A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury.

Abstract

BACKGROUND:

Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease.

METHODS AND MATERIALS:

We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals.

RESULTS:

At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis.

CONCLUSIONS:

The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

• Authors: Govardhana Rao Yannam, Bing Han, Kentaro Setoyama, Toshiyuki Yamamoto, Ryotaro Ito, Jenna M Brooks, Jorge Guzman-Lepe, Csaba Galambos, Jason V Fong, Melvin Deutsch, Mubina A Quader, Kosho Yamanouchi, Rafi Kabarriti, Keyur Mehta, Alejandro Soto-Gutierrez, Jayanta Roy-Chowdhury, Joseph Locker, Michio Abe, Charles A Enke, Janina Baranowska-Kortylewicz, Timothy D Solberg, Chandan Guha, Ira J Fox
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 88 Issue 2 Pg. 404-411 (Feb 01 2014) ISSN: 1879-355X [Electronic] United States
• PMID: 24315566 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Albumins
• Alanine Transaminase
• Alkaline Phosphatase

Topics

• Alanine Transaminase (analysis)
• Albumins (analysis)
• Alkaline Phosphatase (analysis)
• Animals
• Body Weight (radiation effects)
• Disease Models, Animal
• Dose Fractionation, Radiation
• Hepatic Veno-Occlusive Disease (diagnostic imaging, etiology, pathology)
• Hepatocytes (diagnostic imaging, pathology, radiation effects)
• Liver (diagnostic imaging, pathology, radiation effects, surgery)
• Liver Failure, Acute (etiology)
• Macaca fascicularis
• Male
• Radiation Dosage
• Radiation Injuries, Experimental (diagnostic imaging, etiology, pathology)
• Radiosurgery (adverse effects)
• Retreatment
• Tomography, Emission-Computed, Single-Photon (methods)