Mechanism of the alcohol cyclic pattern: role of
the hypothalamic-pituitary-thyroid axis
J.
Li1,
V.
Nguyen1,
B. A.
French1,
A. F.
Parlow2,
G. L.
Su3,
P.
Fu1,
Q. X.
Yuan1, and
S. W.
French1
1 Department of Pathology, Harbor-UCLA Medical Center,
Torrance, California 90509; 3 Department of Internal
Medicine, University of Michigan Medical Center, Ann Arbor,
Michigan 48109-0666; and 2 Department of Obstetrics and
Gynecology and the National Pituitary Hormone Center, Harbor-UCLA
Medical Center, Torrance, California 90509
 |
ABSTRACT |
The cause of the cycle of
urinary alcohol levels (UALs) in rats fed ethanol continually at a
fixed rate is unknown. Rats were fed ethanol intragastrically at a
constant dose for 2 mo, and daily body temperatures and UALs were
recorded. Body temperature cycled inversely to UAL, suggesting that the
rate of metabolism could be mechanistically involved in the rate of
ethanol elimination during the cycle. To document this, whole body
O2 consumption rate was monitored daily during the cycle.
The rate of O2 consumption correlated positively with the
change in body temperature and negatively with the change in UAL. Since
the metabolic rate responds to changes in body temperature, thyroid
hormone levels were measured during the UAL cycle. T4
levels correlated positively with the O2 consumption rate
and negatively with the UALs. In a second experiment using
propylthiouracil treatment, UALs did not cycle and a fall in body
temperature failed to stimulate an increase in the rate of ethanol
elimination. Consequently, rats died of overdose. Likewise, in a third
experiment using rats with severed pituitary stalks, UALs failed to
cycle and rats died of overdose. From these observations it was
concluded that the UAL cycle depends on an intact
hypothalamic-pituitary-thyroid axis response to the ethanol-induced
drop in body temperature by increasing the rate of ethanol elimination.
alcoholic liver disease; oxygen consumption rates; body temperature
 |
INTRODUCTION |
CHRONIC ETHANOL
FEEDING at a constant rate (10-14 g · kg
1 · day
1) causes a cyclic
oscillation in the blood and urinary alcohol levels (UALs)
(18). Ethanol levels peak at ~500 mg/100 ml and then fall to ~100 mg/100 ml over a six-day cycle. The ethanol elimination rate increases at the time that the blood ethanol levels
are falling and vice versa; the ethanol elimination rate decreases when
the blood ethanol levels are rising during the cycle (18).
This correlation between the ethanol elimination rate and the rise and
fall of the blood ethanol level suggests that the cycling is due to
fluctuations in alcohol dehydrogenase activity. However, the mechanism
that drives these cyclic fluctuations has not been determined. Efforts
to demonstrate a role for changes in cytochrome P-450 2E1
levels in the liver using 2E1 inhibitors failed to explain the
mechanism for the cyclic fluctuations (2). It is important
to determine the mechanism of the cyclic fluctuations since an
autoregulatory system that influences the rate of ethanol elimination
is probably involved. This autoregulation mechanism, if understood,
might be exploited to increase the rate of elimination of ethanol in
the blood in a clinical setting when people overdose on alcohol. There
is also evidence that the magnitude of the cyclic fluctuations observed
correlates with the severity of the associated liver pathology
(17). Therefore, the study of the cycling mechanism may
provide insights regarding the pathogenesis of alcoholic liver disease (ALD).
While monitoring daily body temperature during the cycle, it was noted
that the body temperature increased when the UALs fell and decreased
when UALs rose (9). This led to the daily measurement of
O2 consumption, which was also found to cycle in sync with the change in body temperature (10). The present study is
designed to answer the question, What are the roles that the swings in body temperature and O2 consumption rates play in driving
the cyclic increase and decrease in UALs during ethanol feeding? Body temperature and the metabolic rate could change in response to changes
in circulating endotoxin (1) and the endotoxin-induced increase in circulating interleukin (IL)-1 and tumor necrosis factor (TNF)-
. Endotoxin and TNF-
levels increase in the blood in
the intragastric ethanol feeding rat model used here (14) and in clinical ALD (13). Alternatively, the body
temperature and metabolic rate could cycle in response to changes in
circulating hormones such as T4. Accordingly, we studied
changes in the levels of endotoxin, IL-1, and TNF-
as well as
T4 levels at the peaks and troughs of the urinary ethanol
cycle caused by continuous feeding of ethanol at a constant rate.
 |
METHODS |
Animals.
