Serum parathyroid hormone-related protein concentration in a dog with a thymoma and persistent hypercalcemia

A thymoma was tentatively diagnosed by radiographic and cytologic examination in a dog with hypercalcemia and elevated serum parathyroid hormone-related protein (PTHrP) concentration. Following surgical excision, the diagnosis of thymoma was confirmed via histopathologic examination, the hypercalcemia resolved, and the PTHrP concentration decreased to below detectable limits.     

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.     

Canine schistosomiasis in Kansas: five cases (2000-2009)

This is a retrospective case series consisting of five dogs diagnosed with schistosomiasis. The purpose of this article is to report the presence of naturally occurring canine schistosomiasis in Kansas and to provide clinical details regarding schistosomiasis. Medical records of dogs diagnosed with schistosomiasis from 2000 to 2009 were reviewed, and information extracted included signalment, history, clinical signs, diagnostic test results, treatment, and outcome. Affected dogs were primarily medium to large breed and young to middle aged. All dogs were considered outdoor dogs, with three having known access to surface water. Common clinical signs included gastrointestinal disease and signs associated with hypercalcemia. Fecal flotation was negative in all dogs in contrast to fecal saline sedimentation and fecal polymerase chain reaction, which were both positive in all dogs in which it was performed. All dogs treated specifically for schistosomiasis fully recovered. This article describes the first reported cases of canine schistosomiasis in the Midwest and the first reported case of intestinal intussusception secondary to schistosomiasis. Recognizing that canine schistosomiasis is present in Kansas and possibly other Midwestern states should prompt veterinarians to perform appropriate diagnostic investigation in suspect animals as the diagnosis is straight forward and relatively inexpensive.     

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.     

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.     

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.     

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.     

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.     

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.     

Endocrine Causes of Calcium Disorders

Endocrine diseases that may cause hypercalcemia and hypocalcemia include hyperparathyroidism, hypoparathyroidism, thyroid disorders, hyperadrenocorticism, hypoadrenocorticism, and less commonly pheochromocytoma and multiple endocrine neoplasias. The differential diagnosis of hypercalcemia may include malignancy (lymphoma, anal sac carcinoma, and squamous cell carcinoma), hyperparathyroidism, vitamin D intoxication, chronic renal disease, hypoadrenocorticism, granulomatous disorders, osteolysis, or spurious causes. Hypocalcemia may be caused by puerperal tetany, pancreatitis, intestinal malabsorption, ethlyene glycol intoxication, acute renal failure, hypopararthyroidism, hypovitaminosis D, hypomagnesemia, and low albumin. This article focuses on the endocrine causes of calcium imbalance and provides diagnostic and therapeutic guidelines for identifying the cause of hypercalcemia and hypocalcemia in veterinary patients.     

Humoral hypercalcemia of malignancy in female F344 rats implanted with a transplantable rat pulmonary carcinoma line (IP).

A transplantable rat pulmonary carcinoma line (IP) in F344 rats is a useful animal model for humoral hypercalcemia of malignancy (HHM). The present study analyzed the degree of HHM by implanting IP into F344 female rats aged 6, 20 or 45 weeks. IP-bearing females developed elevated plasma parathyroid hormone-related protein levels, hypercalcemia and increased osteoclastic activity as well as calcification in various organs. The severity of such HHM differed depending on age; particularly, calcification showed age-dependent reduction. HHM development in IP-bearing females may be influenced by age-related factors.     

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.     

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.     

