Six month abstinence rule for liver transplantation in severe alcoholic liver disease patients

Alcoholic liver disease(ALD) is the second most common diagnosis among patients undergoing liver transplantation(LT). The recovery results of patients transplanted for ALD are often at least as good as those of patients transplanted for other diagnoses and better than those suffering from hepatitis C virus, cryptogenic cirrhosis, or hepatocellular carcinoma. Inthe case of medically non-responding patients with severe acute alcoholic hepatitis or acute-on chronic liver failure, the refusal of LT is often based on the lack of the required alcohol abstinence period of six months. The obligatory abidance of a period of abstinence as a transplant eligibility requirement for medically non-responding patients seems unfair and inhumane, since the majority of these patients will not survive the six-month abstinence period. Data from various studies have challenged the 6-mo rule, while excellent survival results of LT have been observed in selected patients with severe alcoholic hepatitis not responding to medical therapy. Patients with severe advanced ALD should have legal access to LT. The mere lack of pre-LT abstinence should not be an obstacle for being listed.     

Liver transplantation for patients with alcoholic liver disease: An open question

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase.In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.     

Long-term survival after liver transplantation for alcoholic liver disease

Currently,alcoholic cirrhosis is the second leading indication for liver transplantation in the United States and Europe.The quality of life and survival after a liver transplantation(LT)in patients with alcoholic liver disease(ALD)are similar to those in patients with other cirrhosis etiologies.The alcoholic relapse rate after a LT varies from 10%-50%,and these relapse patients are the ones who present a reduced long-term survival,mainly due to cardiovascular diseases and the onset of de novo neoplasms,including lung and upper aerodigestive tract.Nearly 40%of ALD recipients resume smoking and resume it early post-LT.Therefore,our pre-and post-LT follow-up efforts regarding ALD should be focused not only on alcoholic relapse but also on treating and avoiding other modifiable risk factors such as tobacco.The psychiatric and psychosocial pre-LT evaluation and the post-LT follow-up with physicians,psychiatrists and addiction specialists are important for reversing these problems because these professionals help to identify patients at risk for relapse as well as those patients who have relapsed,thus enabling responsive actions.     

Liver transplantation for alcoholic liver disease: Lessons learned and unresolved issues

The use of liver transplantation(LT) as a treatment for alcoholic liver disease(ALD) has been highly controversial since the beginning. The ever increasing shortage of organs has accentuated the low priority given to patients suffering from ALD, which is considered a "self-inflicted" condition. However, by improving the long-term survival rates, making them similar to those from other indications, and recognizing that alcoholism is a primary disease, ALD has become one of the most common indications for LT in Europe and North America, a situation thought unfathomable thirty years ago. Unfortunately, there are still many issues with the use of this procedure for ALD. There are significant relapse rates, and the consequences of excessive drinking after LT range from asymptomatic biochemical and histological abnormalities to graft failure and death. A minimum three-month period of sobriety is required for an improvement in liver function, thus making LT unnecessary, and to demonstrate the patient's commitment to the project, even though a longer abstinence period does not guarantee lower relapse rates after LT. Recent data have shown that LT is also effective for severe alcoholic hepatitis when the patient is unresponsive to corticosteroids therapy, with low relapse rates in highly selected patients, although these results must be confirmed before LT becomes a standard procedure in this setting. Finally, LT for ALD is accompanied by an increased risk of de novo solid organ cancer, skin cancer, and lymphoproliferative disorders, which has a large impact on the survival rates.     

Challenges in transplantation for alcoholic liver disease

Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist’s assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient’s pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key factor determining the outcome of transplantation for alcoholic cirrhosis is intensive lifelong medical and psychological care. Post-transplant surveillance might be much more important than pre-transplant selection.     

Liver transplantation in alcoholic liver disease current status and controversies

Alcoholic cirrhosis remains the second most common indication for liver transplantation.A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list.Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients.Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation(recidivism).These patients need to be identified and require alcohol rehabilitation treatment before transplantation.Recidivism to the level of harmful drinking is reported in about 15%-20%cases.Although,recurrent cirrhosis and graft loss from recidivism is rare,occurring in less than 5%of all alcoholic cirrhosis-related transplants,harmful drinking in the post-transplant pe-riod does impact the long-term outcome.The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease.Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome.The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids.Emerging data from retrospective and prospective studies has challenged the 6 mo rule,and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids.     

