Parathyroid Hormone-related Peptide Production Research Articles

FRI693 Pthrp Mediated Hypercalcemia In A Patient With Recurrent Hepatocellular Carcinoma

Abstract Disclosure: D. Bondarenko: None. M. Ahmad: None. M. Mack: None. P. Ucciferro: None. Background: Humoral hypercalcemia is seen in 30 percent of cancer patients, most commonly driven by parathyroid hormone related peptide (PTHrP) production, osteolytic cytokine production, and 1,25-OH vitamin D production. The most common malignancies associated with PTHrP mediated hypercalcemia are squamous cell carcinomas and breast cancer. Less often hepatocellular cancer presents with hypercalcemia. We describe the case of a patient presenting with hepatocellular carcinoma presenting with recurrent episodes of severe hypercalcemia due to excessive PTHrP production. Clinical Case: The patient was a 68-year-old male with a past medical history of recurrent hepatocellular carcinoma with liver transplant in the past and type 2 diabetes mellitus who presented to the emergency department (ED) for one day of altered mental status. The patient was noted to be extremely agitated and confused by his home health aide and EMS was called. In the ED the patient’s vital signs were as follows: blood pressure of 196/80 mmHg, heart rate of 82 beats per minute, respiratory rate of 18 breaths per minute and temperature of 36.6 degrees Celsius. Initial lab work showed: calcium 13.5 mg/dL, albumin 4.2 g/dL, ionized calcium of 1.63 mmol/L, creatinine 0.99 mg/dL (baseline 0.5 mg/dL), glucose of 438 mg/dL, bicarbonate 23 mmol/L, anion gap 19, and beta hydroxybutyrate 51 mg/dL. Hypercalcemia workup revealed a suppressed PTH of 5 pg/mL (normal 11-67 pg), normal 25-OH vitamin D 43.6 ng/ml (normal 30-100 ng/ml), normal 1,25-OH vitamin D 38 pg/ml (normal 18-72 pg/ml), and elevated PTHrp 36 pg/ml (normal 11-20 pg/ml). The patient was started on aggressive IV fluid resuscitation with normal saline, administered a one-time dose of zoledronic acid and administered a three-day course of calcitonin. For his significant hyperglycemia the patient was started on an insulin infusion and was eventually transitioned to his home basal bolus insulin regimen. On discharge, the patient was scheduled with his oncologist to begin denosumab as an outpatient; however, he chose a palliative approach due to the terminal nature of his disease and recurrent hospitalizations for hypercalcemia. Conclusion: Hypercalcemia of malignancy is common in many different carcinomas with squamous cell cancer, renal cell cancer, breast cancer and multiple myeloma being commonly associated with this phenomenon. Reports of hepatocellular carcinoma associated with hypercalcemia are less common and occur in only 4-8 % of cases. With this case report, we hope to highlight PTHrP as a potential mechanism of humoral hypercalcemia in patients with hepatocellular carcinoma and propose denosumab as a possible treatment for patients with refractory hypercalcemia of malignancy. Presentation: Friday, June 16, 2023

A Scoping Review of the Apparent Phenomenon of the Improvement in Hypoparathyroidism in Pregnant and Postpartum Females.

Hypoparathyroidism requires management with both calcium supplementation and active vitamin D to avert a state of hypocalcemia. During late gestation and the postpartum period (specifically lactation), there is an under-recognized, yet intriguing occurrence of apparent 'pseudohyperparathyroidism', whereby supplementation dosages may need to either be reduced or discontinued, to prevent hypercalcemia. The explanation for this apparent phenomenon of improved parathyroid status ('remission' or 'resolution') is incompletely understood; the purpose of this review is to analyze the case reports of this enigma within the medical (and grey) literature, providing an overall pathophysiological explanation and recommendation for the management of such patients. A literature search was conducted through PubMed/Medline, CINAHL, Cochrane Library Database, Scopus, UpToDate, Google Scholar, and the grey literature without a time-restricted period, analyzing all available articles within the literature describing an apparent improvement in parathyroid status in late-gestation and postpartum (lactating) females. Non-hypoparathyroid case reports were also included to further analyze and synthesize an overall likely pathophysiological explanation. Through the literature search, 24 papers were identified covering such a phenomenon in patients with hypoparathyroidism, alongside multiple additional reports of a similar occurrence in patients without underlying hypoparathyroidism. The pathophysiology is believed to occur due to the placental production of parathyroid hormone-related peptide (PTHrP) during gestation, with further production from the lactating mammary glands during the postpartum period. A typical pattern is observed, with increased PTHrP and suppressed PTH throughout both gestation and lactation (present in both normal and hypoparathyroid subjects). The concept of PTHrP-induced hypercalcemia is further demonstrated in patients without hypoparathyroidism, including subjects with placental hypersecretion and mammary gland enlargement. It is evident that patients with hypoparathyroidism may require a dosage reduction during late gestation and lactation, due to the risk for hypercalcemia. In addition to patients with hypoparathyroidism, this pathophysiological phenomenon occurs in unsuspecting patients, demonstrating the need for all clinicians in contact with pregnant females to be aware of this uncommon - yet perilous - occurrence.

CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence.

The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide nuclear localization sequence (PTHrP87-139 ), and their role in the proliferation behaviors of the superficial zone cells. A gain- and loss-of-function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening. CaSR and PTHrP87-139 were modulated through treating the isolated superficial zone cells with activator/SiRNA and via deleting CaSR or parathyroid hormone-related peptide (PTHrP) gene in mice with the promoter gene of proteoglycan 4 (Prg4-CreERT2 ) in the tamoxifen-inducible pattern with or without additional injection of Cinacalcet, the CaSR agonist, or PTHrP87-139 peptide. FFSS stimulated CaSR and PTHrP expression, and accelerated proliferation of the Prg4-expressing superficial zone cells, in which process CaSR acted as an up-streamer of PTHrP. Proteoglycan 4 specific knockout of CaSR or PTHrP reduced the cartilage thickness, suppressed the proliferation and early differentiation of the superficial zone cells, and inhibited cartilage thickening and matrix production promoted by bilateral elevation bite. Injections of CaSR agonist Cinacalcet could not improve the phenotype caused by PTHrP mutation. Injections of PTHrP87-139 peptide rescued the cartilage from knockout of CaSR gene. CaSR modulates proliferation of the superficial zone cells in mandibular condylar cartilage through activation of PTHrP nuclear localization sequence. Our data support the therapeutic target of CaSR in promoting PTHrP production in superficial zone cartilage.

Hypercalcemia of malignancy with simultaneous production of parathyroid hormone-related peptide and 1,25-Dihydroxyvitamin D by non-Hodgkin lymphoma: Case report & brief review

We report the case of a 63-year-old man with severe hypercalcemia, acute kidney injury, and concomitant diagnosis of germinal center diffuse large B-cell lymphoma (nHL). Hypercalcemia is a common finding in patients with cancer. Multiple mechanisms can lead to hypercalcemia of malignancy, and different malignancies are often associated with a specific mechanism of hypercalcemia. Parathyroid hormone-related protein (PTHrP) and excessive production of 1,25-dihydroxyvitamin D can independently (and rarely, concomitantly) lead to development of hypercalcemia in patients with a variety of malignancies. Literature review of hypercalcemia related with PTHrP and 1,25-dihydroxyvitamin D co-secretion shows that most reported cases are associated with solid tumors and responded to tumor directed therapy. Our case of nHL was associated with increased PTHrP and 1,25-dihydroxyvitamin D making this an unusual presentation.

Hypercalcaemia secondary to hypophysitis and cortisol deficiency: another immunotherapy-related adverse event.

Hypercalcaemia is a common complication seen in malignancy, frequently due to paraneoplastic parathyroid hormone-related peptide production or osteolytic bony metastases. We present a 58-year-old female with immunotherapy-mediated hypophysitis causing secondary cortisol deficiency resulting in severe glucocorticoid-responsive hypercalcaemia. Whilst hypophysitis is a well recognised adverse event in those receiving immunotherapy for advanced malignancy, it does not typically present with hypercalcaemia. The mechanism responsible for hypercalcaemia due to hypocortisolaemia has not been fully elucidated although hypotheses include the effects of volume depletion and thyroxine's action on bone. Prompt treatment with glucocorticoids caused an improvement in the patient's symptoms and corrected her hypercalcaemia which later returned after an attempted glucocorticoid wean. With the increasing uptake of immunotherapy, clinicians should be aware of this unusual presentation of immunotherapy-related hypophysitis and secondary hypocortisolaemia which can be life-threatening if the diagnosis is delayed. Immunotherapy can cause inflammation of the pituitary gland resulting in secondary hypocortisolaemia, which can, though rarely, present as hypercalcaemia. Secondary hypocortisolaemia requires prompt recognition and treatment with glucocorticoids. Glucocorticoid replacement leads to rapid clinical and biochemical improvement in these patients. The differential diagnosis for glucocorticoid-responsive hypercalcaemia extends beyond granulomatous disorders (e.g. sarcoidosis, tuberculosis) to adrenocorticotrophic hormone and cortisol deficiency, particularly in patients receiving immunotherapy. Hypocortisolaemia can lead to hypercalcaemia through various proposed mechanisms. Low serum glucocorticoids are associated with reduced blood volume, thus reducing renal calcium excretion. In addition, without glucocorticoid's inhibitory action, thyroxine appears to drive calcium mobilisation from bone.

RF30 | PSAT135 Rare Case of Hypercalcemia Mediated by an Ectopic Parathyroid Hormone (PTH), and Parathyroid Hormone-Related Peptide (PTHrP) Co-Secretion Secondary to Metastatic Cervical Carcinoma

Abstract Introduction Hypercalcemia of malignancy occurs in ∼20-30% of cancer patients. This mostly occurs by three mechanisms: humoral mediated from excess production of PTHrP, osteoclast mediated bone resorption from osteolytic metastasis and calcitriol mediated in granulomatous diseases such as lymphoma. Very rarely, PTH mediated hypercalcemia can occur in the setting of ectopic PTH production from tumor cells. Case presentation A 57 year- old woman with a medical history of hypertension and hyperthyroidism presented to the emergency department with several days of fatigue, nausea, vomiting, constipation and abdominal pain. Exam was remarkable for a heart rate (HR) of 140, lethargy, dry mucous membranes and chronic bilateral proptosis. Labs were remarkable for corrected calcium level of 18.38 mg/dl, Phosphorous of 3.2 mg/dL, Mg level of 1.2 mEq/L, blood urea nitrogen (BUN) of 20 mg/dL, creatinine of 1.6 mg/dL alkaline phosphatase of 170 units/L, and Lactic acid was 3.0 mmol/L. TSH 0.291 (0.40-4.7), FT4 1.51 ng/dl (0.70-1.80), FT3 3.2 pg/ml (2.8-5.3). Patient was treated with IV fluids, calcitonin 4u/kg bid, zoledronic acid 4 mg and started on cinacalcet. Further workup revealed elevated PTH of 1351 pg/ml (16-80), PTH-rP of 28 (<2), 25-hydroxyvitamin D of 25.5 ng/ml (30-100), 1,25-dihydroxy vitamin D level of 59.8 pg/ml (19.9-79.3). Patient couldn't tolerate sestamibi scan. 4DCT couldn't be performed due to creatinine elevation Bedside US performed did not show any evidence of parathyroid adenoma. CT, abdomen and pelvis a large mass in the cervix and cecum. Cervical biopsy revealed necrotic tumor with vary rare nests of viable atypical cells. Given persistent hypercalcemia, despite additional treatment, CRRT was initiated on hospital day 15 with rapid normalization of calcium level. However, patient continued to rapidly deteriorate with multi-organ failure and was transitioned to comfort care before expiring. Autopsy revealed poorly differentiated necrotic cervical carcinoma measuring 12×6×8 cm with metastasis to the left ovary as well as multiple tumor lesions in the liver. Parathyroid glands were normal on gross exam. PTH staining could not be performed given degree of tumor necrosis Discussion Hypercalcemia with elevated PTH and negative localization studies, should raise suspicion for ectopic PTH production from underlying malignancy. In PTHrP mediated hypercalcemia, PTH as well as 1,25 (OH) D are expected to be suppressed. This patient had an elevated PTHrP but not enough to suppress PTH or 1,25 (OH) D level. Given that parathyroid glands were normal on gross exam; this is consistent with ectopic PTH mediated hypercalcemia with component of PTHrP co-secretion. Hypercalcemia of malignancy presents late and portends a poor prognosis and therefore appropriate diagnosis and management is critical. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

Stones, Bones, and Groans with Cancerous Overtones - A Rare Case of Diffuse Large B Cell Lymphoma Presenting as Hypercalcemia

