Hypercalcemia and high serum parathyroid hormone-related protein concentration in a horse with multiple myeloma

A 13-year-old gelding was examined because of weight loss, hyperglobulinemia, and hypercalcemia. Possible causes of hypercalcemia that were considered included renal failure, primary hyperparathyroidism, vitamin D toxicosis, and malignancy. There was no history of vitamin D ingestion, and serum creatinine and parathyroid hormone concentrations were normal, making renal failure and primary hyperparathyroidism unlikely. The hypercalcemia was suspected to be a result of malignancy, but thorough testing did not reveal any neoplastic disease. Eight months later, serum parathyroid hormone-related protein (PTHrP) concentration was high, supporting the suggestion that hypercalcemia was a result of malignancy. In addition, radial immunodiffusion confirmed a selective 300-fold increase in serum IgA concentration. The horse was euthanatized, and postmortem examination revealed neoplastic infiltrates in the kidneys, lymph nodes, liver, and bone marrow. Neoplastic cells had morphologic characteristics of plasma cells, and immunohistochemical staining confirmed that neoplastic cells were expressing PTHrP and IgA. The final diagnosis was multiple myeloma with expression of IgA paraprotein.     

Parathyroid hormone-related protein (PTHrP) produced by dog lymphoma cells

Parathyroid hormone-related protein (PTHrP) was investigated in a canine lymphoma case with hypercalcemia by means of immunoradiomentric assay (IRMA) and molecular analysis. The plasma calcium level of the patient dog was 13.7 mg/dl. The PTHrP concentration examined by IRMA was 6.1 pmol/L in the plasma sample from the dog, but it was undetectable (< 1.1 pmol/L) in plasma samples from 4 lymphoma cases without hypercalcemia or 5 normal dogs. The PTHrP concentration examined in the culture supernatant of the lymphoma cells from this case was 1.3 pmol/L, whereas those of the lymphoma cells from a lymphoma case without hypercalcemia was undetectable. PTHrP mRNA was clearly detected not only in the lymphoma cells from this dog with hypercalcemia but also in lymphoma cells from 4 lymphoma cases without hypercalcemia and 2 canine lymphoma cell lines.     

Hypercalcemia and high parathyroid hormone-related peptide concentration in a dog with a complex mammary carcinoma

A 10-year-old female Dachshund was presented with a history of mammary masses, slight lethargy, polyuria, and polydipsia. Physical examination findings included masses involving the first, second, and fourth mammary glands of the left side. The mandibular, axillary, and right popliteal lymph nodes were mildly enlarged. Serum chemistry results included hypercalcemia (13.9 mg/dL, reference interval 8.0-11.5 mg/dL). Although intact parathyroid hormone (PTH) concentration (1.05 pmol/L) was below the reference interval (2-13 pmol/L), PTH-related protein (PTHrP) concentration was markedly increased (9.40 pmol/L, reference value < 2 pmol/L). The masses were surgically removed, and the histopathologic diagnosis was complex mammary carcinoma. Three weeks after surgery, serum total calcium concentration had decreased to 10.5 mg/dL. Resolution of the hypercalcemia and clinical signs supported a diagnosis of humoral hypercalcemia of malignancy associated with mammary gland carcinoma.     

Elevated parathyroid hormone-related protein and hypercalcemia in two dogs with schistosomiasis.

Two adult dogs were evaluated for hypercalcemia. Diagnostic evaluation identified elevated parathyroid hormone-related protein (PTHrP) and presumptive humoral hypercalcemia of malignancy. At necropsy, schistosomiasis was diagnosed. North American schistosomiasis is caused by Heterobilharzia americana. Clinical findings may include dermatitis, coughing, diarrhea, and anorexia. Clinicopathological findings may include hypercalcemia, hyperglobulinemia, hypoalbuminemia, anemia, and eosinophilia. Diagnosis by fecal examination is difficult. Praziquantel or fenbendazole treatment may be curative or palliative. These are the first reported cases of hypercalcemia with elevated PTHrP in animals without diagnosed malignancy. Elevation of PTHrP has not been previously reported in hypercalcemic humans or in animals with granulomatous inflammation.     

