Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma

ABSTRACT— A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/1), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64 787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.     

Severe hypercalcemia associated with hepatocellular carcinoma secreting intact parathyroid hormone: a case report

Here we describe a 73-year-old woman with hypercalcemia caused by a hepatocellular carcinoma (HCC) secreting intact parathyroid hormone (iPTH). Serum tumor markers and dynamic CT findings indicated a diagnosis of HCC. The source of the elevated serum iPTH was not obvious. Transarterial chemoembolization (TACE) was effective against the HCC, and the serum iPTH level fell to within the normal range, suggesting a correlation between the carcinoma and the iPTH. About 2 months later, the tumor had grown and the serum calcium level increased leading to physical deterioration and death. This clinical course suggested that HCC can ectopically secrete iPTH.     

Different routes bridging calcium in Japanese hemodialysis patients

There is growing evidence that not only serum calcium concentration but also excess calcium load is associated with vascular calcification and mortality in hemodialysis patients. Calcium load in hemodialysis patients cumulatively comes from three different routes: oral intake of calcium including calcium-based phosphate binders, traffic of calcium from/to dialysate, and calcemic action of vitamin D. The K/DOQI guidelines recommend sevelamer hydrochloride instead of calcium-containing phosphate binders to control serum phosphate concentration. However, in Japan, both kinds of phosphate binders are used concomitantly, mainly because Japanese patients are prone to a higher incidence of sevelamer-associated adverse events such as gastrointestinal symptoms. Regarding the calcium concentration of dialysate (D-Ca) in Japan, 3.0 mEq/L is more popular than 2.5 mEq/L. Calcium loaded through 3.0 mEq/L dialysate may lead to metastatic calcification rather than to bone formation because serum phosphate concentration rebounds several hours after the end of each hemodialysis session when plasma pH is still high. In contrast, use of 2.5 mEq/L dialysate may result in an unfavorable increase of intact parathyroid hormone particularly when the amount of oral calcium intake is reduced. Although a higher dose of vitamin D is required to counteract the stimulation of parathyroid glands, hypercalcemia is less likely with 2.5 mEq/L dialysate. As the new K/DOQI guidelines are released, it is time to discuss the appropriate D-Ca as well as doses and kinds of phosphate binders and vitamin D for the comprehensive management of Japanese hemodialysis patients.     

Is 2.5 mEq/L the Optimal Calcium Concentration of Dialysate in the Use of Sevelamer Hydrochloride? A Study of the Dialysate Calcium Concentration Recommended by K/DOQI Guidelines

We tested the effect of three different dialysate calcium concentrations on calcium-phosphorus metabolism during the use of sevelamer hydrochloride. After a calcium-containing phosphate binder was switched to sevelamer, the serum calcium, phosphorus, and intact parathyroid hormone levels and the markers of bone turnover were measured in the patients whose dialysate calcium concentrations were 2.5, 2.75, and 3.0 mEq/L. As a result, in the 2.75-mEq/L group, the serum calcium concentrations decreased and the intact parathyroid hormone level increased significantly. In the 2.5-mEq/L group, transient hypocalcemia occurred and the levels of both bone-alkaline phosphatase and osteocalcin increased. In the 3.0-mEq/L group, the serum calcium concentrations did not change significantly and only bone-alkaline phosphatase increased. If a calcium-containing phosphate binder is completely switched to sevelamer, dialysis using a dialysate calcium concentration below 3.0 mEq/L may result in hypocalcemia and acceleration of bone turnover.     

Parathyroid hormone-related protein and interleukin-1 alpha synergistically stimulate bone resorption in vitro and increase the serum calcium concentration in mice in vivo

To elucidate the mechanism of humoral hypercalcemia elicited by human esophageal carcinoma cells (EC-GI), which constitutively produced interleukin-1 alpha (IL-1 alpha) and PTH-like factor, the effects of IL-1 alpha and PTH-related protein (PTH-rP) on bone resorption in vitro and on serum calcium concentrations in vivo were investigated. Nude mice transplanted with EC-GI cells invariably developed hypercalcemia, although their urinary cAMP excretion remained within the normal range. IL-1 alpha or PTH-rP-(1-34) stimulated 45Ca release from prelabeled fetal mouse forearm bones in a concentration-dependent manner, and when combined, IL-1 alpha and PTH-rP-(1-34) synergistically stimulated bone resorption in vitro. Injection of PTH-rP-(1-34) into mice three times a day for 2 days increased the serum calcium concentration in a dose-dependent manner. Continuous infusion of IL-1 alpha occasionally increased the serum calcium concentration. Simultaneous administration of IL-1 alpha at rates of 1-2.7 micrograms/day and PTH-rP-(1-34) at doses of 15-30 micrograms/day synergistically increased the serum calcium concentration in vivo. These findings suggest that PTH-rP and IL-1 alpha produced by the tumor cells were synergistically responsible for the humoral hypercalcemia observed in both the original patient and the tumor-bearing nude mice, and that at least two bone-resorbing factors [PTH-rP and another nonadenylate cyclase-stimulating bone-resorbing factor(s)] are active in patients with malignancy-associated hypercalcemia, in whom nephrogenous cAMP excretion is neither increased nor decreased.     

Effects of Lowering Dialysate Calcium Concentration on Mineral and Bone Disorders in Chronic Hemodialysis Patients: Conversion from 3.0 mEq/L to 2.75 mEq/L

Selection of a lower dialysate calcium concentration (DCa) can reduce calcium burden and prevent vascular calcification in hemodialysis patients. However, decreased DCa can worsen mineral and bone disorders. This 1‐year retrospective observational study evaluated 121 hemodialysis patients at Fukuoka Renal Clinic who underwent conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. The primary outcomes were changes in serum levels of calcium, phosphate, and parathyroid hormone (PTH). The effects of baseline serum calcium and PTH levels on changes in biochemical parameters were also determined. One year after DCa conversion, mean serum calcium level decreased, while serum phosphate, alkaline phosphatase, and PTH concentrations increased. The rate of achievement of target PTH was higher in patients with lower serum PTH level at baseline, while patients with higher baseline serum PTH level tended to exceed the upper limit of the PTH target range. Patients with higher baseline serum calcium concentration showed a greater decrease in serum calcium level and a greater increase in serum PTH level at 1 year. Patients with a lower baseline serum PTH level can benefit from optimal PTH control following conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. However, secondary hyperparathyroidism may be exacerbated in some patients with higher baseline serum calcium (Ca) and PTH levels. These results indicate that an individualized approach can maximize the benefits of Ca unloading after conversion to lower DCa.     

Effects of Lowering Dialysate Calcium Concentration on Bone Metabolic Markers in Hemodialysis Patients With Suppressed Serum Parathyroid Hormone: A Preliminary Study

Although the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a dialysate calcium concentration between 2.5 and 3.0 mEq/L, its optimal concentration remains unclear. A total of 53 hemodialysis patients with intact parathyroid hormone (PTH) levels <150 pg/mL were enrolled in this prospective observational study. A dialysate calcium concentration was converted from 3.0 to 2.75 mEq/L and bone metabolic markers including bone alkaline phosphatase (BAP) and tartrate‐resistant acid phosphatase‐5b (TRACP‐5b) were examined. After 3 months, serum corrected calcium levels decreased (P < 0.001), while serum intact PTH, BAP and TRACP‐5b levels increased (P < 0.05, P < 0.05 and P < 0.001, respectively). Multiple regression analyses showed that the amount of change in BAP was significantly associated with dialysis vintage (P < 0.01). In conclusion, the lowering of dialysate calcium concentration stimulated parathyroid gland and bone remodeling in hemodialysis patients with suppressed PTH, particularly with longer dialysis vintage.     

Administration of bisphosphonates for malignant hepatic tumor with hypercalcemia

Background/Aims: Hypercalcemia is a paraneoplastic syndrome that is a serious condition requiring urgent treatment. We administered alendronate to hypercalcemia patients with advanced cancer with metastasized liver tumors or hepatocellular carcinoma (HCC) and then evaluated the mechanism and anticancer function of this compound. Methodology: We retrospectively studied 17 patients with hypercalcemia associated with metastatic liver tumor or HCC. Alendronate (10mg) was administered via the intravenous route for patients with metastatic liver tumor (n=12) and via the hepatic artery for patients with HCC (n=5). Results: Intravenous administration of alendronate resulted in decrease in serum calcium levels in all patients. The serum levels of tumor markers also decreased in 66.7% (8/12) of these patients. After intra-arterial alendronate administration, the serum calcium and parathyroid hormone-related protein levels decreased in all the patients. The serum levels of tumor markers such as AFP and PIVKA-II were decreased in 80% (4/5) of these patients. Electron microscopic examination of the resected hepatic tumor revealed an increase in the vascularization and formation of apoptotic vesicles in the vascular endothelial cells. Conclusions: Alendronate is effective not only for controlling hypercalcemia but also for directly enhancing the apoptosis of HCC cells.     

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.     

Low dose calcitriol versus placebo in patients with predialysis chronic renal failure

The effects of a small dose of calcitriol (less than or equal to 0.50 micrograms/day) on parathyroid and renal function, bone histomorphometry, and aluminum (Al) metabolism were studied in a randomized double blind study of 30 patients with predialysis chronic renal failure. The patients were followed at least monthly for 8 months. Serum Al levels were measured, and transiliac bone biopsies, double labeled with tetracycline, were obtained at both the beginning and end of the 8-month treatment period. Serum calcium and ionized calcium concentrations increased in the treatment group, and the calcitriol dosage had to be reduced in 8 patients at least once because of hypercalcemia. Calcitriol treatment did not significantly influence either serum A1 levels or the presence of stainable Al in bone. Serum PTH, urinary cAMP excretion, and bone resorption indices decreased in the treatment group, indicating suppression of parathyroid hyperfunction. Throughout the study renal function decreased at a similar rate in both groups, suggesting that calcitriol treatment had no depressive effect on renal function. We conclude that a low dose of calcitriol may be used to preserve or even restore bone metabolism in patients with predialysis chronic renal failure if serum calcium is closely followed and hypercalcemia promptly treated.     

Hypercalcemia and parathyroid disorders.

Primary hyperparathyroidism and malignancy are responsible for the majority of reported cases of hypercalcemia. Suspected hypercalcemia should be documented on more than one occasion, preferably with the measurement of ionized calcium. Determination of intact parathyroid hormone with a modern two-site immunoassay is the single most important laboratory analysis in the differential diagnosis of hypercalcemia. Intact parathyroid hormone is increased or inappropriately high in primary hyperparathyroidism and suppressed or low normal in hypercalcemia of malignancy. Midregion and carboxylterminal radioimmunoassays are less effective in separating parathyroid and nonparathyroid hypercalcemia. In malignancy, hypercalcemia may result from local osteolysis or humoral factors. Although ectopic parathyroid hormone is produced rarely and certain lymphomas secrete 1,25-dihydroxyvitamin D, parathyroid hormone-related protein is elevated in the majority of patients with humoral hypercalcemia of malignancy. Recent developments in the measurement of parathyroid hormone-related protein should help to define the physiologic function of parathyroid hormone-related protein and its role in the differential diagnosis and therapy of hypercalcemia.     

Serum parathyroid hormone-related protein concentrations in patients with hematologic malignancies or solid tumors.

The clinical significance of parathyroid hormone-related protein in humoral hypercalcemia of malignancy was investigated by determining the serum parathyroid hormone-related protein concentrations in 167 normal subjects, 56 patients with hematologic malignancy and 144 patients with solid tumor. Serum parathyroid hormone-related protein was measured with a radioimmunoassay kit that recognizes the C-terminal portion of the molecule. The serum parathyroid hormone-related protein concentrations were 20.2-50.8 pmol/l (mean +/- 2 SD) in normal subjects, and were elevated in 80% of the patients with malignancies with hypercalcemia, including squamous cell carcinoma and adult T cell leukemia. Moreover, two cases of B cell non-Hodgkin's lymphoma with hypercalcemia had high serum parathyroid hormone-related protein concentrations, which varied in parallel with the tumor size during the clinical course. Of 136 patients with solid tumors with normocalcemia, the serum parathyroid hormone-related protein concentration was slightly elevated in only 5.1%, all of whom were at an advanced stage. These data indicate that determination of the serum parathyroid hormone-related protein concentration is useful for differential diagnosis of humoral hypercalcemia of malignancy and prediction of its development.     

Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.     

Parathyroid hormone-related protein (PTH-rP)-associated hypercalcemia in a patient with an atypical chronic lymphocytic leukemia

We describe a patient with an atypical chronic lymphocytic leukemia (CLL) of the mixed cell type with a hypercalcemia due to parathyroid hormone-related protein production by the malignant B cells. On regard of the elevated serum calcium level without overt lytic bone lesions we found elevated serum levels of PTH-rP and demonstrated the presence of PTH-rP on the malignant lymphocytes. PTH-rP-related hypercalcemia in CLL is very rare. The role in PTH-rP in humoral hypercalcemia of malignancy is discussed.     

Humoral hypercalcemia in Hodgkin's disease. Association with elevated 1,25-dihydroxycholecalciferol levels and subperiosteal bone resorption

A 58-year-old man was initially seen with fatigue and weight loss. Laboratory examination detected hypercalcemia, elevated 1,25-dihydroxycholecalciferol levels, low parathyroid hormone (PTH) concentrations, and subperiosteal bone resorption. The patient underwent subtotal parathyroidectomy for presumed hyperparathyroidism, but serum calcium and 1,25-dihydroxycholecalciferol levels remained elevated following surgery. Search for another cause of the hypercalcemia disclosed enlarged para-aortic lymph nodes, biopsy specimens of which demonstrated Hodgkin's disease. After treatment of the patient with two cycles of chemotherapy with mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone, serum calcium, 1,25-dihydroxycholecalciferol, and PTH levels normalized. We speculate that the humoral hypercalcemia in this patient resulted from tumor production of 1,25-dihydroxycholecalciferol.     

Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia.

Circulating N-terminal PTH-related protein (PTHrP), N-terminal PTH, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were measured in normal dogs and dogs with cancer-associated hypercalcemia (CAH), parathyroid adenomas, and miscellaneous tumors. PTHrP was undetectable (less than 1.8 pM) in normal dogs and increased in dogs with CAH due to adenocarcinomas derived from apocrine glands of the anal sac (44.9 +/- 27 pM), lymphoma (8.3 +/- 4.4 pM), and miscellaneous carcinomas (13.3 +/- 11.4 pM). The PTHrP concentration decreased in dogs with lymphoma and anal sac adenocarcinomas after successful treatment of CAH. The PTHrP concentration had a significant linear correlation with total serum calcium in dogs with anal sac adenocarcinomas and hypercalcemia, but not in dogs with lymphoma and hypercalcemia. Serum N-terminal PTH concentrations were usually in the normal range (12-34 pg/ml) for all groups of dogs except dogs with parathyroid adenomas (83 +/- 38 pg/ml). The serum PTH concentration increased after successful treatment of CAH. Serum 1,25-(OH)2D concentrations were decreased, normal, or increased in dogs with CAH, and 1,25-(OH)2D levels decreased after treatment of CAH. In summary, circulating concentrations of PTHrP are consistently increased in dogs with CAH, and PTHrP appears to play an important role in the induction of hypercalcemia.     

A case of esophageal carcinoma with hypercalcemia caused by PTH-rP--the effect of therapy on the bone and calcium metabolism]

The changes in the bone and in calcium metabolism during cisplatin or bisphosphonate administration is reported in a 50-year-old patient with esophageal carcinoma who had humoral hypercalcemia of malignancy (HHM). Laboratory findings on admission showed that ionized calcium was 1.65mmol/L, phosphorus was 2.4mg/dl, and PTH-rP was 151pmol/L, without any evidence of bone metastasis. After admission, cisplatin and/or bisphosphonate were administrated for hypercalcemia. These administrations ameliorated serum ionized calcium, urinary pyridinoline and hydroxyproline level within a few days. Although cisplatin administration decreased the serum osteocalcin level, bisphosphonate administration kept up the level, suggesting that bisphosphonate maintained bone formation and cisplatin decreased its formation. The discrepancy may be due to the coupling with the reduction of bone resorption and/or direct toxic effect on osteoblasts during cisplatin administration, and preservation of osteoblastic activity during bisphosphonate administration. Cisplatin and bisphosphonate may have different effects on bone formation. Serum 1,25(OH)2D level was slightly decreased or unchangeable after cisplatin administration, although the level was increased after bisphosphonate administration. Direct toxic effect on 1 alpha-hydroxylase of the kidney or increase in phosphrous level may explain the change of 1,25(OH)2D after cisplatin administration. These results suggested that cisplatin and bisphosphonate have the same effect of preventing bone resorption but different effects on bone formation and/or serum 1,25(OH)2D level.     

Humoral hypercalcemia of malignancy: A syndrome in search of a hormone

A woman with hypercalcemia and a hypernephroma confined to the left kidney underwent nephrectomy and subsequent resolution of hypercalcemia. Serum parathyroid hormone was undetectable in peripheral blood as well as in the left renal vein at surgery. Parathyroid hormone was also undetectable in the tumor extract using three different antisera to parathyroid hormone. Measurement of plasma prostaglandin E and 13,14-dihydro-15-keto-prostaglandin E₂ revealed levels within the normal range. The serum 1,25-dihydroxyvitamin D concentration was below normal and nephrogenous cyclic adenosine monophosphate was markedly elevated. The humoral agent responsible for hypercalcemia in this patient was not identified. This case emphasizes the need to search for new hypercalcemic factors in patients with hypercalcemia of malignancy.     

Pathophysiology of hypercalcemia and the therapeutic role of bisphosphonates

When hypercalcemia is found in patients with malignancy, it is necessary to measure circulating parathyroid hormone -related peptide concentrations and to search for bone lesions. Because accelerated bone resorption mainly contributes to malignancy associated hypercalcemia, bisphosphonates, which strongly suppress osteoclastic resorption, is most effective. Upon administration of bisphosphonates, serum calcium begins to fall within two days, reaches the bottom after one week, and the effects disappear after two or three weeks. In case of need to lower the serum calcium concentration rapidly, calcitonin should be used at the same time.     

Parathyroid hormone responsiveness in hypoparathyroidism with hypomagnesemia.

The failure to respond normally to parathyroid hormone (PTH) administration has been reported in patients with severe hypomagnesemia. A patient with hypoparathyroidism and a markedly decreased serum concentration of magnesium (0.7 mEq/liter), but a normal red blood cell magnesium level, is described who increased serum calcium concentration and decreased per cent renal tubular reabsorption of phosphate when parathyroid extract was given. It is suggested that PTH responsiveness in hypomagnesemic patients may, at least in part, be dependent upon the adequacy of intracellular magnesium stores. This interpretation is supported by the normal cellular (red blood cell) magnesium concentrations observed in this patient and in comparable studies in which PTH responsiveness in the presence of hypomagnesemia was demonstrated. In addition, a failure of optimal renal conservation of magnesium was noted to occur in this patient since, despite hypomagnesemia, urinary magnesium excretion was greater than the 1 mEq/day loss that is seen when magnesium conservation is induced by means such as dietary restriction.