Diffuse large B cell lymphoma (DLBCL) is a type of non-Hodgkin lymphoma that can present in a variety of ways including fever, weight loss, weakness, and drenching night sweats. Uncommonly, hypercalcemia of malignancy can be associated with DLBCL through multiple mechanisms that include synthesis of parathyroid hormone related peptide (PTHrP) or elevated calcitriol levels. It is estimated that hypercalcemia in the setting of DLBCL is present in 18% of newly diagnosed cases. This report details a case of an 80-year-old man with history of chronic anemia and CKD stage 3b that presented with weakness, decreased oral intake, and self-reported weight loss. Initial labs showed a corrected calcium of 14.1 mg/dL and normal phosphorous and alkaline phosphatase levels. PTH was decreased at 4 pg/mL. Serum protein electrophoresis and skeletal survey were unremarkable. A continued anemia of 8.1 g/dL in the setting of hypercalcemia prompted further investigation with endoscopy and colonoscopy which showed a large malignant-appearing mass in the mid gastric body. Pathology identified the mass as DLBCL germinal center type. Labs taken after endoscopy reported elevated 1,25-dihydroxyvitamin D levels, consistent with vitamin-D induced hypercalcemia seen in DLBCL. This case report highlights an uncommon yet important presentation of DLBCL. It is imperative that a differential diagnosis for undifferentiated hypercalcemia in an older patient should include malignancies such as DLBCL and workup should include extrarenal causes of hypercalcemia such as PTHrP production and calcitriol levels.

Electrolyte and Acid-Base Disorders Associated with Cancer Immunotherapy.

Novel immunotherapy drugs have changed the landscape of cancer medicine. Immune checkpoint inhibitors and chimeric antigen receptor T cells are being used and investigated in almost all types of cancers. Immune-related adverse events have been associated with immunotherapies. AKI has been the most commonly associated kidney adverse event. In this review, we showcase the several associated electrolyte disorders seen with immunotherapy. Immune checkpoint inhibitors can lead to hyponatremia by several mechanisms, with the syndrome of inappropriate antidiuresis being the most common. Endocrine causes of hyponatremia are rare. Hypokalemia is not uncommon and is associated with both proximal and distal renal tubular acidosis. Hypercalcemia associated with immune checkpoint inhibitors has led to some interesting observations, including immune checkpoint inhibitor-induced parathyroid hormone-related peptide production, sarcoid-like granulomas, and hyperprogression of the disease. Hypocalcemia and hyperphosphatemia may be seen with immune checkpoint inhibitor-induced tumor lysis syndrome. Chimeric antigen receptor T cell therapy-associated electrolyte disorders are also common. This is associated chiefly with hyponatremia, although other electrolyte abnormalities can occur. Early recognition and prompt diagnosis may help providers manage the mechanistically varied and novel electrolyte disorders associated with immunotherapy.

