Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone

Chronic hypomagnesemia is closely associated with hypocalcemia, which is caused by impaired parathyroid hormone (PTH) secretion or the refractoriness of bone and renal tubules to PTH. The dominant mechanism of acute-onset, hypomagnesemia-induced hypocalcemia is currently unclear. An 83-year-old man who had undergone chemotherapy with carboplatin for prostate cancer suffered from acute diarrhea and finger paresthesia. Laboratory data confirmed hypocalcemia as well as hypomagnesemia. Urinary calcium levels were not measured. However, the urinary fractional excretion of Mg (FE_Mg) was elevated. Despite elevated PTH levels, the renal tubular maximal reabsorption rate of phosphate to GFR (TmP/GFR) was elevated, and bone formation and resorption markers were suppressed. A magnesium loading test revealed a clear magnesium deficiency. After administration of magnesium, bone marker levels were increased, and TmP/GFR was reduced to normal levels, despite the persistent elevation of PTH. Serum calcium levels eventually increased to approximately the reference range. Clinical histories and these observations both suggest that when patients with hypomagnesemia-induced hypocalcemia rapidly lose magnesium through complications such as diarrhea, the primary cause may be the refractoriness of bone and renal tubules to PTH, rather than impaired PTH secretion.     

Development of hungry bone syndrome after rapid lowering of PTH with intravenous maxacalcitol therapy in a patient with non-uremic secondary hyperparathyroidism

A 41 year-old woman complained of general bone pain and polyuria. She did not have Albright hereditary osteodystrophy. Laboratory examination revealed hypokalemia, hypocalcemia, and an elevation of serum intact PTH concentration. The patient was polyuric and relatively hypercalciuric, though her glomerular filtration rate (GFR) was normal. Neither urinary Pi nor cAMP excretion was remarkably promoted by an exogenous PTH load. An iliac bone biopsy revealed osteopenia, active osteoclastic bone resorption, fibrous transformation in bone marrow tissue, and severely disturbed calcification. Although the oral administration of alfacalcidol showed no effects, 3 weeks of intermittent intravenous injection of maxacalcitol therapy decreased the serum intact PTH concentration from 597 pg/ml to 40 pg/ml, and the bone pain was greatly relieved. However, plasma Ca concentration also decreased and symptoms of tetany appeared. Pseudohypoparathyroidism type Ib was the most likely diagnosis in this patient. In conclusion, maxacalcitol therapy satisfactorily suppressed parathyroid function in a patient with secondary hyperparathyroidism without uremia. Appropriate Ca supplementation was required to perform it safely.     

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.     

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.     

Postoperative Elevated Serum Levels of Intact Parathyroid Hormone after Surgery for Parathyroid Adenoma: Sign of Bone Remineralization and Decreased Calcium Absorption

Increased levels of intact parathyroid hormone (PTH) have been documented after surgery for primary hyperparathyroidism (pHPT) despite normocalcemia. The pathogenesis remains to be elucidated. Seventeen consecutive patients operated on for solitary parathyroid adenoma were investigated before and at 8 weeks and 1 year after surgery with serum levels of intact PTH, biochemical variables known to reflect PTH activity, and bone mineral content (BMC). In addition, an oral calcium loading test was performed 8 weeks after the operation. All patients had low or normal serum calcium levels during follow-up. Eight weeks after operation six patients (35%) had an increased serum PTH level. These patients (group I) preoperatively had higher serum levels of PTH and alkaline phosphatase than patients with normal PTH levels (group II). They also had lower BMC and larger parathyroid adenomas. They did not differ in renal function. At 8 weeks after operation group I showed higher mean serum levels of osteocalcin and propeptide of type I procollagen but lower urinary calcium excretion. In contrast to patients in group II, they also showed a lower calciuric response and a trend to a lower calcemic response during the oral calcium load. The two groups showed similar parathyroid sensitivity for calcium. Patients in group I demonstrated a significant increase in BMC the first year after the operation. Increased serum PTH 8 weeks after surgery for sporadic parathyroid adenoma was not due to persistent pHPT or impaired renal function. Instead, the results imply there is diminished calcium absorption and increased bone turnover with cortical bone remineralization.     

