Margaret Wilkinson

Osteoporosis and skeletal fractures in chronic liver disease.

In order to determine the prevalence and severity of hepatic osteodystrophy by non-invasive means we compared 115 consecutive ambulant patients with histologically proven chronic liver disease to 113 age and sex matched control subjects. Methods used included the assessment of fracture prevalence rates, spinal radiography, and measurements of bone mineral density in the spine and the forearm. Spinal and peripheral fractures were more prevalent in the patients than in the control subjects (p less than 0.03 and p less than 0.01 respectively). The type of the underlying liver disease did not significantly affect the fracture prevalence rates, but alcoholic patients sustained more peripheral fractures than patients with other hepatic disorders (p less than 0.05). The bone mineral densities of the spines and the forearms were significantly reduced in male patients of all age groups and in female patients aged 60 years or more (p less than 0.001 for men and p less than 0.01 for women for both measurements). The prevalence rates of spinal and forearm osteoporosis were twice as high among patients with liver disease than in control subjects regardless of the definitions used. The presence of cirrhosis and hypogonadism were major risk factors for development of both spinal (Beta coef = 0.190 and 0.176; SE = 0.079 and 0.086 respectively) and forearm osteoporosis (Beta coef = 0.20 and 0.29; SE = 0.073 and 0.80 respectively). Spinal bone density was the predominant determinant of spinal fractures (Beta coef = -0.007; SE = 0.001), while hypogonadism (Beta coef = 0.363; SE = 0.075) and cirrhosis (Beta coef = 0.185; SE = 0.068) were the major predictors of peripheral fractures. The concentrations of serum calcium and serum vitamin D metabolites and the use of corticosteroids were apparently without effect on the prevalence of skeletal fractures or bone density.

PARATHYROID HORMONE ASSAY PREDICTS HYPOCALCAEMIA AFTER TOTAL THYROIDECTOMY

Background:  Postoperative parathyroid gland function after total thyroidectomy (TT) has traditionally been monitored by the measurement of serum calcium concentrations. The purpose of this study is to determine whether measurement of parathyroid hormone (PTH) concentrations in the early postoperative period accurately predicts patients at risk of developing hypocalcaemia.

Characteristics of tumor cell bioactivity in oncogenic osteomalacia

Oncogenic osteomalacia is a condition where renal phosphate wasting occurs causing defective mineralisation, in the presence of a tumor. Cultures of cells were established from a hemangiopericytoma resected from a patient with oncogenic osteomalacia. Conditioned media from the cells inhibited phosphate uptake in opossum kidney cells and stimulated of cAMP in rat osteosarcoma cells, a standard parathyroid hormone (PTH)-like assay. This cAMP stimulation was suppressed by the PTH analogue, 3-34 bPTH and also by heat and trypsin treatment of the media. Tests of conditioned media for PTH and parathyroid hormone related protein (PTHrP) immunoreactivity were negative, however, and no hybridisation to probes for PTH, PTHrP or human stanniocalcin was detected in tumor cell RNA on Northern blot. These data support the hypothesis that tumors responsible for oncogenic osteomalacia produce a humoral substance that reduces renal phosphate reabsorption and provide evidence that the factor may act via PTH/PTHrP receptors.

Minimally invasive parathyroidectomy using the lateral focused mini-incision technique without intraoperative parathyroid hormone monitoring

Minimally invasive parathyroidectomy (MIP) involves scan‐directed removal of a single adenoma through a 2·0‐cm mini‐incision without intraoperative monitoring. The aim of this study was to analyse the outcomes of MIP using such a simplified technique.

Forearm mineral content in normal men: relationship to weight, height and plasma testosterone concentrations.

We measured forearm bone mineral content by single photon absorptiometry together with height, weight and the plasma concentrations of testosterone, free testosterone and sex steroid binding globulin in 66 normal Caucasian males aged 29-46 years. Multiple regression analysis suggests that bone mineral content in either the dominant or the nondominant arm is correlated with weight and sex steroid binding globulin (p less than 0.05 for both parameters). The partial negative correlation of bone mineral content (corrected for weight and sex steroid binding globulin) with plasma testosterone failed to reach statistical significance (p = 0.07). The parsimonious regression equation which best explained the bone mineral content measurements in the nondominant forearm in these men was bone mineral content = 29.1-0.374 (plasma testosterone) + 0.383 (weight) + 0.220 (sex steroid binding globulin) with an R2 value of 29.7%. A similar equation was generated for the dominant arm.

Routine Parathyroid Autotransplantation during Total Thyroidectomy: the Influence of Technique

OBJECTIVE To find out whether injecting a suspension of finely minced parathyroid tissue into the muscle bed had any adverse outcomes as it is simpler and potentially safer than implanting parathyroid tissue into muscle pockets. DESIGN Prospective, randomised, controlled clinical trial. SETTING University hospital, Australia. PATIENTS 50 patients who were to have total thyroidectomy and routine parathyroid autotransplantation. INTERVENTIONS Patients were randomised to either the injection technique or the implantation technique. MAIN OUTCOME MEASURES Clinical assessment; corrected serum calcium and intact parathyroid hormone concentrations (PTH) measured immediately before, and at 1 day, 2 weeks, and 3 months after operation. RESULTS Calcium was reduced significantly in both groups immediately after thyroidectomy. Although mean PTH concentrations decreased immediately after thyroidectomy and parathyroid autotransplantation in both groups, these changes were significant only in the implantation group. By 2 weeks and again by 3 months, calcium and intact parathyroid hormone concentrations had returned to baseline in both groups. At 3 months, 2 patients in each group still required some form of calcium supplement. At 6 months, no patients in the injection group required supplement. CONCLUSIONS Injection of a suspension of parathyroid tissue is a simple, safe, and rapid technique for parathyroid autotransplantation during total thyroidectomy and is not associated with any more adverse outcome than is the standard technique.

A 6-hour human parathyroid hormone (1-34) infusion protocol: studies in normal and hypoparathyroid subjects.

SummaryParathyroid hormone (PTH)-resistant states are usually diagnosed by the failure of an acute PTH injection to elicit a rise in urinary cAMP and phosphate or, less commonly, by the failure of repeated PTH injections to raise serum calcium. We have established a 6 hour infusion of human PTH (1–34) which identifies PTH-resistant hypoparathyroid subjects on the basis of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium responses. 1.25-Dihydroxyvitamin D levels increased by at least 58 pmol/liter and serum calcium by at least 0.1 mmol/liter in PTH-responsive hypoparathyroid subjects (n=6), whereas in pseudohypoparathyroid subjects (n=5) these levels rose by less than 22 pmol/liter and 0.06 mmol/liter respectively. The responsiveness of urinary phosphate excretion, expressed as the renal threshold phosphate concentration (TmPO4/GFR), to PTH also clearly separated the pseudohypoparathyroid patients from the other subjects. Differences in urinary calcium responses were observed though this parameter was less reliable in the identification of individual PTH-resistant or PTH-sensitive hypoparathyroid patients. Nephrogenous cAMP did not discriminate between groups when this protocol was used. This test has the potential to facilitate and extend the classification of PTH-resistant states.

Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat.

A 3-year-old Ragdoll cat was referred for investigation of polyuria, polydipsia, vomiting, weight loss and hypercalcaemia. Serum biochemical abnormalities included total and ionised hypercalcaemia and hypophosphataemia. Following clinical investigations a diagnosis of idiopathic hypercalcaemia was made. Because of the severity of the hypercalcaemia and the associated clinical signs, treatment for hypercalcaemia was commenced with pamidronate. Major electrolyte abnormalities were detected but, remarkably, were accompanied by minimal clinical signs. The cat was subsequently treated with oral alendronate and is clinically normal 15 months later. Reports of the use of bisphosphonates in cats are limited and close monitoring of patients is recommended.

Adenomatous Human Parathyroid Cells Exhibit Impaired Sensitivity to l-Amino Acids

CONTEXT Primary hyperparathyroidism, which occurs most commonly in patients with adenomatous disease of a single parathyroid gland, arises as a result of impaired extracellular Ca(2+) (Ca(2+)(o))-dependent feedback on PTH secretion, a process mediated by the calcium-sensing receptor (CaR). OBJECTIVE Because the Ca(2+)(o) sensitivity of the CaR is positively modulated by L-amino acids, we decided to investigate whether the impaired feedback of PTH secretion in adenomatous parathyroid cells might arise from decreased sensitivity to L-amino acids. DESIGN Samples of normal and adenomatous human parathyroid cells were prepared by collagenase treatment and then exposed in vitro to various concentrations of Ca(2+)(o) or the CaR-active amino acid, L-phenylalanine (L-Phe). SETTING AND PATIENTS Excess normal parathyroid tissue was obtained from parathyroid autotransplants at the time of thyroid surgery. Samples of adenomatous tissue were obtained from histologically confirmed parathyroid adenomas. MAIN OUTCOME MEASURES The primary measure was sensitivity of Ca(2+)(o)-dependent PTH secretion to the amino acid L-Phe. The secondary measure was sensitivity of Ca(2+)(o)-dependent intracellular Ca(2+) mobilization to L-Phe. RESULTS Parathyroid adenomas exhibited reduced sensitivity to the CaR-active amino acid L-Phe, which affected both Ca(2+)(o)-dependent PTH secretion and Ca(2+)(o)-dependent intracellular Ca(2+) mobilization as a measure of CaR-dependent signaling in parathyroid cells. CONCLUSIONS Impaired L-amino acid sensing by calcium-sensing receptors in adenomatous parathyroid cells contributes to the loss of feedback control of PTH secretion in primary hyperparathyroidism. The CaRs amino acid binding site may be exploited as a target in the medical treatment of primary and perhaps other forms of hyperparathyroidism.

Vitamin D-Dependent Non-Type 1, Non-Type 2 Rickets in a 3-Month-Old Cornish Rex Kitten

Case presentation and assessment A 3-month-old female Cornish Rex kitten was found to have non-painful swelling of the carpal and tarsal regions when presented for routine neutering. The kitten was smaller in stature and less active than its siblings and, according to the owner, had a bunny-hopping gait, was reluctant to climb stairs and strained during defecation. Radiography of the affected limbs and a subsequent radiographic survey of the entire skeleton demonstrated features consistent with rickets. The three littermates were clinically and radiographically normal. As a nutritionally complete diet was being fed, it seemed most likely that the kitten had an inborn error related to vitamin D metabolism. Serum biochemistry demonstrated reduced total alkaline phosphatase activity and increased concentrations of parathyroid hormone. Concentrations of 1,25- and 25-hydroxycholecalciferol were markedly reduced, confirming the diagnosis of rickets. Treatment The kitten was treated with calcitriol, administered orally once daily, and improved rapidly both clinically and radiologically. Serial laboratory studies suggested that the error in vitamin D metabolism was transient, and, at the time of writing, as an adult, the cat appears to require no ongoing replacement calcitriol therapy. Clinical relevance This case emphasises the value of examining a full ‘calcium profile’ via a human or veterinary reference laboratory, and a favourable prognosis in some kittens with rickets makes such investigations worthwhile. Even when finances preclude detailed investigation, trial therapy using a nutritionally complete diet and physiological doses of calcitriol or cholecalciferol is inexpensive and can produce a good response.