1

PTHrP

PTH/PTHr

Receptor

PTH1R

(Fukuzumi et al. 2000). The production of PTH-like compound is detected in vivo in patients with renal cell carcinoma, as well as in the supernatant of human renal cell carcinoma cells transplanted into nude mice (Weissglas et al. 1995; Strewler et al. 1986). Recent studies have examined a possible contribution of IL-6, known to stimulate osteoclastic bone resorption, to the hyper-calcemia of renal cell carcinoma (Weissglas et al. 1995). PTHrP was purified from renal cell carcinoma as a hy-percalcemic factor. It has 70% homology to the first 13 amino acids of the N-terminal portion of the parathyroid hormone (PTH), binds to PTH receptors, and shares similar biologic activity to PTH. Specifically, it stimulates adenylate cyclase in renal and bone systems. PTHrP mimics many of the effects of PTH on renal tubular function by binding to and activating the PTH receptor (Fig. 14.1). This leads to alterations in normal calcium homeostasis, including increased bone resorption, decreased renal calcium clearance, increased nephrogenous cyclic adenosine monophosphate levels, and increased phosphorous excretion. Of patients with hypercalcemia, 50% had bone metastasis (Braasch 1952; Papac et al. 1977; Warrell and Bockman 1989; Chasan et al. 1989; Weissglas et al. 1995). The clinical manifestations of hypercalcemia are influenced by many factors, including the duration of hypercalcemia, performance status, age, prior chemotherapy, hepatic and or renal dysfunction, and metastatic disease. Many of the signs and symptoms, such as nausea, anorexia, fatigue, lethargy, and confusion are nonspecific, and the physician must have a high index of suspicion for the presence of hypercalcemia. This is important, because the symptoms are generally reversible with therapy. These can include muscle weakness, fatigue, volume depletion, nausea, and vomiting, and in severe cases, coma and death. Neuropsychiatric manifestations are particularly common and may include depression, confusion, or subtle deficits that are often characterized poorly and may not be noted by the patient. Increased calcium can increase gastric acid secretion, and people with hyperparathyroidism may have a higher prevalence of peptic ulcer disease. Hypercalce-mia is often the immediate leading cause of death in patients with ectopic PTHrP production. These patients may rarely survive more than a few weeks or months. Bone metastases tend to cause morbidity and mortality from nerve compression and other orthopedic compli-

Catabolic

/antimetabolic metabolism

CYTOKINES

TNF alpha, IL5, IL6, IL8

Catabolic

/antimetabolic metabolism

Fig. 14.1. Relationship between parathyroid hormone-related protein (PTHrP), PTH1 receptor, proinflammatory cytokines and cancer related morbidity. TNF tumor necrosis factor, IL interleukin cations. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high. Ideally, treatment of the primary cancer leads to resolution of this paraneoplastic disorder. However, elevated calcium levels often require urgent, nonspecific measures, including hyperhydration therapy, diuretics, and biphosphonates.

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