Alcohol-associated liver disease: Natural history, management and novel targeted therapies

Epidemiology

Chronic liver diseases are a prominent cause of mortality at the global level, accounting for 4% of all deaths worldwide [10]. ALD is one of the most prevalent causes of liver disease. It is the leading cause of cirrhosis, accounting for almost 60% of cirrhosis diagnoses in Europe, North America, and Asia [11,12]. Moreover, ALD is the second-leading cause of liver-related deaths worldwide and by far the leading cause in Europe [13]. The Asia-Pacific region is home to more than half of the world’s population and is reported to account for 62.6% of global deaths from liver disease [14]. Previous studies analyzing the burden of liver disease in Asian populations have either focused on individual countries or regions, individual years, or a subset of the most common etiologies, such as hepatitis B or C virus (HBV or HCV, respectively). However, due to the hepatitis B vaccine and the effective application of antiviral therapy, the status of HBV as a major cause of chronic liver disease is gradually declining, while alcohol has gained increasing attention. According to the World Health Organization (WHO) 2018, the Western Pacific region has had the second-highest increase in alcohol consumption. The disease burden of ALD in Asia is likely to have increased in a similar way over the last 21 years and is expected to emerge as a leading cause of chronic liver disease [14,15]. ALD-related mortality has been increasing since the start of the COVID-19 pandemic in 2020 [16,17], possibly owing to a shift in drinking patterns and decreased accessibility to health care.

Stages of ALD

The term ALD encompasses several clinical phenotypes and different degrees of anatomopathological liver injury, ranging from asymptomatic disease in patients with steatosis to life-threatening complications in patients with advanced fibrosis and steatohepatitis. The pathogenesis of ALD begins with the deposit of fatty droplets in the cytoplasm of the hepatocytes as a result of alcohol metabolization; this phenomenon, called steatosis, occurs in most patients with a pattern of prolonged heavy alcohol use [18] (Fig. 1). In approximately one out of four patients, intrahepatic fat deposition generates a local inflammatory response, leading to the development of steatohepatitis. Sustained inflammation in the liver is known to be the main trigger of liver fibrosis, which consists of progressive collagen deposition and extracellular matrix remodeling. Liver fibrosis is the main driver of ALD progression [19]. In the advanced stages, collagen bridges develop between portal tracts and central veins and ultimately form nodules within the liver. Cirrhosis occurs in 8–20% of patients with fibrosis throughout the natural history of the disease [20-22], with an increase in intrahepatic vascular resistance and a subsequent onset of portal hypertension [23]. A cross-sectional analysis of patients with liver disease worldwide found that patients with ALD are characterized by a more advanced-stage disease than patients with HCV-associated liver disease [24].

Figure 1.

Pathogenesis of alcohol-associated hepatitis. ADH, alcohol dehydrogenase; DAMPs, danger-associated molecular patterns; GCSF, granulocyte-colony stimulating factor; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; ROIs, reactive oxygen intermediates; SIRS, systemic inflammatory response syndrome.

Regarding the clinical presentation of ALD, two different stages can be distinguished: the first stage of asymptomatic or scarcely symptomatic disease, in which patients may not have any clinical manifestation of liver disease, and the clinical stage of the disease, characterized by the development of liver cirrhosis and portal hypertension complications such as ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury (AKI), and infections. The symptomatic stage of the disease, termed decompensated cirrhosis, arises in 20–40% of patients with cirrhosis [25]. Moreover, liver cirrhosis significantly increases the probability of developing hepatocellular carcinoma, which occurs in 3–10% of patients [25].

Alcohol-associated hepatitis (AH) is the most severe manifestation of ALD and is characterized by steatosis, bilirrubinostasis, massive pericellular fibrosis, neutrophil infiltration, and profound metaplasia of hepatocytes [26,27]. AH can occur at any stage of liver disease, yet most patients have advanced fibrosis/cirrhosis [28,29], which greatly impacts the prognosis of patients with ALD. In severe cases, bacterial infections and/or a systemic inflammatory response trigger acute-on-chronic liver failure (ACLF), a syndrome characterized by multiorgan failure and associated with very high short-term mortality [30,31].

Determinants of disease progression

The development and progression of ALD are dependent on several factors, including a) the amount of alcohol intake [32,33], b) the pattern of alcohol consumption, such as binge drinking (drinking 4–5 alcoholic beverages in a short period), is a pattern of alcohol consumption associated with changes in multiple inflammation-related markers, all of them implicated in alcohol metabolism and hepatocellular damage [34], c) the type of alcohol, which could impact the degree of liver injury (e.g., wine drinkers, but not exclusive beer drinkers, are less likely to have advanced liver fibrosis) [35].

