NATURAL HISTORY OF ALCOHOL-ASSOCIATED LIVER DISEASE: UNDERSTANDING THE CHANGING LANDSCAPE OF PATHOPHYSIOLOGY AND PATIENT CARE

Abstract

Alcohol and consequent liver disease are a major burden, which has worsened during the COVID-19 pandemic. There are several facets to the pathophysiology and clinical consequences of alcohol-use disorder (AUD) and progression to alcohol-associated liver disease (ALD), which needs a concerted effort by clinicians, translational and basic science investigators. Several recent advances from bedside to bench and bench to bedside have been made in ALD. We focus this review on a case-based approach that gives a human context to these important questions across the spectrum of ALD.

INTRODUCTION:

Alcohol and consequent liver disease is increasing as a burden for patients, family members and health systems worldwide. With the COVID-19 pandemic, emerging evidence indicates an increase in alcohol consumption and incidence of alcohol-use disorder (AUD), as well as a predictive long-term impact on the incidence of alcohol-associated liver disease (ALD)¹. The current world situation thus requires clinicians, translational and basic science investigators to urgently focus on this major disease process. ALD results in a wide range of presentations from pre-cirrhotic disease all the way through alcohol-associated hepatitis (AH). There have been several rapid advances in bench to bedside and from bedside to bench in ALD that focus on the patho-physiology, integration of clinical and mental health care, and liver transplantation. This review is focused on a case-based approach across the spectrum of ALD to provide a human context to these important questions.

CASE 1:

A 46-year-old man is referred to the liver clinic because of high ALT (78 IU). He is obese (BMI 35 kg/m²) with recently diagnosed hyperlipidemia. On questioning, he drinks 2–3 drinks of vodka per night and several more over the weekend. The patient’s AUDIT-10 score today is 14. He does not report any psychosocial consequences of his alcohol use, but his wife has often pointed out his drinking habits to him. His father is estranged but according to his mother had issues with alcohol. He is a Veteran of the Gulf war and was previously diagnosed with PTSD. However, he is not under therapy for this or any other mental health condition currently. A transient elastogram shows F2 fibrosis, which is also confirmed by MR elastography. MRI also shows a steatotic liver.

1. Can we predict if and when he will develop cirrhosis if these drinking patterns continue?

2. What is the impact of concomitant obesity and hyperlipidemia on risk of cirrhosis development?

3. How does the family history and mental health history contribute towards this risk?

4. What are newer biomarkers and therapies that can be used to modulate this risk?

5. Do we need a multi-disciplinary approach?

ALD progresses through mild steatosis, inflammation, and fibrosis to cirrhosis (ALC) and an increased risk for hepatocellular carcinoma (HCC). Heavy drinkers can develop alcohol-associated hepatitis (AH) at any stage in the progression of chronic disease. While most heavy drinkers will develop steatosis, progression to later stages of disease occurs only in a subset of heavy drinkers and likely involve interactions with both genetic and environmental factors that either offer protection for disease progression or increased risk. Both sex and genetic ancestry contribute to the risk of AUD and ALD. For example, while men may typically consume more alcohol than women, there is a growing incidence of AUD in women with greater susceptibility to the pathophysiological effects of alcohol². Similarly, risk for AUD varies with genetic ancestry, with Native Americans at higher risk and Asians with reduced risk, but these risks may be modified by cultural influences³. Genetic ancestry/ethnicity is also a major factor in the onset and severity of ALD with Hispanic patients presenting at earlier ages than White/Caucasian patients, while African-American patients presented with less severe AH⁴. Development of strong protocols for risk prediction for the progression of liver disease in heavy drinkers is an important unmet clinical and public health need⁵

Genetic risk for progression of ALD

In addition to the role of sex and race in progression of ALD, family history/genetics can also contribute to risk for heavy drinking, as well as obesity and liver injury, three conditions present in the Veteran in this case study. Many GWAS and whole exome sequencing studies have identified multiple genetic polymorphisms, including PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13, that contribute to NAFL/NASH⁶. However, large population based studies identifying genetic risk for ALD have been more limited⁷. The PNPLA3 polymorphism is also associated with increased risk of ALC and conveys a higher risk for mortality in patients with severe AH enrolled in the STOPAH trial⁸. A recent GWAS study with 1128 patients with ALC with Caucasian ancestry identified PNPLA3 and HSD17B13 as risk factors for ALC; conditional analysis, considering the PNPLA3 and HSD17B13 alleles, identified variants in Fas-associated factor family member 2 (FAF2) as protective⁹. These associations were validated using GWAS data from the UK Biobank⁹. Importantly, these data were used to develop a genetic risk score for ALC based on a combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status⁹.

Most of the genetic risk factors for ALD identified to date modify lipid metabolism and lipid droplet formation, consistent with abnormal lipid homeostasis in the development of steatosis. However, how these polymorphisms contribute to later stages of disease progression is not well understood. It is likely that additional genetic variants will target processes that contribute to later stage disease, including inflammation, fibrosis, and HCC. For example, a recent case control GWAS study identified polymorphisms in Wnt family members as a susceptibility locus for alcohol-related HCC¹⁰. Interestingly, these data identify germ-line polymorphisms in the Wnt-β-catenin pathway in alcohol-associated HCC¹⁰, while other studies also implicate somatic modifications in the Wnt-β-catenin family in HCC development^{11, 12}. Genetic variance in Wnt-β-catenin pathway is consistent with aberrant regulation of cell proliferation and development of HCC¹⁰.

Heavy drinking and AUD are also moderately heritable disorders^{13, 14}. Meta-analyses of multiple GWAS studies of AUD found that the most consistently identified SNPs associated with AUD were in genes related to alcohol metabolism¹⁵. Interestingly, recent GWAS analysis making use of the Million Veterans Program finds genetic risk for heavy drinking is not sufficient for the development of AUD¹⁴. Relatively few studies have compared the genetic risk for AUD to that for ALD¹⁶. Future analysis of genetic influences on heavy drinking and liver disease are needed to help identify specific targets for therapeutic intervention, as well as to identify patients at risk.

Environmental factors impacting progression of ALD

Obesity and risk for progression of ALD

Epidemiological data suggests that obesity and metabolic syndrome exacerbate progression of ALD^17–19. This is likely related to common pathogenic mechanisms between NAFL/NASH, including increased oxidative stress, aberrant regulation of lipid metabolism and disruption of autophagy and regulation of cell death pathways¹⁹. Further, while it is well recognized that obesity and metabolic syndrome are associated with a dysfunctional and inflamed adipose tissue, more recent work finds that alcohol consumption also profoundly disrupts the function of adipose tissue, contributing to the pathogenesis of ALD^{20, 21}. Important for treatment of heavy drinkers, cessation of drinking rapidly normalizes adipose tissue function²². Similarly, weight loss in obese patients reduced adipose inflammation²³.

Microbial dysbiosis and impaired barrier function of the gut is another common feature in ALD and other forms of fatty liver. Even a single heavy bout of alcohol consumption impairs the barrier function of the intestine, leading to an increase in circulating concentrations of endotoxin/LPS²⁴. Circulating concentrations of LPS, as well as other microbial products, are increased in patients with ALD²¹ and non-alcohol associated fatty liver/steatohepatitis (NAFL/NASH)²⁵ and dysbiosis is common in both diseases²⁵.

Importantly, as in our Case#1, it is increasingly common for patients to present with both obesity and heavy drinking^{18, 19, 26}, likely related to the increased prevalence of obesity in the general population. The patient in our case study is typical of veterans, as more than 7 in 10 veterans who receive VA care are obese or overweight, putting them at high risk for the development of complications of metabolic syndrome, including type 2 diabetes and liver disease²⁷. Common genetic polymorphisms associated with increased risk for NAFL/NASH and ALD also indicate common pathophysiological mechanisms^{18, 19}. Since obesity is a risk factor for the development of diabetes, the modifying role of diabetes in genetic risk for ALC⁹ also points to common pathogenesis and the importance for clinicians to treat both obesity and AUD.

