Alcoholic liver disease (ALD) is the most common liver disease in the Western world. For many reasons, it is underestimated and underdiagnosed. An early diagnosis is absolutely essential since it (1) helps to identify patients at genetic risk for ALD; (2) can trigger efficient abstinence namely in non-addicted patients; and (3) initiate screening programs to prevent life-threatening complications such as bleeding from varices, spontaneous bacterial peritonitis or hepatocellular cancer. The two major end points of ALD are alcoholic liver cirrhosis and the rare and clinically-defined alcoholic hepatitis (AH). The prediction and early diagnosis of both entities is still insufficiently solved and usually relies on a combination of laboratory, clinical and imaging findings. It is not widely conceived that conventional screening tools for ALD such as ultrasound imaging or routine laboratory testing can easily overlook ca. 40% of manifest alcoholic liver cirrhosis. Non-invasive methods such as transient elastography (Fibroscan), acoustic radiation force impulse imaging or shear wave elastography have significantly improved the early diagnosis of alcoholic cirrhosis. Present algorithms allow either the exclusion or the exact definition of advanced fibrosis stages in ca. 95% of patients. The correct interpretation of liver stiffness requires a timely abdominal ultrasound and actual transaminase levels. Other non-invasive methods such as controlled attenuation parameter, serum levels of M30 or M65, susceptometry or breath tests are under current evaluation to assess the degree of steatosis, apoptosis and iron overload in these patients. Liver biopsy still remains an important option to rule out comorbidities and to confirm the prognosis namely for patients with AH.

Associations between occupational styrene exposures and impairment of visual functions were investigated with a view to answering three questions: (1) are the published findings for colour vision deficiencies and impaired contrast sensitivity to reproduce in a new study approach, (2) if such effects exist, are they related to current or chronic exposures and (3) if effects exist, are there reductions in the effects during an exposure-free period?

Workers from a boat building plant were examined in groups of current low [n = 97, mean mandelic acid (MA) + phenylglyoxylic acid (PGA) = 51 mg/g creatinine], medium (n = 115, mean = 229 mg/g creatinine) and high (n = 30, mean = 977 mg/g creatinine) level exposure to styrene. Job tenure was about 6 years. In addition, subgroups chronically exposed to low-short (n = 34, lifetime weighted mean 200 mg/g creatinine for 6 years) and high-long (n = 17, mean = 660 mg/g creatinine, 15 years) styrene levels were analysed. The examinations were carried out during normal working days and during the company holidays. Colour vision was investigated with the Lanthony desaturated panel D-15d using the colour confusion index (CCI) as a relevant variable. Contrast sensitivity was investigated with the Vistech charts VCTS 6500 using frequency-related results as well as total scores as variables. Co-variance analyses with repeated measurements and multiple linear regressions were used for statistical analysis.

There was no evidence of significant associations between exposure parameters and CCI. This is true for the analyses with all participants as well as for those with the subgroups with high-long versus low-short exposure. Thus, no exposure related changes in the relevant variables were found during the exposure-free period. The analyses for contrast sensitivity show similar results. The largest portions of the variances in both tests were explained by age. German as mother tongue covered a considerable portion of the CCI variances. Education, long-term alcohol use and job tenure explain only partly significant portions of the test variances exhibited.

Both acute styrene exposure levels of 40 ppm (range of standard deviation up to 54 ppm) and long term exposures to 27 ppm (range of standard deviation up to 44 ppm with higher exposure levels in the past) for a period of about 15 years were not identified as causing elevated risks for the investigated parameters of colour vision and contrast sensitivity. This statement contradicts the published results for styrene-related colour vision deficiencies but it seems to be compatible with published results for contrast sensitivity due to styrene exposure.

Associations between occupational styrene exposure and impairment of hearing function were investigated, guided by three questions: are there hearing losses concerning high frequency and standard audiometric test? Are there dose-response relationships and measurable thresholds of effects? Are there signs of reversibility of possible effects if the workers are examined during times of improvement from their work?

A group of workers from a boat building plant, some of whom were laminators, were examined in subgroups of current low (n = 99, mean mandelic acid MA + phenylglyoxylic acid PGA = 51 mg/g creatinine), medium (n = 118, mean 229 mg/g creat.) and high (n = 31, mean 970 mg/g creat.) exposure to styrene. In addition, subgroups chronically exposed to high-long (n = 17) and low-short (n = 34) styrene levels were analysed. The examinations were carried out during normal work days and during the company holidays. Hearing thresholds and transient evoked otoacoustic emissions (TEOAE) were measured. Statistics included multiple co-variance analyses with repeated measures, linear regressions, and logistic regressions.

The analyses of all participants demonstrated no clear exposure effects. Particularly no sufficient proof of dose-response relationship measured against parameters of current exposure (MA + PGA, styrene/blood) and of chronic exposure (cumulative and average life time exposure resp.) was found. The analyses of groups exposed to high levels show elevated thresholds at frequencies up to 1,500 Hz among the subgroup exposed to high styrene levels (e.g. 40-50 ppm as average) for a longer period of time (e.g. more than 10 years). These participants also demonstrated signs of "improvement" at frequencies above 2,000 Hz during work holidays, when they were not exposed to styrene. A significantly elevated odds ratio for cases of hearing loss (more than 25 dB (A) in one ear, 3,000-6,000 Hz) was found among the group exposed to high levels (above 30 ppm as average) for a longer period of time (more than 10-26 years). The measurements of TEOAE did not exhibit significant results related to exposure.

This study found, that chronic and intensive styrene exposure increases the hearing thresholds. At levels of about 30-50 ppm as an average inhaled styrene per work day over a period of about 15 years with higher exposure levels above 50 ppm in the past, an elevated risk for impaired hearing thresholds can be expected. The formerly published results on ototoxic effects below 20 ppm could not be confirmed. With few exceptions (at frequencies of 1,000 and 1,500 Hz) no dose-response relationship between threshold and exposure data was found. Improvements of hearing thresholds during work- and exposure-free period are possible.

Data of a follow up study with four examinations were summarized by odds ratio statistics in order to scrutinize the results of the earlier studies with cross sectional approaches. For a "high"- (n=106) and a "low"-exposed group (references, n=86) current toluene exposures of 26ppm versus 3ppm and lifetime weighted average exposures of 45ppm versus 9ppm were ascertained. As measures of sensory functions vibration thresholds, colour discrimination, and auditory thresholds were used. Measures of psychological performances were attention (symbol-digit substitution, switching attention, simple reaction), memory (digit span forward, delayed reproduction of pictures), and psychomotor functions (steadiness, line tracing, aiming, tapping, peg board). Additionally, the frequency of diseases and symptoms were ascertained. By odds ratio statistics including relevant cofactors no significant increase of "cases with impaired functions" among the high-exposed workers was found. Evidence for neurobehavioral effects due to long-term toluene exposure below 50ppm was not established.

Carbohydrate-deficient transferrin (CDT) is a biomarker for chronic alcohol intake of more than 60 g ethanol/d. It has been reported to be superior to conventional markers like gamma-glutamyltransferase (GGT) and mean corpuscular volume MCV). This review covers theoretical and analytical aspects, with data from controlled drinking experiments and from different population subgroups such as subjects with different liver diseases or different drinking patterns. CDT determinations are particularly indicated in (1) cases of chronic alcohol consumption and relapses after withdrawal, (2) license reapplication after driving under alcohol influence, (3) differentiating patients with enzyme-inducing medication from those with alcohol abuse, 4) congenital disorders of glycosylation such as carbohydrate-deficient glycoprotein syndrome Ia (CDGS Ia), and (5) patients treated for galactosemia. The main advantage of CDT is its high specificity, as evidenced in combination with increased alcohol consumption. CDT values are not markedly influenced by medication except in immunosuppressed patients, who may show low CDT values. In general, CDT values appear less elevated after alcohol intake in women. The main disadvantage is the relatively low sensitivity. Hence, this parameter is not suitable for screening for subjects with alcohol abuse in the general population. As CDT, GGT, and MCV are connected with chronic alcohol consumption by different pathophysiological mechanisms, a combination of these parameters will further improve the diagnostic value.

Potential effects of human occupational exposures to toluene on colour vision were investigated in a follow-up study over 4 years with three repeated examinations. Colour vision was measured with the Lanthony desaturated colour vision test D-15d, and the colour confusion index (CCI) was calculated. The mean current exposures were 26+/-21 ppm for printers (high toluene level) and 3+/-4 ppm for end-processors (low toluene level). The mean exposure durations were 23+/-6 years for "long-time exposed" and 7+/-2 years for "short-time exposed" subjects. Repeated analyses (n=162) and multiple regressions (maximum available n=267) did not reveal significant effects of toluene with respect to intensity or duration of current or long-term exposure. Age and occupational qualification were significantly associated with CCI in both kinds of analysis, whereas alcohol consumption (carbohydrate-deficient transferrin, CDT) and smoking habits (cigarettes per day) were not. It is concluded that current industrial exposure limits of toluene provide sufficient protection against possible disturbance of colour vision.

This is a systematic review of the studies in which carbohydrate-deficient transferrin (CDT) has been compared to other laboratory markers in different experimental conditions, clinical settings, and populations. Only the studies (n = 54) in which CDT was compared either to the conventional or new biological markers of alcoholism, heavy drinking, or alcohol use were selected for further evaluation. Two prospective studies indicate that in men CDT is slightly more sensitive than gamma-GT in reflecting changes in these markers caused by drinking of a moderate and fixed amount of alcohol during three to four weeks. In one prospective study, in which the drinking history of male heavy drinking volunteers was as close the golden standard as possible; that is, obtained by a prospective anonymous drinking diary, CDT was slightly but not significantly better marker than conventional laboratory markers (ASAT, ALAT, gamma-GT and beta-Hex) in the identification of men drinking more than 400 g of alcohol daily. Similar prospective studies concerning women have not been done. Six prospective treatment outcome studies indicate that CDT may be a significantly more sensitive marker than gamma-glutamyltransferase (gamma-GT) in the detection of relapses in male alcoholics. However, these two tests can also be considered to be complementary markers. Furthermore, in the detection of relapses the baseline values of CDT and gamma-GT should be measured and compared on individual basis to the pretreatment values. Comparable data are not available from female alcoholics. In selective materials comprising male alcoholics and heavy drinkers, CDT was found to be a slightly more sensitive marker than gamma-GT in seven retrospective studies. In five studies, gamma-GT was slightly better. However, the differences between CDT and gamma-GT in general were not statistically significant. In three studies, the combined use of CDT and gamma-GT improved the sensitivity but with the expense of specificity. Only four studies included women and in three of these the sensitivity of gamma-GT was better than that of CDT, whereas in one study CDT was better than gamma-GT in the detection of female heavy drinkers. Seven studies performed in primary health care settings and among young populations demonstrate that the performance of CDT in the identification of heavy and problem drinkers in this type of populations is very low, although comparable to the poor performance of the conventional laboratory markers, too. According to seven studies, the sensitivity of gamma-GT is slightly better than that of CDT in the identification of excessive alcohol consumption among hospitalized male and female patients. However, in this type of hospital setting, the specificity of CDT is markedly higher than that of gamma-GT. There is some evidence indicating that the performance of the tests can be improved with the combined use of both tests. Eight studies indicate that both in men and women CDT is a better marker than gamma-GT in the identification of alcohol abuse among patients with alcoholic and nonalcoholic liver diseases. This is mostly due to the higher specificity of CDT as compared to that of gamma-GT.

The role of carbohydrate-deficient transferrin (CDT) as a reliable marker for the detection of chronic alcohol abuse has been discussed controversially.

Therefore, we investigated CDT in the sera from 405 subjects with different alcohol intake. Besides healthy control subjects (n = 42), inpatients and outpatients in a department of gastroenterology (n = 325) and patients admitted to a department of otorhinolaryngology (n = 38) were studied. A total of 213 patients suffered from various forms of liver diseases, and 89 patients had liver transplantation. CDT values were determined by a double-antibody radioimmunoassay.

In the 241 alcohol-abstinent subjects, CDT levels ranged from 3 to 90 units L-1 (median = 12); the 92 moderate drinkers (20-60 g of alcohol per day) showed values from 3 to 40 units L-1 (median = 12), and the 72 subjects with chronic alcohol abuse (> 60 g per day) revealed CDT levels from 3 to 100 units L-1 (median = 16). The diagnostic specificity for alcohol abuse was 86.8% for men (sensitivity 36.9%) and 95% for women (sensitivity 0%).

Our data indicate that measurement of CDT does not reach clinical use in the detection of chronic alcohol abuse in an unselected population because of its insufficient specificity and sensitivity.

The determination of carbohydrate-deficient transferrin (CDT) in serum has been found useful as a marker of increased alcohol consumption of > 60 g/day. It is not clear why the reference range is different for women (0 to 26 units/liter) and men (0 to 20 units/liter). We evaluated serum CDT in 286 healthy subjects (209 women, 77 men) using a commercially available radioimmunoassay. Premenopausal women had higher CDT levels than postmenopausal women, whereas no age-related difference of CDT levels was found in men. In postmenopausal women, higher CDT levels were associated with estrogen replacement therapy. In premenopausal women, however, neither the phase of the menstrual cycle nor contraceptive steroid use showed a significant association with the increase in CDT levels. No significant correlations were found between CDT and either serum estradiol or serum iron. In conclusion, both premenopausal state and postmenopausal estrogen replacement therapy seem to increase serum levels of CDT. Therefore, menopausal status and exogenous estrogens should be considered when interpreting CDT values in women.

Glycoconjugates play important roles in biological reactions (for example sialyl Lewis(x) in 'homing' of leukocytes and mannose-6-phosphate in targeting of lysosomal enzymes) and thus aberration in carbohydrate structures in glycoconjugates can lead to abnormal biological behaviors. In fact, glycoconjugates expressed on the surfaces of tumor and cancer cells are considerably different from those of the normal cells, at least quantitatively. There are many known carbohydrate-deficient glycoprotein syndromes. As recognition of carbohydrate groups is mostly performed by carbohydrate-binding proteins, aberration in these proteins also results in disease status (for example I-cell disease). Many pathogens use carbohydrates as recognition markers for invasion (examples are influenza virus and cholera toxin). The carbohydrate receptors in various organs can be used for targeting drugs, antibodies and even DNAs. Conjugation of polysaccharides derived from pathogenic micro-organisms with appropriate proteins provides effective vaccines against the micro-organisms. Copyright 1996 S. Karger AG, Basel