1 Department of Anesthesiology, Oregon Health Sciences University and Veterans Affairs Medical Center, Portland, Oregon 97201; and 2 United States Department of Agriculture/Agricultural Research Services Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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On the basis of the
finding that plasma glycerol concentration is not controlled by
clearance in healthy humans, it has been proposed that elevated plasma
free fatty acid (FFA) and glycerol concentrations in cirrhotic subjects
are caused by accelerated lipolysis. This proposal has not been
validated. We infused 10 volunteers, 10 cirrhotic subjects, and 10 patients after orthotopic liver transplantation (OLT) with
[1-13C]palmitate and
[2H5]glycerol to compare fluxes
(Ra) and FFA oxidation. Cirrhotic subjects had higher
plasma palmitate (52%) and glycerol (33%) concentrations than
controls. Palmitate Ra was faster (1.45 ± 0.18 vs. 0.85 ± 0.17 µmol · kg1 · min
1)
but glycerol Ra and clearance slower (1.20 ± 0.09 vs.
1.90 ± 0.24 µmol · kg
1 · min
1
and 21.2 ± 1.2 vs. 44.7 ± 4.9 ml · kg
· h
1,
respectively) than in controls. After OLT, plasma palmitate and
glycerol concentrations and palmitate Ra did not differ,
but glycerol Ra (1.16 ± 0.11 µmol · kg
1 · min
1)
and clearance (26.7 ± 2.4 ml · kg
· h
1)
were slower than in controls. We conclude that 1) impaired
reesterification, not accelerated lipolysis, elevates FFA in cirrhotic
subjects; 2) normalized FFA after OLT masks impaired
reesterification; and 3) plasma glycerol concentration poorly
reflects lipolytic rate in cirrhosis and after OLT.
palmitate; glycerol; reesterification; insulin; humans
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INTRODUCTION |
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PLASMA FREE FATTY ACID (FFA) and glycerol concentrations are elevated in patients with end-stage liver disease. In general, plasma glycerol concentration has been interpreted as an indicator of accelerated lipolysis because glycerol liberated by lipolysis is not reincorporated into triglyceride and glycerol clearance is not rate limiting for its plasma concentration in healthy or injured humans (2). The observation that plasma glycerol concentration is not dictated by its clearance in healthy or injured humans has been extrapolated to patients with liver disease, in whom it has been proposed that increased plasma FFA and glycerol concentrations are caused by an accelerated rate of lipolysis (9, 21). This proposal is based on the assumption that glycerol clearance, which occurs mainly in the liver, is not impaired in patients with end-stage liver disease. Indirect evidence from two nonisotopic studies, however, demonstrates that the underlying assumption that glycerol clearance is not impaired by liver disease is untrue (10, 15). The only direct evidence that lipolysis may be accelerated in early cirrhosis, despite hyperinsulinemia, comes from a single study in which glycerol flux, measured by isotope dilution, was used to index lipolytic rate (11). This observation is consistent with the finding in hyperinsulinemic type 2 diabetes without liver disease (17) but differs from the findings in obese individuals in whom the ability of insulin to inhibit lipolysis is preserved (1, 22) and suggests that a compromised antilipolytic effect of insulin may be responsible for an increased rate of lipolysis in cirrhotic subjects. Whether lipolysis is accelerated in end-stage cirrhosis, to what extent this can be predicted by the circulating glycerol concentration, and the role of impaired insulin action as a mediator of the changes in lipid metabolism in end-stage cirrhosis remain uncertain.
After orthotopic liver transplantation (OLT), patients frequently develop a hypertriglyceridemia that persists for years (5, 8). The mechanism producing the hypertriglyceridemia remains unknown. Moreover, the extent to which the abnormalities of lipid metabolism associated with end-stage cirrhosis are reversed after OLT is untested. This study was designed to directly compare the flux and clearance of palmitate and glycerol, their plasma concentrations, and palmitate oxidation rates among patients with end-stage cirrhosis, patients 1 wk after OLT, and healthy volunteers.
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MATERIALS AND METHODS |
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Subjects.
This study was approved by the Institutional Review Boards at Oregon
Health Sciences University (OHSU) and the Portland, OR Veterans Affairs
Medical Center. Twenty patients with stable end-stage cirrhosis were
enrolled after written informed consent. Of these, 10 patients were
studied in the OHSU Clinical Research Center while awaiting OLT.
Inclusion criteria for cirrhotic patients were end-stage liver disease;
hemodynamic stability; no history of insulin-dependent diabetes
mellitus; no recent history of cigarette smoking; medications that did
not include -adrenergic agonists,
-adrenergic antagonists, or
steroids; and adequate renal function, as indexed by plasma creatinine
concentration <1.4 mg/dl. Severity of liver disease was assessed by
the Pugh-Childs scoring system (20). The remaining 10 patients were
studied on day 7 after OLT. The seventh postoperative day was
chosen because it is a time of stability when many patients are ready
for hospital discharge, the prednisone steroid taper is almost
complete, and chronic oral immunosuppression therapy has optimized. An
inclusion criterion for postoperative subjects, in addition to those
for preoperative subjects, was good liver graft function as indicated
by circulating albumin, prealbumin, and bilirubin concentrations and
coagulation status in the absence of blood product transfusion. Ten
healthy volunteers without clinical or laboratory evidence of liver
disease were enrolled as controls. Control subjects were studied in the OHSU Clinical Research Center. Dietary intake on the day before the
study was measured for cirrhotic and control subjects but not
postoperative OLT subjects. All three subject groups were awake and
alert and postabsorptive for at least 8 h, during which time they
received no intravenous glucose or other sources of calories. Screening
venous blood samples were drawn before the start of the stable isotope
infusion protocol.
Infusion protocol. The protocol began at 0700, when one intravenous catheter was placed in an upper extremity for stable isotope tracer infusion and a second intravenous catheter was placed in the dorsum of the contralateral hand for sampling of "arterialized" blood. The sampling hand was warmed with a heating pad. An indwelling central venous catheter was used for isotope infusion in postoperative patients.
After baseline blood and breath sampling, each subject received NaH13CO3 (5 µmol/kg iv; 99% 13C, Cambridge Isotope Laboratories, Woburn, MA) followed by a 60-min constant infusion at 10 µmol · kgAnalytical procedures. Plasma palmitate isotope ratio was determined by negative chemical ionization gas chromatography-mass spectroscopy (NCI-GC/MS) on a Hewlett-Packard 5989B GC/MS system (Hewlett Packard, Fullerton, CA) as described by Hachey et al. (6). The pentafluorobenzyl derivative was prepared and analyzed by selective ion monitoring at mass-to-charge ratios (m/z) 255 and 256. Plasma glycerol isotope ratio was also measured by NCI-GC/MS, on the pentafluorobenzyl derivative, with selective monitoring of ions at m/z 680-685 as described by Gilker et al. (4).
Breath 13CO2 content was determined by gas isotope ratio mass spectrometry (Europa Scientific, Crewe, UK). Plasma glucose concentration was assayed by glucose oxidase using an autoanalyzer (Glucose Analyzer 2, Beckman Instruments, Brea, CA). Serum total FFA content was determined by acyl-CoA synthetase and acyl-CoA oxidase using a commercial kit (Wako Chemicals, Richmond, VA) with each sample as its own control to overcome the effect of hyperbilirubinemia. Plasma palmitate and glycerol concentrations were determined by in vitro isotope dilution as described by Gilker et al. (4), using [2,2-2H2]palmitate (98% 2H) and [2-13C]glycerol (99% 13C, Cambridge Isotope Laboratories) as internal standards. Briefly, a known quantity of each internal standard was added to a 1.0-ml aliquot of the baseline plasma sample and the isotope ratios of palmitate and glycerol in the sample were measured as described above. For palmitate, the monitored ions were from m/z 255-257, and for glycerol the ions were m/z 680 and 681. These techniques theoretically provide a more accurate assay than corresponding colorimetric techniques because they are not affected by hyperbilirubinemia, which is characteristic of patients with end-stage cirrhosis.Calculations.