Is there a distinction between the pathogenesis of lean ALD vs obese ALD that could be leveraged into development of biomarkers and therapeutics? Little data is available on this important question. At this time, pre-clinical studies are in progress which may eventually impact clinical practice for the diagnosis and treatment of patients with ALD with concomitant obesity. One recent study found that the chemokine CXCL11 could distinguish patients with AH who were lean compared to obese²⁸. Interestingly, biomarkers related to pathways of cell death can distinguish ALD from NAFL/NASH^{29, 30}. Hepatocellular death occurs via multiple mechanisms, including apoptosis, necrosis, necroptosis and pyroptosis³¹. Apoptosis and necroptosis can be distinguished by the accumulation of cytokeratin-18 cleavage product M30 in the circulation. M30 is a caspase-dependent cleavage product of M65, the full-length cytokeratin 18^{30, 32}. Interestingly, cytokeratin-18 cleavage products can distinguish patients with NASH from AH³³ and the concentration of full-length cytokeratin-18 (M65), indicative of necrotic/necroptotic cell death, increases with severity of AH^{33, 34}. Recent data also suggests that circulating concentrations of RIP3, a mediator of necroptosis, can also efficiently distinguish patients with mild AH compared to NASH²⁹. These recent studies indicate that markers of specific cell death pathways, as well as specific chemokines, may be developed into biomarkers to distinguish ALD from NASH and also provide prognostic information in cases of mild liver disease³⁴.

Nutrition

Undernutrition and malnutrition are commonly associated with ALD, due at least in part to the consumption of alcohol, which provides calories, but little nutritional value^{35, 36}. Both micro and macronutrient status is compromised in ALD, likely contributing to poor clinical outcomes. Low nutritional intake is associated with increased mortality in patients with severe AH³⁷. While nutritional support can improve outcomes in severe AH³⁵, a recent clinical trial testing the impact of enteral nutrition in patients with AH reported that it is difficult to provide adequate nutrition to this population³⁷. However, it is possible that outcomes for patients with more moderate ALD, particularly when associated with obesity, as in our Case#1, would be improved by routine nutritional assessment and involvement of a dietician^{35, 36}.

PTSD:

A major factor in AUD development are concomitant mental health disorders. This Veteran suffers from PTSD, which could play a key role in AUD and ALD³⁸. Co-existent mental health disorders such as depression, anxiety and PTSD have the potential to encourage AUD and worsen the progression towards cirrhosis and alcohol-associated hepatitis. The bidirectional transition between PTSD and AUD is sex-specific with greater vulnerability in women compared to men³⁹. The risk of AUD is higher overall in patients with PTSD, especially within the Veterans system³⁸. However, even in situations unrelated to deployment or war, there is a robust association with PTSD and AUD⁴⁰. Cognitive testing in Veterans with cirrhosis with and without PTSD showed worsened impulse control, which was also subsequently associated with differences in gut microbial structure and function^{41, 42}. A recent systematic review concluded that PTSD substantially increases the cue reactivity for alcohol craving⁴³. Therefore, undiagnosed mental health disorders, especially PTSD, such as in the case of our patient, should be sought out and treated in conjunction with AUD to reduce craving and potentially improve outcomes. It is encouraging that studies have shown that continued AUD did not reduce attendance or treatment for PTSD and vice-versa⁴⁴.

Treatment for heavy drinking and alcohol use disorder

AUD is diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria. AUDIT scoring makes use of 10 questions that assess alcohol intake, likelihood for dependence and experience of alcohol related harm; scores range from 0 (abstinence), 1–7 (low consumption and risk); 8–14 (potential harmful drinking) and >15 (likely alcohol dependence, moderate to severe AUD). Since AUDIT-10 assessment is time consuming and requires a highly trained interviewer; use of the condensed AUDIT-C has proven useful in Hepatology clinics⁴⁵. However, a full AUDIT screen is necessary to complete a diagnosis of AUD. Cessation of alcohol consumption improves symptoms and mortality from ALD; however, our understanding of best practices for treatment of AUD in ALD patients is limited^{46, 47}. Further, initiation of treatment, while available, has been limited, particularly for Veterans, perhaps due to a difficulty in the ability of hepatologists/gastroenterologists to initiate treatment^{48, 49}. On subsequent study, there were specific patient and provider factors that underlie these AUD therapy offers and acceptance⁵⁰. Recent approaches to treatment have made use of multi-disciplinary clinics including hepatologists, psychologists and social workers have shown promising preliminary results in reducing hospitalizations of ALD patients^{45, 46, 51, 52}. These strategies are often difficult to apply in practice because of perceived knowledge gaps on behalf of hepatology and GI practitioners, especially when there is limited access to addiction specialists. These barriers can be overcome by the encouraging trend towards educating hepatology and GI staff about the pros and cons of specific medications for AUD harm reduction, relapse prevention and craving reduction to provide direct prescription and supervision of these therapies in liver clinics^{53, 54}. In addition, it is important to rally resources related to addiction therapy in the community. It is important to recognize the treatment strategies for AUD may of necessity vary, depending on the stage of disease (see below for Cases#2 and #3). For example, pharmacotherapeutic protocols for AUD need to account for changes in hepatic drug metabolism, renal function, and interactions with immunosuppressive drugs^{45, 47, 52}. A recent meta-analysis concluded that integrated therapy including cognitive behavioral therapy with medical care was most effective at reducing alcohol relapse in patients with ALD⁵¹.

CASE 2:

A 57-year-old woman is seen in the hepatology clinic for routine follow-up of her decompensated cirrhosis. The patient had an episode of confusion two years ago diagnosed as hepatic encephalopathy and also developed ascites. These are now controlled on lactulose and diuretics, but she occasionally has episodes of “slowing down” according to her husband. Her cirrhosis was presumed to be due to hepatitis C and alcohol. HCV was cured four years ago. The patient was a heavy alcohol user in the past with several DUIs and missed work but over the last 5 years had cut down significantly. Currently she drinks 5–8 beers over the weekend, which was corroborated by the husband who accompanied her.

In clinic today, she appears slow but is oriented to time, place, and person. She is tremulous and feels like she has trouble remembering things. Her MELD score is 18.

Questions:

1. What is the natural history of disease progression in those who continue to drink despite HCV eradication?

2. What AUD-cessation therapies can be administered in this patient group?

3. How do we differentiate between HE and alcohol-associated brain syndromes in this patient?

4. Should she be placed on the transplant waiting list?

5. What are the consequences of declining to place this patient on the transplant waiting list?

HCV and alcohol interaction:

HCV and alcohol are synergistic in progression to cirrhosis and further alcohol misuse worsens the progression⁵⁵. During the era of interferon-based therapies, where HCV eradication was relatively difficult, there was still evidence that continued alcohol misuse despite HCV eradication could worsen cirrhosis progression^{56, 57}. In this current day and age with DAA therapy, there is ample evidence that HCV cure can reduce progression to decompensation and reduce the development of HCC. However, after HCV cure, continued insults to the liver i.e., alcohol misuse and obesity or weight gain will enhance the progression to complications (BAVENO VII consensus in press). Therefore, it is important to counsel patients to continue to work on all etiologies of cirrhosis and for clinicians to be vigilant regarding both alcohol misuse and weight gain in patients in whom HCV has been eradicated. This is relevant even in decompensated patients such as in case 2, where there is good quality evidence that alcohol abstinence can reduce the progression to HCC and further decompensation⁵⁸. Therefore, due to continued alcohol misuse, this patient remains at high-risk for HCC and should be candidate for AUD pharmacotherapy and/or behavioral therapy.

AUD Cessation therapies in decompensated cirrhosis:

In decompensated cirrhosis without AH, there is a relatively high urgency to reduce alcohol consumption, prevent relapse, and ensure that disease does not progress^{59, 60}. AUD therapy becomes challenging in patients with decompensated cirrhosis due to hepatic and renal handling of drugs such as disulfiram and naltrexone⁶⁰. However, others such as baclofen, acamprosate and topiramate can be potentially used under close multi-disciplinary supervision^{45, 47, 52}. The evidence basis for some medications such as baclofen and gabapentin are evolving and further data are needed⁶¹. For this patient, it is also important to determine the underlying psychiatric or psychological reasons for continuing to drink despite decompensated cirrhosis⁶². Those conditions should also be treated simultaneously. In addition to pharmacotherapy, behavioral approaches are needed to integrate the patient’s motivations, insight into the disease process, and to assess adherence, which would be important for subsequent transplant assessment. An intriguing recent trial showed that fecal microbiota transplantation (FMT) was associated with reduction in craving and alcohol consumption in cirrhosis⁶³.