Three animal feeding experiments were performed using the intragastric
tube feeding model as previously described (19). In
experiment 1, six male rats weighing ~270-280 g were fed
ethanol at 13 g · kg
1 · day
1
for 2-3 mo. Six control rats were pair fed a dextrose solution that was isocaloric with the ethanol solution fed to ethanol-fed rats. The diet was fed to provide 271 kcal · kg
1 · day
1 in both groups. The diet
used was modified to include a salt and vitamin mix (Dyets, Bethlehem,
PA) as described by the American Institute of Nutrition Mineral Mix and
Vitamin Mix for Optimum Growth of Rats (10). The
source of protein was lactalbumin. The diet was supplemented with 500 mg choline and 1 g methionine per liter of diet. The dietary
calories derived were 33.3% from fat, 25.9% from protein, 6.7% from
dextrose, and 34% from ethanol. In the second experiment, five rats
were fed ethanol together with their pair-fed controls for 18 days at
10 g · kg
1 · day
1 ethanol,
and at day 19 the ethanol was increased to 11 g · kg
1 · day
1. In this second
experiment, propylthiouracil (PTU) was fed at 50 mg · kg
1 · day
1 (12) to both
groups. In the third experiment, ethanol (10-11 g · kg
1 · day
1) and the diet were fed
intragastrically for 2 wk after pituitary stalks were cut. The
procedures were approved by the Research and Education Institute Animal
Care Committee in accordance with the guidelines for animal care as
described by the National Academy of Sciences (1996).
Experiment 1 was carried out as outlined in Fig.
1. UAL was measured daily. Urine was
collected under toluene over 24 h. Stool weight was measured on
24 h collections. Body temperature was measured rectally each day
using a thermistor thermometer. Body weight was measured daily to
determine the dietary calories fed. Blood was drawn monthly (0.6 ml
retroorbitally) as well as at some of the peak and trough UALs.
Endotoxin levels were determined using endotoxin-free collection tubes
and a chromogenic assay kit (Whitaker Bioproducts). UALs were measured
using a Radiative Energy Attenuation assay (Abbot AXSYM system; Abbott
Labs, Abbott Park, IL). T4 levels were measured using
fluorescence polarization immunoassay (FPIA) (Abbott AXSYM). Alanine
aminotransferase (ALT) levels were measured using a clinical
laboratory analyzer (a kinetic rate method) on SYNCH RON CX Systems
(Beckman Instruments, Brea, CA). TNF-
and IL-1
levels
were measured using ELISA kits (Biosource International, Camarillo, CA)
per the manufacturer's instructions. O2 consumption was
measured using an OxyMax (Columbus Instruments, Columbus, OH). Basal
levels were determined over a 30-min monitoring period at 30-s
intervals, and the lowest data obtained was used for statistical
analysis using Bonferroni's t-test. Liver tissue obtained
at the termination of the experiment was processed for light
microscopy. The pathology was scored as reported previously (17).
Experiment 2 was designed to test the role of the thyroid
gland in the mechanism of the urinary alcohol cycle. Four groups of
five male Wistar rats each were fed the same diet as in
experiment 1. In addition, the control group (group
1) was fed dextrose in amounts isocaloric to the ethanol fed in
group 4. Group 2 was fed dextrose in amounts
isocaloric to ethanol fed in group 4 plus PTU (50 mg
· kg
1 · day
1). Group 3 was fed ethanol isocalorically to group 4. Group
4 was fed ethanol (10 g · kg
1 · day
1) and PTU (50 mg · kg
1 · day
1). The ethanol fed was 10 g · kg
1 · day
1 because higher doses,
such as 11 g · kg
1 · day
1,
killed rats in preliminary studies.
