Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD. METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD. RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL. DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.

Behavioral responses in people affected by alcohol use disorder and psychiatric comorbidity: correlations with addiction severity.

AIM: In this study, we investigated in people suffering from alcohol use disorder (AUD) with or without dual diagnosis (concomitant psychiatric disability) how they feel their dependence condition. We predicted that AUD people with a dual diagnosis could feel potentiated their addiction. METHODS: Alcohol habits and psychiatric conditions of 183 AUD men and 62 AUD women were measured by using the DSM-5, the severity of alcohol dependence questionnaire (SADQ), the alcohol anamnesis and psychiatric examination by the symptom check list 90-R (SCL-90-R). RESULTS: We have shown that alcohol drinking does not correlate with both psychiatric examination and self-reported psychopathology. SADQ shows that severe alcohol dependence correlates with highest psychiatric symptoms and with the levels of alcohol consumption. CONCLUSIONS: This finding suggests that high SADQ scores may represent a tool to early disclose only patients with dual diagnosis. SADQ may provide information to address pharmacological interventions because revealing aspects of the dark side of addiction potentiated by AUD associated psychopathology.

A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption.

Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption. Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves. Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity. Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.

Drop-out, relapse and abstinence in a cohort of alcoholic people under detoxification.

The Obsessive Compulsive Drinking Scale (OCDS) was developed to reflect obsessionality and compulsivity related to craving and drinking behaviour for revealing in the long-term drop-out, abstinence and relapse. This study evaluates the early OCDS predictive value in drop-out, abstinence and relapse of patients suffering from Alcohol Use Disorders (AUD) for discovering an OCDS total score cut-off capable of disclosing patients most at-risk of relapse during the beginning of the therapeutic intervention in the Day-Hospital period. The sample includes 263 AUD patients, with 192 men and 71 women. The OCDS scores were measured during the two-weeks Day Hospital treatment for detoxification and after 30, 60, 90 and 180 days after discharge. We also investigated the association between the all OCDS scores and abstinence and between craving, relapse and drop-out. We found that high values of OCDS during Day Hospital detoxification may predict a lower ability to maintain abstinence with elevated relapsing probabilities. Surprisingly, early dropping-out AUD people had lower OCDS total scores. However, significant differences in OCDS values in dropping-out AUD people were revealed mainly 90 and 180 days after discharge compared to no dropping-out AUD subjects. Craving measured also after 30, 60, 90 and 180 days from discharge in AUD relapsers, with OCDS values comprised between 6 and 10, could indicate a lower ability to continue abstinence. In conclusion, OCDS may be a useful tool to early discriminate AUD people at-risk for relapse and drop-out and for addressing the specialist to adjust both medical treatment and psychological support during crucial moments of patients' treatment and follow-up.

Treatment of alcohol dependence. Alcohol and homelessness: social point of view.

The phenomenon of homeless people is eliciting a devastating social impact with an estimated prevalence in the USA and in Europe between 5.6% and 13.9%. These persons have a poor quality of life, a limited or no social life. They are often unemployed or work only occasionally. They are at risk for problems with the law and often suffering from addiction to other drugs, psychiatric and other medical diseases. Alcohol is often not the cause of their social status, but only the result of other discomforts thus contributing to their bio-psycho-social degradation. In 2009 the US Department of Housing and Urban Development's Homelessness Assistance Programs and in 2010 the European Consensus Conference on Homelessness discussed about the social rehabilitation of these people, using the concept of case management. In particular, the Standard Case Management was able to improve the housing stability, to reduce the use of drugs and to remove the working barriers. The Assertive Community Treatment was able to improve the housing stability and had a better efficacy for patients suffering from double diagnosis.

Treatment of alcohol dependence. Alcohol and the young: social point of view.

