Characteristic histological findings of AH include macro vesicular steatosis, lobular infiltration of neutrophils with hepatocyte damage (Mallory–Denk bodies and/or ballooning), bilirubin stasis and liver fibrosis, which is typically described as peri cellular and sinusoidal (“chicken wire” appearance) (58) (Figure 4). These features are indistinguishable from non-ASH and the alcohol–non-ALD index (including body mass index, gender, AST, ALT, and mean cell volume of the red blood cells or mean corpuscular volume) can be helpful to distinguish the two in cases of unclear alcohol consumption (59). The majority of AH patients have underlying macronodular cirrhosis, which is not easily distinguishable from other forms of cirrhosis. When cirrhosis is established, steatosis may be less prominent. On electron microscopic examination, megamitochondria may be observed. If liver biopsy is performed for diagnosis of AH, the findings may also have prognostic value. For example, one recent study showed that presence of severe fibrosis, megamitochondria, degree of neutrophil infiltration, and cholestasis could predict prognosis in patients with AH (60).
Many scoring systems have been developed to predict severity of AH. The Maddrey Discriminant Function is the most time tested and validated scoring system, with severe AH defined by Maddrey Discriminant Function ≥32 (61). Retrospective and prospective analysis of this score indicates that Maddrey Discriminant Function ≥32 predicts a mortality rate of ˜20–50% over 30 days (62). Most clinical trials for AH have used this score based on its use in the original corticosteroid trials. A number of other scoring systems have also been validated and generally performed similar to the Maddrey score, including the MELD score, Age Bilirubin INR Creatinine (ABIC) score, and the Glasgow scale (62). The MELD score is being increasingly used to assess severity of AH given its better accuracy, worldwide use in organ allocation, INR as standard in reporting prothrombin time, and incorporation of renal function and serum creatinine, which is a major determinant of outcomes in AH patients. A MELD score >20 has been proposed as defining severe AH with an ˜20% mortality (63). Lille score (a continuous score with a scale from 0 to 1) at 4–7 days of corticosteroids therapy can be used to assess the response to corticosteroids (Lille score <0.45) (64). Most of these scores by themselves do not predict prognosis accurately after 90 days and are most predictive at 30 days. A number of other variables influence prognosis after 30–90 days, most notably the ability to maintain abstinence from alcohol or not (5,6). Recent studies have shown that combination use of MELD at baseline and Lille score at day 7 has best discrimination and calibration for 2-month and 6-month mortality (65). In addition, serum lipopolysaccharide levels, SIRS criteria, and other serum markers may also serve as biomarkers of mortality (56).
General measures and supportive treatment: provided to all AH patients irrespective of disease severity.
Patients hospitalized with severe AH often have history of active heavy alcohol use and present with manifestations of the SIRS (56). Sepsis and malnutrition are common among this population (4). Ascites, variceal bleeding, and hepatic encephalopathy may also be present. In-patient management should therefore focus on alcohol withdrawal, nutritional supplementation, infections and sepsis, complications of cirrhosis and portal hypertension, and specific treatment of AH. Patients may also develop acute on chronic liver failure, which manifests with hepatic and extrahepatic organ failure requiring intensive care (see below).
Sepsis surveillance should be performed and broad-spectrum antibiotics should be administered before transfer to the ICU, or within one hour of admission. The choice of antibiotics depends on prevailing local antimicrobial resistance patterns. Piperacillin-tazobactam is generally the preferred drug used for sepsis, although vancomycin and meropenem may be considered in patients with penicillin hypersensitivity. As sepsis is difficult to diagnose in this group and about 40– 50% of patients may be culture negative, there should be a low threshold for diagnosis of infection and initiation of antibiotic therapy. Diagnosis of infections in patients with AH and cirrhosis should be performed using standardized definitions and guidelines (78). It is important to differentiate community acquired infections from nosocomial infections (onset after 48 h of admission to hospital) or healthcare-associated infections (within first 48 h of admission in patients with hospitalization within past 6 months, clinic visit within past 30 days, or those residing in nursing homes), as the empiric antibiotics for nosocomial or healthcare-associated infections should cover broadly for multidrug resistant bacteria, and in select high-risk cases for atypical organisms and fungal infections.