EP20 Hypercalcaemia in sarcoidosis

Case report - IntroductionSarcoidosis often classically presents as Lofgren’s syndrome in up to 30% of cases, a triad of erythema nodosum, bilateral hilar lymphadenopathy and polyarthritis. However, the lack of identification and awareness of extrapulmonary manifestations of sarcoidosis can often lead to delayed diagnosis and treatment. In sarcoidosis, hypercalcaemia is a feature in only 10-20% of all cases. However, the manifestation of hypercalcaemia may be the first presentation of sarcoidosis in patients who do not show the classical features of acute sarcoidosis. Case report - Case descriptionA 38-year-old man presented with a 5-month history of profound fatigue, poor concentration, and non-specific joint pains. He reported earlier swelling of his ankles and feet. He had lost 1 stone in weight over the last month. There was no history of fever or night sweats. He smoked 10 cigarettes per day but was otherwise fit and well. On examination urine dipstick testing was negative. There was no evidence of lymphadenopathy. Cardio-respiratory and abdominal examinations were unremarkable. Examination of his skin and joints was also unremarkable. There was mild non-tender ankle oedema.His first blood tests showed a raised adjusted calcium of 3.25 and a raised white cell count of 11.8, with an eosinophilia of 0.75. Other preliminary blood results were unremarkable (normal Hb, U+Es, LFTs, CRP, ESR, RF, anti-CCP, ANA and TFTS). His chest X-ray was reported as clear.His PTH was appropriately suppressed and vitamin D level was adequate with normal urinary calcium and normal serum protein electrophoresis. Serum ACE level was raised at 114 (normal 8-52). PTH related peptide test was not available.A CT chest abdomen and pelvis scan carried out to rule out malignancy was normal with no notable lymphadenopathy. A subsequent PET CT scan was normal. Acutely, his hypercalcaemia was treated with IV fluids and IV pamidronate. Although his calcium rapidly normalised, he reported feeling only 10% better. He complained of ongoing ankle pain. An MRI scan of both ankles with contrast showed mild synovitis of ankle, subtalar and talonavicular joints. There was also evidence of tenosynovitis.Given the constellation of hypercalcaemia, raised serum ACE level and ankle synovitis on MRI scan, he was treated for sarcoidosis with prednisolone 20mg. This led to a rapid improvement in his symptoms and normalisation of serum ACE. He was started on azathioprine as a steroid-sparing agent. Case report - DiscussionIn cases series, hypercalcaemia due to sarcoidosis accounts for only 6% of all hypercalcaemic patients. The mechanism of hypercalcaemia in sarcoidosis is thought to be via activated pulmonary macrophages and sarcoid lymph node granulomas which upregulate the enzyme 1-alpha hydroxylase, resulting in the increased formation of calcitriol (1,25(OH)2D3). This increases calcium absorption from the gastrointestinal tract, stimulates renal calcium reabsorption and promotes calcium release from skeletal stores, causing hypercalcaemia.This case was particularly unusual as earlier literature suggests that sarcoidosis-associated hypercalcaemia is a result of activated pulmonary macrophages and sarcoid granulomas. However, this patient had significant hypercalcaemia without any radiological lung involvement or granulomata, posing the question whether there are other pathways causing hypercalcaemia in sarcoidosis. Hypercalcaemia without pulmonary involvement may be due to the presence of small amounts of sarcoid granulomata in extra-pulmonary locations such as the porta hepatis. These may not be as easily detectable on radiological investigations but may contribute to the upregulation of 1-alpha hydroxylase and subsequent hypercalcaemia. Another explanation for the significant hypercalcaemia in this patient may be due to the production of parathyroid hormone-related peptide (PTHrP) from sarcoid granulomas and bone marrow, which upregulates renal 1-alpha hydroxylase enzymes and increases the formation of calcitriol.There was no area to obtain a tissue biopsy given the normal CT and PET CT scans, resulting in a greater reliance on history, examination, and serological investigations. In addition, 30-50% of all patients with sarcoidosis have hypercalciuria, yet this patient interestingly had only an isolated hypercalcaemia with a normal urinary calcium. Case report - Key learning points Hypercalcaemia is rare in the absence of pulmonary involvement with only 10 cases reported in literature.Although non-specific, an elevated serum ACE level may be a useful pointer to the diagnosis of sarcoidosis in the absence of other classical signs.In this case, granulomatous tissue responsible to produce 1,25(OH)2D3 might be below the limits of radiological detection. Production may originate from extra-pulmonary sarcoid granulomatous tissue such as in the porta hepatis. Another possible mechanism for hypercalcaemia may be the production of PTHrP which has been reported in sarcoid tissue specimens and in the bone marrow.

SAT-495 1-α-Hydroxylase Activity-Mediated Hypercalcemia Associated with Ovarian Dysgerminoma

Background: Humoral hypercalcemia of malignancy is classically associated with increased tumor production of parathyroid hormone-related peptide (PTHrP). While 1,25 dihydroxy vitamin D (1,25D) mediated hypercalcemia has been demonstrated with a range of granulomatous disorders and lymphomas, there have only been 11 cases reported in ovarian dysgerminomas, of which only 2 were in adults. Ovarian dysgerminoma is the most common ovarian malignancy in childhood but is much more infrequent in adults. We present a case of a rare ovarian malignancy in an adult woman with an even more rare presentation of 1,25D mediated hypercalcemia. Case: A 23 year old African American female with a history of intravenous drug abuse was admitted for dilation and curettage for suspected molar pregnancy. Her operative course was complicated by uterine perforation requiring diagnostic laparoscopy which revealed a large, firm, irregular left ovarian mass concerning for malignancy. Laboratory findings were pertinent for calcium 13.4mg/dl (8.5-10.5), albumin 3.5g/dl (3.5-5.0), creatinine 1.61mg/dl (0.6-1.2), phosphorus 4.0mg/dl (2.5-4.5), alkaline phosphatase elevated at 170 Units/L (25-125) and appropriately suppressed PTH of 4 pg/ml (10-65). Previous calcium levels were all normal. Additional work-up revealed normal PTHrP, 25-OH Vitamin D 14.2 mg/dl (20-50) and high-normal 1,25 dihydroxy vitamin D at 76pg/ml (19.9-79.3). Tumor markers β-hCG, LDH, α-fetoprotein, and CA 19-9 were all elevated. CT scan of the abdomen and pelvis characterized the lesion to be a heterogenous 16.5 x 10.0 x 18.3 cm pelvic mass. The patient was initially given intravenous isotonic fluids and 4mg of intravenous zoledronic acid which decreased calcium to 10mg/dl. Biopsy of the mass performed during initial laparoscopy confirmed the suspected diagnosis of ovarian dysgerminoma. A left salpingo-oophorectomy was performed and the patient developed mild hypocalcemia post-operatively to a nadir of 6.7mg/dl (adjusted for albumin: 7.7) requiring calcium supplementation. The 1,25D level on post-operative day 2 was low at 9.1 pg/ml. Surgical pathology demonstrated metastatic ovarian dysgerminoma with para-aortic lymph node involvement. Conclusion: Our case demonstrates an unusual case of humoral hypercalcemia of malignancy. Exogenous 1-α-hydroxylase expression has been reported exceedingly rarely in solid tumors other than lymphomas. While we were unable to stain the tumor for 1-α-hydroxylase, the abrupt drop in 1,25D and calcium levels post resection strongly support our diagnosis. To our knowledge, our patient is the second oldest patient reported in literature to have 1,25D mediated hypercalcemia associated with an ovarian dysgerminoma.