Over the last few years, there has been significant progress in our understanding of the pathogenesis and natural history of ALD. Genome-wide association studies have revealed some of the genetic risk factors of ALD, such as variations in the genes encoding patatin-like phospholipase domain-containing protein 3 [36], transmembrane six superfamily two and membrane-bound O-acyltransferase domain containing 7 [37]. Furthermore, population-based studies have identified specific characteristics, such as alcohol consumption [38], female sex [39], previous bariatric surgery [40,41], and metabolic risk factors as important accelerators of disease progression [31-34,42]. Metabolic risk factors have come under intense scrutiny in recent years; several studies, some of which derive from large databases like the Genomic Alcohol Cohort Consortium or the United Kingdom Biobank, have found body mass index, diabetes, and metabolic syndrome to be associated with the development of advanced liver disease in both ALD patients [28] and the general population [42-47]. Moreover, the presence of metabolic risk factors has also been linked to increased overall and liver-related mortality in patients with ALD [43,44]. The high prevalence of coexisting alcohol and metabolic risk factors for liver disease has led to the proposal of the new nomenclature of MetALD, which refers to patients with both etiological factors [5].

Other known risk factors for ALD progression are Hispanic ethnicity [48], tobacco smoking [49], and other underlying liver diseases [50]. Several protective factors for ALD have also been proposed, mainly genetic variants in hydroxysteroid 17-beta dehydrogenase 13 and mitochondrial amidoxime-reducing component 1 gene [51,52] and coffee consumption [53,54]. Many determinants of disease progression are associated with specific genetic alterations or with comorbid conditions.

Therefore, targeted treatment for ALD in the future might include other strategies, such as gene therapy or medications for metabolic syndrome in selected patients.

Psychosocial interventions

The cornerstones of AUD management are psychosocial interventions, which focus on promoting the motivation to stop drinking. Among the strategies available are brief interventions and counseling, psychotherapy (motivational enhancement therapy and cognitive behavioral therapy), peer-support groups, and contingency management. These strategies have proven to be very effective in reducing harmful drinking in primary health care [59] and have even been shown to reduce the risk of developing ALD [60]. Nevertheless, information on their effectiveness in key groups, such as comorbid drinkers, is limited. Several studies have investigated the use of psychosocial interventions in patients with liver diseases. Most of these studies included patients with AUD and viral hepatitis infection with or without advanced fibrosis [61-64]. In this setting, psychotherapy alone, with either motivational enhancement or cognitive behavioral therapy, is effective in the induction but not in the maintenance of alcohol abstinence [65]. These strategies might be less effective in patients with ALD, who, by definition, have a more severe AUD. In a classical clinical trial including hospitalized patients with alcohol-related digestive conditions (most with cirrhosis), a 2-hour in-hospital motivational intervention did not improve alcohol abstinence at three months compared to medical care alone [66]. In contrast, in another trial in liver transplant candidates, the authors reported a reduction in drinks per drinking day in patients receiving motivational enhancement therapy [67].

Pharmacological interventions

Several anti-craving medications for AUD have proven to be effective, either alone or in combination with psychosocial interventions. Medications approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of AUD are disulfiram, naltrexone, and acamprosate (Table 1) [68,69]. The EMA also approves Nalmefene. Additionally, sodium oxybate is approved for AUD only in Italy and Austria and baclofen only in France [70]. Disulfiram was the first treatment to be approved for AUD and is still widely used by addiction specialists. It is an inhibitor of acetaldehyde dehydrogenase and thus causes distressing symptoms when consumed together with alcohol, acting as a dissuasive medication. Disulfiram should be avoided in patients with ALD, especially those with advanced fibrosis, as it can cause acute liver failure and death [71,72]. Naltrexone is an opioid receptor antagonist that acts by reducing dopamine release and decreasing the sensation of reward. Despite a warning being issued by the FDA regarding its potential to induce hepatocellular injury, two recent observational studies have suggested it is safe and effective in patients with ALD [73,74]. Nalmefene is another opioid receptor antagonist that has been shown to reduce heavy drinking; therefore, it is also indicated for harm-reduction strategies [75], but its use in patients with ALD is lacking. Acamprosate is an N-methyl-D-aspartate glutamate receptor antagonist that reduces withdrawal-induced hyper-glutamatergic states, which are thought to trigger relapse. Data on its efficacy and safety in patients with ALD is limited to retrospective cohorts [76]. Sodium oxybate is a gamma-aminobutyric acid agonist that reduces craving in patients with AUD [77]. However, there are some concerns regarding the potential abuse of the drug, especially in patients with a psychiatric comorbidity [78]. Its efficacy and safety in patients with ALD are unknown. Finally, baclofen is a selective gamma-aminobutyric acid B receptor agonist approved for spasticity conditions. It has an inhibitory effect on the dopamine network, reducing alcohol-reinforced behaviors. Several cohort studies and randomized clinical trials support its efficacy and safety in patients with alcohol-associated cirrhosis [79,80]. Other medications have shown beneficial effects in ALD, such as topiramate [81], ondansetron, and gabapentin [82]. Lastly, fecal microbiota transplantation (FMT) has shown promising preliminary results for the treatment of AUD in both animal models and humans [83,84].