Ulcer prophylaxis is recommended using proton pump inhibitors. Both proton pump inhibitors and H2 antagonists increase the risk of infections such as aspiration pneumonia and clostridium difficile, but decrease the risk of chemical pneumonitis and gastrointestinal bleeding. Proton pump inhibitors are superior to H2 antagonists for the prevention of gastrointestinal bleeding. Glucose control is targeted to levels <200 mg/dL and transfusion is required with the hemoglobin target of 7–8 g/dL.
Organ failure scores are used to determine severity of acute on chronic liver failure. Patients with renal failure and acute kidney injury should receive diligent care with the aim to identify and reverse precipitating factors and improve renal function. Renal replacement therapy is recommended in the presence of acute kidney injury in the presence of sepsis-associated acute tubular necrosis, or if the cause of acute kidney injury is unclear. In the presence of hepatorenal syndrome, a therapeutic trial of renal replacement therapy may be considered in patients who are potential liver transplant candidates. Patients requiring pulmonary support should receive low tidal volume to avoid lung injury. Vasoconstrictors and pressor may be needed to maintain mean blood pressure of >65 mm Hg.
Prednisolone is preferred over prednisone, as the latter requires conversion to prednisolone, which may be impaired in patients with impaired liver synthetic function. Moreover, prednisone did not improve patient survival in a randomized clinical trial (89). Prednisolone is used in a dose of 40 mg per day for a total duration of 4 weeks. Methylprednisolone 32 mg per day by intravenous route is used for patient unable to take oral medications. There are no studies examining different doses and durations of corticosteroid therapy. Response to therapy is determined at 1 week of therapy using the Lille score. About 50–60% of patients do not respond to steroids (Lille score>0.45) and these patients do not derive further benefit from continuing steroids (Figure 3) (64). Recently, the Lille score at day 4 of corticosteroid therapy has been shown to be as accurate as day 7 Lille score in predicting the outcome and response to treatment, although this observation needs further validation studies (93). Unpredictable response to corticosteroids combined with fear of adverse effects, especially risk of infections limit the use of these drugs in routine clinical practice, with only 25–45% providers using them as reported in two different surveys (94,95). There is a clear unmet need for development of safer effective pharmacological options for management of AH patients and for biomarkers to predict response to corticosteroids at the time of presentation (96,97,98).
Active hepatitis B virus infection and active tuberculosis are contraindications for use of corticosteroids (99). Although HCV infection may potentially worsen the outcome of AH patients (30,100,101,102), there are no data on whether 4 weeks of corticosteroid therapy will increase HCV replication or that HCV infection worsens the response to corticosteroids. Active infection or sepsis, uncontrolled diabetes mellitus, and gastrointestinal bleeding remain relative contraindications to the use of corticosteroids. In these situations, corticosteroids can be used once the contraindication has been reversed with appropriate therapy. For example, use of corticosteroids after adequate control of infection has been reported to provide similar benefit as in uninfected patients (103). However, development of infections remains a concern among patients treated with corticosteroids, as these drugs compromise the immune status of an individual, putting them at risk for infections (104). In pooled data from 12 randomized studies comparing corticosteroids and placebo, infections during treatment occurred in about 20%, with steroid use associated with risk of fungal infections (105). In one study comprising patients with high bacterial DNA levels (>18.5 pg/mL) enrolling in the STOPAH study, the use of prophylactic antibiotics improved patient survival in corticosteroids treated patients (106). There remains an unmet need to determine accurate biomarkers with a potential for earlier diagnosis of infections, and randomized studies exploring benefit of antibiotics used as prophylaxis or as adjuvant to corticosteroids among patients with AH at high risk for development of infections (56).
LT is a definitive therapy for patients with cirrhosis and end-stage liver disease. Alcoholic cirrhosis is the third most common indication for LT after hepatitis C and non-alcoholic fatty liver disease. LT for alcohol related cirrhosis accounts for about 15% of all liver transplants in the United States and about 20% in Europe (145,146,147). Similarly, of all the LT performed, about 10% and 6% are performed for HCV-infected drinkers in the United States and Europe, respectively (145,146,147).
Involvement of addiction specialists and incorporation of an addiction unit within the LT center is useful in reducing frequency of drinking and recidivism compared to referring these patients to an outside center for addiction therapy (161). However, the patient's degree of illness and transportation issues may be significant limiting factors in these patients' ability to complete therapy sessions (40).
