Authors: Katie Witkiewitz (1Katie Witkiewitz, PhD, Distinguished Professor of Psychology and Director, Center on Alcohol, Substance use, and Addictions, University of New Mexico, 2650 Yale Blvd SE, Albuquerque NM 87106), Anne C. Fernandez (2Anne C. Fernandez, PhD, Associate Professor, Department of Psychiatry, University of Michigan), Ellen Green (3Ellen W. Green, MD, PhD, Fellow, Division of Gastroenterology & Hepatology, University of North Carolina), Jessica Mellinger (4Jessica Mellinger, MD MSc, Assistant Professor, Department of Medicine, Department of Psychiatry, University of Michigan.)
Categories: Article, Alcohol use disorder, alcohol dependence, harm reduction, alcohol-associated liver disease, alcohol-associated hepatitis, liver transplantation
Source: Clinics in liver disease
Authors: Katie Witkiewitz, Anne C. Fernandez, Ellen Green, Jessica Mellinger
Alcohol has been consumed by humans and non-human animals for as long as we have historical records, with earliest evidence of human alcohol consumption dating back to 7000 BC^1^. Paleogenetic analyses have identified that a mutation in the enzyme alcohol dehydrogenase class 4 (AHD4), which improved primates’ ability to metabolize alcohol, first appeared over 10 million years ago^2^. In present day, alcohol is the most commonly used psychoactive substance worldwide. Data from 2017 indicate 47% of the world population are current drinkers of alcohol, and the adult per-capita consumption of alcohol is estimated at 6.5 liters of per alcohol per adult^3^.
Given the high level of consumption worldwide, it follows that alcohol use disorder (AUD) is one of the most prevalent psychiatric disorders, globally. Recent estimates of global lifetime prevalence of AUD has been estimated at 8.6%^4^ (range: 3.8% to 97.1% within individual countries). There are also tremendous human and social costs of AUD. More than 3 million people die annually worldwide due to causes related to alcohol, and alcohol is attributable to 5.1% of the global burden of disease and injury^5^.
One of the many factors that has contributed to the burden of harmful alcohol use and AUD worldwide is the lack of treatment access and very low rates of seeking treatment for alcohol-related problems. The majority of individuals who engage in harmful alcohol use and those with AUD will never seek treatment^6^ with recent estimates of 17.3% of individuals with AUD worldwide receiving AUD treatment services and even lower rates in lower and middle income countries^7^. The primary reasons for not seeking treatment include not wanting to stop drinking, lack of access to treatment, and concerns about stigma^6^.
Given high rates of AUD and lack of treatment, it is not surprising that alcohol-associated liver disease (ALD) is also a prevalent and costly disease. Previously thought of as a disease of older, white males, recent changes have demonstrated a marked and disproportionate increase in ALD in younger people, females, and some minoritized racial and ethnic groups. While overall ALD prevalence is approximately 8.1% in the United States, the prevalence of more severe forms of ALD has risen disproportionately over time, with an increase in more advanced ALD from 2.2% to 6.6% from 2001 to 2016^8^. In the United States, cirrhosis-related mortality increased 65% from 1999 to 2016 and was driven almost entirely by ALD^9^. The most severe form of ALD, alcohol-associated hepatitis, which carries a 30-50% mortality rate at 6 months, has also increased in recent years, particularly during the COVID-19 pandemic which saw a 60% increase in waitlisting and transplants for alcohol-associated hepatitis^10,11^. Increased alcohol use, especially amongst females and young people, has fueled the rising ALD rates. Metabolic-associated steatotic liver disease (MASLD), a liver disease similar to ALD histologically, occurs in the presence of the metabolic syndrome (obesity, hypertension, diabetes, dyslipidemia) and results in synergistic damage to the liver^10^. Liver disease from both alcohol use and metabolic syndrome has been termed MetALD^12^, and rising rates of metabolic syndrome and obesity in the United States are almost certainly contributing to the increase in MetALD.
The diagnosis of AUD has shifted substantially over the past 74 years. The first edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM) published by the American Psychiatric Association in 1952^13^ described “alcoholism” within a broader classification of Sociopathic Personality Disorder. The second edition of the DSM, published in 1968^14^, included text descriptions for problems caused by alcohol use that were divided into three alcohol dependence, episodic excessive drinking, and habitual excessive drinking. In the 1970s Feighner^15^ and Spitzer^16^ published diagnostic criteria for the disease of “alcoholism” based on observational research studies to inform research and practice^17^. The third and fourth editions of the DSM would take a similar approach of creating diagnostic categories based on symptoms, with the designation of alcohol abuse and alcohol dependence as separate diagnostic categories^18,19^. In 2013, the fifth edition of the DSM was published^20^ and AUD was considered a single diagnosis, based on endorsing two or more of eleven criteria (see Figure 1) measuring impaired control over alcohol use, social and occupational impairment from drinking, alcohol use that causes harm, and physiological consequences of heavy drinking. DSM-5 also added a severity continuum based on the number of criteria endorsed such that individuals can now be classified as mild (2-3 criteria), moderate (4-5 criteria), or severe (6 or more criteria).
