title: 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
  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: Department of Surgery, University of Nebraska Medical Center, Omaha, NE, United States.
authors: Govardhana Rao
authors: GR
authors: Yannam
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.|Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Bing
authors: B
authors: Han
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Kentaro
authors: K
authors: Setoyama
authors: Department of Surgery, University of Nebraska Medical Center, Omaha, NE, United States.
authors: Toshiyuki
authors: T
authors: Yamamoto
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Ryotaro
authors: R
authors: Ito
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Jenna M
authors: JM
authors: Brooks
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.|Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.
authors: Jorge
authors: J
authors: Guzman-Lepe
authors: Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.
authors: Csaba
authors: C
authors: Galambos
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Jason V
authors: JV
authors: Fong
authors: Department of Radiation Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.
authors: Melvin
authors: M
authors: Deutsch
authors: Department of Radiation Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.
authors: Mubina A
authors: MA
authors: Quader
authors: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States.|Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Kosho
authors: K
authors: Yamanouchi
authors: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Rafi
authors: R
authors: Kabarriti
authors: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Keyur
authors: K
authors: Mehta
authors: Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Alejandro
authors: A
authors: Soto-Gutierrez
authors: Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.|Department of Medicine (Hepatology Division), Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Jayanta
authors: J
authors: Roy-Chowdhury
authors: Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.|Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Joseph
authors: J
authors: Locker
authors: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States.
authors: Michio
authors: M
authors: Abe
authors: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States.
authors: Charles A
authors: CA
authors: Enke
authors: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States.
authors: Janina
authors: J
authors: Baranowska-Kortylewicz
authors: Department of Radiation Oncology, University of Texas Southwestern, Dallas, TX, United States.
authors: Timothy D
authors: TD
authors: Solberg
authors: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States.|Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.|Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States.
authors: Chandan
authors: C
authors: Guha
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Ira J
authors: IJ
authors: Fox
mesh_terms: D000410:Alanine Transaminase / Q000032:analysis; D000418:Albumins / Q000032:analysis; D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D001835:Body Weight / Q000528:radiation effects; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D006504:Hepatic Veno-Occlusive Disease / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D022781:Hepatocytes / Q000000981:diagnostic imaging / Q000473:pathology / Q000528:radiation effects*; D008099:Liver / Q000000981:diagnostic imaging / Q000473:pathology / Q000528:radiation effects* / Q000601:surgery; D017114:Liver Failure, Acute / Q000209:etiology; D008252:Macaca fascicularis; D008297:Male; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D016634:Radiosurgery / Q000009:adverse effects; D019233:Retreatment; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D000418:Albumins; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase