Pathogenesis of parathyroid hyperplasia in renal failure

In chronic kidney disease, secondary hyperparathyroidism (HPTH) is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). Elevated PTH levels cause renal osteodistrophy and cardiovascular complications, with significantly increased morbidity and mortality in renal failure. The three main direct causes of renal HPTH are hypocalcemia, hyperphosphatemia and vitamin D deficiency. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells which respond to the stimulus of chronic hypocalcemia, not only by an increase in PTH release but also with a consequent parathyroid cell proliferation. The mechanisms responsible for this link, however, remain poorly understood. In this review, we analyze the current understanding concerning the new insights into the molecular mechanisms of parathyroid hyperplasia and PTH secretion in renal failure regulated by calcium, phosphate and vitamin D.     

Phenytoin-associated severe hypocalcemia with seizures in a patient with a TSC2-PKD1 contiguous gene syndrome

Abstract

We report the case of an inaugural episode of generalized seizures in a 40-year-old male with a history of chronic kidney disease associated with TSC2-PKD1 contiguous gene syndrome. This patient was under prophylactic treatment of phenytoin since 2 years because of a subarachnoid hemorrhage due to a ruptured cerebral aneurysm. Laboratory results revealed therapeutic range of phenytoin levels, but severe hypocalcemia associated with profound vitamin D deficiency that could not be explained by secondary hyperparathyroidism alone. The interaction of phenytoin on the P-450 cytochromes activity has been demonstrated to accelerate the rate of 25-hydroxivitamin D₃ and 1α,25-dihydroxivitamin D₃ catabolism into inactive metabolites, leading to hypocalcemia. Physicians should be aware of significant phenytoin interactions on vitamin D metabolism which may lead to symptomatic hypocalcemia in patients with chronic kidney disease.     

Parathyroid growth and suppression in renal failure

In advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid hyperplasia has to be accepted. Uremia is associated with parathyroid growth. In experimental studies, proliferation of the parathyroid cells is induced by uremia and further promoted by hypocalcemia, phosphorus retention, and vitamin D deficiency. On the other hand, parathyroid cell proliferation might be arrested by treatment with a low-phosphate diet, vitamin D analogs, or calcimimetics. When established, parathyroid hyperplasia is poorly reversible. There exists no convincing evidence of programmed parathyroid cell death or apoptosis in hyperplastic parathyroid tissue or of involution of parathyroid hyperplasia. However, even considerable parathyroid hyperplasia can be controlled when the functional demand for increased PTH levels is removed by normalization of kidney function. Today, secondary hyperparathyroidism can be controlled in patients with long-term uremia in whom considerable parathyroid hyperplasia is to be expected. PTH levels can be suppressed in most uremic patients and this suppression can be maintained by continuous treatment with phosphate binders, vitamin D analogs, or calcimimetics. Thus modern therapy permits controlled development of parathyroid growth. When nonsuppressible secondary hyperparathyroidism is present, nodular hyperplasia with suppressed expression of the calcium-sensing receptor (CaR) and vitamin D receptor (VDR) has been found in most cases. An altered expression of some autocrine/paracrine factors has been demonstrated in the nodules. The altered quality of the parathyroid mass, and not only the increased parathyroid mass per se, might be responsible for uncontrollable hyperparathyroidism in uremia and after kidney transplantation.     