The International Classification of Diseases (ICD), published by the World Health Organization, has followed a similar trajectory as the DSM. The diagnosis of alcohol dependence in ICD-11^21^ changed from prior versions of the ICD and also was a point of departure from the 11 criteria of DSM-5, as shown in Figure 1, with only three diagnostic features and at least two required for a impaired control over alcohol use, alcohol interferes with life and often continues despite problems, and physiological features indicative of neuroadaptations to alcohol^22^. ICD-11 has better concordance with earlier versions of the ICD and DSM-IV, and DSM-5 may be inclusive of a larger group of people with problems related to alcohol^23^.
Alcohol use occurs across a spectrum. As alcohol use increases in quantity and frequency so does the risk of developing or worsening medical conditions (e.g. liver disease), mental health problems, and AUD. Heavy alcohol use is also more likely to lead to acute health risks such as accidents and injuries. These harms from alcohol use increase in a dose dependent fashion. For this reason, alcohol-related harm or risk is typically defined as the quantity and frequency of standard drinks consumed over a given time interval (e.g. average standard drinks a day in the past month).
In the United States, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines harmful alcohol use as having more than 4 (males)/3 (females) drinks on any day or more than 14 (males)/7 (females) standard drinks per week. Another useful definition that takes into account a broader spectrum of alcohol risk is The World Health Organization (WHO) risk drinking levels^24^. The WHO defines four sex-specific levels of drinking risk, based on average grams of alcohol consumed per day (g/d), that correspond to low (1-40 g/d males; 1-20 g/d females), medium (41-60 g/d males; 21-40 g/d females), high (61-100 g/d males; 41-60 g/d females) or very high risk (> 100 g/d males; > 60 g/d for females). Corresponding conversions of these cut-offs to standard drinks in the United States and other countries for these cut-offs are available and shown in Table 1. The WHO risk drinking levels provide a clinically meaningful and validated endpoint, and reduction in WHO risk level is associated with improvements in health and liver functioning making it a useful metric in clinical care^25-27^.
Drinking reductions should be encouraged among all individuals, however even very low levels of alcohol use can incur increased risk of morbidity and mortality, and there is no current amount of alcohol use that is considered safe. Furthermore, harmful alcohol use in a patient with, or at-risk for, liver disease may be quite different than these standard recommendations for healthy adults. The NIAAA and WHO risk drinking levels, somewhat align with guidance for steototic liver disease subclassification, for which ALD is defined as increasingly predominant as alcohol use reaches and exceeds 30–60 g/d for males, or 20–50 g/d for females.
AUD is a medical condition characterized by impaired control over alcohol use, consequences from use, increasing time and priority given to alcohol in one’s life, and physiological changes in the body such as alcohol tolerance and withdrawal. AUD is also a chronic and relapsing condition that occurs across a spectrum of severity. AUD remission and recurrence can happen multiple times across the lifespan. AUD can occur at any level of alcohol use but is more likely to occur at higher levels of alcohol use. AUD diagnosis is based on the presence or absence of behavioral symptoms and can be diagnosed using the DSM-5^20^ or ICD-11^21^, shown in Figure 1. Those who do not meet AUD diagnostic criteria for 3 months are considered in early remission, and those who do not meet criteria for 12 months are considered in sustained remission.
Alcohol consumption and AUD should be evaluated at regular intervals. Regular assessment can lead to timely intervention and treatment given that changes in alcohol use and return to drinking are common even after a period of abstinence. In addition to standard clinical interviews, we recommend three types of assessment to capture key alcohol-related 1) self-report questionnaires and interviews that assess alcohol consumption, 2) AUD symptom assessments, and 3) alcohol-related biomarkers.
Alcohol consumption should be assessed using validated alcohol screening instruments. These instruments are often short and easy to embed into measurement-based care digitally or given in person at clinics. One such instrument is the AUDIT-C^28^, a 3-item assessment of alcohol quantity and frequency. Alternatively, the 10-item AUDIT^29^ assesses alcohol use as well as domains related to AUD symptoms. The Timeline Follow-Back is a gold standard for measuring frequency and intensity of alcohol consumption using a calendar-based method^30^.
