Excessive Secretion Of Parathyroid Hormone Research Articles

The severe course of hyperparathyroidism in the elderly: Clinical cases

Primary hyperparathyroidism (PHPT) is a disease of the endocrine system caused by excessive secretion of parathyroid hormone (PTH) and is characterized by a pronounced violation of calcium and phosphorus metabolism. More recently, in Russia, PHPT was detected extremely rarely and often hid under the mask of recurrent urolithiasis, generalized osteoporosis and other pathologies. As a result, patients did not receive adequate treatment, which in a certain percentage of cases led to the development of serious complications.The clinical cases of severe PHPT in postmenopausal women are presented in this article.

Pathophysiology of parathyroid hyperplasia in chronic kidney disease: preclinical and clinical basis for parathyroid intervention.

Secondary hyperparathyroidism is characterised by excessive secretion of parathyroid hormone and parathyroid hyperplasia, resulting in both skeletal and extraskeletal consequences. Recent basic and clinical studies have brought considerable advances in our understanding of the pathophysiology of parathyroid hyperplasia and have also provided practical therapeutic approaches, especially with regard to indications for parathyroid intervention. In this context, it is quite important to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to calcitriol treatment. Patients with nodular hyperplasia should undergo parathyroid intervention including percutaneous ethanol injection therapy (PEIT). Selective PEIT of the parathyroid gland is an effective approach in which the enlarged parathyroid gland with nodular hyperplasia is ‘selectively’ destroyed by ethanol injection, and other glands with diffuse hyperplasia are then managed by medical therapy. With a more focused attention to applying parathyroid intervention, we can expect significant improvement in the management of secondary hyperparathyroidism in dialysis patients.

Cellular changes following direct vitamin D injection into the uraemia-induced hyperplastic parathyroid gland.

Background. Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity and low contents of vitamin D and calcium-sensing receptors). The control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism (SHPT), because the advanced stage of hyperplasia is considered irreversible. For the better control of the PTH level in dialysis patients with such advanced SHPT, percutaneous vitamin D injection therapy (PDIT) under ultrasonographic guidance was developed and various cellular changes caused by this treatment were also investigated using an animal model.Methods. The PTGs of Sprague–Dawley rats, which had been 5/6-nephrectomized and fed a high-phosphate diet, were treated with the direct injections of vitamin D agents, and cellular effects focusing the above-mentioned characters were investigated.Results. An adequacy of the direct injection technique into the rats’ PTGs and the successful effects of this treatment in various biochemical parameters were confirmed. Such characteristics of advanced SHPT were simultaneously improved; in particular, it was confirmed that this treatment may be effective in controlling PTG hyperplasia by, at least in part, apoptosis-induced cell death.Conclusions. A locally high level of vitamin D strongly may suppress PTH secretion and regress hyperplasia, which is involved in the induction of apoptosis in PTCs, based on the simultaneous improvements of cellular characters of advanced SHPT. The PTH control introduced by this treatment successfully ameliorated osteitis fibrosa (high bone turnover rate).

Brown Tumor of the Ulna and Radius: An Unusual Presentation of Primary Hyperparathyroidism

Brown tumors are erosive bony lesions caused by chronic excessive secretion of parathyroid hormone. Since the introduction of routine calcium measurement, the diagnosis of hyperparathyroidism has usually been made in asymptomatic patients and as a result, brown tumors are rarely observed as an initial manifestation of hyperparathyroidism. We report the case of a 70-year-old woman who presented with right wrist pain. A roentgenogram showed erosive bone tumors of the ulna and radius, which were mistaken for primary or metastatic bone tumors. Extensive workups were performed to determine the cause(s); however, these lesions were finally diagnosed as brown tumors associated with primary hyperparathyroidism due to a parathyroid adenoma. This case illustrates the diagnostic pitfall in patients who present with skeletal manifestations of hyperparathyroidism and the need for vigilance and a high level of suspicion by physicians. (J Korean Endocr Soc 23:347~351, 2008)

Lumbar Spine Bone Mineral Density Changes in Patients with Primary Hyperparathyroidism According to Age and Gender

Primary hyperparathyroidism (PHPT) results from excessive secretion of parathyroid hormone (PTH), and catabolic and anabolic effects of PTH on bone may lead to overall deleterious effects on skeleton. The aim of this study was to analyze the changes in lumbar spine bone mineral density (BMD) in patients with PHPT who underwent parathyroidectomy (PTx), and to correlate the main demographics and biochemical parameters with pre- and postoperative BMD values. Two groups of age-matched patients (group A = 14 postmenopausal women; group B = 13 men, overall median age 53 years, range 26-56 years) with confirmed PHPT were enrolled in the study. All patients underwent lumbar (L2-L4 region) spine osteodensitometry using a dual-energy X-ray absorptiometry (DXA) prior to surgery. A significant correlation between alkaline phosphatase (ALP) and PTH (R = 0.73, P = 0.003) was found in group A patients. In group B correlations were found between calcemia and ALP (R = 0.71, P = 0.007), and between osteocalcin and both PTH (R = 0.65, P = 0.01) and ALP (R = 0.59, P = 0.03). No correlation (P = NS) was found between BMD, both basal and postoperative, and age or biochemical parameters. The 1-year BMD were 0.937 +/- 0.115 and 0.940 +/- 0.201 g/cm(2) (P = NS) in group A and B, respectively. A significant (P = 0.03) difference between basal and 1-year BMD was found only in group A, while in group B the difference was not significant. In conclusion, in patients with PHPT bone turnover is increased and consequently the BMD is reduced, but unfortunately PTx does not allow for complete bone restoring. However, in premenopausal women the BMD values of the lumbar spine significantly improve after PTx, suggesting a higher bone sensitivity to serum PTH normalization due to a synergic action with estrogens.

Asymptomatic primary hyperparathyroidism

Primary hyperparathyroidism is a common disorder of mineral metabolism characterized by incompletely regulated, excessive secretion of parathyroid hormone from one or more of the parathyroid glands. In adults with the disease, a single, benign adenoma is seen approximately 80 percent of the time, with multiple gland involvement comprising most of the remaining patients. Very rarely, a parathyroid cancer is responsible but it is seen in less than 0.5 percent of patients with primary hyperparathyroidism. In this article, we will review important clinical and diagnostic features of asymptomatic primary hyperparathyroidism as well as considerations for surgical or medical management of the disease.

Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells

Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity, and low contents of vitamin D and calcium-sensing receptors). Control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism, but the advanced stage of hyperplasia is considered irreversible. In the present study, dialysis patients with PTG hyperplasia underwent direct injection of calcitriol or maxacalcitol (OCT) into the PTG. Ultrasonography showed that this treatment had significantly reduced PTG volume and tissue analysis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method and DNA electrophoresis indicated that cellular apoptosis had been induced. The mechanism of apoptosis was evaluated in detail in uremic rats fed a high-phosphate diet. OCT or its vehicle was directly injected into the rats' PTGs. In the PTGs treated by OCT, there was a significantly increased number of TUNEL-positive PTCs and DNA electrophoresis revealed the characteristic ladder pattern of DNA fragmentation, both findings indicative of apoptosis. There was also a significant upregulation of both vitamin D and Ca-sensing receptors in the PTCs and a clear shift of the Ca-PTH response curve to the left and downward. None of these findings was observed in the PTGs treated by vehicle. This novel treatment is successful in causing regression of PTG hyperplasia. Thus, it is expected to significantly reduce the PTH level and ameliorate the abnormal bone turnover and mineral metabolism.

Hypercalcaemia induced by excessive parathyroid hormone secretion in a patient with a neuroendocrine tumour