Protection of Bone Density in Sarcoidosis: Can we Give Vitamin D without Causing Hypercalcemia?

ABSTRACT Objective: Sarcoidosis is commonly complicated by hypercalcemia due to extrarenal 1,25-dihydroxyvitamin D and parathyroid hormone–related peptide production. Bisphosphonates are often give...

Endocrine Paraneoplastic Syndromes: A Review

Paraneoplastic endocrine syndromes result from ectopic production of hormones by different tumors. Hypercalcemia of malignancy is the most common, mostly caused by ectopic parathyroid hormone related peptide (PTHrP) production which increases bone resorption. Other causes include the rare ectopic parathyroid hormone (PTH) production, ectopic production of 1, 25-(OH)2 vitamin D by the tumor and its adjacent macrophages and bone metastasis which by itself in addition to the local production of PTHrP at the level of the bone lead to bone resorption and thus hypercalcemia. Treatment includes extracellular fluid volume repletion, bisphosphonates or denosumab and calcitonin. Ectopic Cushing's syndrome caused by ectopic ACTH production results in hypokalemia, proximal muscle weakness, easy bruisability, hypertension, diabetes and psychiatric abnormalities including depression and mood disorders. Different diagnostic measures help to differentiate Cushing's disease from ectopic Cushing's syndrome. Treatment includes surgical resection of tumor and medical therapy to suppress excess cortisol production. Ectopic secretion of ADH has been associated with different tumor types. The best treatment options include removal of the underlying tumor, chemotherapy, or radiotherapy in addition to free water restriction, demeclocycline and vaptans. Ectopic growth hormone releasing hormone secretion has been identified with carcinoids, phechromocytoma and other tumors. Surgery is the mainstay of therapy with systemic therapy used in metastatic disease. Other rare ectopic hormone syndromes have also been identified including ectopic prolactin, ectopic erythropoietin, and thrombopoetin in addition to others.

Hypercalcemia in Disseminated Coccidioidomycosis: Expression of Parathyroid Hormone-Related Peptide Is Characteristic of Granulomatous Inflammation

Hypercalcemia is an uncommon complication of disseminated granulomatous infections. The pathogenesis of hypercalcemia associated with infection is not clear. We investigated a case of disseminated coccidioidomycosis with hypercalcemia. We used a sensitive radioimmunoassay to measure serum parathyroid hormone-related peptide (PTHrP) and a mouse monoclonal antibody to PTHrP to immunostain biopsies. We found elevated serum levels of PTHrP while the patient was hypercalcemic that became undetectable when serum calcium normalized. We also found that the inflammatory cells and some surrounding tissues in skin biopsies expressed PTHrP. PTHrP was expressed by all biopsied lesions of patients with coccidioidomycosis that we examined, whether localized to the lung or disseminated, but no other cases were hypercalcemic. PTHrP was also expressed by the 3 mycobacterial granulomas we examined, and in a lymph node from a patient with sarcoidosis. The expression of PTHrP is a property of infectious granulomas regardless of etiology or the tissue involved, suggesting that PTHrP expression is part of the normal granulomatous immune response. Hypercalcemia may result if there is disseminated infection and multiple granulomas. We propose that excess production of PTHrP is the cause of hypercalcemia in granulomatous infections.

