Radiation Hepatitis: Possible Prevention by Combined Isotopic and External Radiation Therapy

UNTIL RECENT years, the liver had been regarded as a relatively radioresistant organ. This erroneous view stemmed largely from studies on animals subjected to whole-body or large-field irradiation (4, 16). There were remarkably few reports of radiation effects on the human liver during the era in which 200-250 kV x-ray beams were the only available modality for external radiation therapy, presumably because of the limiting skin dose and relatively poor penetration of such beams. In 1924, Case and Warthin (2) described inflammation of the bile duct epithelium with little change in blood vessels or hepatic cells in a human case. Nine instances of liver injury encountered at autopsy after doses of 5,000 R or more to the left lobe of the liver were reported by Brick (1) in 1955. The principal lesion was necrosis of the liver parenchyma with severe fibrosis in three cases. With the advent of megavoltage radiation therapy apparatus, it has become technically feasible to deliver high doses of radiation to the entire liver. Such treatment has been employed in an endeavor to control or eradicate hepatic involvement by metastatic carcinoma or lymphoma. The first clinical report of whole-liver irradiation, by Phillips et al. (10), appeared to confirm the expectation that such treatment would be well tolerated. In a series of 36 patients in whom the entire liver was irradiated to doses of 2,000 to 3,750 R for known metastatic disease, radiation damage to the liver was suspected in only one, given 3,500 R. It soon became clear, however, that the tolerance of the liver is strongly radiation-dose-dependent. In a review of 40 cases in which the entire liver was irradiated with 5 to 6 MeV linear accelerator x rays to a median dose of 3,900 rads (range: 1,300 rads in eighteen days to 5,100 rads in forty days), Ingold, Reed, Kaplan, and Bagshaw (6) observed clinical evidence of hepatic injury in 13 cases, 7 of which were substantiated by needle biopsy. A clinical syndrome, provisionally termed “radiation hepatitis,” was described by these authors. It was characterized by the development of abnormal liver function tests, hepatomegaly, and ascites, progressing to a fatal outcome in 3 of the 13 clinically apparent cases. There was an obvious resemblance to the clinical features of the Budd-Chiari syndrome (9). No instances of radiation hepatitis were observed after total liver doses less than 3,000 rads. In contrast, radiation hepatitis occurred in 1 of 8 patients receiving doses in the range of 3,000 to 3,450 rads; in 5 of 9 treated to doses of 3,500 to 3,950 rads; and in 7 of 18 patients treated to doses of 4,000 rads or more. The degree of severity of the clinical syndrome varied greatly. Several patients with abnormal liver function tests and needle biopsy evidence of hepatic radiation injury were asymptomatic.