Addiction specialist's role in liver transplantation procedures for alcoholic liver disease

Although liver transplantation(LT) is performed increasingly for patients with end-stage alcoholic liver disease(ALD), the topic remains controversial. Traditionally, the role of an addiction specialist focused on the screening and identification of patients with a high risk on relapse in heavy alcohol use. These patients were in many cases subsequently excluded from a further LT procedure.Recently, awareness is growing that not only screening of patients but also offering treatment, helping patients regain and maintain abstinence is essential, opening up a broader role for the addiction specialist(team)within the whole of the transplant procedure. Within this context, high-risk assessment is proposed to be an indication of increasing addiction treatment intensity,instead of being an exclusion criterion. In this review we present an overview regarding the state of the art on alcohol relapse assessment and treatment in patients with alcohol use disorders, both with and without ALD.Screening, treatment and monitoring is suggested as central roles for the addiction specialist(team) integrated within transplant centers.     

重症酒精性肝炎与肝移植

饮酒相关性肝病包括酒精性脂肪肝（alcoholic steatosis,AS）、酒精性肝炎（alcoholic hepatitis,AH）和酒精性肝硬化（alcoholic liver cirrhosis,ALC）等一组疾病[1]。重症酒精性肝炎（severe alcoholic hepatitis, SAH）是AH的严重类型,可发生于无肝病史的人群（急性酒精中毒）,也可发生在AS或ALC患者。主要表现为发热、肝脏肿大伴触痛、血清胆红素和外周血白细胞显著升高,可伴有慢性肝损伤和门脉高压的表现。 SAH 患者Maddrey 判别函数（Maddrey discrimi-nant function,MDF）［MDF=4.6x（PT-正常对照）＋TBIL （mg/dl）］通常≥32分,极易并发感染和多器官功能衰竭[2]。即使积极治疗,SAH 患者近期病死率仍可高达35%至50%[3]。     

Therapy for alcoholic liver disease

Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function ≥ 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and portopulmonary hypertension. Alcoholic cirrhotics have increased risk of developing hepatomas. Liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 mo of proven abstinence for eligibility. Alcoholic cirrhotics who maintain abstinence generally have a relatively favorable prognosis after liver transplantation.     

Management of chronic hepatitis B in severe liver disease

In the past few decades,chronic hepatitis B(CHB)has evolved from a disease that was untreatable and progressive,to one that can be easily controlled with antiviral therapy.However,patients with severe liver disease still remain difficult to treat despite the availability of highly potent nucleos(t)ide analogs.These include those with underlying cirrhosis,severe flares of CHB,hepatocellular carcinoma(HCC),and for those undergoing liver transplantation.For those with established cirrhosis,antiviral therapy should be considered for all,as unpredictable flares can still occur,which can be fatal for those with advanced chronic liver disease.However,even with effective viral suppression,the development of HCC can still occur.For patients with severe flares of CHB,although the use of antiviral can improve long term outcomes,a significant proportion may still die without liver transplantation.The short term prognosis of these patients is dependent on both the severity of flare and underlying pre-existing liver disease.In patients with decompensated cirrhosis,liver failure secondary to severe flares,or those with HCC,liver transplantation may be curative.After liver transplantation,long term antiviral therapy is required to prevent graft loss from recurrent hepatitis B infection.The use of hepatitis B immune globulin(HBIG)in combination with an oral antiviral agent has been the mainstay of post-transplant antiviral regimen for over adecade.With newer and more potent antiviral agents such as tenofovir and entecavir,use of these agents along with HBIG have demonstrated to be effective in preventing significant recurrence in the long term.     

Candidates for liver transplantation with alcoholic liver disease: Psychosocial aspects

In Europe, 30% to 50% of liver transplantations are currently due to alcoholic liver disease(ALD). In the United States, this percentage is 17.2%. Post-transplantsurvival and other predictors of clinical course do not differ significantly from those in other types of transplanted patients, as long as there is no relapse of drinking. However, 20%-25% of these patients lapse or relapse to heavy drinking post-operatively, which has been associated with an increased risk of liver damage and mortality. It is therefore crucial to design specific selection and follow-up strategies aimed at this particular type of patient. Several good and poor prognosis factors that could help to predict a relapse have been suggested, among them the duration of abstinence, social support, a family history of alcoholism, abuse diagnosis versus alcohol dependence, non-acceptance of diagnosis related to alcohol use, presence of severe mental illness, nonadherence in a broad sense, number of years of alcoholism, and daily quantity of alcohol consumption. In this article, we discuss these and other, more controversial factors in selecting ALD patients for liver transplantation. Abstinence should be the main goal after transplantation in an ALD patient. In this article, we review the several definitions of post-transplant relapse, its monitoring and the psychopharmacological and psychotherapeutic treatment.     

