Monday, 8 October 2007

How do cancers cause hypercalcaemia?

Two causes dominate the differential diagnosis of hypercalcaemia - primary hyperparathyroidism and cancer. Together they account for the raised calcium in around 90% of cases. The mechanism behind this in primary hyperparathyroidism may seem obvious enough, but what about in cancers?

One's initial reaction might be to blame it on the cancer eroding into bone, thereby releasing calcium. Actually, this is only of minor importance. The bulk of the hypercalcaemia is caused by humoral factors released by the tumour.

First up, and most common, is the awkwardly named parathyroid hormone related protein (PTHrP). Despite its title, it is actually produced by many cell types physiologically, acting at a local level (paracrine) and regulating such things as tooth development and cartilage growth. However, in many cancers it is overproduced and it spills out into the bloodstream. Unfortunately, one end of this protein is identical to its legitimate namesake (parathyroid hormone). The result: PTHrP binds to PTH's receptors, and the body dutifully raises the serum calcium.

In many haematogical malignancies (such as multiple myeloma, the lymphomas and the leukaemias) another method is prevalent, however. These tumours have a penchant to secrete a variety of substances that act on osteoclasts to increase bone resorption (and hence calcium 'liberation' into the blood stream). Together, these substances are called osteoclast activating factors, and they include such famous cytokines as IL-1, IL-6 and TNF-α. (Multiple myeloma is famous for 'punched out' lesions on bone X-rays, and osteoclast activating factors account for them).

These are the two main mechanisms behind cancer's hypercalcaemia. There are numerous other rarer ones, though, but we needn't trouble ourselves with them for now!

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