Caspase-cleaved keratin-18 fragments increase during alcohol withdrawal and predict liver-related death in patients with alcoholic liver disease.

Noninvasive assessment of disease activity in patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is still unsettled, but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase-cleaved (M30) serum keratin-18 fragments (n = 204) with histological parameters (n = 106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age-, sex-, and fibrosis-stage matched NAFLD cohort (n = 30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed-up cohort of 230 patients with alcoholic cirrhosis (AC) using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage, such as ballooning (r = 0.65; P < 0.001), followed by lobular inflammation (0.48; P < 0.001), steatosis (0.46; P < 0.001), but less with fibrosis (0.24; P < 0.001). Area under the receiver operating characteristics curves to detect ballooning, steatosis, or steatohepatitis (SH) were slightly better for M30 (P < 0.005). Optimal M30 cut-off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for SH grades 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to aspartate-amino-transferase and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non-hepatocellular carcinoma liver-related mortality in patients with AC during a mean observation interval of 67.2 months. CONCLUSION: Our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis, as determined by M30 levels, occurs during alcohol withdrawal, and survival data point toward a novel underestimated role of apoptosis in patients with ALD. (Hepatology 2017;66:96-107).

Clinical predictors for delirium tremens in patients with alcohol withdrawal seizures.

BACKGROUND: Delirium tremens (DT) is the severest form of alcohol withdrawal syndrome, frequently after alcohol withdrawal seizures. Delirium tremens occurs in a small proportion of patients with alcohol withdrawal seizures; nevertheless, early identification of high-risk patients is important for intensive preventive management of unexpected episodes due to agitation and its associated increased mortality. However, there are limited studies on clinical predictors of the development of DT in patients with alcohol withdrawal seizures. METHODS: Patients who visited the emergency department with acute seizures were included in the study when alcohol withdrawal was the only or the strongest precipitating factor for seizures. All patients were carefully observed for at least 48 hours in the intensive care unit after the initial assessment to closely monitor vital signs and development of DT. Clinical and laboratory findings were analyzed for predicting the development of DT. RESULTS: Of the 97 patients (82 males; mean age, 48.6 ± 13.3 years) with alcohol withdrawal seizures, 34 (35.1%) developed DT. Low platelet count, high blood level of homocysteine, and low blood level of pyridoxine were associated with the subsequent development of DT. Low platelet count and high blood level of homocysteine were independent risk factors with high diagnostic sensitivity and specificity for the development of DT. CONCLUSIONS: The study indicated that some easily determined parameters are potential clinical predictors for the development of DT in patients with alcohol withdrawal seizures. These findings would be helpful in clinical identification and management patients at high risk for DT.

Influence of microelement concentration on the intensity of alcohol withdrawal syndrome.

AIMS: To establish a nutritional and constitutional profile concerning the micronutrient plasma concentration of patients who suffer from AWS. METHOD: Observational case control study to determine whether patients who exhibited symptoms of AWS (N = 60) had micronutrient plasmatic concentration deficiencies when compared with healthy controls (N = 34). RESULTS: There were statistically significant differences between the concentrations of nutrients that are correlated with glutamate hyperactivity (zinc, magnesium and folate/vitamin B12/homocysteine). CONCLUSION: Evidence from literature and our experiment suggests that brain activity, especially the glutamatergic system, might be directly involved in micronutrient concentrations. Therefore, their supplementation to the AWS patient might improve symptom evolution.

Comparison of oxidative DNA damage between alcohol-dependent patients with and without delirium tremens.

BACKGROUND: Chronic and excessive alcohol consumption increases oxidative stress. We previously found that levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, are elevated in alcohol-dependent patients without delirium tremens (DTs). The aim of this study was to compare serum 8-OHdG levels between alcohol-dependent patients with and without DTs. METHODS: We recruited 16 alcohol-dependent patients with DTs (DTs group) and 58 patients without DTs (non-DTs group). Alcohol withdrawal severity was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Serum levels of 8-OHdG and other biological indices were assayed at baseline and after 1 week of detoxification. RESULTS: The mean 8-OHdG level in the DTs group was significantly higher than that in the non-DTs group (0.50 vs. 0.34 ng/ml, p < 0.001). A significant correlation was found between the highest CIWA-Ar-C scores and serum 8-OHdG levels (ß = 0.43, p = 0.001) in the non-DTs group, but not in the DTs group (ß = 0.34, p = 0.19). An area under receiver operating characteristic curve of 0.83 suggests that 8-OHdG levels potentially differentiate patients with DTs from those without DTs. After dividing the patients into quartiles by 8-OHdG level, we found that compared to the patients in the third and fourth quartiles, the patients in the highest quartile had an odds ratio of 24.1 (p < 0.001) to have DTs, while those in the second highest quartile had an odds ratio of 3.5 (p = 0.19). Serum 8-OHdG levels did not significantly change after 1 week of detoxification in either group. CONCLUSIONS: Alcohol-dependent patients with DTs have higher serum 8-OHdG levels than those without DTs, suggesting that higher oxidative stress carries a greater risk of the occurrence of DTs.

Predictors of severe alcohol withdrawal syndrome: a systematic review and meta-analysis.

BACKGROUND: Severity of alcohol withdrawal syndrome (AWS) is associated with hospital mortality and length of stay. However, as there is no consensus regarding how to predict the development of severe alcohol withdrawal syndrome (SAWS), we sought to determine independent predictors of SAWS. METHODS: We conducted a systematic review and meta-analysis of studies evaluating hospitalized patients with AWS versus SAWS-delirium tremens (DT) and/or seizures. Random-effects meta-analysis [PRISMA guidelines] was performed on common baseline variables and predictive effects for development of SAWS were calculated using RevMan v5.2. Funnel plots were constructed, and tests of heterogeneity were performed. RESULTS: Of 226 studies screened, 17 met criteria and 15 were included in the meta-analysis. The primary findings were that an incident occurrence of DT or alcohol withdrawal seizures was significantly predicted by history of a similar event (OR 2.58 for DT vs. no-DT, 95% CI 1.41, 4.7; OR 2.8 for seizure vs. no-seizure, 95% CI 1.09, 7.19). Both a lower initial platelet count and serum potassium level were predictive of an incident occurrence of DT (platelet count mean difference [MD] -45.64/mm(3) vs. no-DT, 95% CI -75.95, -15.33; potassium level MD -0.26 mEq/l vs. no-DT, 95% CI -0.45, -0.08), seizures, and SAWS. Higher initial alanine aminotransferase was seen in patients with SAWS (MD 20.97 U/l vs. no-SAWS, 95% CI 0.89, 41.05). Higher initial serum gamma-glutamyl transpeptidase was seen in patients with incident alcohol withdrawal seizures (MD 202.56 U/l vs. no-seizure, 95% CI 3.62, 401.5). Significant heterogeneity was observed, and there was evidence of publication bias. Notably, neither gender nor comorbid liver disease was predictive. CONCLUSIONS: The course of prior episodes of AWS is the most reliable predictor of subsequent episodes. Thrombocytopenia and hypokalemia also correlate with SAWS. We propose further research into drinking patterns, gender, and medical comorbidities.

Differential patterns of serum brain-derived neurotrophic factor levels in alcoholic patients with and without delirium tremens during acute withdrawal.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with alcohol addiction and withdrawal-related neurotoxicity. Delirium tremens (DT) is the most serious complication of alcohol withdrawal syndrome (AWS). In this study, we explored the differences in serum BDNF levels, measured at baseline and 1 week after alcohol withdrawal among alcoholic patients with and without DT. METHODS: Sixty-five inpatients, fulfilling the DSM-IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were divided by the appearance of DTs into the DT group (n = 25) and non-DT group (n = 40). We collected blood samples of the patient groups on the first and seventh days of alcohol withdrawal and measured serum BDNF levels by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum BDNF levels differed significantly among the three groups: (i) control group 14.8 ± 4.7 ng/ml; (ii) non-DT group 12.3 ± 3.3 ng/ml; (iii) DT group 6.2 ± 2.6 ng/ml (p < 0.001). One week after alcohol withdrawal, the BDNF levels increased significantly for both alcoholic groups. While non-DT group had comparable BDNF levels (13.4 ± 3.5 ng/ml) with controls, the DT group still exhibited lower levels (8.9 ± 4.4 ng/ml). CONCLUSIONS: This study suggests chronic drinking leads to a reduction in BDNF levels, and patients with more deficient BDNF expression are vulnerable to the development of DTs. Additionally, BDNF levels elevated after prompt alcohol detoxification treatment. These findings indicate that BDNF could involve modifying the phenotypes of AWS as well as the pertinent neuroadaptive processes of alcohol dependence.

Serum levels of vascular endothelial growth factor A increase during alcohol withdrawal.

Vascular endothelial growth factor A (VEGF-A) is a key regulator of angiogenesis. This study investigated VEGF-A serum levels during alcohol withdrawal (days 1, 7 and 14, 76 male patients, 38 healthy controls). Patients showed significantly higher VEGF-A serum levels (t = 2.620, P = 0.010), which increased significantly during withdrawal (F = 4.484, P = 0.014, mean difference = -36.835, P = 0.037). The increase of VEGF-A serum levels was significantly associated with initial breath alcohol concentration and the sumscore of the severity scale of alcohol dependence (SESA questionnaire, F = 5.252, P = 0.008). Increase of VEGF-A serum levels is closely associated to alcohol intoxication and severity of alcohol dependence.

Two routine blood tests-mean corpuscular volume and aspartate aminotransferase-as predictors of delirium tremens in trauma patients.

BACKGROUND: Delirium tremens (DT) in trauma patients is associated with significant morbidity and mortality. Short interview tools have been used to determine the risk of DT but require an alert, compliant patient and a motivated physician. The mean corpuscular volume (MCV) and aspartate aminotransferase (AST) levels are parts of routine laboratory testing, influenced by excessive alcohol consumption, and may serve as predictors of DT. This study examines the predictive ability of these two readily available biological markers. METHODS: The records of 423 consecutive trauma patients who presented to a Level I trauma center with a positive toxicology screen for alcohol were reviewed. The outcome variable was DT, as defined by the presence of tremor, diaphoresis, autonomic instability, and hallucinations. The positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio (LR) of the admission MCV and AST values were calculated for the prediction of DT. RESULTS: Of the 336 patients who met the criteria for study participation, 110 were diagnosed with DT due to alcohol withdrawal. When the admission MCV and AST were normal, only 3 patients (3.8%) developed DT. The NPV, PPV, and LR with two normal values together were 58.2%, 3.8%, and 0.080, respectively. When both were abnormal, 72 patients (64.3%) developed DT. The NPV, PPV, and LR with two abnormal values together were 83%, 64.3%, and 3.698, respectively. CONCLUSION: Normal admission MCV and AST values in intoxicated trauma patients nearly exclude the development of DT.

Serum creatine kinase activity differentiates alcohol syndromes of dependence, withdrawal and delirium tremens.

Previous reports described significant differences in serum creatine kinase (CK) activity in bipolar disorder and various forms of depression. The comorbidity of depression and alcohol syndromes was also widely described. We aim to examine potential differences in serum CK level in different alcohol-related syndromes. We assessed morning serum CK activity in 114 inpatients, diagnosed by the Structured Clinical Interview for DSM-IV: Fifty-five subjects with alcohol dependence, 28 with alcohol withdrawal and 31 with delirium tremens (DT's). We found low normal CK activity for the alcohol dependence, higher for alcohol withdrawal and the highest for DT's. Peripheral CK activity of four patients that were admitted during each of the three phases showed similar pattern. These findings may be related to enhanced dopamine activity in alcohol dependence and conversely, to a significant decrease in dopamine activity during withdrawal syndromes. We suggest a supplementary simple laboratory tool for the detection of alcohol-related states.

Nerve growth factor in serum is a marker of the stage of alcohol disease.

Long-term alcohol abuse has deleterious effects on the peripheral and central nervous system. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein involved in development, maintenance of function and regeneration of nerve cells. We examined patients in different stages of alcohol disease and measured their NGF serum concentrations based on the hypothesis that these reflect the state of disease. We examined 57 patients suffering from alcohol-dependence for more than 2 years (DSM IV) on day 8 of a qualified withdrawal, 18 patients with Korsakoff's syndrome and 40 healthy controls. In addition to clinical examination, careful history taking and a standard neuropsychological test battery, serum NGF concentrations were measured by a highly sensitive enzyme-immunoassay. Of the 57 patients 9 had suffered from severe withdrawal delirium in the past, other clinical parameters were alike. Cognitive test performance did not differ from the control group. Mean NGF levels of controls amounted to 42.1pg/ml (S.D. 68.0); mean levels of patients with alcohol dependence were raised significantly to 401.5pg/ml (S.D. 932.6) without delirium in the past and even further to 3292.5pg/ml (S.D. 4879.6) with former withdrawal delirium. By contrast, patients with persistent amnestic disorder (Korsakoff's syndrome) showed values identical to the controls. NGF serum levels were significantly elevated in alcohol-dependent patients, more so in those with prior delirium. Their cognitive tests being normal, this possibly reflects the activity of NGF as an endogenous repair mechanism for damaged neurons. In accordance with this hypothesis, NGF values are "normal" in patients with persistent alcohol-related cognitive decline.

Alteration of prolactin serum levels during alcohol withdrawal correlates with craving in female patients.

Dopaminergic transmission has been suggested to be a main mechanism mediating reinforcement, withdrawal and craving in alcohol dependency. Dopamine is associated with prolactin secretion, acting as a prolactin inhibitor. The aim of the present study was to investigate whether there is an association between altered prolactin levels and craving during early and late alcohol withdrawal. Therefore, we examined 145 patients suffering from alcohol dependency after admission to the detoxification unit, assessing craving with the Obsessive Compulsive Drinking Scale (OCDS) and measuring prolactin serum levels during early withdrawal (-EW: day 0 or day 1) and late withdrawal (-LW: day 7-day 10). We observed a significant influence of the alteration of prolactin during withdrawal on craving in female patients (Spearman's rho, OCDS-EW: r=-0.607, p=0.001; OCDS-LW: r=-0.730, p<0.001; n=26). The association between prolactin alteration in percentage and craving in females was confirmed with general linear models (OCDS-EW: F=15.819, p=0.001, r(2)=0.530; OCDS-LW: F=17.091, p<0.001, r(2)=0.535). In male patients we did not find any significant results. Our findings support the previously described role of the hypothalamic-pituitary-adrenal (HPA) axis in the neurobiology of alcohol craving and show evidence of an association between increased prolactin serum levels and lower craving during alcohol withdrawal in female patients.

Alcohol withdrawal severity in inbred mouse (Mus musculus) strains.

Male mice (Mus musculus) from 15 standard inbred strains were exposed to a nearly constant concentration of ethanol (EtOH) vapor for 72 hr, averaging 1.59 +/- 0.03 mg EtOH/mL blood at withdrawal. EtOH- and air-exposed groups were tested hourly for handling-induced convulsions for 10 hr and at Hours 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of control values), and by design these differences were independent of strain differences in EtOH metabolism. Correlation of strain mean withdrawal severity with other responses to EtOH supported previously reported genetic relationships of high EtOH withdrawal with low drinking, high conditioned taste aversion, low tolerance to EtOH-induced hypothermia, and high stimulated activity after low-dose EtOH. Also supported were the positive genetic correlations among EtOH, barbiturate, and benzodiazepine withdrawal. Sensitivity of naive mice to several chemical convulsant-induced seizures was also correlated with EtOH withdrawal.

[Hypomagnesemia in patients with chronic alcoholism in the course of alcohol withdrawal syndrome]. / Gipomagniemiia u bol'nykh khronicheskim alkogolizmom vo vremia abstinentnogo sindroma.

AIM: To ascertain hypomagnesemia (HM) rate in patients with chronic alcoholism (CA) with alcohol withdrawal syndrome (AWS); correlation between AWS severity and HM rate. MATERIAL AND METHODS: Mg in plasm was measured at photometry in 129 CA patients treated in Kaunas Mental Hospital. RESULTS: Plasma Mg in CA patients with AWS was reduced (< 0.749 mmol/l), normal (0.750-1.250 mmol/l) or high (> 1.251 mmol/l) in 28.7, 65.1 and 6.2% patients, respectively. HM was diagnosed in 42.3% with a severe, 19.1% with a moderate and 20.0% with weak AWS. CONCLUSION: HM in AWS was registered in 28.7% patients. It occurred significantly more frequently (p < 0.05) in patients with a severe AWS. Pathogenetic mechanisms of HM in AWS are described.