Parathyroidectomy for tertiary hyperparathyroidism associated with X-linked dominant hypophosphatemic rickets

BACKGROUND: X-linked dominant hypophosphatemic rickets (XLHR) is a hereditary metabolic bone syndrome that is only beginning to be understood and is rarely associated with progression to irreversible tertiary hyperparathyroidism. We report our surgical experience with 6 patients with XLHR who underwent parathyroidectomy for associated autonomous parathyroid hyperfunction. HYPOTHESIS: Parathyroidectomy can successfully treat tertiary hyperparathyroidism in the setting of XLHR, although an understanding of expected operative findings and postoperative complications is essential. DESIGN: The study group comprised 6 patients with XLHR identified from our endocrine surgery database. Presentation, surgical procedure, parathyroid pathologic findings, and subsequent outcome are outlined. RESULTS: There were 4 women and 2 men. All were exposed to long-term vitamin D and phosphate supplementation therapy. All had persistently elevated preoperative levels of parathyroid hormone and serum calcium. The patients were treated as follows: 3 had total parathyroidectomy, 2 had 3 parathyroid glands identified and resected, and 1 had 2 abnormal parathyroid glands resected with 2 normal-appearing parathyroid glands left in situ. One patient subsequently required completion parathyroidectomy for recurrent disease. Pathologic examination results revealed hyperplasia of all resected parathyroid glands in 4 of 6 patients. One patient had a single adenoma with 3-gland hyperplasia, and 1 patient had a double adenoma. The principal complication of this procedure was profound symptomatic hypocalcemia requiring intravenous calcium infusion. Hungry bone syndrome was also observed in most subjects. Long-term, all patients achieved normocalcemia. CONCLUSION: Tertiary hyperparathyroidism is a rare but recognized complication of XLHR. Parathyroidectomy effectively treats this complication caused by autonomous parathyroid hyperfunction, but profound postoperative hypocalcemia necessitates careful management.     

Role of vitamin d receptor activators in cardio-renal syndromes

The involvement of vitamin D deficiency in cardiovascular morbidity and mortality is attracting great interest. In patients with chronic kidney disease this association is stronger because vitamin D levels decrease as a result of renal progressive impairment. In chronic kidney disease secondary hyperparathyroidism commonly occurs in response to persistent hypocalcemia and hyperphosphatemia; moreover, parathyroid gland volume increases, vascular calcification is accelerated, and structural and functional modifications of the left ventricle are observed. These alterations entail both cardiac and renal involvement, resulting in cardio-renal syndrome. Recent studies concluded that vitamin D administration seems to have cardioprotective and renoprotective effects and improve peripheral vascular disease, vascular calcification, cardiac outcome, and blood pressure control. In clinical practice, therefore, the use of this hormone may play an important role in cardio-renal syndrome prevention.     

关注甲状旁腺功能增强和正常血钙型原发性甲状旁腺功能亢进症的防治

随着血钙及甲状旁腺素（PTH）等各种实验室检查技术的发展,大量无症状或正常血钙型原发性甲状旁腺功能亢进症（primary hyperparathyroidism,PHPT）得以早期诊断。PHPT已成为影响人类健康的第三大常见内分泌系统疾病。目前部分PHPT,尤其是多数正常血钙型PHPT,并非原发,可能是长期钙摄入不足和...     

Renal osteodystrophy in chronic renal failure

Bone disease develops relatively early in the development of chronic renal failure. Much of what is known about the evaluation and management of renal osteodystrophy in chronic renal failure is based on knowledge obtained in the dialysis population. The classic bone lesion found in the dialysis population is osteitis fibrosa, the high turnover lesion of secondary hyperparathyroidism. Clearly, hypocalcemia, hyperphosphatemia, and calcitriol deficiency play major roles in the development and maintenance of the high turnover disease. Interestingly, in both the dialysis and nondialysis patients, the incidence of adynamic bone disease, a low turnover lesion, is increasing. It is postulated that the aggressive use of calcium-containing phosphate binders and the use of calcitriol and other vitamin D analogs to treat secondary hyperparathyroidism may contribute to this shift in bone lesions. Treatment in the nondialysis kidney disease patient remains aggressive correction of hypocalcemia and hyperphosphatemia. The use of calcitriol and other agents to maintain serum calcium and to suppress elevated parathyroid hormone remains well supported. However, the increase in extraskeletal calcifications and incidence of adynamic bone disease in these patients raises concern about current management techniques.     