The rats were monitored as shown in Fig. 1 for 19 days, except that
body temperature was used as a measure of metabolic rate because body
temperature correlated positively with the O2 consumption rate in experiment 1. On day 19, the dose of
ethanol was increased to 11 g · kg
1 · day
1 and the UALs and the body temperatures were
monitored daily until death on the 25th or 26th day. Liver and thyroid
tissues were obtained at autopsy to determine the histopathology.
T4 was measured by FPIA technology. Thyroid-stimulating
hormone (TSH) levels were measured by radioimmunoassay.
In experiment 3, five ethanol fed and five pair-fed control
male Wistar rats weighing ~250 g were fed the diet
intragastrically for 2 wk. Ethanol was fed at 10 g · kg
1 · day
1 for 2 wk. The rats were
first subjected to pituitary stalk severance with aluminum foil
interposed to prevent reestablishment of blood flow from the
hypothalamus to the pituitary. They were operated on by Zivic-Miller
Laboratories (Porterville, PA). This experiment tested the
supposition that the cycle was dependent on the change in body
temperature. The drop in body temperature caused by high UALs initiated
hypothalamic secretion of thyrotropin-releasing hormone (TRH).
The urinary ethanol cycle and body temperature were monitored as
before. The blood levels of TSH, T4, ALT, and ethanol were
measured after 2 wk of receiving 10 g ethanol · kg
1 · day
1. At this point, the
ethanol dose was increased to 11 g · kg
1 · day
1 as in the PTU-feeding experiment (experiment
2). The UALs and the body temperature were then monitored daily
until the death of the rats, which was caused by terminal ethanol toxicity.
 |
RESULTS |
Experiment 1.
The rats were monitored for 72 days. The rats in experiment 1 gained weight as follows. Starting weight for the ethanol-fed rats
(n = 5) was 274 ± 9.9 g and for the pair-fed
controls was 266 ± 6.9 g. The ending weight for the ethanol
fed rats was 410 ± 9.7 g and for the pair-fed controls was
462 ± 22.5 g. The difference was significant (P
0.001), indicating that energy wastage had occurred in the
ethanol-fed rats, perhaps due to heat generation induced by the
ethanol. The liver weights were likewise significantly different in the
two groups (P < 0.001). The livers of the ethanol-fed rats weighed 22.3 ± 2.3 g compared with those of the
pair-fed control rats, which weighed 14.5 ± 0.8 g.
The UALs fluctuated between 50 and 500 mg/100 ml at variable intervals
(Fig. 2). The body temperature (Fig.
3) and the O2 consumption
rate (Fig. 4) fluctuated at the same
time intervals as did the UAL. Likewise, the body temperature
fluctuated at the same time intervals as the O2 consumption
(Fig. 5). When the body temperature and
the O2 consumption rates were graphed together, the peaks
and troughs were superimposed on each other. This correlation was
statistically significant for all five rats fed ethanol (R = 0.894, P
0.001). When the rate of O2
consumption was compared with the UAL, the peaks and troughs correlated
inversely. (Fig. 4). Likewise, when the UAL went up, the body
temperature went down and vice versa (Fig. 3).

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Fig. 2.
Urinary alcohol levels (UALs) of a representative rat fed
ethanol (13 g · kg 1 · day 1).
Note that the interval of each oscillation varies but the peaks and
troughs are similar, with a few exceptions. The arrow
indicates when the O2 consumption rates were measured (by
OxyMax).
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Fig. 3.
Representative negative correlation between body
temperature and UAL. , Body temperature (°C); , UAL (mg/dl).
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Fig. 4.
Representative negative correlation between
O2 consumption rate ( ) and UAL ( ). Note that the
O2 consumption rate decreases when the UAL increases and
vice versa.
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Fig. 5.
All UAL peaks at 500 mg/100 ml or higher, all UAL troughs
at 100 mg/100 ml or lower, and controls were compared. The difference
between the peak values compared with the trough and control values was
significant (P 0.001). Number of measurements made
were as follows: peak = 9, trough = 11, and control = 17.