Palmitate flux (Ra palmitate) was calculated by the
equation
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Statistical analysis. Data are expressed as means ± SE. One-way ANOVA with Tukey's post hoc test was used to compare plasma substrate and hormone concentrations, Ra values for palmitate, FFA, and glycerol, palmitate and FFA oxidation rates, and clearance of palmitate, FFA, and glycerol among groups. Statistical tests were performed using a specialized software program (Crunch 4, Crunch Software, Oakland, CA). Differences were considered statistically significant at P < 0.05.
Ten subjects per group for comparison of Ra palmitate provided statistical power (1 ![]() |
RESULTS |
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Baseline characteristics.
The control group, eight men and two women, were 28 ± 2 (SE) years
old, weighed 70.3 ± 4.5 kg, and had a body mass index (BMI) of 23.4 ± 0.9 kg/m2. Table 1 shows
demographic characteristics of the two patient groups. The most common
etiology for cirrhosis in preoperative patients was concomitant ethanol
abuse and hepatitis C viral infection. A broad spectrum of initial
presenting liver disease was represented in the postoperative OLT
group. Compared with controls, the two patient groups were older
(P < 0.001) but had similar body weight and BMI. Cirrhotic
patients did not differ from postoperative patients in any demographic
characteristic, including the severity of liver disease immediately
before OLT. Mean time since last ethanol intake for the cirrhotic
patients with a history of ethanol abuse was 41 mo, with median 42 mo
and range 7-60 mo. For postoperative OLT subjects with a history
of ethanol abuse, the mean time since last intake was 30 mo with median
24 mo and range 13-62 mo. Dietary intake on the day before the
isotope study for the cirrhotic subjects was diminished compared with
controls, in terms of carbohydrate (2.30 ± 0.30 vs. 3.09 ± 0.28 g/kg), protein (0.61 ± 0.08 vs. 0.95 ± 0.08 g/kg), fat (0.37 ± 0.04 vs. 0.66 ± 0.06 g/kg), and total calories (14.9 ± 1.6 vs. 21.8 ± 1.8 kcal/kg) (all P < 0.05).
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Effect of cirrhosis and liver transplantation on bicarbonate
kinetics and gas exchange.
The primed-constant infusion of NaH13CO3 led to
a steady-state enrichment of expired CO2 in all groups.
Recovery of NaH13CO3 as exhaled breath
13CO2 was not statistically different among
controls (0.772 ± 0.031%), cirrhotic patients (0.862 ± 0.036%),
and OLT patients (0.793 ± 0.051%). Total CO2 production
was 119 ± 6, 114 ± 3, and 125 ± 4 µmol · kg1 · min
1
for controls, cirrhotic patients and OLT patients, respectively (not
different). Respiratory quotient in controls (0.83 ± 0.02), cirrhotic patients (0.80 ± 0.02), and OLT patients (0.84 ± 0.02) also did not differ among groups.
Hormonal profile in cirrhosis and after OLT.
Both cirrhotic patients and liver transplant patients exhibited a
marked hyperinsulinemia, with serum insulin concentration two- and
threefold higher, respectively, than in controls (Table 3). Hyperinsulinemia was paralleled by an
elevated circulating C-peptide concentration. Concomitantly, serum
glucagon concentration was higher than control value by more than
threefold in cirrhotic patients and by almost fivefold in OLT patients.
OLT patients showed higher serum concentrations of insulin, C-peptide,
and glucagon compared with preoperative cirrhotic patients. Thus the hormonal profile did not correct toward corresponding control values
after OLT. The isotope infusion protocol did not change the hormonal
profile of any subject group.
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Effect of cirrhosis on lipid flux and oxidation in vivo.
Cirrhotic subjects had increased plasma concentrations of palmitate (by
52%), FFA (by 76%), and glycerol (by 33%) compared with
corresponding control values (Table 4).
Plasma palmitate and glycerol isotopic enrichment reached a steady
state during the isotope infusion protocol in both subject groups.
Ra palmitate in cirrhotic patients was 71% higher and
total FFA flux was almost twofold higher, compared with their
respective control values. FFA clearance in cirrhotic patients was
unchanged compared with that of controls.
