AIMSDue to methodological heterogeneity, conflicting views have been expressed on the validity of CDT measurements in the detection of alcohol misuse.METHODSWe compared the characteristics of the conventional CDTect method and the Axis turbidimetric CDT assays in the assessment of 62 alcoholics, who were either with (n = 33) or without (n = 29) liver disease, as analysed by combined clinical, laboratory, and morphological indices. Controls were 45 healthy volunteers who were either social drinkers or abstainers.RESULTSIn the total sample of alcoholics, the sensitivity of the %CDT method, which excludes the trisialotransferrin isoform from the measurement, was 63% for men and 46% for women, as compared to 65% and 36% of CDTect, respectively. Both of these methods showed higher sensitivities than the %CDT-TIA method, which reacts with trisialotransferrin (32% and 25%, respectively). The assay specificities were 100% for men and 91% for women with %CDT, and 96% and 87% with the CDTect, respectively. The correlation between the CDTect and %CDT method was higher in men (r = 0.86) than in women (r = 0.57). The presence of liver disease was found to influence the results of the CDTect method, such that the highest CDT concentrations were observed in patients with mild to moderate liver disease, especially among women, whereas the %CDT method was less sensitive to the effect of liver pathology. The self-reported alcohol consumption from the 4 weeks prior to sampling showed a higher correlation between the %CDT results (r = 0.64, P < 0.0001) than with the CDTect results (r = 0.40; P < 0.01).CONCLUSIONSThe data indicate that the new %CDT method offers advantages over the previous versions of the CDT methods. The improved characteristics may be most useful in assays for excessive alcohol consumption in female alcoholics, patients with liver disease, and in patients with abnormal serum transferrin concentrations.

BACKGROUND:Studies in experimental animals have indicated that chronic ethanol ingestion triggers the formation of antibodies directed against proteins modified with reactive metabolites of ethanol and products of lipid peroxidation. However, the nature and prevalence of such antibodies have not been compared previously in alcoholic patients.METHODS:Autoantibodies against adducts with acetaldehyde- (AA), malondialdehyde- (MDA), and oxidized epitopes (Ox) were examined from sera of 54 alcohol consumers with (n = 28) or without (n = 26) liver disease, and from 20 nondrinking controls.RESULTS:Anti-AA-adduct IgA and IgG antibodies were elevated in 64% and 31% of patients with biopsy-proven alcoholic liver disease (ALD, n = 28), respectively. The IgA titers were significantly higher than those from nondrinking controls (p < 0.001), or heavy drinkers without significant liver disease (p < 0.001). Anti-MDA adduct titers (IgG) were elevated in 70% of the ALD patients. These titers were significantly higher (p < 0.001) than those from nondrinking controls, or heavy drinkers without liver disease. Antibodies (IgG) against Ox epitopes occurred in 43% of ALD patients, and the titers also were significantly higher (p < 0.05) than those from nondrinking controls. The anti-AA and anti-MDA adduct titers in ALD patients correlated significantly with the combined clinical and laboratory index (CCLI) of liver disease severity (r(s) = 0.449, p < 0.05; r(s) = 0.566, p < 0.01, respectively), the highest prevalences of anti-AA-adducts (73%) and anti-MDA-adducts (76%) occurring in ALD patients with cirrhosis.CONCLUSIONS:The present results indicated that autoantibodies against several distinct types of protein modifications are generated in ALD patients showing an association with the severity of liver disease.

For > 150 y, clinicians and investigators have observed that high protein intakes accelerate the progression of renal disease and that low protein intakes have beneficial effects. Some studies suggest that the effects of soy-protein intake resemble those of a low-protein diet. The Brenner hypothesis suggests that high protein intakes by diabetic individuals create hyperfiltration and glomerular hypertension eventuating in renal damage. On the basis of the available evidence, we are proposing the soy-protein hypothesis, which states that substituting soy protein for animal protein in diabetes patients results in less hyperfiltration and glomerular hypertension and, therefore, resultant protection from diabetic nephropathy. Furthermore, substituting soy protein for animal protein should have therapeutic value in diabetic nephropathy with resultant slowing of deterioration of renal function and decreasing proteinuria. The preliminary results of the study of 8 type 2 diabetes patients with obesity, hypertension, and proteinuria are reported. Under the conditions of the study, providing soy protein as half of the daily protein intake had no distinct effects on renal function or proteinuria in these subjects. Soy-protein intake was associated with a significant reduction in serum cholesterol and triacylglycerol concentrations. Further studies are required to critically examine the effects of soy-protein intake on the renal function of diabetes patients.

Intracytoplasmic injection with late spermatids: a successful 1200 procedure in achieving childbirth for couples in

Chronic ethanol ingestion has been suggested to trigger the formation of antibodies that recognize acetaldehyde-protein condensates. In this study, assays for immunoglobulin (Ig) A, IgG, and IgM antibodies to acetaldehyde-derived adducts were performed on sera of 140 alcohol consumers, 19 patients with nonalcoholic liver disease (NALD), 35 healthy nondrinking controls, and 10 nondrinking patients with IgA or IgG myeloma. Anti-acetaldehyde (Ach)-adduct antibodies of each Ig isotype were found from the alcohol abusers. In alcoholic liver disease (ALD, n = 86) IgA titers were elevated in 69% of the patients. These titers were significantly higher than those from patients with NALD (P < .001), nondrinking controls (P < .001), or heavy drinkers (n = 54) without any clinical and biochemical signs of liver disease (P < .001). In contrast, anti-adduct IgG titers were significantly elevated both in ALD and in heavy drinkers as compared with patients with NALD (P < .001) or nondrinking controls (P < .01 and P < .05, respectively). The anti-adduct immunoglobulin (Ig)A, IgG, and IgM titers in patients with alcoholic liver disease (ALD) correlated with the combined clinical and laboratory index of liver disease severity (r(s) = .497, P < .001; r(s) = .361, P < .01; and r(s) = .322, P < .01). Anti-adduct IgA titers also correlated with serum bilirubin (r = .768, P < .001) and interleukin 6 (r = .504, P < .001). Anti-adduct IgG titers were, in turn, found to correlate with the presence of inflammation (P < .01) and necrosis (P < .01). During follow-up studies of individual patients, parallel changes were observed in the anti-adduct IgG titers, disease severity, and serum markers of fibrogenesis. The present results provide evidence that antibodies representing distinct Ig classes directed against acetaldehyde (Ach)-derived adducts of proteins are formed in alcoholic patients showing an association with the severity of liver disease. The follow-up data also support an association between such immune responses and the aggravation of liver disease.

Objective: To evaluate gonadotropins, estrogen, and insulin-like growth hormone factor (IGF)-I and its binding proteins throughout the normal menstrual cycle and during aging within the reproductive life span.Design: Daily blood samples were obtained from 17 normally cycling women.Setting: Center for Fertility and Reproductive Medicine, Newark, New Jersey.Participants: Ten women aged 19 to 34 years old and seven women aged 42 to 47 years old.Main Outcome Measures: Luteinizing hormone (LH), FSH, E(2), and P were assayed in daily blood samples. Early follicular, late follicular, midluteal phase, and samples taken at ovulation were also assayed for IGF-I and IGFBP-I and IGFBP-III.Results: Follicle-stimulating hormone (FSH) increased significantly with reproductive aging. IGF-I and its binding proteins did not fluctuate through the menstrual cycle. IGF-I and its binding proteins did not change over the 28-year time span studied, in the face of significantly increased circulating estradiol associated with reproductive aging.Conclusion: Rising E(2) may be a subtle harbinger of the perimenopause. IGF-I and its binding proteins did not decrease with cycle stage or with aging during the reproductive years, perhaps because of increased estradiol stimulation of the somatotrophic axis. (C) 1997 by American Society for Reproductive Medicine.

