Alcohol use disorders and liver fibrosis: an update.

Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance.

RATIONALE & OBJECTIVE: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. STUDY DESIGN: Single-center, case series. SETTING & PARTICIPANTS: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. OBSERVATIONS: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. LIMITATIONS: Retrospective design and inclusion of outpatients partially based on family pedigree. CONCLUSIONS: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Osteoporosis and Celiac Disease: Updates and Hidden Pitfalls.

Celiac disease (CD) is an autoimmune disorder caused by gluten ingestion in genetically predisposed individuals. In addition to the typical gastrointestinal symptoms (e.g., diarrhea, bloating, and chronic abdominal pain), CD may also present with a broad spectrum of manifestations, including low bone mineral density (BMD) and osteoporosis. The etiopathology of bone lesions in CD is multifactorial and other conditions, rather than mineral and vitamin D malabsorption, may affect skeletal health, especially those related to the endocrine system. Here, we describe CD-induced osteoporosis in an attempt to enlighten new and less-known aspects, such as the influence of the intestinal microbiome and sex-related differences on bone health. This review describes the role of CD in the development of skeletal alterations to provide physicians with an updated overview on this debated topic and to improve the management of osteoporosis in CD.

Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review.

Inflammatory bowel diseases show a gender bias, as reported for several other immune-mediated diseases. Female-specific differences influence disease presentation and activity, leading to a different progression between males and females. Women show a genetic predisposition to develop inflammatory bowel disease related to the X chromosome. Female hormone fluctuation influences gastrointestinal symptoms, pain perception, and the state of active disease at the time of conception could negatively affect the pregnancy. Women with inflammatory bowel disease report a worse quality of life, higher psychological distress, and reduced sexual activity than male patients. This narrative review aims to resume the current knowledge of female-related features in clinical manifestations, development, and therapy, as well as sexual and psychological implications related to inflammatory bowel disease. The final attempt is to provide gastroenterologists with a roadmap of female-specific differences, to improve patients' diagnosis, management, and treatment.

Symptoms of Protracted Alcohol Withdrawal in Patients with Alcohol Use Disorder: A Comprehensive Systematic Review.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is characterized by different phases (acute, early and protracted). Protracted alcohol withdrawal (PAW) presents some symptoms, which may persist for several weeks, months or even years after drinking cessation. METHODS: We conducted a systematic review of the literature in major scientific databases on selected AWS symptoms (craving, sleep disorders, and anhedonia) in patients with alcohol use disorder. RESULTS: Of the 102 eligible publications (70 RCTs and 32 cohort studies), 88 provided data on craving, 21 on sleep disorders, and 1 on anhedonia. Overall, 37 studies assessed craving using the Obsessive Compulsive Drinking Scale (OCDS). Pooled OCDS decreased from 24.2 at baseline to 18.8 at 1 week, 10.3 at 1 month and 9.7 at 3 months. The corresponding estimates for treated individuals were 23.9, 18.8, 8.7, and 8.8, and for non-treated subjects, they were 25.3, 13.9, 13.2, and 11.4, respectively. In 4 studies assessing sleep disorders using the Epworth Sleeping Scale (ESS), the scale remained stable in time, i.e., 7.3 at baseline, 7.3 at 1 week, 7.2 at 1 month, and 7.1 at 3 months. CONCLUSION: This study confirms the presence of PAW after the resolution of the acute phase of AWS. The pharmacological approach to managing PAW may ensure a more rapid reduction of symptoms in three weeks. We highlight the importance of studying PAW and the ability of pharmacological treatment to reduce its symptoms. This review protocol is registered in Prospero (registration number: CRD42020211265). SUMMARY: This systematic review summarizes literature on major symptoms of protracted alcohol withdrawal in patients with alcohol use disorder. The pharmacological approach to manage protracted alcohol withdrawal ensures a more rapid reduction of symptoms (craving in particular), achieving in three weeks similar results obtained only after almost 6 months without treatment.

Efficacy and safety of capsule endoscopy in octogenarian patients: a retrospective study.

BACKGROUND: Life expectancy and the number of ultra-octogenarians increased significantly, thus making crucial the appropriateness of several endoscopic procedures in elderly patients. The aim of our study was to provide a retrospective analysis of the efficacy and safety of capsule endoscopy (CE) in patients aged over 80 years. METHODS: In this single-centre study, 900 patients underwent capsule endoscopy between 2002 and 2015 for different indications; of these 106 patients aged ≥80 years (group A) and 99 patients aged 40-60 years (control group B) were retrospectively selected. RESULTS: Occult gastrointestinal bleeding accounted for 62.1% of all indications for capsule endoscopy in group B, compared to 95.2% in group A (P<0.001). Although not statistically significant, the diagnostic yield was higher in group A (71%) vs. group B (62%). The percentages of reaching the cecum and the median gastric transit time were uniform within the two groups. In contrast, small bowel transit time was longer in group A vs. B. Small bowel preparation was similar in the two groups. The exam was generally well tolerated in both groups, with capsule aspiration being one of the main adverse events, which occurred in two elderly patients. CONCLUSIONS: Our data expand previous findings confirming that capsule endoscopy can be performed safely even in very old patients and show that the diagnostic yield is similar to that of younger patients.

Alcohol use disorder in the COVID-19 era: Position paper of the Italian Society on Alcohol (SIA).

Coronavirus disease 2019 (COVID-19) first emerged in China in November 2019. Most governments have responded to the COVID-19 pandemic by imposing a lockdown. Some evidence suggests that a period of isolation might have led to a spike in alcohol misuse, and in the case of patients with alcohol use disorder (AUD), social isolation can favour lapse and relapse. The aim of our position paper is to provide specialists in the alcohol addiction field, in psychopharmacology, gastroenterology and in internal medicine, with appropriate tools to better manage patients with AUD and COVID-19,considering some important topics: (a) the susceptibility of AUD patients to infection; (b) the pharmacological interaction between medications used to treat AUD and to treat COVID-19; (c) the reorganization of the Centre for Alcohol Addiction Treatment for the management of AUD patients in the COVID-19 era (group activities, telemedicine, outpatients treatment, alcohol-related liver disease and liver transplantation, collecting samples); (d) AUD and SARS-CoV-2 vaccination. Telemedicine/telehealth will undoubtedly be useful/practical tools even though it remains at an elementary level; the contribution of the family and of caregivers in the management of AUD patients will play a significant role; the multidisciplinary intervention involving experts in the treatment of AUD with specialists in the treatment of COVID-19 disease will need implementation. Thus, the COVID-19 pandemic is rapidly leading addiction specialists towards a new governance scenario of AUD, which necessarily needs an in-depth reconsideration, focusing attention on a safe approach in combination with the efficacy of treatment.

Beyond biologics: advanced therapies in inflammatory bowel diseases.

INTRODUCTION: Inflammatory bowel diseases (IBDs) are conditions affecting the gut at different levels characterized by an abnormal activation of the intestinal immune system. In this narrative review, we will provide the reader with an update on the efficacy and safety of new pharmacological strategies to treat IBD patients. EVIDENCE ACQUISITION: We performed a thorough literature review via PubMed, EMBASE, MEDLINE and Science Direct databases addressing studies reporting on new therapies for IBD management published in the last ten years (January 2010-December 2020). Data from pharmaceutical companies and abstracts of conferences/meetings have also been considered. EVIDENCE SYNTHESIS: The discovery of monoclonal antibodies blocking pro-inflammatory cytokines, e.g., tumor necrosis factor-α (TNF-α) radically changed the management of IBDs. Anti-TNF-α agents represent the prototype molecule of "biologics"/"biologicals." These compounds have significantly improved the therapeutic management of IBDs refractory to standard medications as they provide clinical remission, mucosal healing and prevent extra-intestinal manifestations. However, about 50% of patients treated with biologicals experienced drawbacks, including primary failure or loss of response, requiring new effective treatments. Translational studies have identified new strategies, different from the TNF-α blockade, and new molecules, e.g. sphingosine-1-phosphate agonists and the JAK kinase inhibitors, have been proposed as potential therapeutic options for IBDs. CONCLUSIONS: With the availability of novel approaches reviewed in this article, physicians and especially gastroenterologists will increase the therapeutic options to provide a better management of IBD patients, particularly those poorly responsive to biologicals.

Alcohol-Related Liver Disease in the Covid-19 Era: Position Paper of the Italian Society on Alcohol (SIA).

BACKGROUND: Coronavirus Disease 2019 (COVID-19), firstly reported in China last November 2019, became a global pandemic. It has been shown that periods of isolation may induce a spike in alcohol use disorder (AUD). In addition, alcohol-related liver disease (ALD) is the most common consequence of excessive alcohol consumption worldwide. Moreover, liver impairment has also been reported as a common manifestation of COVID-19. AIMS: The aim of our position paper was to consider some critical issues regarding the management of ALD in patients with AUD in the era of COVID-19. METHODS: A panel of experts of the Italian Society of Alcohology (SIA) met via "conference calls" during the lockdown period to draft the SIA's criteria for the management of ALD in patients with COVID-19 as follows: (a) liver injury in patients with ALD and COVID-19 infection; (b) toxicity to the liver of the drugs currently tested to treat COVID-19 and the pharmacological interaction between medications used to treat AUD and to treat COVID-19; (c) reorganization of the management of compensated and decompensated ALD and liver transplantation in the COVID-19 era. RESULTS AND CONCLUSIONS: The COVID-19 pandemic has rapidly carried us toward a new governance scenario of AUD and ALD which necessarily requires an in-depth review of the management of these diseases with a new safe approach (management of out-patients and in-patients following new rules of safety, telemedicine, telehealth, call meetings with clinicians, nurses, patients, and caregivers) without losing the therapeutic efficacy of multidisciplinary treatment.

Nutritional Treatment in Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) which can affect any part of the whole gastrointestinal tract (from mouth to anus). Malnutrition affects 65-75% of CD patients, and it is now well acknowledged that diet is of paramount importance in the management of the disease. In this review, we would like to highlight the most recent findings in the field of nutrition for the treatment of CD. Our analysis will cover a wide range of topics, from the well-established diets to the new nutritional theories, along with the recent progress in emerging research fields, such as nutrigenomics.

Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review.

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene.

Recurrent myocarditis in a patient with active ulcerative colitis: a case report and review of the literature.

Inflammatory bowel diseases such as ulcerative colitis (UC) may be complicated by several extraintestinal manifestations. These involve joints, skin, eyes and less commonly lungs and heart. Myocarditis may result from the toxic effect of drugs (ie, mesalazine) commonly used for the treatment of UC or due to infections (eg, Coxsackieviruses, enteroviruses, adenovirus). Here, we report a case of a 26-year old man affected by UC and complicated by two episodes of myocarditis. Both episodes occurred during two severe exacerbations of UC. However, in both cases the aetiology of myocarditis remains uncertain being ascribable to extraintestinal manifestation, drug toxicity or both.

The recognition and management of protracted alcohol withdrawal may improve and modulate the pharmacological treatment of alcohol use disorder.

About 50% of persons with an alcohol use disorder may have symptoms of alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption. Protracted alcohol withdrawal (PAW), an underestimated and not yet clearly defined clinical condition that follows the acute stage of AWS, is characterized by the presence of substance-specific signs and symptoms (i.e. anxiety, irritability, mood instability, insomnia, craving) common to acute AWS, but persisting beyond the generally expected acute AWS time frames. Considering that PAW symptoms are mainly related to the neuro-adaptive changes of gamma-aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) systems, naltrexone, nalmefene, and disulfiram may not be able to suppress the symptoms of PAW. After treatment of the acute phase of AWS, a more specifically pharmacological therapy able to suppress PAW symptoms could perhaps be used earlier and may be more helpful in preventing the risk of alcohol relapse, which remains higher during the first months of treatment. In light of this, medications acting on GABA and NMDA neurotransmitter systems to counterbalance the up-regulation of NMDA and the down-regulation of GABA could be employed in combination and started as soon as possible.

Effect of Gluten-Free Diet on Gut Microbiota Composition in Patients with Celiac Disease and Non-Celiac Gluten/Wheat Sensitivity.

Celiac disease (CD) and non-celiac gluten/wheat sensitivity (NCG/WS) are the two most frequent conditions belonging to gluten-related disorders (GRDs). Both these diseases are triggered and worsened by gluten proteins ingestion, although other components, such as amylase/trypsin inhibitors (ATI) and fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), seem to be involved in the NCG/WS onset. Therefore, the only effective treatment to date is the long-life adherence to a strictly gluten-free diet. Recently, increasing attention has been paid to the intestinal barrier, a dynamic system comprising various components, which regulate the delicate crosstalk between metabolic, motor, neuroendocrine and immunological functions. Among the elements characterizing the intestinal barrier, the microbiota plays a key role, modulating the gut integrity maintenance, the immune response and the inflammation process, linked to the CD and NCG/WS outbreak. This narrative review addresses the most recent findings on the gut microbiota modulation induced by the gluten-free diet (GFD) in healthy, CD and NCG/WS patients.

