Alcohol, smoking and the liver disease patient

Alcohol, smoking and the liver disease patient

Best Practice & Research Clinical Gastroenterology xxx (2017) 1e7 Contents lists available at ScienceDirect Best Practice & Research Clinical Gastro...

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Best Practice & Research Clinical Gastroenterology xxx (2017) 1e7

Contents lists available at ScienceDirect

Best Practice & Research Clinical Gastroenterology journal homepage: https://ees.elsevier.com/ybega/default.asp

Alcohol, smoking and the liver disease patient € m a, b, * Hannes Hagstro a b

Centre for Digestive Diseases, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

a b s t r a c t Keywords: Alcohol Smoking Cirrhosis Fibrosis Liver disease

Alcohol is an established risk factor for cirrhosis. Current recommendations for a “safe” limit for alcohol consumption are usually set to around 30 g of alcohol per day for men and 20 g per day for women, but evidence is mounting that these cut-offs might be set too high. Also, inter-individual differences in the hepatic sensitivity for alcohol likely play into the risk of development of cirrhosis. In patients with concomitant liver diseases, a synergistic effect on fibrosis progression and high consumption of alcohol is evident. The role of low to moderate consumption is less clear. Alcohol can also lead to a specific inflammatory state in the liver, alcoholic hepatitis (AH). Treatment of severe AH consists of corticosteroids, which are at best moderately effective, and new treatments are needed. Liver transplantation is an option in severe alcoholic liver disease, although selection of patients that are at a very low risk of post-transplantation alcohol consumption is paramount. There is some evidence to suggest an increased risk for fibrosis progression and development of hepatocellular carcinoma specifically for smoking. © 2017 Elsevier Ltd. All rights reserved.

1. Introduction Practising gastroenterologists are highly likely to come across patients with alcoholic liver disease during one's career. There is a large disease spectrum, including patients with only mild elevation of liver transaminases, to end-stage cirrhotic patients and development of hepatocellular carcinoma. Knowledge of how to best care for these patients are of importance to increase patient survival. This review covers several aspects of alcoholic liver disease, including alcoholic hepatitis and development of hepatocellular carcinoma.

1.1. Epidemiology Consumption of alcohol might have started as early as 10.000 BCE [1,2], and is today common in most human cultures. 86% of US citizens report any lifetime consumption of alcohol [3], and the mean yearly consumption of alcohol in the US is currently 8.6 L of pure alcohol, compared to 6.2 L per year globally [4]. Alcohol

* Centre for Digestive Diseases, Division of Hepatology, Karolinska University Hospital, 141 86 Stockholm, Sweden. E-mail address: [email protected].

accounts for roughly 85.000 deaths per year in the US [5]. In Europe, alcohol is estimated to be responsible for around 6.5% of all deaths, and globally 5.9% of mortality can be attributed to alcohol [4]. Alcoholic liver disease (ALD) can be defined as different stages of liver damage due to consumption of alcohol, and is a major cause of cirrhosis [6]. 1.2. Pathophysiology Alcohol is mainly metabolised into acetaldehyde by intestinal and hepatic alcohol dehydrogenase, but can also be oxidized by microsomal CYP2E1 [7e9]. The CYP2E1 system normally accounts for a smaller proportion of alcohol oxidation, but is inducible by its substrates and can be highly upregulated in persons who consume high quantities of alcohol [8,10]. Induction of CYP2E1 leads to increased production of reactive oxygen species and DNA damage, thought to increase the risk of cancer development [11]. Independent of pathway, the intermediate product of ethanol metabolism, acetaldehyde, is highly reactive and carcinogenic [12], and thought to be a main contributor to alcoholic liver disease [13]. Acetaldehyde is further metabolised into acetate, which is then broken down into water and carbon dioxide. Enzymes involved in ethanol metabolism are highly expressed in hepatocytes, which can explain why the most harmful effect of

http://dx.doi.org/10.1016/j.bpg.2017.09.003 1521-6918/© 2017 Elsevier Ltd. All rights reserved.

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ethanol is seen in the liver. A more extensive review of the pathophysiological mechanisms in alcoholic liver disease was recently published [13].

cirrhosis. These finding are promising for understanding the pathophysiology behind severe ALD, however none are to date used in clinical practice.

