Department of Physiology and Biophysics, Finch University of Health Sciences, The Chicago Medical School, North Chicago, Illinois 60064-3095
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ABSTRACT |
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Previous studies showed that portacaval shunting causes metabolic and behavioral changes in rats. Most metabolic changes reversed within 1-2 wk after restoration of normal circulation. However, the rate of cerebral glucose metabolism (CMRGlc) remained depressed in some areas. The question arose whether complete recovery was possible. Therefore, a long-term behavioral study was undertaken to determine the time course of recovery. Diurnal activity was monitored for 48 h each week over a period of 14 wk: 2 wk before shunting, 6 wk after shunting, and 6 wk after restoration of normal hepatic circulation. Nighttime activity was depressed within 1 wk of shunting and did not change. Normal circulation to the liver was reestablished after 6 wk. The diurnal cycle was normal 3 wk later. Thus, although recovery of the diurnal rhythm is possible, the relatively long period necessary suggests the correction of a significant structural or chemical abnormality. A study of CMRGlc was made using the behavioral study as an index of the time necessary for recovery. CMRGlc returned to normal throughout the brain 6 wk after cessation of shunting except in the hippocampus and amygdala (7-8% decrease).
hepatic encephalopathy; liver dysfunction; hyperammonemia; circadian rhythm; night and day activity; brain glucose consumption
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INTRODUCTION |
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THIS IS THE FOURTH in a series of articles (11-13) designed to examine the permanency of the various changes that occur with hepatic encephalopathy, with special emphasis on the central nervous system and behavior. The question as to whether the changes associated with liver dysfunction are completely reversible has been hypothetical and the evidence anecdotal. To answer this question definitively, it was necessary to create liver dysfunction in a controlled model and later to restore it to normal.
The side-to-side portacaval shunted rat (20) was used because all the characteristic abnormalities of hepatic encephalopathy caused by end-to-side shunting are created, but the hepatic portal vessel remains patent (13). The unique nature of this model, with restoration of liver function after a chronic period of disuse, permitted the demonstration that various metabolic abnormalities of portacaval shunting could be eliminated by restoring the normal pattern of liver blood flow (11).
A prominent change in hepatic encephalopathy is decreased cerebral energy consumption. Thus humans and animals have a lower cerebral metabolic rate of glucose (CMRGlc) throughout the brain after portacaval shunting (15). When normal liver circulation was restored in rats, CMRGlc in some structures returned to control values. However, other areas of the brain, notably those associated with the hippocampus and the auditory systems, remained depressed (12). The rest of the brain fell in between the control and shunted values. It was not, therefore, clear from these results that function was restored completely to normal throughout the brain, or that brain function would improve further after a longer period of recuperation.
Normally rats are most active at night and sleep throughout the day. After portacaval shunting, the ratio of activity between day and night is markedly reduced or abolished (4, 5, 26), as is the diurnal variation in pineal melatonin content (9, 32). The diurnal rhythm of activity is a useful behavioral parameter because it can be measured objectively.
In the following study the disruption of the diurnal rhythm, an index of central nervous system integrity, was measured in side-to-side shunted rats, and the period of time necessary for complete recovery after restoration of normal portal blood circulation to the liver was determined. With these results in hand, a second experiment was undertaken to analyze whether long-term recovery from portacaval shunting allowed complete reparation of neuronal activity as measured by regional CMRGlc.
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MATERIALS AND METHODS |
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Chemicals. Enzymes and cofactors were purchased from Boehringer Mannheim (New York, NY) and from Sigma Chemical (St. Louis, MO). Other reagents used were of the best grade available.
Rats. Adult male Long-Evans rats, weighing 332 ± 35 (SD) g, were bought from Charles River Laboratories (Wilmington, MA). All rats were acquired, cared for, and handled in conformance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication no. 86-23, revised 1985) and the Guiding Principles for Research Involving Animals and Humans (recommendations from the Declaration of Helsinki) approved by the Council of the American Physiological Society. The rats were kept in an environment at 20°C with a 12:12-h light-dark cycle. Food and water were freely available. All experimental protocols were approved by the Animal Care and Quarters Committee of Finch University.
Experiments. Two distinct experiments were performed, one behavioral and one metabolic. For the behavioral experiment, the activity of nine rats was measured hourly around the clock 2 days/wk before, during, and after a period of portacaval shunting. Additional measurements included blood ammonia levels, blood glucose levels, and body weight at the time of each surgery. The liver weight was measured on the final day.
For the metabolic experiment, CMRGlc was determined by quantitative autoradiography in two groups of rats: 1) 10 rats received side-to-side portacaval shunts followed by restoration of hepatic circulation 6 wk later; 2) 11 rats received sham operations followed by a sham operation 6 wk later. CMRGlc was measured at the end of the experiment (6 wk after restoration of normal liver flow or sham operation). Other measurements included plasma ammonia and glucose levels and body weight at the time of each operation and liver weight on completion of the experiment. These data (not shown) were obtained to ensure surgical success of the side-to-side portacaval shunt.Surgical procedures. Anesthesia for all procedures was induced by administering 4% halothane in air and was maintained by (0.6-1.5%) halothane in 70% N2O-30% O2 for the remainder of the surgery. Side-to-side shunts were performed as described previously (13, 20). Briefly, a midline abdominal incision was made, and the intestines and stomach were retracted to expose the inferior vena cava and the portal vein. Both vessels were cleaned of fascia and clamped. The portal vein was sewn to the inferior vena cava, and the clamps were removed. The shunt was examined to ensure that it was patent. The muscle was approximated with uninterrupted sutures, and the skin was closed with metal clips. The portal veins were clamped for 15 ± 1 (SD) and 17 ± 1 (SD) min for the behavioral and CMRGlc studies, respectively.
Sham-operated rats received the same surgery, except no incisions were made on either vessel. The portal veins were clamped for 15 ± 0 (SD) and 16 ± 1 (SD) min for the behavioral and CMRGlc studies, respectively. To restore blood circulation to the liver, portacaval-shunted rats received a second operation 6 wk after the first surgery. This operation has been described in detail previously (11). An incision was made along the same suture line as the initial surgery, and the intestines and stomach were retracted, leaving the portacaval anastomosis visible. A sample of blood was taken at this time for determination of glucose and ammonia. A 1 × 8-mm microaneurysm clip was placed along the suture line, causing hepatic portal blood to flow to the liver. The muscle was approximated with uninterrupted sutures and the skin was closed with metal clips. The sham-operated rats also received a second operation. The procedure was identical to the shunt reversal operation described above except that no microaneurysm clip was placed. All rats used in the study recovered from surgery quickly, and no infections were observed.Behavioral monitoring. Activity was monitored in behavioral boxes (San Diego Instruments, San Diego, CA) (19). Each monitor had three beams of light. When two beams were broken consecutively, an event (ambulation) was recorded signifying that the rat had moved from one point in the cage to another. The monitors were linked to a computer that collected this information hourly. The information was then used to compute average nighttime activity, average daytime activity, and the night-to-day ratio of activity. The rats were placed in the cages on Friday afternoon with sufficient food, water, and bedding and were removed on Monday mornings. Rats were monitored over a 48-h period starting at 7:00 PM Friday night, when the lights were turned off for the 12:12-h light-dark cycle, and ended at 7:00 PM Sunday evening. Rats and room conditions (temperature and humidity) were observed daily behind a one-way mirror without any disruption of the recordings. Light was monitored with a photosensor attached to a chart recorder to ensure accurate recordings of light and dark periods.
On completion of the behavioral experiments, the rats were anesthetized and the abdomen was opened. A sample of blood was removed from the aorta, and the liver was excised. The rats died of exsanguination under anesthesia.Calculation of CMRGlc.
The rats were weighed and anesthetized with halothane (see
Surgical procedures), and catheters
were inserted in the left femoral vessels. The rats were placed in
restraining cages and allowed to recover for 1 h. Rectal temperature
was continuously monitored, and heat was provided by an infrared lamp
as needed to maintain the rats at 37-38°C. Heparin, 200 U, was
injected 15 min before the first sample of blood (0.6 ml) was taken.
The blood was placed in ice and centrifuged immediately for analysis of
plasma ammonia. [6-14C]glucose (35 µCi in 500 µl of 0.15 M NaCl) was injected into the femoral vein
and chased with 200 µl of 0.15 M NaCl. Blood (0.2 ml) samples were
withdrawn at 0.5, 1, 2, 3, and 4.5 min and placed immediately in ice. A
150-mg dose of pentobarbital sodium was injected at 5 min, which was
sufficient to stop the heart within 2-3 s, and the rats were
decapitated within 10-12 s. The brains were removed within
2-3 min and stored at 80°C until further processed. The
liver was removed and weighed.
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Analyses.
