapy [20]. Another difference is the fate of hyperplastic tissue. Parathyroidectomy physically removes the affected tissue, whereas intervention may lead to necrosis or apoptosis of parathyroid cells.
Selection of the optimal method for parathyroid intervention depends on the number and location of enlarged glands, as well as the presence of ectopic glands. As stated in the guidelines for selective percutaneous ethanol injection therapy (PEIT), if three or more glands are enlarged to the dimensions specified, PEIT will probably be ineffective in the long term (Fukagawa et al., this issue) due to the total volume of ethanol needed to destroy the glands and the high proliferative potency of the cells. Location of the glands is another important selection factor as parathyroid intervention may not be possible if the target gland is beyond the reach of ultrasonographic guidance [27]. Such cases should be treated by parathyroidectomy. However, patients with only a fair general status may not be an indication for surgery.
In contrast, in patients with poor compliance, this can lead to hyperplasia of the residual parathyroid glands in the long term even after successful parathyroid intervention. The availability of kidney transplants is limited in Japan, meaning that patients have renal replacement therapy for long periods, even after parathyroid intervention or surgery. When there is a high risk of recurrent hyperparathyroidism, total parathyroidectomy with autotransplantation is the most successful method of treatment.
Treatment for patients with three or more enlarged glands suggestive of nodular hyperplasia (e.g. patient 8; Figure 2) is parathyroidectomy, but patients with only one or two enlarged glands (e.g. patients 6 and 7; Figure 2) need not have urgent surgical intervention. In such cases, the question is whether to operate immediately or wait until the hyperplasia progresses to a more severe stage. If such patients are treated with intravenous or oral vitamin D pulse therapy for 
12 months and it is unsuccessful, there is a higher risk of ectopic calcification [28]. New vitamin D analogues [4,5] or calcimimetics [6], or a combination of these, can be temporarily effective, but their long-term success remains to be determined. At present, parathyroid intervention is the best therapy for such patients.
If hyperparathyroidism persists despite successful ablation of nodular hyperplasia by intervention, other nodular hyperplastic glands that have not been detected by ultrasonography should be sought (e.g. patient 9; Figure 2). If ectopic glands are found before the procedure, parathyroidectomy is the first choice of therapy.
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Conclusion |
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TopAbstractIntroductionPathogenesis and assessment of...Management of patients without...Management of patients with...ConclusionReferences |
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Routine evaluation of parathyroid size assists in the selection of therapy for secondary hyperparathyroidism in chronic dialysis patients. Nodular hyperplasia is seldom responsive to intravenous vitamin D pulse therapy, so early parathyroid intervention should be instituted.
The indication for parathyroid intervention can be determined by the number of parathyroid glands with nodular hyperplasia, the location of the glands, the existence of ectopic glands, the prognosis, compliance and general status of the patient, as well as the availability of an experienced surgeon.
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Notes |
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Correspondence and offprint requests to: Masafumi Fukagawa, MD, PhD, Division of Nephrology and Dialysis Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: fukagawa{at}med.kobe-u.ac.jp
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