Thorotrast toxicity: the safety of gadolinium compounds.

In this issue of the Netherlands Journal of Medicine, Kampen et al. describe a patient with a hepatic angiosarcoma resulting from exposure to Thorotrast. Thorotrast was developed in 1928 and used as a radiocontrast agent in the period 1930 to 1960. Thorotrast is a colloidal solution containing the naturally occurring radionuclide Thorium. Thorotrast particles are deposited in the reticulo-endothelial cells of the liver, spleen, bone marrow and lymph nodes, retained lifelong, and lead to continuous exposure of surrounding tissue to radiation. It was not until the late 1940s that the first cases of Thorotrast-related malignancies were described, consistent with the long latency interval. In fact, malignancies may occur more than 45 years after drug exposure. Most practising physicians will not be familiar with Thorotrast or only have a vague recollection of this agent from their old study books. As such, the description by Kampen et al. may be considered outdated and a case for the historical archives. Still, patients who were exposed to Thorotrast in the 1950s are at increased risk for malignancies, with an estimated cumulative incidence of 35 to 86%! More importantly, the Thorotrast story points to an important weakness in the procedures that are used for the registration of new drugs, i.e. the detection of unexpected, late occurring, infrequent but severe side effects. Postmarketing surveillance has become more important and is being heavily discussed in the light of recent withdrawals of drugs because of side effects. Examples of drugs that have been removed from the market are listed in table 1. It is not very surprising that side effects are not recognised in the randomised controlled trials that are used for registration of the drugs. Many studies include no more than 1000 to 4000 patients. In fact, health authorities are satisfied with safety issues if 1500 patients are exposed overall, with 300 treated for at least one year. Side effects that occur in less than one in every 500 patients will not be detected. Furthermore, in the randomised controlled trials patients with comorbidities, such as renal failure, and patients who use other drugs are often excluded. Side effects may thus occur more frequently in a real-life population but may stay unnoticed for a long time. In the past year, a new example of an unexpected severe side effect related to a contrast agent has become apparent: gadolinium-induced fibrosing dermatopathy in patients with severe renal failure. International drug authorities such as the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) have recently issued warnings for patients and healthcare professionals. In 2000, Cowper et al. described a new skin disorder involving dialysis patients, characterised by thickening of the skin, predominantly involving the limbs. Histologically the skin lesions consisted of irregular bundles of collagen, and an increase in spindled fibroblast-like cells. Shortly thereafter the term nephrogenic fibrosing dermopathy (NFD) was coined. Several years later it became apparent that in some patients the disorder may progress to a systemic disease (nephrogenic systemic fibrosis, NSF) with involvement of muscle, diaphragm and organs, ultimately leading to death. In 2006, a relationship between NFD/NSF and the use of gadolinium was suggested.