All plasma samples were kept frozen at a temperature of 80°C
until analyses were performed. Plasma ammonia and glucose were measured
with specific enzymes (3). Radioactivity was measured by scintillation
counting.
Statistical analyses.
The data were analyzed by analyses of variance and tests of comparison
by use of SAS procedures (Statistical Analysis System; SAS Institute,
Cary, NC). Differences were considered significant at
P 0.05.
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RESULTS |
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Rats were monitored for 2 wk before any surgery, 6 wk after portacaval shunting, and an additional 6 wk after the second surgery to restore normal liver circulation. Plasma ammonia was sampled 6 wk after portacaval shunting to confirm the hyperammonemic state of shunted rats (Table 1). Shunted rats had, as expected, plasma ammonia concentrations several times that of sham controls and lower glucose values. Plasma ammonia returned to normal by the end of the experiment, but glucose was above control values. Portacaval shunting causes a lower than normal liver-to-body weight ratio and a lower rate of weight gain (11, 13). At the time of shunting, the rats weighed 345 ± 16 g. Six weeks later, they showed little weight gain (358 ± 15 g), but after redirection of blood back to the liver, they rapidly gained and weighed 490 ± 12 g at the end of the experiment. The ratio of liver-to-body weight was in the normal range (0.31 ± 0.01). These metabolic and physical changes and their recovery were as expected in rats with liver dysfunction.
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After portacaval shunting, the ratio of night-to-day activity decreased (Fig. 1) within 3-4 days after surgery and remained lower for a period of 6 wk. After 6 wk of portacaval shunting and the subsequent restoration of normal circulation, recovery of the normal rhythm required a period of 2-3 wk. After this time, rats with restored blood circulation to the liver showed no alteration in the ratio of night-to-day activity compared with the control period but significantly increased the night-to-day ratio of activity compared with the period when they were shunted.
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Examination of the records from each individual rat over the entire period showed a decrease in night-to-day activity in all rats, with a subsequent recovery in all but one rat (data not shown). This single rat showed no improvement after the reestablishment of portal blood circulation to the liver despite the fact that the liver-to-body weight ratio and plasma ammonia both returned to normal. Whether this was an experimental aberration or represented permanent damage consequent to the period of shunting would require the study of a much larger population.
The diurnal rhythm during the control period was characterized by greater activity at night, with a peak in activity when the lights were turned off and a second peak just before the lights were turned on (Fig. 2A). The diurnal rhythm in portacaval-shunted rats was altered, but not completely eliminated (Fig. 2B). The primary difference was a reduction in nighttime activity. After restoration of blood circulation to the liver, the diurnal activity returned to normal levels (Fig. 2C).
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For the CMRGlc studies, rats were also divided into two groups: 1) the control group was sham operated, allowed to recover for 6 wk, and then again sham operated with a 6-wk recovery time; and 2) side-to-side portacaval-operated rats were shunted for 6 wk, received a subsequent "clip" operation, and were allowed to recover for 6 wk.
Plasma was collected for ammonia and glucose assays at the time of restoration of blood flow to the liver in rats with side-to-side portacaval shunts and after the second sham operation in the control group; plasma was also collected at the end of the experiment for the same assays. Body weights were measured before the first and second operations and at the end of the experiment in both groups. These data (not shown) assured that rats receiving side-to-side portacaval operations were indeed shunting blood from the portal vein to the inferior vena cava. The rats' livers were weighed at the end of the experiments, and there were no differences between the two groups.
The group of rats that received portacaval shunts followed by restoration of hepatic circulation had significantly decreased levels of CMRGlc in limbic regions, including the anterior and posterior hippocampus and the amygdala (Table 2). CMRGlc was decreased by 7-8% in each of these areas. All other regions of brain, as well as an unweighted average of all structures, were indistinguishable from control.
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DISCUSSION |
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Various metabolic abnormalities develop after portacaval shunting. Most
are established within 2 days and remain fixed for months (10, 21).
Depression of CMRGlc, for
instance, is detectable only 6 h after shunting and reaches a nadir by
2 days, where it remains thereafter. Virtually all other important
changes are also present by 2 days and remain constant for 60 days
(10, 21). Recently, it was shown that many of the abnormalities may be
reversed within 1 wk by restoring normal blood circulation to the liver
(11, 13).