1.3. Alcoholic liver disease with cirrhosis

1.4. Alcoholic hepatitis

Alcohol accounts for up to 50% of all deaths in liver cirrhosis globally [4], with this figure being 60e80% in Europe [14]. Conversely, 1% of all alcohol-attributed deaths are attributed to alcoholic liver disease, including cirrhosis [15]. Alcoholic liver disease is also a major cause for liver transplantation world-wide, and is the second most common indication for liver transplantation in Europe and the third in the US [16,17].

Alcoholic hepatitis (AH) is a complication of long-standing ingestion of ethanol [36]. The diagnosis of AH can be difficult to differentiate against acute-on-chonic liver failure, and the goldstandard diagnosis of AH is liver biopsy although it is rarely performed due to risk of bleeding and infection. If needed, a transjugular approach is considered safest [36]. Histologically, AH is defined as ballooning degradation of hepatocytes, parenchymal inflammation and steatosis, with or without fibrosis. Cirrhosis might be present, but is not mandatory for the diagnosis of AH. Patients with alcoholic hepatitis usually present after an extended period of binge-drinking, and at presentation jaundice, fever and abdominal pain are common attributes. It is vital to rule out acuteon-chronic liver failure and precipitating bacterial infections [36]. After this, staging of disease into severe and non-severe AH is appropriate as cases with severe AH have a high mortality of around 30e40% six months after presentation [37], and should be considered for treatment with corticosteroids, unless contraindications such as uncontrolled infection is present. Cases with nonsevere AH have a good prognosis without pharmacotherapy, and treatment consists of abstinence and proper nutrition. There are several scoring systems to identify cases with severe AH, including the Maddrey score [37] the Glasgow alcoholic hepatitis score [38] and the MELD score [39], as presented in Table 1. The most important factor for all forms of AH is cessation of alcohol consumption, as recidivism is associated with a pessimistic prognosis including increased mortality [40]. Following diagnosis of severe AH, pharmacotherapy should be initiated in selected patients. Initial results with corticosteroids indicated a survival benefit [37], and this has been the mainstay of therapy since more than 40 years [41,42]. However, results from the large STOPAH trial in UK in which more than 1000 patients with severe AH were randomized to receive therapy with either prednisolone-placebo, prednisolone-pentoxifylline, pentoxifylline-placebo or placeboplacebo has somewhat challenged this, as no clear overall survival benefit was seen after 28 days or one year for patients on prednisolone treatment compared to placebo [43]. Nevertheless, mortality in the prednisolone-treated groups was relatively increased due to a higher proportion of patients that developed bacterial infections. Thus, some patients might indeed benefit from prednisolone treatment, but strong vigilance for detection of bacterial infections is needed, and these should as stated above be actively screened for before initiation and during therapy. Importantly, one week after initiation of steroid treatment,

1.3.1. Risk modifiers Although approximately 90% of persons who consume more than 60 g of alcohol per day, roughly equivalent to five to six units of alcohol depending on the definition of a unit, develop steatosis [18], significant fibrosis or cirrhosis is only seen in up to 30% of this population [19e21]. In contrast, a low to moderate consumption of alcohol, usually defined as below 20 g per day in women and 30 g per day in men is currently considered safe in most countries [22,23], although a more restrictive approach is currently advocated in some countries, including the UK where the recommended maximum intake for men is now two drinks per day [23]. Importantly, data from meta-analyses suggests that the risk for cirrhosis is present already for persons consuming more than 25 g of alcohol per day [24], and another study found that an increased risk for liver-related mortality can also be found in persons consuming between 12 and 24 g of alcohol per day, corresponding to 1e2 drinks per day [25]. Nevertheless, it is obvious that there are inter-individual differences on the risk of developing severe ALD including cirrhosis. These include environmental and genetic differences, many of which are currently unknown. Environmental factors include binge-drinking, usually defined as consuming more than five units of alcohol at the same occasion for men and four for women. Binge-drinking has been associated with a higher risk of both ALD and mortality [26] and drinking outside of meals was in the landmark Dionysos study associated with a 2.7-fold increased risk for ALD compared to drinking only at mealtimes [22]. Some epidemiological evidence suggests that persons that primarily drink wine might be at a lower risk for development of cirrhosis compared to patients that drink spirits or beer independent of the quantity of consumption [27,28]. However, caution must be taken when interpreting the results of these studies. Persons that drink wine might be at a lower risk for cirrhosis due to other factors, including a lower risk of increasing the level of alcohol consumption (and thus de facto drinking more) [29], as well as other factors such as smoking, use of narcotics and differences in binge-drinking. Of genetic risk modifiers, the most obvious one is gender. Women are at a higher risk for developing ALD given the same exposure to alcohol, which can partly be explained by differences in gastric alcohol dehydrogenase and a higher proportion of body fat leading to higher serum concentrations of ethanol [30]. In a twin study of more than 15 000 male twins, presence of alcoholic cirrhosis was three times more common in monozygotic twins compared to dizygotic twins [31], which can be considered a strong indication for genetic risk modification on fibrosis progression in ALD. Recently, several genome-wide association studies have identified a strong association between mutations in the PNPLA3, TM6SF2 and MBOAT7 genes [32e35] with ALD and alcoholic