Life-threatening onset of coeliac disease: a case report and literature review.

BACKGROUND: Coeliac disease (CD) results from an immune-mediated reaction to gluten in genetically predisposed individuals. In rare cases CD may occur with acute features deferring the diagnosis and exposing these patients to possible life-threatening complications. Herein we present the case of a young woman with a coeliac crisis, that is, a sudden clinical onset characterised by severe electrolyte imbalance due to an unknown (previously unrecognised) CD. METHODS: This is a case report and literature review revealing that coeliac crisis is under-reported, with a total of 48 adult cases so far published. The diagnosis in our case was established by histopathological analysis of multiple duodenal biopsies. The patient's serum was tested by enzyme-linked immunoassay to detect antitransglutaminase IgA antibodies. RESULTS: In contrast to cases reported in the literature, with male gender predominance and a mean age of 50±17 years, our patient was a young female case of coeliac crisis. However, like in our patient, a higher incidence of coeliac crisis was associated with the human leucocyte antigen (HLA)-DQ2 haplotype, versus HLA-DQ8, and a severe (Marsh-Oberhüber 3c) duodenal mucosa atrophy. Notably, there is no clear correlation between the antitissue transglutaminase 2 IgA antibody titre and coeliac crisis onset/severity, as confirmed by our case report. CONCLUSIONS: The present case highlights that CD may manifest quite abruptly with a severe malabsorption syndrome, that is, electrolyte abnormalities and hypoproteinaemia. Our case should alert physicians, in particular those in the emergency setting, that even a typically chronic disorder, such as CD, may show life-threatening complications requiring urgent management.

Therapeutic options for coeliac disease: What else beyond gluten-free diet?

Coeliac disease is a chronic and systemic autoimmune condition triggered by gluten ingestion in genetically predisposed subjects. Currently, the only effective treatment available is a strict, lifelong gluten-free diet. However, patients perceive gluten withdrawal as an unsustainable burden in their life and some of them can exhibit persistent symptoms despite a strict diet. Thus, gluten-free diet represents a challenge, leading scientists to look for alternative or complementary treatments. This review will focus on non-dietary therapies for coeliac disease highlighting six therapeutic strategies: (1) decreasing gluten immunogenic content before it reaches the intestine; (2) sequestering gluten in the gut lumen before absorption; (3) blocking the passage of gluten through a leaky intestinal barrier; (4) preventing the enhancement of immune response against gliadin; (5) dampening the downstream immune activation; (6) inducing immune tolerance to gluten. Most developing therapies are only in the pre-clinical phase with only a few being tested in phase 2b or 3 trials. Although new approaches raise the hope for coeliacs giving them a chance to come back to gluten, for the time being a cautionary appraisal of new therapies suggests that they may have a complementary role to gluten withdrawal, mainly to prevent inadvertent gluten contamination.

[Major gastrointestinal hemorrhage during anticoagulant therapy in patients with atrial fibrillation: when should treatment be resumed?] / Emorragia gastrointestinale maggiore in corso di terapia anticoagulante nei pazienti con fibrillazione atriale: quando riprendere il trattamento?

