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Int J Radiat Oncol Biol Phys. 2014 Feb 1;88(2):404-11. doi: 10.1016/j.ijrobp.2013.10.037. Epub 2013 Dec 5.

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

Author information

1
Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.
2
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
3
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
5
Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
6
Department of Radiation Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
7
Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York.
8
Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York.
9
Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
10
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine (Hepatology Division), Albert Einstein College of Medicine, Bronx, New York.
11
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
12
Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
13
Department of Radiation Oncology, University of Texas Southwestern, Dallas, Texas.
14
Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York. Electronic address: cguha@montefiore.org.
15
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: foxi@upmc.edu.

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.

PMID:
24315566
PMCID:
PMC3905315
DOI:
10.1016/j.ijrobp.2013.10.037
[Indexed for MEDLINE]
Free PMC Article

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