Alcoholic Hepatitis: Advances, Controversies, And Unanswered Questions

Introduction

Controlling alcohol consumption in society remains a major challenge. The effects of alcohol place a significant burden on healthcare systems and contribute to the development of alcoholic liver disease. One of the most severe forms of this condition is alcoholic hepatitis (AH), a complex disease associated with high mortality rates. Research into AH has provided a broader and deeper understanding of its diagnosis, severity assessment, treatment, and outcome prediction [1, 2]. The aim of this article is to review key studies and their influence on clinical decision-making, while also identifying gaps in current knowledge about the disease.

Methods

A literature search was conducted using the PubMed database with the keywords alcoholic hepatitis and alcoholic liver disease. Studies were selected based on their impact on disease diagnosis, severity assessment, and treatment selection.

Prognostic Calculators

Several prognostic models can be used to assess outcomes in patients with AH, including the Glasgow Alcoholic Hepatitis Score (GAHS), Modified Discriminant Function (mDF), Model for End-Stage Liver Disease (MELD), and ABIC (Age, Bilirubin, INR, and Creatinine). Among these, mDF is considered one of the first major tools developed for evaluating disease severity. However, its accuracy is limited because it relies on variables that may vary between laboratories, similar to MELD-based calculations [3]. Although mDF remains widely used in clinical practice, its precise role in guiding treatment decisions remains uncertain. Comparisons of these prognostic calculators have demonstrated differences in their ability to predict treatment outcomes. Among them, mDF appears to be the least accurate [4, 5]. Significant variations have been identified in sensitivity, specificity, and recommended cut-off values. The mDF score is characterized by high sensitivity but relatively low specificity, creating a risk that some patients may receive unnecessary or inappropriate treatment. In contrast, calculators with higher specificity but lower sensitivity, such as ABIC, may fail to identify some patients with a poor prognosis [5]. Studies have shown that GAHS is more specific and accurate than mDF in predicting outcomes in patients with AH [6]. MELD is also considered relatively accurate, although its performance depends heavily on the selected threshold value. Recommended cut-offs vary between 18 and 25, and no universal consensus has been reached [7]. The values generated by MELD, mDF, ABIC, and GAHS may differ depending on laboratory techniques and assay sensitivity. As a result, the same patient may receive different prognostic assessments in different clinical laboratories. Variations in reagents used to calculate INR have the greatest influence on these discrepancies [3, 8]. In addition, hyperbilirubinemia, which is common in AH, may affect measured creatinine concentrations even when enzymatic methods are used [9]. For this reason, GAHS evaluates renal function using urea rather than creatinine levels. The value of prognostic calculators extends beyond identifying patients with poor outcomes. In clinical practice, these tools should also help determine which treatment strategy is most likely to benefit an individual patient. A retrospective study demonstrated that corticosteroid therapy was ineffective in patients with mDF >32 but GAHS ≤8, whereas patients with mDF >32 and GAHS >8 experienced improved survival with corticosteroid treatment [10]. Whether corticosteroid therapy remains effective in patients with very high MELD scores remains unclear. Further analyses of prospective trials, including STOPAH, are expected to provide additional insight. At present, the choice of prognostic calculator largely depends on clinician preference and experience.

Significance of Sepsis

Bacterial infection significantly worsens the condition of patients with liver cirrhosis and increases the risk of death by approximately twentyfold [11–13]. The most commonly identified pathogens include Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, Klebsiella spp., and Escherichia coli. These organisms are responsible for infectious complications such as spontaneous bacterial peritonitis, pneumonia, urinary tract infections, and bacteremia. Infection may spread into the systemic circulation through bacterial translocation from the intestine or through the movement of bacterial products such as lipopolysaccharides [14, 15]. Circulating endotoxins also play an important role in the pathogenesis of alcoholic liver disease. Lipopolysaccharides, which are endotoxins found in the cell wall of Gram-negative bacteria, are detected more frequently in patients with alcoholic cirrhosis than in those with cirrhosis caused by other etiologies [16, 17]. Elevated endotoxin levels have also been observed in patients with mild AH, even in the absence of fibrosis or cirrhosis [18].

Significance of Sepsis

Patients treated with prednisolone show improved 28-day survival. Unfortunately, the incidence of infectious complications also increases. It was previously believed that infection was not a contraindication to corticosteroid therapy if it was adequately treated before initiation [19]. However, findings from the STOPAH trial challenged this assumption. The study demonstrated that infections are associated with poorer outcomes of prednisolone therapy, even when adequately controlled before corticosteroid treatment begins. This negative effect may be mitigated when patients receive concomitant antibiotic therapy [20]. Interestingly, patients with AH who experience upper gastrointestinal bleeding appear to have a lower incidence of infections and better clinical outcomes [21]. In severe cases of AH, particularly among patients requiring prolonged hospitalization and corticosteroid treatment, the risk of fungal and opportunistic infections should also be considered. Pneumonia and invasive fungal infections have been reported in this population and are associated with high mortality rates [22, 23]. Lack of response to corticosteroid therapy may be related to underlying infection. Patients with elevated levels of circulating bacterial DNA have been shown to respond less favorably to prednisolone treatment. Another study reported that hospital-acquired infections occurred more frequently in non-responders to corticosteroid therapy (42.5%) than in patients who responded to treatment (11.1%) [19]. These findings suggest that an apparent lack of therapeutic response may not necessarily reflect pharmacological failure but rather the progression of infectious complications. This raises an important clinical question: how can high-risk patients be identified so that unnecessary corticosteroid exposure and its associated infectious complications can be avoided? Procalcitonin measurement may be useful, as it has been proposed as a marker for diagnosing sepsis in patients with AH [24]. In addition, the neutrophil-to-lymphocyte ratio may provide prognostic information, as it has been shown to predict outcomes in patients with liver disease [25].

Liver Biopsy

Liver biopsy remains the gold standard for the diagnosis and staging of many liver diseases [26, 27]. However, indications for performing a biopsy have varied considerably across clinical studies and have only recently been incorporated into guidelines for patients being considered for corticosteroid therapy [28]. Other clinical recommendations remain less restrictive [29]. One recently proposed histological classification system is the Alcoholic Hepatitis Histological Score (AHHS), which has been shown to predict early mortality in patients with AH [30]. Performing a liver biopsy in patients with AH can be challenging, particularly because obtaining a tissue sample is often complicated by coagulopathy and ascites. Both conditions increase the risks associated with percutaneous biopsy. As a result, the procedure frequently needs to be performed via the transjugular route. Today, transjugular liver biopsy is considered a safe and widely available procedure in many specialized centers [31, 32]. However, obtaining a biopsy sample is only part of the challenge. Accurate interpretation requires significant expertise, which may not always be available. Consequently, a diagnostic strategy relying heavily on liver biopsy may be impractical for many patients with AH [33]. Histological interpretation itself can also be complex. One might assume that histological findings characteristic of AH are specific to the disease, but one study found that 27% of patients with chronic decompensated alcoholic liver disease, despite lacking acute jaundice, demonstrated moderate-to-severe AH on liver biopsy [34]. Studies have shown that clinicians’ diagnoses based on clinical findings agree with histological diagnoses in approximately 70–80% of cases [29]. However, these observations were based on patient cohorts in which diagnostic criteria for AH were relatively broad. When stricter criteria are applied, particularly regarding the degree of hyperbilirubinemia, concordance between clinical and histological diagnoses increases to approximately 96% [35]. These findings raise questions about the necessity of routine liver biopsy. Recent guidelines state that AH can be diagnosed clinically in patients who have had jaundice for less than eight weeks, consumed alcohol within the previous 60 days, have no alternative causes of liver injury, and show no evidence of sepsis [36]. Jaundice is defined by a bilirubin concentration above 50 µmol/L (80 µmol/L in the STOPAH study). Aspartate aminotransferase (AST) activity should exceed 50 U/L, and the AST/ALT ratio should be greater than 1.5. When these diagnostic criteria are fulfilled, routine liver biopsy and serological diagnostic tests such as the AshTest are generally not justified [37]. To evaluate the usefulness of AHHS in predicting treatment outcomes, histological samples from patients enrolled in the STOPAH trial were analyzed. Although AH was histologically confirmed in 88% of patients, approximately 15% of biopsy specimens were considered inadequate for diagnostic evaluation. More severe liver disease was associated with a higher frequency of alcoholic steatohepatitis identified in biopsy samples, being present in 82% of patients with GAHS ≤8 and 97% of patients with GAHS >8. AHHS severity was positively correlated with both mDF and GAHS scores. While these findings support the potential value of AHHS, there is currently no evidence that it provides greater clinical utility than non-invasive prognostic calculators that can be calculated rapidly at the bedside. Therefore, liver biopsy appears most appropriate in patients whose diagnosis remains uncertain after standard clinical evaluation [31].