Paraneoplastic Hypercalcemia

Paraneoplastic syndromes (PNSs) are neoplasm-associated alterations in bodily structure or function or both that occur distant to the tumor. They are an extremely diverse group of clinical aberrations that are associated with the noninvasive actions of the tumor. In many situations, the PNS parallels the underlying malignancy, and therefore, successful treatment of the tumor leads to disappearance of the PNS. Alternatively, recurrence of the PNS after successful treatment signals recurrence of the tumor, and the return of the PNS often significantly precedes the detectable recurrence of the tumor. This is often the case with paraneoplastic hypercalcemia, often referred to as hypercalcemia of malignancy (HM). The most common cause of hypercalcemia in dogs is cancer. Neoplasia is diagnosed in approximately two-thirds of dogs with hypercalcemia vs. approximately one-third in cats. A variety of tumors have been associated with HM. Lymphoma is the most common cause of HM, and the most common anatomical site for dogs with lymphoma-associated HM is the cranial mediastinum. Other tumors associated with HM in dogs and cats include anal sac apocrine gland adenocarcinoma, thyroid carcinoma, multiple myeloma, bone tumors, thymoma, squamous cell carcinoma, mammary gland carcinoma/adenocarcinoma, melanoma, primary lung tumors, chronic lymphocytic leukemia, renal angiomyxoma, and parathyroid gland tumors. As HM is a potential medical emergency, the primary goal in cases of HM is the elucidation of the underlying cause and thereby instituting the appropriate specific therapy.     

Acute Management of Calcium Disorders

Acute management of hypercalcemia and hypocalcemia is an important part of small-animal emergency practice. In addition to hypercalcemia of malignancy and hyperparathyroidism, vitamin D toxicosis is becoming more common in companion animals as new and improved rodenticides and human pharmaceutical preparations (vitamin D analog skin creams) become more available. This article provides complete details regarding the emergency management of life-threatening hypercalcemia with focus on vitamin D intoxication. At the other end of the spectrum, hypocalcemic emergencies, such as periparturient hypocalcemia (eclampsia), may be less common but are often life threatening. This article contains guidelines for the emergency management of hypocalcemia. In summary, the urgent care of calcium disorders in small animals is reviewed.     

Laboratory abnormalities in patients with cancer

In this problem-oriented review of abnormalities associated with cancer, we have emphasized distinctive diagnostic points related to pathogenesis for each condition and outlined how the approach to management is determined by pathogenesis. For abnormalities of the complete blood count, it is important to distinguish between abnormalities directly related to marrow malignancy and abnormalities associated with extramarrow malignancy. Hemopoietic tumors consist of developmentally deficient blood cells produced by a clonal population of malignant stem cells. Tumors infiltrating marrow cause overcrowding in the limited marrow microenviroment. Extramarrow malignancies cause blood abnormalities, but the potential for normal marrow function is present. Abnormalities of blood cells secondary to therapy are usually clearly identified by consideration of clinical history. The initial differential diagnosis for hypercalcemia is malignancy. An aggressive diagnostic approach may be needed to identify the neoplasm, and therapy should incorporate measures to prevent renal failure. Hypoproteinemia and hyperproteinemia may be caused by neoplasia. Monoclonal gammopathies should be identified and may be associated with hyperviscosity syndrome. Hypoglycemia in the adult animal is most frequently caused by insulin-secreting tumors, but it has also been associated with hepatic and other tumors. Increased blood urea nitrogen, creatinine, lipase, amylase, and liver enzyme activities may also be caused by malignancy. Inadequate urine concentrating ability may be caused by hypercalcemia or malignancy-associated renal insufficiency. Hematuria in older animals is suggestive of urinary tract neoplasia. Exfoliated tumor cells may be identified in the urine sediment of these patients.     

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.     

Electrolyte disturbances and cardiac arrhythmias in a dog following pamidronate, calcitonin, and furosemide administration for hypercalcemia of malignancy

A 13-year-old dog was diagnosed with hypercalcemia of malignancy associated with adenocarcinoma of the anal sacs. Hypercalcemia was treated with intravenous (IV) 0.9% sodium chloride (NaCl), furosemide, calcitonin, and pamidronate. Hypomagnesemia was documented by 72 hours following a single, IV dose of pamidronate. The dog subsequently underwent surgery to remove the primary tumors, and multiple cardiac arrhythmias occurred during anesthesia. This case documents electrolyte abnormalities in a dog following treatment with pamidronate in conjunction with other therapies used to manage hypercalcemia. The authors postulate that hypomagnesemia may have contributed to the arrhythmias that occurred during anesthesia. Electrolyte abnormalities should be anticipated and corrected following pamidronate therapy in canine patients.