Hepatic Radiation Toxicity: Avoidance and Amelioration

https://doi.org/10.1016/j.semradonc.2011.05.003Get rights and content

The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. “Classic” RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a “critical volume” of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.

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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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