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Effect of liver transplantation on lipid flux and oxidation in vivo. Seven days after OLT, patients had plasma concentrations of palmitate, total FFA, and glycerol that did not differ from those of controls (Table 4). The isotopic infusion protocol led to steady-state plasma isotopic enrichment of palmitate and glycerol in all OLT patients, as it did in controls and preoperative cirrhotic patients. Palmitate and total FFA fluxes in OLT subjects did not differ from those in controls, although there was a trend toward faster flux of both substrates. Clearance of fatty acids by OLT patients was 79% higher than in controls. Glycerol flux and clearance by OLT patients were ~40% slower than those in healthy controls (P < 0.01). The Ra palmitate-to-Ra glycerol ratio in OLT subjects was twofold higher, and the Ra FFA-to-Ra glycerol ratio almost threefold higher, than in controls. This flux relationship was not reflected in the ratio of plasma substrate concentrations. Neither palmitate nor total FFA oxidation by OLT subjects differed from that of healthy controls, with either the NaHCO3 or the acetate correction factor. Similarly, the fraction of palmitate flux that was oxidized to CO2, which indicates the relationship between fatty acid production and oxidation, did not differ between groups.
OLT patients had lower plasma concentrations of palmitate (by 37%), total FFA (by 51%), and glycerol (by 25%) than preoperative cirrhotic patients. Ra palmitate and Ra FFA did not differ from those in preoperative cirrhotic patients, with lipid flux by OLT patients being intermediate between that by controls and cirrhotic patients (Table 4). Clearance of fatty acid by OLT subjects did not differ from that of preoperative cirrhotic patients, although there was a trend toward greater clearance in OLT patients. OLT patients oxidized palmitate and total FFA at a rate comparable to that of preoperative cirrhotic patients, with a similar fraction of palmitate flux fated to oxidation. Ra glycerol, the ratio of Ra palmitate to Ra glycerol, and the ratio of Ra FFA to Ra glycerol flux did not differ between OLT patients and preoperative cirrhotic patients. ![]() |
DISCUSSION |
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Our results showed that, although both FFA (palmitate) and glycerol concentrations are elevated in patients with end-stage cirrhosis, the kinetics underlying these alterations differ. Whereas the flux of FFA is faster, the flux of glycerol is slower than that of controls. Glycerol flux is a more accurate index of triglyceride breakdown rate (lipolysis) than palmitate flux because glycerol, unlike palmitate, cannot be recycled into triglyceride within the adipocyte. The slower glycerol flux indicates that the rate of lipolysis is slower in patients with end-stage cirrhosis than in healthy volunteers; hence their hyperglycerolemia compared with controls results from decreased glycerol clearance rather than accelerated lipolysis. On the other hand, the faster FFA flux in cirrhotic patients, despite a slower rate of lipolysis, coupled with unimpaired FFA oxidation indicates that there is a defect in the nonoxidative disposal of FFA. Because nonoxidative disposal of FFA is reincorporation into triglyceride (reesterification), we propose that the cirrhosis-induced defect in lipid metabolism is not accelerated lipolysis but probably an impairment of FFA reesterification into triglyceride within the adipocyte. One week after OLT, normalization of plasma palmitate and glycerol concentrations masks a continued inhibition of lipolysis, as indicated by the lower glycerol flux compared with controls, and an apparent impairment of FFA reesterification into triglyceride.
We measured palmitate flux and oxidation as indices of FFA metabolism
because palmitate kinetics reflect those of total FFA in healthy
volunteers (7) and the higher plasma palmitate concentration in
cirrhotic subjects parallels that of total FFA (21). Our findings of
elevated plasma concentrations of palmitate and glycerol in cirrhotic
subjects agree with previous observations (9, 11, 21). Similarly,
higher plasma total FFA concentration in cirrhotic subjects has also
been reported previously (18, 21, 23). The somewhat less marked
increase in FFA and glycerol plasma concentrations of our cirrhotic
patients may reflect the exclusion of cigarette smokersa large
percentage of patients with end-stage cirrhosis
and patients receiving
-agonist therapy, because nicotine and
-adrenergic stimulation
directly stimulate lipolysis (25).