Predicting utility of a model for end stage liver disease in alcoholic liver disease

AIM: To validate the statistic utility of both the Maddrey Discriminant Function score and the Model for End-Stage Liver Disease as predictors of short term (30 d and 90 d) mortality in patients with alcoholic hepatitis and to assess prognostic factors among clinical characteristics and laboratory variables of patients with alcoholic hepatitis. METHODS: Thirty-four patients with the diagnosis of alcoholic hepatitis admitted to Hippokration University Hospital of Athens from 2000 to 2005 were assessed in the current retrospective study and a statistical analysis was conducted. RESULTS: 30- and 90-d mortality rates were reported at 5.9% (2/34) and 14.7% (5/34), respectively. Significant correlation was demonstrated for the Model for End-Stage Liver Disease (P30=0.094, P90=0.046) and the Maddrey Discriminant Function score (P30= 0.033, P90= 0.038) with 30- and 90-d mortality whereas a significant association was also established for alanine aminotrans-ferase (P = 0.057), fibrin degradation products (P= 0.048) and C-reactive protein (P = 0.067) with 90-d mortality. For 30-d mortality the Area Under the Curve was 0.969 (95%CI: 0.902-1.036, P = 0.028) for the Model for End-Stage Liver Disease score and 0.984 (95%CI: 0.942-1.027, P = 0.023) for the Maddrey Discriminant Function score with the optimal cut off point of 30.5 (sensitivity 1, specificity 0.937) and 108.68 (sensitivity 1, specificity 0.969), respectively. Accordingly, for 90-d mortality the Area Under the Curve was 0.762 (95%CI: 0.559-0.965, P = 0.065) for the Model for End-Stage Liver Disease score and 0.752 (95%CI: 0.465-1.038, P = 0.076) for the Maddrey Discriminant Function score with the optimal cut off point of 19 (sensitivity 0.6, specificity 0.6) and 92 (sensitivity 0.6, specificity 0.946), respectively. The observed Kaplan Meier survival rates for different score-categories were compared with log-rank tests and higher score values were correlated with a lower survival. CONCLUSION: Equivalency of the Model for End-Stage Liver Disease and the Maddrey Discriminant Function score is implied by the current study, verified by the plotted Receiver Operative Curves and the estimated survival rates. A statistically significant utility of C-reactive protein, fibrin degradation products and alanine aminotrans-ferase as independent predictors of 90-d mortality has also been verified.     

Perceptions of post-transplant recidivism in liver transplantation for alcoholic liver disease

Although alcoholic liver disease (ALD) is regarded as a common indication for liver transplantation (LT), debatable issues exist on the requirement for preceding alcoholic abstinence, appropriate indication criteria, predictive factors for alcoholic recidivism, and outcomes following living-donor LT. In most institutions, an abstinence period of six months before LT has been adopted as a mandatory selection criterion. Data indicating that pre-transplant abstinence is an associated predictive factor for alcoholic recidivism supports the reasoning behind this. However, conclusive evidence about the benefit of adopting an abstinence period is yet to be established. On the other hand, a limited number of reports available on living-donor LT experiences for ALD patients suggest that organ donations from relatives have no suppressive effect on alcoholic recidivism. Prevention of alcoholic recidivism has proved to be the most important treatment after LT based on the resultant inferior long-term outcome of patients. Further evaluations are still needed to establish strategies before and after LT for ALD.     

Liver transplantation for alcoholic liver disease among Canadian transplant centres: A national study

BACKGROUND/OBJECTIVE:

Alcoholic liver disease (ALD) is a controversial yet established indication for liver transplantation (LT), and there is emerging evidence supporting a survival benefit in selected patients with severe acute alcoholic hepatitis. The aim of the present survey was to describe policies among Canadian transplant centres for patients with ALD.

METHODS:

A survey was distributed to the medical directors of all seven liver transplant centres in Canada.