Hyperparathyroidism associated with renal disease. Pathogenesis, natural history, and surgical treatment

Hyperparathyroidism associated with renal failure is due to chronic parathyroid stimulation by hypocalcemia, which, in turn, results from hyperphosphatemia and low circulating 1,25(OH)2D3. If prophylactic measures and medical treatment of hyperparathyroidism fail, parathyroidectomy should be performed to prevent the progression of bone disease. Resolution of renal hyperparathyroidism is often seen after kidney transplantation, but some hypercalcemic patients require prophylactic or therapeutic parathyroidectomy. Hypocalcemia is the most common complication after parathyroidectomy. Our long-term results with subtotal parathyroidectomy are satisfactory. Total parathyroidectomy plus parathyroid autograft should be used in selected cases.     

Vitamin D receptor ligand therapy in chronic kidney disease

Chronic kidney disease is a growing public health concern, and secondary hyperparathyroidism is one of the most serious associated comorbidities. In healthy individuals, precisely controlled feedback loops dynamically modulate parathyroid hormone (PTH) levels. As kidney function declines, phosphate retention, decreased 1a,25-dihydroxyvitamin D3, and a tendency to hypocalcemia leads to overstimulation of PTH production and parathyroid hyperplasia. Vitamin D receptor (VDR) ligands are essential tools for controlling parathyroid activity. This review highlights the current clinical and biochemical VDR ligand studies, focusing on the differences between selective and nonselective VDR ligands. It is apparent that VDR ligands have important roles in the management of secondary hyperparathyroidism. Selective VDR ligands, in particular, may offer additional benefits in the treatment of bone disease, and may potentially reduce adverse effects related to cardiovascular disease.     

Persistently elevated parathyroid hormone levels after parathyroid surgery

BACKGROUND: Persistent elevation of serum parathyroid hormone (PTH), despite normocalcemia, occurs in 8% to 40% of patients after parathyroidectomy. Explanations have included hypocalcemia owing to vitamin D deficiency or bone remineralization, and persistent hyperparathyroidism. METHODS: A retrospective chart review of 816 consecutive patients who underwent surgery for primary hyperparathyroidism was conducted. RESULTS: One hundred fourteen patients (15%) had persistently elevated PTH levels (PPTH). Patients with PPTH had higher preoperative PTH levels than those with normal PTH levels postoperatively. They also had lower postoperative Ca(++) and vitamin D levels. Multiple gland enlargement was identified in fewer patients with PPTH than in those with normal postoperative PTH levels. In patients with PPTH and a postoperative Ca(++) less than 9.6 mg/dL (group I), there was a greater decrease in IOPTH, a higher initial postoperative PTH level, and a lower postoperative vitamin D level than in PPTH patients whose postoperative Ca(++) was > or =9.6 mg/dL (group II). Postoperative Ca(++) and vitamin D levels were also lower in patients whose PPTH did not ultimately resolve. Three patients in group II had recurrent disease. CONCLUSIONS: Persistent elevation of postoperative serum PTH levels in normocalcemic patients is associated with mild hypocalcemia, probably owing to vitamin D deficiency. In some patients it may also be indicative of mild persistent hyperparathyroidism.     

Reoperative parathyroid surgery for persistent hyperparathyroidism

In a 2-year period 30 patients with persistent hyperparathyroidism following 59 prior unsuccessful procedures underwent reoperation. Preoperative arteriography was useful in planning the surgical approach in 56%, and retrospectively was correct in 63%. Selective venous catheterization gave localizing information in 83%, correctly predicting site or side in 60% of the total. Computerized axial tomography was helpful in identifying mediastinal glands before operation. Reoperation was successful in rendering the patient hypocalcemic or normocalcemic in 83%. Of the 11 patients (37%) who were rendered profoundly hypocalcemic, two were subsequently weaned from vitamin D and calcium support; seven have received either fresh or cryopreserved parathyroid autografts. Persistent hyperparathyroidism is a difficult surgical problem which we believe warrants aggressive localization attempts prior to operation. Autotransplantation with cryopreserved parathyroid tissue may be of value in the long-term management of the high incidence of postoperative hypocalcemia in this patient group.     

Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism.

BACKGROUND. This study investigates 410 persons (median age, 67 years) who underwent parathyroid operation for sporadic primary hyperparathyroidism 6 to 32 years (mean, 14.2 years) before 1991. METHODS. Patient records and operative specimens were scrutinized, the patients answered a questionnaire, and fasting serum samples were analyzed for calcium, albumin, creatinine, and intact parathyroid hormone (PTH) values. RESULTS. After primary parathyroid operations were performed with a conservative surgical approach, persistent and recurrent hypercalcemia were noticed in 3.7% and 1.7% of patients, respectively, whereas 4.7% of patients required vitamin D substitution or had essentially mild hypocalcemia. The PTH values were generally increased in patients with postoperative hyperparathyroidism, low in those with vitamin D substitution, and normal to elevated in the patients with hypocalcemia and in those with postoperative normocalcemia. The mean serum creatinine concentration was just below the upper reference range and correlated strongly with serum PTH value. No significant differences in serum PTH values were present between the normocalcemic patients and matched control patients after operation (n = 107), but the patients who underwent operation exhibited greater variation in the PTH concentration. CONCLUSIONS. The results substantiate the efficacy of parathyroid operation in sporadic primary hyperparathyroidism. Biochemical derangements compatible with secondary hyperparathyroidism may evolve during long-term follow-up and contribute to decreases in serum calcium values and increases in serum PTH values of these patients.     

Surgical management of secondary hyperparathyroidism

Most patients with renal failure maintained on chronic dialysis have elevated parathyroid hormone (PTH) levels and PTH-mediated bone disease (secondary hyperparathyroidism [sHPT]). Elevated PTH production in this setting represents a progressive, exaggerated physiologic response to hypocalcemia by the parathyroid glands, and generalized growth of the parathyroids is an adaptive response to chronic stimulation. Effective medical strategies to reduce PTH secretion and PTH-mediated bone turnover in sHPT (eg, controlling hyperphosphatemia, normalizing serum calcium, and administering vitamin D analogs) has decreased the need for parathyroidectomy in recent years. However, failure of medical therapy because of inadequate treatment, persistent hyperphosphatemia, or acquired parathyroid neoplasia still leads to recommendations for parathyroidectomy in select patients. Furthermore, increased awareness of potential long-term, irreversible cardiovascular effects of uncorrected hyperparathyroidism has led some to advocate parathyroidectomy earlier in the course of this disease. This monograph will review parathyroidectomy for secondary and tertiary hyperparathyroidism.     

Calcimimetics versus parathyroidectomy: What is preferable?

Secondary hyperparathyroidism (SHPT) is common among patients with end-stage renal disease (ESRD). SHPT is associated with high-turnover bone disease, interstitial and vascular calcifications, cardiovascular morbidity and mortality. The pharmacological management of SHPT has progressed in recent years. The introduction of targeted therapies, such as selective vitamin D receptors activators and calcium-sensing receptor modulators, offers an increased opportunity to adequately control elevated parathyroid hormone (PTH), especially in patients with chronic kidney disease under dialysis treatment. Calcimimetic medications such as cinacalcet negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation. However, there are no randomised, prospective data that demonstrate improved quality of life, improvement in anemia, reduction in phosphate binders, reduction in use of vitamin D analogs, or reduction in mortality. Literature supports cinacalcet therapy to improve patient outcomes, especially with regard to vascular calcifications and presumably the very lethal condition of calciphylaxis. However, cinacalcet is administered orally and has been associated with gastrointestinal intolerance along with hypocalcemia. In addition, poor adherence has been observed among dialysis patients self-administering oral cinacalcet. On the other hand, successful surgical parathyroidectomy (sPTX) can yield a dramatic reduction in PTH level and clinical symptoms. The advanced pharmacological treatments of SHPT often obviate parathyroidectomy; however, some researchers have reported that sPTX may be more cost-effective than cinacalcet in some patients with ESRD and suffering uncontrolled SHPT.     