Table 1 Scoring systems used to define severe alcoholic hepatitis. Scoring system

Parameters included

Maddrey score

Patient PT, lab PT, Bilirubin

Glasgow alcoholic hepatitis score MELD

Cut-off for treatment initiation

Link to calculator

32 or higher https://www.mdcalc.com/ maddreys-discriminantfunction-alcoholic-hepatitis 9 or more http://www.gastrotraining. Age, WBC, urea, com/calculators/glasgowBilirubin, patient PT, alcoholic-hepatitis-score lab PT (or INR) Dialysis, creatinine, 18 or higher https://www.mdcalc.com/ meld-score-model-end-stagebilirubin, INR, liver-disease-12-older sodium

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calculation of the Lille-score should be performed [44]. The Lillescore (available online at http://www.lillemodel.com/score.asp) is a tool to identify patients with a poor response to steroid treatment. A score above 0.45 is associated with a lack of response to steroid treatment and a six-month mortality of 75%. In patients with a Lillescore of >0.45, steroid treatment should therefore be stopped to reduce the risk of infections. Patients with a Lille-score below 0.45 should continue steroid therapy for four weeks, after which treatment is either stopped or tapered. Patients who recover from an episode of severe AH should be informed of the pessimistic prognosis in the case of continued drinking [40]. 1.5. Liver transplantation ALD is one of the leading indications for liver transplantation, and cases listed for liver transplantation due to ALD has seen an absolute increase by 45% between 2004 and 2013 in the US [45]. Although no formal recommendation on alcohol consumption exist for non-ALD cases either in American or European guidelines after liver transplantation [46,47], a careful approach is often advocated. Indeed, around 60% of non-ALD cases continue to consume alcohol after liver transplantation, although often in small amounts [48]. Excessive drinking after liver transplantation, independent of the primary indication, is associated with increased mortality [49] and graft loss [50]. Usually, a “six-month rule” is applied for cases with ALD to achieve abstinence. This is due to two main reasons. First, it allows for liver regeneration in the subset of patients that have potential for recovery and thereby reduce the need for liver transplantation. Secondly, it allows the transplant team to identify cases that cannot achieve abstinence. However, this rule also effectively shuts out cases with severe AH and ALD with a high short-term mortality that can achieve abstinence. Transplantation for severe AH that does not respond to corticosteroids has been tried with good results in a highly-selected setting. Mathurin et al. randomized 26 patients with high Lille-scores to either liver transplantation or best supportive care. After six months, mortality was 23% in the transplanted group versus 77% in the non-transplanted group. Less than 2% of cases with severe AH were selected for liver transplantation during the pre-operative assessment [51]. Similar results have been reported from the US [52]. Cases in these studies that did undergo liver transplantation due to AH had a low risk of recidivism during the reported follow-up time. Practically, these results suggest that there indeed are cases with AH where liver transplantation is a lifesaving intervention, and a multi-disciplinary approach including hepatologists, transplant surgeons, anaesthesiologists and addiction specialists as well as nurses is of importance to select patients that are best suited for the procedure. 1.6. Alcohol and NAFLD Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, insulin resistance and the metabolic syndrome [53e55]. Tracing the global obesity pandemic, NAFLD is now the most common liver disease, affecting up to 25% of the global population [56] and is expected to become the leading indication for need of liver transplantation in the US in the near future [45,57]. Epidemiological studies have suggested an interactive effect between high-grade consumption of alcohol and obesity. In a study of almost 10 000 British men followed for 29 years, an increased risk for liver-related mortality was found for consumption over 15 drinks of alcohol per week. This risk was most pronounced in obese men (RR 18.9, 95% CI 6.84e52.4) compared to normal weight men (RR 3.16, 95%CI 1.28e7.80) [58]. Similar findings have been found for women in the Million Women Study, where women who

