Hypercalcemia due to sun exposure in a patient with multiple myeloma and elevated parathyroid hormone-related protein

A patient with multiple myeloma who developed hypercalcemia during three different stages of his disease, with a different hypercalcemic agent elevated in his serum on each occasion, is described. The initial episode of hypercalcemia was associated with high serum interleukin-6 (IL-6). After treatment for myeloma normocalcemia was achieved. Subsequently, a relapse of hypercalcemia occurred, this time characterized by frankly elevated plasma parathyroid hormone-related protein (PTHrP) but normal IL-6. Monotherapy with pamidronate infusions resulted in remission of the hypercalcemia and a significant fall in PTHrP levels. A third spell of hypercalcemia characterized by an acute rise in serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to abnormally high levels occurred during the summer season after prolonged and intense exposure to the sun.     

An elderly case of non-Hodgkin's lymphoma (NHL) with hypercalcemia]

A 93 year-old woman was admitted due to anorexia and unconsciousness. Biochemical examination of serum showed hypercalcemia (corrected Ca; 16.6 mg/dl). The level of intact parathyroid hormone (i-PTH) was suppressed, whereas parathyroid hormone-related peptide (PTHrp) was to 5.0 pM (normal range: below 0.6 pM). IL-6 and renal cAMP were also elevated. We started to ameliorate hypercalcemia by saline infusion, furosemide and calcitonin. However, hypercalcemia was not improved and the patient died of DIC and renal failure. Autopsy revealed primary lesion of NHL (diffuse large B cell type) to be in the stomach with infiltration of lymphoma into the liver, pancreas, spleen, adrenal glands, jejunum, and lumbar vertebrae. The results of immunohistochemical examination demonstrated the expression of PTHrP in lymphoma cells. PTHrP was also found in lymphoma cells of the spleen by the RT-PCR technique. These findings indicated that hypercalcemia was caused by overexpression of PTHrP from lymphoma cells.     

Severe hypercalcemia in a child with acute nonlymphocytic leukemia: the role of parathyroid hormone-related protein and proinflammatory cytokines

Among the hematological malignancies, hypercalcemia has often been reported in lymphoid malignancies such as multiple myeloma and adult T cell leukemia/lymphoma, but it has only rarely been described in acute nonlymphocytic leukemia. We describe here a 14-month-old girl with acute monocytic leukemia complicated by severe hypercalcemia (4.6 mmol/l) at presentation. A bone survey showed generalized bone resorption, but no localized osteolytic lesions. A search for the etiology of the hypercalcemia revealed that the serum levels of parathyroid hormone-related protein (PTHrP) and also proinflammatory cytokines with stimulatory effects on osteolytic bone resorption - TNF-alpha, IL-6 and M-CSF - were elevated. The patient achieved complete remission with induction chemotherapy, and the levels of PTHrP and the cytokines became normalized. In this case, PTHrP and cytokines might have acted cooperatively to exacerbate bone resorption, resulting in severe hypercalcemia.     

Hypercalcaemia caused by a carcinoid tumour

Humoral hypercalcaemia resulting from carcinoid tumours is uncommon. We report a case of hypercalcaemia because of excessive secretion of parathyroid hormone-related protein (PTHrP) in a 77-year-old woman with an advanced carcinoid tumour. Fibroblast growth factor 23 levels were also elevated. The hypercalcaemia responded to adjunctive therapy with long-acting octreotide analogue therapy, bisphosphonates and steroids. The role of PTHrP in humoral hypercalcaemia of malignancy, its association with neuroendocrine tumours, as well as the therapeutic use of somatostatin analogues are reviewed.     