Regulation of parathyroid function in chronic kidney disease (CKD)

In chronic kidney disease (CKD), several abnormalities in bone and mineral metabolism develop in the majority of patients. The parathyroid plays a very important role in regulating bone and mineral metabolism; thus, control of parathyroid function is one of the main targets of the management of CKD-mineral and bone disorder (CKD-MBD). In the development of secondary hyperparathyroidism, it has recently been suggested that fibroblast growth factor 23 (FGF23) plays a crucial role, both as a phosphaturic factor and as a suppressor of active vitamin D (1,25D) production in the kidney. FGF23 is originally secreted to prevent hyperphosphatemia in CKD, but this occurs at the expense of low 1,25D and hyperparathyroidism (“trade-off” hypothesis revisited). Furthermore, recent data suggest that FGF23 could be another useful marker for the prognosis of hyperparathyroidism, because a high serum level may reflect the cumulative dose of vitamin D analogues previously administered. We have also demonstrated that severe hyperparathyroidism was associated with the production and secretion of a new form of parathyroid hormone (PTH) molecule, which can be detected by third-generation assays for PTH, but not by the second-generation assays. For the regression of already established nodular hyperplasia, the more advanced type of parathyroid hyperplasia, it is certainly necessary, in the near future, to develop new agents that specifically induce apoptosis in parathyroid cells. Until such agents are developed, prevention and early recognition of nodular hyperplasia is mandatory for the effective and safe management of hyperparathyroidism in CKD.     

Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the calcimimetic agent cinacalcet

Calcimimetic agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium <10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the calcimimetic agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.     

Spontaneous and serial rupture of both Achilles tendons associated with secondary hyperparathyroidism in a patient receiving long-term hemodialysis

The spontaneous and serial rupture of the bilateral Achilles tendons without history of significant trauma is an uncommon complication in long-term hemodialysis (HD) patients. The majority of these patients have additional predisposing factors, such as previous use of fluoroquinolone antibiotics or corticosteroids. In general, this condition is associated with a coexisting systemic disease, including chronic kidney disease (CKD), secondary hyperparathyroidism, systemic lupus erythematosus (SLE), and diabetes mellitus (DM). Here, we report a 46-year-old man who had been undergoing regular HD for 11 years. He developed a spontaneous and consecutive rupture of both Achilles tendons. Based on previous reports of tendon ruptures in uremic patients and on the patient’s lack of corticosteroid or fluoroquinolone use, we believe that secondary hyperparathyroidism was the predisposing factor in this patient. The mechanism seems to be related to a high parathyroid hormone (PTH) level, which results in osteolytic bone resorption at the tendon insertion site. Treatment and prevention of such tendon ruptures include early surgical repair and control of secondary hyperparathyroidism, by use of vitamin D analogs, and total parathyroidectomy, with or without autotransplantation of a parathyroid gland.     