Serial changes in bone mineral density and bone turnover after correction of secondary hyperparathyroidism in a patient with pseudohypoparathyroidism type Ib.

Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and secondary hyperparathyroidism caused by primarily renal resistance to the effects of parathyroid hormone (PTH). However, as an indication of normal PTH responsiveness in bone, some patients with PHP develop skeletal disease because of longstanding secondary hyperparathyroidism. A patient is described with hypocalcemia, hyperphosphatemia, marked secondary hyperparathyroidism, and an increased alkaline phosphatase level. Subsequent evaluation revealed a diagnosis of PHP type Ib. The patient had radiographic evidence of skeletal disease caused by secondary hyperparathyroidism. A urinary level of N-telopeptide cross-links of type I collagen (NTX) was elevated markedly. Bone mineral density (BMD) was in the normal range at all measured sites, with BMD at the spine being higher than at the femur and distal radius. Treatment was initiated with calcium and calcitriol. Seven months later, calcium and PTH levels had normalized. The level of urinary NTX fell by 83%. Spinal BMD improved by 15%, and BMD at the femoral neck improved by 11%. Radial BMD was unchanged. This case emphasizes the importance of evaluating patients with PHP for hyperparathyroid bone disease and shows that correction of secondary hyperparathyroidism in patients with PHP can result in a significant suppression of previously accelerated bone turnover and to substantial gains in BMD at sites containing a major percentage of cancellous bone. The case also implies that assessment of bone turnover with urinary NTX and measurement of BMD with dual-energy X-ray absorptiometry (DEXA) may be useful in following the response of the skeleton to therapy in these patients and suggests the need for more studies of both NTX and BMD in patients with PHP.     

Diagnosis and treatment of primary hyperparathyroidism

Summary The leading symptom of primary hyperparathyroidism is renal lithiasis which was present in 64 of 100 cases, whereas bone disease was noted in 11 per cent only. The diagnosis of primary hyperparathyroidism is generally made on the basis of raised serum levels of calcium and of immunoreactive parathyroid hormone (PTH). With antibodies detecting primarily COOH-terminal fragments of intact PTH-(1-84) there was an almost total discrimination of serum levels of PTH in normal subjects and in patients with primary hyperparathyroidism. Serum PTH was in the upper normal range in only 5 per cent of 128 patients with surgically verified hyperparathyroidism, whereas PTH was normal or undetectable in 35 hypercalcaemic patients with tumours unrelated to the parathyroid glands. A comparable discrimination of patients with primary hyperparathyroidism from normal subjects can be achieved with the measurement of the urinary cyclic adenosine 3, 5-monophosphate excretion, provided it is related to the glomerular filtration rate. With the measurement of the urinary excretion of calcium and phosphate, on the other hand, there is a large overlap in control subjects and in patients with primary hyperparathyroidism.The surgical removal of parathyroid tumours is the treatment of choice of primary hyperparathyroidism. In the routine preoperative evaluation, we do not recommend PTH measurements in the venous effluent of parathyroid tumours, since all parathyroid glands have to be surgically localized. In previously explored patients the interpretation of selective PTH measurements is difficult because of distorsion of the venous drainage from the parathyroid glands.     

Primary hyperparathyroidism associated with hypocalcemia in a patient presenting with kidney disease

Elevated serum parathyroid hormone (PTH) level together with hypocalcemia in chronic kidney disease usually suggests secondary hyperparathyroidism. However, primary hyperparathyroidism should also be considered, especially if concomitant vitamin D deficiency is suspected. We report a case of parathyroid adenoma associated with hypocalcemia and metabolic bone disease in a patient presenting with kidney disorder. The patient was successfully treated by parathyroidectomy that was preceded and followed by intensive calcium and vitamin D supplementation.     

Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD

Normophosphatemia and normocalcemia are maintained in chronic kidney disease (CKD) by increased levels of fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH), but the stimuli for secretion of these hormones in early CKD are incompletely understood. Most human physiologic studies have focused on random or fasting measurements of phosphorus, calcium, FGF-23, and PTH, but in this study, the hypothesis was that measurements in the postprandial state may reveal intermittent stimuli that lead to increased FGF-23 and PTH levels. The 4-h postprandial response in 13 patients with CKD and fasting normophosphatemia and normocalcemia (mean GFR 41 +/- 8 ml/min per m(2)) was compared with 21 healthy volunteers. Compared with healthy subjects, fasting patients with CKD had significantly higher levels of FGF-23 and fractional excretion of phosphorus; lower fractional excretion of calcium; and no difference in serum calcium, phosphorus, and PTH levels. After standardized meals, urinary phosphorus excretion in both groups increased despite unchanged serum phosphorus and FGF-23 levels. Postprandial urinary calcium excretion also increased in both groups, and this was accompanied by significantly reduced serum calcium and increased PTH levels in patients with CKD only; therefore, FGF-23 does not seem to be an acute postprandial regulator of phosphaturia in CKD or in health, but inappropriate postprandial calciuria with episodic, relative hypocalcemia may represent a previously unreported mechanism of secondary hyperparathyroidism in CKD.     

Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients.

BACKGROUND: Cinacalcet rapidly normalizes serum calcium and reduces intact parathyroid hormone (PTH) levels in renal transplant patients with hypercalcaemia and persistent hyperparathyroidism. The aim of this study is to evaluate the 6 months efficacy of cinacalcet and the effect of cinacalcet withdrawal on serum calcium and PTH in such patients. Furthermore, the impact of cinacalcet on bone turnover and quality of life was assessed. METHODS: Twelve renal allograft recipients with hypercalcaemia due to persistent hyperparathyroidism were treated with cinacalcet for 26 weeks. Cinacalcet was then withdrawn to check for recurrence of hypercalcaemia. RESULTS: Cinacalcet maintained normocalcaemia in all patients from week 4 to 26, and PTH significantly decreased and remained suppressed. Serum phosphate increased, whereas the serum calcium-phosphate product remained unchanged. The excretion of calcium and phosphate in the 24 h urine had tendency to decrease. After cinacalcet was withdrawn, hypercalcaemia recurred rapidly and PTH increased to baseline values. Renal function remained stable, proteinuria was unchanged and no allograft rejection was observed. During treatment with cinacalcet, total and bone-specific alkaline phosphatase increased, whereas the urinary deoxypyridinoline-creatinine ratio did not change significantly, suggesting enhanced bone formation. Quality of life assessed at weeks 10 and 26 remained unchanged compared with baseline. CONCLUSIONS: In conclusion, continued treatment with cinacalcet is required to maintain long-term normocalcaemia and to suppress the enhanced PTH production in renal transplant recipients with persistent hyperparathyroidism.     

Understanding and managing hyperphosphatemia in patients with chronic renal disease

Controlling serum phosphorus levels continues to be a challenge in patients with chronic renal disease. Hyperphosphatemia is implicated in the development and worsening of secondary hyperparathyroidism and renal osteodystrophy (ROD) through its effects on serum calcium and calcitriol levels, parathyroid hormone (PTH) overproduction, and parathyroid cell hyperplasia. In the past serum phosphorus control with aluminum-containing phosphate binders was associated with insidious but serious development of aluminum toxicity. More recent approaches using non aluminum-containing calcium salts as phosphate binders are limited because of the excessive calcium load resulting from concomitant enhanced intestinal calcium absorption. Moreover serum phosphorus does not only result from dietary phosphate intake but also from enhanced bone breakdown due to secondary hyperparathyroidism. Strategies for managing ROD including early control of serum phosphorus and PTH, prevention of parathyroid hyperplasia; establishment of optimal PTH levels for bone health, and the availability of new therapeutic tools for controlling phosphorus may help prevent complications and improve patient outcomes.     

Basal parathyroid activity and renal calcium handling during an intravenous calcium load

Urinary excretion of calcium and urinary cyclic AMP (cAMP), plasma parathyroid hormone (PTH) and ionized serum calcium concentration, and creatinine clearance were measured in 15 healthy humans. In the same subjects, renal tubular reabsorption of calcium was evaluated by analyzing the regression line of urinary calcium excretion rate on rising the level of serum calcium during an intravenous calcium infusion. The regression line intercept on the y-axis, which has been proposed to depend on the calcium reabsorption in the renal distal tubule, was found to be significantly related to both urinary cAMP and PTH levels. The theoretical renal threshold for calcium excretion was directly related to the y-axis intercept and thus also to the index of parathyroid activity. No relationship was found between urinary cAMP or plasma PTH levels and the regression line slope of urinary calcium to serum calcium. In healthy subjects, parathyroid activity significantly affects the extrapolated regression line of urinary calcium to serum calcium by changing the intercept, but not the slope.     

The calcimimetic agents: perspectives for treatment

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca++), and control of urinary calcium excretion with small changes in blood Ca++. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca++ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca++, can suppress PTH levels with a resultant fall in blood Ca++. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca++, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.     

Cinacalcet-induced hungry bone syndrome

Cinacalcet is a type II calcimimetic approved for treatment of secondary hyperparathyroidism in patients with end-stage renal disease. It is generally well tolerated with the most common side effects being nausea and vomiting. Symptomatic hypocalcemia is rare, and persistent hypocalcemia has not been reported to date. We present a case of a 66-year-old woman on chronic outpatient hemodialysis who was initiated on cinacalcet when her intact parathyroid hormone was 1091 pg/mL (normal 15-75 pg/dL). Two weeks later she developed diffuse muscle twitching. The patient required a 72-hour hospitalization and treatment with a continuous intravenous calcium infusion for symptomatic hypocalcemia. The intact parathyroid hormone level at this time was 176 pg/mL. This case is the first report of cinacalcet-induced prolonged and symptomatic hypocalcemia, closely resembling the hungry bone syndrome described in some patients with secondary hyperparathyroidism following surgical parathyroidectomy.     

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...     

Urine calcium excretion, nephrogenous cyclic-adenosine monophosphate and serum parathyroid hormone levels in patients with essential hypertension.

To evaluate the role of calcium and the parathyroid gland in the pathophysiology of essential hypertension, creatinine clearance, urinary excretion of sodium, calcium and nephrogenous cyclic adenosine monophosphate (NcAMP) and serum parathyroid hormone (PTH) levels were measured in 25 newly diagnosed essentially hypertensive patients before institution of any treatment and in 25 age- and sex-matched normal volunteers. While no significant differences in creatinine clearance, serum total calcium levels or 24-hour sodium excretion existed between the two groups, hypertensives had a higher mean (+/- SD) 24-hour calcium excretion rate (199.0 +/- 44.7 vs. 152.8 +/- 33.6 mg, p less than 0.001), a higher mean NcAMP excretion rate (2.54 +/- 0.8 vs. 1.87 +/- 0.5 nmol/100 ml glomerular filtrate, p less than 0.001) and a higher mean serum PTH concentration (1.87 +/- 0.6 vs. 1.53 +/- 0.4 ng/ml, p less than 0.001) than the normotensives. A significant positive correlation existed between calcium and sodium excretion in both hypertensives (r = 0.66, p less than 0.001)) and normotensives (r = 0.67, p less than 0.001), but given the same levels of creatinine clearance and sodium excretion, hypertensives excreted more calcium than normotensives (p less than 0.001)). In both hypertensives and normotensives, serum PTH levels were positively correlated with NcAMP excretion (r = 0.42, p less than 0.05, and r = 0.41, p less than 0.05, respectively) and the ratio of urinary sodium to urinary calcium excretion (r = 0.59, p less than 0.001, and r = 0.75, p less than 0.001), respectively). The above results suggest that in essential hypertension, increased activity of parathyroid glands may occur as a consequence of increased urinary calcium losses which are presumably due to an intrinsic defect in renal calcium handling.     

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.