The situation in this person is further complicated due to HE, which often reduces insight, attention and short-term memory^64–66. This requires greater collaboration between hepatologists, addiction medicine specialists, and behavioral therapists to ensure understanding of the processes. As with any therapy, the insight as well as willingness to undergo therapy for AUD on the part of the patient is critical for success and adherence.

Differentiation between brain complications associated with alcohol use and cirrhosis:

The patient in question has several competing or concomitant reasons for brain dysfunction. Prior HCV, current and prior alcohol misuse, nutritional abnormalities, and HE can all contribute to her current altered mental status and prior “slowness”⁶⁷. It is important to differentiate between HE and other complications since they respond differently to alcohol cessation and transplantation⁶⁸ (Figure 1). The approach towards actively confused patients versus those who are outpatients with slowness differs. The following flowcharts show the approaches towards these patients (Figures 2 and 3).

Figure 1:

Overlaps between symptoms in inpatients with cirrhosis and alcohol use disorder (AUD) (adapted from Davis et al)⁶⁹

Figure 2:

Proposed flowchart for evaluation of altered mental status in inpatients with alcohol-associated cirrhosis. (adapted from Davis et al)⁶⁹

Figure 3:

Proposed flowchart to work up outpatients with alcohol-associated cirrhosis (adapted from Davis et al)⁶⁹

A global view of several influences on brain function is critical early during the inpatient period given the major risk of withdrawal and related consequences of delirium tremens^{69, 70}. In this patient, there is tremulousness and difficulty remembering things, but she remains oriented to time, place, and person. This is likely going to develop into withdrawal and therefore a CIWA protocol should be followed⁷¹. Given the overall “slowness” there could also be an overlay of HE in this person, which is why the evolution of brain changes over the next few hours is important. Intoxication, withdrawal, and HE have distinct symptoms; HE rarely has symptoms of excitatory motor activity, hallucinations, or confabulation which are typical in alcohol withdrawal⁶⁴. In the outpatient setting, specialized neuropsychological referral may be needed. In general, covert or minimal HE does not affect long-term memory and impairment of that cognitive domain is likely related to alcohol-associated dementia^{65, 67}. As always, caregivers and substance abuse treatment specialists are important pieces of this management plan. Specialized nutritional evaluation is also necessary to recognize and treat micronutrient deficiencies⁷².

Liver transplantation considerations:

There was intense debate regarding the 6-month abstinence rule for patients being considered for liver transplant, which has now been replaced by a growing consensus that a one-size fits all approach fixed-time approach is not optimal for good outcomes post-transplant^{45, 73}. Relapse after LT has major consequences on the graft and patient health, which includes rejection and death⁷³. These are related to sustained heavy drinking rather than occasional slips and the thinking has evolved beyond absolute abstinence towards reduction of sustained drinking^{74, 75}. Classification of post-LT relapse as heavy or not reduces the stigma when this is encountered and could encourage patients to communicate truthfully without judgement. In a recent meta-analysis of patients with all forms of AUD in the setting of chronic liver disease, psychiatric co-morbidities, pre-transplantation abstinence <6 months, single status and smoking predicted relapse and heavy relapse⁷⁶.

Therefore, we need to develop an individualized multi-disciplinary plan. For this patient, we may have time to set up a substance abuse program with monitoring of alcohol use extensively using serum biomarkers. It is also likely that the MELD would decrease with abstinence and often patients with relatively lower MELD score recover enough to be de-listed⁷⁷. However, her MELD is relatively high so listing with encouraging abstinence may be an important option⁷⁸. If she had additional AH, we would need a more rapid combination of behavioral and medical therapies to approach her alcohol cessation while ensuring her HE and ascites are managed appropriately. This is important because the consequences of not listing patients with AH despite abstinence are dire and can be predicted^{79, 80}. This is further explored in case 3. The caregiver and support system needs to be present and engaged for success in pre- and post-LT settings.