Association of oral calcitriol with improved survival in nondialyzed CKD

Parenteral vitamin D is associated with improved survival among long-term hemodialysis patients. Among nondialyzed patients with chronic kidney disease (CKD), oral activated vitamin D reduces parathyroid hormone levels, but the impact on clinical outcomes is unknown. We evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1418 nondialysis patients with CKD and hyperparathyroidism in the Veterans' Affairs Consumer Health Information and Performance Sets database. Incident calcitriol users and nonusers were selected on the basis of stages 3 to 4 CKD, hyperparathyroidism, and the absence of hypercalcemia before calcitriol use and then were matched by age and estimated kidney function. During a median follow-up of 1.9 yr, 408 (29%) patients died and 217 (16%) initiated long-term dialysis. After adjustment for demographics; comorbidities; estimated kidney function; medications; and baseline levels of parathyroid hormone, calcium, and phosphorous, oral calcitriol use was associated with a 26% lower risk for death (95% confidence interval 5 to 42% lower; P = 0.016) and a 20% lower risk for death or dialysis (95% confidence interval 1 to 35% lower; P = 0.038). The association of calcitriol with improved survival was not statistically different across baseline parathyroid hormone levels. Calcitriol use was associated with a greater risk for hypercalcemia. In conclusion, oral calcitriol use is associated with lower mortality in nondialysis patients with CKD.     

Primärer Hyperparathyreoidismus

Introduction

Normocalcemic hyperparathyrinemia, i.e. elevated parathyroid hormone (PTH) levels after parathyroidectomy in patients with primary hyperparathyroidism (pHPT) may occur in the course of postoperative recovery without the development of persistence or relapse.

Materials, methods and results

Intraoperative and long-term (7 year) postoperative PTH and calcium levels after curative parathyroidectomy are demonstrated on the basis of a case report of a 62-year-old female patient with severe pHPT and pronounced osseous and renal manifestations. The intraoperative PTH gradient displayed a decrease from 1072 pg/ml to 13 pg/ml (normal range 11–67 pg/ml) followed by an increase of up to 287pg/ml. The hyperparathyoid values decline to subnormal levels on administration of calcium and vitamin D and increase again after tapering these medications. The inverse calcium/PTH correlation in the course of the 7-year observation period suggests an intact feed-back mechanism. Preoperative PTH screening was performed in 316 consecutive normocalcemic thyroid patients to evaluate the rate of incidental hyperparathyroidism in patients with normal serum calcium levels. Of these patients 31 (9.8%) with normocalcemia (average 2.28 mmol/l, normal range 2.1–2.7 mmol/l) exhibited increased PTH levels averaging 84.2 pg/ml. A parathyroid adenoma was found intraoperatively as the cause for normocalcemic pHPT in only 1 of these 31 patients.

Discussion and conclusions

A review of the literature revealed that late postoperative elevated parathyroid hormone levels after successful pHPT surgery occur in 21.5%. Multiple causes are discussed, e.g. reactive hyperparathyroidism in cases of relative hypocalcemia, hungry bone syndrome, vitamin D deficiency, renal dysfunction and ethnic or lifestyle differences. In mild cases of postoperative hyperparathyrinemia observation of the patient may be sufficient. In cases of reactive hyperparathyroidism due to hypocalcemia, administration of calcium is indicated, in symptomatic patients, additional administration of vitamin D or calcitriol is necessary. Vitamin D deficiency per se needs adequate substitution. In cases of ongoing hyperparathyrinemia an interdisciplinary diagnostic and therapeutic approach is required.     

Vitamin D treatment in chronic kidney disease

Activated vitamin D continues to be the major treatment for suppressing parathyroid hormone (PTH) levels in dialysis patients who have secondary hyperparathyroidism. Active vitamin D compounds are distinguished by their ability to bind with high affinity to vitamin D receptors (VDRs) not only in the parathyroid glands, but in cells throughout the body. Because of recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population, there is new interest in understanding the systemic effects of VDR activation, particularly in the predialysis stages of chronic kidney disease (CKD), where high mortality rates from cardiovascular disease have recently been documented. Previous underutilization of calcitriol treatment to control PTH levels in stages 3 and 4 CKD was often due to concerns about its potential for accelerating the progression of CKD as a consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia. Vitamin D analogs with selective VDR activity (such as paricalcitol) have great potential for preventing parathyroid hyperplasia and bone loss in early CKD without adversely affecting kidney function. Whether they also reduce cardiovascular morbidity and mortality in early CKD, as they appear to do in dialysis patients, remains to be determined.