Despite a number of investigations suggesting the value of carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse, a variety of issues on the applicability of CDT measurements in clinical settings have remained unexplored. Earlier studies in this field have focused on the relationship of CDT and the amount of alcohol consumption or presence of liver disease, whereas the influence of alterations in serum transferrin concentrations on CDT has received less attention. In this study, we compared two different methods for measuring CDT (CDTect and %CDT) and total transferrin concentrations in a sample of 83 alcohol abusers (20 patients with alcoholic liver disease and 63 heavy drinkers who were devoid of liver disease, despite excessive alcohol consumption) and 89 controls, who were social drinkers or abstainers. The control population included 53 hospitalized patients with expected abnormalities in serum transferrin concentrations caused by conditions such as negative iron balance, pregnancy, or nonalcoholic liver disease. Both methods gave significantly higher values in alcohol abusers than in controls (p < 0.01), but the overall sensitivity for detecting alcohol abuse was clearly higher for CDTect (59%) than for %CDT (34%). The correlation between the results obtained by the two methods (r = 0.629) significantly improved, when the CDTect values were replaced by the ratio of CDTect/total transferrin (r = 0.770) (p < 0.05). There was a positive correlation between the CDTect and serum transferrin (r = 0.201, p < 0.01), which was significant both in the alcoholics (r = 0.240, p < 0.05), and especially in the controls (r = 0.727, p < 0.001). A significant inverse correlation emerged between %CDT and total transferrin (r = -0.302, p < 0.01). The sensitivities of CDTect and %CDT for correctly classifying alcohol abusers in the subgroup of alcoholic liver disease patients were 90% and 70% and in the subgroup of heavy drinkers without liver disease (49% and 22%), respectively. Specificities for CDTect and %CDT in this sample were 81% and 100%, respectively. However, in the subgroup of hospitalized control patients with abnormal serum transferrin, the specificity of CDTect was only 48%. According to present data, CDTect seems to be more sensitive than %CDT for detecting alcohol abuse. However, any alteration in serum total transferrin concentration markedly decreases the assay specificity. This should be considered when interpreting the assay results in patients with elevated serum transferrin, such as iron deficiency, pregnancy, or liver diseases.

Carbohydrate‐deficient transferrin (CDT) measurements have been widely examined as a marker of excessive alcohol consumption, yet the information on the sensitivity of this method has remained controversial. In addition, little is known of the relationship of this marker and the severity of alcoholic liver disease (ALD). To clarify these Issues, we analyzed serum samples from 373 alcohol abusers, including 200 problem drinkers with no apparent liver pathology, 173 patients with clinical or morphological evidence of ALD, and 42 healthy controls. CDT was analyzed by anion‐exchange chromatography followed by radioimmunoassay. At a specificity of 100%, the sensitivity of CDT was 36% in problem drinkers reporting a mean of 710 ± 80 (mean ± 2SE) g of ethanol/week, as compared with the sensitivities of 44% and 35% for γ‐glutamyltranspeptidase (GGT) and mean corpuscular volume (MCV), respectively. In a subgroup of problem drinkers (n= 51) with the highest ethanol intakes (1160 ± 180 g of ethanol/week) and severe dependence, the sensitivity of CDT increased to 64%, compared with 55% for GGT and 39% for MCV. In ALD, the CDT values were significantly higher than in the alcoholics with nonliver pathology. However, when such patients were classified according to the clinical, laboratory, and morphological severity of liver disease, CDT was found to be primarily elevated in those with the early stage of ALD, such that there was a significant negative correlation between CDT and the combined morphological index of disease severity (rs= ‐0.315, p < 0.05). ALD markers of fibrogenesis were elevated more frequently than CDT, showing significant positive correlations with the indices of disease severity. Current data indicates that, although CDT concentration correlates with the amount of alcohol consumed, it lacks diagnostic sensitivity in alcohol abusers consuming < 100 g of alcohol per day, thus hampering its use as a screen for consumption in community samples. The finding that CDT is increased in an early phase of ALD may prove to be of diagnostic value.

We assessed the relationship of serum type I collagen propeptide concentrations with various severity indices of alcoholic liver disease, including clinical and morphological severity, the amount of alcohol consumption, and the serum levels of other components of connective tissue. The serum concentration of the carboxyterminal propeptide of type I procollagen (PICP) was measured with a new radioimmunoassay that is devoid of a crossreaction caused by type III procollagen-derived fragments. A significant correlation was found between serum PICP and the Combined Clinical and Laboratory Index (CCLI) (rs = 0.58, p < 0.001) and the Combined Morphological Index (CMI) (rs = 0.57, p < 0.01). However, PICP was elevated less frequently than serum type III collagen propeptide (PIIINP), type IV collagen or laminin, and the correlations with the latter three parameter with both the CCLI (PIIINP: rs = 0.80, type IV collagen: rs = 0.80; and laminin: rs = 0.81) or CMI (PIIINP: rs = 0.75, type IV collagen: rs = 0.72; and laminin rs = 0.61) were all stronger than that of PICP. Furthermore, although during a follow-up period of 6 months, the mild or moderately drinking patients had a significant decrease in PIIINP and the heavily drinking patients had no improvement. PICP was, however, found to improve in both the mild and heavy drinkers. These results point to differences in handling of type I and type III collagen propeptides in alcoholic liver disease. The latter appears to be a more sensitive indicator of disease severity, presence of alcoholic hepatitis, and the amount of alcohol intake.

We have examined the relationship between blood markers of fibrogenesis and basement membrane formation and alcohol intake in patients with a wide range of clinical and histological severity of alcoholic liver disease (Niemelä et al., 1990). While the patients with a mean of less than 8 mM alcohol in morning urines (mild or moderate drinkers) had a significant (p < 0.00001) decrease in serum aminoterminal propeptide of type III procollagen, type IV collagen and laminin in a period of 27 +/- 1 weeks, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. There was also a significant decrease in serum gamma glutamyl transferase activity in the group with lower, but not in that with the higher urinary alcohol concentrations. The Combined Clinical and Laboratory Index (CCLI) decreased in both groups, although the recovery was significantly (p < 0.03) greater in those with the lower urinary alcohol levels (66% +/- 6%) than in the group with a urinary alcohol level of > or = 8 mM (28% +/- 15%). We suggest that connective tissue metabolism in alcoholic liver disease is closely related to alcohol intake and thus affects the prognosis of the alcoholic patient.

This study investigated the relationships of the serum markers of fibrogenesis and basement membrane formation to the clinical and morphological severity of alcoholic liver disease and to the degree of alcohol abuse. The concentrations of the aminoterminal propeptide of type III collagen, type IV collagen, and laminin were measured from 87 samples representing a wide range of clinical and histological severities of the disease, which were assessed with indices that have been shown to correlate well with the risk of dying within 1 yr. Significant correlations (p less than 0.00001) were found between the markers of connective tissue metabolism and the Combined Clinical and Laboratory Index: (aminoterminal propeptide of type III collagen, rs = 0.82; type IV collagen, rs = 0.82; laminin, rs = 0.81), as well as between these markers and the Combined Morphological Index: (aminoterminal propeptide of type III collagen, rs = 0.70; type IV collagen, rs = 0.68; laminin, rs = 0.64). Whereas the patients with less than 8 mM of alcohol in their morning urine (mild or moderate drinkers) showed a significant (p less than 0.00001) decrease in these markers in a period of 27 +/- 1 wk, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. It is proposed that both fibrogenesis and basement membrane formation are associated with disease severity, degree of alcoholic hepatitis, and alcohol intake, which are important determinants of prognosis in alcoholic liver disease.

In 108 patients with alcoholic liver disease who died during a 10-year follow-up, the diagnoses from the liver biopsies were compared with that from the Death Certificates. Data show that the currently used ICD-9 category of cirrhosis with or without mention of alcohol has a 47.2% chance of missing the diagnosis of cirrhosis. On the other hand when the mention of liver disease in the Death Certificate is used for the diagnosis of cirrhosis, the percentage of undiagnosed cirrhosis decreases to 19.4% (p less than 0.0001).

Liver biopsy specimens (178 percutaneous and 39 transjugular) were assessed from 217 consecutive patients with alcoholic liver disease, 77 noncirrhotics and 140 cirrhotics, whose cases were followed for 5 yr. Cirrhotic patients were categorized into two groups, with and without "hepatitis" using a criteria to define "hepatitis" that included only degrees of inflammation, necrosis, and Mallory bodies that had a prognostic weight in terms of mortality in 1 yr. This classification resulted in a sharp separation between a group of 42 patients with cirrhosis without "hepatitis" and with low mortality, both at 1 yr (7.1% +/- 4.0%) and at 5 yr (31% +/- 7%), and another group of 98 patients with cirrhosis and "hepatitis" and a high mortality both at 1 yr (26.5% +/- 4.5%, p less than 0.01), and at 5 yr (47% +/- 5%, p less than 0.02). Importantly, the 1-yr mortality in patients with cirrhosis and no "hepatitis" was not statistically different from that of patients with no cirrhosis or "hepatitis" (most of whom had only fatty liver) both at 1 yr (6.9% +/- 3.3%) and at 5 yr (24% +/- 6%). There were marked differences in several variables between cirrhosis with and without "hepatitis" [combined clinical and laboratory index: no "hepatitis": 4.9 +/- 0.7, with "hepatitis": 7.8 +/- 0.5, p less than 0.01; score of collagen in space of Disse: no "hepatitis": 2.1 +/- 0.4, with "hepatitis": 3.7 +/- 0.3, p less than 0.01; hepatocyte cross-sectional surface area: no "hepatitis": 682 +/- 51 micron 2, with "hepatitis": 841 +/- 31 micron 2, p less than 0.01]. These findings were more severe in the transjugular group than in the percutaneous group. Collagen in the space of Disse and hepatocyte surface area were not statistically different when cirrhosis without "hepatitis" was compared with a similar no "hepatitis" group of patients having noncirrhotic alcoholic liver disease. In this patient sample the presence of parenchymal nodules and fibrous septa, per se, did not result in an increase in mortality with respect to alcoholic patients without cirrhosis and with no "hepatitis."

Propylthiouracil has been shown experimentally to protect against alcohol-induced hepatocellular necrosis in hypoxic conditions. An earlier, short-term study of patients with alcoholism and liver disease indicated clinical improvement with propylthiouracil, but the effect on mortality could not be assessed. In the present study, we investigated the effect of propylthiouracil on mortality in patients with alcoholic liver disease in a long-term, double-blind, randomized clinical trial involving 310 compliant patients who received propylthiouracil (n = 157) or placebo (n = 153) for a maximum of two years. There were no differences between the two groups in demographic and clinical characteristics and biopsy-confirmed diagnoses at randomization, or in daily urinary alcohol levels during the study. The cumulative dropout rate over two years was not significantly different (propylthiouracil group, 0.68; placebo group, 0.60). The group receiving propylthiouracil (300 mg per day) had a cumulative mortality rate half that in the group receiving placebo (0.13 vs. 0.25 [P less than 0.05] in the total sample, and 0.25 vs. 0.55 [P less than 0.03] in a subgroup of severely ill patients [propylthiouracil group, n = 56; placebo group, n = 41]). Proportional-hazards stepwise regression analyses indicated that only propylthiouracil treatment, prothrombin time, hemoglobin levels, and mean daily urinary alcohol levels significantly affected mortality. The hazards ratio for the complete group indicated that mortality in the propylthiouracil group was 0.38 (95 percent confidence interval, 0.20 to 0.83) that of the placebo group. Protection by propylthiouracil was not observed in patients with high morning urinary alcohol levels. No clinically important side effects of propylthiouracil were observed at the dose used. We conclude that the administration of propylthiouracil can reduce mortality due to alcoholic liver disease.