Parathyroid hormone‐related protein‐induced hypercalcemia due to osteosarcoma in a cat

A 15‐year‐old castrated male mixed‐breed cat was presented with a history of sarcoma of the distal right hind limb. Biochemical analysis revealed increased concentrations of blood urea, creatinine, total calcium, ionized calcium, and parathyroid hormone‐related protein (PTHrP). The mass was removed surgically by amputation of the hind limb. Osteosarcoma was diagnosed based on histopathologic examination. All abnormal serum analyte concentrations improved immediately after surgery, including azotemia, total calcium, ionized calcium, and PTHrP. The biochemical results were attributed to osteosarcoma causing PTHrP‐induced hypercalcemia.     

A case of hypercalcemia in a heifer presumably due to mammary carcinoma bovine hypercalcemia of malignancy

Mammary carcinoma is rare in cattle with only a handful of cases found in the literature, and none have reported an associated hypercalcemia. An 8‐year‐old Holstein‐Friesian heifer was presented to the Purdue University Veterinary Teaching Hospital's Large Animal Hospital with a 3‐month history of lethargy. Laboratory abnormalities included ionized hypercalcemia and hypophosphatemia (2.28 mmol/L and 1.8 mg/dL, respectively). Physical examination revealed a mammary mass that was cytologically described as a suspected mammary carcinoma, which was later confirmed by histologic evaluation. On surgical removal of the mass, calcium initially decreased rapidly, and within a few days was within the RI, further supporting a diagnosis of hypercalcemia of malignancy in a heifer. However, attempts to confirm this using hormone profiles (parathyroid hormone [PTH], parathyroid hormone‐related protein [PTHrp], and calcitriol) were inconclusive due to the lack of validated assays and RIs for cattle. Immunohistochemical staining for PTHrP showed scattered cytoplasmic staining among the neoplastic cells, suggesting PTHrP production by these cells.     

Immunohistochemistry for parathyroid hormone-related protein (PTHrP) in benign and malignant mammary mixed tumors of dogs with and without hypercalcemia

We evaluated the expression of parathyroid hormone-related protein (PTHrP) by immunohistochemistry in eight benign and malignant mammary mixed tumors of dogs with (n = 4) and without (n = 4) hypercalcemia. Positive immunoreactive staining for PTHrP was observed in all four tumors from hypercalcemic dogs. The mammary tumors from 2 of the 4 normocalcemic dogs stained positively for PTHrP, but the numbers of immunoreactive cells and intensity of the immunoreaction were less than in the hypercalcemic dogs. In the other 2 tumors without hypercalcemia, the tissue samples were negative for PTHrP.     

Detection of parathyroid hormone-related protein in cats with humoral hypercalcemia of malignancy