It is important to emphasize that LT cures the liver disease, but not the underlying AUD (150). Prevalence of recidivism varies from 10 to 60% across different studies due to variations on definition of recidivism (any or harmful alcohol use) and on follow-up time after LT. In a pooled data from 50 studies on LT for alcoholic cirrhosis, annual incidence of recidivism was 5.7% and 2.5% for any alcohol use and for harmful use, respectively (166). Recidivism is most likely to be reported after 2 years of LT with the majority of recidivists reporting intermittent use of alcohol (155,167). Patients with harmful use of alcohol after LT have 10-year survival rates 45–71%, compared with 75–93% among abstinent patients or those with occasional slips (168,169,170,171). Self-reported alcohol use is often unreliable (159,172), and biomarkers of alcohol consumption can help in identifying patients with ongoing alcohol consumption (please refer to the section on ‘Diagnosis of AUD’).
The limited data comparing outcomes of patients receiving LT for liver disease due to combined ALD and HCV infection with LT for alcoholic cirrhosis have shown conflicting findings, likely due to variations on HCV treatment before LT and on data source (registry based vs. single-center chart review) (173,174,175). Whether outcomes of transplant recipients of HCV infected drinkers will improve with the advent of newer potent and safer anti-HCV therapy, remains a testable hypothesis, yet to be answered.
The risk for aero-digestive cancers is higher among transplant recipients with a history of smoking prior to LT and who continue to smoke after LT (179,180). The risk of malignancy may be also related to dose and type of immunosuppression. Compared with other immune-suppressing drugs, malignancy risk is lower with agents targeting mammalian target of rapamycin inhibitors such as sirolimus an everolimus, given their anti-tumor effects (181,182).
Recurrent alcoholic cirrhosis is reported in about 5% of all LT performed for alcoholic cirrhosis, with cumulative probability of 33–54% at 10 years after LT among recidivists (183,184). Survival of patients with recurrent cirrhosis is about 41 and 21% at 10 and 15 years after LT respectively, compared to similar survival rates of about 70 and 50% among abstainers (183). Immunosuppression should be maintained at the lowest safe levels as with all patients who undergo a liver transplant; it is unclear whether everolimus or sirolimus are superior to calcineurin inhibitors among patients transplanted for alcoholic cirrhosis (185).
To minimize the risk of recidivism, most transplant centers require a minimum of 6 months of abstinence before considering LT for a patient with ALD. However, patients with severe AH not responding to medical therapy cannot afford to meet this requirement given their short-term mortality at 1 month from presentation as high as 50% (96). The lack of effective rescue medical therapies for non-responders to prednisolone provides the rationale for considering early LT.
Despite these encouraging data, there remain barriers at every level to use this treatment modality for AH. For example, in a recently reported survey, LT center directors in the US reported center protocol, socio-cultural issues, organ shortage, and insurance approval as barriers to LT in AH (190). In this survey, there was agreement among the transplant centers on excellent psychosocial support and non-response to corticosteroids as criteria for patient selection. However, only 50% of LT centers were using all the five criteria proposed in the study by Mathurin et al. (190). Further, 1-year survival of 77% as reported in the prospective study is inferior to historic survival of over 90% after LT for alcoholic cirrhosis, with majority of deaths being due to invasive fungal infections (145,186). Patients with severe AH are prone to fungal infections, especially those who are non-responders to corticosteroids (105,193). Prospective multicenter studies are needed as basis for deriving guidelines for selection of AH patients for LT, antibiotic protocol for infection prevention in the perioperative period, and immunosuppression protocol on long-term follow-up of these patients.
Alcohol use constitutes a huge economic and population burden in the United States and worldwide. Despite the known hepatotoxic effect of alcohol use, the field lacks availability of effective safe pharmacotherapies for management of ALD patients. With growing interest of the research community and increasing funding from National Institute of Alcoholism and Alcohol Abuse and other organizations, the future holds promise for overcoming some of these urgent unmet clinical needs in this field (Table 5).
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to David W. Wan, MD, FACG, who served as guideline monitor for this document. We acknowledge and thank the services from the librarian from the Mayo Clinic on systematic literature search, and Deb Frank for administrative assistance support.
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