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

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 Arthur Enke, Janina Baranowska-KortylewiczTimothy D. Solberg, Chandan Guha, Ira J. Fox

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)404-411
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume88
Issue number2
DOIs
StatePublished - Feb 1 2014

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primates
liver
Primates
Liver Diseases
Hepatocytes
Radiation
monkeys
Wounds and Injuries
radiation
dosage
Macaca fascicularis
pathogenesis
Asialoglycoproteins
Hepatic Veno-Occlusive Disease
animals
radiation therapy
therapy
Tunica Intima
Radiation Injuries
Investigational Therapies

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. / Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; Roy-Chowdhury, Jayanta; Locker, Joseph; Abe, Michio; Enke, Charles Arthur; Baranowska-Kortylewicz, Janina; Solberg, Timothy D.; Guha, Chandan; Fox, Ira J.

In: International Journal of Radiation Oncology Biology Physics, Vol. 88, No. 2, 01.02.2014, p. 404-411.

Research output: Contribution to journalArticle

Yannam, GR, Han, B, Setoyama, K, Yamamoto, T, Ito, R, Brooks, JM, Guzman-Lepe, J, Galambos, C, Fong, JV, Deutsch, M, Quader, MA, Yamanouchi, K, Kabarriti, R, Mehta, K, Soto-Gutierrez, A, Roy-Chowdhury, J, Locker, J, Abe, M, Enke, CA, Baranowska-Kortylewicz, J, Solberg, TD, Guha, C & Fox, IJ 2014, 'A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury', International Journal of Radiation Oncology Biology Physics, vol. 88, no. 2, pp. 404-411. https://doi.org/10.1016/j.ijrobp.2013.10.037
Yannam, Govardhana Rao ; Han, Bing ; Setoyama, Kentaro ; Yamamoto, Toshiyuki ; Ito, Ryotaro ; Brooks, Jenna M. ; Guzman-Lepe, Jorge ; Galambos, Csaba ; Fong, Jason V. ; Deutsch, Melvin ; Quader, Mubina A. ; Yamanouchi, Kosho ; Kabarriti, Rafi ; Mehta, Keyur ; Soto-Gutierrez, Alejandro ; Roy-Chowdhury, Jayanta ; Locker, Joseph ; Abe, Michio ; Enke, Charles Arthur ; Baranowska-Kortylewicz, Janina ; Solberg, Timothy D. ; Guha, Chandan ; Fox, Ira J. / A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. In: International Journal of Radiation Oncology Biology Physics. 2014 ; Vol. 88, No. 2. pp. 404-411.
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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.",
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T1 - A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury

AU - Yannam, Govardhana Rao

AU - Han, Bing

AU - Setoyama, Kentaro

AU - Yamamoto, Toshiyuki

AU - Ito, Ryotaro

AU - Brooks, Jenna M.

AU - Guzman-Lepe, Jorge

AU - Galambos, Csaba

AU - Fong, Jason V.

AU - Deutsch, Melvin

AU - Quader, Mubina A.

AU - Yamanouchi, Kosho

AU - Kabarriti, Rafi

AU - Mehta, Keyur

AU - Soto-Gutierrez, Alejandro

AU - Roy-Chowdhury, Jayanta

AU - Locker, Joseph

AU - Abe, Michio

AU - Enke, Charles Arthur

AU - Baranowska-Kortylewicz, Janina

AU - Solberg, Timothy D.

AU - Guha, Chandan

AU - Fox, Ira J.

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N2 - 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.

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