Our flux values for lipid kinetics in healthy volunteers are in general
agreement with previous reports for Ra palmitate (27), Ra FFA (11), and Ra glycerol (1, 11, 17). With
regard to the kinetics underlying the elevated plasma palmitate and FFA concentrations of cirrhotics, the increased Ra palmitate in
the present study is consistent with the findings of two previous isotope dilution studies (11, 23). Romijn et al. (23) administered a
constant infusion of [14C]palmitate, and Kaye et al. (11)
used a [13C]palmitate infusion protocol similar to ours.
Our finding that glycerol flux is slower in cirrhotic patients,
however, contrasts with the faster glycerol flux reported by Kaye et
al. (11), despite similar stable isotope tracer protocols. It is
possible that the qualitative difference in glycerol fluxes reflects
more severe liver disease in our patients. All 10 of our patients had end-stage disease, whereas Kaye et al. (11) studied five Pugh class A
and three Pugh class B patients. Alternatively, it is possible that
either nicotine from cigarette smoking or -adrenergic therapy in the
cirrhotic patients stimulated lipolysis independently of liver disease
in the study by Kaye et al. (11, 25). It is noteworthy that our
patients and those of Kaye et al. exhibited a comparable
hyperinsulinemia relative to healthy controls. Our observation in
cirrhotic patients that plasma glycerol concentration is higher than
that in controls despite slower glycerol flux indicates that plasma
glycerol concentration is increased because of decreased clearance
rather than increased production. The concomitantly higher plasma FFA
concentration, FFA flux, and FFA oxidation despite slower glycerol flux
indicate that there is a reduced rate of FFA reesterification within
the adipocytes of cirrhotic patients.
One week after OLT, fatty acid flux and oxidation are intermediate between that of patients with end-stage cirrhosis and healthy controls. Lipolytic rate, as indexed by glycerol flux, is concomitantly slower than that of healthy volunteers. Together, these findings indicate that the rate of FFA reesterification within the adipocyte remains decreased, resulting in a faster FFA flux. Because the absolute rate of FFA oxidation is not increased to the same extent as FFA flux in the OLT patients, more FFA will be available to the liver to be reincorporated into triglyceride and released into the circulation in the form of very low-density lipoprotein-triglyceride. This may explain the hypertriglyceridemia reported in OLT patients by Jindal et al. (8) and Gisbert et al. (5).
The underlying mechanism that impairs FFA reesterification within the
adipocytes of cirrhotic and OLT patients is unknown. It is possible
that the supply of glycerol phosphate is limited in adipocytes of
cirrhotic subjects, either by decreased availability of
dihydroxyacetone secondary to impaired glucose uptake (11, 19) or
consequent to a possible defect in glycerol-3-phosphate dehydrogenase
activity. Alternatively, either acyl-CoA synthetase or any of the
acyltransferase reactions, which catalyze fusion of acyl-CoA with
glycerol-3-phosphate, may be impaired. We were surprised by the failure
of OLT to reverse the effects of liver disease on lipid metabolism by
the seventh postoperative day. Given the present results, it would be
of interest to study patients further removed from their transplant
surgery, perhaps at 6 or 12 mo postoperatively. It is possible that the
immunosuppressive drugs used in OLT patientscyclosporine,
azathioprine, and prednisone
may contribute to the observed
derangement in lipid metabolism. Glucocorticoid treatment increases
plasma FFA concentration and lipid oxidation (26). Our OLT patients
were receiving prednisone 1.5 mg · kg
1 · day
1 at the time of study, as part of a taper
protocol that gradually decreased to 5-10 mg/day. The actions of
cyclosporine and azathioprine on lipid metabolism is less well
understood. After our study was completed, the introduction of
tacrolimus for immunosuppression has increased the incidence of
post-OLT hypertriglyceridemia relative to that observed with
cyclosporine (8). As a practical matter, it is difficult to evaluate
the effect of a transplanted liver without the potentially confounding
effects of immunosuppressive therapy.