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consumed over 150 g of alcohol per week were at a higher risk for development of liver cirrhosis if they were obese, compared to women with a normal BMI [59]. Heavy episodic drinking has been shown to increase the risk of fibrosis progression in biopsy-proven NAFLD [60], although this study did not evaluate life-time consumption. Paradoxically, data from cross-sectional studies and meta-analysis suggest that consumption of alcohol is associated with a lower risk of NAFLD [61], a finding that might be biased [62]. There have been no randomized controlled trials on the effect of alcohol consumption on the severity of NAFLD, which also is complicated by ethical concerns. However, a randomized controlled trial of consumption of red wine in healthy volunteers found that consumption of 33 g per day in men and 16 g per day in women for three months did not induce MRI-measured steatosis in single subject compared to alcohol abstinence, indicating that to develop steatosis, either a higher dose or a longer duration of alcohol consumption is needed to induce steatosis [63]. In a recent study of 120 biopsy-proven NAFLD patients that all reported consumption of less than 13 drinks per week in clinical interviews and validated questionnaires, 13 patients (11%) had high levels of phosphatidyl ethanol, a sensitive marker of recent alcohol consumption [64]. This suggests that some patients with NAFLD should be classified as ALD patients, and that phosphatidyl ethanol measurement could be a way to support either diagnosis. 1.7. Alcohol and viral hepatitis Chronic viral hepatitis C (HCV) is highly prevalent, with between 2.7 and 5.2 million infected individuals in the US [65,66], and approximately 130 million persons are affected worldwide [67]. HCV-induced liver disease, such as cirrhosis and hepatocellular carcinoma, accounts for around 700.000 deaths each year [68]. Alcohol consumption is increased in a subset of patients with HCV, especially those that has contracted HCV through intravenous drug abuse [69,70]. There is a large sum of evidence that points to an interaction between HCV and high consumption of alcohol, defined as at least 30 g per day on the risk for fibrosis progression and development of cirrhosis [71e74]. The role of low to moderate alcohol consumption in HCV is less clear. In a French cross-sectional study of 260 HCV patients, no increased risk of fibrosis progression in subjects consuming below 30 g per day was seen [75]. By contrast, in a group of 78 untreated patients with HCV that underwent paired liver biopsies with a median time of 6.3 years between biopsies, higher alcohol consumption and higher drinking frequency was independently associated with fibrosis progression. All of these patients drank below 40 g of alcohol per day (median 4.8 g per day), suggesting that even a low consumption of alcohol is harmful in HCV [76]. For hepatitis B virus infection, as for HCV, a high consumption of alcohol is associated with adverse outcomes, including an increased risk for mortality [77]. Alcohol consumption in patients with concurrent HBV or HCV should therefore be kept to a minimum. Patients with viral hepatitis not able to stop drinking should be referred to an addiction specialist. 1.8. Alcohol and other selected liver diseases An increased risk of development of cholangiocarcinoma in patients with primary sclerosing cholangitis, a rare chronic cholestatic disease associated with inflammatory bowel disease, was suggested in patients with a high alcohol consumption in an American case-control study [78]. However, only four patients with current alcohol consumption and CCA were included, and therefore the dose-response effect is unclear. A Swedish study indicated that