Treatment for AH: Influence of Clinical Trials, STOPAH, and Other Studies

To identify effective treatments for AH, numerous therapeutic agents have been investigated. However, only two medications—pentoxifylline and prednisolone—have been included in treatment guidelines published by the European Association for the Study of the Liver (EASL) [28] and the American Association for the Study of Liver Diseases (AASLD) [29]. Nevertheless, considerable debate remains regarding the appropriateness of their use. Five large clinical trials demonstrated a significant reduction in early mortality among patients treated with corticosteroids compared with placebo [38]. In contrast, a systematic review of 15 clinical trials failed to demonstrate a clear overall benefit of corticosteroid therapy, although a possible short-term survival advantage was identified [39]. The effectiveness of pentoxifylline was demonstrated in only one clinical trial, which reported lower early mortality in patients treated with pentoxifylline compared with placebo (24.5% versus 46.1%, respectively) [40]. This benefit was attributed primarily to reduced mortality from hepatorenal syndrome (HRS), which occurred in 6 patients (50%) in the pentoxifylline group compared with 22 patients (91.7%) in the placebo group (p=0.009). However, another study comparing corticosteroids and pentoxifylline found no differences in the incidence of HRS or HRS-related mortality [41]. Thus, the superiority of either treatment remained unproven. A randomized, double-blind, placebo-controlled trial known as STOPAH (Steroids or Pentoxifylline for Alcoholic Hepatitis) further evaluated the effects of prednisolone and pentoxifylline in AH [43]. Participants were assigned to one of four treatment groups: prednisolone plus pentoxifylline, prednisolone plus placebo, pentoxifylline plus placebo, or double placebo. More than 1,000 patients from the United Kingdom were enrolled. Three major conclusions emerged from the study: • A reduction in early mortality was observed among patients treated with prednisolone (13.9% versus 18% at 28 days), although the primary analysis narrowly missed statistical significance (HR 0.72, p=0.056). Further analysis demonstrated that prednisolone significantly reduced 28-day mortality (HR 0.61, p=0.02). When STOPAH data were incorporated into a subsequent meta-analysis, the short-term survival benefit became even more apparent [44]. However, neither the STOPAH trial nor the meta-analysis demonstrated significant improvements in 90-day or 12-month survival. Continued alcohol consumption after hospitalization likely contributed to these findings, as alcohol use was shown to influence 12-month survival. Another possible explanation is inflammatory rebound following abrupt cessation of corticosteroids after 28 days, potentially leading to renewed inflammation and deterioration in liver function. In clinical practice, many specialists gradually taper prednisolone after initial treatment, although this approach was not used in clinical trials. • Pentoxifylline, whether administered alone or in combination with prednisolone, did not improve outcomes compared with prednisolone monotherapy [45]. Its effectiveness as second-line therapy in patients who failed to respond to corticosteroids was also not established [46]. Although some analyses suggested a slight reduction in mortality, the supporting evidence was of low quality [43]. Consequently, the role of pentoxifylline in AH treatment remains questionable, even when corticosteroids are contraindicated. • The study reported relatively low 28-day mortality rates. Mortality among patients who did not receive prednisolone was 18%, whereas previous studies had reported average mortality rates of approximately 35% [38]. Among prednisolone-treated patients, mortality rates ranged from 14% to 20% [44]. These lower mortality rates may reflect advances in modern supportive care for liver disease. This observation is particularly important when evaluating prognostic calculators for AH, many of which were developed using older patient cohorts. Future refinement of these models may be necessary to reflect contemporary clinical outcomes.

Other Treatment Strategies

N-acetylcysteine (NAC) has been investigated as an adjunctive therapy to corticosteroids. Studies evaluating combinations of antioxidant therapies, including NAC, have generally produced disappointing results, with no clear survival benefit compared with corticosteroid therapy alone [47, 48]. However, a large clinical trial demonstrated that adding NAC to prednisolone reduced the frequency of infectious complications [49]. After one month of follow-up, mortality was significantly lower in the combination therapy group than in the prednisolone monotherapy group (8% versus 24%, p=0.006). This benefit appeared to result primarily from a lower incidence of infection. After six months of follow-up, however, mortality differences between the groups were no longer statistically significant (27% versus 38%, p=0.07). Additional studies are therefore required to confirm whether NAC provides a meaningful long-term survival benefit. Malnutrition is common among patients with AH, highlighting the importance of nutritional assessment and support by a dietitian. One study demonstrated that enteral nutrition reduced infection rates and improved outcomes compared with corticosteroid therapy alone. Notably, the enteral formula used in that study differed substantially from formulations commonly used in clinical practice. A more recent study examined the combined effects of corticosteroids and enteral nutrition. Intensive enteral feeding through a nasogastric tube for 14 days failed to improve outcomes [50]. Treatment adherence was poor, with nearly half of participants removing the feeding tube before completing therapy. Despite the lack of benefit from intensive enteral feeding, patients who consumed more than 21.5 kcal/kg/day had better outcomes. This suggests that the ability to tolerate adequate caloric intake may itself be a marker of improved prognosis, particularly among malnourished and cachectic patients.

Evaluation of Treatment Effectiveness

AH is a dynamic disease, and patients may present at different stages of progression. Some individuals improve rapidly after hospitalization and treatment initiation, whereas others deteriorate despite abstinence and appropriate therapy. To assess the effectiveness of corticosteroid treatment, researchers have studied changes in bilirubin concentrations during therapy. Traditionally, any reduction in serum bilirubin after one week of prednisolone treatment was considered evidence of response [51]. Subsequent studies demonstrated that a decrease of more than 25% from baseline after one week is a stronger indicator of treatment response [52]. To improve prognostic assessment, the Lille score was developed for patients receiving corticosteroids [53]. Comparative studies have shown that the Lille model offers only a modest advantage over simple measurement of bilirubin reduction after one week of treatment [5]. Some investigators have suggested calculating the Lille score after only four days of therapy and discontinuing corticosteroids in patients unlikely to benefit. Early identification of non-responders may help avoid unnecessary exposure to corticosteroid-related adverse effects and provide an opportunity to explore alternative management strategies [54]. The use of the Lille score after four days of treatment still requires validation in additional studies. Recent research suggests that combining static prognostic models with dynamic response-based tools may improve prediction of patient outcomes [55].

Liver Transplantation

Liver transplantation in patients with AH remains a highly debated topic. Many transplantation centers in the United States require six months of documented abstinence before transplantation. Similar practices are followed in many European countries, including Lithuania. In the United Kingdom, however, the six-month rule is considered more advisory than mandatory because evidence supporting improved survival is lacking. For patients identified as high risk by the Lille score, six-month mortality exceeds 70% [1, 51]. This has prompted growing interest in early liver transplantation. A European study demonstrated that patients with severe, prednisolone-resistant AH achieved a six-month survival rate of 77% following liver transplantation, compared with only 23% among comparable patients who did not undergo transplantation [56]. This survival advantage persisted for more than two years. Patient selection criteria were extremely strict. Eligible patients had to be experiencing their first episode of liver decompensation, have histological evidence of corticosteroid non-response, demonstrate strong family support, have no significant psychiatric or medical comorbidities, and commit to lifelong abstinence. Approval was also required from physicians, nurses, addiction specialists, and family members. A similar study conducted in the United States reported comparable results. Despite higher average MELD scores at the time of transplantation, six-month survival reached 89%, exceeding the 77% reported in the European study. As in Europe, the survival benefit persisted for more than two years. These findings suggest that early liver transplantation may be a viable option for carefully selected patients with severe AH [57]. However, identifying candidates with the poorest prognosis remains challenging. Until more accurate prognostic systems are developed, indications for early transplantation will remain difficult to standardize.

Abstinence

Complete abstinence from alcohol remains a cornerstone of AH management [29]. A recent review evaluating pharmacological treatments for alcohol dependence in patients with alcoholic liver disease identified acamprosate as the safest option. Baclofen has also shown promising results in several studies [58]. However, pharmacological treatment alone is rarely sufficient. Successful long-term recovery requires integrated multidisciplinary care, including addiction specialists, psychologists, hepatologists, and social support services.

Summary

The evaluation and treatment of AH remain challenging and, in many areas, controversial. Recent clinical studies have improved understanding of disease management and clarified several aspects of patient care. Current evidence does not support routine use of pentoxifylline in AH. Liver biopsy is generally unnecessary when patients meet established clinical diagnostic criteria. Careful monitoring for infection and prompt treatment of infectious complications are critical because infection significantly influences outcomes and response to therapy. Corticosteroids remain the only treatment shown to reduce short-term mortality. Despite these advances, important gaps remain. Current prognostic calculators lack sufficient precision to accurately predict treatment response and identify patients who are unlikely to benefit from medical therapy. More accurate prediction tools would help determine which patients should be considered for early liver transplantation. At present, corticosteroids remain the cornerstone of pharmacological treatment for AH. However, mortality rates remain high, highlighting the urgent need for more effective therapeutic strategies. Dr. Benediktas Kurlinkus, Vilnius University Hospital Santaros Clinic. "Gastroenterology," SUPPLEMENT TO THE JOURNAL "INTERNIST" 2017, No. 1 (16)