For patients who drink at any level of risk, a full diagnostic assessment of AUD should occur via clinical interview by a trained provider for diagnostic accuracy. Common comorbid conditions, such as depression, anxiety, and other substance use disorders, should also be assessed. This may require the involvement of a psychosocial team member, or referral to an addiction specialist. However, when this is not possible we recommend using a brief alcohol symptom checklist^31^ or using the AUDIT to assess domains relevant to AUD symptoms which can inform clinical decision making.
Direct alcohol biomarkers are also recommended^32^. Phosphatidylethanol (PEth) is a highly specific and sensitive biomarker that can detect alcohol use or cessation over a 3-4 week period^33^. Interpretive guidelines for PEth levels provide ability to categorize consumption levels corresponding no/light, moderate, or heavy alcohol consumption^34^. PEth has been shown to correspond with objective measures of alcohol consumption^35^. Other biomarkers, such as urine ethyl glucuronide (EtG) or urine ethyl sulfate, are relatively common and inexpensive and can detect alcohol use in the past 3-5 days. With patient consent, family member or loved ones can also be useful sources of information when assessing alcohol use to corroborate self-report or when an individual is unable to self-report (e.g. cognitively impaired or unconscious).
The era of deepened understanding of ALD pathophysiology abutted the first liver transplantation in humans by Thomas Starzl in 1963^36^. Though early attempts yielded short survival durations and a brief international moratorium on the surgery, improvement in immunosuppression with cyclosporine extended survival in the late 1970s and liver transplantation was accepted by the American Association of the Study of Liver Diseases (AASLD) in November 1982. It was approved by the National Institutes of Health Consensus Development Conference the following June, including ALD as an appropriate liver transplantation indication if alcohol abstinence was achieved giving rise to the informal recommendation of 6 months of alcohol abstinence as a liver transplantation prerequisite^37-39^.
Liver transplantation for ALD, though hampered by stigma, was undertaken but considered exceptionally challenging in the 1980s with the perspective that increased risk of complications due to malnourishment and infection, and overall lower survival was noted^40-42^. Advocates of liver transplantation in ALD emerged, including Starzl, who published not only on the equal post-operative survival with cyclosporine immunosuppression in patients with ALD as compared to those with other causes of liver failure in 1988^43^. As heterogeneity developed among liver transplantation centers in approach to liver transplantation in ALD, physicians from the University of Michigan Alcohol Research Center proposed a pre-liver transplantation evaluation based on 4 domains (diagnosis, patient/family recognition of the disease, social stability, and prognostic factors) on the basis that pre-operative abstinence did not predict surgical or return to drinking outcomes^44^. This group went on to demonstrate excellent, equivalent survival of 45 patients with ALD requiring liver transplantation who underwent multidisciplinary evaluation, and only 2 patients were found to return to hazardous alcohol use^45^.
The growth of liver transplantation for ALD indications continued to revolve around the controversy of the pre-transplant sobriety period^46^. This was most notably restrictive of liver transplantation for patients suffering from severe alcohol-associated hepatitis. This barrier to transplant for alcohol-associated hepatitis was prominently challenged by the 2011 French-Belgian study which demonstrated 70% survival of the 26 carefully selected patients with alcohol-associated hepatitis as compared to the dismal 20% of the matched controls, and that return to alcohol was late and rare^47^. The ACCELERATE-AH consortium then re-demonstrated 94%, 1-year survival of 147 patients transplanted for severe alcohol-associated hepatitis^48^.
As the AASLD sought to decrease stigma by reforming its lexicon, “alcoholic” for “alcohol-associated,^49^” and encourage concomitant AUD treatment^50,51^, the COVID-19 pandemic ignited the rates of AUD and ALD in the United States and doubled the rates of liver transplantation for alcohol-associated hepatitis^52,53^. This prompted the Dallas Consensus Conference’s proposal of criteria to evaluation patients for liver transplantation in alcohol-associated hepatitis^54^. Understanding of AUD and return to use after liver transplantation in patients transplanted for ALD indications continues to evolve, with further nuanced means of monitoring^55,56^ and understanding of patterns of post-liver transplantation return to alcohol use^57^. There continues to be lack of consensus in the liver transplantation field and in the AUD research field, generally, regarding how to define relapse, slip, versus return to heavy drinking^58^.