Adolescents are the most vulnerable group for alcohol-related diseases, as starting to drink at a young age is associated with an increased risk of alcohol dependence in adulthood. Young people tend to drink large amounts of alcohol to seek out strong emotions and for reaching fun at all costs through the psychotropic properties of alcohol. The behavioural motivations of this kind of drinking (binge drinking) depend on the lack of awareness of the harmful effects of alcohol, in the rite of social conviviality (a condition for which alcohol is attributed to the function of facilitating the aggregation among young people), in the absence of personal interests, lack of controls and family habits. Actions to be taken to limit or stop harmful alcohol consumption in young people should be based on interventions aimed at delaying the age of first contact with alcoholic beverages through the implementation of educational campaigns aimed at young people, their families and the whole society.

Alcohol withdrawal syndrome: diagnostic and therapeutic methods.

Alcohol withdrawal syndrome (AWS) is a medical emergency, rare in the general population, but very common among alcoholic individuals, which can lead to severe complications when unrecognized or late treated. It represents a clinical condition which can evolve in few hours or days following an abrupt cessation or reduction of alcohol intake and is characterized by hyperactivity of the autonomic nervous system resulting in the development of typical symptoms. According to DSM-5 criteria, the alcohol withdrawal syndrome is defined as such: if patients present at least two of typical signs and symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised version (CIWA-Ar), is the tool for assessing the severity of AWS. The support to patient with AWS includes pharmacological intervention as well as general support, restoration of biochemical imbalances and specific therapy. Regarding the pharmacological treatment, benzodiazepines represent the gold standard, in particular long-acting benzodiazepines, administered with a gradual reduction up to cessation.

Pharmacological treatment of alcohol use disorder. Scientific evidence.

Pharmacological treatment of alcohol use disorder represents an essential core of the therapeutic project in a multidisciplinary approach. While non-drug treatment is evolving, from a medical perspective few pharmacotherapies are available; in particular acamprosate, naltrexone and more recently nalmefene among anticraving drugs, disulfiram as an antidipsotropic medication. New studies are focusing on off-label drugs. Moreover, scientific evidence has to support any therapeutic indication which should be tailored on patient needs and comorbidity by considering the individual bio-psycho-social profile. Follow-up is essential in order to assess patient compliance to treatment and monitoring outcomes.

Diagnosis of alcohol use disorder from a psychological point of view.

Alcohol use disorder (AUD) is one of the most common psychiatric disease in the general population, characterized by having a pattern of excessive drinking despite the negative effects of alcohol on the individual's work, medical, legal, educational, and/or social life. Currently, the bio-psycho-social model describes properly AUD as a multidimensional phenomenon including biological, psychological, and socio-cultural variables affecting the nature, maintenance, and expression of the disorder. The AUD diagnostic process is crucial since the treatment success depends heavily on the accuracy and the adequacy of the diagnosis. The diagnosis is based on a comprehensive assessment of the patient's characteristics and uses interviews and psychometric instruments for collecting information. This paper will provide insights into the most important psychological dimensions of AUD and on the best psychometric instruments for proposing AUD diagnosis.

Dual diagnosis: an intriguing and actual nosographic issue too long neglected

Background: The term "dual diagnosis" (DD) has been used in clinical practice for years. However, there is confusion about these medical cases, which consist in the presence of both a psychiatric disorder and a substance abuse disorder (in this case, alcohol). There are evidences that in the alcohol use disorder (AUD) population, 50.3% of patients had a psychiatric comorbidity during their lifetime. Nevertheless, to these days there are not any thorough guidelines for the management of these patients. A precise nosography would prevent delay in diagnosis and treatment and all the self-evident negative outcomes of those delays. Materials and methods: A literature search was performed in PubMed, Web of Science, and Scopus, including studies published between 1980 and 2015. Search terms were: "guidelines", "treatment", "comorbidity", "substance abuse", "alcohol", "dual-diagnosis", "etiopathogenesis", "outpatient", "inpatient", "unit", "diagnosis". Out of 1045 titles, 43 studies were included in this article for their relevance on definition and nosography of DD. Results: Taking into account the state of art available in the literature, we contributed to clarify the definition of DD in the alcohol addiction field. Clinical data confirm high prevalence of DD, and allow to better describe and understand the complex relationship between alcohol dependence and other psychiatric diseases. Conclusions: We believe that a clear nosographic framework and a precise diagnostic process are essential for a timely management of every case, using specific guidelines to standardize and improve clinical practice. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which introduces dimensional approach, could be a useful tool to improve diagnostic accuracy.

Pharmacological treatment for dual diagnosis: a literature update and a proposal of intervention

Background: It has long been appreciated that alcohol use disorder (AUD) is associated with increased risk of psychiatric disorder. As well, people with history of mental disorder are more likely to develop lifetime AUD. Nevertheless, the treatment of dual diagnosis (DD) in alcohol addiction still remains a challenge. The efficacy of pharmacological treatment for these patients has been widely investigated with controversial results. Patients with untreated psychiatric disorder are at higher risk to return to drinking and tend to do so more quickly. The aim of this review was to collect clinical data for developing guidelines for the pharmacological treatment of psychiatric diseases in a population with AUD. Materials and methods: A literature review was conducted using the following databases: PubMed-NCBI, Cochrane database, Embase Web of Science, and Scopus, including studies published between 1980 and 2015. Search terms were: "guideline", "treatment", "comorbidity", "substance abuse", "alcohol", "dual-diagnosis", "antidepressant", "antipsychotic", "mood-stabilizer". Out of 1521 titles, 84 studies were included for their relevance on pharmacological treatment of psychiatric disorders in people with AUD. Results: Different drugs were collected in major pharmacological classes (antidepressant, mood-stabilizer, antipsychotic), in order to identify their proved efficacy for treating specific psychiatric disorder in the AUD population. Data were selected and verified for publications from randomized clinical trials, open-label trials and case reports. Conclusions: DD in alcohol dependence is a complex clinical entity, and its high prevalence is supported by epidemiological data. Pharmacological management of psychiatric disorders in patients with AUD remains partially anecdotal. Based on reviewed articles, we propose a classification of psychiatric medications for treatment of mental disorders comorbid with AUD, listed with evidence-based recommendations. More research is needed to obtain and collect clinical data, in order to organize and share evidence-based guidelines.

The multidisciplinary support in preventing alcohol relapse after liver transplantation: A single-center experience.

BACKGROUND AND AIM: Alcoholic liver disease (ALD) represents a frequent indication for liver transplantation (LT). Since 2004, we have adopted a program of multidisciplinary support(MS) to assist patients undergoing LT for ALD. We aimed at analyzing the relapse rate and the risk factors for relapse. The relapse rate was also compared with that of a historical group of patients who underwent transplantation. Their survival rate was also analyzed. PATIENTS AND METHODS: Consecutive patients with ALD transplanted from 2004 were included. The most important demographic, psychosocial, and clinical characteristics known to be associated with alcohol relapse were recorded. RESULTS: Sixty-nine patients underwent MS: 8.7% presented alcohol relapse. At multivariate analysis female gender (sHR 9.02, 95% CI 1.71-47.56, P = .009), alcohol withdrawal syndrome (sHR 5.89, 95% CI 1.42-24.46, P = .015) and a shorter time of MS program before LT (sHR 0.928 per month, 95% CI 0.870-0.988, P = .021) were identified as independent risk factors for relapse. The rate of alcohol relapse was significantly lower than that of the historical group who did not undergo MS (sHR 0.21, 95% CI: 0.06-0.68; P = .009). CONCLUSION: This study shows that a MS program may contribute to alcohol relapse prevention after LT in ALD patients. However, the relevance of this support needs to be confirmed by clinical trials.

Neurophysiological Measures and Alcohol Use Disorder (AUD): Hypothesizing Links between Clinical Severity Index and Molecular Neurobiological Patterns.

