Discussion
Since the liver is highly sensitive to radiation, the radiation-induced liver injury caused by radiotherapy is difficult to avoid, but has a high degree of reversibility. RILD occurred 4 weeks after radiotherapy and based on the sub-acute damage of liver function is known as local radiation-induced hepatic injury. Previous findings performed on acute radiation-induced liver injury in animal models differ slightly in the radiation range, radiation dose, and inspection method (3). Preliminary results led to selection of the right lobe of the liver as the irradiation target area, and was determined as: the upper boundary was diaphragm, the lower boundary was 3 cm from the upper one, the medial boundary was right of the spine, and there was no lateral boundary. The radiation field was ~3×3 cm and was drawn on the surface. Single dose X-ray stereotactic irradiation was 20 Gy. The observation time was 1–28 days following irradiation.
VOD is a vein occlusion type of disease which is the pathological manifestation of radiation-induced liver injury, characterized by congestion in the central area of the hepatic lobule and necrosis of the central area in impaired hepatic sinus under a microscope. The pathological change is a dynamic process, initially involving a cell dysfunction phase, followed by a radioactive hepatitis phase and subsequently a liver fibrosis and cirrhosis phase (3,4). It has been previously shown that the specific functional abnormality occurs at a very early stage after irradiation (mostly in the first month) and is known as acute radiation-induced liver injury (5). The main manifestations include dilatation of the central venous and sinus in hepatic lobules as congestion is the main response to irradiation, and endothelial cell injury throughout the process, which is the basis of hepatic veno-occlusive lesions. Hepatic sinus congestion after endothelial cell injury and inflammatory cell infiltration is the main lesion of early radiation-induced hepatic injury. The degeneration and necrosis of liver cells are observed two weeks after irradiation, mainly including eosinophilic necrosis and punctate necrosis.
The blood supply to normal liver is mainly derived from the hepatic artery and portal vein, and the terminal branches of hepatic arterioles and portal vein converge with hepatic vein in sinus hepaticus (6). The arteriovenous direct path is closed under normal circumstances; however, it opens in some liver diseases manifested as hepatic hemodynamic changes (6). The microbubble ultrasound contrast agent currently used possesses hemodynamic characteristics that are similar to red blood cells, and can filter through pulmonary circulation to reach microvascular organs and lesions allowing images to be captured (6). The ultrasound contrast agent can evaluate the perfusion of the organs and tumor from the perspective of microcirculation, and reflect the changes of organic hemodynamics and eventually contribute to the understanding of organ function (7).
The present study indicates that the hepatic hemodynamic changes have important effects on the liver blood perfusion in the process of the formation and development of acute radiation-induced liver injury. The TIC curve of the liver parenchyma contrast-enhanced ultrasound showed that with the aggravation of the liver injury, PI continued to decrease and TP was gradually extended with statistically significant differences. Possible reasons for this finding include, fat degeneration and swelling of liver cells occurring in the early phase of acute radiation-induced liver injury may lead to compression and degeneration of the hepatic duct structure and an increase in the resistance, resulting in the reduction of liver parenchyma blood perfusion (6,7). Additionally, with the development of hepatic injury, liver cell necrosis, inflammatory cell infiltration and hepatic sinusoid capillarization occurred, which eventually leads to the formation of blood stasis in the hepatic sinusoids, the increase of sinus pressure and further formation of intrahepatic shunt, resulting in a blood flow reduction in the liver parenchyma (8). Furthermore, formation of fiber spacing due to injury of the oppressed sub-lobular vein, central vein and hepatic venous sinus leads to disturbance of the recovery of the portal vein, an increase in portal vein pressure, and reduced liver perfusion, resulting in a decrease in the extension of PI and TP. The abovementioned three changes are increased with aggravation of liver injury.
In the present study, HA-HVTT was gradually reduced along with the severity of liver damage, and these differences were statistically significant in the inter-group comparison. Possible reasons for this finding include the fact that in the early phase of acute liver injury, liver sinusoidal endothelial cells are impaired; endothelial fenestrae are reduced or gradually dissipate; and a continuous structure-like capillary endothelium.is formed beneath the endothelial, which leads to the formation of hepatic sinusoid capillarization. These changes form the exchange barrier between substances in liver cells and oxygen and eventually lead to liver cell atrophy and hepatic sinusoidal collapse. Blood flow in hepatic sinusoid gradually bypasses the damaged liver tissue and enters the hepatic venous system directly. As a result, blood circulation is accelerated in the liver and HA-HVTT is shortened (9–11). In the process of liver injury, a variety of neurotransmitters responding to the course such as histamine, serotonin, and vasoactive factors, including vascular endothelium-derived relaxing factor, cause damage to the hepatic sinusoids as well as hepatic vein system and the disturbance of liver microcirculation. Therefore, the hepatic blood flow at a high level of circulation, which accelerates the distribution of contrast agent microbubbles in vivo (12–14). Additionally, with the aggravation of liver injury, the formation of cytokines containing transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), and connective tissue growth factor (CTGF), promotes collagen synthesis by hepatic stellate cells (HSCs) and accelerates the transformation from HSCs to fibroblast cells. Proliferous fibroblasts and their connection with fiber bundles around them form a fibrous septum, in which the blood vessels form rami communicantes among hepatic arteries, portal veins and hepatic veins. Blood bypasses due to rami communicantes, resulting in enhancement of HVAT and shortening of HA-HVTT (8). However, radiation-induced liver injury is a gradual process, in which the expression of cytokines is not obvious in the early stages and gradually increases after 2 weeks. No significant differences were observed in the mild and control groups (P>0.05). Thus, HA-HVTT as a sensitive index to evaluate the severity of liver fibrosis is important in the early diagnosis of moderate and severe acute radiation-induced liver injury.
Radiation-induced liver injury is a progressive process, and early detection and early intervention in the acute period is of great significance to the recovery treatment of the liver. Contrast-enhanced ultrasound as a non-invasive, simple and highly repetitive examination can more intuitively reflect the changes of the microvascular circulation dynamics. The circulatory physiology of the contrast agent in liver is analyzed to identify the sensitive parameters applied in the quantitative diagnosis of acute radiation-induced liver injury. The present findings have shown that in the quantitative analysis of contrast-enhanced ultrasonography, PI, TP and HA-HVTT may be used as important reference indices for the early diagnosis of acute radiation-induced liver injury.