Hyperparathyroidism and neoplasia account for80–90% of the patients with hypercalcaemia. Serumlevels of 1-84 parathyroid hormone (PTH) is the keyparameter for the diagnosis and treatment of hyper-calcaemia.PTHiselevatedinhyperparathyroidismandlow in neoplasia [1]. Hypercalcaemia associated withmalignancy is most often secondary to a plasma factor,the PTH-related protein (PTHrP), which is responsiblefor bone resorption. This factor has a PTH-like effectrelated to its similarity with the PTH N-terminalsequence. However, the biological effects of PTHrPare different from those of PTH as the C-terminalsequences of the two hormones are not the same [2].PTHrP is not detected by the new technique usedfor PTH, the immunoradiometric assay (IRMA) [3].Using this method, both N- and C-terminal sequencesof PTH are recognized. PTH level is consistently lowin paraneoplastic hypercalcaemia related to PTHrP [4],but exceptionally hypercalcaemia can be due to anonparathyroid tumour secreting PTH.We report on a patient with hypercalcaemiarelated to a PTH-secreting neuroendocrine tumour ofthepancreas.Inouropinion,thisisthefirstobservationof a PTH-secreting neuroendocrine tumour of thepancreas.

Radionuclide Imaging of the Parathyroid Glands

The parathyroid glands, which usually are situated behind the thyroid gland, secrete parathyroid hormone, or PTH, which helps maintain calcium homeostasis. Primary hyperparathyroidism results from excess parathyroid hormone secretion. In secondary hyperparathyroidism, the normal PTH effect on bone calcium release is lost. Serum PTH rises, causing generalized hyperplasia. In tertiary hyperparathyroidism, a complication of secondary hyperparathyroidism, normal feedback mechanisms governing PTH secretion are lost, parathyroid gland sensitivity to PTH decreases, and the threshold for inhibiting PTH secretion increases. 99mTc sestamibi, or MIBI, the current radionuclide study of choice for preoperative parathyroid localization, can be performed in various ways. The "single-isotope, double-phase technique" is based on the fact that MIBI washes out more rapidly from the thyroid than from abnormal parathyroid tissue. However, not all parathyroid lesions retain MIBI and not all thyroid tissue washes out quickly, and subtraction imaging is helpful. Many MIBI avid thyroid lesions also accumulate pertechnetate and iodine, and subtraction reduces false positives. Single-photon emission computed tomography provides information for localizing parathyroid lesions, differentiating thyroid from parathyroid lesions, and detecting and localizing ectopic parathyroid lesions. The most frequent cause of false-positive MIBI results is the solid thyroid nodule. Other causes include thyroid carcinoma, lymphoma, and lymphadenopathy. False-negative results occur because of several factors. Lesion size is important. Cellular function also may be important. Parathyroid tissue that expresses P-glycoprotein does not accumulate MIBI. Parathyroid adenomas that express either P-glycoprotein or the multidrug resistance related protein MRP are less likely to accumulate MIBI. MIBI scintigraphy is less sensitive for detecting hyperplastic parathyroid glands. In secondary hyperparathyroidism, MIBI uptake is more closely related to cell cycle than to gland size. Mitochondria-rich oxyphil cells presumably account for MIBI uptake in parathyroid lesions. Fewer oxyphil cells, and hence fewer mitochondria, may explain both lower uptake and rapid washout of MIBI from some lesions. MIBI is also less sensitive for detecting multigland disease than solitary gland disease.

Osteoporosis in Adult Survivors of Adolescent Cardiac Transplantation May Be Related to Hyperparathyroidism, Mild Renal Insufficiency, and Increased Bone Turnover

Osteoporosis is common in adults who undergo cardiac transplantation. We hypothesized that adolescent cardiac transplant recipients also develop osteoporosis, which would persist into adulthood. We evaluated 9 adult survivors of adolescent cardiac transplantation, aged 21-32, in a cross-sectional, case-control study comparing bone mineral density, indices of mineral metabolism, and bone turnover markers. Osteoporosis (Z score < or = -2.0) was present in 56% of transplant recipients at the lumbar spine, 33% at the femoral neck, and 100% at the one-third radius. Subjects had mean bone mineral density Z scores of -2.3 +/- 0.9 at the spine, -1.6 +/- 0.7 at the femoral neck, and -3.2 +/- 0.7 at the one-third radius, significantly lower than controls at all sites (p < 0.001). Serum creatinine and vitamin D metabolites were normal and did not differ between subjects and controls. Serum calcium was lower, blood urea nitrogen was elevated, and creatinine clearance tended to be lower in transplant recipients. Parathyroid hormone (PTH) levels were 3-fold higher in subjects than controls, and 75% of subjects had elevated PTH levels. Markers of bone turnover were significantly higher in subjects than controls. Adult survivors of adolescent cardiac transplantation have mild renal insufficiency, secondary hyperparathyroidism, and biochemical evidence of increased bone turnover. Osteoporosis is common in these patients, particularly at the one-third radius, a site sensitive to the catabolic effects of sustained excessive PTH secretion. We conclude that adult survivors of adolescent cardiac transplantation should be evaluated for hyperparathyroidism and osteoporosis.

Pathogenesis of secondary hyperparathyroidism and renal bone disease

Patients with chronic renal disease (CKD)almost always develop secondary hyperparathyroidism (SHPT) due to hypocalcemia, phosphate retention, and abnormalities in vitamin D (VD) metabolism. Concomitant decreases in VD receptor and calcium sensing receptor in the parathyroid glands render them more resistant to the action of VD and calcium, and accelerate parathyroid cell growth. Several types of bone diseases are known to occur in CKD patients. Excessive secretion of parathyroid hormone (PTH) due to SHPT causes high-turnover bone disease, called osteitis fibrosa. Among low-turnover bone disease (LTBD), osteomalacia which is characterized by calcification defect is often complicated with VD deficiency and/or aluminum accumulation. Recently, frequency of adynamic bone disease caused by PTH suppression, another type of LTBD, is increasing probably due to calcium salts as phosphate binder with or without VD treatment.

Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR). In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. Calcimimetic compounds thus represent a novel way of controlling excess PTH secretion in clinical disorders such as secondary hyperparathyroidism (SHPT) due to chronic renal failure. Clinical trials have documented that the calcimimetic agent cinacalcet hydrochloride effectively lowers plasma PTH levels without increasing serum calcium or phosphorus concentrations in adult hemodialysis patients with SHPT. Serum phosphorus levels and values for the calcium-phosphorus ion product in serum often decline as plasma PTH levels fall during treatment. Experimental evidence suggests that calcimimetic agents may also impede the development of parathyroid gland hyperplasia, an integral component of SHPT due to chronic renal failure. Calcimimetic agents have considerable potential, therefore, as part of new therapeutic strategies for SHPT.

Limitations of Technetium 99m Sestamibi Scintigraphic Localization for Primary Hyperparathyroidism Associated with Multiglandular Disease

Successful surgical treatment of primary hyperparathyroidism requires the localization and excision of the parathyroid tissue responsible for excessive parathyroid hormone secretion while ensuring that the patient will have sufficient endogenous parathyroid hormone production to maintain eucalcemia. In selecting patients with primary hyperparathyroidism for unilateral parathyroidectomy the surgeon should be able to diagnose multiglandular disease either preoperatively or intraoperatively. We performed a retrospective review of 123 patients who underwent surgical treatment for primary hyperparathyroidism to determine the potential feasibility of selecting patients for minimally invasive surgery based on preoperative imaging studies. All patients were studied preoperatively with 99m technetium-sestamibi scintigraphy. High-resolution ultrasonography was performed in 119 of these patients. All patients except one underwent bilateral cervical exploration. A patient with an intrathoracic adenoma was successfully diagnosed by scintigraphy thereby allowing treatment by a limited thoracotomy. One hundred eight patients had solitary adenomas and 15 had multiglandular disease. In none of the patients with bilateral multiglandular disease were all abnormal glands localized preoperatively. Patients in our study with primary hyperparathyroidism and multiglandular disease were underdiagnosed by preoperative imaging. A minimally invasive approach based solely on preoperative imaging studies may result in treatment failure in patients with multiglandular involvement.

Future role of calcimimetics in end-stage renal disease.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium-sensing receptor. In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. These compounds offer a novel way of controlling excess PTH secretion in clinical disorders associated with excess PTH secretion, including secondary hyperparathyroidism due to chronic renal failure. The first calcimimetic agent to be evaluated in clinical trials was R-568, but studies were discontinued because of its limited bioavailability and inconsistent pharmacokinetic profile. Extensive assessments are currently underway by using a second-generation calcimimetic compound, AMG 073, to treat secondary hyperparathyroidism. Work completed thus far has shown that AMG 073 effectively lowers plasma PTH, without increasing values for the calcium-phosphorus ion product in serum in patients with end-stage renal disease. Indeed, serum phosphorus levels often decline as plasma PTH levels fall during treatment. Recent experimental evidence also suggests that calcimimetic agents may impede the development of parathyroid gland hyperplasia, an integral component of secondary hyperparathyroidism due to chronic renal failure. Calcimimetics agents have considerable potential therefore as a new approach to the medical management secondary hyperparathyroidism.

Parathyroid disorders

The parathyroid glands play a crucial role in maintaining plasma calcium within the narrow limits required to allow normal neuromuscular activity. Their principal product is parathyroid hormone which is secreted in response to hypocalcaemia. Disorders of the parathyroid glands may therefore result in both hypocalcaemia and hypercalcaemia. In children the former is more common than the latter.Hypoparathyroidism usually results either from failure of development of the glands or from their destruction by antibodies. Pseudohypoparathyroidism is the consequence of end-organ unresponsiveness to parathyroid hormone. Magnesium deficiency may also interfere with parathyroid hormone secretion, causing functional hypoparathyroidism. In hyperparathyroidism excess parathyroid hormone secretion results from either gland hyperplasia, adenoma or, occasionally, carcinoma. Both hypercalcaemia and hypocalcaemia can result from abnormalities in the calcium-sensing receptor located on the parathyroid gland. Many of these conditions seen in children are genetic in origin and are frequently associated with abnormalities of other organs.

Calcimimetic agents for the treatment of hyperparathyroidism.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor. They lower the threshold for receptor activation by extracellular calcium ions and, in parathyroid cells, diminish parathyroid hormone secretion. Calcimimetic compounds represent a novel class of therapeutic agents that may provide a way of controlling excess parathyroid hormone secretion in several clinical disorders. Although experience from clinical trials in humans is limited, available data suggest that calcimimetic agents effectively lower plasma parathyroid hormone levels in patients with primary hyperparathyroidism and those with secondary hyperparathyroidism caused by end-stage renal disease. Calcimimetic compounds thus have considerable potential as a new approach to the medical management of several important clinical disorders of bone and mineral metabolism.

No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients

Although hyperparathyroidism is a common feature in renal transplant recipients, the long-term course of parathyroid hormone (PTH) secretion in these patients is not well established, and the actual contribution of PTH to posttransplant bone disease remains incompletely understood. Therefore, we studied calcium-regulating hormones and serum osteocalcin, as a marker of bone remodeling, in 82 normocalcemic renal transplant recipients with good renal function who had received a graft 6 to 73 months previously and in 82 healthy subjects matched for age and sex. In all subjects, fasting serum and 24-hour urinary samples were collected. The transplant recipients had excessive PTH secretion (serum PTH, 6.9 ± 0.5 pmol/L in recipients v 3.0 ± 0.1 pmol/L in healthy subjects; P < 0.001) and high bone turnover (osteocalcin, 16.6 ± 0.8 μg/L v 8.0 ± 0.3 μg/L; P < 0.001). (Values are mean SEM.) In addition, transplant recipients had a slightly higher ionized calcium than the healthy subjects, providing definite evidence of an inappropriate PTH secretion in renal transplant recipients. Furthermore, in subgroups of 25 recipients and 25 healthy controls matched for creatinine clearance, the results superimposed those obtained in the whole groups, suggesting that excessive PTH secretion and high bone turnover in renal transplant recipients did not merely reflect the moderately reduced renal function of some recipients. In the whole group of transplant recipients, PTH correlated positively with osteocalcin (r = 0.40; P < 0.001), suggesting that PTH contributes at least partly to posttransplant bone disease. Conversely, there was no correlation between serum PTH or osteocalcin and the delay from grafting. Therefore, our results provide no evidence for a spontaneous improvement of either persistent hyperparathyroidism or high bone turnover in normocalcemic long-term renal transplant recipients.

