Carbohydrate deficient transferrin (CDT) in alcoholic cirrhosis: a kinetic study

doi:10.1016/S0168-8278(97)80043-8

Journal of Hepatology

Volume 26, Issue 2, February 1997, Pages 287-292

https://doi.org/10.1016/S0168-8278(97)80043-8 Get rights and content

Abstract

Background/Aims: Carbohydrate deficient transferrin has been introduced as a marker of excessive alcohol intake. The present study was undertaken in order to measure the circulating level of carbohydrate deficient transferrin in patients with alcoholic cirrhosis and to assess arteriovenous kinetics of carbohydrate deficient transferrin in liver and kidney.

Methods/Results: The median value of serum carbohydrate deficient transferrin was 16.0 U/l in patients with alcoholic cirrhosis (n=41), and this value was not significantly different from that of a normal control group (median 17.4 U/l, n=55, ns). Carbohydrate deficient transferrin was significantly higher in patients with cirrhosis and high current alcohol intake than in abstaining patients (2- vs. 14 U/l, p<0.5). Similarly, controls with a high current alcohol intake (>50 g/day) had a significantly higher carbohydrate deficient transferrin concentration than controls with a low alcohol intake (<10 g/day) (36 vs. 14.9 U/l, p<0.005). No significant differences were detected between carbohydrate deficient transferrin in artery and liver vein or artery and renal vein, either in patients with alcoholic cirrhosis (n=11) or in controls (n=8), which indicates a slow turnover rate of carbohydrate deficient transferrin. Food ingestion did not affect the circulating level of carbohydrate deficient transferrin, and the analysis of carbohydrate deficient transferrin was almost unaffected by the presence of ethanol in plasma within the biological range (ethanol 0–100 mmol/l).

Conclusions: Our results suggest that measurement of carbohydrate deficient transferrin may be used in patients with alcoholic cirrhosis. High current alcohol intake is associated with higher carbohydrate deficient transferrin levels than in those with alcohol intake, but the overlap is substantial in patients with cirrhosis. Carbohydrate deficient transferrin has a low turnover rate in both patients with cirrhosis and normals.

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2016, Neuropharmacology
Citation Excerpt :
Rats were fed ethanol or control diets 3× daily (every 8 h at 7:00AM, 3:00PM, and 11:00PM) for 4 days, following a well-established 4-day binge ethanol model (Majchrowicz, 1975) which induces physical dependence on ethanol and neurodegeneration (Obernier et al., 2002a, 2002b; Crews and Braun, 2003; Kelso et al., 2011). The daily dose of ethanol (∼9 g/kg/day) resulted in a mean blood alcohol content (BAC) of 95 mM, a level that is routinely found in models of binge ethanol exposure (Nixon and Crews, 2002; Obernier et al., 2002b) and among alcohol abusers who drink heavily (Majchrowicz, 1975; Henriksen et al., 1997). After the initial loading dose of 5 g/kg, administration of subsequent doses of ethanol was dependent on behavioral intoxication scores (Table 1).
Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial.
In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague–Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol.
Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge.
These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities.
A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase and Monoamine Oxidase B Cascade in Ethanol-Induced Cellular Damage
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Because EtOH is volatile, a closed chamber system was used to stabilize the EtOH concentration in the culture medium as described previously (25,26). The EtOH concentrations used in this study (75 mmol/L) are within the level that results in physiological effects observed in alcoholics, because EtOH at 50–100 mmol/L reflects blood levels of EtOH in chronic alcoholics (27,28). Total RNA was isolated from each group by using RNA isolation reagent (Invitrogen).
Alcoholism is a major psychiatric condition at least partly associated with ethanol (EtOH)-induced cell damage. Although brain cell loss has been reported in subjects with alcoholism, the molecular mechanism is unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction under stressful conditions and might contribute to EtOH-induced cell damage.
Expression of GAPDH and MAO B protein was studied in human glioblastoma and neuroblastoma cell lines exposed to physiological concentrations of EtOH. Expression of these proteins was also examined in the prefrontal cortex from human subjects with alcohol dependence and in rats fed with an EtOH diet. Coimmunoprecipitation, subcellular fractionation, and luciferase assay were used to address nuclear GAPDH-mediated MAO B activation. To test the effects of inactivation, RNA interference and pharmacological intervention were used, and cell damage was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP Nick End Labeling (TUNEL) and hydrogen peroxide measurements.
Ethanol significantly increases levels of GAPDH, especially nuclear GAPDH, and MAO B in neuronal cells as well as in human and rat brains. Nuclear GAPDH interacts with the transcriptional activator, transforming growth factor-β-inducible early gene 2 (TIEG2), and augments TIEG2-mediated MAO B transactivation, which results in cell damage in neuronal cells exposed to EtOH. Knockdown expression of GAPDH or treatment with MAO B inhibitors selegiline (deprenyl) and rasagiline (Azilect) can block this cascade.
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Carbohydrate-deficient transferrin has been proposed to be useful in evaluating alcohol consumption but there is no consensus on its use in routine practice. The aim of this retrospective study was to compare carbohydrate-deficient transferrin and gammaglutamyl transpeptidase assays for the evaluation of alcohol consumption.
Six hundred thirty-three outpatients attending one outpatient care center were included in this study. Patients were divided into five categories according to alcohol consumption: category 1 included non-weaned patients drinking more than 30 g/day for women and more than 50 g/day for men, category 2 included relapse patients, category 3 included moderate drinkers, category 4 included patients weaned less than one month, and category 5 included patients weaned more than one month. One experienced physician estimated alcohol intake from patient declarations during a face-to-face interview.
Sensitivity of carbohydrate-deficient transferrin varied, depending on patient category, from 32% to 92% versus 41% to 72% for gamma-glutamyl transpeptidase. Specificity of carbohydrate-deficient transferrin varied from 71% to 96% versus 23% to 62% for gamma-glutamyl transpeptidase. After one month of abstinence, specificity of carbohydrate-deficient transferrin was 62% versus 19% for gamma-glutamyl transpeptidase.
This study confirms that carbohydrate-deficient transferrin is more accurate in predicting alcohol consumption compared with gamma-glutamyl transpeptidase in alcoholic outpatients.
La place de la carbohydrate-deficient transferrine dans l’évaluation de la consommation d’alcool par rapport aux autres marqueurs n’est pas clairement établie.
Le but de cette étude rétrospective était de comparer la carbohydrate-deficient transferrine et la gammaglutamyl transpeptidase chez des malades suivis dans un centre de cure ambulatoire en alcoologie.
Les 633 malades inclus dans cette étude étaient classés selon 5 statuts: statut 1: malades non sevrés consommant plus de 30 g/j d’alcool pour les femmes et plus de 50 g/j pour les hommes, statut 2: malades présentant une rechute, statut 3: malades tempérants, statut 4: malades sevrés depuis moins d’un mois, statut 5: malades sevrés depuis plus d’un mois. Un malade pouvait appartenir à plusieurs statuts mais un seul prélèvement a été retenu par statut, soit un total de 993 prélèvements. La consommation déclarée d’alcool a été évaluée par le même médecin lors d’un entretien en face-à-face.