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When the peaks and troughs of the UALs from all of the ethanol-fed rats
were correlated with the corresponding O2 consumption rates, there was a significant difference between the peak and trough values and between the peak and control values
(P < 0.001) but not between the trough and control
values (Fig. 5). This indicated that the O2 consumption
rates at the trough of the UALs were not different from the normal
O2 consumption rates. Thus the abnormality occurred at the
peaks of UAL. A similar relationship between the UAL peaks and troughs
existed with the body temperature, except that the data from the
controls was significantly different from both the peaks and troughs
(Fig. 6). The total UAL and
O2 consumption rates from individual ethanol-fed rats
correlate negatively (R =
0.472; P < 0.001). Likewise, UAL correlated negatively with body temperature
(R =
0.921, P < 0.001).

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Fig. 6.
Body temperature at all of the peaks and troughs of UAL
and controls. Differences between each are significant
(P 0.05). Number of measurements made were as
follows: control = 276, peak = 30, and trough = 30.
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There is a question as to whether or not there was a difference in the
liver injury at the peaks and troughs in the cycle of UAL. When the
serum ALT levels were measured at the peaks and troughs, a significant
increase was found at the trough (P
0.05) compared
with the control and the peaks (Fig. 7).
This was substantiated when serum ALT levels were correlated with the
corresponding UALs (R =
0.879; P < 0.001).

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Fig. 7.
Graph showing that the alanine aminotransferase (ALT)
levels were significantly higher (P 0.05) in the
trough (n = 10) than in control (n = 5)
or peaks (n = 10). n, No. of rats.
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Histology of livers from the rats fed ethanol for 72 days showed both
macro- and microvesicular steatosis in the centrilobular hepatocytes.
Apoptosis, megamitochondria, and mononuclear inflammation were also
present. Controls appeared without pathological abnormalities.
The histopathology of the livers was significantly different when the
pathology scores for the ethanol-fed rats were compared with the
pathology scores for the pair-fed control rats. The pathology scores
for the ethanol-fed rats were 5 ± 1.3 arbitrary units
compared with the pair-fed control rats, which showed no pathological
change (P
0.001). (Pathology score units were 0 to 10+)
Endotoxin levels in the serum were higher at peak UALs compared with
the trough values (peak = 3.1 ± 0.8 and trough = 1.1 ± 0.2 EU/ml; P
0.044, n = 18). (EU unit + endotoxin unit per Limulus Amebocyte
Lysate method supplied by BioWhittaker) Plasma TNF-
levels were
elevated equally at both the peak and trough of the UAL (control = 36 ± 3, peak = 112 ± 36, and trough = 100 ± 25 pg/ml; P
0.004; n = 18).
IL-1
levels tended to be elevated but not at significant
levels (control = 27.9 ± 3.5, peak = 38.3 ± 5.6, and trough = 39.5 ± 8 pg/ml) Serum T4
levels were decreased in the ethanol-fed rats at 1 mo compared with
controls (ethanol-fed = 1.9 ± 0.5 and control = 5.1 ± 0.2 µg/dl; P
0.001; n = 5-6 rats). When T4 levels were measured at
the peak and trough UALs, they were significantly lower than at the
peak and control levels (Fig. 8). There
was a negative correlation between the T4 levels and UALs
when only the peak UALs were compared (R =
0.961;
P
0.001; n = 10 rats). When the UAL
peak, trough, and control levels of TSH were measured, no significant
differences were found (Fig. 9).

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Fig. 8.
T4 levels in serum taken when the UALs were
at peak and trough in rats fed ethanol. The values at the peak were
significantly lower than the trough (P 0.03) and
the pair-fed controls (P 0.003). Values are
means ± SE; n = 10 serum samples.
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Fig. 9.
Thyroid-stimulating hormone (TSH) levels in serum taken
when the UALs were at the peak and trough (TR), from pair-fed controls
(C) or pair-fed controls given propylthiouracil (PTU) (C A) or not
given PTU (C B), or from ethanol-fed rats given PTU (ROH A) or not
given PTU (ROH). PTU treatment increased TSH levels significantly in
the control and ethanol-fed rats (P < 0.001).