Calcium-regulated parathyroid hormone release in patients with mild or advanced secondary hyperparathyroidism

Differences in the regulation of parathyroid hormone (PTH) release by calcium are thought to account for excess PTH secretion in patients with secondary hyperparathyroidism (2 degrees HPTH). To determine whether calcium-regulated PTH release varies with the severity of 2 degrees HPTH in patients with end-stage renal disease, dynamic tests of parathyroid gland function were done using the four-parameter model in 26 patients with 2 degrees HPTH documented by bone biopsy. Estimates of the set point did not differ among patients categorized as mild (basal serum PTH < 400 pg/ml), moderate (basal PTH 400 to 600 pg/ml) or severe (basal PTH > 600 pg/ml) 2 degrees HPTH; values were 1.23 +/- 0.06 mmol/liter, 1.24 +/- 0.06 mmol/liter and 1.23 +/- 0.05 mmol/liter, respectively, and none of these set point estimates differed from results obtained in normal volunteers, 1.21 +/- 0.02 mmol/liter (NS). The slope of the sigmoidal ionized calcium-PTH curve also did not differ among groups. Set point values did not correspond to basal serum PTH levels, to the maximum serum PTH level observed during hypocalcemia or to the minimum serum PTH level seen during hypercalcemia in patients with 2 degrees HPTH. In contrast, basal serum PTH values were positively correlated with both the maximum serum PTH level observed during hypocalcemia (r = 0.76, P < 0.01), and the minimum serum PTH level attained during calcium infusions (r = 0.78, P < 0.01). Calcium-regulated PTH release does not differ with the degree of 2 degrees HPTH, and set point abnormalities do not account for excess PTH secretion in patients with chronic renal failure as judged by in vivo dynamic tests of parathyroid gland function. The results suggest that variations in parathyroid gland size are the major contributor to excessive PTH secretion in patients with chronic renal failure.

Primary hyperparathyroidism and parathyroid hormone-related protein.

Hypercalcemia is most commonly associated with primary hyperparathyroidism and malignancy due to parathyroid hormone-related protein (PTHrP). Primary hyperparathyroidism is characterized by excessive secretion of parathyroid hormone in association with hypercalcemia. The modern presentation of primary hyperparathyroidism is as an asymptomatic disorder. Diagnostic tools such as bone mineral densitometry, bone histomorphometry, and the measurement of markers of bone turnover, as well as other clinical assessments, have all led to the development of guidelines to help direct decisions for parathyroid surgery or for medical management. Hypercalcemia of malignancy is often distinguishable from primary hyperparathyroidism by the presence of an obvious tumor. Primary hyperparathyroidism is excluded by the immunoradiometric assay for parathyroid hormone, which is suppressed. A number of clinical characteristics of hypercalcemia of malignancy can be explained on the basis of the tumor product, PTHrP, which directly causes hypercalcemia in many cases. Assays for PTHrP show elevated levels in patients in whom hypercalcemia is associated with the classic syndrome. Recent recognition that PTHrP is found ubiquitously in virtually all normal tissues and that it is possibly involved in a number of normal physiologic processes, apart from its pathologic role, provides an exciting basis for future research.

Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis: Evaluation of the pathophysiologic role of parathyroid hormone

Two siblings with impaired distal renal tubular acidification and nephrocalcinosis associated with vasopressin-resistant polyuria are described. They also exhibit decreased renal bicarbonate threshold and defective renal magnesium conservation with a concomitant hypomagnesemia. Evaluation of other family member revealed no such abnormalities. Parathyroid hormone (PTH) has been shown to affect the renal tubular handling of both bicarbonate and magnesium. The role of the hormone in the development of the observed abnormalities of excretion of these substances was evaluated in both siblings. Following initial determinations, which in the older child suggested increased PTH effect, studies were performed on the two siblings to assess levels of PTH secretion both by indirect methods and by direct immunoassay of their sera. The results indicated excessive PTH secretion in the older sibling, but not in the younger. It was concluded that increased PTH secretion was not responsible either for the abnormalities of bicarbonate excretion or for the excessive urinary magnesium losses demonstrated in the two siblings. Further, neither vitamin D resistance nor secondary hyperparathyroidism appears necessary for the development of nephrocalcinosis in such disorders. Finally, responses to therapy indicate that the acidosis in both siblings was corrected, as expected, by alkali administration, but the hypomagnesemia did not correct (due to increased urinary losses) with either oral on parenteral magnesium supplements.