Fok‐I gene polymorphism of vitamin D receptor in patients with beta‐thalassemia major and its effect on vitamin D status

Abstract

Most of the biological actions of vitamin D are mediated by an intracellular receptor (VDR) in which several single nucleotide gene polymorphisms have been identified. Vitamin D deficiency is increasingly identified among thalassemic patients and recent evidence links it with myocardial iron accumulation. The aim of this work was to assess the distribution of the Fok‐I polymorphism of the VDR gene among Greek children and young adults with beta‐thalassemia major and to investigate its association with 25(OH)D₃ and 1,25(OH)₂D₃ serum levels. Sixty‐nine thalassemic patients (35 females and 34 males), with a mean age of 23·05±6·07?years, participated in the study. Genotype frequencies of Fok‐I were similar to those previously reported for other populations; 44·9% of the patients were homozygotes for F allele, 43·5% were heterozygotes and 11·6% were homozygotes for the f allele. Low levels of serum 25(OH)D₃ were recorded, as 41 patients (59·4%) were below the cut‐off limit of 50?nmol/l that determines deficiency, whereas, levels of 1,25(OH)₂D₃ showed wide variability ranging from deficiency (?50?pmol/l) in 34 patients (49·3%) to excess (?125?pmol/l) in 13 patients (18·8%). When stratifying patients according to serum 1,25(OH)₂ D₃ concentrations, a higher prevalence of the f allele was observed in the deficiency group (P?=?0·03). A comparison of the serum concentrations of the two vitamin D metabolites produced a trend towards a negative correlation (r?=??0·204, P?=?0·09). Further studies are required to assess the genetic contribution to the regulation of vitamin D metabolites in the serum of patients with beta‐thalassemia major.     

Circulating levels of midregional parathyroid hormone-related protein in hypercalcaemia of malignancy

OBJECTIVE: We have developed and evaluated a sensitive radioimmunoassay directed against the midregional part of parathyroid hormone-related protein (PTHrP), which is involved in the syndrome of humoral hypercalcaemia of malignancy. PATIENTS: Midregional PTHrP levels were studied in 41 consecutive inpatients with malignancy and hypercalcaemia, 32 normocalcaemic patients with malignancy, 21 patients with primary hyperparathyroidism, 34 patients with renal failure, and 87 normals. MEASUREMENTS: The assay used an antiserum against the midregional amino acid residues 53-84 of PTHrP and PTHrP(1-86) as label and standard. Midregional PTHrP was stable in serum and plasma and could be measured directly without sample extraction. RESULTS: Normal plasma concentrations ranged from undetectable (< 5 pmol/l) to 21 pmol/l. In renal failure, PTHrP was positively correlated with serum creatinine, but PTHrP elevations of up to 30 pmol/l were found only in severe renal dysfunction with creatinine > 850 mumol/l. In hypercalcaemia caused by solid tumours, midregional PTHrP was elevated in 81% (22 of 27) of patients, ranging from undetectable to 203 pmol/l (median: 40 pmol/l). In these patients serum calcium correlated positively with PTHrP (P < 0.01). Mean PTHrP levels were indistinguishable in subgroups with and without metastatic skeletal disease. The mechanism of hypercalcaemia in 14 patients with haematological malignancy was apparently different, since all but one had normal or only marginally elevated PTHrP levels. In 21 patients with primary hyperparathyroidism midregional PTHrP was normal in 20. The assay was therefore especially useful in distinguishing the latter condition from humoral hypercalcaemia of malignancy as the second major cause of hypercalcaemia. PTHrP was normal in all 32 patients with normocalcaemic malignancy. CONCLUSION: This radioimmunoassay of midregional PTHrP provides high diagnostic sensitivity in the identification of humoral hypercalcaemia of malignancy caused by solid tumours. The assay should therefore be useful in the differential diagnosis of hypercalcaemia.     

The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly

OBJECTIVE The somatostatin analogue octreotide (Sandostatin, Sandoz) is effective in reducing growth hormone levels in patients with acromegaly. Early and transient gastrointestinal side-effects are frequent. The aim was to evaluate whether gastrointestinal side-effects during the initial phase of octreotide treatment affect calcium homeostasis, and whether effects on calcium homeostasis are seen during long-term treatment with octreotide in patients with optimal effect on GH and subjectively normal gastrointestinal function. DESIGN We first studied short-term treatment with octreotide during 14 days. From day 15 of the study medication was withdrawn, and on day 20 follow-up measurements were made. We then observed the effects of long-term treatment with octreotide. Mean duration of treatment until the day of blood sampling was 32 months (range 9–48 months). PATIENTS Sixteen patients with acromegaly were studied, ten in the short-term study and ten in the long-term study; four were included in both. MEASUREMENTS Serum levels of calcium, phosphate, PTH, alkaline phosphatase, 1,25(OH)₂ Vit D, vitamin D-binding protein and sex hormone-binding globulin (SHBG) were measured before treatment (day 0) and on days 4, 6, 8,14 and 20 during the short-term study and, except SHBG, before treatment and during therapy in the long-term study. RESULTS During the short-term treatment mean (± SEM) serum calcium decreased significantly (on days 6 and 8, 2.21 ±0.08 and 2.15 ± 0.09 mmol/l, respectively vs basal level, 2.38 ± 0.08 mmol/l), whereas significant increments were seen in mean serum PTH (on day 14, 36 ± 4 vs basal, 24 ± 3 ng/l; ng/l ± 9.425 = pmol/l), mean serum 1,25(OH)2 Vit D (on day 8, 112 ± 7 vs basal 96 ± 8 pmol/l), and ‘free 1,25(OH)2 Vit D-index', i.e. molar ratio of 1,25(OH)2 Vit D and vitamin D-binding protein (on days 8 and 14, 1.72 ± 0.09 ± 105 and 1 66 ± 0.11 ± 10–5, respectively vs basal, 1.33 ± 0.09 ± 10–5). The changes were within the normal range. No changes were seen in serum phosphate, alkaline phosphatase, or vitamin D-binding protein. During the long-term study mean serum calcium and phosphate decreased significantly, 2.32 ± 0.04 vs basal 2.42 ± 0.04 mmol/l and 1.24 ± 0.07 vs basal 1.40 ± 0.09 mmol/l, respectively, whereas mean serum PTH increased significantly, 40 ± 8 vs basal 21 ± 5 ng/l. The changes were within the normal range. No changes were seen in serum alkaline phosphatase, 1,25(OH)₂ Vit D, free 1,25(OH)₂ Vit D-index, or vitamin D-binding protein. CONCLUSION Altered calcium homeostasis during octreotide treatment in acromegaly is not only initial and temporary, but can also be seen after several years of treatment. The clinical relevance of these long-standing effects needs to be further investigated.     

Parathyroid hormone and parathyroid hormone-related protein in the investigation of hypercalcaemia in two hospital populations

BACKGROUND AND OBJECTIVE Parathyroid hormone-related protein (PTHrP) produced by cancers has a central role as a humoral mediator of hypercalcaemia in patients with malignancy. Since the prevalences of hypercalcaemia of malignancy and parathyroid disease reflect the population studied, hypercalcaemia patients from a district general hospital (DGH) and an oncology centre (OC) were studied in order to assess the diagnostic role of assays for serum PTH and plasma PTHrP in different clinical settings. DESIGN A prospective study of consecutive patients presenting with their first episode of hypercalcaemia during an 18-month period. PATIENTS A total of 123 patients (DGH, n= 69; OC, n= 54) had corrected serum calcium concentrations > 2·65mmol/l. MEASUREMENTS PTH, PTHrP, calcium and albumin were measured together with urine calcium and creatinine, enabling fractional calcium excretion to be assessed. Urine cyclic adenosine monophosphate was also measured. RESULTS Hypercalcaemia was attributed to malignancy alone in 72 patients (DGH, n= 20; OC, n= 52), benign causes in 42 (DGH, n= 42) and parathyroid disease coexisting with malignancy in 9 (DGH, n = 7; OC, n= 2). Plasma PTHrP levels were increased in 59/72 (82%) patients with hypercalcaemia due to malignancy. Measurements of both analytes contributed to a change in the final diagnosis in 12 patients (10%). Thus serum PTH was Increased In seven patients with parathyroid disease coexisting with malignancy, and plasma PTHrP was increased in five patients with previous undiagnosed malignancy. Median survival for patients with parathyroid disease and coexisting malignancy was 13 months compared with 3 months for those with hypercalcaemia due to malignancy alone (P < 0.02). CONCLUSIONS Since hypercalcaemia was attributable to parathyroid disease In 10% of ail patients with malignancy we advise measurement of serum PTH at the Initial presentation of hypercalcaemia in ail patients, while plasma PTHrP may be useful to identify those patients in whom malignancy may not be clinically apparent, or coexist with primary hyperparathyroidism.     

Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy

The incidence of hypercalcaemia and its association with humoral mechanisms involving parathyroid hormone-related protein (PTHrP), parathyroid hormone (PTH), or 1,25(OH)₂ vitamin D were assessed in a prospective study of patients admitted to a clinical haematology unit. Hypercalcaemia was detected in 18/165 patients, and was due to primary hyperparathyroidism in 3/17 patients in whom results of humoral mediator assessments were obtained. In the other patients, hypercalcaemia was associated in nine instances with myeloma, in five with B-cell non-Hodgkin's lymphoma (NHL), and in one with myeloid neoplasia. No evidence was obtained of a humoral mechanism involving 1,25(OH)₂ vitamin D, but elevated circulating levels of PTHrP, comparable with those in humoral hypercalcaemia of malignancy, were present in 2/4 patients with NHL, and in 3/9 with myeloma. The relationship between presence or absence of elevated circulating PTHrP, and presence or absence of hypercalcaemia during the course of treatment, indicated PTHrP was involved in the production of hypercalcaemia. Such an association raises the possibility that PTHrP released by neoplastic cells in these disorders acts in a paracrine manner to produce local bone resorption, and when produced in greater amounts causes elevated circulating levels which make an additional humorally-mediated contribution to the development of hypercalcaemia.     

Parathyroid hormone-related peptide, measured by a midmolecule radioimmunoassay, in various hypercalcaemic and normocalcaemic conditions.

The diagnosis of humoral hypercalcaemia of malignancy often presents considerable clinical problems. We have studied parathyroid hormone-related peptide (PTHrP) in serum from patients with humoral hypercalcaemia of malignancy (N = 22), hypercalcaemia of malignancy with skeletal metastases (17), histologically confirmed primary hyperparathyroidism (21) and hypercalcaemic patients with various benign diseases (9). PTHrP measurements were also made in normocalcaemic patients with various malignancies (23), endocrine diseases (13), sarcoidosis (22) and chronic renal failure (17). PTHrP was measured by a novel radioimmunoassay using rabbit antibodies directed towards the midregion of the molecule. Immuno- or silica cartridge extraction of serum before radioimmunoassay enabled us to measure PTHrP in all samples, which may add further information about circulating forms of PTHrP. PTHrP was clearly elevated in patients with humoral hypercalcaemia of malignancy (5.0 +/- 4.7 pmol/l) (mean +/- SD, N = 12) and when the kidney function was impaired (4.0 +/- 0.9 pmol/l) (N = 15) (silica cartridge extraction), whether the subject was hypercalcaemic or not. Some patients with endocrine diseases, including two with primary hyperparathyroidism, had slightly elevated serum PTHrP concentrations, while they were normal in sarcoidosis. In healthy subjects the levels were 1.1 +/- 0.5 pmol/l (N = 15) after immunoextraction and 0.8 +/- 0.2 pmol/l (N = 33) after silica cartridge extraction.     

Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism

Objectives Bone metabolism is only superficially described in familiar hypocalciuric hypercalcaemia (FHH). We describe and compare biochemical and osteodensitometric variables in FHH and primary hyperparathyroidism (PHPT) and assess whether they can improve the diagnostic discrimination between the groups. Design Cross‐sectional. Patients Sixty‐six FHH patients with known calcium‐sensing receptor (CASR) gene mutations and 147 PHPT patients. Measurements We determined calcium, creatinine, phosphate, magnesium, parathyroid hormone (PTH), 25OHD, 1,25(OH)₂D and alkaline phosphatase (AP) in plasma, NTx/creatinine ratio in urine and calculated the calcium/creatinine clearance ratio (CCCR). We performed dual energy X‐ray absorptiometry at the lumbar spine, hip, forearm and whole body. Results When compared with normal controls, the FHH patients had increased levels of PTH and AP with normal U‐NTx and regional Z‐scores. Increased phenotypic expression of CASR mutations in terms of hypercalcaemia was associated with higher lumbar spine bone mineral density, but not with bone markers. FHH were younger and leaner than the PHPT patients. They had comparable plasma Ca²⁺ and 25OHD, but lower levels of PTH, 1,25(OH)₂D, AP and U‐NTx. They had higher Z‐scores in the hip and in the forearm. We achieved the best discrimination between groups by multiplying CCCR with AP, 1,25(OH)₂D and PTH, but the difference between the area under the curves by receiver operating characteristic analysis remained insignificant. Conclusion Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations. A multiplicative model including CCCR, AP, 1,25(OH)₂D and PTH insignificantly improved the power of the CCCR to differentiate between FHH and PHPT. However, we still recommend CASR gene analysis in patients with a CCCR <0·020.     

Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism

Background Primary hyperparathyroidism (PHPT) is associated with reduced bone mineral density (BMD) mainly at sites rich in cortical bone. However, successful parathyroidectomy causes an increase in BMD especially at sites rich in trabecular bone. Plasma 25‐hydroxyvitamin D (25OHD) levels are typically reduced and plasma 1,25‐dihydroxyvitamin D [1,25(OH)₂D] slightly increased in PHPT. These variations in vitamin D metabolites may influence variations in BMD and fracture risk. Aim To investigate relations between preoperative vitamin D metabolites and skeletal consequences in patients with untreated PHPT and to appraise the influence of preoperative vitamin D metabolites on postoperative changes in BMD. Design Cross‐sectional and cohort study. Materials Two hundred and forty‐six consecutive Caucasian PHPT patients aged 19–91 years. (median 63, 87% females). Results BMD was reduced at the femoral neck (P < 0·001) and forearm (P < 0·001), but normal at the lumbar spine (P = 0·11). Levels of biochemical bone markers were associated with high plasma PTH, high plasma 1,25(OH)₂D and low plasma levels of 25OHD. Moreover, low plasma 25OHD was associated with low levels of BMD at the femoral neck (r_p = 0·23), the forearm (r_p = 0·19) and the whole body (r_p = 0·30), whereas plasma 1,25(OH)₂D was inversely associated with BMD at all regional sites and the whole body. Plasma PTH only showed an inverse association with BMD at the forearm (r_p = –0·21). No association was observed between biochemical variables and prevalent spinal fractures, all peripheral fractures or osteoporotic peripheral fractures. The annual increase in spinal BMD after surgery was positively associated with preoperative plasma PTH (r_p = 0·40), whereas the annual increase in whole body BMD was inversely associated with plasma 25OHD (r_p = –0·32). No change in BMD at the femoral neck and forearm was observed 1 year after surgery. Conclusion Low vitamin D status and high plasma 1,25(OH)₂D are associated with increased bone turnover and decreased BMD in patients with PHPT.     

Primary hyperparathyroidism masked by antituberculous therapy-induced vitamin D deficiency

Antituberculous chemotherapy agents, particularly rif-ampicin and isoniazid, affect vitamin D metabolism and can create biochemical evidence of vitamin D deficiency. Vitamin D deficiency induces a state of resistance to parathyroid- hormone. This study sought to explain the temporary resolution of hypercalcaemia and hyper-calciuria, during antituberculous chemotherapy with rifampicin and isonizid, in a subject with a surgically proven parathyroid adenoma and coincidental spinal tuberculosis. Serum ionized calcium, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, plasma Parathyroid hormone, and 24-hour urine excretions of calcium, inorganic phosphorus and hydroxyproline were sequentially measured over a 3-year interval that included 18 months of antituberculous chemotherapy. Initial serum Ionized calcium was 152mmol/l (normal 1·20-1·35 mmol/l), 24-hour urine calcium excretion was 9·40 mmol/day (normal 1·25 to 7·50 mmol/day) and plasma intact PTH was 9·2pmol/l (normal 0·0–4·5 pmol/l). During antitubercuious chemotherapy the serum ionized calcium and 24 hour urine calcium excretion were normal but the plasma PTH rose to higher levels. Following completion of the chemotherapy, hypercalcaemia and hypercalciuria returned with levels similar to those observed pretreatment. Serum 25-hydroxyvltamin D was low at 8·25 nmol/l (normal 20 to 90 nmol/l) during antituberculous chemotherapy, but was normal before and after. Serum 1,25-dihydroxyvltamin D was normal throughout the 3-year Interval. We conclude that the antituberculous chemotherapy induced relative vitamin D deficiency and resistance to parathyroid hormone action, thereby masking the hyperparathyroidism and hypercalcaemia until the chemotherapy was completed.     

Vitamin D status in primary hyperparathyroidism in India

OBJECTIVES Primary hyperparathyroidism is a syndrome with variable clinical expression, presenting as asymptomatic hypercalcaemia in Western countries and with predominant bone disease in developing countries. Vitamin D deficiency has been implicated as the cause of bone disease. There is a paucity of information on the vitamin D (25-OHD₃) status of patients with primary hyperparathyroidism presenting with bone disease. The present study aims to evaluate the vitamin D status in patients with primary hyperparathyroidism and to correlate it with the bone disease. DESIGN Twenty consecutive patients with primary hyperparathyroidism admitted to the endocrinology and metabolism wards of the All India Institute of Medical Sciences were analysed to assess their clinical, radiological and biochemical features, as well as parathyroid hormone (mid-molecular, PTH-MM) and 25-OHD₃ levels. MEASUREMENTS PTH-MM levels and 25-OHD₃ levels were measured using RIA kits. RESULTS Bone disease (osteitis fibrosa cystica) was the mode of presentation in 90%. Radiologically, sub-periosteal resorption was present in 90% of the total group of patients, brown tumours in 60%, and pathological fractures in 40%. Renal stones and/or nephrocalcinosis was present in 50% of patients. Mean serum calcium, phosphate and alkaline phosphatase concentrations (mean of 3 days values) were 2.72 ± 0.24 mmol/l; 1.01 ± 0.28 mmol/l and 425 ± 249 IU/l respectively. The 24-hour (mean of 3 days values) urine calcium and phosphate excretions were 8.0 ± 4.2 mmol and 19.0 ± 13mmol. Only 50% of the patients had hypercalcaemia (> 2.7 mmol/l). However, 90% of the whole group of patients had hypercalciurla. The mean serum creatinine concentration of patients with hypercalcaemia was 108 ± 38 μmol/l and of those with normocalcaemia 89 ± 33 pmol/l. The mean serum PTH-MM was 438 ± 350 pmol/l (the detection limit for the kit was 34 pmol/l). Ultrasound examination detected adenomas in 72% of the cases and computerized tomography of the neck localized adenomas in 71 % of the cases. The median weight of the adenoma was 4.6 g (range 0.125–25 g). Two patients had coexistent hyperplasia of the other parathyroid glands and two had recurrent adenomas. 25-OHD₃ levels were assessed in all 20 patients under fasting conditions. The mean value of 25-OHD₃ observed (8.4 ± 51 μg/l) was comparable to the mean value measured in 14 healthy age and sex matched controls (83 ± 25 μg/l). CONCLUSION Patients with primary hyperparathyroidism in India presented with bone and renal diseases; half were normocalcaemic. All the patients had hypercalcuria despite the bone disease. The PTH-MM levels were increased and 25-OHD₃ levels were low. The predominant bone disease is probably due to prolonged primary hyperparathyroidism coexisting with low calcium intake and/or 25-OHD₃ deficiency. The mean weight of the adenoma was higher than that reported for patients in the Western literature.     