ALD comprises a spectrum of liver damage. The earliest form of liver damage from alcohol use is steatosis, or fatty liver. Steatosis from alcohol occurs in most patient (>90%) when chronically consuming 20-50 grams per day for females or 60-80 grams per day for males for at least 2 weeks^49^. With 4-6 weeks of total abstinence, steatosis can resolve. With continued heavy drinking, however, approximately 20-40% of these patients who develop steatosis will go on to develop inflammation (steatohepatitis) and scarring (fibrosis). Grades F3 and F4 are considered advanced chronic liver disease (ACLD) as such patients have increased risk of mortality over time^59^. Patients who have cirrhosis but who have not developed symptoms of portal hypertension (e.g., ascites, variceal bleeding, jaundice, or hepatic encephalopathy) are termed compensated cirrhosis or compensated ACLD (cACLD) and those who have developed such symptoms are considered decompensated ACLD or decompensated cirrhosis. Decompensated cirrhosis portends significantly worse prognosis overall^59^. However, for those with ACLD secondary to alcohol use, complete alcohol cessation can lead to recompensation and fibrosis regression^59^. Finally, the most severe form of liver disease, alcohol-associated hepatitis, which is defined by clinical diagnosis and biopsy^60^, can occur at any timepoint in the specttimerum of liver disease, though most frequently co-occurs with cirrhosis^61^. Alcohol-associated hepatitis is a severe hepatic and systemic inflammation that occurs in the presence of heavy alcohol use, but is likely influenced by other factors, such as genetic predispositions as well.
The diagnosis of ALD involves diagnosing alcohol use and AUD, as noted above, and diagnosing the stage of ALD. Earlier stages of ALD, particularly steatosis, may be challenging to diagnose as these early stages are usually asymptomatic and may not be accompanied by liver enzyme changes. In some cases, physical exam will disclose an enlarged liver by palpation. Common liver enzyme elevations of aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) may indicate the presence of alcohol use. Other liver enzyme elevations (alanine aminotransferase (ALT), alkaline phosphatase, and/or bilirubin) may also be elevated with steatohepatitis and more advanced stages, though this is not uniform. Diagnosis of steatosis can be made with imaging such as ultrasound, computed tomography, or magnetic resonance imagery (MRI). Liver biopsy is not required for steatosis diagnosis typically.
Staging of fibrosis can be performed using non-invasive tests or liver biopsy. Non-invasive tests (NITs) are more popular due to their relative ease of performance and the avoidance of liver biopsy and its potential complications. Commonly performed lab tests, such as the FIB-4, performed reasonably well for ruling in advanced ALD with specificity of 89-91% for F3-F4 fibrosis and negative predictive value of 88%, but with poorer sensitivity (58-71%)^62^. The Enhanced Liver Fibrosis (ELF) test, also performed well with comparable specificity and slightly improved sensitivity, but is not widely available in the United States. NITs based on elastography, an imaging-based exam that uses vibration to determine liver stiffness, have traditionally performed even better than lab-based NITs, but have the disadvantage of being more costly and less widely available. Transient elastography performs well to diagnosis advanced CLD (F3 or F4) with sensitivity and specificity over 90% and a negative predictive value of 96%^62^. Though no formal care pathways exist for guiding the diagnosis of ALD, initial evaluation for staging ALD should start with basic labs, including liver enzymes (AST, ALT, alkaline phosphatase, and bilirubin) as well as a complete blood count to obtain platelet counts to enable calculation of a FIB-4 score. A FIB-4 score greater than or equal to 3.25 should prompt further evaluation with transient elastography and a potential referral to gastroenterology or hepatology for further diagnostic evaluation for ACLD. Lower than normal platelet levels may denote the presence of portal hypertension so should be investigated further with imaging. Cirrhosis may be directly seen on imaging, but the absence of cirrhotic morphology of the liver does not rule out the presence of F3-F4 fibrosis. Patients with evidence of cirrhosis by NIT, physical exam, clinical symptoms (e.g. ascites, jaundice), or imaging should be referred to hepatology for further evaluation.
Alcohol is widely consumed in society and many individuals worldwide meet criteria for harmful use of alcohol and/or AUD. Alcohol can affect all human organ systems and any medical provider may find themselves as first to learn of a patient’s struggle with alcohol use, necessitating universal preparation of medical professionals, either through education and intent to treat or up-to-date referral options at hand. ALD is also common and increasing with rising rates of drinking in some population groups, and with increases in metabolic diseases. There are many diagnostic tools for AUD and ALD, and clinicians are encouraged to use these tools to intervene early in the progression of AUD and/or ALD. Integrated medical and psychosocial care has been highly effective in supporting patients with AUD and ALD in achieving recovery and as such the standard of care has become specialized multidisciplinary clinics^44,49,63^. Patients with AUD and ALD can recovery through early, coordinated intervention, reductions in stigma, and through careful management with integrated medical and psychosocial care. AUD treatment is effective even for those with advanced ALD with reduced risk of decompensation and patient mortality^64-66^. Future research on integrated treatments and how to best support patients with AUD and ALD is needed.