RESULTS:

All seven liver transplant programs in Canada participated in the survey. Every centre requires patients to have a minimum of six months of abstinence from alcohol before listing for LT. Completion of a rehabilitation program is only mandatory in one program; the remaining programs do not mandate this if patients have demonstrated prolonged abstinence, and sufficient insight and social supports. No program considers LT for patients with severe acute alcoholic hepatitis, although six of the seven programs are interested in exploring a national policy. Random alcohol checks for waitlisted patients are performed routinely on patients listed for ALD at only one centre; the remaining centres only perform checks if there is clinical suspicion. In the past five years, the mean (± SD) number of patients per centre with graft dysfunction from recidivism was 10±4.36; a mean of 2.5±4.36 patients per centre developed graft failure.

CONCLUSIONS:

With minor exceptions, LT policies for subjects with ALD are uniform across Canadian transplant programs. Presently, no centres perform LT for acute alcoholic hepatitis, although there is broad interest in exploring a national policy. Recidivism resulting in graft loss is a rare phenomenon.     

Trends in hospitalization for alcoholic hepatitis from 2011 to 2017: A USA nationwide study

BACKGROUNDSevere alcoholic hepatitis (AH) is one of the most lethal manifestations of alcohol-associated liver disease. In light of the increase in alcohol consumption worldwide, the incidence of AH is on the rise, and data examining the trends of AH admission is needed.AIMTo examine inpatient admission trends secondary to AH, along with their clinical outcomes and epidemiological characteristics.METHODSThe National Inpatient Sample (NIS) database was utilized, and data from 2011 to 2017 were reviewed. We included individuals aged ≥ 21 years who were admitted with a primary or secondary diagnosis of AH using the International Classification of Diseases (ICD)-9 and its correspondent ICD-10 codes. Hepatitis not related to alcohol was excluded. The national estimates of inpatient admissions were obtained using sample weights provided by the NIS.RESULTSAH-related hospitalization demonstrated a significant increase in the USA from 281506 (0.7% of the total admission in 2011) to 324050 (0.9% of the total admission in 2017). The median age was 54 years. The most common age group was 45–65 years (range 57.8%–60.7%). The most common race was white (63.2%–66.4%), and patients were predominantly male (69.7%–71.2%). The primary healthcare payers were Medicare (29.4%–30.7%) and Medicaid (21.5%–32.5%). The most common geographical location was the Southern USA (33.6%–34.4%). Most patients were admitted to a tertiary care center (50.2%–62.3%) located in urban areas. Mortality of AH in this inpatient sample was 5.3% in 2011 and 5.5% in 2017. The most common mortality-associated risk factors were acute renal failure (59.6%–72.1%) and gastrointestinal hemorrhage (17.2%–20.3%). The total charges were noted to range between $25242.62 and $34874.50.CONCLUSIONThe number of AH inpatient hospitalizations significantly increased from 2011 to 2017. This could have a substantial financial impact with increasing healthcare costs and utilization. AH-mortality remained the same.     

Ohio solid organ transplantation consortium criteria for liver transplantation in patients with alcoholic liver disease

AIM To evaluate risk of recidivism on a case-by-case basis.METHODS From our center's liver transplant program,we selected patients with alcoholic liver disease who were listed for transplant based on Ohio Solid Organ Transplantation Consortium(OSOTC) exception criteria.They were considered to have either a low or medium risk of recidivism,and had at least one or three or more months of abstinence,respectively.They were matched based on gender,age,and Model for End-Stage Liver Disease(MELD) score to controls with alcohol-induced cirrhosis from Organ Procurement and Transplant Network data.RESULTS Thirty six patients with alcoholic liver disease were approved for listing based on OSOTC exception criteria and were matched to 72 controls.Nineteen patients(53%) with a median [Inter-quartile range(IQR)] MELD score of 24(13) received transplant and were followed for a median of 3.4 years.They were matched to 38 controls with a median(IQR) MELD score of 25(9).At one and five years,cumulative survival rates(± standard error) were 90% ± 7% and 92% ± 5% and 73% ± 12% and 77% ± 8% in patients and controls,respectively(Log-rank test,P = 0.837).Four(21%) patients resumed drinking by last follow-up visit.CONCLUSION Compared to traditional criteria for assessment of risk of recidivism,a careful selection process with more flexibility to evaluate eligibility on a case-by-case basis can lead to similar survival rates after transplantation.     

Advances in alcoholic liver disease:An update on alcoholic hepatitis

Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality(25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material(Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline.