Management of alcohol-associated hepatitis

INTRODUCTION — 

Liver disease related to harmful alcohol use ranges from acute liver inflammation (ie, alcohol-associated hepatitis) to chronic diseases including steatosis alone (fatty changes), advanced fibrosis, and ultimately cirrhosis. The term alcohol-associated hepatitis refers to the recent onset of symptomatic hepatitis, characterized by jaundice and elevated liver biochemistries. The amount and duration of alcohol intake that puts an individual at risk for developing alcohol-associated hepatitis is uncertain, but most patients have a history of heavy alcohol use. Several definitions of heavy or high-risk alcohol use exist (table 1), but we typically use >280 g per week for females and >420 g per week for males as the threshold for risk of developing alcohol-associated hepatitis. One standard drink contains 14 g of alcohol (figure 1).

This topic will review the management of alcohol-associated hepatitis. Other aspects of alcohol-associated liver disease are discussed separately:

●Clinical manifestations and diagnosis of alcohol-associated hepatitis – (See "Clinical features and diagnosis of alcohol-associated hepatitis".)

●Pathogenesis of alcohol-associated liver disease (ALD) – (See "Pathogenesis of alcohol-associated liver disease".)

●Clinical features and diagnosis of alcohol-associated steatosis and cirrhosis – (See "Clinical manifestations and diagnosis of alcohol-associated steatosis and cirrhosis".)

●Management of chronic alcohol-associated steatosis and cirrhosis – (See "Management of alcohol-associated steatosis and alcohol-associated cirrhosis".)

Issues regarding alcohol use disorder are presented separately:

●(See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment".)

●(See "Alcohol use disorder: Treatment overview".)

PRETREATMENT EVALUATION

Determining disease severity — Several scoring systems have been proposed to determine the severity of alcohol-associated hepatitis [1]. For selecting patients who are more likely to benefit from pharmacologic therapy, commonly used systems are the Model for End-stage Liver Disease (MELD) score and the Maddrey (or modified) discriminant function (DF) [2-4]. (See 'MELD score' below and 'Maddrey discriminant function' below.)

The Lille score determines whether a patient is responding to pharmacologic treatment [5]. (See 'Patients with severe hepatitis' below.)

MELD score — We use the original MELD score to assess severity of liver disease in patients with alcohol-associated hepatitis. MELD score >20 indicates severe alcohol-associated hepatitis, with an estimated 90-day mortality rate of 20 percent [2]. The score ranges from 6 to 40 and is based on serum bilirubin, creatinine, and international normalized ratio (INR) [6].

The original MELD score was developed to predict survival in patients with cirrhosis and has also been used to predict mortality in patients hospitalized for alcohol-associated hepatitis [2,3,7,8]. Older prognostic studies in alcohol-associated hepatitis have typically used the original MELD score; it is uncertain whether MELD-Na or MELD 3.0 performs as well or better. However, a subsequent study validated the use of MELD 3.0 [9].

Studies suggested that MELD score was more accurate for predicting short-term mortality than DF. In a study including 2581 patients with alcohol-associated hepatitis, the median MELD score was 23.5 (interquartile range 20.5-27.8) [8]. Mortality rates at 28 and 90 days were 20 and 31 percent, respectively. The area under the receiver operating characteristic curve for 28-day mortality was higher for MELD compared with DF (0.775 versus 0.701). The performance of MELD-Na was not significantly more accurate than the original MELD score. In an earlier study, a MELD score of ≥21 had a sensitivity of 75 percent and a specificity of 75 percent for predicting 90-day mortality [2].

Other factors supporting the MELD score are its application for organ allocation worldwide, its use of INR rather than prothrombin time, and the incorporation of kidney function [7]. The original MELD score and subsequent versions of MELD are discussed in more detail separately. (See "Model for End-stage Liver Disease (MELD)".)

Maddrey discriminant function — Historically, disease severity and risk of mortality in patients with alcohol-associated hepatitis were estimated using the Maddrey (or modified) discriminant function (DF). The DF uses prothrombin time and serum bilirubin (calculator 1) [4,10]. Patients with a DF value ≥32 have higher risk of short-term mortality and may benefit from pharmacologic treatment. Although DF has been used to determine disease severity in clinical trials, it does not include kidney function and may have lower accuracy for predicting mortality than the MELD score [11-13]. (See 'MELD score' above and 'Disease course' below.)

Other severity scores — Less commonly used severity scores include the Glasgow alcohol-associated hepatitis (GAH) score. The GAH score predicts mortality in alcohol-associated hepatitis and is based on a model that includes age, serum bilirubin, blood urea nitrogen, prothrombin time, and peripheral white blood cell count (calculator 2) [14,15]. A validation study with 225 patients with alcohol-associated hepatitis and a DF ≥32 suggested that patients with a GAH score ≥9 who were treated with glucocorticoids had higher survival rates compared with no glucocorticoid therapy (78 versus 52 percent survival at 28 days and 59 versus 38 percent survival at 84 days) [14]. However, no survival benefit with glucocorticoids was seen among the patients with a GAH score <9.

Assess risk of infection — We assess patients for symptoms or signs of possible infection (eg, fever, worsening mental status, hemodynamic instability). However, when alcohol-associated hepatitis is suspected, many patients may not present with obvious signs of infection (eg, fever, leukocytosis, hemodynamic instability) due to reduced production of antibodies [16,17]. Given the high prevalence of infection at presentation [18,19], all patients with suspected alcohol-associated hepatitis should have an infectious workup including:

●Blood cultures (aerobic and anaerobic)

●Urine culture

●Chest radiograph

For selected patients, the workup also includes:

●For patients with ascites, we perform diagnostic paracentesis to obtain ascitic fluid for culture, cell count with differential, total protein, and albumin level. (See "Spontaneous bacterial peritonitis in adults: Pathogenesis, clinical features, and diagnosis".)

●For patients with productive cough or who require mechanical ventilation, we obtain sputum culture.  

●For patients with fever and neurologic symptoms suggestive of central nervous system infection (eg, headache with fever, nuchal rigidity, or focal neurologic deficits), we perform cerebrospinal fluid examination and culture. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

Studies suggested that infections were common in patients with alcohol-associated hepatitis. In a meta-analysis of 12 studies including over 1000 patients with severe alcohol-associated hepatitis, the overall rate of infection was 20 percent [20]. However, data from randomized trials have not shown a benefit of antibiotics as a preventive strategy in the absence of documented infection [21].

There is growing recognition that the microbiome is altered in patients with alcohol-associated hepatitis and may contribute to disease severity because of toxin production by either bacteria or fungi [22-26]. However, this observation has not resulted in changes in management.

Assess for acute kidney injury — We assess patients for acute kidney injury by measuring blood urea nitrogen and creatinine. Patients with alcohol-associated hepatitis may develop kidney failure, which is associated with increased mortality [27,28]. The goal is to identify and treat conditions (eg, sepsis) that may lead to acute kidney injury or kidney failure. (See 'Assess risk of infection' above.)

Hepatorenal syndrome is a potential etiology of kidney dysfunction in patients with rising creatinine despite fluid resuscitation and discontinuation of diuretics. The diagnosis and treatment of hepatorenal syndrome are discussed in detail elsewhere. (See "Hepatorenal syndrome: Clinical presentation and diagnosis" and "Hepatorenal syndrome: Treatment and prognosis".)

Assess the need for critical care support — Admission to an intensive care unit may be necessary for patients who are hemodynamically unstable or uncooperative. In addition, patients with acute alcohol intoxication or hepatic encephalopathy may require airway protection. Critical care support also includes sepsis surveillance and stress ulcer prophylaxis. (See 'Ulcer prophylaxis' below and "Evaluation and management of suspected sepsis and septic shock in adults".)

GENERAL SUPPORTIVE CARE — 

Patients with alcohol-associated hepatitis are usually treated in an inpatient setting, and some patients may require critical care support if they are hemodynamically unstable. Patients may require therapy for alcohol withdrawal, infections, and nutritional support.

Patients with alcohol-associated hepatitis may also have underlying cirrhosis. These patients may present with complications of cirrhosis and portal hypertension such as hepatic encephalopathy, ascites, or variceal bleeding. The management of complications of cirrhosis is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

The diagnosis and treatment of hepatic encephalopathy are discussed in more detail separately. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis" and "Hepatic encephalopathy in adults: Treatment".)

Alcohol abstinence — The cornerstone of managing alcohol-associated hepatitis is abstinence from alcohol. Patients are referred for treatment for alcohol use disorder (AUD) to establish and maintain abstinence. Therapies for AUD, including pharmacologic and psychosocial approaches, are discussed separately. (See "Alcohol use disorder: Treatment overview" and "Alcohol use disorder: Psychosocial management".)

Patients with alcohol-associated hepatitis are at risk for acute alcohol withdrawal because many patients have a long history of heavy alcohol use. Management of alcohol withdrawal syndrome is discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes".)

Fluids and electrolytes — Intravenous fluid and electrolyte replacement are necessary to correct and prevent dehydration or electrolyte imbalance. Limited oral intake prior to presentation may result in dehydration, so many patients require fluid resuscitation. (See "Hepatorenal syndrome: Clinical presentation and diagnosis".)

However, we avoid overhydration since it may increase the severity of ascites, lower the plasma sodium concentration, and occasionally precipitate gastrointestinal bleeding from varices. Thus, we do not routinely administer maintenance intravenous fluids to patients without prerenal azotemia, particularly if they are tolerating oral intake. The approach to fluid resuscitation in hospitalized patients is discussed separately. (See "Maintenance and replacement fluid therapy in adults".)

Nutrition support — Most patients with alcohol-associated hepatitis are undernourished and require nutritional support [29-31]. We consult a registered dietitian for an individualized nutritional plan that addresses the following:

●Vitamin and mineral repletion – The goal of nutritional support is to provide adequate calories and protein, in addition to repleting vitamins (eg, thiamine, folate, and pyridoxine) and minerals (eg, phosphate, magnesium). Of note, vitamin K is usually given to patients with a prolonged prothrombin time, even though this regimen is often ineffective because the laboratory findings are more a reflection of underlying liver disease than vitamin K deficiency. Before administering vitamin K, we confirm that the patient does not have portal vein thrombosis by reviewing imaging results (abdominal ultrasound with Doppler study).

We administer vitamin K parenterally because oral vitamin K is not well absorbed. Vitamin K administration and dosing, in addition to managing hemostatic abnormalities in patients with liver disease, are discussed separately:

•(See "Overview of vitamin K".)

•(See "Nutrition status in patients with sustained heavy alcohol use", section on 'Management of nutritional deficiencies'.)

•(See "Hemostatic abnormalities in patients with liver disease".)

●Target daily intake – The target daily caloric intake is typically 35 kcal/kg with a target daily protein intake of 1.2 to 1.5 g/kg. We do not restrict protein intake in patients with alcohol-associated hepatitis because protein is usually well tolerated. (See "Nutritional issues in adult patients with cirrhosis", section on 'Management principles'.)

●Feeding route – For patients who cannot meet caloric goals with oral intake, enteral tube feeding is generally preferred over parenteral nutrition. In our experience, patients with severe alcohol-associated hepatitis have limited oral intake. If calorie counts demonstrate inadequate oral intake, we provide nutrition via a nasogastric feeding tube.

Although undernutrition is a risk factor for mortality in observational studies, data from randomized clinical trials have not established a survival benefit in patients receiving enteral nutrition [29,30,32-34]. In a randomized trial of 136 patients with alcohol-associated hepatitis, intensive enteral nutrition (1500 calories and 75 g protein per day via nasogastric tube) did not improve six-month survival compared with conventional nutrition (44 versus 55 percent) [33]. However, daily calorie intake less than 21.5 kcal/kg was associated with increased mortality rates compared with daily calorie intake greater than 21.5 kcal/kg (63 versus 33 percent).

Adjusting medications — We hold nonselective beta-blockers in selected patients with alcohol-associated hepatitis (eg, those with hypotension [systolic blood pressure <90 mmHg]). We do not routinely discontinue nonselective beta-blockers in all patients because the benefit of such an approach has not been established [35].

Ulcer prophylaxis — We administer pharmacologic prophylaxis against stress-related peptic ulcer disease to patients who are at higher risk (ie, those who are critically ill requiring intensive care unit admission). Choosing an agent for ulcer prophylaxis, route of administration, and duration of therapy are discussed separately. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'Prophylaxis'.)

Specialty consultation — We suggest consultation with a hepatology specialist for input during the inpatient hospitalization in addition to providing long-term management.

PATIENTS WITH NONSEVERE HEPATITIS — 

Abstinence from alcohol is the mainstay of treatment in patients with nonsevere alcohol-associated hepatitis (ie, those with MELD ≤20 or DF <32). In addition, we provide general supportive care (eg, nutritional support, fluid replacement, electrolyte replacement). (See 'General supportive care' above.)

We do not use glucocorticoids or other drug therapy (eg, N-acetylcysteine, pentoxifylline) in patients with nonsevere alcohol-associated hepatitis because data have not demonstrated improved outcomes with pharmacologic therapy. (See 'Glucocorticoids (begin on hospital day 3)' below.)

We assess for clinical improvement or progression to severe alcohol-associated hepatitis by reassessing symptoms, measuring laboratory studies daily during hospitalization, and calculating the original MELD score (see 'MELD score' above):

●For patients who improve with supportive care, we arrange for close outpatient follow-up including measuring laboratory studies and scheduling an office visit within one to two weeks following hospital discharge.

●For patients who progress to severe hepatitis, our approach is similar to the care of patients who presented with severe hepatitis, as discussed below. (See 'Patients with severe hepatitis' below.)

PATIENTS WITH SEVERE HEPATITIS

Pharmacologic therapy — In addition to supportive care, we use pharmacologic therapy for patients with severe alcohol-associated hepatitis (ie, those with MELD score >20 or DF ≥32). Pharmacologic therapy consists of N-acetylcysteine and systemic glucocorticoid therapy (algorithm 1). (See 'General supportive care' above.)

N-acetylcysteine (begin on hospital day 1) — We administer N-acetylcysteine (also referred to as acetylcysteine or NAC) for patients with severe alcohol-associated hepatitis. Patients receiving intravenous (IV) N-acetylcysteine warrant close monitoring, and all essential medications and equipment necessary to manage anaphylaxis should be readily available when the initial infusion is administered (table 2). (See "Anaphylaxis: Emergency treatment".)

Potentially serious adverse reactions to IV N-acetylcysteine include a nonallergic anaphylactic reaction with symptoms such as flushing, urticaria, angioedema, or hypotension. Patients with a history of asthma appear to be at higher risk. Reactions vary in intensity and are tolerable for most patients. Pretreatment precautions and management of adverse reactions related to N-acetylcysteine are discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Acetylcysteine administration and monitoring'.)

We initiate N-acetylcysteine on admission to the hospital and use the following intravenous dosing protocol [36]:

●Day 1: N-acetylcysteine, 150 mg/kg in 250 mL of 5 percent dextrose (5 percent glucose), infused over 30 minutes, followed by 50 mg/kg in 500 mL of 5 percent dextrose infused over four hours, and then 100 mg/kg in 1 L of 5 percent dextrose infused over 16 hours.

●Days 2 through 5: N-acetylcysteine, 100 mg/kg in 1 L of 5 percent dextrose infused over 24 hours; repeat daily for four days.

For patients weighing >100 kg, the maximum dose is based on 100 kg [37].

N-acetylcysteine, an antioxidant, has been studied primarily as adjunctive therapy for severe alcohol-associated hepatitis. Use of N-acetylcysteine is supported by society guidelines, although the benefits seem limited to short-term outcomes [36,38-41]. In a network meta-analysis of 22 randomized trials, N-acetylcysteine plus glucocorticoid therapy resulted in a lower risk of short-term mortality compared with glucocorticoids alone (relative risk [RR] 0.35, 95% CI 0.16-0.78) [39]. In a trial comparing prednisolone (four-week course) plus N-acetylcysteine (five-day course) with prednisolone alone, mortality rates were lower at one month (8 versus 24 percent), but there was no significant difference in mortality rates at six months (27 versus 38 percent) [36]. However, given the trend toward increased survival with N-acetylcysteine and its generally good safety profile, additional study is warranted.

N-acetylcysteine is an antioxidant and may improve alcohol-associated hepatitis by reducing levels of free radicals and by reconstituting glutathione stores in hepatocytes [36].

Glucocorticoids (begin on hospital day 3)

Indications and precautions — We use glucocorticoid therapy for patients with severe alcohol-associated hepatitis who are not at high risk for glucocorticoid-related adverse events. Higher-risk patients include those with active, untreated infection (eg, bacterial pneumonia), active gastrointestinal bleeding, or acute kidney injury (typically defined as serum creatinine >2.5 mg/dL) [42,43]. We specifically evaluate for bacterial infections such as pneumonia, urinary tract infection, and in patients with ascites, spontaneous bacterial peritonitis. We typically do not begin glucocorticoids until the patient is afebrile, hemodynamically stable, and the infection has been treated with antimicrobial therapy for 48 hours [44].

We typically begin glucocorticoid therapy on hospital day 3 at the earliest and after a thorough assessment for potential contraindications [45]. (See 'Pretreatment evaluation' above.)

Careful monitoring for evidence of infection, gastrointestinal bleeding, or glucose intolerance is essential during a course of glucocorticoid therapy. In one report, infection developed in 24 percent of 57 patients who received glucocorticoids and was more likely to develop in those who did not respond to glucocorticoids (43 versus 11 percent) [46]. (See "Major adverse effects of systemic glucocorticoids".)

Initial dosing and administration — Initial regimens for glucocorticoid therapy include intravenous methylprednisolone, 32 mg per day, or oral prednisolone 40 mg per day. Oral prednisone, 40 mg per day, is an alternative if prednisolone is unavailable [47,48]. In an observational study comparing glucocorticoid formulations in patients with severe alcohol-associated hepatitis, survival rates were not significantly different among patients who were treated with intravenous methylprednisolone, oral prednisolone, or oral prednisone (83, 79, and 91 percent, respectively) [47].

For patients who respond to treatment, we continue oral glucocorticoid therapy for a total of 28 days [49]. (See 'Monitoring response to therapy' below.)

If the patient required intravenous methylprednisolone initially, we transition to oral glucocorticoid therapy (usually prednisone 40 mg, once daily).

Efficacy — The efficacy of glucocorticoids in alcohol-associated hepatitis has been evaluated in multiple randomized trials and meta-analyses with mixed results, possibly related to varying endpoints [16,48,50,51]. In a meta-analysis of 11 trials including 2111 patients with severe alcohol-associated hepatitis, glucocorticoid therapy resulted in a lower risk of mortality at 28 days compared with placebo (17 versus 24 percent, hazard ratio [HR] 0.64, 95% CI 0.48-0.86) [48]. However, there were no significant differences in mortality risk between the groups at six months. In addition, in the largest randomized trial from the meta-analysis, which included 1103 patients with severe alcohol-associated hepatitis, the mortality risk was not significantly lower in the glucocorticoid therapy group (odds ratio [OR] 0.72, 95% CI 0.52-1.01) [16]. In a meta-analysis that examined patient-level data from five randomized trials including 221 patients with severe alcohol-associated hepatitis, glucocorticoid therapy resulted in lower 28-day mortality rates compared with placebo (20 versus 34 percent) [50]. Conversely, in an earlier meta-analysis of 15 trials including 1861 patients with alcohol-associated hepatitis, mortality risk was not significantly different for patients treated with glucocorticoids compared with those given placebo (28 versus 30 percent; RR 0.90, 95% CI 0.70-1.15) [52]. When the analysis was restricted to trials with patients with severe alcohol-associated hepatitis, there was also no significant difference in mortality risk (RR 0.92, 95% CI 0.73-1.16). The investigators assessed the quality of the evidence as low or very low due to a high risk of bias; they also noted that adverse events were not clearly reported in many trials.

Monitoring response to therapy — We assess response to glucocorticoid therapy by measuring the Lille score on day 7 of therapy, and the results inform further management:

●Patients with Lille score ≤0.45 – Lille score ≤0.45 indicates response to glucocorticoids, and we continue glucocorticoid therapy for a total of 28 days. (See 'Transition to outpatient care' below.)

