Original Contributions |
From the Department of Internal Medicine and Biocenter Oulu, University of Oulu, Finland.
Correspondence to Marita Paassilta, MD, Department of Internal Medicine, University of Oulu, Kajaanintie 50, FIN-90220 Oulu, Finland. E-mail marita.paassilta{at}oulu.fi
| Abstract |
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Key Words: lipoprotein(a) alcohol insulin-like growth factor-I insulin-like growth factor binding protein-1 lipoprotein
| Introduction |
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Plasma Lp(a) levels are largely genetically determined.6 Dietary and pharmacological attempts to reduce Lp(a) have been mainly unsuccessful.7 Nicotinic acid,8 9 estrogen,10 11 and alcohol12 13 14 15 are among the few factors that appear to lower Lp(a) levels. Lowered Lp(a) levels have also been observed during IGF-I administration.16 17 GH therapy has increased Lp(a) levels in normal subjects18 and in patients with GH deficiency19 and idiopathic osteoporosis.17 However, GH therapy with near physiological doses in GH deficiency20 21 has no effect on Lp(a) levels.
Plasma Lp(a) levels are mainly determined by the apolipoprotein(a) production rate in the hepatocytes and the Lp(a) assembly.22 Liver is also the main synthesis site of IGF-I23 and IGFBP 1.24 In fact, low levels of IGF-I have been detected during both estrogen replacement therapy25 26 and niacin therapy,27 ie, in conditions with low Lp(a) levels. In addition, low levels of IGFBP-1, which is considered an acute regulator and inhibitor of IGF-I action,28 were recently shown to be associated with multiple factors predisposing to atherogenesis.29
Low Lp(a) levels have been observed in heavy alcohol consumers,12 13 15 but the mechanisms behind the alcohol-related reduction in Lp(a) are unknown. Since Lp(a) levels have been shown to rise rapidly after alcohol withdrawal,13 we decided to study the changes in the GH/IGF-I/IGFBP-1 axis after alcohol withdrawal to evaluate whether GH, IGF-I, and IGFBP-1 might be related to the change seen in Lp(a) after alcohol withdrawal.
| Methods |
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All of the subjects had a good nutritional status and were clinically free from liver, kidney, or heart dysfunction. In one subject, albumin and Thrombotest Simplastin A (TT-SPA) levels were lower than normal (31 g/L and 59%, respectively), while the others presented with normal albumin levels [39 g/L (34 to 46 g/L) mean (range)] and TT-SPA values. The mean values (reference value) for alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), and mean corpuscular volume of erythrocytes (MCV) in the alcohol abusers were 57 U/L (<50 U/L), 162 U/L (<80 U/L), and 98 fL (<96 fL), respectively. MCV and the activities of ALT and GGT were analyzed in the laboratory of the Oulu University Hospital using standard methods. Written informed consent was obtained from all the participants, and the Ethical Committee of the University of Oulu approved the study.
Study Design
Venous blood samples were drawn after an overnight fast (between
7 and 8 AM) from the alcohol abusers on the first day after
admission to the Alcoholism Treatment Unit and thereafter on three
consecutive days during the abstinence period to investigate the
changes in Lp(a), other lipids and lipoproteins, IGF-I, and IGFBP-1
related to alcohol withdrawal. An overnight (7 PM to 7
AM) urine collection for GH analyses was performed
on 9 consecutive alcoholics on admission (before the first blood
sampling day) and during the night before the fourth day of monitoring.
Five control subjects were monitored for a 4-day period for Lp(a),
IGF-I, IGFBP-1, and GH, while a single blood sample was obtained from
the rest (n=21). Urine collection was performed among 11 control
subjects. The plasma samples were stored at -70°C and the urine
samples at -20°C.
Biochemical Assays
After isolating VLDL (d<1.006 g/mL) by
ultracentrifugation, the HDL cholesterol
concentration in the VLDL-free fraction was determined by an enzymatic
method after precipitation of LDL with heparin-manganese
chloride.31 Plasma cholesterol and
triglyceride concentrations were determined by enzymatic
colorimetric methods (Boehringer, Mannheim
GmbH) using a Kone Specific analyzer (Kone Specific, Selective
Chemistry Analyzer, Kone Instruments).
Plasma Lp(a) concentrations were determined by an enzyme-linked immunosorbent assay method (Biopool Ltd), which has been shown to correlate well with the other Lp(a) assay methods.32 The CVs within and between Lp(a) assays were 5.0% and 6.6%, respectively. IGF-I was determined by a double antibody disequilibrium RIA (Incstar Stillwater) after an extraction procedure. The intra-assay CV was 5.9% and the interassay CV 11.8%. IGFBP-1 was measured by using an immunoenzymometric assay (IEMA TEST, Medix Biochemica), the intra-assay and interassay CVs being 4.1% and 8.6%, respectively. Urinary GH was determined by a sandwich RIA technique (125I hGH U Coatria, bioMérieux) with a detection limit of 0.5 pg/mL. The intra-assay CVs at 1.4 and 13.6 pg/mL were 9.3% and 8.1%, respectively.
Statistical Analysis
Statistical analysis was carried out with the software
package SPSS for Windows (Release 6.1, SPSS Inc.). The results are
presented as mean±SD unless otherwise stated. Logarithmic
transformation was used to normalize the distribution of the data for
Lp(a), GH, IGF-I, plasma, and VLDL triglycerides. A
standard t test of means was then used to compare the
homogeneity of the study groups. The strength of the linear association
between two variables was measured using Pearson correlation
coefficients. For analyses of the time-dependent changes in the
variables, repeated-measures ANOVA module of SPSS was used.
Thereafter, paired t tests were performed to evaluate the
difference in the variables between days. GH and the variables
that gave statistical significance (P<.05) after ANOVA were
analyzed in a stepwise multiple linear regression model. In
this procedure, independent variables that best predicted the value
of the dependent variable were estimated by means of
R2 (explanatory value of the model).
| Results |
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Plasma lipids and lipoproteins, IGF-I, and IGFBP-1 in the alcoholics
during the 4-day observation period after alcohol withdrawal are
presented in Table 2
. Lp(a)
levels increased by 64% after alcohol withdrawal (P<.001).
Total and HDL cholesterol concentrations showed a reduction
of 8% and 21%, respectively, while VLDL cholesterol and
plasma TG did not change during the same period. An increase of 41% in
IGF-I and a decrease of 59% in IGFBP-1 (P<.001 for both
comparisons) levels were observed after the cessation of drinking.
Urinary GH levels tended to decline during the monitoring period (from
2.56±3.14 to 1.10±1.00 pg/mL, P=NS; mean±SD). In the five
control subjects who were monitored for 4 days, Lp(a), IGF-I, IGFBP-1,
and GH levels did not change during a 4-day monitoring period (data not
shown).
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IGFBP-1, Lp(a), and Other Lipids
At the end of the drinking period, IGFBP-1 showed a correlation
with LDL cholesterol (r=-.62,
P=.001) and the other lipids (HDL and VLDL
cholesterol and plasma and VLDL triglycerides,
r=.41, -.46, -.47, and -.41; P<.05 for all).
The change in IGFBP-1 during the 4-day observation was correlated
negatively with the changes in plasma and VLDL
triglycerides (r=-.48, -.43, respectively,
P<.05 for both). Multiple-regression analysis
showed that the best predictor for the change in IGFBP-1 was Lp(a)
(R2=.608, P=.013).
The change (from day 1 to day 4) in Lp(a) levels during the 4-day
monitoring showed a negative association with the change in IGFBP-1
(r=-.63, P<.001) (Fig 1
). In multiple regression
analysis, the main predictors of the change in Lp(a) were
IGFBP-1 alone or together with GH (R2=.650,
P=.016 and R2=.828,
P=.005, respectively). IGFBP-1 was also the main predictor
of the change in plasma triglycerides
(R2=.530, P=.026).
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IGF-I
The change in IGF-I during the monitoring period did not show any
correlation with the other variables. Multiple regression
analysis revealed the best predictive parameters
for the change in IGF-I to be plasma cholesterol and
triglycerides (R2=.850,
P=.003).
GH
The change in nocturnal (12 hours) urinary GH secretion correlated
negatively with the change in plasma Lp(a) levels (r=-.70,
P<.05) (Fig 2
), but not with
any other variables. The change in GH was best predicted by Lp(a)
in the multiple regression analysis
(R2=.492, P=.035).
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| Discussion |
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Acute moderate alcohol intake has been shown to increase IGFBP-1 levels33 and reduce GH levels.34 Therefore, social alcohol consumptionshown to decrease Lp(a) levels14may also have affected the GH/IGF-I/IGFBP-1 axis in the control group of the present study. This may partly explain why the control group, which mainly consisted of social drinkers, did not differ from the alcohol abusers in GH, IGF-I, IGFBP-1, and Lp(a) levels.
How could cessation of alcohol intake affect IGFBP-1 and Lp(a)? Alcohol alters the redox state of the liver by increasing the NADH/NAD ratio and thus promoting reduced intracellular state.35 High NADH/NAD ratio is also characteristic for metabolic acidosis, a condition shown to increase plasma levels of IGFBP-1 and the IGFBP-1 content in the rat liver.36 Theoretically, normalization of the redox state after alcohol withdrawal might have contributed to the observed reduction in IGFBP-1 levels. It is also possible that the removal of the hepatotoxic agent, ie, alcohol, allows the liver to resume its normal synthetic function and thus normalize IGFBP-1 and Lp(a) production. Since the rise in Lp(a) occurs rapidly, the mechanisms behind it may also be related to changes in the catabolism of Lp(a).
Nutritional factors are important in the regulation of IGF-I and IGFBP-1.37 38 Alcohol abusers may often present with hepatic damage and nutrient deprivation.39 40 However, a careful clinical examination of the subjects ruled out severe liver damage, and the normal BMI and serum albumin levels revealed that the subjects were in a good nutritional condition.
Previous data on the effects of alcohol on stress hormones, such as catecholamines and cortisol, are inconsistent. Increased41 or unchanged42 plasma cortisol levels have been observed after alcohol intake. IGF-I levels may be reduced43 or unaffected44 by corticosteroid excess. IGFBP-1 levels have been shown to decrease45 or increase46 during cortisol administration. In addition, dexamethasone treatment after renal transplantation has been shown to induce a dose-dependent reduction in Lp(a).47 Therefore, the changes in Lp(a), IGF-I, and IGFBP-1 and the observed association between Lp(a) and IGFBP-1 during alcohol withdrawal are possibly not related to cortisol. Unfortunately, neither plasma nor urinary catecholamines and cortisol were measured in the present study.
Enhanced expression of IGF-I has been observed in human atherosclerotic plaques48 and in rat allograft arteriosclerosis.49 In addition, low levels of IGFBP-1 have recently been associated with low HDL cholesterol, increased insulin, proinsulin, and BMIfactors known to increase the risk for cardiovascular disease.29 IGF-I was not shown to be associated with cardiovascular risk factors in that study. The present data provide new evidence that IGFBP-1 may also be associated with Lp(a), a risk factor for CHD. In the present study, alcohol withdrawal may have enhanced the bioavailability of IGF-I due to a concomitant increase in IGF-I and a decrease in IGFBP-1 levels. The role of GH may also be important in the modulation of Lp(a) levels, but this requires further studies, because the number of subjects analyzed for GH in the present study was limited.
In conclusion, alcohol withdrawal induces a rapid rise in plasma Lp(a) levels. The increase in Lp(a) is associated with the decrease in IGFBP-1. After cessation of drinking, IGF-I levels increase simultaneously with Lp(a), but they do not correlate with each other. Alcohol-induced changes in the liver, such as reduced redox state, could partly explain the observed changes in Lp(a) and IGFBP-1 levels seen after alcohol withdrawal. These changes, low IGFBP-1 together with high Lp(a), may be important factors predisposing to atherosclerosis. The possible interrelationship between Lp(a) and IGFBP-1 in a normal population awaits further studies.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received September 4, 1997; accepted December 10, 1997.
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