Table 1.

Pharmacological interventions in alcohol use disorder management

Despite the absence of high-quality evidence, particularly clinical trials, regarding the effects of anti-craving medications for AUD on patients with ALD, recent cohort studies have found an association between anti-craving medications for AUD and long-term survival in patients with cirrhosis [85-87]. Moreover, the use of these drugs in patients with compensated alcohol-associated cirrhosis provides cost-savings, meaning that they provide more benefits than no intervention, with lower costs [88]. Consequently, their use should be key in inducing and maintaining alcohol abstinence in patients with ALD, in whom psychosocial interventions alone are not effective and are hindered by treatment adherence.

Other interventions

Several interventional studies have demonstrated that screening for liver disease with transient elastography associated with a brief counseling session increases alcohol abstinence rates [89,90]. However, we need studies to assess the impact of follow-up with transient elastography on AUD.

Advances in technology in recent years have also provided physicians with interesting tools to improve AUD management. A recent study including patients with ALD and AUD suggested that monitoring the signs associated with alcohol craving using a smartphone application was feasible [91], which is a step forward in the prediction of alcohol relapses. Concerning novel treatment approaches, a recently published trial showed that proactive therapy for AUD by videoconference increased treatment initiation and compliance rates and reduced alcohol consumption compared to standard of care with on-site visits [92].

Integrated care

An important hurdle for effective treatment is adherence, which is highly variable and influenced by poor physical condition [93], a common feature in patients with ALD. Consequently, integrating psychosocial interventions into the routine medical care of these patients in the same clinic is feasible and increases treatment adherence [94]. Multidisciplinary-based models aimed at providing integrated psychosocial and pharmacological interventions for patients with ALD and AUD have been associated with increased abstinence [78,79] and even higher survival rates in some settings [80].

Pathogenesis of alcohol-associated liver disease and AH

Our understanding of the cellular and molecular mechanisms underlying ALD remains incomplete. ALD encompasses a wide range of liver conditions, from an initial stage of alcoholic fatty liver/steatosis to more severe liver injury, such as steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. Most research employs animal models, primarily exhibiting signs of moderate ALD, such as steatosis and mild inflammation [89]. However, there is a lack of models encompassing advanced fibrosis and cholestasis, two key histological features in the evolution from early to advanced ALD.

The pathogenesis of ALD varies according to the disease stage. Initially, steatosis emerges as the liver’s primary response to alcohol abuse but is clinically asymptomatic, characterized by fat deposition in the hepatocytes [95,96]. Additionally, alcohol intake increases fatty acid and triglyceride synthesis and enhances the influx of free fatty acids from adipose tissue, chylomicrons from the intestinal mucosa, and hepatic lipogenesis while reducing lipolysis [97]. Moreover, alcohol damages the mitochondria and microtubules, accumulating very low-density lipoprotein [96]. In addition, alcohol leads to reduced fatty acid synthesis and increased fatty acid oxidation, promoting steatosis [92,93] and inducible nitric oxide synthase, which contributes to steatosis development [95,98,99] and hepatocellular lipid accumulation.

In individuals with prolonged alcohol abuse, simple steatosis is followed by hepatocellular injury and inflammatory changes, alcohol-associated steatohepatitis (ASH). Patients with ASH are usually asymptomatic and associated with liver biochemistry abnormalities. In the liver, alcohol is primarily metabolized into acetaldehyde by alcohol dehydrogenases and the cytochrome P450 2E1 enzyme. This oxidate metabolism induces glutathione depletion, mitochondrial damage and endoplasmic reticulum stress, reactive oxygen species, altered autophagy, lipid peroxidation, and finally, a significant hepatocyte injury [100,101]. Damaged hepatocytes release danger-associated molecular patterns (DAMPs), such as mitochondrial DNA and high mobility group box protein 1 [102]; chemokines (e.g., CXC chemokine-ligand-1/5, monocyte chemoattractant protein-1, macrophage migration inhibitor factor), and inflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-α], interleukins [IL]-1/8/13). This increase in the release of DAMPs drives the activation of the inflammasome caspase-1 complex [96], as well as inflammatory cytokines, promoting an inflammatory infiltrate consisting mainly of neutrophils and CD4+ T cells, which ultimately results in sterile hepatic inflammation [103], which plays a crucial role in the pathogenesis of AH [104-106] (Fig. 1).

Chronic alcohol intake leads to an intestinal endotoxin build-up and increased intestinal wall permeability, intestinal dysbiosis, with a significant increase in pathogenic bacteria [107] (e.g., Enterococcus faecalis), and is characterized by fungal (mycobiome) alterations and an abundance of immunogenic fungi (e.g., Candida) [108-110]. All these alterations facilitate lipopolysaccharide (LPS) and fungal (exotoxins) translocation from the gut to the portal and systemic circulation [111]. The translocation of bacterial and gut-derived microbial products to the liver (PAMPs, pathogen-associated molecular patterns) and microbe-associated molecular patterns (MAMPS) increases inflammation and induces hepatocyte death and fibrotic response. LPS recognition is mediated by the receptor (TLR4) on the macrophage resident in the liver - Kupffer cells - in the hepatic stellate cells (HSCs) and sinusoidal endothelial cells. This interaction triggers the release of cytokines and inflammatory substances, the promotion of fibrogenesis, and the regulation of angiogenesis [112,113]. Recent studies have shown that miRNAs and extracellular vesicles play a critical role in controlling liver inflammation in ALD [103] (Fig. 1).

All these inflammatory processes culminate in hepatocyte ballooning, the development of hepatic inclusions that aggregate cytokeratin, which is known as the Mallory–Denk body, accompanied by a superimposed inflammatory infiltrate [100,101]. The final step is the activation and proliferation of HSC, enhancing transforming growth factor-β (TGF-β) secretion, collagen synthesis, and accumulation of extracellular matrix around hepatocytes and sinusoidal cells, generating a “chicken wire” pattern and favoring the development of portal hypertension [114,115]. Some studies have indicated that bilirubinostasis and severe fibrosis are major histological components of AH and are associated with a poor prognosis [116,117]. Interestingly, the presence of neutrophils is associated with a better prognosis, probably reflecting the fact that livers with active wound healing are more prone to regenerating upon cessation of alcoholic intake [104]. However, as well as inducing liver injury, inflammation can also play a key role in promoting liver repair and anti-bacterial immunity in ALD (Fig. 1).

Several mechanisms have been associated with cell death pathways, such as apoptosis, necroptosis-pyroptosis, and ferroptosis (related to AH endotoxemia) [103]. Some studies of liver explants from patients with AH showed an accumulation of hepatic progenitor cells, which differentiated mainly into biliary cells, considering that impaired regeneration is a hallmark finding in patients with severe AH [118]. It has been suggested that the action of upstream regulators such as TGF-β1 leads to the impairment of hepatocyte regeneration and dedifferentiation. These effects are mediated by an inefficient activation of hepatocyte nuclear factor 4 α and a defective Hippo-yes-associated pathway in the hepatocytes [112,119]. This failure in differentiation results in a ductular reaction, which does not yield mature hepatocytes and is related to a worse prognosis [9,118,120]. Intriguingly, in patients with AH, the ductular reaction is associated with hepatocyte dedifferentiation into a cholangiocyte-like phenotype [118,120], hampering hepatocyte turnover, which is crucial for adequate liver function and regeneration. Interventions aimed at reducing the futile ductular reaction and promoting hepatocyte differentiation appear to be promising approaches as AH therapies (Fig. 1).

General management

The cornerstone of the management of patients with ALD and AH is prolonged alcohol abstinence. This essential intervention improves long-term prognosis but requires a multidisciplinary approach by liver disease specialists, together with psychiatrists and addiction units [121]. Several anti-craving medications for AUD in ALD [122] (see pharmacological and other interventions) are effective either alone or in combination with psychosocial interventions in the management of these populations.

The second strategy in the management of ALD-AH patients is the evaluation of malnutrition and micronutrient deficiencies; malnutrition is directly associated with liver disease severity and survival impairment [123-125]. For enteral nutrition, an intake of 35 to 40 kilocalories per kilogram of body weight daily, along with 1.5 grams of protein per kilogram per day [126,127], is the recommended goal. The benefits of micronutrients (e.g., Zinc) with corticoids or Anakinra were limited in clinical trials [128].

The specific treatment approaches in the setting of acute episodes of AH (Fig. 2) glucocorticoids have demonstrated a short-term impact on patients with AH since 1971 [129]. A randomized control trial (RCT) demonstrated a tendency towards enhanced 28-day survival, with an elevated risk of infections [130]. A meta-analysis from 2018 showcased improved 30-day survival rates, though there was no impact on 60- or 90-day mortality [131]. Two large, real-world studies have identified a Model for End-Stage Liver Disease (MELD) 21–39 as the optimal therapeutic window for the use of corticosteroids [132,133]. Similarly, people with AH and a rapid decline in total bilirubin (rapid fallers) do not benefit from corticosteroids. Current evidence underscores the ineffectiveness of pentoxifylline [130]. There have been promising findings regarding the addition of N-acetylcysteine (NAC), a potent antioxidant, to prednisolone therapy. This combination notably improved 1-month survival rates and reduced infection occurrences [134]. However, when survival was assessed at six months, no discernible differences were observed between applying combination therapy and prednisolone alone. In addition, when combined with granulocyte-colony stimulating factor (G-CSF), NAC failed to demonstrate a mortality benefit [135]. Response to steroid treatment should be assessed by the Lille score (dynamic score) on the fourth and seventh days. A Lille score of >0.45 indicates no response, and corticosteroids must be discontinued. A Lille score of <0.45 identifies corticosteroid responders, and treatment should be maintained for 28 days [136,137].

Figure 2.

Algorithm for the management of patients hospitalized for alcohol-associated hepatitis. AH, alcohol-associated hepatitis; MELD, Model for End-Stage Liver Disease; CIWA, Clinical Institute Withdrawal Assessment for Alcohol; GI, gastrointestinal; AKI, acute kidney injury; AKI-HRS, acute kidney injury due to hepatorenal syndrome.

In the last 13 years, early liver transplantation has been explored as a therapeutic option for patients who do not respond to corticoids. A pioneering European study demonstrated that a small cohort (26 patients with severe AH) who had failed to respond to glucocorticoids underwent early liver transplantation and had a significantly higher cumulative 6-month survival rate than in a historical series of patients with similarly severe disease [138]. Follow-up studies, including the American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE-AH) trial, have confirmed the benefits of early liver transplantation in selected patients with AH [139-142]. Furthermore, in 2022, a follow-up study from the European group showed that 2-year survival was similar in the early and standard transplantation groups [143]. One of the main problems with this therapeutic approach is the high incidence of alcohol relapse; the international cohorts have shown a higher incidence of relapse than other transplant recipients with advanced ALD (20% to 35% in the early transplant groups compared with 10% to 25% in the standard transplant groups). Nevertheless, there is a high degree of heterogeneity in how alcohol relapses are detected in the different studies and the biomarkers or strategies used to assess alcohol use after liver transplantation [144]. In future studies, it will be necessary to identify risk factors for worse outcomes after liver transplantation to make a better selection of patients.

Regarding the clinical limitations of corticoid treatment, it is essential to perform an early screening of infections (bacterial or fungal) and appropriate treatment [145-147]. Moreover, AKI can occur frequently, affecting up to a third of patients with AH and escalating the 90-day mortality risk [148,149]. Alcohol-withdrawal syndrome (AWS) and Wernicke’s encephalopathy are two conditions that should be prevented. A recent study showed that AWS commonly occurs in patients hospitalized with AH and complicates the course of hospitalization [56]. Routine prophylaxis is associated with a lower prevalence of AWS. Severe AWS (CIWA-R >21 points) requires intravenous benzodiazepine administration, which is usually contraindicated in these patients because it may precipitate an episode of hepatic encephalopathy.

Emerging targeted therapies for AH

From a pharmacological point of view, several biological molecules have been tested to identify new therapeutic strategies for AH, focusing on three main mechanisms: (1) anti-inflammatory and antioxidative stress agents, (2) gut-liver axis modulators, (3) hepatocyte regenerative agents, 4) other emerging therapies (Table 2).

Table 2.

Emerging treatment options