Hyperparathyroid disorders in the dog: primary, secondary and cancer-associated (pseudo)

Hyperparathyroid disorders were diagnosed in four dogs: one had primary hyperparathyroidism, characterized by parathyroid adenoma and hyper-calcaemia; one had renal secondary hyperparathyroidism, characterized by parathyroid gland hyperplasia, hypocalcaemia and renal failure; and two had cancer-associated hyperparathyroidism (pseudohyperpara-thyroidism), characterized by the presence of neoplasia, parathyroid gland atrophy, hypercalcaemia and absence of skeletal metastases. Significant clinicopathologic findings included serum concentrations of calcium, phosphorus and immunoreactive parathyroid hormone (PTH), presence or absence of parathyroid and bone lesions, and the presence of non-parathyroid neoplasia.     

Calcium metabolism in birds.

Calcium is one of the most important plasma constituents in mammals and birds. It provides structural strength and support (bones and eggshell) and plays vital roles in many of the biochemical reactions in the body. The control of calcium metabolism in birds is highly efficient and closely regulated in a number of tissues, primarily parathyroid gland, intestine, kidney, and bone. The hormones with the greatest involvement in calcium regulation in birds are parathyroid hormone, 1,25-dihydroxyvitamin D(3) (calcitriol), and estrogen, with calcitonin playing a minor and uncertain role. The special characteristics of calcium metabolism in birds, mainly associated with egg production, are discussed, along with common clinical disorders secondary to derangements in calcium homeostasis.     

Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between 1992 and 1995

Eighty cats with chronic renal failure (CRF) were evaluated in a prospective study to investigate the prevalence and aetiopathogenesis of renal secondary hyperparathyroidism (RHPTH), using routine plasma biochemistry and assays of parathyroid hormone (PTH), blood ionised calcium and 1,25 dihydroxycholecalciferol (1,25[OH]₂D₃). Hyperparathyroidism was a frequent sequela of CRF, affecting 84 per cent of cats with CRF, the severity and prevalence of RHPTH increasing with the degree of renal dysfunction. Compared with an age-matched control population, plasma concentrations of phosphate and PTH were significantly higher and 1,25(OH)₂D₃ concentrations were significantly lower in the two groups of cats presenting with clinical signs of CRF. Significant ionised hypocalcaemia was present only in cats with end-stage renal failure. However, a number of cats were hyperparathyroid in the absence of abnormalities in the parameters of calcium homeostasis measured in this study. There was a significant correlation between plasma phosphate and PTH concentrations.     

Measurement of feline intact parathyroid hormone: Assay validation and sample handling studies

A two-site intact immunoradiometric assay was validated for the measurement of parathyroid hormone (PTH) in the cat, by assessment of precision, sensitivity and specificity. The mean intra- and interassay coefficients of variation were 12·7 and 12·8 per cent, respectively. The sensitivity of the assay was 3·90 pgl/ml. The presence of carboxyl fragment interference was suspected from the non-parallel dilution of two of seven feline samples and the decreased recovery of PTH on addition of carboxyl terminal fragment PTH to samples. The plasma PTH concentration, measured using this assay, in 40 clinically healthy cats was 10·9 ± 5·3 pg/ml (mean ± SD). The assay demonstrated appropriate responses in cases of secondary renal hyperparathyroidism, hypercalcaemia of malignancy and iatrogenic hypoparathyroidism. Storage characteristics would permit posting of samples. This assay will therefore provide a useful non-invasive tool for the diagnosis of disorders of calcium metabolism in the cat.     

成纤维细胞生长因子23在骨矿物质代谢中的作用及其调控机理

骨源性激素成纤维细胞生长因子23(FGF23)介导由甲状旁腺、肾脏、骨骼和维生素D组成的负反馈回路,建立"骨骼-肾脏-甲状旁腺"内分泌轴,参与骨矿物质代谢并发挥重要作用。钙、磷、铁、维生素D、甲状旁腺素(PTH)、成纤维细胞生长因子受体(FGFR)/FGF以及蛋白质翻译后修饰调控FGF23的分泌、活性和胞内过程。随着深入的研究,探索出了一些以FGF23为靶点治疗骨矿物质代谢障碍疾病的新疗法。本文综述了FGF23在骨矿物质代谢中的作用及其调控机理的研究进展,以期为相关研究提供参考依据。     

Plasma 1,25 dihydroxycholecalciferol and its free index are potentiated by ovulation dependent factors and shell formation induced hypocalcemia in the laying hens.