Values are means ± SE; n = 5 rats.
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Experiment 2.
Rats fed ethanol and PTU for 19 days had relatively stable UALs,
varying between 100 and 200 mg/100 ml. Likewise, the body temperatures
fluctuated only slightly (35-36.5°C; Fig.
10). However, over the first 13 days
the UAL went from 100 to 200 mg/100 ml and the body temperature fell
1.5°C, suggesting that the body temperature fall was a response to
the increase in the level of alcohol. However, when the dose of ethanol
was increased to 11 g · kg
1 · day
1 on day 19, the UAL increased daily (Fig.
10). When the UAL reached 350 mg/100 ml on day 25, the body
temperature began to fall (32°C). As the UALs increased, the body
temperature continued to plummet until fatal levels of UAL were reached
(700 mg/100 ml). At this time the body temperature was 25°C. All five
rats given PTU showed the same pattern, i.e., the body temperature fell
gradually until the UAL reached 300-450 mg/100 ml, at which time
the body temperature dropped sharply and the rat died. Thus PTU
treatment prevented the increase in metabolic rate normally induced by
rising UAL and falling body temperature, presumably because thyroid
secretion of T4 did not increase. PTU treatment, therefore,
blocked the UAL-body temperature cycle. Control rats given PTU had
stable body temperatures over a 29-day period. T4 levels
were markedly reduced in both the ethanol-fed and pair-fed control rats
given PTU. T4 levels in ethanol-fed rats that were not
given PTU were decreased below the levels of the control rats not given
PTU (Fig. 11). TSH levels were
significantly elevated in the rats given PTU (Fig. 9). The ethanol-fed
rats without PTU had reduced levels of TSH compared with pair-fed
controls (Fig. 9).

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Fig. 10.
Body temperature and UALs recorded daily from a
representative rat fed ethanol and given PTU daily in the diet for 28 days until death from ethanol overdose. Ethanol was fed at 10 g
· kg 1 · day 1 until day 19 (arrow), when ethanol was increased to 11 g · kg 1 · day 1. Rats not on PTU can
tolerate ethanol at 13 g · kg 1 · day 1 without dying of ethanol overdose. Rats fed ethanol
without PTU will increase the rate of ethanol elimination when the UAL
increases to higher levels. Without a thyroid response, this increase
in metabolic rate does not happen and the UAL increases until the rat
dies of ethanol overdose.
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Fig. 11.
Serum T4 values in rats fed ethanol (ETOH)
and pair-fed controls (CONT) for 19 days with (+PTU) or without PTU.
Note that the T4 levels are markedly reduced by
PTU feeding. Values are means ± SE; P < 0.001;
n = 5 rats.
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The liver histopathology of the rats fed ethanol and given PTU showed a
shift in the location of the steatosis to the periportal region of the lobule, and the fat was microvesicular. The thyroid glands of all the PTU-treated rats showed diffuse follicular hyperplasia.
Experiment 3.
The rats that were fed ethanol and whose pituitary stalks had
previously been severed and separated by aluminum foil showed similar
flat UALs until the dose of ethanol was increased from 10 to 11 g
· kg
1 · day
1 on day 8 of ethanol feeding. At that point, the UALs slowly increased until
death at 700 mg/100 ml. The results were the same as those obtained
with PTU treatment. The UAL cycle was completely blocked. This happened
because the fall in body temperature caused by the high UAL could not
trigger the hypothalamic-pituitary response. This was a result of the
pituitary stalks being cut. The TSH and T4 levels did not
respond to the high ethanol-induced drop in body temperature.
T4 values were below 1 µg/ml for all rats in both
ethanol-fed and dextrose control rats. TSH values were all below 2 ng/ml in the same rats, and the values were not significantly different
between groups.
 |
DISCUSSION |
The pathogenesis of the UAL cycle has eluded investigators since
its first description (18). In an early study, it was
suggested that the cycling of the urine and blood ethanol levels were
due to a two-step induction of cytochrome P-450 2E1
(3). In that study, 24-h UALs were excellent indicators of
the blood alcohol levels in the intragastric tube feeding rat model.