●Patients with Lille score >0.45 – Lille score >0.45 indicates lack of response, and we stop therapy in such patients [5].

For patients who have improved symptomatically and meet criteria for hospital discharge within a few days, an alternative is to measure the Lille score on day 4 of therapy [53].

The Lille score is a continuous score on a scale from zero to one, and a higher score indicates greater mortality risk at six months, with >0.45 as the threshold for indicating lack of response to glucocorticoids [5,50,54-57]. The main driver of the Lille score is the change in bilirubin on the day of testing (eg, pretreatment bilirubin minus bilirubin at day 7). Other variables are age, creatinine, albumin, and prothrombin time (or INR). In a study involving a cohort of 118 patients with severe alcohol-associated hepatitis, Lille score greater than 0.45 was associated with higher mortality rates at six months compared with a lower score (85 versus 25 percent) [5].

Some studies suggest that combining prognostic scores may be useful for predicting outcomes [58]. As an example, a cohort study including 538 patients with alcohol-associated hepatitis combined a static score (MELD) with a dynamic score (Lille score) to estimate prognosis. When the MELD score was between 15 and 45, the predicted six-month mortality for complete responders (Lille score 0.16) was between 8.5 and 49.7 percent, respectively, whereas the predicted mortality for nonresponders was between 16.4 and 75.2 percent, respectively [58].

Therapies of uncertain or no benefit — We do not use pentoxifylline for treating alcohol-associated hepatitis because data from clinical trials have not demonstrated that pentoxifylline improves survival [16,39,48]. In addition, pentoxifylline was not effective as subsequent therapy for patients who did not respond to glucocorticoids, although it does have a good safety profile [59]. A meta-analysis of four trials including 350 patients showed no significant differences in risk of mortality with pentoxifylline compared with placebo (RR 0.74, 95% CI 0.46-1.18) [39]. A meta-analysis of four trials including 459 patients showed that the combination of a glucocorticoid and pentoxifylline was not superior to treatment with a glucocorticoid alone with regard to short- or medium-term mortality (RR 0.94, 95% CI 0.69-1.30).

Pentoxifylline is a phosphodiesterase inhibitor, and it inhibits tumor necrosis factor (TNF), a cytokine involved in the pathogenesis of alcohol-associated hepatitis [60].

Clinical trials involving anakinra (an IL-1 inhibitor), or larsucosterol (a DNA methyl transferase inhibitor), have shown no benefit [61,62]. In fact, combining anakinra with zinc increased the risk of acute kidney injury [61].

Patients who do not respond to therapy — Subsequent interventions for patients with severe alcohol-associated hepatitis who do not improve with pharmacologic therapy include continued supportive care (eg, nutrition), evaluation for liver transplantation, and transition to palliative care. (See 'General supportive care' above.)

Liver transplantation — We evaluate patients with severe alcohol-associated hepatitis who do not respond to supportive care and pharmacologic therapy for liver transplantation [63,64]. Liver transplantation may be the only treatment option for patients with severe alcohol-associated hepatitis and has been lifesaving for some patients [65-67]. These issues are discussed separately. (See "Liver transplantation for alcohol-associated liver disease".)

Other options — Patients with severe alcohol-associated hepatitis who do not respond to supportive care, nutritional therapy, and pharmacologic therapy and who are not candidates for liver transplantation may be considered for palliative therapy. Such patients often have multiple organ failure. (See "Palliative care for patients with end-stage liver disease".)

TRANSITION TO OUTPATIENT CARE

Criteria for discharge — Hospitalized patients are assessed daily to determine if they are eligible for discharge. While resolution of jaundice is not a requirement, patients should meet all criteria below before they are discharged from the hospital:

●Hemodynamic stability

●Infections have been adequately ruled out and/or treated with antimicrobial therapy (ie, the patient is afebrile and has received a minimum of 48 hours of antimicrobial therapy)

●No signs of alcohol withdrawal (ie, no tremor, diaphoresis, or hallucinations) (see "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis", section on 'Clinical presentation and course')

●Sufficient social support

Enrollment in an outpatient alcohol rehabilitation program during or shortly after hospital discharge can improve outcomes by reducing the risk of readmission and mortality [68-70]. The approach to treating alcohol use disorder is presented separately. (See "Alcohol use disorder: Treatment overview" and 'Alcohol abstinence' above.)

We typically see patients for an office visit within two weeks following hospital discharge, and we measure the following laboratory studies:

●Complete blood count with platelets

●Complete metabolic profile including total bilirubin, alkaline phosphatase, and liver enzymes

●International normalized ratio (INR)

●Serum phosphatidylethanol (PEth) levels

Tapering glucocorticoids — For patients who responded to glucocorticoid therapy, we continue oral glucocorticoids (eg, prednisone, 40 mg by mouth, once daily) for 28 days. Next, we gradually taper glucocorticoids over two weeks and then discontinue them.

Glucocorticoid dosing and tapering regimens vary among studies, clinicians, and institutional protocols [45,71]. Although a 28-day course of higher dose glucocorticoid therapy is commonly used, other dosing regimens have been studied. As an example, in a trial including 254 patients with severe alcohol-associated hepatitis, a rapid tapering regimen (prednisolone 40 mg per day tapered by 10 mg per day every week over four weeks) was compared with the standard, fixed-dose regimen (prednisolone 40 mg per day for four weeks). The rapid tapering regimen resulted in lower risk of infection after 90 days (33 versus 20 percent, HR 0.57, 95% CI 0.35-0.94), whereas there were no significant differences in mortality, kidney injury, or hospitalizations between groups [71].

DISEASE COURSE

Mortality — Reported rates of mortality vary among studies and by severity of hepatitis:

●Severe hepatitis – For patients with severe alcohol-associated hepatitis, the estimated rates of longer-term mortality (≥1 year) ranged from 35 to 70 percent [16,72,73]. Short-term mortality rates were approximately 10 to 45 percent at one month [16,50,74].

●Nonsevere hepatitis – For patients with nonsevere alcohol-associated hepatitis, mortality rates at one year ranged from 2 to 20 percent [75-78]. In one study including 255 patients with alcohol-associated hepatitis, patients with nonsevere hepatitis had lower mortality at one, three, and 12 months compared with severe hepatitis (2, 3, and 10 percent, respectively, versus 14, 23, and 31 percent, respectively) [76].

Mortality is often related to liver failure in patients with alcohol-associated hepatitis. In a study including 661 patients with alcohol-associated hepatitis, the mortality rate was 34 percent with a median observation time of nearly six months [74]. The primary causes of death were liver failure (55 percent), gastrointestinal bleeding (21 percent), and sepsis (7 percent).

Long-term outcomes are also limited for patients who presented with acutely decompensated cirrhosis, with mortality rates of 50 percent at five years [78].

Risk factors for increased mortality include [16,27,78-85]:

●Older age

●Acute kidney injury

●Persistently elevated bilirubin level

●Elevated INR

●Leukocytosis

●Ongoing alcohol use

●Infection (sepsis, spontaneous bacterial peritonitis, pneumonia, urinary tract infection, fungal infection)

●Hepatic encephalopathy

●Upper gastrointestinal bleeding

●Systemic inflammatory response syndrome (see "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions')

An important determinant of outcome among patients with alcohol-associated hepatitis is whether patients continue to drink alcohol. In a series including 87 patients with alcohol-associated hepatitis who survived their index hospitalization, the overall estimated five-year survival rate was 32 percent [85]. However, among those who abstained from alcohol, the estimated survival rate was 75 percent, whereas for relapse or continuous alcohol use, survival rates were 27 and 21 percent, respectively.

Liver disease progression — Studies have suggested that most patients with severe alcohol-associated hepatitis already have underlying cirrhosis [86-90]. As an example, in a trial including 61 patients with biopsy-proven alcohol-associated hepatitis, 57 patients (93 percent) had histologic evidence of cirrhosis [86].

Whether liver function improves significantly after recovering from an episode of alcohol-associated hepatitis is uncertain. In a cohort study including 145 patients who survived an episode of severe alcohol-associated hepatitis without liver transplantation, the likelihood of achieving recompensated liver disease (ie, defined as MELD score <15 with no ascites, hepatic encephalopathy, and gastrointestinal bleeding) was 10 percent [89].  

For patients who recover from the initial episode of alcohol-associated hepatitis, who did not require a liver biopsy to establish a diagnosis, and who do not have signs of portal hypertension (eg, ascites), we evaluate for liver fibrosis using a noninvasive imaging study such as ultrasound-based transient elastography. This is discussed separately. (See "Clinical features and diagnosis of alcohol-associated hepatitis", section on 'Post-diagnosis evaluation'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Alcohol-associated liver disease".)

SUMMARY AND RECOMMENDATIONS

●Pretreatment evaluation – The pretreatment evaluation includes (see 'Pretreatment evaluation' above):

•Define disease severity – Management of patients with alcohol-associated hepatitis is informed by disease severity because patients with severe disease are more likely to benefit from pharmacologic therapy. (See 'Determining disease severity' above.)

We use the original MELD score to assess disease severity, and MELD score >20 indicates severe alcohol-associated hepatitis. An alternative scoring system is the Maddrey discriminant function (DF) (calculator 1), and DF ≥32 indicates severe hepatitis.

•Assess risk of infection – We assess patients for symptoms or signs of possible infection (eg, fever, worsening mental status, hemodynamic instability). However, all patients with alcohol-associated hepatitis have an infectious workup, even in the absence of symptoms.

•Assess for acute kidney injury.

•Assess need for critical care support.

●General supportive care – Patients with alcohol-associated hepatitis require general supportive care, including (see 'General supportive care' above):

•Alcohol abstinence, including referral for treatment of alcohol use disorder

•Prevention and treatment of alcohol withdrawal (see "Management of moderate and severe alcohol withdrawal syndromes")

•Fluid and electrolyte management

•Nutritional support

We administer prophylaxis against peptic ulcer disease for patients at high risk (ie, those with critical illness). (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'Prophylaxis'.)

●Patients with nonsevere alcohol-associated hepatitis – Management of nonsevere alcohol-associated hepatitis involves general supportive care (eg, nutritional support, fluid replacement, electrolyte replacement) in addition to abstaining from alcohol. (See 'Patients with nonsevere hepatitis' above.)

●Patients with severe alcohol-associated hepatitis – For patients with severe alcohol-associated hepatitis (MELD >20 or DF ≥32), we recommend N-acetylcysteine combined with glucocorticoid therapy rather than glucocorticoid therapy alone or supportive care alone (algorithm 1) (Grade 1B). (See 'Patients with severe hepatitis' above.)

The therapeutic regimen includes:

•Hospital day 1 – We begin intravenous N-acetylcysteine on day 1 of hospital admission and continue therapy for five days. (See 'N-acetylcysteine (begin on hospital day 1)' above.)

•Hospital day 3 – For patients without risk factors such as active infection, gastrointestinal bleeding, or acute kidney injury, we typically initiate glucocorticoid therapy on hospital day 3 at the earliest. Initial options include intravenous methylprednisolone, 32 mg per day; oral prednisolone, 40 mg per day; or oral prednisone, 40 mg per day. (See 'Glucocorticoids (begin on hospital day 3)' above.)

We assess response to glucocorticoids by measuring the Lille score on day 7 of therapy:

-For patients who respond (Lille score ≤0.45), we continue glucocorticoid therapy for a total of 28 days.

-For patients who do not improve (Lille score >0.45), we stop glucocorticoids. Subsequent options include continued supportive care (eg, nutrition), evaluation for liver transplantation, or transition to palliative care. (See 'Patients who do not respond to therapy' above.)

●Transition to outpatient care – For patients who improve with supportive care and/or pharmacologic therapy, the following criteria should be met prior to hospital discharge (see 'Transition to outpatient care' above):

•Hemodynamic stability

•Infections have been ruled out and/or adequately treated with antimicrobial therapy

•No signs of alcohol withdrawal (eg, tremor, diaphoresis, hallucinations) (see "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis", section on 'Clinical presentation and course')

•Sufficient social support