The influence of prior ethanol and other dietary intake on lipid metabolism deserves mention. It had been many months since the subjects in either liver disease group had consumed ethanol, and we feel that the effects of acute ethanol ingestion were not a factor in the present study. What remained in our patients in whom ethanol had been an etiologic factor in developing end-stage liver disease was the liver disease itself rather than an acute nutritional alteration. The previous dietary intake of our preoperative cirrhotic subjects was less than that of controls. Unfortunately, we were unable to document the dietary intake of post-OLT subjects, but we surmise that it too may have been decreased relative to that of controls. It is important to emphasize that all subjects were studied in the postabsorptive state. Nevertheless, it could be argued that the decreased dietary intake of our cirrhotic and post-OLT subjects would mimic a protracted fast that extended the effects of the overnight fasting. However, altered diet would not explain the decreased lipolysis and impaired reesterification observed in our cirrhotic and post-OLT subjects because protracted starvation stimulates rather than inhibits lipolysis, with parallel increases in glycerol and palmitate fluxes (29).
The role of hyperinsulinemia as a mediator of the changes in lipid
metabolism observed in cirrhotic and OLT patients is subject to
speculation. On the basis of their findings that accelerated lipolysis
in cirrhotic patients coincided with hyperinsulinemia, Kaye et al. (11)
concluded that cirrhotic patients must be resistant to the
antilipolytic action of insulin, but they did not rule out other
potential stimulators of lipolysis such as cigarette smoking or
-adrenergic therapy. Insulin inhibits glycerol flux in healthy
humans in a dose-dependent manner, such that a modest increase in serum
insulin concentration from 9.8 to 14-20 µU/ml suppresses
Ra glycerol by 50% (16). Furthermore, the maximal restraining effect of insulin on lipolysis occurs well within physiological hyperinsulinemia (16). Hyperinsulinemia to the level
exhibited by our cirrhotic and OLT patients could theoretically retard
lipolysis in these patients relative to the rate in healthy controls.
The ability of insulin to inhibit glycerol flux is preserved in
obesity, when corrected for fat mass, despite "insulin
resistance" of glucose metabolism (1, 22). In contrast, lipolysis is accelerated and peripheral tissue FFA uptake and oxidation are diminished in type 2 diabetic patients without liver disease, despite a
well-documented hyperinsulinemia (12, 17). Both plasma concentrations
and fluxes of FFA and glycerol decrease in cirrhotic patients during
insulin infusion, indicating that at least some of the ability of
insulin to inhibit lipolysis is retained (11). More extensive
evaluation of the role of insulin as a modulator of lipolysis and FFA
oxidation remains to be performed in patients with cirrhosis and after OLT.
Finally, it is clear that plasma glycerol concentration cannot be utilized as an index of lipolytic rate in the setting of liver disease. Glycerol utilization has been considered to occur predominantly in the liver (14). Although glycerol clearance is not the limiting factor in the relationship between its flux and plasma concentration in healthy or injured humans (2), the marked impairment of glycerol clearance secondary to cirrhosis causes an increase in its plasma concentration despite a decreased flux. The extent to which glycerol clearance must be impaired before plasma glycerol concentration no longer reflects glycerol flux remains to be determined. Johnston et al. (10) found a 35% decrease in glycerol clearance in 14 cirrhotic patients, most of whom had less marked liver disease than those in the present study. They further reported an inverse correlation between plasma glycerol concentration and glycerol clearance rate in their cirrhotic subjects. Nosadini et al. (15) reported decreased glycerol clearance in cirrhotic patients when hepatocellular perfusion was compromised either by marked fibrosis or portocaval shunting. It should be pointed out that all 10 of our cirrhotic patients had evidence of portal hypertension and that 2 of them had an indwelling portosystemic shunt at the time of study. The notion that 70-90% of glycerol clearance occurs across the liver has recently been challenged by data from Brunengraber and his associates (13), which indicates that the liver may directly account for only ~30% of whole body glycerol disposal. Further investigation is required to determine the mechanism for, including whether and to what extent extrahepatic tissue contributes to, the decreased whole body glycerol clearance in cirrhosis and after OLT.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-40566-05, DK-19525, and M01-RR-00334.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. E. Shangraw, Dept. of Anesthesiology, UHS-2, Oregon Health Sciences Univ., 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098 (E-mail: shangraw{at}ohsu.edu).
Received 18 May 1999; accepted in final form 25 August 1999.
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