More recently, it was shown that inhibitors of cytochrome
P-450 2E1 did not abolish the cycling of the UALs
(2), leaving the mechanism of the cycle unresolved. In the
current study, it was noticed that the cycling of the body temperature
peaked when the UAL reached the trough. Since O2
consumption rates parallel the changes in body temperature, these rates
were measured, and it was found that the resulting data correlated
positively with body temperature and negatively with the corresponding UALs.
What is the connection between the increased metabolic rate as
indicated by the increased rate of O2 consumption and the
decrease in UALs? We postulate that the increased metabolic rate
increases the ethanol elimination rate by generating NAD+
from the increase in the rate of mitochondrial respiration. The rate of
the oxidation of ethanol and acetaldehyde is limited by the
availability of NAD+, a cofactor with alcohol and
acetaldehyde dehydrogenase. We measured the levels of alcohol
dehydrogenase (ADH) apoprotein and cytochrome P-450 2E1
apoprotein by Western blot, and it was found that the levels were not
significantly different at the UAL peaks and troughs (unpublished
observations). Since ADH and cytochrome P-450 2E1 did not
vary, this adds credence to the idea that the level of available
NAD+ is the variable that accounts for the difference in
the rate of alcohol oxidation at the UAL peaks and troughs. However,
most investigators feel that enzyme concentration is more important, since NAD+ has been reported to regenerate at rates greater
than necessary for the rates of ethanol metabolism (5,
6).
What is the mechanism of the increased metabolic rate that occurs when
the UALs fall? We postulate that the metabolic rate increases as a
result of increased blood levels of T4 released from the
thyroid, since the body temperature and the rate of O2 consumption are regulated by T4 levels (10).
In the present study, T4 increased when the body
temperature and O2 consumption rates peaked, as expected.
If the T4 cycling was mechanistically involved in the UAL
cycle, PTU inhibition of T4 synthesis by the thyroid should
then eliminate the UAL cycle. Such proved to be the case. However, the
change in T4 between the UAL peaks and troughs is small
and, while suggestive, the data are far too limited to conclude that
the urine alcohol cycling is due to changes in the levels of
T4. Further studies are required. For instance, thyroid
hormones are potent and reversible inhibitors of alcohol oxidation
catalyzed by isozymes of class I and II ADH (12a). This would suggest
that UALs may rise at the trough because the elevated T4
levels inhibit the oxidation by ADH. Against this idea, however, is the
finding that when the T4 levels were reduced by PTU
treatment or stalk severance, the rate of alcohol oxidation fell from
13-14 g · kg
1 · day
1 to
10 g · kg
1 · day
1.
What is the reason for the increase in T4 blood levels
during the cycle? T4 levels are regulated by hypothalamic
neuronal receptors, which are sensitive to cold and heat
(11). Therefore, we postulate that when the UALs become
elevated during the cycle to the point at which the rat becomes
hypothermic, the cold temperature-sensitive neurons in the hypothalamus
are stimulated to secrete TRH into the portal circulation of the
pituitary stalk. To test this idea, rats with their pituitary stalks
severed were subjected to ethanol feeding intragastrically. This would
interrupt the cycle by disconnecting the hypothalamic thermoregulator
mechanism and thus prevent UAL cycling, just as the PTU treatment did.
This theory depends on the fact that ethanol, like other strong
sedatives, depresses the body temperature by reducing the reactivity of
the hypothalamus temperature controller (11) when the
blood ethanol levels become sufficiently elevated during the cycle,
i.e., ~400 mg/100 ml UAL. Severing the stalk did prevent the cycling.
Therefore, we suggested that the UAL cycle was initiated by a drop in
body temperature caused by rising UALs.
As the UALs rise, the body temperature slowly falls over several days.