BACKGROUND: In 1987, Cloninger proposed a clinical description and classification of different personality traits genetically defined and independent from each other. Moreover, he elaborated a specific test the TCI to investigate these traits/states. The study of craving in Alcohol Use Disorder (AUD) assumed a greater significance, since ever more data seems to suggest a direct correlation between high levels of craving and a higher risk of relapse in alcoholics. Thus, our study aim is to explore the possible correlations among TCI linked molecular neurobiological pattern (s), craving and alcohol addiction severity measures in a sample of Italian alcoholics. MATERIALS AND METHODS: 191 alcoholics were recruited in a Day Hospital (DH) setting at the Alcohol Addiction Program Latium Region Referral Center, Sapienza University of Rome. After 7 days detoxification treatment a psychodiagnostic protocol was administered, including TCI, VAS-C, ASI and SADQ. All patients signed an Institutional Review Board (IRB) approved informed consent. RESULTS: Principally, we detected a significant positive correlation between HA-scale scores and the VAS scale: increasing in HA-scale corresponds to an increase in craving perception for both intensity (r=0.310; p ≤ 0.001) and frequency (r=0.246; p ≤ 0.001). Moreover, perception of dependence severity, measured with SADQ was also found to be significantly associated positively to both HA-scale (r=0.246; p ≤ 0.001) and NS-scale (r=0.224; p ≤ 0.01). While, for character scales, Persistence (r=-0.195; p=.008) and Self-directedness (r=-0.294; p ≤ 0.001) was negatively associated with ASI linked to alcohol problems. Self-directedness was also negatively correlated with ASI linked to family and social problems (r=-0.349; p ≤ 0.001), employment and support problems (r=-0.220; p=0.003) and psychiatric problems (r=-0.358; p ≤ 0.001). Cooperativeness was a negative correlate with Legal Problems (r=-0.173; p=0.019). and Self-Transcendence was positive correlated with Medical Problems (r=0.276; p ≤ 0.001). CONCLUSIONS: In view of recent addiction neurobiological theories, such as the "Reward Deficiency Syndrome (RDS)" and the Koob model, our data could suggest that our cohort of patients could possibly be in a particular stage of the course of their addiction history. Thus, if our hypothesis will be confirmed, the TCI-based assessment of alcoholics would allow an optimization of the treatment. Clinicians understanding these newer concepts will be able to translate this information to their patients and potentially enhance clinical outcome (s), because it could suggest a functional hypothesis of neurotransmitter circuits that helps to frame the patient in his/her history of addiction.

Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study.

The hypothalamic pituitary adrenal axis and dopamine have a key role in transition from alcohol social use to addiction. The medial prefrontal cortex was shown to modulate dopaminergic activity and cortisol releasing factor (CRF) release in hypothalamic and extra-hypothalamic systems. The recent advancements in non-invasive neurostimulation technologies has enabled stimulation of deeper brain regions using H-coil transcranial magnetic stimulation (TMS) in humans. This randomized double-blind placebo-controlled pilot study aims to evaluate H-coil efficacy in stimulating the medial prefrontal cortex. Cortisolemia and prolactinemia were evaluated as effectiveness markers. Alcohol intake and craving were considered as secondary outcomes. Eighteen alcoholics were recruited and randomized into 2 homogeneous groups: 9 in the real stimulation group and 9 in the sham stimulation group. Repetitive TMS (rTMS) was administered through a magnetic stimulator over 10 sessions at 20 Hz, directed to the medial prefrontal cortex. rTMS significantly reduced blood cortisol levels and decreased prolactinemia, thus suggesting dopamine increase. Craving visual analogic scale (VAS) in treated patients decreased, as well as mean number of alcoholic drinks/day and drinks on days of maximum alcohol intake (DMAI). In the sham group there was no significant effect observed on cortisolemia, prolactinemia, mean number of alcoholic drinks/day, or drinks/DMAI. Thus, deep rTMS could be considered a potential new treatment for alcoholism.

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

BACKGROUND & AIMS: Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence. METHODS: A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested. RESULTS: A higher incidence of alcoholic cirrhosis was observed in individuals with an older (≥24 years) compared with a younger (<24) age at onset of at-risk alcohol consumption (P-value < 0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value < 0.001; 1.53(1.07-2.19), P-value = 0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38). CONCLUSIONS: Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.

Blood thiamine, zinc, selenium, lead and oxidative stress in a population of male and female alcoholics: clinical evidence and gender differences.

INTRODUCTION: Long term alcohol abuse is associated with deficiencies in essential nutrients and minerals that can cause a variety of medical consequences including accumulation of toxic metals. AIM: The aim of this research is to get evidence-based data to evaluate alcohol damage and to optimize treatment. Thiamine and thiamine diphosphate (T/TDP), zinc (Zn), selenium (Se), lead (Pb) and oxidative stress in terms of reactive oxygen metabolites (ROMs) were examined in blood samples from 58 alcohol dependent patients (17 females and 41 males). RESULTS: T/TDP concentration in alcoholics resulted significantly lower than controls (p < 0.005) for both sexes. Serum Zn and Se did not significantly differ from reference values. Levels of blood Pb in alcoholics resulted significantly higher (p < 0.0001) than Italian reference values and were higher in females than in males. ROMs concentration was significantly higher than healthy population only in female abusers (p = 0.005). CONCLUSION: Alcoholics show a significant increase in blood oxidative stress and Pb and decrease in thiamine. Impairment occurs mainly in female abusers confirming a gender specific vulnerability.

Acute alcoholic hepatitis.

Acute alcoholic hepatitis (AAH) is a frequent inflammatory liver disease with high short-term mortality rate. In this review, relationships between alcohol abuse and the epidemiology and the outcomes of AAH are discussed, as well as AAH pathogenesis. The role of endotoxins, tumor necrosis factor alpha, fibroblasts, and immune response to altered hepatocyte proteins is discussed. The need of a careful prognosis, supported by the use of Maddrey score, by the model for end-stage liver disease [Mayo end-stage liver disease (MELD)] score or by the Glasgow alcoholic hepatitis score, is outlined, as the use of the most effective drugs (glucocorticoids and anti-tumor necrosis factor alpha infliximab) is recommended only in severe AAH cases. The problems of liver transplant in severe AAH, and the need of a 6-month alcohol abstinence before transplant, are discussed, as well as the need of a careful psychologic assessment before the transplant.

National Institute on Alcohol Abuse and Alcoholism and the study of fetal alcohol spectrum disorders. The International Consortium.

Fetal alcohol syndrome (FAS) is a large and rapidly increasing public health problem worldwide. Aside the full-blown FAS, multiple terms are used to describe the continuum of effects that result from prenatal exposure to alcohol, including the whole fetal alcohol spectrum disorders (FASD). The revised Institute of Medicine (IOM) Diagnostic Classification System and the diagnostic criteria for FAS and FASD are reported, as well as the formation of the four-state FAS International Consortium and its aims, as the development of an information base that systematizes data collection that helps to determine at-high-risk populations, and to implement and test a scientific-based prevention/intervention model for at risk women. The Consortium was further enlarged, with the inclusion of some more states (including Italy), leading to the formation of the International Consortium for the Investigation of FASD. The objectives of the Consortium are reported, as well as its previous activities, the South Africa and Italy Projects (active case ascertainment initiatives), and its future activities.

Fetal alcohol syndrome disorders: experience on the field. The Lazio study preliminary report.

In Italy, little is known about the problems related to alcohol drinking during pregnancy. In this paper, the Italian literature about this subject is briefly reviewed. This first Italian experience of a field study, aimed to the assessment of the prevalence of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) in an area in the Rome province (Lazio region) is reported. This in-field study was performed in the school years 2003-2004 and 2004-2005 in cooperation with American researchers, most from University of New Mexico (Albuquerque), and Italian researchers from University "la Sapienza" of Rome. First grade children (n(o) = 1,086) of primary school were contacted to enter in the in-school study for the detection of FAS and FASD and were examined by the experts team of clinicians, pediatrics, psychologists. Preliminary consideration and the implications of this study for FASD prevention are discussed.