Bone resorption associated with uncoupling of osteoclastic and osteoblastic activities in adult T cell leukemia with hypercalcemia: case report

A 64-year-old woman with adult T cell leukemia (ATL) was admitted to our hospital with severe hypercalcemia. The serum calcium level was elevated to 14.9 mg/dl. Biochemical parameters for bone formation including serum osteocalcin (bone Gla protein, BGP) and alkaline phosphatase (ALP) were normal. The serum levels of tartrate-resistant acid phosphatase (TRAP), a parameter for bone resorption, were increased (4.6 KAU). The serum level of parathyroid hormone-related protein (PTHrP) was elevated (343 pmol/l). The cytokines with stimulatory effects on bone resorption, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha, were not detected. Serum Ca levels, PTHrP levels, and TRAP levels decreased with the decrease in ATL cells after chemotherapy, while serum BGP levels and ALP levels increased. On the 29th hospital day, ATL cells began to increase again. Then serum PTHrP levels, Ca levels, and TRAP levels increased, while serum BGP levels and ALP levels decreased. A marked excessive bone resorption with suppressed bone formation (uncoupling) occurred in this patient. The ATL cells produced not only PTHrP but also IL-1alpha and IL-1beta. These results suggest that PTHrP may act as a humoral factor and IL-1 may act as a local factor in bone metabolism of ATL patients.     

Hypercalcemia in disseminated coccidioidomycosis: expression of parathyroid hormone-related Peptide is characteristic of granulomatous inflammation

Background.?Hypercalcemia is an uncommon complication of disseminated granulomatous infections. The pathogenesis of hypercalcemia associated with infection is not clear. Methods.?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. Results.?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. Conclusions.?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.     

PTHrP-producing tumor: squamous cell carcinoma of the liver accompanied by humoral hypercalcemia of malignancy,increased IL-6 and leukocytosis

A 77-year-old man was admitted to our hospital showing symptoms of general fatigue and appetite loss. He had leukocytosis, thrombocytosis and hypercalcemia with elevated serum levels of parathyroid hormone related peptide (PTHrP) and interleukin-6 (IL-6). An increase in tumor markers SCC and CYFURA21-1 was observed. The liver contained a huge tumor, which was proved to be PTHrP producing squamous cell carcinoma by immuno-histochemical analysis. Since the tumor did not express IL-6, it was assumed to be induced by PTHrP in osteoblasts. This is the first report of PTHrP producing squamous cell carcinoma of the liver.     

Elevation of circulating plasma cytokines in cancer patients with high plasma parathyroid hormone-related protein levels

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.     

Hypercalcemia and systemic lupus erythematosus

Hypercalcemia is commonly caused by the increased production of parathyroid hormone—related protein (PTHrP) by a malignancy. In fact, the demonstration of increased PTHrP production in a patient with hypercalcemia is virtually pathognomonic of malignancy. We studied a patient with systemic lupus erythematosus (SLE), generalized lymphadenopathy, and hypercalcemia. Immunohistology of 2 biopsied lymph nodes revealed the abundant expression of PTHrP and the absence of malignant transformation. Although apparently rare, PTHrP production by nonmalignant lymphoid tissue may occur in SLE and should be considered in the differential diagnosis of hypercalcemia.     

Hypercalcemia secondary to leprosy

Despite the high prevalence of leprosy in undeveloped countries, hypercalcemia secondary to leprosy is rare. One of most important mechanisms responsible for this disorder seems to be high serum concentrations of 1,25-dihydroxyvitamin D produced extrarenally by the granulomatous tissue. Serum levels of parathyroid hormone-related protein (PTHrP) have never been analyzed in this disorder. We report here a case of hypercalcemia in a patient with leprosy. Serum levels of 1,25-dihydroxyvitamin D were normal in spite of low levels of 25-dihydroxyvitamin D and acute renal failure. Suppressed serum levels of parathyroid hormone and PTHrP were also remarkable. In this case, PTHrP seems not to play an important role in the pathogenesis of hypercalcemia. Our data indicate that this disorder may be due, at least in part, to abnormal calcitriol overproduction by granulomatous tissue. Further investigations of the prevalence and pathogenesis of this type of hypercalcemia are needed.     

Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1

We report a patient with multiple endocrine neoplasia type 1 presenting with elevation of parathyroid hormone-related protein (PTHrP) from a metastatic pancreatic neuroendocrine tumor (PNET), and parathyroid hormone (PTH) from primary hyperparathyroidism, resulting in severe hypercalcemia. Parathyroid hormone-related protein production by the PNET was confirmed by immunohistochemical analysis. Hypercalcemia and elevated PTHrP improved markedly with hepatic artery chemoembolization of liver metastasis. Thus, in multiple endocrine neoplasia type 1, correct identification of the cause of hypercalcemia as PTHrP production from a PNET or PTH production from a parathyroid tumor has important therapeutic implications.     

Hypercalcemia induced with the plasma levels of parathyroid hormone-related peptide in multiple myeloma

A 69-year-old man visited our department of neurology with symptoms of paresthesia on the lower extremities and lumbago. Biochemical examination of serum samples showed hypercalcemia (serum concentration 15.6 mg/dl). The levels of intact parathyroid hormone (i-PTH) and 1,25-dihydroxyvitamin D were suppressed, whereas parathyroid hormone-related peptide (PTHrP) was elevated up to 5.4 pM (normal range: below 0.6 pM). Additionally, bone survey revealed a punched-out lesion in radiological examinations of the skull. Bone marrow aspiration demonstrated many atypical plasma cells suggesting multiple myeloma. Nephrogenous cyclic adenosine monophosphate (cAMP), urinary deoxypyridinoline, plasma interleukin 6 (IL-6) and transforming growth factor beta (TGF beta) concentrations were elevated, whereas % of renal tubular reabsorption of phosphate (%TRP) was decreased. The immunohistochemical results demonstrated the expression of PTHrP in atypical plasma cells. These data indicated that hypercalcemia complicating multiple myeloma causes an elevation of renal calcium reabsorption and an increase of bone resorption mediated by PTHrP action.     

Megakaryoblastic transformation of polycythemia vera with hypercalcemia

Polycythemia vera (PV) is known to occasionally transform into acute leukemia. Administration of alkylating agents seems to be associated with an increased risk of leukemic transformation of PV. Hypercalcemia is a serious complication of malignancies, but it is uncommon in acute leukemia. In the majority of malignancies with hypercalcemia, elevated parathyroid hormone-related protein (PTHrP) is thought to be the main cause of hypercalcemia. We report a rare case of megakaryoblastic transformation of PV with hypercalcemia. A 62-year-old man was diagnosed as having PV in 1983, and he had received ranimustine and busulfan. He developed acute megakaryoblastic leukemia 17 years after the initial diagnosis of PV. Serum calcium was elevated, the serum level of intact parathyroid hormone (PTH) was suppressed, and the level of intact PTHrP was slightly elevated. He had no lytic bone lesions; however, uncoupling of bone turnover due to an increase in bone resorption and a decrease in bone formation was detected by using biochemical markers. Since the level of PTHrP was slightly elevated from the normal value, we speculated that PTHrP produced in the local field by leukemic cells might have been more abundant than circulating PTHrP. Pamidronate and adrenocortical hormone were effective in reducing the serum calcium level. However, the patient died shortly after the start of induction chemotherapy. The prognosis of cases of PV that has transformed into acute leukemia is generally poor because the majority of such cases are refractory to chemotherapy.     

Inhibition by human interleukin-1 alpha of parathyroid hormone-related peptide effects on renal calcium and phosphorus metabolism in the rat.

Humoral hypercalcemia of malignancy (HHM) is at least partly caused by tumor secretion of PTH-related peptide (PTHrP), but there is growing evidence for cosecretion with PTHrP of other bone-resorbing peptides, such as the cytokine interleukin-1 alpha (IL-1 alpha). Administration of PTHrP in vivo and in vitro generally mimics the actions of PTH itself, with increases in both resorption and formation of bone. However, bone in HHM is characterized by uncoupling of bone turnover, with increased resorption and decreased formation. We performed experiments to determine whether IL-1 alpha might alter the effects of PTHrP and produce uncoupling. Thus, we administered to 100-g male rats by sc osmotic minipumps synthetic PTHrP-(1-34) alone (2 micrograms/100 g/day), recombinant IL-1 alpha alone (1.5 micrograms/100 g/day), both peptides together at the previous doses, or vehicle only. We infused 5 groups of 12 rats each (PTHrP, IL-1 alpha, PTHrP plus IL-1 alpha, ad libitum fed control, and controls pair-fed to the PTHrP plus IL-1 alpha group) for 14 days. At the end of the study, blood and urine were taken for chemical measurements, and tibias and femurs were harvested for histomorphometry and extraction of RNA from periosteal cells. As expected, PTHrP induced hypercalcemia, relative hypophosphatemia, phosphaturia, and reduced bone mass. Osteoblast number was increased, but osteoclast number was not. Indices of bone formation were unchanged or reduced. The dose of IL-1 alpha chosen had no statistically significant effect, except for reduced longitudinal bone growth, but when combined with PTHrP, IL-1 alpha reduced hypercalcemia, hypophosphatemia, and phosphaturia. In contrast to the blood and urine effects, IL-1 alpha did not interact significantly with PTHrP's effect on bone measurements. Northern analysis of periosteal cell mRNA showed that PTHrP reduced expression of osteocalcin, but not glyceraldehyde-3-phosphate dehydrogenase; IL-1 alpha had no additional effect. These data suggest that 1) continuously administered PTHrP alone may induce uncoupled bone turnover with decreased cortical bone formation; 2) IL-1 alpha appears to inhibit strongly the renal effects of PTHrP and weakly (if at all) its actions on bone and, thus, to decrease its hypercalcemic, phosphaturic, and hypophosphatemic actions; and 3) cosecretion of IL-1 alpha, and possibly other peptide cytokines, with PTHrP may modify the clinical expression of HHM.     

Dramatic response of a metastatic carcinoid tumour to a combination of interferon and octreotide.

The combination of alpha-interferon and octreotide has rarely been tested in the treatment of carcinoid syndrome. We describe a patient who was moribund when treated with interferon alone, but enjoyed a dramatic response leading to disappearance of all symptoms, normalization of dU-5-HIAA, and restoration of his normal life-style when octreotide was initiated. Neither interferon nor octreotide could be withdrawn without reappearance of the symptoms, suggesting that the combination of alpha-interferon and octreotide may have synergistic effects in carcinoid syndrome.     

Lung cancer associated with hypercalcemia induced by concurrently elevated parathyroid hormone and parathyroid hormone-related protein levels

In general, many cases of malignancy-associated hypercalcemia are due to HHM. In patients with humoral hypercalcemia of malignancy (HHM), it has been reported that plasma parathyroid hormone-related protein (PTHrP) and cyclic adenosine monophosphate (cAMP) levels were elevated, while plasma PTH and active vitamin D(3) levels were suppressed. Our patient showed hypercalcemia with a concurrent increase in plasma and tumor tissue PTHrP and PTH concentrations and also high cAMP and low 1-25(OH)(2)VD(3) levels in the plasma. These data suggest that the hypercalcemia exhibited by our patient was consistent with HHM due to lung cancer and its liver metastasis. Moreover, diagnostic imaging and autopsy findings showed no appreciable lesions of the parathyroid gland. In addition, histopathologic examination of the primary and metastatic tumors revealed the existence of PTH immunohistochemically stained with anti-PTH antibodies, suggesting an ectopic-PTH-producing lung tumor. From these data, our patient was diagnosed with a rare case of lung cancer, which produced both ectopic PTH and PTHrP.     

Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney

 A patient with primary non-Hodgkin's (B-cell type) lymphoma of the kidney developed hypercalcemia at the terminal stage of the disease. Although the plasma parathyroid hormone level was low, urinary cyclic AMP excretion was elevated. Serum osteocalcin (BGP) was suppressed and the plasma level of 1,25(OH)₂D was within the normal range. Serum concentrations of PTH-related protein (PTHrP)-like immunoreactivity (PRP-LI) were elevated, and the tissue concentration of PRP-LI in the postmortem lymph node showed high level along with elevated serum PRP-LI, furthermore the production of PTHrP by the tumor was demonstrated by immunohistochemistry and Northern blotting analysis. These findings indicate that the hypercalcemia of the patient was caused by the PTHrP-producing B-cell lymphoma. Hypercalcemia was restored to normocalcemia by bisphosphonate treatment. Our case will add further information on humoral hypercalcemia in B-cell lymphoma, which rarely has been demonstrated to produce PTHrP. Received: 17 July 1997 / Accepted: 2 February 1998     

Hypercalcemia during pregnancy, puerperium, and lactation: review and a case report of hypercalcemic crisis after delivery due to excessive production of PTH-related protein (PTHrP) without malignancy (humoral hypercalcemia of pregnancy)

Hypercalcemia during pregnancy or after delivery is uncommon, and mostly associated with primary hyperparathyroidism (PHPT). If unrecognized, it may increase maternal and fetal morbidity. In a very few patients with PHPT, hypercalcemic crisis develops during pregnancy and particularly after delivery, since calcium transport from the mother to the fetus is abruptly disrupted. Hypercalcemia may also develop in pregnant women due to PTH-related protein (PTHrP)-producing malignant tumors (humoral hypercalcemia of malignancy). Since PTHrP is produced physiologically in fetal and maternal tissues, hypercalcemia may occasionally develop during pregnancy, puerperium, and lactation due to excessive production of PTHrP in the placenta and/or mammary glands. PTHrP may also be involved in milk-alkali syndrome that develops during pregnancy. Although non-malignant hypercalcemia is usually mild, we report a 28-years-old pregnant woman who developed hypercalcemic crisis after normal delivery of an infant. On the first postpartum day, the corrected serum calcium concentration increased to 19.4 mg/dl with a markedly increased serum level of PTHrP (28.4 pmol/L) (normal <1.1 pmol/L). After administration of saline and pamidronate, the serum levels of calcium and PTHrP rapidly normalized. Extensive examination revealed no malignant lesion, suggesting that the placenta may have been producing an excessive amount of PTHrP (humoral hypercalcemia of pregnancy). We review case reports of non-malignant hypercalcemic crisis associated with pregnancy indexed in PubMed in which serum levels of intact PTH and/or PTHrP were described, and stress that rapid control of hypercalcemia is mandatory to save the life of the mother and the infant.     

Use of Imatinib Mesylate for Favorable Control of Hypercalcemia Mediated by Parathyroid Hormone-Related Protein in a Patient with Chronic Myelogenous Leukemia at Blast Phase

The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.     

Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia

PURPOSE: Parathyroid hormone-related peptide (PTHrP) is the predominant cause of malignancy-associated hypercalcemia. However, its prognostic utility is unclear. We aimed to determine the prognostic value of serum PTHrP levels in patients who had hypercalcemia associated with malignancy. METHODS: In this prospective case series, we evaluated 76 patients with a diagnosis of cancer and hypercalcemia (serum calcium level >/=10.3 mg/dL on at least two occasions). PTHrP levels >/=1 pmol/L were considered elevated. We used multivariate Cox regression analysis to identify factors associated with mortality. RESULTS: Fifty patients (66%) died during follow-up. In a multivariate analysis, higher pretreatment calcium levels and elevated PTHrP levels were associated with increased mortality, with effects of PTHrP varying by age (P = 0.03). Survival was associated with pretreatment calcium levels both in patients over 65 years of age (hazard ratio [HR] per mg/dL = 1.5; 95% confidence interval [CI]: 1.2 to 1.8; P <0.001) and in patients aged 65 years or less (HR = 1.3; 95% CI: 1.1 to 1.5; P = 0.003). Adjusted for pretreatment calcium levels, elevated PTHrP levels were associated with increased mortality in patients aged 相似文献