When it drops to 36.5°C or lower, it abruptly increases to peak
within 1 day to ~38°C. Then the cycle begins again. It appears that
this abrupt and dramatic increase in body temperature initiates the
fall in the peak UAL. If the hypothalamic-pituitary-thyroid axis is
interrupted by cutting the stalk or by giving PTU, then the blood
ethanol levels continue to rise and the body temperature continues to
fall. The rat then dies of ethanol overdose. These findings support the
idea that ethanol overdose would respond to therapeutic hyperthermia,
but this has not yet been tested with the intragastric tube feeding rat model.
There are questions left unanswered regarding these hypotheses. First,
why does the cycle take several days and why is there a delay in onset
between the peak UAL and the increase in metabolic rate at the trough
UAL? The answer to both questions requires further experiments.
The second question yet to be answered is, What is the proof that
NAD+ levels fluctuate during the cycle? Ethanol metabolism
causes a shift in the redox state when the NAD+/NADH ratio
changes to a reduced state. This is further worsened by the
centrilobular hypoxia induced by chronic ethanol ingestion (7). However, it remains to be shown that the ratio
changes between the UAL peaks and troughs in a cyclic manner. Data on the levels of NAD+ in freeze-clamped livers taken at the
UAL peaks and troughs indicate that the levels of NAD+ are
higher at the troughs (unpublished observations).
The UAL cyclic phenomenon may have some relevance to the pathogenesis
of ALD. For example, the serum ALT levels were higher at the troughs of
UAL compared with the ALT levels when UAL peaked, indicating that the
liver injury may be occurring at a time when O2 consumption
is increased. Israel et al. (12) reported that PTU
prevented liver necrosis when ethanol-fed rats were subjected to
hypoxia, suggesting that the metabolic rate was increased in the
ethanol-fed rats and that this increase made the livers susceptible to
damage caused by hypoxia. High blood ethanol levels did increase the
vulnerability of the liver to hypoxia when the intragastric tube
feeding rat model was used (8). This may be how PTU
therapy worked in patients with ALD, since hypothyroidism had to first be established before survival improved. (15). Of course,
PTU may protect the liver from injury through a number of other
mechanisms, such as inhibiting myeloperoxidase or preventing free
radical damage (16). PTU protection of the liver in the
ethanol-fed rats was apparent, in that the fatty liver was
microvesicular and not macrovesicular as was seen in the ethanol-fed
rats to which no PTU was fed.
Initially, the fluctuation in body temperature during the UAL cycle was
suspected to be in response to endotoxin. Endotoxin injected into the
portal vein induced an increase in O2 consumption (1) and body temperature elevation, probably through an
increase in the serum IL-1 and TNF-
levels. Endotoxin levels are
increased in the serum in ALD, as are the IL-1 and TNF-
levels
(13). The serum endotoxin levels were higher, however, at
the peaks rather than the troughs of the UAL cycles in the present
study. Also, the serum TNF-
levels were elevated equally at the
peaks and troughs of the UAL cycle. The IL-1 serum levels were not
significantly elevated either at the peaks or the troughs of the UAL
cycle. It was concluded that the UAL was not due to oscillation of the serum endotoxin levels.
It is concluded that UAL cycling requires an intact
hypothalamic-pituitary-thyroid axis. The signal that initiates the
reversal of the rising UAL may be the fall in body temperature. This
signal does not initiate the fall in UAL when either the thyroid
function is suppressed by PTU or the pituitary stalk is cut. It is
postulated that the drop in temperature initiates the fall in UAL by
stimulating the cold-sensitive neurons in the hypothalamus.
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ACKNOWLEDGEMENTS |
We acknowledge the assistance of Adriana Flores, who typed the
manuscript, and Charles Peoples, who prepared the glossy prints.
 |
FOOTNOTES |
This study was supported by a National Institute of Alcohol Abuse and
Alcoholism Grants AA-8116 and AA-P50-11999.
Address for reprint requests and other correspondence: S. W. French, Dept. of Pathology, Harbor-UCLA Medical Center,
1000 W. Carson St., Torrance, CA 90509 (E-mail:
french{at}afp76.humc.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
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