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patients with primary sclerosing cholangitis in general have a low consumption of alcohol (mean 0.4 units per day), and no obvious association between transient elastography-measured fibrosis and alcohol was found [79]. For another chronic cholestatic disease, primary biliary cholangitis, a case-control study of over 2500 patients with primary biliary cholangitis in the UK found that alcohol use, defined as if a person had ever consumed alcohol regularly, was negatively associated with the presence of primary biliary cholangitis [80]. An association between any alcohol consumption and HCC was found in a smaller case-control study of 52 Chinese primary biliary cholangitis patients with HCC, where alcohol consumption was more common in HCC cases (31%) than in controls (8%, p ¼ .01) [81]. In a larger European study, however, no association was found between alcohol consumption of more than 40 g per day and HCC in 716 primary biliary cholangitis patients [82]. Hereditary hemochromatosis is a genetic disorder of iron metabolism that leads to an excess absorption of iron from the gut, with iron loading in various organs, including the liver, that eventually can lead to fibrosis progression and cirrhosis. In a study of 224 patients with hereditary hemochromatosis, 61% of subjects who consumed more than 60 g/day of alcohol had evidence of severe fibrosis or cirrhosis, compared to seven per cent of subjects who consumed less than 60 g per day [83]. 1.9. Alcohol and HCC Hepatocellular carcinoma is now the fifth most common malignancy worldwide, and the second most common cause of cancerrelated mortality, with 782 000 new cases and 745 000 deaths estimated globally in 2012 [84]. The majority of HCCs occur in less developed parts of the world, and are attributable to viral hepatitis [85], but alcohol consumption is also an important contributor to cirrhosis and development of HCC [86,87], especially in countries with lower prevalence of hepatitis B and C. Alcohol per se is generally associated with a number of malignancies, primarily in the upper aerodigestive tract [86], but also with hepatocellular carcinoma. Primarily, the pathophysiological mechanism for the excess risk of HCC attributed to alcohol is thought to be through induction of alcoholic cirrhosis. Around 80% of all HCCs occurs in cirrhotic livers [88]. Indeed, a recent meta-analysis of the risk of HCC attributed to alcohol found no association between moderate (below three drinks per day) and development of HCC, while a moderately increased risk (RR 1.16 compared to non-drinkers) was seen in persons consuming equal to or more than three drinks per day [87], although the authors were unable to specifically study the risk in cirrhotic individuals. The incidence for development of HCC in the setting of alcoholic cirrhosis differs between studies, with five-year risk ranging from 1.0% to 13.2%. The annual incidence was reported to be low as 0.2% per year in a population-based register study from Denmark [89]. However, the register-based approach might misclassify patients with alcoholic liver disease without cirrhosis as indeed having cirrhosis, and further might fail to correctly identify HCC cases. Both these factors may lead to falsely low estimates, but the size of the study is the largest so far reported. In contrast, in 450 Spanish patients with known alcoholic cirrhosis undergoing surveillance for HCC, the five-year risk was as high as 13.2%, with higher age and a platelet count of below 75 significant risk factors for HCC development [90]. A table of selected studies of the risk of HCC development in pure alcoholic cirrhosis is presented in Table 2 [89e94]. Of note, these studies have relatively short follow-up periods, therefore it is possible that the life-time risk of HCC in alcoholic cirrhosis might be higher than reported. Importantly, there seem to exist a synergistic effect between

Table 2 Selected cohort studies of the annual risk of HCC development in patients with alcoholic cirrhosis. Study

Country

N patients

Follow-up (years)

Annual HCC incidence

Toshikiuni, 2009 Jepsen, 2012 Ioannou, 2007 N'Kontchou, 2006 Mancebo, 2013 Lin, 2013