A prominent change in hepatic encephalopathy is a decrease in cerebral rate of energy consumption, indicated by the lower rate of CMRGlc, that occurs throughout the brain. Presumably, the decrease in neuronal activity reflects the severity of the encephalopathic state (17, 22) caused by hepatic dysfunction. Recently, it was shown that CMRGlc is improved, but not entirely normal, after portal blood circulation has been returned to the liver (12). Most regional values remained numerically lower after 2 wk of normal circulation, although they were not distinguishable statistically from either control or shunted rats. A few values, however, notably those associated with the hippocampus and the auditory systems, remained significantly depressed compared with controls. Although it was clear from these results that there was progress toward normalization, brain function did not seem to be restored completely.
This raised the question whether complete recovery of normal function is possible or whether there are some long-lasting or irreversible changes. Portacaval shunting has been shown to produce pathological changes to the morphology of rat brain, primarily to the astrocytes, but there are reports suggesting that there is some neuronal damage as well. It is conceivable that these changes may have long-lasting effects on behavior (1, 7, 8, 31).
Several studies have demonstrated alterations in behavioral activity after a portacaval shunt, including a decrease in spontaneous activity and exploration (2), a decrease in the startle response to tactile and auditory stimuli (30), decreased response to light and electric shock (28), and a loss of day-night rhythm (4, 5). Clinical cases of portal-systemic shunting and encephalopathy show decreased activity (such as drowsiness or coma), depending on precipitating factors (18, 25). Although there are various behavioral abnormalities that can be measured quantitatively (1, 5, 26, 27, 32), perhaps, as mentioned, the most reliable are measurements of diurnal activity. The advantage of this approach is that each rat can serve as its own control, and information can be obtained continuously as a function of time. On the other hand, there is the disadvantage that the measurement of activity is an indicator of only one aspect of cerebral function.
The results demonstrated that shortly after portacaval shunting (within
3 or 4 days) there was a marked decrease in night-to-day activity that
remained lower for a period of 6 wk. This decrease in activity
paralleled the decrease in CMRGlc;
depression of CMRGlc was found to
be detectable within 6 h, reaching a minimum between 24 and 48 h, and
remained depressed for 7-8 wk (10, 21). Restoration of normal
diurnal activity accompanied by restoration of the normal pattern of
liver blood flow was not as rapid as the onset. Not until 1.5 wk after
reestablishing normal blood circulation to the liver was activity
indistinguishable from control. Furthermore, it took 2.5 wk after
restoration of portal circulation for the night-to-day ratio of
activity to be statistically elevated compared with that of shunted
rats. Although, as shown previously, the liver-to-body weight ratio was
normal after only 1 day and all metabolic abnormalities including
hyperammonemia were brought back to control levels within 1 wk (11),
behavior took a longer period to return to normal. This indicates that
the changes in brain function do not recover as rapidly; certainly
recovery takes considerably longer than the onset of cerebral
dysfunction. The slowness of recovery is consonant with the
interpretation that structural changes take place in brain, whether
these changes are to astrocytes or neurons or both, and have relatively
long-lasting effects on cerebral function.
Previous CMRGlc experiments, as discussed above, showed that the depression in CMRGlc was brought back only to near normal. In view of the behavioral studies, it seems possible that 2 wk, the recovery used previously to study CMRGlc, may not have been a sufficient period for restoration of normal cerebral activity. Therefore, in this study, CMRGlc was measured after a longer period of recovery, 6 wk, to parallel the behavioral experiment time course. In the present experiment, CMRGlc returned to normal in almost all brain structures except certain limbic structures: the anterior and posterior hippocampus, and the amygdala.
Considerable evidence exists that the primary abnormality found in brain during liver dysfunction is to astrocytes (6, 23, 29). There are, however, data in humans and rats suggesting that some neuronal damage may occur as well (6, 29). The studies described herein, and in previous articles (11-13), showed that almost all detectable signs of encephalopathy, including metabolic, cerebral, and behavioral abnormalities caused by portacaval shunting in rats, could be brought to normal after restoration of liver function (Table 3). It would appear that the changes to the brain are not, with the possible exception of the hippocampus and amygdala, permanent. Nevertheless, the contrast between the rapid onset and slow recovery suggests that encephalopathy is a consequence of both toxic factors and structural changes. The slow time course of recovery after restoration of liver function is important to be kept in mind in the quest for therapeutic agents and treatments.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Neurological Disorders and Stroke Grant NS-16389.
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FOOTNOTES |
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Address for reprint requests: R. Hawkins, Dept. of Physiology and Biophysics, Finch Univ. of Health Sciences/The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064-3095.
Received 6 August 1997; accepted in final form 12 November 1997.
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