Parathyroid hormone-related peptide and primary hyperparathyroidism

The parathyroid hormone-related peptide (PTHrP) has been shown to be the major pathogenic factor to humoral hypercalcemia of malignancy (HHM). The presence of PTHrP in many normal tissues and in normal or abnormal parathyroids has been described in literature and its role has been investigated. PTHrP release from parathyroid cells into the extracellular space has been demonstrated to depend on the extracellular calcium concentration. The hormone binds to PTH type 1 Receptor (PTH1R) with a high affinity, as well as parathyroid hormone (PTH). These hormones' amino-terminal (1-34) peptide fragments are considered sufficient to achieve efficient receptor activation and action on mineral ion homeostasis. Generally, diagnosis of primary hyperparathyroidism (PHPT) is based on hypercalcaemia and elevated levels of PTH. The advent of intact-PTH immunoradiometric assay allowed us to distinguish PHPT from non-parathyroid-dependent hypercalcaemia, but the presentation of normal PTH level and hypercalcaemia due to a parathyroid adenoma is possible. The aim of the study is to identify the relationship between the production of PTHrP without malignancy and the diagnosis of PHPT by a systematic review.

Calcium-sensing receptor in cancer: good cop or bad cop?

The extracellular calcium-sensing receptor (CaR) is a versatile 'sensor' for di- and polycationic molecules in the body. CaR plays a key role in the defense against hypercalcemia by "sensing" extracellular calcium levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. Although mutation of CaR gene has so far not been associated with any malignancy, aberrant functions of CaR have implications in malignant progression. One situation is loss of CaR expression, resulting in loss of growth suppressing effects of elevated extracellular Ca(2+) by CaR, reported in parathyroid adenoma and in colon carcinoma. Another situation is activation of CaR, resulting in increased production of parathyroid hormone-related peptide (PTHrP), a primary causal factor in hypercalcemia of malignancy and a contributor to metastatic processes involving bone. CaR signaling and effects have been studied in several cancers including ovarian cancers, gastrinomas, and gliomas in addition to comparatively detailed studies in breast, prostate, and colon cancers. Studies on H-500 rat Leydig cells, a xenotransplantable model of humoral hypercalcemia of malignancy has shed much light on the mechanisms of CaR-induced cancer cell growth and survival. Pharmacological agonists and antagonists of CaR hold therapeutic promise depending on whether activation of CaR is required such as in case of colon cancer or inactivating the receptor is required as in the case of breast- and prostate tumors.

Primary Pulmonary Squamous Cell Carcinoma Associated with Elevated IL-6, Leukocytosis, Hypercalcemia, Phagocytosis, Reactive Lymphadenopathy and Glomerular Mesangial Cell Proliferation via the Production of PTH-rP and G-CSF

We report an autopsied case of a 74-year-old man with primary pulmonary squamous cell carcinoma (SCC) associated with leukocytosis, hypercalcemia, phagocytosis in the bone marrow, reactive lymphadenopathy and mesangial cell proliferation in the glomerulus. Laboratory examination revealed increased serum levels of parathyroid hormone-related peptide (PTH-rP), granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6) and soluble interleukin 2 receptor (s-IL2R). An autopsy showed moderately differentiated SCC at the left lower lobe of the lung, of which tumor cells distinctly showed cytoplasmic immunoreactivity to anti-G-CSF and anti-PTH-rP antibodies. Thus, pulmonary SCC seemed to produce both G-CSF and PTH-rP, causing leukocytosis, hypercalcemia, and IL-6 production from the bone. IL-6 also might have stimulated the proliferation of SCC and glomerular mesangial cells, and induced phagocytosis, reactive lymphadenopathy and hepatosplenomegaly by interacting with the mononuclear phagocytic system.

Regulatory Factors on Parathyroid Hormone-related Peptide Production by Primary Culture of Lactating Rat Mammary Gland

Parathyroid hormone-related protein (PTHrP) is a major cause of humoral hypercalcemia of malignancy, but has also been widely found in fetal and adult non-neoplastic tissues. Lactating mammary gland has been shown to produce large amounts of PTHrP, and high levels of PTHrP have been measured in milk. We have examined the influences of several substances on the secretion of two different forms of PTHrP by primary cultures of mammary cells isolated from lactating rats to examine the regulatory mechanisms of PTHrP production by mammary cells. Primary cultures of mammary cells seeded at a density of 10(5) cells per 35 mm culture dish were grown on collagen gels. First, after cells were left 24 hours for attachment and incubated in 2 % FCS containing medium with for 12 hours, PTHrP (1 - 87) secretions were measured in conditioned medium with hormone supplementation for 1, 24 and 48 hours. Progesterone (10(-7) - 10(-5) mol/l) significantly suppressed PTHrP (1 - 87) secretion in a dose-dependent manner (p < 0.01), while 17beta-estradiol had no influence on PTHrP (1 - 87) secretion. Prolactin, a known stimulator of PTHrP expression in vivo, had no effect in this in vitro model. Second, PTHrP (1 - 34) secretion levels from confluent lactating mammary cells for 24 hours were evaluated. The same results were obtained in the case of PTHrP (1 - 87) secretion from non-confluent cells. Furthermore, dexamethasone (10(-6) mol/l) significantly suppressed PTHrP (1 - 34) secretion (p < 0.01). These results suggest that PTHrP production from the lactating mammary gland is suppressed by progesterone as well as dexamethasone. Progesterone dramatically falls after delivery, thus possibly accelerating PTHrP production by lactating mammary glands and resulting in considerable amounts of PTHrP secreted into the milk.

Regulation of calcification by bisphosphonates

Etidronate, an analogue of first generation of bisphosphonates, has inhibitory actions on mineralization and hydroxyapatite crystal formation, which is therefore used as a drug to treat ectopic ossification in cases with total hip arthroplasty and spinal cord injury. The effect of bisphosphonates to prevent calcification could be associated with the physical property to attach tightly to hydroxyapatite crystals in bone matrix. A recent investigation suggested that bisphosphonates might prevent arterial calcification through a mechanism associated with the enhanced production of parathyroid hormone-related peptide from vascular smooth muscle cells. A derivative of bisphosphonates to inhibit vascular calcification in atherosclerosis is expected and should be developed in the near future.

Calcium and vitamin D supplementation during bisphosphonate administration may increase osteoclastic activity in patients with bone metastasis

Bone metastasis are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. The consequences of bone metastasis are often devastating. Osteolytic metastasis can cause different kinds of skeletal related events including severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. These skeletal-related events are the result of the resorption of mineralized bone by osteoclasts. Bisphosphonates are synthetic analogues of naturally occurring pyrophosphate compounds that inhibit bone resorption. Potent bisphosphonates, pamidronate and, more importantly zoledronic acid may cause hypocalcemia, but mostly asymptomatic, mild, transient in most cases. Sufficient calcium and vitamin D intake needs to be ensured in patients with malignancy who have borderline or low levels of calcium when commencing treatment with bisphosphonates. Vitamin D itself induce the formation of osteoclasts by increasing the expression of RANKL on marrow stromal cells. Local calcium also promotes tumor growth and the production of parathyroid hormone-related peptide which in turn stimulates bone resorption. Vitamin D and calcium supplementation during bisphosphonate administration for the purpose of elimination of the side effects related to hypocalcemia in patients with bone metastasis may increase the bone resorption and decrease the efficacy of bisphosphonates. Therefore, vitamin D and calcium supplementation must not be routinely recommended during bisphosphonate administration.

Disorders of calcium homeostasis.

To ensure a multitude of essential cellular functions, the extracellular concentration of calcium is maintained within a narrow physiological range. This depends on integrated regulation of calcium fluxes with respect to the intestine, kidneys and bone. The precise regulation of serum calcium is controlled by calcium itself, through a calcium receptor and several hormones, the most important of which are parathyroid hormone and 1,25(OH)(2) vitamin D. This balance can be disturbed by mutations in the calcium-sensing receptor, inappropriately high or low levels of parathyroid hormone, resistance to parathyroid hormone effects, insufficient intake or production of 1,25(OH)(2) vitamin D and inactivation of the vitamin D receptor. Mineral homeostasis is moreover influenced by many other systemic factors (e.g. sex steroid, thyroid and glucocorticoid hormones) or humoral factors (e.g. cytokines and growth factors). A specific example is the major abnormalities of mineral homeostasis in case of malignancy by excessive production of parathyroid hormone-related peptide resulting in hypercalcaemia. Several new drugs have been developed based on factors in this axis, including calcimimetics, calcilytics, vitamin D analogues and parathyroid hormone-related peptide inhibitors.