Japan Denmark USA France Spain Taiwan

75 8482 734 478 450 202

4.9 4.1 3.6 4.2 3.5 5.2

0.6% 0.2% 0.6% 3.2% 2.6% 2.1%

alcohol and several liver diseases on the risk of HCC development. This has mostly been studied in patients with viral hepatitis and high consumption of alcohol [94e99]. Recently, in a study of 192 patients with HCV-related cirrhosis, Vandenbulcke et al. found that alcohol also in moderate amounts (median 15 g per day) was associated with an increased risk of HCC development compared to non-drinkers (hazard ratio 3.4) [100]. Thus, patients with viral hepatitis should clearly be advocated to abstain from alcohol. To reduce HCC mortality, it is vital to discover incident HCC cases early, when curative therapy can be considered. Surveillance with ultrasound semiannually is associated with increased detection of early tumors and increased survival [101]. Therefore, it is recommended that patients with cirrhosis undergo ultrasound surveillance twice per year [102]. Accompanying reviews in this journal issue further discuss the association between alcohol and survival in HCC patients, as well as the impact of alcohol on potential surgical management and outcomes of patients, including those with liver disease. 1.10. Hepatic effects of alcohol reduction Abstinence from alcohol consumption is the key factor in determining the prognosis in alcoholic liver disease [103]. Several classical studies have clearly shown that abstinence is associated with a better prognosis [40,104]. This is true even in end-stage liver disease. In a French study of patients with severe alcoholic cirrhosis (Child Pugh C), 66% of patients that managed abstinence had a reduction in the Child Pugh score [105]. Assisting the alcoholic liver disease patient, independent of the stage of disease, to achieve abstinence is therefore of utmost importance, and should be the key target for a multi-disciplinary team including gastroenterologists, addiction specialists and paramedical professionals. 1.11. Smoking and liver disease Although the association between alcohol and liver disease is well established, the same cannot be said for smoking. Partly, this is attributed to difficulties in disentangling the specific role of smoking from confounding factors that are common in smokers, such as alcohol consumption. Nevertheless, there are some evidence pointing to an increased risk of liver disease in smokers. For example, in a French study of 310 patients with hepatitis C, smoking was an independent risk factor for a higher fibrosis stage, with a relative risk of 1.9 for patients with more than 15 pack-years of smoking compared to non-smokers [106]. Researchers using the EPIC cohort, with data on more than 4.4 million person-years of follow found that current smoking was a strong risk factor for HCC (OR 4.55), and contributed more to HCC than chronic HBV and HCV infections. A non-significant risk for former smokers was found [107]. Also, a meta-analysis of almost 100 cohort and case-control studies found an increased RR for HCC for current smokers of 1.51 compared to non-smokers, and non-significant RR of 1.12 for

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previous smokers [108]. This indicates that smoking clearly is associated with an increased risk for HCC, and indirectly that cessation of smoking likely reduces this risk. Patients with chronic liver diseases should be informed of the excess risk, and be offered appropriate counselling and/or pharmacotherapy to assist them in this.

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Grant support (funding) None. Guarantor of article HH.

2. Summary Alcohol consumption is common, and leads to substantial societal as well as individual consequences. The cut-off for developing liver-related disease due to alcohol is usually set to 30 g of alcohol per day for men and 20 g per day for women, although some evidence suggests these limits are set too high. Patients with concomitant liver diseases, especially when fibrosis is present, should be advised to reduce or cease alcohol consumption. In alcoholic hepatitis, selecting cases that will achieve abstinence and/ or respond to corticosteroid treatment is a challenge, as is making sure these patients are not affected by infections. Likewise, proper selection of patients suitable for liver transplantation by identifying those with a low probability of continued drinking posttransplantation is of paramount importance.

Practice points  Alcohol-induced liver disease is common, with most evidence pointing to a dose-response effect, particularly in susceptible individuals.  Women are at an increased risk for alcohol-induced cirrhosis.  Patients with alcoholic cirrhosis are at risk for development of hepatocellular carcinoma, especially if infected with viral hepatitis. Patients with cirrhosis should undergo surveillance ultrasound semi-annually.  Abstinence is key to therapeutic success in all forms of alcohol-induced liver diseases.  Smoking is associated with an increased risk of hepatocellular carcinoma, and possibly with increased progression of fibrosis in chronic liver disease.

Research agenda  The long-term, unbiased natural history of the risk alcohol poses on liver health is still unclear.  It remains to be understood why some persons develop cirrhosis and some do not, given the same amounts of ingested alcohol. Long-term studies with longitudinal data on alcohol exposure as well as risk modifiers including genetic data are eagerly awaited.  Therapeutic alternatives for alcoholic hepatitis other than corticosteroids is urgently needed.

Conflict of interest None.

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€m H, Alcohol, smoking and the liver disease patient, Best Practice & Research Clinical Gastroenterology Please cite this article in press as: Hagstro (2017), http://dx.doi.org/10.1016/j.bpg.2017.09.003