In patients with atrial fibrillation (AF) under oral anticoagulant therapy (OAT), over half of the hemorrhagic complications occur in the gastrointestinal (GI) tract, with an incidence of 1-4% per year. This complication mainly involves older patients, often very compromised from the clinical point of view; mortality rates are not negligible, varying between 4% and 15%. The purpose of the present review was to evaluate the utility of resuming OAT after a major GI hemorrhage in patients with AF. Four observational studies were found in the literature that specifically investigated this issue; three of them had a retrospective design. In these studies almost exclusively warfarin was utilized. OAT was discontinued in all patients at the beginning of GI hemorrhage; in about half of the patients anticoagulation was then restarted and in the other half it was definitively stopped. The results of these studies suggest a beneficial effect of OAT resumption, since it reduced the incidence of thromboembolic events and mortality with a not marked increase in hemorrhagic recurrences. However, these results should be interpreted with caution since, very likely, OAT was resumed in patients in good clinical condition - as suggested by the very low mortality rate during hemorrhagic recurrences (0.7%) - and not in those with very severe hemorrhage and/or very compromised from the clinical point of view. Because of this type of patient selection, we do not know the real hemorrhagic risk in patients resuming OAT after GI hemorrhage. This is a strong limitation in the decision making; in order to acquire this knowledge, randomized studies should be carried out. The evaluation whether or not to restart OAT should be made in the clinical context by a team including the gastroenterologist (or the physician taking care of the GI pathology) and the cardiologist. At present, clinical variables such as site and/or cause of GI bleeding, severity of the anemia and the degree of prolongation of the international normalized ratio, do not appear useful for decision making. The available data suggest that OAT should be resumed in "robust" elderly patients, if the source of bleeding has been identified and corrected, whereas in frail patients and/or with multiple comorbidities, the doubt often remains. The available literature does not offer clear data on the optimal duration of OAT discontinuation after an episode of major GI bleeding. The evaluation should be made in the clinical context; however, therapy discontinuation between 1 week and 1 month appears to be adequate in most cases. On the basis of indirect comparisons, which show many limitations, the most appropriate anticoagulants after GI hemorrhage appear to be warfarin, apixaban and low-dose edoxaban.

Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies, linkage disequilibrium and association studies.

BACKGROUND: Alcohol use disorder (AUD) is a complex trait with genetic and environmental influences. Several gene variants have been associated with the risk for AUD, including genes encoding the sub-units of the γ-aminobutyric acid (GABA) receptors. AIM: This study evaluated whether specific single nucleotide polymorphisms (SNPs) in genes encoding GABAB receptor sub-units can be considered as candidates for the risk of AUD. SUBJECTS AND METHODS: Seventy-four AUD subjects and 128 Italian controls were genotyped for 10 SNPs in genes encoding GABA-B1 and GABA-B2 sub-units (GABBR1 and GABBR2). Allele, genotype, and haplotype frequencies were tested for the association with the AUD trait. RESULTS: A significant difference between AUD individuals and controls was observed at genotype level for rs2900512 of GABBR2 gene. The homozygous T/T genotype was not found in the controls, whereas it was over-represented in the AUD individuals. Under the recessive model (T/T vs C/T + C/C) this result was statistically significant, as well as the Odds Ratio for the association with the AUD trait. CONCLUSIONS: The results provide preliminary data on the association between GABAB receptor gene variation and risk of AUD. To confirm this finding, studies with larger samples and additional characterisation of the phenotypic AUD trait are required.

Mortality risk in a cohort of Italian alcoholic individuals treated for alcohol dependence.

INTRODUCTION AND AIMS: The aim of this study was to investigate the mortality risk and to explore the presence of subjects more at risk of dying in a cohort of alcoholic individuals treated for alcohol dependence over a lengthy follow-up period. DESIGN AND METHODS: A total of 2363 subjects attending 10 centres for addiction treatment for alcohol dependence were recruited. RESULTS: During the 17 year follow-up period, 14.7% of the entire cohort died. Total standardised mortality rates (SMR) were higher in women (SMR = 5.94) as compared with men (SMR = 4.65). Higher SMRs were found for several diseases, for traumatic episodes (SMR = 6.65) and in younger patients (18-44 age group) (SMR = 8.16). Alcoholic women showed a higher survival rate as compared with men. In addition, a higher risk of death for men and unemployed subjects, with a progressive increase of risk in line with the increase of the age of admission to treatment, and with a progressive decrease of risk after 1 year from the beginning of the treatment, was also found. DISCUSSION AND CONCLUSIONS: This study confirms that mortality risk in alcoholic individuals in treatment is higher in comparison with the general population. Moreover, alcoholics men, unemployed, >40 years at time of admission and during the first year of treatment are more at risk to die. Thus, much more attention to patients with these characteristics should be planned by the professional staff working in centres for addiction treatment. [ Pavarin R M, Caputo F, Zoli G, Domenicali M, Bernardi M, Gambini D. Mortality risk in a cohort of Italian alcoholic individuals treated for alcohol dependence Drug Alcohol Rev 2017;36:186-191].