CASE 3:

A 32-year-old woman was brought in by her mother to this hospital after being found collapsed in her house. The patient had been laid off during the pandemic and had missed several AA meetings and remote meetings with her alcohol counselor. According to the mother, the patient had been increasingly despondent over the last few weeks, and she suspects that “she had gone back to drinking”. Apart from the mother, the patient was in contact with her sister during the pandemic.

In the hospital, she was confused with respect to time and place but not person. She is jaundiced and has asterixis and ascites with pedal edema. These were not present during her last primary MD visit. There is also suspicion of aspiration pneumonia on her chest X ray for which she is started on antibiotics. Her MELD score is 31 and her Maddrey’s Discriminant Function is 36. On reassessment at day 4 after antibiotics, fluids and other supportive therapy, the patient is now completely alert and oriented. She is still jaundiced with MELD of 29 and Maddrey’s Discriminant Function of 32. Steroids are now started.

Questions:

1. What prognostic models will help define the outcome of patients with AH?

2. What is the role of microbial modification in the prognostication and therapy of patients with severe and moderate stages of AH?

3. Is this person a transplant candidate?

4. What are the predictors of relapse to problem drinking in this patient either before or after liver transplant?

Prognosis in AH

Traditional static scores that assess severity and prognosis for patients in AH include Maddrey’s Discriminant Function, MELD, ABIC (Age, serum Bilirubin, INR, and serum Creatinine) and GAHS (Glasgow Alcoholic Hepatitis Score). These scores are routinely used to determine if patients should be treated or not with prednisolone, the only approved treatment for AH^{5, 81}. The more dynamic Lille score for predicting outcomes to steroid treatment in patients with AH is also widely used^{5, 81}. Over time, changes in serum bilirubin trajectory in hospitalized patients and those placed on prednisolone over time (days 1 through 4) could determine the prognosis for the patient in Case #3⁸². Additional prognostic indicators of specific complications contributing to mortality in AH, including bacterial or fungal infections, acute kidney injury or systemic infections, are less robust. Recent collaborative studies in many countries combining clinical trials with translational studies have begun to improve our understanding of potential biomarkers that will provide better prognostic indicators. However, very little data is available to differentiate prognosis between men and women, as well as different age groups.

Risk of bacterial and fungal infection

Patients with severe AH often develop severe infections that negatively impact short-term prognosis. Prednisolone is the first-line therapy for AH; however, the effectiveness of prednisolone in suppressing inflammatory responses in the liver is also associated with impaired resistance to microbial infections, thus negatively impacting patient survival. A recent meta-analysis, including 11 studies with more than 2000 patients with severe AH, concluded that while prednisolone improved outcomes at 28 days with a hazard ratio of 0.64; 6-month mortality was not improved⁸³. Data from the double-blind placebo controlled STOPAH trial found that patients treated with prednisolone had almost twice the incidence of infection after treatment with prednisolone⁸⁴. Fungal infections may also be increased in patient treated with prednisolone. In a meta-analysis of over 1000 patients, there was a strong association between steroid treatment and fungal infections impacting short term prognosis⁸⁵. A recent multicenter cohort study of patients with AH used a combination of MELD score, ascites, WBC count, and use of corticosteroids to develop a predictive model for identifying patients at high risk of infection⁸⁶.

Inflammatory signal and cell death markers as prognostic indicators

Given the critical role of the innate immune system, cell death and impaired hepatocyte regeneration in the development of ALD, recent studies have focused on identifying prognostic biomarkers within these pathways for morbidity and mortality in AH. For example, higher circulating concentrations of several markers of macrophage activation and immune danger signals were strong predictors of infection, organ failures and 90-day mortality in patients with severe AH⁸⁷. Complement, another important arm of the innate immune response, is also activated in patients with AH and circulating concentrations of complement factor I and soluble C5b9 predicted mortality in AH patients as well as MELD score⁸⁸. The M65 cleavage fragments of cytokeratin-18, associated with non-apoptotic hepatocyte death^{33, 89} and RIP3, a member of the necroptotic cell death pathway²⁹, are both strong predictors of mortality in AH. miRNAs, both circulating or as cargo within extracellular vesicles, are another promising source for prognostic biomarkers, particularly related to regulation of hepatocyte regeneration^{90, 91}. Other cargo in extracellular vesicles, including sphingolipids, are also potential prognostic indicators in AH⁹². Although these biomarkers related to inflammation and cell death are promising prognostic tools, further validation is required before they become part of clinical practice. An overview of the biomarkers and unmet needs for AH is shown in Table 1.

Table 1:

Unmet Clinical Needs in Alcohol-Associated Hepatitis

Improved approaches to decrease alcohol intake
Development of multi-disciplinary clinics including hepatologists, psychologists and social workers Address perceived knowledge gaps on behalf of hepatology and GI practitioners, especially when there is limited access to addiction specialists. Educate hepatology and GI staff about the pros and cons of specific medications for AUD harm reduction, relapse prevention and craving reduction to provide direct prescription and supervision of these therapies in liver clinics Rally resources related to addiction therapy in the community
Development of precision medicine biomarkers for risk of poor outcomes
Innate immune related Inflammatory cytokines and chemokines Complement Monocyte/macrophage/neutrophil activation Hepatocyte related Markers of hepatocyte death Gut related Dysbiosis Loss of gut integrity Circulating microbial metabolites EV cargo miRNA signature Sphingolipids Dietetics counseling
Therapeutic avenues for treatment of AH
Innate immune modulation Anti-cytokine therapies (Anakinra, Canakinumab) Chemokine inhibitors (CCR2/CCR5 inhibitor) Hepatocyte Improve hepatoprotection (IL122, GM-CSF) Gut related Probiotics, synbiotics FMT Drug targeting of microbes Nutritional support Enteral nutrition

Modification of the microbiome

There is a growing appreciation for the contributions of intestinal microbiota in progression of ALD; recent studies have begun to interrogate intestinal microbiota as a potential therapeutic target in ALD. Numerous studies have now provided descriptive information as to the impact of alcohol use and ALD on the gut microbiome²⁵. Excessive alcohol use, often coupled with poor nutrition or obesity, leads to intestinal dysbiosis. Dysbiosis is accompanied by additional changes in the barrier function of the intestinal epithelium, mucosal immunity and generation of microbial products into the circulation. Multiple approaches have been taken to normalize the intestinal microbiome, including use of antibiotics, probiotics, synbiotics, and fecal microbiota transfer. As we gain a better understanding of specific impact of alcohol on the microbiome, investigators are increasingly moving from untargeted approaches, e.g., anti-biotics and pro-biotics, to more targeted approaches for treatment.

Early studies used untargeted approaches to modify the gut microbiome. Based on studies in animal models, clinical trials were designed to evaluate the role of antibiotics in ALD and other chronic liver diseases²⁵. While many of the trials showed short term improvement in some clinical parameters, changes in liver-related complications were not consistent²⁵. Similarly, studies utilizing probiotics often show reduction in circulating cytokines and microbial metabolites. As probiotics are known to be well tolerated in patients with liver disease, more recent studies have focused on use of probiotics²⁵. As with antibiotic studies, the clinical trials tend to involve only short-term treatment, with small sample size and only limited measures of efficacy for improving liver injury. As an example of the few randomized controlled clinical trials conducted in this area, Han and colleagues reported that short-term probiotic treatment reduced TNF-a and LPS in the circulation, as well as E. coli colony forming units, but did not improve transaminases⁹³. The value of this study for treatment of patients with AH, as with many studies aimed at modifying the microbiome, may be limited as enrollees in the study had modest degrees of liver injury and transaminases are of limited values in diagnosing ALD. Other generalized approaches to improving the host microbial communities include the use of prebiotics, pro-biotics and synbiotics (combining pre and pro biotics)⁹⁴. Multiple, relatively small studies have shown some promise, but multiple challenges have precluded the use of these compounds in clinical practice⁹⁵

Current clinical trials are designed to restore specific changes in the microbiome observed in patients with ALD. For example, Lactobacillus species are typically decreased in ALD^{25, 95}. Clinical trials to replace Lactobacillus metabolites, rather than the bacteria themselves are underway. One current clinical trial is testing efficacy and safety of the supernatant of Lactobacillus rhamnosus GG in patients with moderate AH (MELD score <21), with primary endpoint as change in MELD score after 30 days (NCT01922895).

FMT is also being investigated as a means to restore healthy gut microbiota in this setting in addition to the trial mentioned above in stable patients with cirrhosis⁶³. Several small open label studies have shown promising results in patients with severe AH with evidence for sustained coexistence of donor and recipient species at 6–12 months after FMT⁹⁵, suggesting that FMT may have a lasting impact on the recipient’s gut microbiota network. However, additional randomized clinical trials are required to confirm that FMT sustainably modifies the recipient microbiota and improves ALD without complications, even in patients with severe AH⁹⁵. Studies in murine models of ALD also point to the promise of therapeutics that specifically target specific microbial species known to contribute to liver injury. For example, Schnabl’s group reported that bacteriophage targeting of cytolysin-secreting Enterococcus faecalis (E. faecalis) reduced harmful concentrations of cytolysin in the liver and reduced ethanol-induced liver⁹⁶. Small molecule inhibitors of bacterial enzymes are also under investigation. For example, Brown and colleagues recently reported that small molecule inhibition of the gut microbial transformation of choline into trimethylamine (TMA), a microbial metabolite elevated in the circulation of patients with AH, prevented ethanol-induced liver injury in a murine model of ALD [Brown, et al in press eLife 2022]. These targeted precision approaches to modifying the gut microbiome hold promise but need to be further explored in clinical trials.

Transplant suitability and risk factors for relapse in patients with AH:

Practice patterns regarding transplantation in AH patients have dramatically shifted over the last decade^{47, 97}. There is an increase in patients with AH being evaluated, listed, and undergoing transplant and a refinement of static and dynamic scoring systems⁹⁸. The rate of this has increased over the COVID-19 pandemic⁹⁹. Selected patients with AH do well from a survival standpoint post-LT but there are differences in the criteria for listing and selection for these patients across sites¹⁰⁰ . A consensus conference determined that a multi-disciplinary approach focused on patients with their first episode of AH, who are not responders to traditional medical therapies without other substance abuse and good social support could be considered⁷³. A detailed analysis by the transplant team, the addiction specialists, social workers is needed before careful transplant committee selection. There is also a recognition that with successful abstinence, it is likely that patients may not ultimately require a LT.

Specific factors that predict return to problem drinking rather than occasional slips need to be considered in consultation with addiction specialists^{73, 99}. In the setting of AH, the SALT score (Sustained alcohol use post-Liver transplant) <5 had a negative predictive value for sustained alcohol use post-LT of 95%. The SALT score consists of >10 drinks per day at initial encounter (+4), multiple prior rehabilitation attempts (+4), prior alcohol-associated legal issues (+2) and prior illicit substance use (+1)¹⁰¹.

These include younger age at drinking, heavy alcohol use, poor insight into ALD, as well as other untreated mental health problems or substance abuse. In addition, a poor social support, and a long track record of non-adherences with visits and therapies are likely to indicate a high risk of alcohol relapse after liver transplantation⁹⁹.

In the case of this patient, although she is young and has heavy alcohol use history, her engagement with AUD specialists, social support, and first decompensating event are favorable indicators of abstinence. There needs to be continued assessment as an inpatient of her medical status, i.e., improvement with steroids and correction of infection over time, as well as her ability to meaningfully engage with addiction specialists. Inpatient linkage with AUD specialists and their assessment of the patient’s insight, ability to follow through and support from family members will remain critical to evaluate her ultimate eligibility in case she does not respond to steroids over the next week.

FUTURE DIRECTIONS:

As illustrated by our case studies, treatment of ALD is complex and dependent on disease stage and co-morbidities. Studies utilizing ALD animal models continue to dissect out the complex interactions between alcohol consumption, diet, and the microbiome. Clinical and genetic studies at various stages of ALD are beginning to identify potential genetic markers that may either protect or contribute to disease progression. Improved phenotypic identification of disease stage, particularly for AH¹⁰², and standardization of clinical trial design¹⁰³ will likely lead to successful clinical trials identifying effective ALD therapeutics. Importantly, advances in biomarker identification related to inflammation, cell death and microbial dysbiosis hold promise for personalized medicine approaches. Finally, recent advances in integrating multi-disciplinary clinics are critical for improved care for patients with ALD.