The time-course of the changes in blood ionized calcium, and in plasma 1,25 dihydroxycholecalciferol (1,25(OH)2D3) concentrations and its free index were studied in hens following suppression and resumption of shell formation and throughout the laying cycle in hens laying hard-shelled eggs, in hens fed a low or normal calcium diet and in hens laying shell-less eggs. The respective roles of the calcium needs for shell formation and of the reproductive status in regulation of 1,25(OH)2D3 production were analysed. Plasma 1,25(OH)2D3 decreased 3 hr after suppression of shell formation following premature egg expulsion and remained lower than that of hens laying hard-shelled eggs when premature expulsion of the eggs was continued for several days. Circulating 1,25(OH)2D3 tended to increase progressively when shell formation was resumed. Ablation of the parathyroid glands abolished this increase. In hens laying hard-shelled eggs, the plasma 1,25(OH)2D3 was higher during the period of shell secretion. Feeding hens a low calcium diet (1.2%) caused a marked increase in the plasma 1,25(OH)2D3. Ionized calcium levels tended to show reciprocal changes to plasma 1,25(OH)2D3 decreasing when calcification took place and increasing after its suppression. In hypercalcemic hens laying shell-less eggs and fed a 3.5% Ca diet, the plasma 1,25(OH)2D3 was at a high level 4 hr after ovulation and diminished thereafter. This additive stimulation does not, therefore, involve the parathyroid gland and may involve hormonal changes induced by ovulation. Vitamin D binding protein (DBP) in the plasma was at a high level in mature hens and was not affected by shell formation. Consequently, the free 1,25(OH)2D3 index fluctuated in parallel with total level of this hormone in mature hens. It is concluded that the calcium demand for shell formation modulates, in the short term, plasma 1,25(OH)2D3, via the homeostatic regulation of blood calcium by PTH, but that a large part of its increase is independent of PTH and is associated with the endocrine events concomitant with ovulation.     

Hormonal calcium regulation and calcium setpoint in offspring of bitches with different calcium intakes during pregnancy

High maternal calcium (Ca) intake may lead to alterations in development and differentiation of fetal tissues and may result in altered 'programming' of Ca homeostasis, with eventual effects on Ca handling and skeletal development in the offspring during later life. In bitches fed a diet with a Ca intake three times above recommendations (3.27 g/100 g vs 1.14 g/100 g dry matter) during the second half of pregnancy, the plasma concentration of 1,25 dihydroxy cholecalciferol (1,25 (OH)₂ vit D) appeared to decrease, while plasma Ca, phosphorus (P), parathyroid hormone (PTH) and calcitonin (CT) concentrations remained unchanged. High maternal Ca intake did not result in altered basal or stimulated plasma concentrations of Ca, P, PTH, CT and 1,25 (OH)₂ vit D in the offspring (n = 7) when compared with pups from bitches fed a normal Ca diet during the entire pregnancy (controls, n = 7). The Ca setpoint for PTH secretion (^Ca S_for PTH) was therefore not different from controls. From this pilot study it may be concluded that excessive Ca intake during late pregnancy in the bitch has no deleterious effects on hormonal Ca homeostasis in the offspring.     

Fanconi's Syndrome in a Dog With Primary Hypoparathyroidism

An 11 -year-old castrated male mixed breed dog was referred for evaluation of muscle twitching, polyuria, polydipsia, anorexia, and periocular alopecia. Primary hypoparathyroidism was diagnosed by documenting decreased serum concentrations of parathyroid hormone and ionized calcium. Neurological, gastrointestinal, and dermatological signs resolved after calcium repletion. Initially, 1,25-dihydroxycholecalcif erol PO was required to correct the hypocalcemia. Dihydrotachysterol, in combination with oral calcium supplementation, was used for long-term maintenance of normal serum calcium concentration. Aminoaciduria, glucosuria, and hyperchloremic metabolic acidosis were consistent with a diagnosis of Fanconi's syndrome. This diagnosis was further supported by the presence of hypokalemia and increased urinary fractional excretion of sodium, potassium, calcium, phosphorus, and magnesium. Renal tubular dysfunction resolved after oral supplementation with calcium and vitamin D₃. Fanconi's syndrome in this dog may have been caused by decreased serum concentration of 1,25-dihydroxycholecalciferol, which was secondary to decreased parathyroid hormone production.     

Parathyroid gland function in the uremic rabbit

Rabbits with renal failure have been reported to be hypercalcemic and to have decreased parathyroid hormone (PTH) concentrations. Thus, it would seem that uremic rabbits are resistant to secondary hyperparathyroidism (HPT). The work reported here was designed to investigate parathyroid gland function in uremic rabbits and the effect of diets with different calcium (Ca) and phosphorus (P) content. The relationship between PTH and ionized calcium (Ca2+), parathyroid gland size and parathyroid cell cycle were studied in three groups of rabbits: Group I, rabbits with normal renal function on a standard diet (Ca = 1.2%, P = 0.6%); Group II, partially nephrectomized rabbits on a standard diet; and Group III, partially nephrectomized rabbits on a low Ca (0.6%)-high P (1.2%) diet. Group I rabbits had baseline Ca2+ = 1.71 +/- 0.05 mmol/l and PTH = 26.9 +/- 3.2 pg/ml. During hypo- and hypercalcemic stimulation PTH reached maximal values (PTHmax) of 94.4 +/- 5.5 pg/ml and minimal concentrations (PTHmin) of 3.2 +/- 0.2 pg/ml. Rabbits from Group II were hypercalcemic (baseline Ca2+ = 2.03 +/- 0.06 mmol/l) and had very low PTH levels (1.7 +/- 0.5 pg/ml); however, they reached a PTHmax that was similar to Group I, 92 +/- 8.7 pg/ml. Group III rabbits were hypocalcemic (baseline Ca2+ = 1.22 +/- 0.08 mmol/l) and had very high basal PTH levels (739 +/- 155 pg/ml). Their PTHmax and PTHmin were 801 +/- 169.4 pg/ml and 102.2 +/- 22.2 pg/ml, respectively. Both parathyroid gland size and parathyroid cell proliferation were increased in Group III. In conclusion, our results show that the Ca and P content of the diet markedly influence PTH secretion in the uremic rabbit and that when placed on a low Ca-high P diet uremic rabbits develop secondary HPT.     

Functional analysis of ectopic parathyroid activity in cats

The ability of ectopic parathyroid tissue to support calcium homeostasis was evaluated by measuring serum concentrations of calcium, phosphorus, albumin, magnesium, and parathyroid hormone before and for 12 weeks after bilateral thyroparathyroidectomy in 14 cats. During the immediate postoperative period, significant decrease was observed in serum calcium, magnesium, and parathyroid hormone (PTH) concentrations. Serum PTH concentration remained subnormal and did not significantly increase during the 12-week observation period. Despite persistent hypoparathyroidism, serum calcium and magnesium concentrations gradually increased. Ectopic parathyroid tissue is not capable of maintaining normal serum calcium concentration immediately after thyroparathyroidectomy. Serum calcium concentration gradually normalizes after thyroparathyroidectomy, apparently by means of a PTH-independent mechanism.     

Primary hyperparathyroidism in cats: seven cases (1984-1989).