Selon le statut, la sensibilité de la carbohydrate-deficient transferrine variait de 32 à 92 % et celle de la gammaglutamyl transpeptidase de 41 à 72 %. La spécificité de la carbohydrate-deficient transferrine variait de 71 à 96 % et celle de la gammaglutamyl transpeptidase de 23 à 62 %. La spécificité de la carbohydrate-deficient transferrine était de 62 % après 1 mois de sevrage alors qu’elle était de 19 % pour la gammaglutamyl transpeptidase.
Cette étude confirme la meilleure valeur informationnelle de la carbohydrate-deficient transferrine par rapport à la gammaglutamyl transpeptidase, pour évaluer la consommation d’alcool chez des malades alcooliques suivis en ambulatoire.
Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease
2003, Mayo Clinic Proceedings
To determine whether isoform separation of carbohydrate-deficient transferrin (CDT) is of value in the diagnosis of alcoholic liver disease (ALD) and is specific to ALD when compared with other liver diseases.
During 1995 and 1996, 47 patients with ALD were evaluated with CDT at the Mayo Clinic in Rochester, Minn. The diagnosis of ALD was based on biochemical and histological analyses and on a history of drinking that exceeded 5 years with an average alcohol intake of more than 60 g/d. Disease controls included nonalcoholic steatohepatitis (NASH) (n=26) and other liver disease (n=22). Normal controls (n=21) were healthy individuals without liver disease. Transferrin isoforms were quantified by densitometry of Coomassiestained transferrins after affinity purification and isoelectric focusing. The pentasialo, tetrasialo, trisialo, disialo, monosialo, and asialo isoforms were quantified as percentages of total band densities.
Receiver operating characteristic (ROC) curves were constructed for each isoform. The curves for total desialated isoforms (sum of disialo, monosialo, and asialo) displayed the best relationship between sensitivity and specificity with an ROC-area under the curve (AUC) of 0.922. The ROC-AUC values for individual transferrin isoforms in ALD vs NASH for pentasialo, tetrasialo, trisialo, disialo, monosialo, and asialo were 0.806, 0.917, 0.885, 0.933, 0.804, and 0.785, respectively. Only 58% of patients with ALD were detected at a specificity that excluded ALD in 84% of those who did not have it.
Within alcohol ingestion times reported to us, no associations with recent drinking were observed. Alcohol as a cause of liver disease is not perfectly established by CDT analysis, although a high total CDT value favors ALD over NASH.
Usefulness of carbohydrate-deficient transferrin and trypsin activity in the diagnosis of acute alcoholic pancreatitis
2001, American Journal of Gastroenterology
Citation Excerpt :
The combination of these variables enabled correct prediction of acute alcoholic pancreatitis in 98% of the cases. Serum CDT levels in the control group of our study were similar than those reported in previous studies (19, 20). However, trypsin activity levels in controls (39 U/L) were lower than those found by Le Moine et al.(16) in a series of 62 healthy subjects (81 U/L).
OBJECTIVE:
The aim of this study was to assess if carbohydrate-deficient transferrin (CDT) and trypsin activity differentiate acute alcoholic pancreatitis from nonalcohol-related pancreatitis, and as a secondary goal to evaluate its use in comparison to healthy controls.
METHODS:
Serum levels of CDT and trypsin activity were measured in frozen sera from 70 nonconsecutive patients with acute pancreatitis and in 16 healthy controls.
RESULTS:
Causes of pancreatitis were gallstones in 51%, chronic alcoholism in 23%, and other or unknown causes in 26% of the patients. Serum CDT was significantly higher in alcoholic pancreatitis than in the nonalcoholic disease (p < 0.0001) with a median (interquartile range) of 30.8 U/L (23.6–41.7 U/L) in chronic alcoholism, 16.7 U/L (13.05–21.1 U/L) in gallstones, 17.5 U/L (15.9–21.6 U/L) in unknown cause, 19.3 U/L (15.1–27.7 U/L) in other etiologies, and 16.1 U/L (12.1–18.8 U/L) in controls. At a cutoff over 22.5 U/L, CDT showed a sensitivity of 87.5% and a specificity of 85.2%. Serum levels of trypsin activity were significantly higher (p = 0.0007) in alcoholic pancreatitis, median 165 U/L (76–405 U/L) than in nonalcoholic pancreatitis, median 73 U/L (46.5–100.5 U/L). At a cutoff value over 152 U/L, the sensitivity of trypsin activity was 60% with a specificity of 100%. In the multivariate analysis, patient’s age (≤44 yr), CDT (>22.5 U/L), and trypsin activity (>152 U/L) enabled correct prediction of acute alcoholic pancreatitis in 98% of the cases.
CONCLUSION:
Serum CDT and trypsin activity are of clinical utility in differentiating alcoholic from nonalcoholic acute pancreatitis.
Carbohydrate deficient transferrin in alcoholic liver disease: Mechanisms and clinical implications
1999, Alcohol
Carbohydrate-deficient transferrin (CDT) is now considered to be the most sensitive and specific biological marker of alcohol abuse. The mechanism by which chronic alcohol consumption causes an elevation of CDT levels in serum is discussed. The sensitivity and specificity of various test procedures are compared, with special emphasis on the impact of liver disease. Clinical applications are reviewed, including the utility of CDT as a marker of relapse in alcoholic patients, and the use of CDT for the systematic screening of drinking in vulnerable populations as part of a public health approach to alcoholism.

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Carbohydrate deficient transferrin (CDT) in alcoholic cirrhosis: a kinetic study

Abstract

J Biol Chem

Clin Chim Acta

Alcohol

Clin Chim Acta

J Hepatol

J Hepatol

Arch Biochem Biophys

Int J Biochem

Chem Phys Lipids

Clin Biochem

Metabolism

J Hepatol

Human transferrin: cDNA characterization and chromosomal localization

Biochemistry

The structural heterogeneity of the carbohydrate moiety of desialylated human transferrin

Can J Biochem

Biosynthetic controls that determine the branching and microheterogeneity of protein-bound oligosaccharides

Cell Biol

Carbohydrate deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed

Clin Chem

Comparison of different methods for detecting carbohydrate deficient transferrin

Alcohol Clin Exp Res