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. Since the characteristic venocclusive 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 venocclusive 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 ≥40Gy, 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 where radiation-induced liver disease was mild or non-existent, 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 venocclusive 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.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans

“…Having previously established the liver’s sensitivity to irradiation in cynomolgus monkeys through dose escalation studies, we selected a radiation dose of 10Gy, well below the threshold for liver or systemic toxicity [17]. Three-dimensional CT-based treatment planning was performed for delivery of intensity modulated radiation therapy to the right lobe of the liver.…”

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

“…Recent technological advances in radiation therapy have sparked renewed interest in understanding radiationinduced liver disease (RILD) 44 Although whole-liver irradiation has generally been restricted to [30][31][32][33][34][35] Gy in standard daily fractions of 1.8-2.0 Gy owing to risk of lethal RILD above these levels, intensity-modulated radiation therapy, 3-dimensional conformal radiation treatment planning, and organ and tumor motion tracking enable treatment of liver cancer with fewer but larger dose fractions. 45 This innovation is called "hypofractionated stereotactic body RT".…”

“…45 This innovation is called "hypofractionated stereotactic body RT". Returning to the original Cynomolgus monkey model of RILD, 26 Yannam et al 44 recently conducted an escalated dose study to examine the effect of newer hypofractionated regimes on the liver. The authors demonstrated a higher tolerance for hypofractionated radiation, but that the characteristic histological lesions of SOS still developed at radiation doses above 40 Gy.…”

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques

“…The effects of radiation exposure on stem cells (Adler and Erbelding 1988), brain electrical activity (Legeza and Turlakov 1991), liver function (Yannam et al 2014), clinical, cardiac, cortisol stress response (Darenskaia et al 1992, 2001), and mitigating effects of gonadotropin hormone releasing hormone (GnRH) antagonism on the testes (Shetty et al 2013) have been studied in this species. Additional studies focusing on immune tissues/organs in this species should facilitate identification of pathways to immune dysfunction and hypothesis generation leading to novel pharmacologic and/or nutritional countermeasures to prevent or treat adverse effects of radiation on at risk organ systems.…”