The medical records of 7 hypercalcemic cats with primary hyperparathyroidism were evaluated. Mean age was 12.9 years, with ages ranging from 8 to 15 years; 5 were female; 5 were Siamese, and 2 were of mixed breed. The most common clinical signs detected by owners were anorexia and lethargy. A cervical mass was palpable in 4 cats. Serum calcium concentrations were 11.1 to 22.8 mg/dl, with a mean of 15.8 mg/dl calculated from each cat's highest preoperative value. The serum phosphorus concentration was low in 2 cats, within reference limits in 4, and slightly high in 1 cat. The BUN concentration was greater than 60 mg/dl in 2 cats, 31 to 35 mg/dl in 2 cats, and less than 30 mg/dl in 3 cats. Abnormalities were detected in serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities from 2 or 3 cats. Parathormone (PTH) concentrations were measured in 2 cats before and after surgery. The preoperative PTH concentration was within reference limits in 1 cat and was high in 1 cat. The PTH concentrations were lower after surgery in both cats tested. A solitary parathyroid adenoma was surgically removed from 5 cats, bilateral parathyroid cystadenomas were surgically resected in 1 cat, and a parathyroid carcinoma was diagnosed at necropsy in 1 cat. None of the cats had clinical problems with hypocalcemia after surgery, although 2 cats developed hypocalcemia without tetany, one of which was controlled with oral administration of dihydrotachysterol and the other with oral administration of 1,25 dihydroxyvitamin D. All 5 of the cta that underwent removal of an adenoma were alive at least 240 days after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathophysiological effects of low dietary phosphorus in pigs

SUMMARY: The homeostasis of inorganic phosphate (P(i)) is regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), and P(i)itself in the intestine, kidney, and bone in all the mammalian species studied. Determinations of the serum concentrations of PTH, 1,25(OH)(2)D and osteocalcin were done in 82 southern Romanian Landrace pigs originating from three herds with dietary P(i)deficiency. Serum P(i)concentrations were negatively correlated with those of 1,25(OH)(2)D. In lactating animals and sucklings, the linear relationships between P(i)and 1,25(OH)(2)D were not present. Serum P(i)concentrations were positively correlated with those of PTH. In lactating animals and young pigs, the linear relationships between P(i)and PTH were not evident. PTH and 1,25(OH)(2)D concentrations were negatively correlated. The serum concentrations of 1,25(OH)(2)D and osteocalcin were positively correlated. Milk P(i)concentrations ranging from 3.10 to 7.49 mmol/L were correlated positively with urinary P(i)concentrations ranging from 0.26 to 11.37 mmol/L. In conclusion, similarly to other species, P(i)homeostasis is achieved in pigs by feedback mechanisms between P(i), PTH and 1,25(OH)(2)D and osteocalcin production is induced by 1,25(OH)(2)D. The effect of lactation on P(i)homeostasis remains to be explored.     

Ciclosporin therapy is associated with minimal changes in calcium metabolism in dogs with atopic dermatitis

Background – Ciclosporin is widely used in the management of canine atopic dermatitis. In humans, ciclosporin therapy has been linked to disturbances in calcium metabolism and resultant skeletal disorders. Objectives – The objective of this study was to assess calcium homeostasis in dogs before and after a 6 week course of once daily oral ciclosporin at the licensed dose (5 mg/kg). Animals – Sixteen client‐owned dogs with spontaneous atopic dermatitis. Methods – Serum concentrations of calcium, phosphate, creatinine, 25‐hydroxyvitamin D, 1,25‐dihyroxyvitamin D and plasma concentrations of ionized calcium and parathyroid hormone (PTH) were measured, together with the urinary fractional excretion of calcium and phosphate. The extent of skin lesions was scored using the Canine Atopic Dermatitis Extent and Severity Index (CADESI)‐03 and the degree of pruritus by the Edinburgh Pruritus Scale prior to and at the end of the study. Results – The CADESI‐03 and the Edinburgh Pruritus Scale scores decreased satisfactorily in all dogs by the end of the study. Plasma PTH concentrations were significantly increased (P = 0.02) following ciclosporin treatment, whereas all other biochemical parameters were not significantly different from their starting values. The increase in PTH was mild in most cases and the proportion of dogs that had a PTH concentration above the reference range was not significantly different following treatment. Conclusions and clinical importance – This study indicates that ciclosporin has minimal impact on calcium metabolism in dogs with atopic dermatitis when used at the licensed and clinically effective dosage for 6 weeks.     

Newer aspects of parathyroid chemistry and physiology.

We have attempted to integrate in this review many recent studies on the formation, packaging and secretion of parathormone by the parathyroid gland. We have shown that substantial new insights have been gained into this complex cellular operation. Continuing investigation should clarify many of the outstanding questions regarding function of the parathyroid in their central role in calcium homeostasis.     

Dietary 135-fold cholecalciferol supplementation severely disturbs the endochondral ossification in growing dogs

The effects of excessive non-toxic dietary Vitamin D₃ supplementation on Ca homeostasis with specific effects on endochondral ossification and skeletal remodeling were investigated in a group of growing Great Dane dogs supplemented with cholecalciferol (Vitamin D₃; HVitD) versus a control group (CVitD) (1350 μg versus 11.4 μg Vitamin D₃ per kilogram diet) from 6 to 21 weeks of age. There were no differences between groups in plasma concentrations of total Ca, inorganic phosphate, growth hormone, and insulin-like growth factor I and no signs of Vitamin D₃ intoxication in HVitD. For the duration of the study in HVitD compared to CVitD, plasma levels of parathyroid hormone (PTH) decreased, calcitonin (CT) increased, 25-hydroxycholecalciferol [25(OH)D₃] increased 30- to 75-fold, 24,25-dihydroxycholecalciferol [24,25(OH)₂D₃] increased 12- to 16-fold, and 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] decreased by approximately 40%. The latter was attributed to the two-fold increased metabolic clearance rate in the HVitD versus CVitD accompanied by the absence of the anabolic effect of PTH on the production of 1,25(OH)₂D₃. Fractional Ca absorption () did not differ between groups at 8 and 14 weeks of age, whereas at 20 weeks of age increased by only 16.4% in HVitD compared to CVitD. Excessive non-toxic Vitamin D₃ supplementation resulted in decreased bone remodeling and focal enlargement of the growth plate with morphology resembling those induced by administration of CT. Hypercalcitoninemia and the imbalanced relationship between 1,25(OH)₂D₃ and 24,25(OH)₂D₃ are potent candidates for the disturbed endochondral ossification.     

Dietary phosphorus restriction affects bone metabolism,vitamin D metabolism and rumen fermentation traits in sheep

Homeostasis of calcium (Ca) and phosphate (P_i) is maintained by a concerted interplay of absorption and reabsorption via the gastrointestinal tract and the kidney and by storage and mobilization from the bone regulated mainly by parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol and calcitonin. The present study aimed at characterizing the effects of dietary P restriction on bone, vitamin D metabolism and rumen fermentation traits reflecting the endogenous P cycle maintaining the ruminal P supply for microbial metabolism. The experiments were done in eleven female, non-pregnant, non-lactating four- to nine-year-old Black Headed Mutton sheep allotted to two feeding groups: "P-restricted" (0.11% P/kg DM and 0.88% Ca/kg DM) and "Control" (0.38% P/kg DM and 0.88% Ca/kg DM). Dietary P restriction did not lead to hypophosphataemia, probably due to a compensation by bone mobilization, demonstrated by increased serum concentrations of a resorption marker and altered gene expression in bone tissue. In addition, the RNA expression of fibroblast growth factor 23, a bone-derived factor involved in the regulation of vitamin D metabolism, was significantly reduced with dietary P restriction. Furthermore, several genes related to vitamin D metabolism and plasma concentrations of 1,25-(OH)₂D were associated with serum concentrations of phosphate (P_i). In the parotid gland, the expression of the P_i transporter NaPi2b was negatively associated with serum P_i and positively with parathyroid PTH expression. Although P_i concentrations in saliva and the gastrointestinal tract were significantly reduced, we found no adverse effects of the P-restricted ration on the production of short chain fatty acids, but slight differences in the production of butyrate as well as its relationship to rumen P_i and ammonia concentrations that might indicate an impact on ruminal fermentation.     

