Hepatic Radiation Toxicity: Avoidance and Amelioration
Section snippets
Clinical Syndromes and Endpoints for Radiation-Induced Liver Toxicity
The clinical scenario commonly called “classic” radiation-induced liver disease (RILD) occurs typically within 4 months after hepatic radiation therapy. The patient presents with fatigue, weight gain, increased abdominal girth, hepatomegaly, anicteric ascites, and an isolated elevation in alkaline phosphatase out of proportion to other liver enzymes. The characteristic initial finding is relatively normal liver function tests and normal bilirubin and ammonia levels.4
In contrast to this
Pathophysiology of Radiation-Induced Liver Toxicity
The pathologic hallmark of RILD, VOD, is characterized by complete obliteration of central vein lumina by erythrocytes trapped in a dense network of reticulin and collagen fibers that crisscross the lumen of the central veins, sublobular veins, and centrilobular sinusoids.2, 23, 24 Collagen proliferates along the hepatic sinusoids and produce mild congestion in periportal areas. Centrilobular hepatocytes are largely absent, presumably because of hypoxic cell death secondary to vascular
Dose-Complication Relationships After Whole-Liver Irradiation
The topic of whole-liver tolerance to external-beam radiation therapy is well analyzed in the Quantitative Assessment of Normal Tissue Effects in the Clinic project review.17 Widely credited with the first report of a dose-response relationship for severe toxicity to the liver are Ingold et al,1 who noted ascites and hepatomegaly in 1 of 8 patients who received 30 to 35 Gy over 3 to 4 weeks versus 12 of 27 patients who received >35 Gy. Later, in the landmark 1991 report by Emami et al,36 the
Potential Biomarkers for Liver Toxicity
Although biomarkers of radiation-related liver toxicity have not been systemically investigated, various markers of sinusoidal endothelial cell injury have been investigated to predict VOD in patients with bone marrow transplantation.10 Elevations in plasminogen activator inhibitor, probably produced by activated stellate cells and damaged endothelial cells,48 confirmed the diagnosis of VOD, particularly when associated with hyperbilirubinemia.49 Serum levels of hyaluronic acid are also
Future Prospects
Various strategies are being investigated to inhibit stellate cell activation and reverse fibrosis in RILD. Anti–TGF-β therapy with monoclonal antibodies against TGF-β and several small molecular agents that inhibit the kinase activity of TGF-β receptors are being investigated to reverse chronic liver fibrosis.75 Further studies reveal that connective tissue growth factor (CTGF) mediates TGF-β–induced fibroblast collagen synthesis and that blockade of CTGF reduces TGF-β–induced granulation
Acknowledgement
This research was supported by NIH grant R01 DK064670, NIH grant U19 AI191175, and NIH grant RC2 A1087612.
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