| Summary: | 博士 === 國立中興大學 === 獸醫學系暨研究所 === 96 === Rabbit hemorrhagic disease (RHD), a notifiable disease for OIE, was first reported in 1984 in China and dispersed into Europe, the Middle East and Asia. In Taiwan, RHD was first reported by Dr. Y. S. Lu by serological tests in 1994 and severely damaged the rabbit-raising industry and the bio-products industry in the following years. The purpose of this study is to use serum biochemistry tests along with histopathological examination to construct the pathogenesis of rabbit hemorrhagic disease virus (RHDV) as a useful index for medical treatment in fulminant viral hepatitis in human and animals.
RHD infection has been characterized as an acute fatal necrotic viral hepatitis in up to 85% adult (older than 2 months) rabbits died within 36 to 72 hours after infection. In the first study, after RHDV inoculation, highly significant elevations in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), r-glutamyltransferase (r-GT) and alkaline phosphatase (ALP) (p<0.0001) were noted. In comparison with baseline values (pair serum comparison), rabbits with leakage enzymes elevated immediately at 18 HPI were 95%, 89% and 61% for AST, ALT and LDH, respectively. In comparisons with the means of baseline, the changes were about 16 times, 4 times and 1.3 times at 18 HPI for AST, ALT and LDH, respectively. The maximal values appeared at 42HPI, there were 47 times, 11 times and 8 times for AST, ALT and LDH, respectively.
Differently from parameters above, the ALP was not elevated until 24HPI. Significant increasing observed later at 30 HPI. The means peaked at 42 HPI with a value of 691.92 IU/ L which was about 5 times of the baseline mean. The elevation of r-GT was even more gradual and later by time proceeded, it significantly increased at 36 HPI in comparison with baseline value. The frequency distribution revealed that only 83% tested samples had values over the upper limit (14.4 IU/L) at 42HPI. The peak mean appeared at 42 HPI (59.85±34.02IU/L) which was 7.8 times of the base line mean. The r-GT /ALT ratios tended to decreasing from baseline to 30HPI and then increasing from 36HPI to 42HPI, but all mean ratios after infection were lower than baseline one. This indicated that the increase of serum ALT and r-GT were mainly from hepatocellular disease instead of biliary tract disease in the first 42 hours. Histopathological findings of the liver from the dead rabbits correlated well chronologically with the release of the liver enzymes into the serum. Our results suggested that profound changes in serum liver enzymes implicated the damage in liver is fast and severe, and the exponential elevations in AST and ALT would be a strong prediction of the fulminant consequence in RHD.
The investigation on the damage of renal function and electrolyte balance found after virus inoculation, serum blood urea nitrogen (BUN), creatinine (CREA) and sodium (Na+) were elevated to a highly significant level (p<0.0001), whereas serum potassium (K+) was moderately elevated to a significant level (p<0.05). Hypoglycemia developed highly significantly (p<0.0001). The rabbits would die within 2 hr when the glucose level was lower than 20 mg/dl (in 5 rabbits). Significant elevation in serum BUN and CREA (p<0.05 vs. baseline) appeared at 30 HPI and 36 HPI, respectively. Although the means of BUN and CREA were higher than the baseline in rabbits prior to death, the surviving 3 rabbits (survived over 58 HPI) had even higher means prior to sacrifice. The mean osmolality value of surviving rabbits was higher than the dead ones. The dying rabbits had significantly lower values than the surviving ones. Renal insufficiency progressed from 30 hr, as indicated by the increases in BUN and CREA; significant changes in electrolytes resulting in the increased osmolality of extracellular fluid that induced flow disturbance which consequently destroy the homeostasis in cells. Therefore, the later impairments in renal function and electrolyte balance following liver injury might be an important threat for rabbits which might have survived from acute fulminant hepatitis in RHD.
On the study of lipid metabolism, hyperlipidemia was observed (p triglyceride <0.0001, p cholesterol =0.0003) along with significant increases in serum AST, ALT and r-GT (p<0.0001) after RHDV inoculation. An exponential increase in serum triglyceride was also seen. Thus, the presence of hyperlipidemia (from 30 hours post-inoculation) in the infected rabbits points to impairment in lipid metabolism.
Serum alpha-fetoprotein (AFP) elevated significantly (p=0.0082) from 24 HPI together with significantly elevated AST, ALT, r-GT and ALP after RHDV inoculation. Rabbits that died tend to have high AFP values prior to death, the mean value being 4.22± 1.61 ng/ml (n=6). By correlation analysis, AFP significantly correlated more strongly to ALP than r-GT, but insignificantly with AST and ALT suggested that the elevation in AFP was later released from severer hepatic necrosis following the leakage of cytoplasmic enzymes.
In conclusion, the results above showed that RHDV mainly caused massively necrosis in liver first. The severe hypoglycemia caused the death of the rabbits in the acute phases. Following the progression of the disease, renal function, electrolyte balance and lipid metabolism were all impaired and threatened the life of the survivals. Although the AFP was elevated later, the lack of normal hepatocytes for regeneration could not save the infected rabbits from systemic failures. Fulminant liver disease is regarded as a group of systemic diseases with the main focus of illness in the liver. Therefore, the measurements of renal function, electrolytes balance, serum glucose level and lipid metabolism as well as liver functional parameters for monitoring the progression in a fulminant viral hepatitis as index for medical treatment are necessary.
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