Primary idiopathic hypoparathyroidism in St. Bernard dogs

Primary hypoparathyroidism was diagnosed in three St. Bernard bitches. Anorexia, behavioural changes, muscle tremors, seizures, panting respiration, and cataracts were the clinical signs observed. The serum concentration of calcium was low, the phosphorus concentration elevated, and the immunoreactive parathyroid hormone level low in all dogs. The aetiology of the hypoparathyroidism was not determined in any of the dogs. Treatment with synthetic vitamin D (1,25-dihydroxycholecalciferol) and an oral calcium supplement was successful in restoring and then maintaining a normal concentration of serum calcium in two of the dogs.     

Intact Parathyroid Hormone Assay and Total Calcium Concentration in the Diagnosis of Disorders of Calcium Metabolism in Dogs

Serum samples from eight dogs with primary hyperparathyroidism, seven dogs with hypercalcemic lymphosarcoma (hypercalcemia of malignancy), and four dogs with primary hypoparathyroidism were submitted to the Animal Health Diagnostic Laboratory at Michigan State University for intact parathyroid hormone (PTH) assay. When compared with the adjusted total serum calcium concentration, the intact PTH concentration was consistent with the correct diagnosis in all cases. Two dogs with hypercalcemic lymphosarcoma were mildly azotemic. In both of these cases the intact PTH concentration was consistent with hypercalcemia of malignancy despite the presence of azotemia. These data support a significant role for intact serum PTH assay in the differential diagnosis of disorders of calcium metabolism.     

Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism

A 10-year-old ovariohysterectomised domestic shorthaired cat was presented with multiple nodular calcifications of the footpads and interdigital spaces. Renal insufficiency was diagnosed by routine biochemistry and urinalysis. Additionally, the cat had a calcium and phosphorus solubility product greater than 70 mg/dl and elevated circulating parathyroid hormone. Dietary management of the renal disease resulted in a reduction in the mineral solubility product and normalisation of the concentration of parathyroid hormone accompanied by concurrent resolution of the pedal lesions.     

Intraoperative parathyroid hormone concentration to confirm removal of hypersecretory parathyroid tissue and time to postoperative normocalcaemia in nine dogs with primary hyperparathyroidism

Objective To determine (1) whether the intraoperative parathyroid hormone concentration ([PTH]) during parathyroidectomy (PTX) can be used to indicate cure in dogs with primary hyperparathyroidism and (2) the time taken for postoperative serum calcium concentration to normalise. Design Retrospective study (2005–10) from a private referral hospital in Sydney, New South Wales, Australia. Procedure Nine client‐owned dogs underwent surgical PTX for naturally occurring primary hyperparathyroidism. [PTH] was measured from serum samples taken immediately post‐induction (pre‐PTX]) and at least 20 min after adenoma removal (post‐PTX) for all dogs, and during parathyroid gland manipulation (intra‐PTX) for six dogs. The concentration of ionised calcium (iCa) was measured at various time points postoperatively until it normalised, then stabilised or decreased below reference ranges. Statistical analysis compared the mean pre‐, intra‐ and post‐PTX [PTH] and the average rate of decline of iCa concentration postoperatively. Results All dogs demonstrated a significant decrease from mean pre‐PTX [PTH] (168.51 pg/mL) to mean post‐PTX [PTH] (29.20 pg/mL). There was a significant increase in mean intra‐PTX [PTH] (279.78 pg/mL). The average rate of decline of iCa concentration postoperatively to within the reference range (1.12–1.40 mmol/L) occurred after 24 h. Conclusion Intraoperative measurements of [PTH] can be used clinically to determine cure of primary hyperparathyroidism. Parathyroid hormone increases significantly during parathyroid gland manipulation. Plasma iCa concentration returns to within the reference range on average 24 h after successful PTX. Not all dogs require vitamin D or calcium supplementation pre‐ or postoperatively.