Background — Increased serum parathyroid hormone‐related peptide (PTHrP) concentration is used to diagnose humoral hypercalcemia of malignancy (HHM) in humans and animals. A commercially available assay for human PTHrP has diagnostic utility in the dog, but has not been assessed in cats. Objectives — The goals of this study were to determine serum or plasma levels of PTHrP in a population of hypercalcemic cats and to determine whether increased PTHrP concentration was associated with malignancy. In addition, we validated immunoradiometric assays (IRMAs) for intact parathormone (iPTH) and PTHrP for use with feline samples. Methods — A retrospective analysis of iPTH and PTHrP results from 322 hypercalcemic cats (ionized calcium concentration >1.4 mmol/L) was performed. Immunoassays for human iPTH and PTHrP (residues 1–84) were validated using standard methods, and reference intervals were calculated using values from 31 healthy adult cats. Hypercalcemic cats were classified as parathyroid‐independent (iPTH <2.3 pmol/L), equivocal (iPTH 2.3–4.6 pmol/L), or parathyroid‐dependent (iPTH >4.6 pmol/L). Seven cats with detectable or increased PTHrP concentrations were evaluated further for underlying disease. Formalin‐fixed neoplastic tissues were immunohistochemically stained using rabbit antibody to human midregion PTHrP. Results — Assays for iPTH and PTHrP showed acceptable precision for feline samples. The reference interval for iPTH was 0.8–4.6 pmol/L and for PTHrP was <1.5 pmol/L. The majority of hypercalcemic cats (263/322, 81.7%) were parathyroid‐independent, with fewer cats in the equivocal (32/322,9.9%) and parathyroid‐dependent (27/322,8.4%) groups. In 31 (9.6%) cats, PTHrP concentration was >1.5 pmol/L (range 1.5–26.6 pmol/L). All 7 cats for which follow‐up information was available had HHM; 6 had carcinomas (4 lung carcinomas, 1 undifferentiated carcinoma, 1 thyroid carcinoma) and 1 had lymphoma. All tumors had mild to moderate positive staining for PTHrP; however, lung carcinomas from normocalcemic cats also stained positive. Conclusions — Human IRMA for PTHrP (1–84) can be used to measure PTHrP in cats. Malignancies, particularly carcinomas, appear to secrete PTHrP and induce HHM in this species. Immunohistochemistry alone cannot predict the occurrence of HHM in cats.     

Hypercalcemia and parathyroid hormone-related protein in a dog with undifferentiated nasal carcinoma.

Hypercalcemia was discovered in a 7-year-old, castrated male basset hound with a suspected nasal tumor. The dog died the day after admission and nasal carcinoma and disseminated intravascular coagulation were diagnosed on postmortem. Detectable levels of serum PTHrP support a diagnosis of hypercalcemia of malignancy.     

Hypercalcemia associated with malignancy in a horse

Hypercalcemia associated with malignancy was diagnosed in a 2-year-old Thoroughbred filly admitted because of weight loss and reduced exercise tolerance of approximately 2 months' duration. Laboratory findings included hypercalcemia, hypophosphatemia, anemia, marked neutrophilia with lymphopenia and eosinopenia, and normal immunoreactive parathyroid hormone concentration. At necropsy, a 53.6-kg tumor was located in the cranioventral aspect of the abdominal cavity. Gross renal lesions were not noticed. Bone tissue appeared to be normal on gross and histologic examinations. The parathyroid glands were not grossly identified at necropsy. A specific test does not exist for detection of hypercalcemia associated with malignancy. The diagnosis of hypercalcemia associated with malignancy was made on the basis of clinical history, physical examination, radiographic interpretation, laboratory findings, histologic examination, and ruling out other causes of hypercalcemia. Hypercalcemia, increased renal phosphate excretion in the presence of hypophosphatemia, absence of bone metastases, and identifying an abdominal mesenchymal tumor that may have originated from the left ovary satisfied the basic criteria for hypercalcemia associated with malignancy from a solid tumor.     

Hypercalcemia and high parathyroid hormone-related protein concentration associated with malignant melanoma in a dog

A 12-year-old Cocker Spaniel with an oral malignant melanoma was evaluated for progressive lethargy and anorexia. No metastases were identified during antemortem evaluation, but severe hypercalcemia was evident. Antemortem diagnostic testing failed to identify a cause for the hypercalcemia. No neoplasms other than the melanoma were identified on postmortem examination. Serum parathyroid hormone-related protein concentration was markedly high, and the melanoma had moderate to marked immunostaining for this protein. Paraneoplastic syndromes are rare in dogs with malignant melanoma.     

Hypercalcemia in a dog: a challenging case

An 18-month-old, spayed female, mixed-breed dog was referred for investigation of persistent hypercalcemia. After extensive diagnostic evaluation, a tentative diagnosis of occult lymphosarcoma (LSA) was made and the dog was euthanized. At necropsy, infection with Heterobilharzia americana was diagnosed. In endemic areas, schistosomiasis should be included in the differential diagnosis of hypercalcemia, and a fecal examination should be performed in every dog with a hypercalcemia of unknown origin.     

Presumptive increase in protein‐bound serum calcium in a dog with multiple myeloma

Abstract: An 11‐year‐old male castrated Australian Shepherd was presented with a history of lethargy, panting, and weight loss for 1 month. Physical examination revealed a moderately enlarged spleen. Laboratory abnormalities included thrombocytopenia and marked hypercalcemia, with hyperglobulinemia, hypoalbuminemia, and a monoclonal spike in the β‐globulin region on serum protein electrophoresis. Serum total calcium concentration was markedly increased (16.5 mg/dL, reference interval 8.9–11.4 mg/dL) but ionized calcium concentration (1.39 mmol/L) was within the reference interval (1.25–1.45 mmol/L). Isosthenuria was noted, but the dog was not polyuric or polydipsic. Serum parathyroid hormone concentration was within reference limits and parathyroid hormone‐related peptide concentration was 0 pmol/L. Radiographic findings were largely unremarkable. Results of cytologic evaluation of a fine‐needle aspirate specimen from the spleen indicated plasma cell neoplasia. Based on the results of the electrophoresis, splenic aspirates, radiographs, and hypercalcemia, a diagnosis of splenic multiple myeloma was made. The marked hypercalcemia, normal ionized calcium and parathyroid hormone concentrations, and lack of osteolytic lesions indicated a presumptive increase in protein‐bound serum calcium, likely due to binding to molecules of the paraprotein (M protein). Protein binding of calcium in dogs with multiple myeloma should be considered as a potential mechanism of elevated total serum calcium concentration.     

Pseudohyperparathyroidism in a mare associated with squamous cell carcinoma of the vulva

An 18-year-old Appaloosa mare was examined because of squamous cell carcinoma of the vulva, anorexia with pronounced weight loss, and hypercalcemia. The tumor had developed rapidly over a period of 3 months and externally extended ventrally involving the perineum and the dorsal aspect of the udder. Necropsy examination demonstrated a large primary squamous cell carcinoma of the vulva, perineum, and mammary gland with metastases to the supramammary, sublumbar, deep inguinal, and mediastinal lymph nodes. No gross renal lesions were observed and, histologically, there was only mild vacuolation of renal tubular epithelium. Based on the normal concentration of serum parathyroid hormone, the absence of evidence of hypervitaminosis D, and normal renal function, a diagnosis was made of hypercalcemia of malignancy or pseudohyperparathyroidism. The mechanism responsible for hypercalcemia was not determined, but the histologic type of the neoplasm and the clinical course suggested possible production of a humoral hypercalcemic factor by the neoplasm, similar to that demonstrated in certain types of human squamous cell carcinoma.     

Severe hypercalcemia in a dog with a retained fetus and endometritis

A 10-month-old sexually intact female German Shorthaired Pointer examined because of lethargy, episodes of fever, inappetence, and vomiting was found to have severe hypercalcemia. Results of laboratory testing, radiography, and ultrasonography excluded previously recognized causes of hypercalcemia in dogs. Instead, the dog was found to have purulent endometritis and an incompletely resorbed fetus. Treatment with fluids i.v., diuretics, and calcitonin failed to adequately reduce serum calcium concentration, but serum calcium concentration was normal within 4 days after the dog underwent an ovariohysterectomy. Retention of one or more fetuses and endometritis should be included in the differential diagnosis for dogs with hypercalcemia.     

Primary Hyperparathyroidism Associated With Atypical Headshaking Behavior in a Warmblood Gelding

A 14-year-old Zweibrücker Warmblood gelding was presented for evaluation of lethargy and headshaking. The horse had a history of bouts of lameness in different limbs and back problems. It also had many mild colic episodes in the past. Results of repeat laboratory tests had shown persistent hypercalcemia (4.8 mmol/L; reference interval [RI]: 2.0–3.2 mmol/L) for 1.5 years and later on hypophosphatemia (0.4 mmol/L; RI: 0.5–1.3 mmol/L) and mild hypermagnesemia (1.0 mmol/L; RI: 0.5–0.9 mmol/L). Parathyroid hormone (PTH) concentration was within the RI. Other causes of hypercalcemia, such as renal failure, vitamin D toxicosis, and granulomatous disease, and nutritional secondary hyperparathyroidism were ruled out. Furthermore, there was no evidence of neoplastic disease. Parathyroid hormone–related protein was measured but inconclusive. A diagnosis of primary hyperparathyroidism was established on the basis of hypercalcemia, hypophosphatemia, low fractional excretion of calcium, and high fractional excretion of phosphorus in combination with a PTH secretion refractory to high calcium levels. Because of the bad prognosis, the owner decided to euthanize the horse. Results of postmortem examination were unremarkable. Hypercalcemia should always be considered abnormal, and further examinations need to be performed to proof hypercalcemia and subsequently find the cause. The main differential diagnoses are renal insufficiency and humoral hypercalcemia of malignancy, but also rare diseases, such as hyperparathyroidism, have to be taken into account.     

Parathyroid hormone-related protein and calcium concentrations in milk and blood of ewes

Parathyroid hormone-related protein (PTHrP) and calcium (Ca) concentrations were measured 2 to 3 months postpartum in milk and plasma or serum of 22 ewes by the use of commercial radioimmunoassay kits for PTHrP concentration, colorimetry for serum total Ca concentration (Ca_tot), and atomic absorption spectrophotometry for milk total Ca concentration. Scatter plots did not reveal dependency between milk Ca and Ca_tot, Ca_tot and plasma PTHrP, milk Ca and milk PTHrP, and milk PTHrP and plasma PTHrP. Thus, the systemic and mammary effects of PTHrP are not major determinants of the endocrine, paracrine, and autocrine regulation of Ca homeostasis during lactation in ewes.     

Effects of transforming growth factor-α on parathyroid hormone- and parathyroid hormone-related protein- mediated bone resorption and adenylate cyclase stimulation in vitro

The effects of transforming growth factor-alpha (TGF alpha) were determined on the ability of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) to stimulate bone resorption and adenylate cyclase in vitro. Bovine PTH-(1-34) and human PTHrP-(1-34) were equipotent in their ability to stimulate bone resorption in neonatal mouse calvaria with maximal stimulation (2.9 and 2.8-fold increases in 45Ca release, respectively) at a concentration of 10 nM. Combinations of TGF alpha with bPTH-(1-34) or hPTHrP-(1-34) had additive effects on their ability to stimulate bone resorption when submaximal concentrations of the agonists were used. There was no evidence of synergism between TGF alpha bPTH-(1-34) or hPTHrP-(1-34) in their ability to stimulate bone resorption in vitro, nor was TGF alpha able to increase bone resorption induced by maximal concentrations of bPTH-(1-34) or hPTHrP-(1-34). TGF alpha potentiated the effects of either bPTH-(1-34) or hPTHrP-(1-34) on the stimulation of adenylate cyclase in osteoblast-like ROS 17/2.8 cells. These data indicate that TGF alpha has additive effects with submaximal concentrations of PTH or PTHrP on their ability to stimulate bone resorption which may be important in the pathogenesis of humoral hypercalcemia of malignancy.     

Cutaneous and systemic blastomycosis, hypercalcemia, and excess synthesis of calcitriol in a domestic shorthair cat

A 9 yr old domestic shorthair cat was diagnosed with cutaneous and pulmonic blastomycosis. Severe persistent ionized hypercalcemia and excess circulating concentration of calcitriol were documented in association with blastomycosis. Ionized hypercalcemia resolved when the granulomatous lesions of blastomycosis resolved and the calcitriol levels decreased.