The pathogenesis of humoral hypercalcaemia of malignancy

The syndrome of humoral hypercalcaemia of malignancy (HHM) is characterised by end-organ manifestations of parathyroid-hormone (PTH)-like effects such as abnormalities of renal tubular calcium and phosphate transport, increased nephrogenous cyclic AMP and 1,25 dihydroxyvitamin D production, and increased osteoclastic bone resorption. Despite this, true ectopic PTH production has seldom been documented in HHM. A number of bone-resorbing factors, including prostaglandins, prostaglandin-stimulating factors, lymphokines, growth factors, and vitamin-D-like sterols, have been implicated as causes of HHM, but none can reproduce the PTH-like biochemical features characteristic of the syndrome. PTH-related peptides have recently been isolated from tumours associated with HHM. These substances are the most likely putative humoral mediators of HHM, since they are structurally similar to PTH in the aminoterminal region and interact with the PTH receptor in vitro. However, the remainder of the molecule is quite distinct from PTH, which accounts for the absence of PTH immunoreactivity in serum and tumour extracts from HHM patients. Since these factors seem to act by binding to the PTH receptor, synthetic PTH antagonists may in the future be a means of treating HHM.