Natriuretic peptides in alcohol withdrawal: central and peripheral mechanisms.

Abrupt cessation of long-term alcohol consumption produces well-defined symptoms called alcohol withdrawal (AW). The exact pathophysiological mechanisms involved in the appearance of AW symptoms and particularly those related to the precipitation of delirium tremens (DT), still await clarification in spite of the fact that the prediction of complicated AW is essential to guarantee that appropriate therapies may be planned in advance. Changes in central nervous system (CNS) glutamate- and GABA-transmission and a role of voltage-operated calcium channels are equally important elements of neuroadaptation to the chronic presence of alcohol. In addition to the CNS regulation, however, changes in peripheral fluid and electrolyte homeostasis may accompany, and are expected to modify the clinical symptoms of AW. In an early phase of acute withdrawal, plasma levels of atrial natriuretic peptide (ANP), plasma renin activity and aldosterone are high. In patients with DT, elevated levels of ANP were observed days before the actual onset of DT. It is concluded that the altered plasma ANP secretion might be associated with, and therefore used as an indicator of the onset of DT. However, ANP is present in and produced by the brain and thus it can be regarded as a neuropeptide. The role of CNS ANP was studied in mice, rendered tolerant to and physically dependent on alcohol. Intracerebroventricular injections of ANP attenuated, whereas those of an antiserum against ANP intensified hyperexcitability during AW. ANP in the brain - the content of which undergoes sensitive changes in the hippocampus during AW appears to interact primarily with glutamate transmission through the NMDA-receptors. This brain structure is of utmost importance for the generation of withdrawal-related hyperexcitability. It is concluded that peripheral secretion of ANP might be a diagnostics indicator, whereas ANP in the CNS might be a modulator of AW.

Plasma homovanillic acid: a significant association with alcoholism is independent of a functional polymorphism of the human catechol-O-methyltransferase gene.

The central dopamine system seems to influence addictive disorders. Plasma homovanillic acid (HVA) is an indicator of central dopaminergic activity. In this study the hypothesis that plasma HVA is associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal was tested. A functional genetic polymorphism of the enzyme catechol-O-methyltransferase (COMT) that participates in converting dopamine into its final metabolite HVA was investigated for an association with alcoholism or DT during alcohol withdrawal. In addition, a relation between the functional polymorphism of COMT and plasma HVA concentrations was studied. Plasma HVA concentrations and COMT genotypes were determined in 142 German alcoholics and 101 German healthy controls. Alcoholic patients were examined after a minimum of 3 weeks after cessation of drinking. Mean plasma HVA concentrations were significantly lower in alcoholic patients compared to healthy controls. A group of alcoholics with a history of DT during alcohol withdrawal (n=62) did not differ significantly in plasma HVA concentrations from alcoholics with a history of only mild withdrawal symptoms (n=67). The functional polymorphism of the human COMT gene was neither significantly associated with the diagnosis of alcoholism or DT during alcohol withdrawal nor with plasma HVA concentrations.

A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function.

BACKGROUND: Norepinephrine and dopamine mediate important aspects of alcoholism and alcohol withdrawal. Dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine. A recent study demonstrated a strong association between variance in plasma DbetaH activity and a novel polymorphism (DBH-1021C-->T) at the structural locus (DBH) encoding DbetaH protein. METHODS: Our study investigated whether the DBH-1021C-->T polymorphism and plasma DbetaH activity were associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal by analyzing 207 German alcoholic and 102 healthy control subjects. We also examined the influence of the polymorphism on enzyme activity. RESULTS: Mean (+SD) plasma DbetaH activity measured in alcoholic subjects abstinent was significantly lower than that observed in control (27.7 + 16.7 vs. 35.6 + 18.8; p =.01). It did not differ between subjects with DT during withdrawal and subjects with mild withdrawal symptoms. The T allele of the DBH-1021C-->T polymorphism was significantly associated with lower plasma DbetaH activity. None of the alleles or genotypes were associated with alcoholism or DT. CONCLUSIONS: The data indicate that the alcoholism-related reduction in plasma DbetaH activity is independent of genotype at DBH-1021C-->T and replicate the finding that DBH-1021C-->T is strongly associated with plasma DbetaH activity in a native Western European population.