Effect of age on plasma 1,25-(OH)2 vitamin D in the rat

Levels of plasma calcium, phosphorus, creatinine and 1,25-(OH)₂-D were measured in healthy male Sprague-Dawley rats aged 6 months (mature) and 20–24 months (senescent). Plasma 1,25-(OH)₂-D levels fell from 95 ± 50 pmol/l in the mature rats to 41 ± 10 pmol/l in the senescent rats (p < 0.01). Despite a significant fall in plasma phosphate from 3.06 ± 0.37 mmol/l to 2.54 mmol/l (p < 0.005) in the two groups, respectively, plasma calcium remained constant at about 2.4 mmol/l in both groups.     

Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma

ABSTRACT— A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/1), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64 787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.     

ORIGINAL ARTICLE: Association between 25‐hydroxyvitamin D,somatic muscle weakness and falls risk in end‐stage renal failure

Objective Suboptimal levels of 25‐hydroxyvitamin D (25OHD) are common in haemodialysis patients (Chronic Kidney disease‐5D: CKD‐5D) and may be associated with reduced muscle strength and increased falls risk. We tested the hypothesis that 25OHD levels may be independently associated with falls risk in CKD‐5D. Background Supplementation with calcium and cholecalciferol reduces hip and other nonvertebral fractures in elderly individuals, and this effect may in part be attributable to reduction in falls frequency. The relationship between 25OHD and falls risk has not been investigated in CKD‐5D. Design and Patients This is a cross‐sectional study of 25 CKD‐5D patients with predialysis 25OHD, 1,25‐dihydroxyvitamin D (1,25(OH)₂D) and intact parathyroid hormone (iPTH) measurement. Falls risk was assessed by quadriceps muscle strength, FallsScreen^© test (FST), Berg Balance Scale (BBS), timed ‘up and go’ (TUG) test, Modified Barthel Index (MBI) and Falls Efficacy Scale (FES). Results Mean age was 69·8 ± 12·1 years, and median time on dialysis was 3·1 years. Median 25OHD level was 55·3 nmol/l (range 20·8–125·8 nmol/l). Muscle strength was significantly positively correlated with 25OHD (P = 0·024) but not with 1,25(OH)₂D (P = 0·477) or PTH (P = 0·461). Statistically significant correlation between 25OHD levels and FST (P = 0·028) plus MBI (P = 0·0046) was noted. No significant correlation was detected between falls risk and 1,25(OH)₂D or PTH. Conclusions Suboptimal levels of 25OHD in CKD‐5D are associated with reduced quadriceps muscle strength and increased falls risk. 25OHD may be more important than the active renal metabolite 1,25(OH)₂D for muscle strength with implications for vitamin D choice and goals of supplementation. Further investigation is required to examine effectiveness of calciferol supplementation on the incidence of falls in CKD‐5D.     

Vitamin D Deficiency after Highly Selective Vagotomy

ABSTRACT While bone disease is occasionally seen after gastrectomy, the influence of vagotomy on calcium and vitamin D metabolism is uncertain. We have, therefore, investigated 23 male patients who had undergone highly selective vagotomy for ulcer 4.3±1.2 years previously. The 25OHD concentrations were decreased (p<0.05), the 1,25(OH)₂D concentrations elevated (p<0.05) and the immunoreactive parathyroid hormone concentrations normal. Local and total bone mass were normal compared to age-matched men, and there was no biochemical evidence of increased bone turnover. We suggest that the changes in calcium absorption, which are described in the literature after vagotomy, are mediated by 1,25(OH)₂D. Although the changes in vitamin D metabolism do not lead to calcium-metabolic disturbances in selected patients, we believe that some will eventually develop vitamin D deficiency and that vitamin D supplementation should be considered. Keywords: vitamin D, bone mass, calcium homeostasis, vagotomy.     

Effect of Sunlight Exposure on Circulating 1,25-Dihydroxyvitamin D in Hemodialyzed Patients and of Exogenous Parathyroid Hormone in Anephric Patients

ABSTRACT. Sunshine exposure increased the serum concentration of 25-hydroxyvitamin D (25-OHD) in 9 hemodialyzed patients. Mean 1,25-dihydroxyvitamin D (1,25-(OH)₂D) was unchanged, but in two patients with low initial 25-OHD values this increase was accompanied by a rise in circulating l,25-(OH)₂D, although not to normal levels. One hemodialyzed patient developed liver insufficiency with a resultant reduction of serum 25-OHD concentration accompanied by a decrease in serum 1,25-(OH)₂D concentration. The results indicate that the circulating levels of 1,25-(OH)₂D in patients with end-stage renal failure are to some extent regulated by the serum 25-OHD concentrations. Injection of parathyroid hormone (PTH) induced minor increases in serum concentrations of 1,25-(OH)₂D in patients with end-stage renal failure and even in anephric patients, suggesting the existence of an extrarenal PTH-sensitive 1-α-hydroxylase. However, the enzyme was stimulated by supra-physiological concentrations of PTH, and therefore not necessarily of importance in the normal regulation of calcium metabolism.     

Very low or undetectable intact parathyroid hormone levels in patients with surgically verified parathyroid adenomas

Objectives To report and explore potential reasons for undetectable or low‐normal serum intact PTH levels in patients with surgically verified primary hyperparathyroidism with parathyroid adenomas, review the relevant literature, and offer suggestions for management of such patients occasionally encountered in clinical practice. For future research, to help understand mechanisms underlying ‘undetectable’ or inappropriately low serum intact PTH levels. Methods Serum intact PTH levels were measured pre‐ and postoperatively by immunochemiluminescent assay (ICMA) and the results were confirmed by at least two repeated measurements on different occasions in each patient. Patients We encountered two unusual patients with primary hyperparathyroidism who had suggestive biochemical and/or clinical features of primary hyperparathyroidism. However, serum intact PTH levels were either very low or undetectable in the context of hypercalcaemia, with no other obvious cause. A ^99mTc sestamibi scan showed increased uptake in one of the parathyroid glands, suggesting a single adenoma in each case that was confirmed at surgery. Results In the first patient, from India, mean ± SD serum calcium was 2·6 ± 0·32 mmol/l (reference range 2·12–2·74 mmol/l) with intact PTH of 0·11 pmol/l (reference range 1·1–7·59 pmol/l). In the second patient, from the USA, mean ± SD serum calcium and intact PTH were 2·9 ± 0·07 mmol/l (reference range 2·17–2·51 mmol/l) and 1·35 pmol/l (reference range 1·1–7·59 pmol/l), respectively. Following curative parathyroidectomy, serum calcium levels normalized in both patients. By contrast, serum intact PTH levels, which were either suppressed or very low before surgery, rose into the low‐normal reference range in all patients. Conclusions When the clinical suspicion is high, the diagnosis of primary hyperparathyroidism should be pursued despite suppressed or low‐normal serum intact PTH levels after carefully excluding other causes of hypercalcaemia. Further research on various intact PTH molecular species secreted by parathyroid adenomas or post‐translational changes in the intact PTH molecule that might interfere with in vitro measurements should be undertaken to understand the precise reason(s) for such anomalous findings.     

HYPERCALCAEMIA IN ASSOCIATION WITH RENAL FAILURE: THE ROLE OF IMMOBILISATION

Hypercalcaemia occurring after ten weeks of immobilisation was observed in four adult patients all of whom had had prior renal failure sufficient to require renal dialysis. In all patients parathyroid hormone levels were normal or low and in three plasma 1,25(OH)₂D₃ levels were low. These findings are consistent with immobilisation induced increases in bone calcium resorption. Renal excretion of calcium may have been impaired by renal dysfunction resulting in hypercalcaemia and suppression of plasma PTH and 1,25(OH)₂D₃ levels. Resolution of the hypercalcaemia was associated with remobilisation. Parathyroidectomy is inappropriate treatment.     

Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney

 A patient with primary non-Hodgkin's (B-cell type) lymphoma of the kidney developed hypercalcemia at the terminal stage of the disease. Although the plasma parathyroid hormone level was low, urinary cyclic AMP excretion was elevated. Serum osteocalcin (BGP) was suppressed and the plasma level of 1,25(OH)₂D was within the normal range. Serum concentrations of PTH-related protein (PTHrP)-like immunoreactivity (PRP-LI) were elevated, and the tissue concentration of PRP-LI in the postmortem lymph node showed high level along with elevated serum PRP-LI, furthermore the production of PTHrP by the tumor was demonstrated by immunohistochemistry and Northern blotting analysis. These findings indicate that the hypercalcemia of the patient was caused by the PTHrP-producing B-cell lymphoma. Hypercalcemia was restored to normocalcemia by bisphosphonate treatment. Our case will add further information on humoral hypercalcemia in B-cell lymphoma, which rarely has been demonstrated to produce PTHrP. Received: 17 July 1997 / Accepted: 2 February 1998     

Calcium and vitamin D metabolism in granulomatous diseases

Summary Overproduction of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)₂D) has been described in sarcoidosis and other granulomatous diseases. High circulating concentrations of 1,25(OH)₂D lead to increased intestinal absorption of calcium, possibly to enhanced bone resorption, and may result in hypercalcaemia and/or hypercalciuria. Data obtained in vivo and in vitro demonstrated that the unregulated production of 1,25(OH)₂D lies within the granulomatous tissue and is controlled by glucocorticoids. This abnormal production of 1,25(OH)₂D seems to be a general phenomenon of granulomatous processes, which is not exceptional in sarcoidosis, but appears seldom in tuberculosis. These abnormalities, however, are not pathognomonic of granulomatous processes, since they have been described in other diseases such as lymphomas.     

COMPARISON OF INTESTINAL CALCIUM ABSORPTION AND CIRCULATING 1,25-DIHYDROXYVITAMIN D LEVELS IN MALIGNANCY-ASSOCIATED HYPERCALCAEMIA AND PRIMARY HYPERPARATHYROIDISM

The relation between circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and intestinal calcium absorption--as determined by an oral calcium load test--was studied in 16 patients with hypercalcaemia of malignancy (HM) and 16 with hypercalcaemic primary parathyroidism (HPT). In the HPT group serum calcium rose significantly after the oral calcium load and the increment correlated significantly with 1,25(OH)2D levels. While 1,25(OH)2D levels were raised to within the hyperparathyroid range in a number of HM patients, there was no correlation between change in serum calcium and 1,25(OH)2D level in the HM group and serum calcium did not rise significantly after the oral calcium load. HM patients with detectable or raised 1,25(OH)2D levels typically had few, or no, bone metastases in association with squamous lung cancers. A high proportion of these patients exhibited other aspects of hyperparathyroid-like activity such as increased renal tubular calcium reabsorption, depressed renal tubular phosphate reabsorption and elevated urinary cyclic AMP excretion. Conversely, HM patients with undetectable 1,25(OH)2D levels typically had extensive metastatic bone disease in association with breast carcinoma and were less likely to exhibit other hyperparathyroid-like features. It is postulated that in the former, the 'inappropriately' detectable or raised 1,25(OH)2D levels may have been due to enhanced renal 1 alpha-hydroxylase activity stimulated by the parathyroid hormone (PTH)-like effect of a non-PTH ectopic humoral mediator. In the latter the suppressed 1,25(OH)2D levels would be the predicted result of a non-humorally mediated hypercalcaemia. It is currently unclear why intestinal calcium absorption was depressed in all HM patients when 1,25(OH)2D levels were normal or raised in some cases. It is possible, however, that in HM there is 'end organ' resistance to the effects of 1,25(OH)2D due to a generalized malabsorptive process.